pentostatin and Leukemia--Lymphocytic--Chronic--B-Cell

A limited evidence exists regarding comparisons of clinical effectiveness of available therapies for first-line treatment of chronic lymphocytic leukemia (CLL).. We compared available therapies for treatment-naïve, symptomatic CLL regarding progression free survival (PFS) and overall survival (OS) in all the identified random control trials and in subgroups composed of younger/fit and older/unfit patients, using a Bayesian network meta-analysis.. In younger/fit patients we obtained median of projected mean PFS of: 19, 26, 31, 43, 51 and 75months for chlorambucil, fludarabine, alemtuzumab, fludarabine with cyclophosphamide (FC), bendamustine and fludarabine with cyclophosphamide and rituximab (FCR), respectively. We noted median OS of: 59, 66, 66, 70months for FC, chlorambucil, FCR and fludarabine, respectively. In older/unfit patients we noted PFS of: 16, 17, 24, 30, 60months for chlorambucil, fludarabine and chlorambucil with ofatumumab (OClb) or rituximab (RClb) or obinutuzumab (GClb), respectively. We obtained median OS of: 44, 58, 59 and 90months for fludarabine, RClb, chlorambucil and GClb, respectively.. Our results suggest that: (1) FCR has higher potential of preventing CLL progression in younger/fit patients over four therapy options, which were subject of previous meta-analysis but also over bendamustine; (2) in these patients FCR does not entail prolonging of OS in comparison with chlorambucil and it is outperformed by fludarabine; (3) in older/unfit patients GClb demonstrates longer projected PFS than all assessed comparators; (4) in this group GClb has also the highest potential of increasing OS.

Topics: Age Factors; Alemtuzumab; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal, Murine-Derived; Antineoplastic Combined Chemotherapy Protocols; Bayes Theorem; Bendamustine Hydrochloride; Chlorambucil; Cyclophosphamide; Disease-Free Survival; Humans; Kaplan-Meier Estimate; Leukemia, Lymphocytic, Chronic, B-Cell; Markov Chains; Nitrogen Mustard Compounds; Pentostatin; Physical Fitness; Proportional Hazards Models; Randomized Controlled Trials as Topic; Rituximab; Vidarabine

There have been great strides in the treatment of chronic lymphocytic leukemia (CLL). Fludarabine is the most widely studied of the purine analogs that have significantly impacted the treatment of this disease. Pentostatin has also been shown to have clinical activity in CLL and appears to be less toxic than its fludarabine counterpart, which may offer some important advantages. This text will review the rationale and more recent clinical trial results for pentostatin-based combinations in both the upfront and relapsed treatment setting for patients with CLL. Attention to the frequency of response, ability to achieve minimal residual disease, and toxicity from these approaches will be emphasized. Where feasible, we will also compare the impact of pentostatin-based treatments to fludarabine-based combinations in CLL. In addition, this review will update the latest relevant work presented at the recent 2008 American Society of Hematology meeting and future directions in regard to the continued study of pentostatin-based combinations will be discussed.

Topics: Age Factors; Aged; Alemtuzumab; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal, Murine-Derived; Antibodies, Neoplasm; Antineoplastic Combined Chemotherapy Protocols; Clinical Trials, Phase II as Topic; Cyclophosphamide; Drug Administration Schedule; Forecasting; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Middle Aged; Mitoxantrone; Multicenter Studies as Topic; Pentostatin; Rituximab; Salvage Therapy; Treatment Outcome; Vidarabine

Chronic lymphocytic leukemia (CLL) is a disease that typically afflicts older individuals with a median age of diagnosis in the eighth decade of life for which treatments available now are not curative. Although purine analogue based combinations produce complete responses (CRs) in many patients, the use of these combinations has been limited by toxicity including myelosuppression and an increased risk of infectious complications.. To identify the role of pentostatin, a specific inhibitor of adenosine deaminase (ADA), in the treatment of CLL. We compare pentostatin to other purine analogues, most notably fludarabine, with regard to safety and efficacy. Finally, we review the use of pentostatin in other diseases.. The scope of this review encompasses the history of treatment for CLL as well as the genesis of modern combination chemoimmunotherapy and the advantages of pentostatin within such a treatment program.. Combination therapy with pentostatin seems to provide response frequencies comparable to fludarabine based combinations but with less toxicity and with greater ease of administration.

Topics: Adenosine Deaminase Inhibitors; Aged; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Clinical Trials as Topic; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Pentostatin; Vidarabine

The introduction of the monoclonal antibodies rituximab (anti-CD20) and alemtuzumab (anti-CD52) has revolutionized the treatment of chronic lymphocytic leukemia (CLL). Both antibodies were first studied as single agents in relapsed CLL, but rituximab is increasingly used in combination chemoimmunotherapy regimens in previously untreated patients. Phase II studies demonstrated that the addition of rituximab to fludarabine-based chemotherapy improves complete response (CR) rates and prolongs progression-free survival (PFS), but a long-term survival benefit has not been shown. Alemtuzumab is less commonly used, due to the greater likelihood of infusion toxicity, as well as hematologic and immune toxicities. Subcutaneous (SC) administration significantly reduces infusion toxicity, but hematologic and infectious complications, most notably cytomegalovirus (CMV) reactivation, still occur with SC dosing. Alemtuzumab's unique clinical properties include its clinical activity in relapsed CLL patients with del(17p13) and its ability to eradicate minimal residual disease (MRD) in bone marrow. Its use as consolidation therapy to eradicate MRD after nucleoside analog therapy is under active study. Several investigational monoclonal antibodies are in preclinical or clinical studies, most notably lumiliximab (anti-CD23) and ofatumumab (HuMax CD20), and are briefly discussed in this review.

Topics: Alemtuzumab; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal, Murine-Derived; Antibodies, Neoplasm; Antineoplastic Combined Chemotherapy Protocols; Clinical Trials as Topic; Cyclophosphamide; Disease Progression; Disease-Free Survival; Drugs, Investigational; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Mutation; Pentostatin; Rituximab; Vidarabine

A dramatic change has occurred in the management of chronic lymphocytic leukemia (CLL) over the past 20 years. The use of newer therapies, including the purine analogues, has resulted in higher frequencies of response. Combination therapy with purine analogues, alkylators, and/or monoclonal antibodies represents a promising new approach to the treatment of patients with CLL. The most commonly studied regimens have utilized fludarabine, but severe myelosuppression and immunosuppression of these combinations require close attention to dosing and schedule. Of the purine analogues that show activity in CLL, pentostatin appears to be the least myelosuppressive. These combination strategies are associated with high-quality responses in the majority of patients and may one day lead to improved survival or possibly even a cure for patients with CLL.

Topics: Antineoplastic Combined Chemotherapy Protocols; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Pentostatin; Purine Nucleosides; Salvage Therapy

B-cell chronic lymphocytic leukemia (B-CLL) is a clonal malignancy characterized by the expansion of small B lymphocytes and accumulation of CLL cells. This disease is the most common form of leukemia in the Western hemisphere and is currently not considered to be curable using currently available therapies. Published reports have suggested that purine analogues have activity in B-CLL and superior to alkylating agents. Even though responses have been observed with purine analogues that are used as single agents, these responses were not durable. The use of combination purine analogue therapy with alkylating agents and/or monoclonal antibodies was then explored in order to take advantage of synergistic actions of these agents to improve the quality of clinical responses. Both fludarabine and pentostatin have shown improved responses when combined with alkylating agents and even higher overall and complete responses (CRs) when combined with monoclonal antibodies.

Topics: Antineoplastic Combined Chemotherapy Protocols; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Pentostatin; Purine Nucleosides; Risk Assessment; Treatment Outcome; Vidarabine

Pentostatin has been shown to be active in a variety of B- and T-cell malignancies. The drug is a tight inhibitor of adenosine deaminase, a key degradative enzyme of purine metabolism present in all human tissues, with the highest levels found in the lymphoid system. Early clinical trials indicated that this agent was highly active in acute lymphoblastic leukemias with high intracellular adenosine deaminase levels. Relatively high doses of the drug were needed, which was associated with severe adverse events. Through the efforts of a few investigators, better tolerated, low-dose regimens have been shown to be extremely active in lymphoproliferative diseases with very low intracellular adenosine deaminase levels such as hairy cell leukemia, B- and T-cell chronic leukemias, T-cell cutaneous lymphomas and low-grade non-Hodgkin lymphomas. Clinical as well as experimental data have indicated that this drug induces lymphocyte-specific cytotoxicity, and myelosuppressive adverse events have been minimal. Although all the purine analogs have shown similar activity, the advantage of pentostatin is the relatively specific cytotoxicity against lymphocytes, which permits treatment even in patients with severe cytopenias. Although no direct comparisons of the purine analogs have been performed, pentostatin may be preferred due to this property.

Topics: Adenosine Deaminase Inhibitors; Antibiotics, Antineoplastic; Humans; Leukemia, Hairy Cell; Leukemia, Lymphocytic, Chronic, B-Cell; Leukemia, Prolymphocytic; Pentostatin; Purine Nucleosides

Recent trials suggest improved response rates for purine analogues compared to alkylator-based regimens in the treatment of B-CLL. However, none was able to show a survival advantage. Thus, a systematic Cochrane review may be able to further define the role of purine analogues in the first-line treatment of B-CLL.. Randomized controlled trials comparing single-agent purine analogues with alkylator-based regimens were included. Medical databases (Cochrane Library, MEDLINE, EMBASE), conference proceedings and trial registers were searched. We included full-text and abstract publications as well as unpublished data. Relative risks (RR) and hazard ratios (HR) were calculated under a fixed-effects model, clinical and statistical heterogeneity was examined with sensitivity analyses and meta-regression. If applicable, numbers needed to treat or harm (NNT, NNH) were also determined.. Five trials with 1838 randomized patients were included. Importantly, four trials had a cross-over design. There was a trend for improved overall survival for patients receiving purine analogues as initial therapy but statistical significance was just not reached (HR 0.89 [95% CI 0.78-1.01]). The RR for achieving an overall (RR 1.22 [95% CI 1.13-1.31]; NNT 8 [95% CI 6-13]) and complete response (RR 1.94 [95% CI 1.65-2.28]; NNT 6 [5-8]) was significantly improved, resulting in a longer progression-free survival (HR 0.70 [95% CI 0.61-0.82]). Incidence of grade III/IV infections (RR 1.83 [95% CI 1.30-2.58]; NNH 20 [95% CI 12.5-50]) and haemolytic anaemia (RR 3.36 [95% CI 1.27-8.91]; NNH 21 [95% CI 6-185]) was significantly higher in patients receiving purine analogues.. Despite significantly increased response rates and longer progression-free survival with purine analogues as first-line therapy, we were not able to detect a statistically significant improvement of overall survival compared to alkylator-based regimens. Furthermore, the use of purine analogues augments the risk for grade III/IV infections and haemolytic anaemia.

Topics: Anemia, Hemolytic; Antineoplastic Agents; Cladribine; Disease-Free Survival; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Pentostatin; Randomized Controlled Trials as Topic; Survival Analysis; Treatment Outcome; Vidarabine

Recent trials suggest improved response rates for purine antagonists compared to alkylator-based regimens in the treatment of B-CLL. However, none was able to show a survival advantage.. To determine if there is any advantage of purine antagonists compared to alkylating agents (alone or in combination) in the treatment of patients with previously untreated B-CLL.. Medical databases (Cochrane Library, MEDLINE, EMBASE), conference proceedings and internet-based trial registers were searched electronically and/or by hand (1990-2003). All references were checked for further trial information. We also contacted experts in the field and pharmaceutical companies.. Randomised controlled trials comparing purine antagonists as single agents with alkylator-based regimens in patients with previously untreated B-CLL were included. We included full-text and abstract publications as well as unpublished data.. Data extraction and quality assessment were done in duplicate by two independent reviewers. Missing data were obtained from original authors. Endpoints included overall survival, overall response rate, rate of complete remissions, progression-free survival, treatment-related morbidity and mortality.. Five trials with 1838 randomised patients were included. There is some evidence for improved overall survival after treatment with purine antagonists compared to alkylators, but statistical significance was not reached (HR 0.89 [95% CI 0.78-1.01], 4 trials, n=1638). However, the relative risk for achieving an overall response (RR 1.22 [95% CI 1.13-1.31], 5 trials, n=1751) and complete remission (RR 1.94 [95% CI 1.65-2.28], 5 trials, n=1751) was significantly higher, resulting in a longer progression-free survival (HR 0.70 [95% CI 0.61-0.82], 4 trials, n=1638). Incidence of grade III/IV infections was significantly higher in patients receiving treatment with purine antagonists (RR 1.83 [95% 1.30-2.58], 4 trials, n=1620). There was no significant difference concerning the relative risk for grade III/IV neutropenia (RR 1.14 [95% CI 0.98-1.34], 4 trials, n=1620) and therapy-related mortality (RR 0.94 [95% CI 0.45-1.95]). Overall incidence of hemolytic anemia was low, but significantly increased in the purine antagonist group (RR 3.36 [95% CI 1.27-8.91], 3 trials, n=1258).. Despite significantly increased overall response and complete remission rates and longer progression-free survival with first-line treatment of B-CLL patients with single-agent purine antagonists, we were not able to detect a statistically significant improvement of overall survival compared to alkylator-based regimens. Furthermore, the use of purine antagonists also augments the risk for grade III/IV infections and hemolytic anemia.

Topics: Antineoplastic Agents; Chlorambucil; Cladribine; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Pentostatin; Randomized Controlled Trials as Topic; Vidarabine

Pentostatin (Nipent), formerly known as deoxycoformycin, is a profound inhibitor of the enzyme adenosine deaminase, resulting in the accumulation of metabolites that inhibit ribonucleotide reductase, which in turn inhibits DNA synthesis. Pentostatin was the first of the purine analogs to undergo extensive testing as an anticancer agent and the first to receive US Food and Drug Administration approval for a treatment indication. It is highly effective as first-line monotherapy in hairy cell leukemia, with a complete response rate of 80% and a 10-year survival rate of around 80%. Pentostatin is also active in chronic lymphocyte leukemia as a single agent, but appears even more promising in combination approaches with the alkylating agents chlorambucil or cyclophosphamide. Due to the increasing recognition of delayed severe stem cell and immune suppression following therapy with other purine analogs, there has been renewed interest in pentostatin, especially in combination with chemotherapy and/or the monoclonal antibody rituximab (Rituxan) in chronic lymphocyte leukemia.

Topics: Antibiotics, Antineoplastic; Clinical Trials as Topic; Enzyme Inhibitors; Humans; Leukemia, Hairy Cell; Leukemia, Lymphocytic, Chronic, B-Cell; Pentostatin

Purine nucleoside analogues are unique drugs that are effective in a variety of hematologic malignancies. Fludarabine and 2-chlorodeoxyadenosine (2-CdA) are active in chronic lymphocytic leukemia (CLL) both as salvage therapy and in newly diagnosed patients. These agents have revolutionized therapeutic strategies for patients with CLL that had remained unchanged for many years and included alkylating agents-based therapy with no potential for long-term remission or cure. Purine analogues have also been successfully combined with a variety of other chemotherapeutic drugs such as mitoxantrone, cyclophosphamide, corticosteroids, and monoclonal antibodies, specifically Rituximab and CAMPATH-1H. These agents are immunosuppressive and have been associated with opportunistic infections, the incidence of which can be significantly reduced by early recognition and administration of prophylactic antibiotics. In this review, the activity and toxicity of 2-CdA, fludarabine, and pentostatin in CLL as single agents and in combination with conventional chemotherapy are discussed. These drugs are increasingly used as initial therapy in CLL. Such strategies are associated with higher remission rates than have been previously achieved and in some cases, molecular remission, suggesting an important step towards cure.

Topics: Alemtuzumab; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal, Murine-Derived; Antibodies, Neoplasm; Antineoplastic Combined Chemotherapy Protocols; Cladribine; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Pentostatin; Rituximab; Vidarabine

In recent years preclinical and clinical studies have been undertaken with selected monoclonal antibodies (MoAbs) either alone or coniugated to toxins in patients with several lymphoid malignancies, including chronic lymphocytic leukemia (CLL), prolymphocytic leukemia (PLL) and hairy cell leukemia (HCL). Two MoAbs, directed against CD20 antigen (Rituximab, RIT) and CD52 antigen (Campath-1H, alemtuzumab, ALT) demonstrate significant activity in CLL. The most notable success to data has been achieved with ALT, both in previously treated and untreated patients with CLL. ALT is a humanized rat IgG1 antibody that binds to the cell membrane of virtually all normal as well as malignant lymphocytes. In the vast majority of CLL patients ALT causes constant reduction of abnormal blood lymphocytes, usually in less than 4 weeks, and disappearance of CD5/CD19 co-expression cells from blood. The regression of lymphoid infiltration from other sites is less clear. ALT is also highly active in patients with CLL in progression, even refractory to fludarabine (FA). Hematological toxicity, especially long-lasting lymphocytopenia, was noted in the majority of patients. The most important clinical side effects of ALT treatment were infections, mainly herpes simplex virus and cytomegalovirus reactivation. RIT is also active in CLL in conventional doses. However some studies suggest that higher doses are more effective than standard doses, used routinely in other lymphoid malignancies. The activity of ALT and RIT in CLL patients resistant to FA and their synergistic interactions with cytotoxic drugs suggests that a combination of these agents may lead to further progress in the treatment of this disease. The T-cell variant of PLL has demonstrated impressive responses to ALT in several trials even if the patients were refractory to deoxycoformycin (DCF) and other agents. However, this MoAb is not curative, because all patients eventually relapsed. Consequently, treatment with ALT may need to be associated with stem cell transplantation to consolidate and maintain long-term remissions. Recently anti-CD22 and anti-CD25 immunotoxins have been investigated in purine analogues refractory or relapsed HCL. The presented results indicate that these agents are highly active and well tolerated even if the patients were resistant to 2-CdA or DCF.

Topics: Adult; Aged; Aged, 80 and over; Alemtuzumab; Animals; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal, Murine-Derived; Antibodies, Neoplasm; Antigens, CD; Antigens, CD19; Antigens, CD20; Antigens, Differentiation, B-Lymphocyte; Antigens, Neoplasm; Antineoplastic Combined Chemotherapy Protocols; CD5 Antigens; CD52 Antigen; Cell Adhesion Molecules; Cell Membrane; Combined Modality Therapy; Glycoproteins; Humans; Immunotherapy; Lectins; Leukemia, B-Cell; Leukemia, Hairy Cell; Leukemia, Lymphocytic, Chronic, B-Cell; Leukemia, Myeloid; Lymphatic Metastasis; Lymphocytes; Middle Aged; Pentostatin; Rats; Rituximab; Sialic Acid Binding Ig-like Lectin 2; Simplexvirus; Stem Cell Transplantation

Topics: Antineoplastic Agents; Apoptosis; Caspases; Cell Division; Cladribine; DNA Damage; Drug Resistance, Neoplasm; Drug Synergism; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Pentostatin; Phosphorylation; Tumor Suppressor Protein p53; Vidarabine

The association of hairy cell leukemia (HCL) with other neoplasms, mainly non-Hodgkin's lymphomas, is well known. However, the simultaneous diagnosis of HCL and chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) is rare, with only few cases of such an association having been reported. We describe three patients with a well-characterized HCL in whom a CLL/SLL population was detected. Of note, these cases represent a significant proportion (11.5%; 95% CI: 0% to 24%) of the total number of HCL cases diagnosed in our institution during the same period of time. All three patients were treated with deoxycoformycin. They achieved a complete response of the HCL, whereas the CLL/SLL population persisted in all cases. The immunoglobulin gene rearrangement analysis, in two informative cases, suggested that the HCL and CLL/SLL populations arose from different B cell clones. This study indicates that the association of HCL and CLL/SLL might be much more frequent than previously recognized. Therefore, a large panel of monoclonal antibodies, including those necessary to detect CLL/SLL, should be employed when studying patients with HCL.

Topics: Antimetabolites, Antineoplastic; B-Lymphocytes; Cell Lineage; Cladribine; Combined Modality Therapy; Comorbidity; Gene Rearrangement, B-Lymphocyte; Genes, Immunoglobulin; Hematopoietic Stem Cell Transplantation; Humans; Immunophenotyping; Leukemia, Hairy Cell; Leukemia, Lymphocytic, Chronic, B-Cell; Male; Mass Screening; Middle Aged; Neoplasms, Multiple Primary; Neoplastic Stem Cells; Pentostatin; Prospective Studies; Remission Induction; Salvage Therapy; Transplantation, Autologous

The recent introduction of new active agents has led to a renaissance of clinical investigation in chronic lymphocytic leukemia (CLL). These agents include three purine analogues, (pentostatin, fludarabine, and cladribine) and two monoclonal antibodies (rituximab and CAMPATH I-H). Careful clinical studies have allowed for the development of novel combinations of two and even three non-cross- resistant agents. These preliminary studies indicate that such combinations can induce complete responses in a larger proportion of patients than can single-agent therapy. In CLL, survival is superior for patients achieving a complete response compared with patients achieving a partial response. Therefore, strategies designed to induce high-quality responses in the majority of patients may one day lead to improved survival or possibly even cure in patients with chronic lymphocytic leukemia.

Topics: Antibodies, Monoclonal; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Chlorambucil; Cladribine; Cyclophosphamide; Female; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Male; Pentostatin; Randomized Controlled Trials as Topic; Sex Factors; Vidarabine

Patients with lymphoid malignancies such as chronic lymphocytic leukemia, particularly those who receive the newer purine analogs, are at increased risk for infectious morbidity and mortality. Defects in cell-mediated immunity appear to be a major predisposing factor in these patients. An expanding spectrum of pathogens associated with lymphocytopenia and depletion of CD4 has been described in the setting of therapy with purine analogs. During the past 2 years new knowledge about the immunosuppression related to that treatment has continued to accumulate.

Topics: Antimetabolites, Antineoplastic; Cladribine; Humans; Immune Tolerance; Infections; Leukemia, Lymphocytic, Chronic, B-Cell; Pentostatin; Vidarabine Phosphate

Renewed interest in chronic lymphocytic leukemia (CLL) has led to an unprecedented number of investigators contributing to all aspects of research in this disease. In fact, the evolution of research in the area of molecular aberrations in CLL and their impact on treatment resistance alone is striking. These data, along with the advent of the purine analogs, have been central to this paradigm shift. The inferior response rate, the abbreviated response duration, and the inability to prolong survival with alkylating agents such as chlorambucil have resulted in purine analogs being used as first- and second-line therapy for patients with CLL. In fact, patients treated with fludarabine have a higher overall and complete response rate as well as a disease-free survival advantage compared with patients treated with alkylator-based therapy. Pentostatin, the first purine analog to enter clinical trials, was never subjected to extensive schedule optimization despite its demonstrated efficacy and its paucity of significant myelosuppression compared with the other purine analogs. However, pentostatin induced a 25% to 30% response rate in heavily pretreated CLL patients, including some who had received prior fludarabine, suggesting possible non-cross-resistance. Based on preclinical data demonstrating synergistic activity when a DNA damaging agent (eg, an alkylating agent) is followed by an inhibitor of DNA repair (a purine analog), a number of purine analog/alkylator combinations have been and are presently being examined in a variety of lymphoid neoplasms. While the clinical data conflict, at least two phase II studies examining a combination of a purine analog and an alkylator in untreated patients with CLL have generated promising data. This report describes the scientific justification and the design of a new phase II study examining the combination of pentostatin and chlorambucil with granulocyte-macrophage colony-stimulating factor support for patients with untreated, treated, and fludarabine-refractory B-cell CLL.

Topics: Antibiotics, Antineoplastic; Antineoplastic Agents; Antineoplastic Agents, Alkylating; Antineoplastic Combined Chemotherapy Protocols; Chlorambucil; Clinical Trials, Phase II as Topic; Disease-Free Survival; Drug Resistance, Neoplasm; Drug Synergism; Granulocyte-Macrophage Colony-Stimulating Factor; Humans; Immunosuppressive Agents; Leukemia, B-Cell; Leukemia, Lymphocytic, Chronic, B-Cell; Pentostatin; Remission Induction; Vidarabine

The main purine analogues with activity against lymphoid malignancies are fludarabine, cladribine and pentostatin, all of which are active against slowly proliferating cells through their inhibition of DNA repair and therefore have significant synergistic activity with cytotoxic agents which cause DNA damage. Combinations of purine analogues and alkylating agents or platinum compounds result in markedly increased activity but at the expense of more severe haematological toxicity, while evidence of synergy with anthracyclines/anthracenediones is apparent in the treatment of malignant lymphoma. Interaction between fludarabine or cladribine with deoxycytidine kinase results in a significant enhancement of the activity of cytarabine. Unexpected evidence of clinical synergy is also apparent in combinations of purine analogues and anti-CD20 monoclonal antibodies.

Topics: Antineoplastic Combined Chemotherapy Protocols; Cladribine; Clinical Trials as Topic; Drug Synergism; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Lymphoma, Non-Hodgkin; Pentostatin; Purines; Vidarabine

Topics: Antineoplastic Agents; Cladribine; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Pentostatin; Randomized Controlled Trials as Topic; Vidarabine

Chronic lymphocytic leukemia (CLL) is considered an incurable disease and therefore the management is palliative and more disease-related symptoms directed. Recently, the high activity of nucleoside analogs as fludarabine (FAMP), 2-chlorodeoxyadenosine (2-CDA) and 2-deoxycoformycin (DCF) in low-grade NHLs has caused a new reawakening interest in CLL concerning new treatment strategies, the biology and prognostic factors of this disease. Predominantly FAMP has widely been studied in CLL with impressive remission rates of 30-70%, including some complete remission (CR) in refractory or relapsed CLL. In previously untreated patients, the remission rate is about 80% with a CR rate of up to 60%. These results open new treatment strategies, even with a curative intention such as high-dose chemotherapy combined with autologous stem cell support or allogeneic stem cell transplantation. The clinical experience with 2-CDA in CLL is limited, but the preliminary results suggest a similar efficacy as FAMP, whereas DCF seems to be less effective. The major treatment-related morbidity is due to myelo- and immunosuppression by long-lasting T cell depletion, which may facilitate a greater susceptibility of infections including those with opportunistic organisms as herpes simplex or herpes zoster, cytomegalovirus, Pneumocystis carinii, mycobacteria, listeriosis, candida and aspergillus in pretreated patients. However, in previously untreated patients no increased incidence of infections has been reported compared with other schedules. Whether FAMP treated patients have any advantage for overall or progression-free survival has to be answered by ongoing randomized trials. Presently, the position of FAMP and 2-CDA as two extremely active single agents in CLL is that of second-line therapy. Their appropriate indication in the first-line strategy of CLL has, however, still to be defined by clinical studies in progress.

Topics: Antineoplastic Agents; Cladribine; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Pentostatin; Prognosis; Recurrence; Remission Induction; Vidarabine

This review deals mainly with the essentials of hairy cell leukemia (HCL) detailing clinical aspects, laboratory findings and morphology. Rare manifestations of HCL are listed. Newer aspects relating to cytokines, soluble interleukin receptors and TNF are reviewed. Differential diagnosis including HCL-variant, SLVL, PLL and CLL/PLL are discussed. Prognostic factors and in particular therapeutic aspects are detailed with particular emphasis on the new purine analogues Pentostatin and 2-CdA. A list of suggested reading is offered.

Topics: Antineoplastic Agents; Biomarkers, Tumor; Cladribine; Diagnosis, Differential; Humans; Interferon-alpha; Leukemia, Hairy Cell; Leukemia, Lymphocytic, Chronic, B-Cell; Leukemia, Prolymphocytic; Lymphoma, Non-Hodgkin; Pentostatin; Prognosis

Chronic lymphocytic leukemia (CLL) is a slow lymphoproliferative disease. The therapy has only a palliative effect and therefore the common attitude to the therapy is conservative (watch and wait policy). Monotherapy with alkylating cytostatics, usually chlorambucil, is considered by most authors to be the therapy of first choice. Only the French study showed superiority of polychemotherapy CHOP over monotherapy. New drugs for the treatment of chronic lymphocytic leukemia are purine-analogs. Fludarabine has been used mostly of this purine-analogs. The response rate to fludarabine therapy is 30-45% in pretreated patients and the response rate in the chemotherapy-naive patients is about 80%. 2-chlorodeoxyadenosine was used in the same indications and it showed that this drug had a similar effect in this disease as fludarabine. The contemporary indication for fludarabine is standard-chemotherapy-refractory disease. Whether this drug will be used for initial therapy, is a question. Interferon alpha is therapeutically active in early stages of chronic lymphocytic leukemia, but it is unclear, if this response has any influence on survival. Interferon alpha is ineffective in advanced stages of this disease. The role of interferon alpha as the maintenance treatment after chemotherapy is heavily discussed.

Topics: Antineoplastic Agents; Cladribine; Humans; Interferon-alpha; Leukemia, Lymphocytic, Chronic, B-Cell; Pentostatin; Prognosis; Vidarabine

Purine nucleoside analogues are a new class of drugs with activity against non-dividing lymphocytes. They should thus play a major role in the treatment of low grade lymphoid malignancies. These drugs have been shown to have strong effect in DNA synthesis on actively dividing cells, mainly through interference with DNA polymerases and ribonucleotide reductase. However, the cell cycle kinetics of low grade lymphocytic lymphomas is characterized by the presence of very low growth fractions. Hence, the action of these drugs in slowly progressing lymphoid malignancies cannot be accounted by the same mechanism observed in actively proliferating tumors and needs to be explained through activity against quiescent resting lymphocytes. Recent work has stressed the role of purine analogues in inducing programmed cell death of quiescent lymphocytes, which could be explained through the induction of accelerated DNA strand breaks. This process leads to consumption of NAD for poly(ADP-ribose) synthesis, which could induce critical depletion of ATP. As this action extends to normal resting lymphocytes deleterious effects related to their immunosuppressive action are also observed, i.e. prolonged lymphopenia predominating in T cells and especially in CD4 subset, increased frequency of opportunistic infections and perhaps increase in autoimmune complications like autoimmune hemolytic anemia. Nevertheless, beneficial effects of this immunosuppressive action have also been reported in the prevention of graft-versus-host disease, graft rejection and in some autoimmune diseases like multiple sclerosis. Work needs to be carried out to define better the mechanisms of action of these drugs on the different immunological effectors, as well as studies in animal models of transplantation and autoimmune diseases.

Topics: Animals; Antineoplastic Agents; Cladribine; Humans; Immunosuppressive Agents; Leukemia, Lymphocytic, Chronic, B-Cell; Pentostatin; Purine Nucleosides; Vidarabine

2'-deoxycoformycin (DCF) is the oldest of the nucleoside analogs in clinical practice. The main use has been in the B and T lymphoproliferative disorders. The early significant activity with a high remission rate reported in hairy cell leukemia (HCL) has been confirmed within our group. Data from a large phase II study, which comprised 165 evaluable patients with HCL treated with DCF 4mg/m2 every 2 weeks until maximal response collected over a ten-year period, shows a very long disease-free interval with 76% of the complete responders still in remission at 6 years. Some activity has been reported in chronic lymphocytic leukemia and an outline of a phase II study with low dose DCF given over five days every month is summarised. DCF has been shown to be active in mature T-cell malignancies, chiefly T-prolymphocytic leukemia (T-PLL) and the cutaneous T-cell lymphoma, Sezary syndrome. Its efficacy in other forms of T-cell lymphoma has been less consistent but, bearing in mind the poor outlook of these disorders, the data suggest that DCF should be considered as part of the treatment strategy. In T-PLL, for example, partial remitters (and non-responders) to DCF have received the monoclonal antibody CAMPATH-1H with excellent results.

Topics: Antibiotics, Antineoplastic; Clinical Trials, Phase II as Topic; Humans; Leukemia, Hairy Cell; Leukemia, Lymphocytic, Chronic, B-Cell; Pentostatin; Sezary Syndrome

The purine analogs fludarabine (FAMP), 2-chlorodeoxy-adenosine (2-CDA) and 2-deoxycoformycin (DCF) comprise a novel group of agents with high activity in low-grade lymphoid malignancies. Although all three agents share several mechanisms of action, such as the induction of apoptosis, and toxic effects, such as prolonged immunosuppression, their activity appears to be different in different disorders. While FAMP and possibly also 2-CDA are highly active in chronic lymphocytic leukemia and low-grade follicular lymphomas, 2-CDA and DCF are most effective in hairy cell leukemia. However, prospective comparative evaluations are in progress and their results may ultimately help to define the appropriate indications for and potential side effects of these highly promising new agents.

Topics: Antibiotics, Antineoplastic; Antineoplastic Agents; Cladribine; Humans; Leukemia, Hairy Cell; Leukemia, Lymphocytic, Chronic, B-Cell; Lymphoma, Non-Hodgkin; Pentostatin; Purines; Vidarabine

Chronic lymphocytic leukaemia (CLL) is a disease characterised by several immune defects such as frequent autoimmune complications and functional T-cell defects, which lead to an increased risk of infections (mostly bacterial) and other tumours. Clonal chromosome abnormalities are identified in half of the patients, and trisomy 12, the most common aberration, is present in about one-third of patients with clonal changes. The commonest structural abnormalities involve chromosome 13 at band q14, the site of the retinoblastoma tumour suppressor gene. A gene located telomeric to the Rb1 gene, identified by the D13S25 probe, might be a better candidate for a pathophysiologically relevant gene in CLL, since repeated reports have identified homozygous deletions of this site. The purine analogues fludarabine and cladribine (2-chloro-2'-deoxyadenosine) and the adenosine deaminase inhibitor deoxycoformycin all have therapeutic effects in a range of lymphoproliferative disorders. Prolonged immunosuppression with low CD4 cell counts frequently occurs and, subsequently, opportunistic infections may be seen. This has to be taken into consideration when treating patients with any of these potent drugs.

Topics: Antineoplastic Agents; Chromosome Aberrations; Chromosomes, Human, Pair 12; Chromosomes, Human, Pair 13; Cladribine; Humans; Immunity, Cellular; Leukemia, Lymphocytic, Chronic, B-Cell; Pentostatin; Vidarabine

The nucleoside analogs fludarabine monophosphate, 2-chlorodeoxyadenosine, and 2-deoxycoformycin (pentostatin) all have activity in chronic lymphocytic leukemia. The most widely studied drug is fludarabine which is able to obtain complete or partial responses in more than 50% of previously treated patients. The response rate is 44% for 2-CDA and approximately 25% for pentostatin. Fludarabine has also been used to treat patients as initial therapy, and has resulted in overall response rate of 79% with 75% of the patients achieving complete remission. The NCI and International Working Group for CLL criteria for complete remission allow for persistent nodules or lymphoid infiltrates in the bone marrow biopsy. Studies have now demonstrated persistent lymphoid aggregates are associated with a shorter time to progression for responders but no survival disadvantage. There is a strong association of documented refractoriness to alkylating agents with probability of response to fludarabine and also survival. The major morbidity associated with the use of these drugs are infections, which, in some circumstances, are associated with neutropenia but in other circumstances are probably related to the hypogammaglobulinemia and T-cell immunodeficiency which are part of the disease. The T-cell immunodeficiency is aggravated by the nucleoside analogs. Even after discontinuation of therapy the immunodeficiency as measured by CD4 cell number is sustained for 12 to 24 months. Opportunistic organisms such as herpes simplex, herpes zoster, Listeria monocytogenes, and pneumocystis carinii are being noted in patients treated with these agents. The potency of these drugs and low incidence of toxicities to other organs suggests that they will be effectively combined with other agents.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Antineoplastic Agents; Cladribine; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Pentostatin; Survival Rate; Vidarabine

Not all patients with B-cell chronic lymphocytic leukemia require therapy. Patients with stable early stage disease do not need treatment, whereas those with progressive early stage disease or advanced stage disease do. The standard initial therapeutic regimen is orally administered chlorambucil and prednisone. The overall response rate to initial chemotherapy is approximately 80%; the median duration of response is 2 years. Conventional chemotherapy, however, does not provide long-term remission for patients in whom the disease becomes refractory to chlorambucil. For such patients, alternative treatment approaches including the use of purine nucleoside analogues or bone marrow transplantation may be considered. Fludarabine, 2-chlorodeoxyadenosine, and pentostatin are three analogues of the naturally occurring deoxypurine nucleoside, deoxyadenosine, and all have shown activity in chronic lymphocytic leukemia. Overall response rates of 57 to 79% have been reported with use of fludarabine. A dose-related toxic effect is myelosuppression. Experience with bone marrow transplantation is limited. The number of eligible patients with histocompatible sibling donors is low. The future role of allogeneic bone marrow transplantation in patients with B-cell chronic lymphocytic leukemia will depend on the ability to identify poor-risk groups and the long-term therapeutic efficacy of the purine nucleoside analogues or other new agents.

Topics: 2-Chloroadenosine; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow; Bone Marrow Transplantation; Chlorambucil; Deoxyadenosines; Dose-Response Relationship, Drug; Histocompatibility Testing; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Pentostatin; Prednisone; Prognosis; Survival Rate; Vidarabine

Adenosine deaminase (ADA), a purine salvage pathway enzyme, appears to play a key role in normal lymphocyte growth, development, and differentiation. Three new purine nucleoside analogues, deoxycoformycin, fludarabine, and 2-chlorodeoxyadenosine, affect the normal function of the purine salvage pathway by inhibiting ADA or by acting as analogs of the ADA substrates. These agents show significant activity in the treatment of chronic B-cell leukemias and low-grade lymphomas. The pharmacology, mechanism of action, and clinical usefulness of these agents are discussed.

Topics: 2-Chloroadenosine; Antineoplastic Agents; Cladribine; Clinical Trials as Topic; Deoxyadenosines; Leukemia, Lymphocytic, Chronic, B-Cell; Pentostatin; Vidarabine

The chronic lymphoid leukemias are a heterogeneous group of disorders with different immunologic, biologic, and clinical features. The most common of these are the B-cell diseases, chronic lymphocytic leukemia and its variants, including prolymphocytic leukemia and hairy cell leukemia. The increased use of immunophenotyping has identified a number of other less common but related disorders. Despite being clonal disorders, the chronic B-cell leukemias exhibit immunologic abnormalities in multiple other lineages, the mechanism for which is not clear. Fludarabine, 2'-deoxycoformycin, and 2-chlorodeoxyadenosine are purine analogues that have advanced the treatment of chronic B-cell leukemias. Fludarabine appears to be the single most effective agent for chronic lymphocytic leukemia, while 2'-deoxycoformycin and 2-chlorodeoxyadenosine are both extremely effective in hairy cell leukemia. A recently completed comparison of alpha-interferon with 2'-deoxycoformycin in hairy cell leukemia may redefine the standard therapy for this disorder. Continued interaction between laboratory and clinical scientists is essential for continued progress in these diseases.

Topics: Adult; Antineoplastic Agents; B-Lymphocytes; Chlorambucil; Humans; Immunologic Factors; Interferon Type I; Leukemia, Hairy Cell; Leukemia, Lymphocytic, Chronic, B-Cell; Middle Aged; Neoplasm Staging; Palliative Care; Pentostatin; Prognosis; Splenectomy

Promising results in the treatment of indolent lymphomas have been reported with the use of 2'deoxycoformycin. This antimetabolite, an adenosine deaminase inhibitor, also shows particular efficacy in hairy cell leukemia. Of 65 patients treated to date, 44 have achieved complete and lasting remission after a limited course of deoxycoformycin. While results are not as striking as those in hairy cell leukemia, deoxycoformycin may also be a valuable adjunct to alkylating agents in the treatment of CLL. The drug also is being studied in the treatment of mycosis fungoides and other lymphoid neoplasms. Side effects in all neoplasms are dose- and schedule-dependent.

Topics: Humans; Leukemia, Hairy Cell; Leukemia, Lymphocytic, Chronic, B-Cell; Lymphoma; Mycosis Fungoides; Pentostatin

In a prospective phase II trial, pentostatin combined with cyclophosphamide and rituximab (PCR) induced strong responses and was well-tolerated in previously untreated patients with advanced-stage, indolent non-Hodgkin lymphoma (iNHL). After a median patient follow-up of more than 108 months, we performed an intent-to-treat analysis of our 83 participants. Progression-free survival (PFS) rates at 108 months for follicular lymphoma (FL), marginal zone lymphoma (MZL) and small lymphocytic lymphoma (SLL) were 71%, 67% and 15%, respectively, and were affected by clinicopathological characteristics. Ten-year PFS rates for those with beta-2-microglobulin levels <2·2 and ≥2·2 mg/l prior to treatment were 71% and 21%, respectively. Patients without bone marrow involvement had 10-year PFS rates of 72% vs. 29% for those with involvement. At time of analysis, the median overall survival (OS) had not been reached. The OS rate was 64% at 10 years and differed significantly based on histology: 94% for FL, 66% for MZL and 39% for SLL. Long-term toxicities included 18 (21·7%) patients with second malignancies and 2 (2·4%) who developed myelodysplastic syndrome after receiving additional lines of chemotherapy. Our 10-year follow-up analysis confirms that PCR is an effective, robust and tolerable treatment regimen for patients with iNHL.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Diseases; Cyclophosphamide; Disease Progression; Disease-Free Survival; Female; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Male; Middle Aged; Neoplasms, Second Primary; Pentostatin; Rituximab; Treatment Outcome

Patients with relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL) may benefit from salvage chemoimmunotherapy (CIT). To explore further the use of CIT in the pre-novel agent era, ECOG-ACRIN undertook a phase 2 trial (E2903) for R/R CLL utilizing pentostatin, cyclophosphamide, and rituximab (PCR) followed by a consolidation course of alemtuzumab. This trial enrolled 102 patients with a median age of 64 years. Treatment consisted of 6 cycles of PCR followed by alemtuzumab for either 4 or 18 weeks depending on the initial response to PCR. The overall response after PCR (complete remission, CR, nodular partial remission, nPR, and partial remission, PR) was 55%. Major responses (CR or nPR) were achieved in 6%. The median overall survival (OS) and the median progression-free survival were 28 and 12 months, respectively. The most serious nonlethal adverse events were myelosuppression, febrile neutropenia, fatigue, nausea, and hyponatremia. PCR is an effective and well-tolerated nucleoside-based regimen for heavily pretreated CLL patients with R/R disease. The addition of alemtuzumab to CLL patients with a minor response (PR) or stable disease did not result in a significant number of higher responses (CR or nPR) nor an improvement in OS.

Topics: Aged; Alemtuzumab; Antineoplastic Combined Chemotherapy Protocols; Cyclophosphamide; Disease-Free Survival; Female; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Male; Middle Aged; Pentostatin; Rituximab; Survival Rate

7 regimens of pentostatin based chemoimmunotherapy (CIT) for progressive previously untreated CLL primarily with long term follow-up to update both efficacy and toxicity.. Prognostic markers including assessment of IGVH and FISH status were done on all. Response rates and 95% binomial confidence intervals were calculated for each regimen and in the combined cohort. Overall survival and treatment-free survival were evaluated using Kaplan-Meier methods.. The initial CIT trial was pentostatin (2 mgs/m2), cyclophosphamide (600 mg/m2) and rituximab (PCR) but subsequent P based CIT trials with modifications in subsequent trials. The cohort (n = 288) included 52% with unmutated IGVH status and del17p (4.5%) and del11q (14.9%). Toxicity profiles were primarily hematologic and no patient has developed MDS or AML after a median follow-up of 6.4 years. The overall response rate across all trials was found to be over 90% with a 41% complete response rate. We validated that the CLL IPI model segregates progressive CLL patients into 4 risk groups associated with OS and TFS.. The high overall and complete response levels in favorable genetic risk CLL along with favorable toxicity profiles provide rationale for consideration of a PC based strategy for previously untreated progressive CLL.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Chromosome Deletion; Chromosomes, Human, Pair 11; Chromosomes, Human, Pair 17; Cyclophosphamide; Disease-Free Survival; Female; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Male; Middle Aged; Pentostatin; Rituximab; Smith-Magenis Syndrome; Survival Rate

Topics: Aged; Antigens, CD19; Behavior Therapy; Cyclophosphamide; Female; Humans; Immunotherapy, Adoptive; Leukemia, Lymphocytic, Chronic, B-Cell; Male; Middle Aged; Neoplasm, Residual; Pentostatin; Rituximab; T-Lymphocytes; Transplantation, Autologous; Treatment Outcome

Although several consolidation strategies to prolong treatment-free survival (TFS) in chronic lymphocytic leukaemia have been investigated, most have proven either ineffective or toxic. Ofatumumab is a human type I anti-CD20 antibody approved by the US Food and Drug Administration as maintenance treatment of patients with recurrent or progressive chronic lymphocytic leukaemia who are in complete or partial response after at least two lines of treatment; higher efficacy might be observed if used as consolidation strategy than without consolidation in previously untreated patients.. We recruited patients with previously untreated progressive chronic lymphocytic leukaemia who had an Eastern Cooperative Oncology Group performance status of 0-2 and adequate renal and hepatic function from centres in the USA. Patients with recent myocardial infarction; class III or IV heart failure; uncontrolled, HIV, or active hepatitis B or C infection; or active haemolytic anaemia were excluded. In the first arm of this study, which has been previously reported, patients were treated with six cycles of induction with pentostatin (2 mg/m(2) on day 1), cyclophosphamide (600 mg/m(2) on day 1), and ofatumumab (cycle 1: 300 mg on day 1 and 1000 mg/m(2) on day 2; cycles 2-6: 1000 mg/m(2) on day 1) given intravenously every 21 days. Here were report the second arm, where patients received the same regimen as the first arm, with the addition of six cycles of consolidation with ofatumumab (1000 mg once every 4 weeks), also given intravenously. The primary endpoint was TFS at 18 months, assessed in those who began consolidation. We estimated the distribution of TFS using the Kaplan-Meier method, assessing between-group differences with log-rank statistics. The phase 2 trial, which is completed, is registered at ClinicalTrials.gov, number NCT01024010.. Between Sept 21, 2011, and Nov 7, 2012, 34 patients were recruited to this second arm of the trial. Among the 31 (91%) patients who completed induction treatment and started consolidation, 26 (84%) completed the planned six cycles of ofatumumab consolidation. TFS at 18 months was 94·1% (95% CI 78·5-98·5). Grade 3 or worse adverse events deemed at least possibly related to treatment were neutropenia (14 [41%] patients), infection (2 [6%]), and one (3%) each with anaemia, haemolysis, fatigue, and a neurological, metabolic, respiratory, and vascular complication.. Ofatumumab-based consolidation appears to be a well tolerated and effective consolidation strategy in patients with chronic lymphocytic leukaemia, which could improve survival.. GlaxoSmithKline.

Topics: Aged; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Cyclophosphamide; Female; Follow-Up Studies; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Male; Middle Aged; Pentostatin; Prognosis; Survival Rate

Bevacizumab is a monoclonal antibody targeting vascular endothelial growth factor (VEGF) with in vitro pro-apoptotic and antiangiogenic effects on chronic lymphocytic leukemia (CLL) cells. As monotherapy in patients with CLL, it has no clinical activity. Here we report the results of an open-label, randomized phase II trial comparing the combination of pentostatin, cyclophosphamide and rituximab (PCR) either without or with bevacizumab (PCR-B) in previously untreated CLL patients. A total of 65 evaluable patients were enrolled, 32 receiving PCR and 33 PCR-B. A higher rate of grade 3-4 cardiovascular toxicity was observed with PCR-B (33% vs. 3%, p < 0.003). Patients treated with PCR-B had a trend for a higher complete remission (CR) rate (54.5% vs 31.3%; p = 0.08), longer progression-free survival (PFS)(p = 0.06) and treatment-free survival (TFS)(p = 0.09). No differences in PFS and TFS by IGHV mutational status were observed with the addition of bevacizumab. A significant post-treatment increase in VEGF levels was observed in the PCR-B arm (29.77 to 57.05 pg/mL); in the PCR-B arm, lower baseline CCL-3 levels were significantly associated with achievement of CR (p = 0.01). In conclusion, the addition of bevacizumab to chemoimmunotherapy in CLL is generally well-tolerated and appears to prolong PFS and TFS.

Topics: Adult; Aged; Aged, 80 and over; Angiogenesis Inhibitors; Antineoplastic Agents, Immunological; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Cyclophosphamide; Cytokines; Disease-Free Survival; Female; Genes, Immunoglobulin Heavy Chain; Humans; Kaplan-Meier Estimate; Leukemia, Lymphocytic, Chronic, B-Cell; Male; Middle Aged; Mutation; Pentostatin; Remission Induction; Rituximab; Time Factors; Treatment Outcome; Vascular Endothelial Growth Factor A

While the renal complications of plasma cell dyscrasia have been well-described, most information in patients with chronic lymphocytic leukemia and monoclonal B-cell lymphocytosis is derived from case reports. This is a retrospective analysis of patients with chronic lymphocytic leukemia or monoclonal B-cell lymphocytosis who underwent kidney biopsy for renal insufficiency and/or nephrotic syndrome. Between January 1995 and June 2014, 49 of 4,024 (1.2%) patients with chronic lymphocytic leukemia (n=44) or monoclonal B-cell lymphocytosis (n=5) had a renal biopsy: 34 (69%) for renal insufficiency and 15 (31%) for nephrotic syndrome. The most common findings on biopsy were: membranoproliferative glomerulonephritis (n=10, 20%), chronic lymphocytic leukemia interstitial infiltration as primary etiology (n=6, 12%), thrombotic microangiopathy (n=6, 12%), and minimal change disease (n=5, 10%). All five membranoproliferative glomerulonephritis patients treated with rituximab, cyclophosphamide and prednisone-based regimens had recovery of renal function compared to 0/3 patients treated with rituximab with or without steroids. Chronic lymphocytic leukemia infiltration as the primary cause of renal abnormalities was typically observed in relapsed/refractory patients (4/6). Thrombotic microangiopathy primarily occurred as a treatment-related toxicity of pentostatin (4/6 cases), and resolved with drug discontinuation. All cases of minimal change disease resolved with immunosuppressive agents only. Renal biopsy plays an important role in the management of patients with chronic lymphocytic leukemia or monoclonal B-cell lymphocytosis who develop renal failure and/or nephrotic syndrome.

Topics: Female; Follow-Up Studies; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Lymphocytosis; Male; Nephrotic Syndrome; Pentostatin; Renal Insufficiency; Retrospective Studies; Rituximab

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Cyclophosphamide; Female; Follow-Up Studies; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Male; Middle Aged; Pentostatin

Ofatumumab (OFA), a human CD20-targeting mAb, kills B lymphocytes using the innate immune system including complement-dependent cytotoxicity (CDC). The efficacy of OFA in patients with chronic lymphocytic leukemia (CLL) is limited by drug resistance, which is not well characterized. To better understand mechanisms of resistance, we prospectively studied CLL cells isolated from blood samples collected before and after in vivo exposure to the initial dose of OFA therapy in 25 patients undergoing their first treatment for progressive CLL. As previously reported, OFA therapy rapidly decreased the absolute lymphocyte count, CD20 expression by CLL cells, and serum complement levels. We now show that after administration of the first dose of OFA, there was a modest rebound in the absolute lymphocyte count and serum complement levels, but substantial ongoing loss of CD20 expression by CLL cells. These post-OFA treatment CLL cells were highly resistant to OFA-mediated CDC but retained sensitivity to alemtuzumab-mediated CDC in vitro. Posttherapy serum OFA levels correlated inversely with both the amount of pretreatment circulating cell-bound CD20 and with the decrease in this value following treatment. In vitro OFA-mediated CDC did not predict clinical responses, and the patients with first-dose reactions to OFA did not have markers of increased complement activation in vivo. We propose that optimal efficacy of CD20- targeted therapy for CLL requires determining an mAb dose size and frequency that optimizes CLL killing without exceeding the capacity of the cytotoxic mechanisms and thus minimizes loss of CD20 expression in the surviving CLL cells.

Topics: Adult; Aged; Aged, 80 and over; Alemtuzumab; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antigens, CD; Antigens, CD20; Antigens, Neoplasm; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; B-Lymphocytes; CD52 Antigen; Complement System Proteins; Cyclophosphamide; Cytotoxicity, Immunologic; Drug Resistance, Neoplasm; Female; Glycoproteins; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Lymphocyte Count; Male; Middle Aged; Pentostatin; Treatment Outcome

Chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL) patients with purine analog refractory disease or TP53 dysfunction still have limited treatment options and poor survival. Alemtuzumab-containing chemoimmunotherapy regimens can be effective but frequently cause serious infections. We report a Phase II trial testing the efficacy and tolerability of a short-duration regimen combining pentostatin, alemtuzumab, and low-dose high-frequency rituximab designed to decrease the risk of treatment-associated infections and to limit the loss of CD20 expression by CLL cells. The study enrolled 39 patients with progressive CLL that was either relapsed/refractory (n = 36) or previously untreated with 17p13 deletion (17p13-) (n = 3). Thirteen (33%) patients had both 17p13- and TP53 mutations predicted to be dysfunctional, and eight patients had purine analog refractory CLL without TP53 dysfunction. Twenty-six (67%) patients completed therapy, with only five (13%) patients having treatment-limiting toxicity and no treatment-related deaths. Twenty-two (56%) patients responded to treatment, with 11 (28%) complete responses (four with incomplete bone marrow recovery). Median progression-free survival was 7.2 months, time to next treatment was 9.1 months, and overall survival was 34.1 months. The majority of deaths (82%) were caused by progressive disease, including transformed diffuse large B-cell lymphoma (n = 6). Correlative studies showed that low-dose rituximab activates complement and natural killer cells without a profound and sustained decrease in expression of CD20 by circulating CLL cells. We conclude that pentostatin, alemtuzumab, and low-dose high-frequency rituximab is a tolerable and effective therapy for CLL and that low-dose rituximab therapy can activate innate immune cytotoxic mechanisms without substantially decreasing CD20 expression.

Topics: Aged; Alemtuzumab; Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal, Murine-Derived; Antigens, CD20; Antineoplastic Combined Chemotherapy Protocols; Chromosome Deletion; Chromosomes, Human, Pair 17; Disease-Free Survival; Female; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Male; Middle Aged; Neoplastic Cells, Circulating; Pentostatin; Recurrence; Remission Induction; Rituximab

Although rituximab-based chemoimmunotherapy (CIT) has substantially improved clinical outcomes in chronic lymphocytic leukemia (CLL), only 40% to 50% of patients achieve a complete remission (CR). There remains interest in identifying new approaches to improve the effectiveness of CIT. Ofatumumab is a fully human anti-CD20 monoclonal antibody with greater apparent single-agent activity than rituximab in CLL patients.. Previously untreated CLL patients in need of therapy received 6 cycles of CIT induction with pentostatin, cyclophosphamide, and ofatumumab (PCO) followed by response assessment.. Of the 48 patients enrolled, 77% completed PCO induction. Adverse events during induction included grade 3+ hematologic toxicity (27%) and grade 3+ nonhematologic toxicity (23%). Median CD4 count after induction and 6 months later were 186 × 10(6)/L and 272 × 10(6) /L. The overall response rate was 96% (46 of 48 patients), and the CR rate was 46% (22 of 48 patients). Among the 38 patients who underwent minimal residual disease evaluation, 7 (18%) were negative for minimal residual disease. After median follow-up of 24 months, 10 (21%) patients have progressed and 8 (17%) have required retreatment. The efficacy and toxicity of ofatumumab-based CIT compare favorably to our historical trials of rituximab-based CIT using an identical chemotherapy backbone (n = 64). Time to retreatment also appeared longer for ofatumumab-based CIT (free of retreatment at 24 months: 86% [95% confidence interval = 75-99] versus 68% [95% confidence interval = 56-81] for rituximab-based CIT).. Ofatumumab-based CIT is well tolerated in patients with previously untreated CLL. The efficacy of ofatumumab-based CIT compares favorably to historical trials of rituximab-based CIT, suggesting randomized trials comparing ofatumumab-based CIT and rituximab-based CIT should be considered.

Topics: Aged; Aged, 80 and over; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal, Murine-Derived; Antineoplastic Combined Chemotherapy Protocols; Cohort Studies; Combined Modality Therapy; Cyclophosphamide; Female; Humans; Immunotherapy; Leukemia, Lymphocytic, Chronic, B-Cell; Male; Middle Aged; Neoadjuvant Therapy; Pentostatin; Rituximab; Treatment Outcome

Uncontrolled studies comparing pentostatin (P), cyclophosphamide (C), and rituximab (R) (PCR) to fludarabine plus C+R (FCR) suggest similar efficacy with fewer infectious complications with PCR. We compared FCR and PCR in previously-untreated or minimally-treated B-cell chronic lymphocytic leukemia (CLL).. FCR (F 20 mg/m(2) Days 1-5, C 600 mg/m(2) Day 1, R 375 mg/m(2) Day 1) (28-day cycles) or PCR (P 4 mg/m(2) Day 1, C 600 mg/m(2) Day 1, R 375 mg/m(2) Day 1) (21-day cycles). Dose 1 of R: 100 mg/m(2) was given on Day 8 Cycle 1 and the remainder on Day 9; in subsequent cycles the entire dose was given on Day 1.. Ninety-two patients were randomly assigned to each group (N = 184). Groups were balanced; ~20% had received prior chemotherapy. The infection rate (FCR/PCR) was 31%/36%, the infective event rate was 38%/45%; 30 (35%)/37 (44%) patients were hospitalized; total hospitalization days was 271/404. 12 (14%)/6 (7%) patients achieved complete remissions (CR); the overall response rate (ORR) including CR+nodular PR (nPR)+PR was 59%/49%. Grade 3-4 treatment related AEs: neutropenia (69%/57%), leukopenia (34%/17%), thrombocytopenia (13%/6%). Grade 3-4 infections: febrile neutropenia (8%/6%), fever (2%/6%), infection (1%/3%), urinary tract infection (1%/0%), pneumonia (3%/1%), and sepsis (1%/2%); 5 deaths (1 FCR/4 PCR) were treatment-related.. PCR and FCR have significant activity in CLL and can be given safely in the community setting despite significant toxicity. ORRs were lower than expected; the CR rate was higher (NS) with FCR. This trial did not demonstrate a lower infection rate with PCR.

Topics: Adult; Aged; Aged, 80 and over; Antibodies, Monoclonal, Murine-Derived; Antineoplastic Combined Chemotherapy Protocols; Cyclophosphamide; Female; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Male; Middle Aged; Pentostatin; Rituximab; Treatment Outcome; Vidarabine

The combination of pentostatin (P), cyclophosphamide (C), and rituximab (R) achieved an overall response (OR) rate >90%, with >40% complete responses (CRs) in patients with untreated chronic lymphocytic leukemia (CLL).. To evaluate whether the tolerability of this regimen could be enhanced without sacrificing efficacy, a phase 2 trial was conducted of P and R without C, using a higher P dose (4 mg/m(2)). Among the 33 patients enrolled, 82% were male, the median age was 65 years (9 patients were aged >or=70 years), and 64% were classified as having Rai stage III to IV disease.. The OR rate was 76%, with 9 CRs (27%), 5 nodular partial responses, and 11 partial responses (PRs) reported. At the time of last follow-up, 29 of 33 patients were still alive at a median follow-up of 14 months (range, 1-34.8 months). Four (12%) patients experienced grade 3 or higher hematologic toxicity, and 5 (15%) experienced grade 3 or higher nonhematologic toxicity. Comparison of this trial with the previous PCR trial demonstrated that patients treated with PCR had a higher OR rate (91% vs 76%) and CR rate (41% vs 27%) compared with patients treated with PR. The median treatment-free survival for all accrued patients was notably longer in patients treated with PCR compared with PR (30 months vs 16 months).. The findings of the current study suggest that increasing the dose of the purine nucleoside analogue does not eliminate the need for cyclophosphamide in chemoimmunotherapy for the treatment of CLL.

Topics: Aged; Aged, 80 and over; Antibodies, Monoclonal; Antibodies, Monoclonal, Murine-Derived; Antineoplastic Combined Chemotherapy Protocols; Cyclophosphamide; Female; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Male; Middle Aged; Pentostatin; Rituximab; Treatment Outcome

Myeloid cell leukemia-1 (Mcl-1) is an antiapoptotic member of the Bcl-2 protein family. Increased Mcl-1 expression is associated with failure to achieve remission after treatment with fludarabine and chlorambucil in patients with chronic lymphocytic leukemia (CLL). However, the influence of Mcl-1 expression has not been examined in CLL trials using chemoimmunotherapy. We investigated Mcl-1 protein expression prospectively as part of a phase 2 study evaluating the efficacy of pentostatin, cyclophosphamide, and rituximab in patients with untreated CLL. No significant difference by Mcl-1 expression was noted in pretreatment or response parameters. However, in patients with higher Mcl-1 expression, both minimal residual disease-negative status and progression-free survival was found to be significantly reduced (57% vs 19%, P = .01; 50.8 vs 18.7 months; P = .02; respectively). Mcl-1 expression may therefore be useful in predicting poor response to chemoimmunotherapy. These findings further support pursuing treatment strategies targeting this important antiapoptotic protein. (Because the trials described were conducted before the requirement to register them was implemented, they are not registered in a clinical trial database.).

Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Murine-Derived; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Cyclophosphamide; Disease-Free Survival; Humans; Kaplan-Meier Estimate; Leukemia, Lymphocytic, Chronic, B-Cell; Myeloid Cell Leukemia Sequence 1 Protein; Pentostatin; Proto-Oncogene Proteins c-bcl-2; Rituximab; Treatment Outcome

Serum levels of pro-[vascular endothelial growth factor (VEGF)] and anti-[thrombospondin-1 (TSP)] angiogenic cytokines were prospectively measured in a phase II trial of chemoimmunotherapy (CIT) for chronic lymphocytic leukaemia (CLL) patients (n = 56). Pretreatment VEGF levels were lower among patients who achieved complete remission (CR) or nodular partial remission (nPR) relative to those with partial remission (PR) or stable/progressive disease (median 122.0 pg/ml vs. 246.8 pg/ml; P = 0.03). VEGF:TSP ratio was lower (anti-angiogenic phenotype) among patients who achieved CR/nPR. The pretreatment VEGF:TSP ratio also correlated with overall survival (P = 0.008). A pro-angiogenic profile appears associated with diminished response and inferior survival in CLL patients receiving CIT.

Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Murine-Derived; Antineoplastic Agents; Combined Modality Therapy; Cyclophosphamide; Fibroblast Growth Factors; Humans; Immunotherapy; Leukemia, Lymphocytic, Chronic, B-Cell; Pentostatin; Prognosis; Prospective Studies; Rituximab; Thrombospondin 1; Vascular Endothelial Growth Factors

Building on the prior work of use of pentostatin in chronic lymphocytic leukemia (CLL), we initiated a trial of combined pentostatin (2 mg/m2), cyclophosphamide (600 mg/m2), and rituximab (375 mg/m2) for 65 symptomatic, previously untreated patients. Of 64 evaluable patients, 34 (53%) were high Rai risk, 71% were nonmutated for the immunoglobulin heavy-chain variable region gene, 34% were CD38+, and 34% were ZAP-70+. Thirty patients (52%) had one anomaly detected by fluorescence in situ (FISH) hybridization, and 21 (36%) had complex FISH defects. Thirty-eight patients (58%) had grade 3+ hematologic toxicity but minimal transfusion needs and no major infections. Responses occurred in 58 patients (91%), with 26 (41%) complete responses (CRs), 14 (22%) nodular partial responses (nodular PRs), and 18 (28%) partial responses (PRs). Many patients with a CR also lacked evidence of minimal residual disease by 2-color flow cytometry. Examination of prognostic factors demonstrated poor response in the 3 patients with del(17p). In contrast, we found this regimen was equally effective in young versus older (>70 years) patients and in del(11q22.3) versus other favorable prognostic factors. Thus, this novel regimen of pentostatin, cyclophosphamide, and rituximab for previously untreated patients with CLL demonstrated significant clinical activity despite poor risk-based prognoses, achievement of minimal residual disease in some, and modest toxicity.

Topics: Adult; Aged; Aged, 80 and over; Antibodies, Monoclonal; Antibodies, Monoclonal, Murine-Derived; Antineoplastic Combined Chemotherapy Protocols; Cohort Studies; Cyclophosphamide; Disease Progression; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Tolerance; Female; Flow Cytometry; Humans; In Situ Hybridization, Fluorescence; Leukemia, Lymphocytic, Chronic, B-Cell; Male; Middle Aged; Neoplasm, Residual; Pentostatin; Predictive Value of Tests; Prognosis; Risk Factors; Rituximab; Sensitivity and Specificity; Survival Rate; Treatment Outcome

We conducted a multicenter, community-based phase II trial of PCR biochemotherapy (pentostatin 4 mg/m2, cyclophosphamide 600 mg/m2, and rituximab 375 mg/m2) every 3 weeks for up to 6 cycles in patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL). The study was stopped after enrolling 24 patients because of diminished investigator interest after 8 patients discontinued treatment because of adverse events, and 5 others died during treatment. The median age of patients was 69 years; 11 patients were over age 70, and 71% had Rai stage III or IV disease. The response rate among the 17 evaluable patients who completed 3 cycles of therapy was 58% (35%-81%, 95% confidence interval), with 2 complete responders (both greater than 70 years of age) and 7 partial responders. No patients developed progressive disease while receiving PCR. This is the first report of a trial in CLL utilizing a combination of purine analog, alkylator, and rituximab, in which most patients were older than 65 years and had high-risk disease. PCR is active in CLL/SLL, but appears to be less active and associated with more complications in the community setting, compared to trials with younger, lower risk patients who travel to academic referral centers for treatment.

Topics: Adult; Aged; Antibodies, Monoclonal; Antibodies, Monoclonal, Murine-Derived; Cyclophosphamide; Delivery of Health Care; Drug Therapy, Combination; Female; Humans; Immunotherapy; Leukemia, Lymphocytic, Chronic, B-Cell; Male; Membrane Glycoproteins; Middle Aged; Pentostatin; Rituximab; Survival Rate; Treatment Outcome

TCL-1 expression is variable in CLL, and no study has examined its association with treatment response. We measured TCL-1 protein in CLL cells from 51 patients who then received pentostatin, cyclophosphamide, and rituximab. TCL-1 expression did not correlate with any pre-treatment characteristics. Lower TCL-1 levels were associated with higher probability of attaining flow cytometry-negative status post-treatment (52% versus 17%, p=0.046). Trends toward improved complete remission rate (49% versus 19%, p=0.064) and progression-free survival (medians: 33 versus 20 months, p=0.199) were noted with lower TCL-1 expression. These data suggest TCL-1 expression may help predict treatment outcome in CLL patients following chemoimmunotherapy, and examination in larger studies is warranted.

Topics: Aged; Antibodies, Monoclonal; Antibodies, Monoclonal, Murine-Derived; Antineoplastic Combined Chemotherapy Protocols; Cyclophosphamide; Disease-Free Survival; Drug Monitoring; Female; Flow Cytometry; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Male; Neoplasm, Residual; Pentostatin; Prognosis; Proto-Oncogene Proteins; Remission Induction; Rituximab; Treatment Outcome

In an attempt to exploit bcl-2 overexpression and aberrant p53 function, two frequently encountered aberrations that predict marked treatment resistance and worse prognosis in patients with chronic lymphocytic leukemia (CLL) and non-Hodgkin's lymphoma (NHL), we combined theophylline, pentostatin, and chlorambucil at two dose levels (cohort I: 30 mg/m(2); cohort II: 20 mg/m(2)) on a 21-day cycle for up to six courses. We employed a phase I/II design to determine feasibility, define the maximum tolerated dose (MTD), and explore the impact of biologic modulation on response and time to progression (TTP) in 20 patients with relapsed or refractory CLL and NHL. Eight patients were enrolled in cohort I. They demonstrated a response rate (RR) of 28% and a 16.5-month TTP after receiving a median of two cycles. A 50% RR was observed in this cohort when patients with adverse histologies were excluded. Because of myelotoxicity, this dose level defined the MTD, and de-escalation occurred. All 12 patients in cohort II received 20 mg/m(2) chlorambucil. A 50% RR and an 18-month TTP were observed after a median of 5.5 cycles. An RR of 47% and a complete remission (CR) of 5% were observed for the entire group, although responses and TTP varied greatly by histology. Significant activity was observed in patients with B-cell CLL and follicular lymphoma (FL). RR and TTP for fludarabine-sensitive/naïve and fludarabine-refractory (FR) B-cell CLL patients were 66 vs 25% and 20 vs 8.5 months, respectively. Both FL patients responded (one with partial remission and one with CR), with a 22.5-monthly median TTP. For responding patients, median TTP and overall survival (OS) was 21 and 69 months, respectively, compared to a median TTP of 2 months and an OS of 13.5 months for nonresponders. The combination of pentostatin, chlorambucil, and theophylline is the active regimen in patients with FL and B-cell CLL.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Chlorambucil; Disease-Free Survival; Female; Follow-Up Studies; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Lymphoma, Non-Hodgkin; Male; Maximum Tolerated Dose; Middle Aged; Pentostatin; Recurrence; Remission Induction; Survival Rate; Theophylline

Pentostatin has demonstrated significant activity as a single agent in patients with low-grade B-cell and T-cell lymphomas and is less myelosuppressive than other purine analogues.. We conducted a phase II trial with the combination regimen of PC-R (pentostatin/cyclophosphamide with or without rituximab) in 14 patients with Waldenstrom's macroglobulinemia (WM) and 3 patients with lymphoplasmacytic lymphoma (LL) without monoclonal serum immunoglobulin M (IgM), followed by a maintenance regimen with rituximab (375 mg/m2 every 3 months) for patients exhibiting a complete response (CR) or a partial response (PR) after 4-6 cycles. Nine patients were untreated, and 8 had been previously treated with 1-3 regimens. The first 9 patients received PC therapy (pentostatin 4 mg/m2 plus cyclophosphamide 600 mg/m2), and 8 patients received the same combination with rituximab 375 mg/m2 on day 1. Cycles were repeated every 3 weeks.. An objective tumor response after PC and PC-R was confirmed in 11 of 17 evaluable patients (64.7%), with 2 CRs (11.7%) and 9 PRs (52.9%). In patients who received rituximab (n = 13) simultaneously or subsequently, the overall response rate was 76.9%. Grade 2/3 nausea and grade 2 vomiting was generally mild based on World Health Organization criteria. Grade 3 hematologic toxicity occurred after 9 of 49 cycles (18.3%), and grade 4 toxicity occurred after 2 cycles (4%). Ten patients were subsequently treated with rituximab every 3 months for 2-9 cycles to date (median, 4 cycles). No patients have had disease relapse to date, and all exhibited stable IgM serum levels. In 3 patients with a PR after completion of chemotherapy, remission has improved further, with normalization of the IgM level in 1 patient and another patient exhibiting a CR.. Our data indicate that PC-R is safe and highly effective in patients with WM. Maintenance therapy with rituximab for WM as a single infusion every 3 months can be administered safely and can improve remission status.

Topics: Adult; Aged; Antibodies, Monoclonal; Antibodies, Monoclonal, Murine-Derived; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Cyclophosphamide; Disease-Free Survival; Female; Humans; Immunoglobulin M; Leukemia, Lymphocytic, Chronic, B-Cell; Male; Middle Aged; Pentostatin; Remission Induction; Rituximab; Waldenstrom Macroglobulinemia

Pentostatin is a purine nucleoside analog with demonstrated activity in low-grade lymphoid malignancies. The purpose of this study was to determine the dose of pentostatin (dCF) that could be combined with chlorambucil and prednisone to treat chronic lymphocytic leukemia (CLL), evaluate the toxicity of the resulting regimen and to estimate its efficacy. This was a multi-institutional Eastern Cooperative Oncology Group (ECOG) phase I-II study. Individuals with active B-CLL were eligible if they had no prior treatment or were in sensitive first relapse, provided they had normal renal and hepatic function. Pentostatin was evaluated in combination with orally administered chlorambucil 30 mg/m2 and prednisone 80 mg/day, 1-5 of each 14-day cycle. The pentostatin dose was 2 mg/m2 IV, day 1 for the first 6 patients; 3 mg/m2 IV, day 1 for the next 6 patients; and 4 mg/m2 IV, day 1 for the last set of 6 patients. Fifty-five patients were entered. Because of increasing toxicity with no apparent improvement in clinical efficacy on escalation of the pentostatin dose, 2 mg/m2 was chosen as the phase II dose, and 43 patients were treated at this level. Thirty-nine of these patients were eligible, of which 38 were evaluable for response, 36 of these 38 had no prior treatment. Complete response (CR) manifested by normal bone marrow morphology, peripheral blood counts and resolution of any lymphadenopathy or hepatosplenomegaly occurred in 17 patients (45%). The overall objective response rate was 87%. The median response duration was 33 months and the median survival 5 years. The median time to treatment failure is 32 months. Severe (Grade 3+) infections were seen in 31% of patients and included bacterial pneumonia (n = 4), Pneumocystis pneumonia (n = 1), fungal pneumonia (n = 2), urinary tract infection with sepsis (n = 1) and Herpes Zoster (n = 5). Overall, 11 patients had H. Zoster while on study. Due to toxicity, 33% of patients stopped therapy. Pentostatin, chlorambucil and prednisone is a highly active regimen in CLL but cannot be recommended in present form because of an unacceptable incidence of opportunistic infections. These findings add to other recent reports which suggest combination therapy with pentostatin and alkylators are active in B-CLL. However, these combination chemotherapies will need to be combined with appropriate addition of anti-bacterial and anti-viral prophylaxis to reduce infection risk for B-CLL patients.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Chlorambucil; Female; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Male; Middle Aged; Pentostatin; Prednisone

Patients with chronic lymphocytic leukemia (CLL) are sometimes resistant to treatment or relapse soon after the administration of the currently available frontline therapy including chlorambucil-prednisolone CHOP and fludarabine. We report the beneficial effect of an alternative chemotherapeutic regimen containing 2'-deoxycoformycin (pentostatin) and the monoclonal antibody anti-CD20 (rituximab) in 5 patients with resistant/relapsing CLL.. Five patients (4 men and 1 woman) with CLL at stage C, according to Binet's classification, were included in the therapeutic protocol. The median age of the patients was 76 years (range 57-84 years). Previous treatment consisted of chlorambucil-prednisolone, fludarabine, and CHOP. The current regimen comprised six 2-week cycles of pentostatin, 4 mg/m(2) i.v., combined with four cycles of rituximab, in a dose of 375 mg/m(2), every other week.. Three patients responded to therapy, 2 achieved complete remission and 1 a partial response. Two patients did not respond to treatment. Toxicity was mild and well tolerated. The median survival duration of the responders was 19 months. These promising results suggest that salvage therapy with a combination regimen including pentostatin and rituximab may have a beneficial effect in patients with resistant/relapsing CLL.

Topics: Aged; Aged, 80 and over; Antibodies, Monoclonal; Antibodies, Monoclonal, Murine-Derived; Antineoplastic Combined Chemotherapy Protocols; Drug Resistance, Neoplasm; Female; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Male; Middle Aged; Pentostatin; Recurrence; Remission Induction; Rituximab; Salvage Therapy; Survival Rate; Treatment Outcome

Within this phase II trial of the European Organization for Research and Treatment of Cancer, we have investigated the safety and efficacy of pentostatin (Nipent; SuperGen, San Ramon, CA) in refractory lymphoid malignancies. Pentostatin was administered at a dosage of 4 mg/m2 every week for the first 3 weeks, then every 14 days, followed by maintenance therapy of 4 mg/m2 monthly for a maximum of 6 months. We have previously reported the results in T- and B-cell prolymphocytic leukemia, B-cell chronic lymphocytic leukemia, and hairy cell leukemia This report focuses on the outcome in T-cell malignancies: T-cell chronic lymphocytic leukemia, Sézary syndrome, mycosis fungoides, and T-zone lymphoma. Of 92 patients with these diagnoses enrolled, 76 were evaluable for response and toxicity, ie, 25 of 28 with T-cell chronic lymphocytic leukemia, 21 of 26 with Sézary syndrome, 22 of 26 with mycosis fungoides, and eight of 12 with T-zone lymphoma. All patients had progressive and advanced disease. Sixteen patients (21%) died during the first 9 weeks of treatment: 12 of progressive disease, two of infectious complications thought to be unrelated to treatment, one of myocardial infarction, and one of renal failure related to administration of intravenous contrast. Major toxicity (grades 3 and 4) included infection in 10.5% of patients, nausea/vomiting in 5%, and hepatotoxicity in 3%. One patient (1.3%) achieved a complete remission and 15 (19.7%) a partial remission. Better results were achieved in patients with Sézary syndrome or mycosis fungoides (complete remission + partial remission = 33.4% and 22.7%, respectively) than in patients with T-cell chronic lymphocytic leukemia (8%) or T-zone lymphoma (25%). We conclude that pentostatin is active in low-grade T-cell malignancies. Toxicities are mild to moderate at the dose schedule administered. Severe hematologic toxicity has not been observed. The efficacy at the present dose level is moderate. A higher dose might be necessary for some T-cell malignancies.

Topics: Adult; Aged; Antibiotics, Antineoplastic; Cause of Death; Disease Progression; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Humans; Immunosuppressive Agents; Leukemia, Hairy Cell; Leukemia, Lymphocytic, Chronic, B-Cell; Leukemia, Prolymphocytic; Leukemia, T-Cell; Lymphoma, T-Cell; Male; Middle Aged; Mycosis Fungoides; Pentostatin; Remission Induction; Sezary Syndrome; Skin Neoplasms; Treatment Outcome

The purpose of this study was to determine the efficacy and toxicity of pentostatin (2'-deoxycoformycin) administered in a five day schedule every 28 days to patients with B-cell chronic lymphocytic leukaemia (B-CLL) relapsed from or refractory to at least one line of prior chemotherapy. The initial dose level of 2 mg/m2/day was adjusted up or down by 0.5 mg/m2 in subsequent cycles on the basis of haematological and non-haematological toxicities. The five day schedule was selected because published pharmacokinetic studies had indicated that although pentostatin had an elimination half-life of approximately six hours and could inhibit plasma adenosine deaminase activity for 24 hours, recovery of enzyme activity rapidly took place and accumulation of dATP which has a toxic effect on non-replicating lymphoid cells could be increased by repeated dosing. Twenty-nine patients were entered into the study and dose-escalation was possible in nine, while dose reductions were required for five patients. Of the 24 patients evaluable for response, complete responses were achieved in two and partial responses in five for an overall response rate of 29.2%. Toxicity consisted of myelosuppression, infection, nausea and vomiting and hepatotoxicity but was experienced at acceptable levels considering the heavily pre-treated nature of the patient population. Pentostatin in this schedule has salvage activity in previously treated or resistant patients with B-CLL.

Topics: Adult; Aged; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Resistance; Female; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Male; Middle Aged; Pentostatin; Recurrence

Topics: Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Cladribine; Cyclophosphamide; Doxorubicin; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Pentostatin; Prednisone; Vidarabine Phosphate

Topics: Drug Evaluation; Europe; Humans; Leukemia, Hairy Cell; Leukemia, Lymphocytic, Chronic, B-Cell; Leukemia, Prolymphocytic; Leukemia, Prolymphocytic, T-Cell; Mycosis Fungoides; Pentostatin; Prospective Studies; Remission Induction; Sezary Syndrome; Skin Neoplasms

Knowledge of the vital role of adenosine deaminase in lymphatic tissues has led to the development of enzyme inhibitors for treatment of lymphoid neoplasms. Deoxycoformycin is a potent ADA inhibitor and has been shown to be active in acute lymphoblastic leukemia at high doses but associated with unpredictable toxicity. In indolent lymphocytic leukemia or lymphoma with low ADA concentrations, this drug is effective at low doses with mild toxicity. The on-going EORTC trial shows that pentostatin is highly effective in hairy cell leukemia and can achieve durable complete remissions even if interferon alpha has failed. It will probably play an important role in the treatment of prolymphocytic leukemia, T- and B-cell chronic lymphocytic leukemia and Sézary syndrome.

Topics: Adenosine; Adenosine Deaminase Inhibitors; Antineoplastic Agents; Coformycin; DNA, Neoplasm; Drug Evaluation; Humans; Leukemia, Hairy Cell; Leukemia, Lymphocytic, Chronic, B-Cell; Leukemia, Prolymphocytic; Multicenter Studies as Topic; Neoplasm Proteins; Pentostatin; Ribonucleosides; Sezary Syndrome

Bendamustine (BEN) has structural similarities to an alkylating agent and a nucleoside analog, and effective against tumor cells that are resistant to standard therapy. In this study we compared the activities of BEN against that of the alkylating agent, chlorambucil (CLB), and the nucleoside analogs, fludarabine (FLU) and deoxyadenosine/pentostatin (dADO/PEN), in primary chronic lymphocytic leukemia (CLL) cells in vitro. Cross-resistance was observed between BEN, CLB and FLU, with previously treated patients or those with a deletion 17p being most resistant. In contrast, some resistant CLL cells retained moderate sensitivity to dADO/PEN. Like FLU and CLB, BEN induced apoptosis through both the mitochondrial and death receptor pathways. There was a greater increase in DNA double-strand breaks (DSB) following FLU, as compared to BEN and CLB. Synergistic cytotoxicity was seen on combining BEN or CLB with FLU or dADO/PEN, but not when combining BEN with CLB. These results demonstrate that BEN acts as an alkylating agent, demonstrates cross-resistance to CLB and FLU and resistance to cells with a del 17p. Synergistic cytotoxic activity was seen between BEN and dADO/PEN suggesting that the combination of BEN and PEN should be evaluated in the clinic.

Topics: Adenosine Deaminase Inhibitors; Antineoplastic Agents, Alkylating; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Bendamustine Hydrochloride; Chlorambucil; Deoxyadenosines; DNA Breaks, Double-Stranded; Drug Synergism; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Pentostatin; Tumor Cells, Cultured

Chronic lymphocytic leukemia (CLL) is a B-cell malignancy characterized by a variable clinical course. Several parameters have prognostic capabilities but are associated with altered response to therapy in only a small subset of patients.. We used gene expression profiling methods to generate predictors of therapy response and prognosis. Genomic signatures that reflect progressive disease and responses to chemotherapy or chemoimmunotherapy were created using cancer cell lines and patient leukemia cell samples. We validated and applied these three signatures to independent clinical data from four cohorts, representing a total of 301 CLL patients.. A genomic signature of prognosis created from patient leukemic cell gene expression data coupled with clinical parameters significantly differentiated patients with stable disease from those with progressive disease in the training data set. The progression signature was validated in two independent data sets, showing a capacity to accurately identify patients at risk for progressive disease. In addition, genomic signatures that predict response to chlorambucil or pentostatin, cyclophosphamide, and rituximab were generated and could accurately distinguish responding and nonresponding CLL patients.. Thus, microarray analysis of CLL lymphocytes can be used to refine prognosis and predict response to different therapies. These results have implications for standard and investigational therapeutics in CLL patients.

Topics: Adult; Aged; Aged, 80 and over; Antibodies, Monoclonal; Antibodies, Monoclonal, Murine-Derived; Antineoplastic Agents; Chlorambucil; Cyclophosphamide; Disease Progression; Female; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Genomics; Humans; Immunotherapy; Leukemia, Lymphocytic, Chronic, B-Cell; Male; Middle Aged; Pentostatin; Pharmacogenetics; Prognosis; Risk; Rituximab

The prevalence of chronic lymphocytic leukemia (CLL) increases with age. Although chemoimmunotherapy (CIT) has dramatically improved response rates in patients with CLL, some CIT regimens are not well tolerated by many patients >or=70 years of age.. Sixty-four previously untreated patients with CLL and serum creatinine <1.5 times the upper limit of normal who met National Cancer Institute (NCI) 96-WG criteria for treatment received pentostatin (2 mg/m(2)), cyclophosphamide (600 mg/m(2)), and rituximab (375 mg/m(2)). The authors measured performance status at study entry and used age, weight, and baseline creatinine to calculate creatinine clearance (CrCl).. Eighteen of 64 (28%) patients were ages >or=70 years. Although individuals ages >or=70 years were more likely to have delayed treatment cycles (28% vs 7%; P=.03), there were no significant differences in the number of cycles administered, need for dose reductions, or grade 3-4 hematologic, infectious, or other toxicities. No significant differences in overall response rate, complete response rate, or progression-free survival were observed by age. Twenty-five (39%) patients had a CrCl < 70 mL/min (range, 34-67). Although individuals with CrCl < 70 were more likely to require dose reduction (24% vs 5%; P=.05), there were no significant differences in the number of cycles administered or grade 3-4 hematologic, infectious, or other toxicities. No significant difference in overall response rate, complete response rate, or progression-free survival were observed between patients with CrCl >or= 70 mL/min and those with CrCl < 70 mL/min.. In this clinical trial, the PCR regimen was well tolerated by older patients and individuals with CrCl

Topics: Aged; Aged, 80 and over; Antibodies, Monoclonal; Antibodies, Monoclonal, Murine-Derived; Antineoplastic Combined Chemotherapy Protocols; Cyclophosphamide; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Pentostatin; Prognosis; Rituximab

Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Murine-Derived; Antigens, CD20; Antineoplastic Agents; Clinical Trials, Phase II as Topic; Cyclophosphamide; Drug Therapy, Combination; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Pentostatin; Rituximab; Treatment Outcome

Purine analogs and alkylators are important agents for treating chronic lymphocytic leukemia (CLL). Early studies combining fludarabine and chlorambucil were abandoned owing to increased toxicity from overlapping myelosuppression and immunosuppression. Of the purine analogs active in CLL, pentostatin appears to be the least myelosuppressive. We previously reported that pentostatin and cyclophosphamide (PC) is active and well-tolerated in patients with relapsed or refractory CLL. Subsequently, we added rituximab, and now report on this three-drug combination.. We treated 46 patients with either previously treated CLL (32 patients) or other low-grade B-cell neoplasms (14 patients). Patients received pentostatin 4 mg/m2, cyclophosphamide 600 mg/m2, and rituximab 375 mg/m2 (PCR). All drugs were administered on the same day (rituximab omitted from cycle 1), and patients received six cycles at 3-week intervals. Filgrastim, sulfamethoxazole/trimethoprim, and acyclovir were administered prophylactically.. The median age was 62 years (range, 30 to 80 years). The median number of prior regimens was two (range, one to seven). For CLL patients, there were 24 responses (75%), including eight complete responses (25%). In fludarabine-refractory patients, 75% responded. Toxicity was acceptable, with grade 3/4 infections (including fever of unknown origin) in 28%. The regimen was well tolerated, with 72% of patients receiving the planned treatment at full dose.. PCR is safe and effective in previously treated patients with CLL. In comparison with our prior two-drug regimen, we find that rituximab did not seem to add significantly to the toxicity, but did appear to confer a survival advantage. Based on these results, we are currently studying PCR as initial therapy for patients with CLL.

Topics: Adult; Aged; Aged, 80 and over; Antibodies, Monoclonal; Antibodies, Monoclonal, Murine-Derived; Antineoplastic Combined Chemotherapy Protocols; Cyclophosphamide; Female; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Male; Middle Aged; Pentostatin; Rituximab

(1) Oral chlorambucil is the reference first-line treatment for patients with symptomatic chronic lymphocytic leukaemia. Intravenous fludarabine is a second-line option. (2) The indications for intravenous fludarabine have now been extended to cover first-line use. (3) The clinical evaluation dossier mainly contains data from two unblinded comparative trials. One trial compared intravenous fludarabine with chlorambucil in 509 patients for one year; the complete remission rate was significantly higher in the group receiving intravenous fludarabine (20% versus 4%) but, after 62 months of follow-up, the survival rate was no different (about 50% in both groups). Note that the dose of chlorambucil used in this trial may have been inadequate. (4) The other unblinded trial included 938 patients treated for six months with fludarabine, the CAP protocol, or the CHOP protocol. The median survival time did not differ among the three groups (67 to 70 months). (5) In the trial versus chlorambucil, the incidence of serious adverse events was significantly higher in the fludarabine group (55% of patients, versus 44%). The commonest serious adverse events were neutropenia, other haematological disturbances, and infections. (6) Oral chlorambucil is more convenient than intravenous fludarabine, which necessitates five infusions per month. Intravenous fludarabine costs 10 times more than oral chlorambucil. (7) In practice, chlorambucil remains the reference first-line treatment for chronic lymphocytic leukaemia.

Topics: Antibiotics, Antineoplastic; Antimetabolites; Antineoplastic Agents, Alkylating; Chlorambucil; Clinical Trials as Topic; Drug Approval; Drug Therapy, Combination; France; Humans; Injections, Intravenous; Leukemia, Lymphocytic, Chronic, B-Cell; Middle Aged; Pentostatin; Randomized Controlled Trials as Topic; Remission Induction; Survival Rate; Treatment Outcome; Vidarabine

Nucleotides (NTPs and dNTPs) have been measured in patient-derived chronic lymphocytic leukaemia (CLL) cells stimulated with TPA plus ionomycin and then exposed to cladribine, fludarabine or deoxycoformycin (1 microM, 16 h). dNTPs were not measurable in 10(8) unstimulated CLL cells which are quiescent. Time-dependent changes in nucleotides in CLL cells showed that the mechanism of action changed as the drug triphosphate accumulated. dCf induced substantial accumulation of dATP in CLL cells in culture, and similar levels of dATP in the same patient during subsequent treatment with dCf. Determination of "metabolic response patterns" of nucleotides in CLL cells treated with drugs might distinguish patients with susceptible and refractory CLL prior to chemotherapy.

Topics: Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Cladribine; Humans; Ionomycin; Kinetics; Leukemia, Lymphocytic, Chronic, B-Cell; Male; Middle Aged; Nucleotides; Pentostatin; Prognosis; Tumor Cells, Cultured; Vidarabine

Purine analogs and alkylators are important agents in the treatment of chronic lymphocytic leukemia (CLL). Previously, combinations of fludarabine and chlorambucil were abandoned because of increased toxicity from overlapping myelosuppression and immunosuppression. Of the purine analogs active in CLL, pentostatin may be least myelosuppressive. We hypothesized that combining pentostatin with cyclophosphamide would have less myelotoxicity than combinations using other purine analogs.. We studied 23 patients with previously treated CLL. All patients received pentostatin 4 mg/m(2). Seventeen patients received cyclophosphamide 600 mg/m(2), and six patients received cyclophosphamide 900 mg/m(2). Both drugs were administered on day 1 of each cycle, and cycles were repeated every 3 weeks for six treatments. Filgrastim, sulfamethoxazole/trimethoprim, and acyclovir were administered prophylactically. The median number of prior treatment regimens was three (range, one to five) with 13 patients (57%) refractory to prior fludarabine therapy.. The cyclophosphamide 900 mg/m(2) dose level was associated with moderate to severe nausea, and we chose cyclophosphamide 600 mg/m(2) as the dose for further study. There were 17 responses (74%; 95% confidence interval, 63% to 85%), including four complete responses. The response rate was 77% in fludarabine-refractory patients. Myelosuppression was acceptable with grade 3/4 neutropenia and thrombocytopenia, seen in 35% and 30% of patients, respectively. The relative sparing of thrombopoiesis can be seen in that only one patient (5%) with an initial platelet count of more than 20,000 required platelet transfusions while receiving therapy.. Pentostatin 4 mg/m(2) with cyclophosphamide 600 mg/m(2) is safe and effective in previously treated patients with CLL. On the basis of these results, we are currently studying pentostatin, cyclophosphamide, and rituximab (PCR) therapy in patients with CLL.

Topics: Adult; Aged; Antibiotics, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow; Cyclophosphamide; Drug Administration Schedule; Drug Resistance; Female; Humans; Immunosuppressive Agents; Leukemia, Lymphocytic, Chronic, B-Cell; Male; Middle Aged; Neutropenia; Pentostatin; Thrombocytopenia; Treatment Outcome; Vidarabine

With a mean age at diagnosis for chronic lymphocytic leukaemia (CLL) of 65 years, development of optimal therapeutic regimens has been hampered by the advanced age of patients. In general, because of comorbidity older patients are not treated with the intent of achieving a complete response and so do not attain the quality of response of younger patients and do not survive as long. We have investigated whether or not ex vivo cellular sensitivity to cytotoxic drugs could be an underlying biological basis for this age differential in response and survival by comparing ex vivo drug response with age in untreated CLL patients. Cells from 365 untreated CLL patients aged 31.1-87.1 years (average 65.3 years) were tested for drug response by differential staining cytotoxicity (DiSC) assay with a panel of 10 drugs. An average of 280 results (range 196-361) obtained for each drug was compared with patient age. For chlorambucil, cyclophosphamide, prednisolone, vincristine, doxorubicin, epirubicin, fludarabine, cladribine and methylprednisolone, no relationship was found between ex vivo drug response and age (r<0.12). For pentostatin, a possible but very weak relationship (r = 0.18; n = 210; P = 0.06) was found. We conclude that cellular sensitivity to cytotoxic drugs does not support the differential treatment of older and younger CLL patients.

Topics: Adult; Age Factors; Aged; Aged, 80 and over; Antineoplastic Agents; Chlorambucil; Cladribine; Comorbidity; Cyclophosphamide; Doxorubicin; Drug Resistance, Neoplasm; Epirubicin; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Methylprednisolone; Middle Aged; Neoplastic Stem Cells; Palliative Care; Pentostatin; Prednisolone; Prognosis; Staining and Labeling; Tumor Cells, Cultured; Vidarabine; Vincristine

We summarize the results of our experience over the past 15 years using pentostatin (Nipent; SuperGen, San Ramon, CA) to treat a range of mature B- and T-cell malignancies. This includes 145 patients with postthymic T-cell malignancies in whom disease subtype was found to be the most significant predictor of response, with the best response rates seen in Sézary syndrome (62%) and T-prolymphocytic leukemia (45%). However, there are no long-term survivors among patients with this group of disorders, and strategies using pentostatin in combination with other therapies, such as CAMPATH-1H, are currently being explored. Among the mature B-cell diseases, pentostatin in both standard- and low-dose regimens is effective in advanced, relapsed/refractory B-chronic lymphocytic leukaemia, showing no cross-resistance with other purine analogs such as fludarabine. Our largest series treated with pentostatin consists of 165 patients with hairy cell leukemia. The follow-up period in this group extends to more than 10 years, with a projected event-free survival rate at 5 years of 60% and an overall survival rate of 97%.

Topics: Antibiotics, Antineoplastic; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Disease-Free Survival; Drug Resistance, Neoplasm; Follow-Up Studies; Humans; Immunosuppressive Agents; Leukemia; Leukemia, B-Cell; Leukemia, Hairy Cell; Leukemia, Lymphocytic, Chronic, B-Cell; Leukemia, Prolymphocytic; Leukemia, T-Cell; Lymphoma; Lymphoma, B-Cell; Lymphoma, T-Cell; Pentostatin; Sezary Syndrome; Survival Rate; Vidarabine

Hairy cell leukemia (HCL) is a chronic lymphoproliferative disease of B-cell origin manifested by pancytopenia and splenomegaly. Before 1980 the only effective treatment for HCL was splenectomy, which resolved the cytopenia but did not eliminate the disease from the bone marrow. In addition, the majority of patients progressed after splenectomy and required further treatment. Pentostatin (Nipent; SuperGen, San Ramon, CA) is a purine antimetabolite that was found in phase I studies to induce profound lymphocytopenia Although in vitro studies suggested that T lymphocytes were most sensitive to pentostatin, patients with B-cell chronic lymphatic leukemia and low-grade non-Hodgkin's lymphoma responded to treatment in the initial phase I trials. Due to evidence that the drug was effective in lymphoproliferative disease, patients with HCL were treated with pentostatin. The promising initial results led to phase II studies in both untreated and previously treated patients. These studies demonstrated that pentostatin was highly effective as a single agent, with complete responses seen in 60% to 90% of patients. These responses were durable without maintenance chemotherapy and were seen in patients previously treated with interferon or chemotherapy. Toxicity was usually mild, with nausea and skin rashes predominating. When seen, infections resulting from neutropenia occurred early in treatment. The high response rates and low toxicity suggest that pentostatin should be considered as one of the standard treatments for HCL.

Topics: Adenosine Deaminase Inhibitors; Antibiotics, Antineoplastic; Clinical Trials, Phase II as Topic; Disease Progression; Drug Eruptions; Enzyme Inhibitors; Exanthema; Humans; Immunosuppressive Agents; Leukemia, B-Cell; Leukemia, Hairy Cell; Leukemia, Lymphocytic, Chronic, B-Cell; Lymphoma, Non-Hodgkin; Nausea; Neutropenia; Pancytopenia; Pentostatin; Remission Induction; Splenomegaly

Purine analogs and alkylating agents are the most active drugs in the treatment of patients with chronic lymphocytic leukemia (CLL). Although fludarabine is the most widely tested purine analog in CLL, myelosuppression has limited its use in combination chemotherapy regimens. Because pentostatin (Nipent; SuperGen, San Ramon, CA), a related purine analog with proven activity in CLL, has less myelosuppression, we postulated that it would prove advantageous and could be more readily combined with alkylating agents. We are conducting a phase I/II trial of combination chemotherapy with pentostatin and cyclophosphamide for previously treated patients with CLL. Patients need to have Rai high-risk disease or "active" intermediate-risk disease. The treatment regimen consists of a fixed dose of pentostatin (4 mg/m2) combined with an increasing dose of cyclophosphamide. We plan to treat cohorts of three patients each at cyclophosphamide dose levels of 600, 900, 1,200, 1,500, and 2,000 mg/m2. Cycles will be repeated every 21 days. If unacceptable toxicity is encountered at one dose level, then three additional patients (total of six patients) will be accrued to that dose level before further dose escalations will be permitted. A second instance of unacceptable toxicity will close that dose level and identify the preceding level as the phase II dose. Additional patients will be accrued to the phase II dose level to better assess response. Supportive measures include the use of granulocyte colony-stimulating factor (5 microg/kg/d) to limit neutropenia. Sulfamethoxazole/trimethoprim will be given as prophylaxis against Pneumocystis carinii pneumonia and acyclovir will be administered as prophylaxis for herpes zoster. Response will be assessed according to standard criteria, and flow cytometry and fluorescent in situ hybridization will be used to assess for minimal residual disease in patients with trisomy 12.

Topics: Acyclovir; Anti-Infective Agents; Antibiotics, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Antiviral Agents; Chemoprevention; Chromosomes, Human, Pair 12; Clinical Trials, Phase I as Topic; Clinical Trials, Phase II as Topic; Cohort Studies; Cyclophosphamide; Dose-Response Relationship, Drug; Flow Cytometry; Granulocyte Colony-Stimulating Factor; Herpes Zoster; Humans; Immunosuppressive Agents; In Situ Hybridization, Fluorescence; Leukemia, Lymphocytic, Chronic, B-Cell; Neutropenia; Patient Selection; Pentostatin; Pneumonia, Pneumocystis; Remission Induction; Risk Factors; Trimethoprim, Sulfamethoxazole Drug Combination; Trisomy

Both pentostatin (Nipent) and rituximab (Rituxan) have single-agent activity in B-cell malignancies, including indolent and intermediate-grade non-Hodgkin's lymphoma (NHL). Pentostatin is also active in pretreated patients with chronic lymphocytic leukemia (CLL). In spite of current treatment modalities, few patients with these diseases are cured. The combination of rituximab and pentostatin is an attractive treatment option because both drugs have a limited toxicity profile and can be delivered on an outpatient basis. We describe the design of a phase II multicenter study to evaluate the safety and efficacy of pentostatin in combination with rituximab in patients with previously treated and untreated low-grade NHL and CLL.

Topics: Adolescent; Adult; Aged; Antibiotics, Antineoplastic; Antibodies, Monoclonal; Antibodies, Monoclonal, Murine-Derived; Antineoplastic Combined Chemotherapy Protocols; Clinical Trials, Phase II as Topic; Female; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Lymphoma, B-Cell; Male; Middle Aged; Pentostatin; Rituximab; Treatment Outcome

Pseudohypoxemia has been reported in leukemic patients with extreme leukocytosis, and it is characterized by a low oxygen saturation on arterial blood gas analysis despite normal saturation on pulse oximetry. We report the case of a 51-year-old man with chronic lymphocytic leukemia and an elevated white blood cell (WBC) count after splenectomy, his progressive postoperative pseudohypoxemia gradually improved as the leukocytosis was lowered by chemotherapy. We believe this is the first report to show a statistically significant correlation between the WBC count and the degree of pseudohypoxemia in a patient with leukemia.

Topics: Antibiotics, Antineoplastic; Blood Gas Analysis; Humans; Hypoxia; Leukemia, Lymphocytic, Chronic, B-Cell; Leukocytosis; Male; Middle Aged; Oximetry; Pentostatin; Postoperative Complications; Pulmonary Embolism; Splenectomy

The nucleoside analogs fludarabine, 2'-deoxycoformycin (DCF), and 2-chlorodeoxyadenosine (CdA), commonly used in the treatment of patients with indolent lymphoid malignancies such as chronic lymphocytic leukemia (CLL) and hairy cell leukemia (HCL), are associated with myelosuppression and profound and prolonged immunosuppression. These complications raise the possibility of an increase in secondary malignancies in patients whose disease already places them at greater risk. The purpose of the present study was to assess the frequency of second tumors in patients with CLL who are treated with fludarabine and in patients with HCL who are treated with DCF and CdA.. We reviewed the long-term follow-up data for 2,014 patients treated on National Cancer Institute Group C protocols with fludarabine for relapsed and refractory CLL and with DCF and CdA for HCL using a Second Cancer Report. The numbers of observed and expected secondary tumors were compared.. Median follow-up periods for the DCF (n = 409), fludarabine (n = 724), and CdA (n = 979) studies were 6.9, 7.4, and 5.1 years, respectively. The 111 malignancies were most commonly lymphoma (25 patients), prostate (19), lung (15), colorectal (nine), bladder (six), and breast (six), but also CNS, stomach, ovary, head and neck, melanoma, sarcoma, testicular, and myeloid leukemias. Compared with age-adjusted 1994 Surveillance and Epidemiology End-Results rates for the general population, the observed/expected frequencies for DCF, fludarabine, and CdA were 1.43 (95% confidence interval [CI], 0.93 to 2.10), 1.65 (95% CI, 1.04 to 2.47), and 1.50 (95% CI, 1.14 to 1.93), respectively, indicating a significant (at P =.05) increase in risk for patients treated on the latter two protocols compared with a normal population. However, these values are consistent with the increase already associated with these diseases.. Despite their immunosuppression, nucleoside analogs can be safely administered to patients with CLL or HCL without a significantly increased risk of secondary malignancies.

Topics: Aged; Antineoplastic Agents; Cladribine; Female; Follow-Up Studies; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Leukemia, Lymphocytic, Chronic, B-Cell; Male; Middle Aged; Neoplasms, Second Primary; Pentostatin; Vidarabine

We assessed the role of human CD52 antibody (Campath-1H) in six patients with chronic lymphocytic leukaemia (CLL) treated to maximal response with purine analogues (fludarabine/deoxycoformycin) in whom persistent leukaemic infiltration of blood and bone marrow had precluded autologous stem cell transplantation. Five patients achieved haematological and histological complete remission following Campath-1H and one had minimal focal residual CLL in a trephine biopsy. Autologous transplantation was performed in two patients without complications and with rapid haemopoietic engraftment. Treatment with Campath-1H may be of value in eradicating residual disease in CLL and may facilitate high-dose therapy in young patients.

Topics: Adult; Alemtuzumab; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antibodies, Neoplasm; Female; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Male; Middle Aged; Neoplasm, Residual; Pentostatin; Vidarabine

Topics: Anemia, Hemolytic; Antineoplastic Agents; Autoimmune Diseases; Fatal Outcome; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Male; Middle Aged; Pentostatin; Recurrence; Vidarabine

Conventional cytogenetic analysis in B-cell chronic lymphocytic leukemia (B-CLL) has been very difficult, and the prognostic significance of specific chromosome aberrations is under discussion. Recent improvements in fluorescence in situ hybridization (ISH) techniques have provided an alternative approach for the detection of chromosome aberrations. Here, an interphase cytogenetic study was performed to analyze the incidence and prognostic significance of a p53 gene deletion in B-CLL and related disorders. We studied mononuclear cells from 100 patients with chronic B-cell leukemias [B-CLL, 90 patients; B-prolymphocytic leukemia (B-PLL), 7; Waldenström's macroglobulinemia (WM), 3] by fluorescence ISH with a genomic p53 DNA probe. In a subset of patients, additional G-banding analysis and single strand conformation polymorphism (SSCP) analysis was performed. Seventeen of the 100 patients [17%; B-CLL, 11 of 90 (12%); WM, 1 of 3; B-PLL, 5 of 7] exhibited a monoallelic p53 gene deletion by ISH. G-banding analysis demonstrated abnormalities of chromosome 17 in 13 of these 17 patients, all leading to loss of band 17p13. SSCP analysis showed aberrant bands in 9 of 14 patients with a p53 gene deletion. None of 12 patients with a p53 gene deletion compared with 20 of 36 patients (56%) without a deletion responded to therapy with fludarabine or pentostatin (P < .001). The difference in survival probabilities from the time of diagnosis and from the start of treatment with purine analogs between the two groups was highly significant (P < .001). In multivariate analysis, p53 gene deletion was the strongest prognostic factor for survival. In conclusion, p53 gene deletion predicts for non-response to therapy with purine analogs and for poor survival in chronic B-cell leukemias.

Topics: Adult; Aged; Aged, 80 and over; Base Sequence; Chromosome Aberrations; Chromosomes, Human, Pair 17; Female; Gene Deletion; Genes, p53; Humans; In Situ Hybridization, Fluorescence; Leukemia, Lymphocytic, Chronic, B-Cell; Male; Middle Aged; Molecular Sequence Data; Pentostatin; Polymorphism, Single-Stranded Conformational; Survival Rate; Vidarabine

The cytotoxic effects and the induction of programmed cell death (apoptosis) by Fludarabine (FLU), 2-chlorodeoxyadenosine (2-CdA), and deoxycoformycin (DCF) with/without alpha-interferon (alpha-IFN) were evaluated in vitro against freshly isolated B-chronic lymphocytic leukemia (B-CLL) cells. Cytotoxicity was evaluated according to the soluble tetrazolium/formazan assay. Regarding the cytotoxicity, FLU, 2-CdA, and DCF showed a mean antitumor activity of 45% +/- 3.39 (mean +/- S.D.), 55% +/- 4.72, and 20% +/- 3.16, respectively. alpha-IFN alone showed a mean cytotoxic activity of 10% +/- 2.72. The cytotoxicity of these purine analogues in combination with alpha-IFN was 52% +/- 2.97, 75% +/- 3.41, and 26% +/- 7.09, respectively. We observed a statistically significant increase of cytotoxicity compared to controls in FLU alone (P < 0.05), 2-CdA (P < 0.05), and their combination with alpha-IFN (P < 0.05). Apoptosis was evaluated by electrophoresis gel of DNA oligonucleosomal fragments and by a cytofluorimetric method. Only FLU and 2-CdA activated the apoptosis and DCF showed a minor apoptotic pathway amount. These apoptosis data were confirmed by both gel electrophoresis of DNA and by propidium iodide cytofluorimetric method. FLU and 2-CdA show activity in B-CLL cells by direct cytotoxic action and the induction of cell death by apoptosis; in the future, it would be interesting to utilize these in vitro assays in monitoring chemosensitivity and predicting response for the clinical use.

Topics: Aged; Apoptosis; Cladribine; DNA Damage; Female; Humans; In Vitro Techniques; Interferon-alpha; Leukemia, Lymphocytic, Chronic, B-Cell; Male; Middle Aged; Pentostatin; Tumor Cells, Cultured; Vidarabine

The nucleoside analog, 2'-deoxycoformycin (dCF), and the alkylating agents, chlorambucil (CLB) and cyclophosphamide, are effective agents in the treatment of chronic B cell leukemias and lymphomas. The cyclophosphamide analog, 4-hydroperoxycyclophosphamide (4-HC), generates the same active metabolite as cyclophosphamide in cells and has been used extensively for bone marrow purging in vitro. We have observed that deoxyadenosine (dAdo) plus dCF (dAdo/dCF) inhibit the repair of x-irradiation-induced and bleomycin-induced DNA damage in vitro, and that this results in either synergistic or additive cytotoxicity, respectively. In the present study we examined whether dAdo/dCF, can enhance the antitumor activity of CLB and 4-HC in chronic lymphocytic leukemia (CLL) cells in vitro. CLL cells were treated with CLB for 6 hr and then with dAdo/dCF for 18 hr and cytotoxicity was measured by the MTT assay. Synergy was observed between CLB and dAdo/dCF in CLL cells from 2 patients, with synergy increasing as the CLB dose was raised. In contrast, similar treatment of human bone marrow cells resulted in little or no synergistic cell kill. Treatment of CLL cells from 2 patients with 4-HC for 30 min followed by dAdo/dCF for 18 hr resulted in little synergistic cytotoxicity, although this drug combination did produce an additive cell kill. Thus, combination therapy with nucleoside analogs and alkylating agents may be useful for improving treatment of CLL.

Topics: Alkylating Agents; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow; Cells, Cultured; Chlorambucil; Cyclophosphamide; Deoxyadenosines; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Pentostatin

Topics: 2-Chloroadenosine; Antineoplastic Agents; Cladribine; Clinical Trials as Topic; Deoxyadenosines; Humans; Leukemia, Hairy Cell; Leukemia, Lymphocytic, Chronic, B-Cell; Lymphoma, Non-Hodgkin; Pentostatin; Vidarabine

Topics: Antineoplastic Agents; Cladribine; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Pentostatin; Vidarabine

Similar to interferon alpha, pentostatin is highly effective in hairy cell leukemia and moderately active in other chronic lymphoid malignancies. In ten patients with hairy cell leukemia (HCL) and seven patients with other B-cell chronic leukemias (BCL), we have studied the intracellular 2',5'-oligoadenylate synthetase (2,5OAS) activity of the mononuclear cells before, 4 h, 24 h, and 48 h after pentostatin administration. In patients with HCL the median level of intracellular 2,5OAS increased 4.6-fold at 4 h and 11.5-fold at 24 h compared to the pretreatment value. Among the other seven patients, the median intracellular 2,5OAS remained unchanged in three patients and rose slightly by 2 to 14 times in four patients. Eleven patients (eight with HCL and two with BCL) responded to pentostatin. The median increase in 2,5OAS among the responders was 13.0-fold (range 4.8-30.0) whereas that among non-responders was 2.2-fold (range 0.2-6.3). The difference was highly significant (p less than 0.0001). In five of the total seventeen patients, the plasma levels of 2,5OAS activity were also determined and changes in plasma levels paralleled those measured intracellularly. To determine if the elevation of 2,5OAS is mediated by induction of interferon alpha, the expressions of mRNA for interferon alpha and beta were investigated by means of reverse transcription and polymerase chain reaction using the corresponding sense primers. In none of the five patients thus studied could we find an induction of mRNA for interferon alpha or beta in the leukemic cells during treatment with pentostatin. Thus, response to pentostatin correlates with induction of 2,5OAS directly and the 2',5'-oligoadenylate system seems to be involved in cytotoxicity.

Topics: 2',5'-Oligoadenylate Synthetase; Adult; Aged; Aged, 80 and over; Enzyme Induction; Female; Humans; Interferon-alpha; Interferon-beta; Leukemia, Hairy Cell; Leukemia, Lymphocytic, Chronic, B-Cell; Leukocytes, Mononuclear; Male; Middle Aged; Pentostatin; Polymerase Chain Reaction; Remission Induction; RNA, Messenger

Hairy cell leukemia is a malignant B-cell disorder characterized by splenomegaly and pancytopenia. The malignant cell is morphologically unique and characterized by fine cytoplasmic projections. Although studies of the cell have revealed important information about its proliferative capacity, cell surface, and membrane composition, less is known about the metabolic characteristics of the cell. We have previously investigated the oxidative metabolism of the hairy cell and have suggested that hairy cells might have a unique glucose metabolism compared to normal lymphocytes. This is indicated by a high rate of [6-14C]glucose oxidation in short-term culture consistent with an active Kreb's cycle and a high ratio of [6-14C]glucose oxidation to [1-14C] glucose oxidation. In this study, we evaluated an additional group of patients with hairy cell leukemia prior to or after treatment with the experimental drug 2'-deoxycoformycin (dCF). We found that in seven of eight patients the leukemic cells had a pattern similar to that previously described and that all of these seven patients had a significant response to therapy. The cells of the eighth patient had minimal Kreb's cycle activity, and at the time of study the patient was resistant to therapy with dCF. The metabolic activity of hairy cells may distinguish them from other lymphoid populations and may be a marker for sensitivity to dCF.

Topics: Adult; Aged; Female; Glucose; Humans; Leukemia, Hairy Cell; Leukemia, Lymphocytic, Chronic, B-Cell; Leukocytes, Mononuclear; Male; Middle Aged; Pentostatin

The combined effects of interferon (IFN) and 2'-deoxycoformycin (DCF) on 2',5'-oligoadenylate (2-5A) synthetase and adenosine deaminase (ADA) activity were examined in vitro in peripheral blood mononuclear cells from patients with hairy cell leukemia (HCL) and chronic lymphocytic leukemia (CLL). In HCL cells, the effects of IFN and DCF on both OAS and ADA activity were strictly antagonistic. Antagonism in inducing OAS activity was also observed in CLL cells, although, in general, little interaction between DCF and IFN occurred in these cells. If OAS and ADA are important in the antitumor effects of IFN and DCF, our results suggest that combination therapy with IFN and DCF could be counterproductive.

Topics: 2',5'-Oligoadenylate Synthetase; Adenosine Deaminase Inhibitors; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Humans; Interferon alpha-2; Interferon-alpha; Leukemia, Hairy Cell; Leukemia, Lymphocytic, Chronic, B-Cell; Male; Middle Aged; Pentostatin; Recombinant Proteins

Pentostatin was used to treat 26 patients with advanced B-cell chronic lymphocytic leukemia resistant to conventional treatment. Twenty patients had progressive disease on previous regimens and six had had partial remission and then relapsed 3-34 months after previous chemotherapy. Eleven patients had previously been treated with three different regimens. 10 had been treated with two regimens, and five had been treated with one regimen. Pentostatin was administered at a dosage of 4 mg/m2 weekly for 3 weeks, then 4 mg/m2 every other week for 6 weeks and once a month for 6 months. Seven of 26 assessable patients (27%) achieved partial remission and five (19%) achieved clinical improvement. The median duration of partial remission until relapse or death was 210 days. Myelosuppression was minor and transient in responsive patients, indicating some degree of selective effect on lymphocytes. Except for one patient who died of cerebral hemorrhage during the first 6 weeks of treatment, no drug-related deaths were registered. Major toxic effects included nausea in 17 patients (mainly grade 1), infections in 15, and liver enzyme elevations in five. Thus, pentostatin is active, even in patients with advanced B-cell chronic lymphocytic leukemia that is refractory to multiple chemotherapy regimens. Response can be achieved with mild myelosuppression.

Topics: Adult; Aged; Drug Evaluation; Female; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Male; Middle Aged; Pentostatin

We conducted a phase II trial of deoxycoformycin (pentostatin [DCF]) in chronic lymphocytic leukemia (CLL). Eligibility criteria included age greater than 18 years, Cancer and Leukemia Group B (CALGB) performance status 0 to 2, lymphocyte count greater than or equal to 15,000 cells/microL, international stage B or C disease (multiple lymph nodes involved and/or hemoglobin [Hgb] less than 11 g and/or platelets less than 100,000/microL) and no more than one prior treatment regimen. DCF dose was 4 mg/m2 intravenously (IV) weekly for 3 weeks and then every 2 weeks. There were 39 eligible patients (35 men and four women; median age, 63 years; median time from diagnosis to study entry, 3 years). Of these 39 patients, 31% were stage B and 33% had no prior treatment. Median laboratory values at entry were Hgb 10.5 g, WBC 96,100/microL, and platelets 93,500/microL. Nodal involvement was present in 90%, splenomegaly in 81%, and hepatomegaly in 47%. Patients received a median of nine DCF injections, with a range of four to 26. Three patients were not evaluable for response. Overall, 3% achieved a complete response (CR), 23% a partial response (PR), 28% showed clinical improvement (CI), and 38% had stable disease (SD). Associated toxicities (grade 2 or worse) observed were infections (52%), worsening of thrombocytopenia (26%) or anemia (33%), nausea and vomiting (31%), rash or pruritus (20%), and stomatitis (8%). We conclude that DCF is an active agent in CLL with acceptable toxicity.

Topics: Adenosine Deaminase Inhibitors; Aged; Antineoplastic Agents; Coformycin; Drug Evaluation; Female; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Lymphocytosis; Male; Middle Aged; Nucleoside Deaminases; Pentostatin; Remission Induction; Ribonucleosides; Thrombocytopenia

Deoxycoformycin (DCF) is a specific inhibitor of adenosine deaminase (ADA) and has been shown to be active in lymphoid neoplasms. Cytotoxicity is thought to be mediated by the accumulation of deoxyadenosine (AdR) and deoxyadenosine triphosphate (dATP) which inhibits ribonucleotide reductase and DNA synthesis in rapidly proliferating cells. Others suggested mechanisms leading to cell death particularly in non-dividing cells include depletion of ATP and NAD pools, inhibition of S-adenosylhomocysteine (SAH) hydrolase and induction of DNA strand breaks. In patients with high leukemic counts who were subsequently treated with DCF, we have studied (a) the levels of ADA, ecto-5'-nucleotidase (5NT), deoxyadenosine kinase (AdR-kinase) and SAH-hydrolase in the leukemic cells; [b) the in-vitro effects of DCF on dATP, ATP, NAD, SAH-hydrolase levels and on DNA strand breaks; and (c) the correlation between these parameters with clinical response to DCF. No significant difference in ADA, 5NT, AdR-kinase and SAH-hydrolase activities could be found between responders and non-responders. Incubation of the leukemic cells in vitro with DCF caused an inhibition of ADA, an accumulation of dATP, a moderate reduction in ATP and NAD levels, a suppression of SAH-hydrolase activity and an increase in DNA strand breaks in practically all the leukemic samples, irrespective of clinical response. Our results show that neither measurement of these enzymes nor studies of these biochemical sequelae of ADA inhibition in vitro predicts clinical responsiveness to DCF therapy.

Topics: Adenosine Deaminase Inhibitors; Adenosine Triphosphate; Adenosylhomocysteinase; Antineoplastic Agents; Coformycin; Deoxyadenine Nucleotides; DNA Damage; Humans; Hydrolases; Leukemia; Leukemia, Hairy Cell; Leukemia, Lymphocytic, Chronic, B-Cell; Leukemia, Prolymphocytic; Leukemia, Prolymphocytic, T-Cell; NAD; Nucleoside Deaminases; Pentostatin; Ribonucleosides

Deoxycoformycin (DCF), an adenosine deaminase (ADA) inhibitor, has been shown to be active in lymphoid neoplasms. The mechanism of cytotoxicity might involve accumulation of deoxyadenosine triphosphate (dATP), depletion of the nicotinamide adenine dinucleotide (NAD) and ATP pool, induction of double-stranded DNA strand breaks, or inhibition of S-adenosyl homocysteine hydrolase (SAH-hydrolase). We have investigated the biochemical changes in the circulating malignant cells of patients with chronic leukemia/lymphoma who were treated with DCF (4 mg/m2 weekly). Blood samples were taken from 17 patients with 60% or more circulating leukemic cells before, 4, 24, and 48 hours and five days after the first administration of DCF. Leukemic cells were separated and studied for changes in ADA, dATP, ATP, NAD, and SAH-hydrolase levels and DNA strand breaks and the data analyzed according to clinical response. Inhibition of ADA activity was found in all except one patient at 4 to 24 hours after the first administration of DCF. dATP started to accumulate at four hours, reached a maximum level between 24 and 48 hours, and returned to base values on the fifth day. Intracellular ATP and NAD levels were transiently reduced in some of the patients. However, no correlation between these changes and a clinical response could be found. DNA strand breaks could be studied in 13 patients. A significant increase in DNA breaks at 24 to 48 hours was found in six of the seven responders but only in one of the six nonresponders. At 24 hours, SAH-hydrolase levels were reduced in all seven responders studied, but only in two of the seven nonresponders. The difference in inhibition of SAH-hydrolase was statistically significant (P = .0023). These results suggest that DNA strand breaks and inhibition of SAH-hydrolase correlate with clinical response.

Topics: Adenosine Deaminase Inhibitors; Adenosylhomocysteinase; Coformycin; DNA, Neoplasm; Drug Evaluation; Humans; Hydrolases; Leukemia, Hairy Cell; Leukemia, Lymphocytic, Chronic, B-Cell; Leukocyte Count; Neoplasm Proteins; Neoplastic Cells, Circulating; Nucleotides; Pentostatin; Ribonucleosides; Sezary Syndrome