pentostatin and Lymphoma--Non-Hodgkin

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

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

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

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; Humans; Leukemia; Lymphoma, Non-Hodgkin; Lymphoproliferative Disorders; Multiple Myeloma; Pentostatin; Vidarabine

Combination chemotherapy regimens achieve complete remissions in 60% to 80% of patients with non-Hodgkin's lymphomas; however, the majority of patients will relapse, and resistant disease remains a problem. Attempts to identify new, effective chemotherapy agents have primarily focused on the development of analogues that, unfortunately, have uniformly failed to provide a substantial therapeutic advantage. Drugs with a unique mechanism of action are more likely to be successful; among these are the purine analogues (e.g., fludarabine, 2'-deoxycoformycin, 2-chlorodeoxyadenosine) and agents that can reverse clinical drug resistance. The number of patients who can be cured can be increased only by incorporating new agents into front-line regimens through carefully designed clinical trials.

Topics: Antimetabolites, Antineoplastic; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Cisplatin; Humans; Lymphoma, Non-Hodgkin; Pentostatin; Vidarabine Phosphate

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

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

Thirty-seven patients with refractory lymphoma or cutaneous T-cell lymphoma were treated with 2'-deoxycoformycin (pentostatin; dCF), 5 mg/m2 intravenous (IV) bolus for 3 consecutive days of every 3-week cycle in this Eastern Cooperative Oncology Group (ECOG) trial. Included were 25 with the diagnosis of non-Hodgkin's lymphoma, three with Hodgkin's disease, eight with cutaneous T-cell lymphoma (CTCL), and one with unknown subtype, of whom 31 were considered eligible. The majority had failed at least two, but no more, conventional chemotherapy regimens. Ten (32%) of the eligible patients had a partial response (PR), including patients with nodular poorly differentiated lymphocytic (NPDL), nodular mixed (NM), diffuse poorly differentiated lymphocytic (DPDL), or diffuse histiocytic (DH), lymphoma mixed-cellularity (MC), Hodgkin's disease, and unknown subtype, and in four patients with CTCL. The overall median time to treatment failure (TTF) was only 1.3 months, but the range extended to 57.3 months. The overall response duration was 16.0 months, and the range extended to 53.4 months. Overall median survival was 2.7 months, with the range extending to 63.2 months. The majority of patients had no toxicity, but there were some instances of severe or life-threatening events. Four fatal toxicities occurred, in two patients with underlying pulmonary conditions and two with prior cardiac histories. From this study, we conclude that dCF is active in refractory lymphomas and CTCLs, should be avoided in patients with a history of serious pulmonary or cardiac diseases, and warrants consideration for incorporation of a low-dosage schedule into conventional combination chemotherapy regimens, including its use with biologic response modifiers.

Topics: Adult; Aged; Aged, 80 and over; Drug Administration Schedule; Drug Evaluation; Female; Hodgkin Disease; Humans; Injections, Intravenous; Lymphoma; Lymphoma, Non-Hodgkin; Lymphoma, T-Cell, Cutaneous; Male; Middle Aged; Pentostatin; Skin Neoplasms; Survival Rate

In a previous study, the authors demonstrated that the combination of pentostatin (P) and rituximab (R) was well tolerated and was active in patients with low-grade non-Hodgkin lymphoma (NHL). In the current study, mitoxantrone (M) was added to P + R to evaluate the toxicity and efficacy of this three-drug combination (PMR).. Twenty-four previously untreated patients with histologically proven, Stage III or IV, low-grade NHL were registered between April and September, 2002. Patients received P (4 mg/m2), M (10 mg/m2), and R (375 mg/m2) every 28 days (M on Day 1; P and R on Days 1 and 8; in Cycle 1, R was given on Day 8 only). Eighty-three percent of patients had Stage IV disease, the median patient age was 62 years (range, 4-81 years), and the performance status was 0-2.. Responses included 9 patients who achieved complete remission (CR) (38%), 3 patients with unconfirmed CR (CRu) (12%), 8 patients who achieved partial remission (33%), and 4 patients who achieved stable disease (17%); the overall response rate (CR + CRu + PR) was 83%. PMR appeared to result in comparable activity in all histologies. The median response duration was 10.0 months (range, 3.5-15.1 months). Patients received a median of 5 cycles (range, 1-10 cycles). Eighteen patients (75%) required dose reduction or delay due to toxicity, mainly neutropenia (the administration of growth factors was not permitted). Three patients died (two patients died of disease progression, and one patient died from unrelated cardiopulmonary arrest). Grade > or = 3 drug-related toxicities included neutropenia (67%), leukopenia and febrile neutropenia (17% each), and sepsis (8%), and 38% of neutropenic episodes occurred in Cycles 1 and 2.. In this study, PMR was active and well-tolerated in patients with low-grade NHL, and the combination is deserving of further study.

Topics: Adult; Aged; Antibodies, Monoclonal; Antibodies, Monoclonal, Murine-Derived; Antineoplastic Combined Chemotherapy Protocols; Disease-Free Survival; Female; Humans; Lymphoma, B-Cell; Lymphoma, Non-Hodgkin; Male; Middle Aged; Mitoxantrone; Pentostatin; Pilot Projects; Rituximab; Survival Rate

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

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

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

To assess the results of treatment with the purine analog 2'deoxycoformycin (pentostatin [DCF]) in patients with postthymic T-cell malignancies.. One hundred forty-five patients with postthymic T-cell malignancies were given DCF intravenously at 4 mg/m2/wk for the first 4 weeks and then every 2 weeks until maximal response; the last 30 patients received weekly injections until maximal response.. The overall response rate was 32% (complete responses [CRs] plus partial responses [PRs]), with marked variation according to diagnosis. The best responses occurred in patients with Sézary syndrome (62%) and T-prolymphocytic leukemia (T-PLL) (45%), with CRs in three of 16 Sézary syndrome and five of 55 T-PLL patients. In contrast, no responses (NRs) were documented in 13 patients with other types of cutaneous T-cell lymphoma, including five mycosis fungoides. Two of five patients with large granular lymphocyte (LGL) leukemia had a CR and two of four with Sézary cell leukaemia had a PR. A low response rate was observed in 27 patients with peripheral T-non-Hodgkin's lymphoma (T-NHL) (19%) and in 25 with adult T-cell leukemia/lymphoma (ATLL) (12%). The latter included two CRs and one PR. Toxicity was low and DCF was generally well tolerated. No significant differences were observed when results were analyzed according to previous treatment. Disease subtype was the most important factor to influence results.. We conclude that DCF is effective as a single agent in T-PLL, Sézary syndrome, and LGL leukemia, but has low activity in other T-cell disorders.

Topics: Adult; Aged; Aged, 80 and over; Humans; Leukemia-Lymphoma, Adult T-Cell; Leukemia, T-Cell; Lymphoma, Non-Hodgkin; Lymphoma, T-Cell; Middle Aged; Pentostatin; Remission Induction; Retrospective Studies; Sezary Syndrome; Survival Analysis; Treatment Outcome

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; Clinical Trials as Topic; Deoxyadenosines; Humans; Leukemia, Hairy Cell; Leukemia, Lymphocytic, Chronic, B-Cell; Lymphoma, Non-Hodgkin; Pentostatin; Vidarabine

Seventy-six eligible patients with relapsed or refractory non-Hodgkin's lymphoma (NHL) were treated with 2'-deoxycoformycin (pentostatin) at a dose of 4 mg/m2 intravenously weekly for three weeks and then every other week for a minimum of five total treatments. All patients had measurable disease, near normal hematologic, renal, and hepatic function, and a performance status of 0 or 1. Severe hematologic toxicity was observed in 13% of patients; severe renal or neurologic toxicity was observed in less than 5% of patients. There were no treatment-related deaths. Objective therapeutic responses were seen in 16% of patients (five complete response [CR] and seven partial response [PR]). However, in three of the patients achieving CR and one patient achieving PR, dexamethasone was employed as an anti-emetic, making the response of these patients to pentostatin difficult to evaluate. There were eight responses (3 CR) in patients with diffuse histologies and four responses (2 CR) in patients with nodular or mixed histologies. Three responses were in patients with a T-cell phenotype. Three of five patients with diffuse well-differentiated lymphoma (IWF A) responded. We conclude that 2' deoxycoformycin is only minimally active at this dose and schedule against refractory or relapsed NHL. The possibility that low grade B- and T-cell malignancies are more sensitive to 2' deoxycoformycin deserves further investigation.

Topics: Aged; Drug Administration Schedule; Drug Evaluation; Female; Humans; Lymphoma, Non-Hodgkin; Male; Middle Aged; Pentostatin; Remission Induction; Survival Rate

Topics: Humans; Leukemia, Hairy Cell; Leukemia, Lymphoid; Lymphoma, Non-Hodgkin; Pentostatin

Deoxycoformycin (dCF), a potent inhibitor of adenosine deaminase (ADA), was explored for its antineoplastic potential in 28 patients with advanced lymphoid malignancy. Both normal and malignant B lymphocytes have low levels of ADA activity, and low doses of dCF profoundly inhibit this enzyme in the peripheral blood of patients with chronic lymphocytic leukemia (CLL). The low doses of dCF administered in this trial (4 mg/m2) were not associated with prohibitive toxicity. Five of 28 patients had an objective response. Four additional patients had clinical improvement. No significant difference in the pretreatment ADA activity existed between responding patients and treatment failures. The demonstration of responses to dCF following failure on standard alkylating agents suggests that dCF may not be cross-resistant with current agents used to treat CLL. Additional studies should be pursued using low-dose dCF in patients with advanced malignancy.

Topics: Adenosine Deaminase Inhibitors; B-Lymphocytes; Candidiasis; Coformycin; Conjunctivitis; Drug Administration Schedule; Gastrointestinal Diseases; Herpesviridae Infections; Humans; Leukemia, Lymphoid; Liver Function Tests; Lymphoma, Non-Hodgkin; Middle Aged; Nucleoside Deaminases; Pentostatin; Respiratory Tract Infections; Ribonucleosides

Topics: Adult; Antibodies, Viral; Antineoplastic Agents; Coformycin; Deltaretrovirus; Female; Humans; Lymphoma, Non-Hodgkin; Pentostatin; Retroviridae Infections