pentostatin and fludarabine

The monoclonal gammopathies of renal significance (MGRS) are a group of disorders characterized by monoclonal Ig deposition in the kidney, but are not associated with systemic lymphoma or overt multiple myeloma. The prevailing hypothesis is that the pathogenic paraproteins in MGRS are produced by underlying B cell or plasma cell clones. However, in the MGRS literature, the yield of detecting a clone has been variable, and progression to ESRD is common. Here, we present an "onco-nephrologic" approach to the MGRS disorders by highlighting recent advances in lymphoma and multiple myeloma that can be used in the evaluation and management of these patients.

Topics: Antineoplastic Combined Chemotherapy Protocols; Bendamustine Hydrochloride; Bortezomib; Cyclophosphamide; Dexamethasone; Humans; Immunoglobulins; Immunosuppressive Agents; Kidney Diseases; Lenalidomide; Melphalan; Oligopeptides; Paraproteinemias; Pentostatin; Rituximab; Thalidomide; Vidarabine

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

Prolymphocytic leukemia (PLL) is a rare lymphoproliferative disorder characterized by marked leukocytosis and splenomegaly. PLL accounts for approximately 2% of chronic lymphoid leukemias. The clinical course is progressive in the majority of cases due to the resistance of the disease to conventional chemotherapy. The disease is divided according to the cell of origin into the B- (B-PLL) and T-cell (T-PLL) types. T-PLL and B-PLL are morphologically identical, but lymphadenopathy and skin involvement are more common in T-PLL than in B-PLL. Approximately 80% of cases are of B-cell phenotype. T-PLL has a more aggressive course, poorer response to chemotherapy, and shorter median survival than B-PLL. PLL has poorer prognosis than chronic lymphocytic leukemia (CLL), and the patients with static disease for a longer period of time are rare. In general, B-PLL patients have better prognosis than T-PLL patients. PLL is still considered an incurable disease. Similarly to CLL, treatment is not indicated in asymptomatic patients. In previous decades, splenectomy, splenic irradiation, leucapheresis, and alkylating agents used alone or in combination with other cytotoxic agents have been used for the treatment of PLL. Subsequently, purine nucleoside analogs (fludarabine, cladribine, and pentostatin) have been introduced for the therapy of these disorders. More recently, monoclonal antibodies, especially alemtuzumab, have been found more effective, especially in T-PLL. Finally, high-dose chemotherapy followed by allogenic or autologous stem cell transplantation seems to be an effective, probably curative, strategy for the treatment of selected patients with PLL. In this review, current therapeutic strategies in PLL are presented.

Topics: Alemtuzumab; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal, Murine-Derived; Antibodies, Neoplasm; Cladribine; Drug Therapy; Humans; Leukemia, Prolymphocytic; Pentostatin; Purine Nucleosides; Rituximab; Splenectomy; Stem Cell Transplantation; Vidarabine

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

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

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

Topics: Antineoplastic Agents; Cladribine; Humans; Leukemia; Pentostatin; Purines; Stem Cell Transplantation; Vidarabine

Hairy-cell leukaemia (HCL) is an uncommon B-cell chronic lymphoproliferative disorder that accounts for about 2% of all leukaemias. Although the disease is generally indolent in its natural course, the majority of patients require treatment for life-threatening infections due to pancytopenia or symptomatic splenomegaly. During the past 20 years, remarkable progress has been made in the treatment of HCL. Since the introduction of interferon-alpha, splenectomy, which was formerly the standard therapy, has been rarely used. With the purine analogues cladribine and pentostatin, response rates are even better than with interferon-alpha and long-lasting remissions can be achieved in most patients. Therefore, these agents are now considered the treatment of choice. Recently, immunotherapeutic approaches which use monoclonal antibodies have increased the number of therapeutic options for HCL and offer promising salvage strategies for patients who relapse or who are refractory to treatment with purine analogues. In this review the different treatment options available are discussed and recommendations for the clinical management of the HCL are summarised.

Topics: Antibiotics, Antineoplastic; Antibodies, Monoclonal; Antibodies, Monoclonal, Murine-Derived; Antigens, CD; Antigens, Differentiation, B-Lymphocyte; Antineoplastic Agents; Cell Adhesion Molecules; Cladribine; Humans; Interferon-alpha; Lectins; Leukemia, Hairy Cell; Neoplasm, Residual; Neoplasms, Second Primary; Pancytopenia; Pentostatin; Receptors, Interleukin-2; Rituximab; Sialic Acid Binding Ig-like Lectin 2; Spleen; Splenectomy; Splenomegaly; Treatment Outcome; Vidarabine

The purine nucleoside analogues (PNA), fludarabine (FA), cladribine (2-chlorodeoxyadenosine, 2-CdA) and 2'-deoxycoformycin (DCF), represent a novel group of cytotoxic agents with high activity in low-grade lymphoid malignancies. However, several investigations have revealed that these agents are active also in acute myeloid leukemia (AML) and chronic myelogenous leukemia (CML). Synergistic interaction between FA or 2-CdA with cytarabine (Ara-C) have been demonstrated in both preclinical and clinical studies. PNA enhance the cell concentration of Ara-CTP, which is active metabolite of Ara-C. It is likely that the addition of granulocyte colony stimulating factor (G-CSF) may further improve the effects of FA (FLAG) or 2-CdA (CLAG). The addition of anthracyclines to induction therapy does not appear to result in a substantial advantage in terms of CR achievement and duration. An alternative approach to increase FLAG activity might be the addition of investigational drugs with novel mechanism of action, such as topoiromerase I inhibitors. The addition of anthracyclines to induction therapy does not appear to result in a substantial advantage in terms of CR achievement and duration. Clinical studies have confirmed the efficacy of PNA alone or in combination protocols in the treatment of AML. These regimens seem to produce superior results with acceptable toxicities in previously treated and relapsed, poor risk AML. However, early relapses remain a significant problem in a majority of refractory or relapsed patients in CR after treatment with PNA based regimens. To prolong remission duration or even cure AML, auto--or allo stem cell transplantation should be considered. However, FAMP or 2-CdA containing regimens may impair mobilization and collection of stem cells from peripheral blood for autotransplantation. Few studies have analyzed the role of PNA in CML. 2-CdA, FAMP and DCF can induce hematologic response in chronic phase of CML but cytogenetic responses have not been observed. Preliminary results suggest, that PNA used alone or in combination may be used as palliation in blast phase of the disease. However, currently, the role of these agents in CML is insignificant because of the high activity of Glivec in this disease. Finally, PNA, especially FA play an important role in non-myeloablative conditioning regimens for allogenic stem cell transplantation in high-risk patients, possibly also with myeloid malignancies.

Topics: Acute Disease; Adolescent; Adult; Aged; Antibiotics, Antineoplastic; Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Child; Child, Preschool; Cladribine; Clinical Trials as Topic; Cytarabine; Drug Synergism; Female; Granulocyte Colony-Stimulating Factor; Hematopoietic Stem Cell Mobilization; Humans; Infant; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Leukemia, Myeloid; Male; Middle Aged; Pentostatin; Peripheral Blood Stem Cell Transplantation; Remission Induction; Salvage Therapy; Transplantation Conditioning; Transplantation, Autologous; Transplantation, Homologous; Treatment Outcome; Vidarabine

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 availability of two groups of pharmacologic agents, the nucleoside analogs and anti-lymphocyte antibody preparations of various specificities has enabled the development of NST. Although these agents are significantly less cytotoxic than high-dose alkylating agents and total-body irradiation (TBI), they are profoundly immunosuppressive. Opportunistic infections such as the reactivation of cytomegalovirus remain clinical obstacles when NST are performed using these agents, especially in elderly and previously immunosuppressed patients. For anti-lymphocyte antibody preparations, the degree of immunosuppression produced and hence the risk of opportunistic infection varies depending upon specificity of the antibody (broad versus narrow). Allergic reactions and infusion related toxicity can occur with any antibody preparation, but the infusion of muromonab-CD3 is sometimes associated with a particularly potent cytokine-release syndrome. Although fludarabine has been the mainstay of nucleoside analog usage for NST, the other nucleoside analogs-cladribine and pentostatin are beginning to be investigated in this context.

Topics: Animals; Antibodies, Monoclonal; Antilymphocyte Serum; Cladribine; Hematopoietic Stem Cell Transplantation; Humans; Immunosuppressive Agents; Pentostatin; Transplantation, Homologous; Vidarabine

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

The nucleoside analogues are a group of antimetabolite cytotoxics which generally have to be metabolised to the equivalent nucleotide before incorporation into DNA. Cytarabine is a well established component of the treatment of acute leukaemias and has its principal action on dividing cells. New formulations include a liposome encapsulated product for intrathecal use and oral cytarabine ocfosfate which may be suitable for long-term outpatient use. Pentostatin acts by causing accumulation of deoxynucleotides and, although active against hairy cell leukaemia, is associated with a poor tolerance profile. Cladribine and fludarabine have substantial activity in the treatment of chronic lymphocytic leukaemia (CLL) and low-grade non-Hodgkin's lymphoma (NHL). Fludarabine is the more thoroughly investigated of the two and is currently being developed in combination therapies for CLL and NHL and also in a combination with cytarabine for acute myeloid leukaemia. Fludarabine's immunosuppressive activity is being exploited in the conditioning of patients for non-myeloablative stem cell transplantation. Gemcitabine is an established agent in the treatment of a number of solid tumours but also has activity in haematological malignancies which might be exploited by the use of extended infusion schedules. Newer agents including nelarabine, clofarabine and troxacitabine are undergoing clinical evaluation and show promising activity.

Topics: Antimetabolites, Antineoplastic; Arabinonucleosides; Biological Transport; Cladribine; Clinical Trials as Topic; Cytarabine; Cytosine; Deoxycytidine; Dioxolanes; Economics, Pharmaceutical; Gemcitabine; Guidelines as Topic; Hematologic Neoplasms; Humans; Molecular Structure; Nucleosides; Pentostatin; Vidarabine

The purine nucleoside analogues, either alone or in combination with other chemotherapeutic agents, are increasingly used in the treatment of patients with indolent B-cell lymphoproliferative disorders. The initial studies in Waldenström's macroglobulinaemia (WM) are very promising. Approximately 40% of patients who have received prior therapy with alkylating agents respond, while response rates of up to 90% have been documented in untreated patients. However, it is not known whether the purine analogues offer any significant advantage over alkylating agents such as chlorambucil. In this review the treatment options in WM and in particular the role of the purine analogues are discussed.

Topics: Alkylating Agents; Antimetabolites; Chlorambucil; Cladribine; Clinical Trials as Topic; Drug Resistance; Drug Therapy, Combination; Guidelines as Topic; Humans; Middle Aged; Pentostatin; Plasmapheresis; Purine Nucleosides; Quality of Life; Vidarabine; Waldenstrom Macroglobulinemia

Topics: Antibiotics, Antineoplastic; Antineoplastic Agents; Cladribine; Clinical Trials as Topic; Humans; Leukemia, Lymphoid; Lymphoma; Nucleosides; Pentostatin; Vidarabine

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

Pentostatin (Nipent) has demonstrated significant activity as a single agent in patients with low-grade B- and T-cell lymphomas, but thus far, clinical experience with combinations of pentostatin and other agents is limited. A study of alternating administration of pentostatin and high-dose interferon-alfa-2a (Roferon A) in cutaneous T-cell lymphoma patients has been undertaken and has demonstrated a 41% response rate, with tolerable toxicity. Studies combining pentostatin with alkylating agents, including chlorambucil (Leukeran) and cyclophosphamide (Cytoxan, Neosar) in patients with chronic lymphocytic leukemia (CLL) have reported significant immunosuppression and have required dose modifications of one or both agents. Recently, a clinical trial was initiated to evaluate the combination of pentostatin and cordycepin, a novel purine analog, in patients with terminal deoxynucleotidyl transferase-positive acute lymphocytic leukemia, based on in vitro data demonstrating the significant synergy of this combination.

Topics: Adult; Aged; Antibiotics, Antineoplastic; Antineoplastic Agents; Antineoplastic Agents, Alkylating; Antineoplastic Combined Chemotherapy Protocols; Clinical Trials as Topic; Deoxyadenosines; Disease-Free Survival; Dose-Response Relationship, Drug; Female; Humans; Interferons; Lymphoma, B-Cell; Lymphoma, T-Cell; Male; Middle Aged; Pentostatin; Purine Nucleosides; Treatment Outcome; 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

Hairy cell leukemia represent 2% of all the leukemias. The etiology is unknown. The diagnosis is based on the peripheral blood examination, showing characteristic lymphoid B cells, with loose lacy chromatin and unconstant cytoplasmic projections. The abnormal lymphoid cells express CD19, CD20, CD22, CD79a, CD25 and CD103. The tumor cells are Sig + with clonal light chain restriction. The treatment is based on recombinant IFN: we discuss the interest and the risks of second malignancy related to the prescription of the purine analogues.

Topics: 2-Chloroadenosine; Antigens, CD; Antimetabolites, Antineoplastic; Antineoplastic Agents; B-Lymphocytes; Bone Marrow; Clinical Trials as Topic; Deoxyadenosines; Humans; Immunologic Factors; Interferon Type I; Leukemia, Hairy Cell; Neoplasm Proteins; Neoplasms, Second Primary; Neoplastic Stem Cells; Pentostatin; Receptors, Antigen, T-Cell, gamma-delta; Recombinant Proteins; Splenectomy; Vidarabine

Hairy-cell leukemia (HCL) is a lymphoproliferative B-cell malignancy--it represents about 2% of all adult leukemias. HCL is associated with pancytopenia and splenomegaly. In the late 1980s, introduction of new purine analogs such as 2-deoxycoformycin (pentostatin, DCF) and 2-chlorodeoxy-adenosine (2-CdA) significantly improved the prognosis of HCL patients. 33-89% patients can achieve a complete remission (CR) following DCF treatment and 85% CR after 2-CdA therapy. There is no cross-resistance between pentostatin and 2-CdA. Residual hairy cells are present in bone marrow of almost all patients after purine analogs therapy, detected by immunohistochemical methods. It is called minimal residual disease (MRD). The spleen may be the source of MRD after purine analogs therapy. Thus splenectomy could be a profitable approach after chemotherapy. Hairy-cell leukemia relapse appears in 47.8% of cases in 30 months after pentostatin treatment and in 23% of cases in 3 years after 2-CdA therapy. There is no perfect treatment of HCL relapse. Thanks to new purine analogs hairy-cell leukemia may be considered a potentially curable disease.

Topics: Antineoplastic Agents; Cladribine; Humans; Leukemia, Hairy Cell; Neoplasm, Residual; Pentostatin; Remission Induction; Splenectomy; 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

Three analogues of the purine 2-deoxyadenosine are available for the treatment of low grade lymphoproliferative disorders: pentostatin, cladribine and fludarabine. They have some common features in their mode of action, but differ both in their detailed pharmacology and the extent to which they have activity against specific lymphoid malignancies. Studies defining the scope of these drugs as single agents are now being followed by plans to exploit their potential synergy with other agents and clinically to define useful combination therapies.

Topics: Antineoplastic Agents; Cladribine; Humans; Lymphoproliferative Disorders; Pentostatin; Vidarabine

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

Topics: Adenosine Deaminase; Antimetabolites, Antineoplastic; Antineoplastic Agents; Cladribine; Humans; Lymphoma; Lymphoma, B-Cell; Lymphoma, T-Cell, Cutaneous; Pentostatin; Vidarabine; Waldenstrom Macroglobulinemia

Three new purine nucleoside analogues, pentostatin, cladribine and fludarabine, have demonstrated remarkable clinical activity in a variety of hematologic malignancies. Although they share structural similarities, their plasma pharmacology, metabolism, and mechanisms of action differ qualitatively and quantitatively. The plasma pharmacokinetics and the cellular pharmacodynamics are reviewed to provide a basis for dose schedules and rationales for combinations with other anticancer drugs.

Topics: Animals; Antineoplastic Agents; Cladribine; Hematologic Neoplasms; Humans; Pentostatin; Purine Nucleosides; 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

The purine analogs, fludarabine, 2-chlorodeoxy-adenosine, and 2'-deoxycoformycin, have revolutionized our approach to the treatment of a variety of indolent lymphoid malignancies. Because of their impressive single agent activity, they should be considered as an initial therapeutic option, not only for hairy cell leukemia, but also for chronic lymphocytic leukemia, indolent non-Hodgkin's lymphomas, and Waldenström's macroglobulenemia. Combinations of purine analogs with alkylatng agents, topisomerase II inhibitors, and other new compounds are in development, and their role as radiation sensitizers is being explored in clinical trials. Substantial activity has also been noted in several of the rheumatologic and immunologic disorders, and in multiple sclerosis. Continued progress requires innovative strategies which can modulate the biology and immunology of these diseases toward the goal of curing these patients.

Topics: Antineoplastic Agents; Cladribine; Forecasting; Humans; Leukemia; Pentostatin; Purines; Vidarabine

Hairy cell leukaemia is an uncommon B cell chronic lymphoproliferative disorder characterised by circulating lymphocytes displaying prominent cytoplasmic projections. Therapy is initiated for severe cytopenias or recurrent infections. Splenectomy, the first standard treatment, is now less commonly used as primary treatment. Interferon-alpha (IFN alpha) induces partial responses in most patients but complete responses in only a few. Adverse effects from IFN alpha are common but not life-threatening. The ability of two newer purine analogues, pentostatin (2'-deoxycoformycin) and cladribine (2-chlorodeoxyadenosine), to induce long-lasting complete remissions in the majority of patients has revolutionised the treatment of this disease. Cladribine is emerging as the treatment of choice because of its favourable toxicity profile, brief duration of treatment, high percentage of unmaintained complete remissions and low incidence of relapse.

Topics: Antineoplastic Agents; Cladribine; Combined Modality Therapy; Granulocyte Colony-Stimulating Factor; Humans; Interferons; Leukemia, Hairy Cell; Pentostatin; Splenectomy; Vidarabine

The purine analogs fludarabine, cladribine, and pentostatin are active agents in the treatment of indolent lymphoid malignancies. This report reviews the pattern, severity, and consequences of the immunosuppression and myelotoxicity associated with these agents.. The literature was searched using MedLine and Cancerline, as well as the bibliographies of published reports through the winter of 1994 and 1995.. Each of these drugs induces profound lymphocytopenia. A marked decrease in CD4 cells may persist for several years, while other mononuclear-cell populations recover more rapidly. The spectrum of infections encountered in these patients appears to be altered to include a wide range of opportunistic organisms. Factors that increase the risk of these infections include concurrent corticosteroids, extensive prior therapy, particularly with another purine analog, and poor response to purine analog treatment.. Because of the frequency of life-threatening infections with unusual pathogens that may occur in patients treated with purine analogs, aggressive and early diagnostic evaluation and appropriate use of myeloid growth factors may be necessary to ensure appropriate antimicrobial therapy.

Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow; Cladribine; Humans; Immune Tolerance; Infections; Pentostatin; Purines; Vidarabine

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

Topics: Antineoplastic Agents; Cladribine; Clinical Trials as Topic; Drug Resistance; Humans; Lymphoproliferative Disorders; Pentostatin; Purine Nucleosides; 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

Purine nucleoside analogues are a new class of drugs with activity against nondividing lymphocytes; thus, they should play a major role in the treatment of low grade lymphoid malignancies. As these drugs are active against resting lymphocytes, harmful effects related to this action were expected and have been reported. However, the toxic effects on resting lymphocytes observed during treatment of lymphoid malignancies may potentially be of some benefit in patients with autoimmune diseases. To substantiate this possibility, a considerable amount of work needs to be carried out in order to better define the mechanism of action of these drugs, as well as their potential activity on different immunological effectors. Also, studies in animal models of autoimmune disease should be undertaken.

Topics: Animals; Antineoplastic Agents; Apoptosis; Cladribine; Humans; Immunosuppressive Agents; Leukemia; Pentostatin; Purine Nucleosides; Vidarabine

The purine analogs, fludarabine, cladribine, and pentostatin, are active against a broad spectrum of indolent lymphoid malignancies. They also have similar toxicities, including myelosuppression, immunosuppression, and sporadic neurotoxicity. This review compares the spectrum of neurotoxicity of each of these agents. Now that these drugs are commercially available and are being widely used, physicians should be aware of potentially serious side effects that may be encountered.. The literature was searched using MedLine and Cancerline, as well as the bibliographies of published reports through the fall of 1993. In addition, case records from National Cancer Institute (NCI) Group C protocols were reviewed for fludarabine in chronic lymphocytic leukemia (CLL), and cladribine and pentostatin in hairy cell leukemia (HCL), as well as adverse drug reactions reported to the NCI from January 1980 through September 1993.. At higher than recommended doses, life-threatening and fatal neurotoxicity were encountered with all three drugs. At the recommended doses, each agent induced neurotoxicity in approximately 15% of patients, mostly mild and reversible. However, severe neurologic complications were reported; these were occasionally delayed, sometimes fatal, but often at least partially reversible.. The doses of these three agents should not be increased above the recommended levels. Development of moderate or worse neurotoxicity should result in discontinuation of that drug.

Topics: Adult; Aged; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Cladribine; Female; Humans; Male; Middle Aged; Nervous System; Nervous System Diseases; Pentostatin; Purine Nucleosides; Vidarabine

Hairy cell leukemia (HCL) is a chronic B-cell malignancy, typically seen in middle-aged men, characterized by pancytopenia, splenomegaly, immunologic abnormalities, and morphologically typical neoplastic mononuclear cells in the blood, bone marrow, liver, spleen, and other tissues. Diagnosis is confirmed by demonstration of hairy cells in biopsy specimens from the bone marrow or spleen or in peripheral blood. The natural history of this lymphoproliferative disorder varies. Patients may die early during the initial phase of therapy; others may require no therapy; and for some, splenectomy alone, without further treatment, may suffice for many years. Recently, the nucleosides pentostatin (2'-deoxycoformycin) (DCF) and 2'-chlorodeoxyadenosine (2-CdA) have been shown to produce greater numbers of durable complete remissions with curative potential in patients with HCL. The treatment options, with emphasis on major therapeutic advances with alpha-interferon, DCF, and 2-CdA, are reviewed in this article.. Studies on HCL published from 1958 to 1992 were reviewed using the Cancerline and Medline retrieval systems and other bibliographies.. Management of HCL has changed in the last decade as a result of three new effective agents: alpha-interferon DCF, and 2-CdA. DCF has produced an overall response rate of 86% and a complete remission rate of 62%. 2-CdA has yielded an overall response rate of 95% and a complete remission rate of 82%. Alpha-interferon has given an overall response rate of 82% and a complete remission rate of 8%. Other agents with limited activities include chlorambucil, cyclophosphamide, cytarabine, vincristine, doxorubicin, and zorubicin hydrochloride. The effects of lithium carbonate, immunotherapy, splenic irradiation, androgens, and leukaphoresis are minimal and transient.. Modern management of HCL with 2-CdA and DCF is now potentially curative rather than palliative in some patients; however, the optimal therapeutic approach remains uncertain. Alpha-interferon has been approved by the Food and Drug Administration as the first-line drug therapy, followed by DCF in non-responding patients. 2-CdA remains an experimental therapy, but its higher response rate and ease of administration may make it the first-line treatment of choice. Additional research into the biology of HCL and further clinical trials are needed to determine the optimal treatment strategy for this disorder. Therefore, the best therapeutic approach at the current time is to include patients with HCL in ongoing clinical trials.

Topics: 2-Chloroadenosine; Deoxyadenosines; Forecasting; Granulocyte Colony-Stimulating Factor; Humans; Interferons; Leukemia, Hairy Cell; Male; Pentostatin; Splenectomy; Vidarabine

There are three new purine analogs, fludarabine, 2'-deoxycoformycin, and 2-chlorodeoxyadenosine, all of which have major activity in the treatment of indolent lymphoid malignancies. These three agents, with cytotoxicity against dividing and resting lymphocytes, have revolutionized the treatment of these diseases and, accordingly, represent a significant therapeutic advance. The development of these drugs emanated from an enhanced understanding of purine metabolism in lymphocytes and the mechanism of lymphocytotoxicity in severe combined immunodeficiency disease. Preclinical studies and phase I clinical trials are reviewed, as are phase II studies of these three purine analogs in chronic lymphocytic leukemia, hairy cell leukemia, non-Hodgkin lymphoma, cutaneous T-cell lymphoma, and the myeloid leukemias. Potential future strategies exploring possible synergy between these purine analogs and the concurrent administration of both alkylators and biologic response modifiers are explored. The development of the purine analogs and their appropriate clinical applications exemplifies the model for rational drug design and development.

Topics: Antineoplastic Agents; Cladribine; Humans; Leukemia; Lymphoma; Pentostatin; Vidarabine

Topics: Antineoplastic Agents; Cladribine; Humans; Leukemia; Lymphoma, Non-Hodgkin; Lymphoproliferative Disorders; Multiple Myeloma; Pentostatin; Vidarabine

Topics: Antineoplastic Agents; Cladribine; Clinical Trials as Topic; Humans; Leukemia; Lymphoma; Molecular Structure; Pentostatin; Purine Nucleosides; 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

Several new antimetabolites have been evaluated in clinical trials in recent years. Those with the most promising activity include the structurally related purine analogs fludarabine, 2-chlorodeoxyadenosine, and 2'-deoxycoformycin. These compounds have shown impressive activity against a broad spectrum of indolent lymphoproliferative disorders, including hairy-cell leukemia, chronic lymphocytic leukemia, and low-grade non-Hodgkin's lymphomas. They may also be useful in the treatment of acute leukemias. In contrast, they lack activity against common solid tumors. They have been generally well tolerated in large clinical trials; however, each of them is myelosuppressive and immunosuppressive. It is unlikely that any one of these drugs, when used as a single agent, will provide optimal therapy for any disease other than, possibly, hairy-cell leukemia. Combinations with other cytotoxic agents and biologics are in development, and perhaps they will lead to more effective regimens in the future.

Topics: Animals; Antimetabolites, Antineoplastic; Cladribine; Clinical Trials as Topic; Drugs, Investigational; Forecasting; Humans; Immunosuppression Therapy; Leukemia; Lymphoma; Pentostatin; Purines; 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

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

T-cell large granular lymphocytic (T-LGL) leukemia is characterized by cytopenia and clonal proliferation of large granular lymphocytes. We identified 26 patients with T-LGL leukemia seen at our institution over a period of 8 years. The majority of the patients were asymptomatic at diagnosis. Nine patients were treated with cyclosporine; one achieved a complete remission, and four had a hematological response. Other treatment modalities included single agent alemtuzumab, alemtuzumab combined with pentostatin, fludarabine, and combination of fludarabine and cyclophosphamide. Significant responses were not seen with any of these treatment regimens. We conclude that cyclosporine therapy may be beneficial for T-LGL leukemia patients. New treatment modalities are needed for these patients.

Topics: Adult; Aged; Alemtuzumab; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antibodies, Neoplasm; Antineoplastic Agents; Cyclosporine; Female; Flow Cytometry; Humans; Immunophenotyping; Leukemia, Lymphoid; Leukemia, T-Cell; Male; Middle Aged; Pentostatin; Retrospective Studies; Vidarabine

In vitro studies suggest that nucleoside analogs have an antileukemic effect against chronic myelogenous leukemia (CML). We investigated the antileukemia effect of deoxycoformycin (DCF) and fludarabine in patients with CML. Four patients with Philadelphia chromosome (Ph)-positive CML were treated with DCF at 4 mg/m2 every week for 4 weeks, then every other week for four doses, and then every month as maintenance. Two patients were in late chronic phase and two in accelerated phase. All had previously failed therapy with interferon-alpha (IFN-A). Nine patients were treated with fludarabine 30 mg/m2/day for 5 days every 28 days. Three had Ph-positive CML, and six Ph-negative disease. Five patients were in accelerated phase and four in late chronic phase. Three patients treated with DCF had normalization of WBC counts while on the weekly schedule but progressed when changed to every other week. The fourth patient had no objective response. There were no cytogenetic responses. DCF was well tolerated with only mild nausea and vomiting in all patients. Patients treated with fludarabine received a median of two courses (range 1-4). In two patients (both Ph-positive), disease progressed to blastic phase upon recovery. Two other patients died of hemorrhagic complications secondary to thrombocytopenia. In all other cases fludarabine produced a transient reduction of WBC counts, but counts recovered to levels equal to or greater than the pre-treatment values. There were no cytogenetic responses. These results, together with previous experience with 2-CDA producing only hematologic responses, suggest that nucleoside analogs may not have a significant role in the management of CML.

Topics: Adult; Aged; Antibiotics, Antineoplastic; Antineoplastic Agents; Drug Administration Schedule; Humans; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Leukocyte Count; Middle Aged; Pentostatin; Vidarabine

Topics: Antineoplastic Combined Chemotherapy Protocols; Cyclophosphamide; Hematopoietic Stem Cell Transplantation; Humans; Pentostatin; Transplantation Conditioning; Vidarabine

We describe a novel animal model of nonmyeloablative bone marrow transplantation (BMT) using the purine analog pentostatin. Other cohorts of mice received another purine analog, fludarabine, which we and others have previously evaluated in nonmyeloablative murine models. We evaluated pentostatin for its ability to (1) operate synergistically with cyclophosphamide to induce host T cell depletion; (2) induce host T cell suppression, as defined by modulation of cytokine secretion in vitro and abrogation of host-versus-graft reactivity in vivo; (3) constrain host T cell recovery post-therapy; and (4) prevent the rejection of T cell-depleted, fully major histocompatibility complex-mismatched bone marrow allografts. Relative to single-agent regimens, combination regimens with pentostatin and cyclophosphamide (PC) and with fludarabine and cyclophosphamide (FC) worked synergistically to deplete host CD4(+) and CD8(+) T cells. PC and FC regimens were developed that yielded similar levels of host T cell and myeloid cell depletion. In the setting of these generally comparable states of host T cell and myeloid cell depletion, the PC regimen was found to be highly immunosuppressive, as evidenced by a reduced host T cell capacity to secrete interleukin-2 and interferon-γ in vitro, to mediate host-versus-graft reactivity in vivo, and to recover numerically and functionally during a 2-week observation period after chemotherapy. Finally, using B6 hosts treated with the 14-day chemotherapy regimens, the PC regimen more consistently prevented the rejection of BALB/c T cell-depleted allografts compared with the FC regimen (rate of alloengraftment, 14/15 [93%] of PC-treated recipients vs 8/14 [57%] of FC-treated recipients; P < .05); similar results were observed using an 8-day conditioning regimen. These data suggest that host T cell suppression, distinct from T cell depletion, may be a critical determinant of engraftment after purine analog-based regimens and also may be preferentially attained by the use of pentostatin.

Topics: Animals; Antineoplastic Agents; Bone Marrow Transplantation; CD4-Positive T-Lymphocytes; CD8-Positive T-Lymphocytes; Cyclophosphamide; Drug Synergism; Female; Graft Survival; Graft vs Host Disease; Immunosuppressive Agents; Interferon-gamma; Interleukin-2; Lymphocyte Depletion; Mice; Mice, Inbred BALB C; Pentostatin; Transplantation Chimera; Transplantation, Homologous; Vidarabine

Hepatosplenic gamma-delta T-cell lymphoma is a rare, usually fatal lymphoma and available literature on management is sparse. Allografting is probably the only curative option. We describe a further case with a dramatic, though transient response to Fludarabine and Alemtuzumab combination, following a failure of conventional chemotherapy. Given the dreadful prognosis with conventional chemotherapy, it is a regimen worth pursuing as a disease reduction strategy prior to allograft where appropriate.

Topics: Adolescent; Alemtuzumab; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antibodies, Neoplasm; Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Cisplatin; Combined Modality Therapy; Crohn Disease; Cytarabine; Epirubicin; Epstein-Barr Virus Infections; Etoposide; Fatal Outcome; Gene Rearrangement, delta-Chain T-Cell Antigen Receptor; Gene Rearrangement, gamma-Chain T-Cell Antigen Receptor; Hematopoietic Stem Cell Transplantation; Humans; Ifosfamide; Immunosuppressive Agents; Liver; Lymphoma, T-Cell, Peripheral; Lymphoproliferative Disorders; Male; Methylprednisolone; Pentostatin; Receptors, Antigen, T-Cell, gamma-delta; Remission Induction; Spleen; Transplantation, Homologous; 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

The differentiation-inducing effect of clinically applicable analogs of deoxyadenosine on myelomonocytic leukemia cells was examined. Monocytoid leukemia cells were more sensitive to the analogs than were erythroid or myeloid leukemia cells based on the inhibition of cell growth and induction of cell differentiation. Monocytoid leukemia cells were highly sensitive to combined treatment with 2'-deoxycoformycin (dCF) and 9-beta-D-arabinofuranosyladenine (Ara A) for inducing cell differentiation. Ara A induced the differentiation of monocytoid leukemia U937 and THP-1 cells at concentrations which were 1/1000-10000 of that at which it induced the differentiation of other cell lines in the presence of dCF. In combination with a low concentration of 1alpha,25-dihydroxyvitamin D3 (VD3), the induction of the monocytic differentiation was greater in monoblastic U937 cells. Adenosine deaminase-resistant analogs such as fludarabine (FLU) and cladribine (CdA) also induced the differentiation of human myelomonocytic leukemia cells, and these analogs synergistically enhanced the differentiation induced by all-trans retinoic acid (ATRA) or VD3. CdA was the most potent analog for inducing the differentiation of myeloid leukemia NB4 and HL-60 cells in the presence or absence of ATRA. These findings indicate that dCF + Ara A and CdA may be effective for the therapy of acute monocytoid and myeloid leukemia, respectively.

Topics: Acute Disease; Adenosine Deaminase Inhibitors; Antimetabolites, Antineoplastic; Calcitriol; Cell Differentiation; Cladribine; Deoxyadenosines; Dose-Response Relationship, Drug; Drug Synergism; Enzyme Inhibitors; HL-60 Cells; Humans; K562 Cells; Leukemia, Myeloid; Monocytes; Neoplasm Proteins; Neoplastic Stem Cells; Pentostatin; Tretinoin; Tumor Cells, Cultured; U937 Cells; 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

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 describe the occurrence of myelodysplastic changes (hypogranular myeloid series and Pelger cells, dyserythropoiesis with ring sideroblasts) in five of 31 patients with chronic lymphoproliferative disorders after treatment with purine analogues. The bone marrows of 31 patients with chronic lymphoproliferative disorders before and after treatment with purine analogues were reviewed. The majority of patients had received extensive prior treatment, but none had dysplastic changes prior to treatment with purine analogues. We suggest that a purine analogue may have been responsible for dysplastic change and that further follow-up of this phenomenon is warranted.

Topics: 2-Chloroadenosine; Antibiotics, Antineoplastic; Antimetabolites, Antineoplastic; Antineoplastic Agents; Deoxyadenosines; Female; Humans; Lymphoproliferative Disorders; Male; Myelodysplastic Syndromes; Pentostatin; Vidarabine

To review the activity of the purine analogues fludarabine, cladribine (2-chlorodeoxyadenosine [2-CdA]), and pentostatin (2'-deoxycoformycin) in the treatment of indolent lymphoid malignancies, including chronic lymphocytic leukemia, hairy cell leukemia, and indolent non-Hodgkin's lymphomas (NHLs).. Patients with previously untreated, relapsed, or refractory indolent NHL and other indolent lymphoid malignancies who have been treated with purine analogues.. Purine analogues have revolutionized the treatment of indolent lymphomas. Fludarabine induces responses in almost 50% of patients with relapsed or refractory indolent NHL and produces complete remissions (CRs) in 10% to 15% of patients. In patients receiving fludarabine as initial treatment, CRs are achieved in almost 40%, with an overall response rate of 70% and a median time to progression > 1 year. Response rates with 2-CdA in previously treated patients appear similar to those with fludarabine, although less durable. Fludarabine and 2-CdA achieve a higher number of durable responses in Waldenström's macroglobulinemia than are generally achieved with alkylating agents in this disease. Pentostatin appears to be less active in NHL. Newer purine analogues currently in clinical trials in lymphomas include gemcitabine and compound 506U. Promising activity has been reported with the combination of fludarabine, mitoxantrone, dexamethasone, and fludarabine plus cyclophosphamide. Combinations of 2-CdA with other agents are also in development. Toxicities associated with these purine analogues primarily include moderate myelosuppression, profound immunosuppression, neurotoxicity at higher than recommended doses, and a possible increase in secondary malignancies.. The purine analogues should provide the basis for new treatment strategies with the goal of curing patients with indolent NHL. For progress to continue, patients must be referred to important and innovative clinical research trials.

Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Cladribine; Deoxycytidine; Drug Resistance, Neoplasm; Gemcitabine; Humans; Lymphoma; Lymphoma, Non-Hodgkin; Pentostatin; Vidarabine

the purine nucleoside analogues cladribine (CdA), fludarabine (F-Ara-AMP) and pentostatin (dCf), are effective therapy for a range of T- and B-cell lymphoid malignancies. The effects upon nucleotide metabolism in human CCRF-CEM T-cell leukaemia and Raji B-cell lymphoma cell lines of these drugs have been compared to assess possible mechanisms of cytotoxicity.. Leukaemia cells were exposed to a purine nucleoside analogue and perchloric acid extracts were analysed by HPLC for 2'-deoxynucleoside-5'-triphosphates (dNTPs), nucleoside-5'-triphosphates (NTPs) and drug metabolites.. After addition of a purine nucleoside analogue, CdA-TP and F-Ara-ATP accumulate in cells while the levels of dCf-TP formed were not detectable by ultra-violet absorbance. In response to accumulating concentrations of drug triphosphate, the cellular levels of dNTPs initially decrease (0-4 h), then accumulate above their initial levels (4-10 h) before slowly declining beyond 10 h. NTPs also accumulate during the period 4-10 h before declining at later times.. The temporal effects on the levels of dNTPs and NTPs of the 3 purine nucleoside analogues are similar against CCRF-CEM and Raji cells. However, CdA induces major depletions of dTTP, dGTP and dATP in CCRF-CEM cells and F-Ara-A induces a major accumulation of dATP in Raji cells.

Topics: Adenosine Deaminase Inhibitors; Antibiotics, Antineoplastic; Antineoplastic Agents; Cell Division; Cladribine; Deoxyribonucleotides; Enzyme Inhibitors; Humans; Kinetics; Leukemia, T-Cell; Lymphoma, B-Cell; Pentostatin; Ribonucleotides; Tumor Cells, Cultured; Vidarabine

The purine nucleoside analogs fludarabine, 2-chlorodeoxyadenosine, and 2'-deoxycoformycin exhibit impressive activity in lymphoproliferative malignancies of adults and children. Their mechanism of action is not clear. Studies have suggested that their use is associated with significant myelosuppression, immunosuppression, and in some circumstances, increased infection with viral and opportunistic pathogens. Because interferons (IFNs) are known to have immunomodulatory activity as well as potent antiproliferative and antiviral activity, we examined whether the chemotherapeutic purine nucleoside analogs alter interferon-beta (IFN-B) gene expression in MG63 in human osteosarcoma cells. Northern blot analysis showed a dose-dependent inhibition of IFN-B mRNA accumulation in response to a known inducer (Poly I-Poly C) all three purine analogs. Hybridization analysis also revealed that inhibition of IFN-beta mRNA accumulation by the purine analogs is not a result of decreased mRNA stability. Further analysis of gene expression by PCR differential display indicated that the effect of the purine analogs was restricted to only a limited number of inducible genes. The data suggest that these molecules alter the signaling process involved in regulating the expression of specific genes, including IFN-beta. These findings predict that the use of purine nucleoside analogs may reduce IFN production in vivo and thereby abrogate host defenses against infectious pathogens.

Topics: Antineoplastic Agents; Cladribine; Dose-Response Relationship, Drug; eIF-2 Kinase; Gene Expression; Humans; Interferon-beta; Neoplastic Stem Cells; Pentostatin; Poly I-C; Protein Serine-Threonine Kinases; RNA, Messenger; 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

One dose of pentostatin was added to a standard cyclophosphamide (CY) based transplant regimen in two patients in an attempt to decrease the rate of non-engraftment in haploidentical allogeneic BMT. Despite a normal cardiac history and evaluation prior to transplant, both patients suffered fatal cardiac toxicity within 48 h of receiving the chemotherapy. This phenomenon was further investigated in an animal model. Laboratory rats were treated with progressive doses of CY in a range that produces acute cardiac toxicity. Successive groups of rats were treated with either pentostatin or fludarabine and CY at 400 mg/kg. Neither pentostatin nor fludarabine alone produced early mortality. However, a marked increase in early mortality was noted in those animals treated with pentostatin and high-dose CY. The addition of fludarabine did not increase the early toxicity of CY. Autopsy revealed no gross or microscopic abnormalities in the animals. The implications of adding agents that interfere with adenosine metabolism to CY based transplant regimens is discussed.

Topics: Adult; Animals; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Purging; Carmustine; Cisplatin; Combined Modality Therapy; Cyclophosphamide; Cytarabine; Doxorubicin; Drug Synergism; Etoposide; Fatal Outcome; Female; Humans; Lymphoma, Large B-Cell, Diffuse; Lymphoma, Non-Hodgkin; Male; Methylprednisolone; Pentostatin; Prednisone; Rats; Rats, Inbred Lew; Salvage Therapy; Shock, Cardiogenic; Ventricular Fibrillation; Vidarabine; Vincristine

Topics: 2-Chloroadenosine; Antineoplastic Agents; Cladribine; Deoxyadenosines; Humans; Leukemia; Lymphoma, Non-Hodgkin; Pentostatin; Vidarabine

Topics: 2-Chloroadenosine; Antineoplastic Agents; Cladribine; Deoxyadenosines; Humans; Leukemia; Pentostatin; Vidarabine

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