pentostatin and Sezary-Syndrome

Sezary syndrome (SS) presents clinically as erythroderma, which may be pigmented, and pruritic, associated with peripheral lymphadenopathies. Erythroderma may also occur in a broad range of reactive and malignant conditions including T-cell prolymphocytic leukemia (T-PLL). We report a case initially diagnosed as SS but ultimately diagnosed as T-PLL based upon skin involvement.. A 70-year-old man was referred by his hematologist for management of SS. Physical examination revealed lymphadenopathies and mild diffuse erythema without infiltration. His WBC count was elevated at 8.3 G/L. A peripheral blood smear showed Sezary-like cells. Flow cytometry of peripheral blood revealed prolymphocytic T-cells staining positively for CD2, CD3, CD4 and CD7. Cytogenetic studies showed chromosomal abnormalities in terms of number and structure with missing chromosomes 6 and13, as well as deletion of chromosome 17. Finally, a diagnosis of T-PLL was made. Pentostatin was initiated pending treatment with alemtuzumab, but the patient's overall condition deteriorated rapidly and he died 10 days later.. Diagnosis of LPLT is based upon a number of factors. In the case presented herein, the clinically atypical nature of the skin lesions prompted the dermatologist to review the diagnosis. The morphology of the circulating T-lymphocytes and their immunologic and phenotypic characteristics finally ruled out the diagnosis of Sezary syndrome, while their association with compatible cytogenetic anomalies enabled a diagnosis of prolymphocytic leukemia to be made instead.. Prolymphocytic leukemia involves complex differential diagnosis with regard to Sezary syndrome, posing potential pitfalls for hematologists and dermatologists.

Topics: Adenocarcinoma; Aged; Antimetabolites, Antineoplastic; Capecitabine; Chromosome Deletion; Combined Modality Therapy; Delayed Diagnosis; Diagnostic Errors; Fatal Outcome; Humans; Immunophenotyping; Leukemia, Prolymphocytic, T-Cell; Male; Neoplasms, Second Primary; Pentostatin; Rectal Neoplasms; Sezary Syndrome; Skin Neoplasms; T-Lymphocytes

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

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

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

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

Mycosis fungoides is an indolent primary cutaneous T-cell lymphoma (CTCL) that usually progresses from localized skin lesions to systemic disease. Sézary syndrome is a distinct variant characterized by generalized erythroderma and circulating cerebriform cells in the peripheral blood. The malignant cell in both diseases is a mature T cell, usually with a CD4-positive, CD8-negative phenotype. Among the treatment modalities used in these diseases are skin-directed therapy, single-agent and combination systemic chemotherapy, and, more recently, bioimmunotherapy. Pentostatin (Nipent), a potent inhibitor of adenosine deaminase, has activity in a wide range of lymphoid malignancies. At The Royal Marsden Hospital, we treated 29 cutaneous T-cell lymphoma patients with pentostatin, including 16 with Sézary syndrome, 5 with mycosis fungoides, and 8 with other cutaneous T-cell lymphomas. The median age of patients was 61 years (range, 26 to 87 years), with a male-female ratio of 2.5:1. The majority (N = 20) had received prior therapy. Pentostatin was administered at a dose of 4 mg/m2/wk for 4 weeks, and injections were continued every 1 to 2 weeks until maximum response. The overall response rate was 35%. However, only patients with Sézary syndrome achieved a good response, demonstrating an overall response rate of 62% (three complete responses plus seven partial responses). The median disease-free interval for responders was 9 months (range, 3 to 84 months). There was no significant treatment-related toxicity. We conclude that pentostatin is an effective single-agent therapy for patients with Sézary syndrome but not for those with other cutaneous T-cell lymphomas.

Topics: Adult; Aged; Aged, 80 and over; Antibiotics, Antineoplastic; Female; Humans; Lymphoma, T-Cell; Male; Middle Aged; Mycosis Fungoides; Pentostatin; Sezary Syndrome; Skin Neoplasms; Treatment Outcome

This phase II study was undertaken to assess the efficacy and toxicity of alternating administration of pentostatin (deoxycoformycin [DCF]) and interferon alfa-2a (IFN) in patients with advanced or refractory mycosis fungoides (MF) or the Sézary syndrome (SS).. Forty-one patients underwent therapy with alternating cycles of DCF 4 mg/m2 intravenously (IV) days 1 through 3 and IFN 10 million U/m2 intramuscularly (IM) day 22, and 50 million U/m2 intramuscularly (IM) days 23 through 26. Twenty-nine patients had not responded to prior chemotherapy or total-skin electron-beam irradiation (TSEB), six had not responded to topical therapies, and six had no previous treatment.. Two patients achieved a complete response (CR) and 15 achieved a partial response (PR), for an overall response rate of 41% (95% confidence interval, 26% to 58%). No responses were observed in the seven patients with visceral involvement. The median progression-free survival of patients who responded was 13.1 months. IFN-related constitutional symptoms were reported in 39% of patients; severe toxicities included cardiomyopathy in one patient, acute and chronic pulmonary dysfunction in four, and reversible mental status changes in two. Seven patients developed herpes zoster during therapy and six had staphylococcal bacteremia.. These results suggest that the combination of DCF and IFN is an active regimen in MF patients without visceral involvement.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Female; Humans; Interferon alpha-2; Interferon-alpha; Male; Middle Aged; Mycosis Fungoides; Neoplasm Staging; Pentostatin; Recombinant Proteins; Sezary Syndrome; Skin Neoplasms; Survival Analysis; Treatment Outcome

We describe the results of treatment with 2'-deoxycoformycin (DCF) in 68 patients with post-thymic (mature) T-cell malignancies. These included: prolymphocytic leukaemia (T-PLL), 31, HTLV-1 + adult T-cell leukaemia/lymphoma (ATLL), 20, cutaneous T-cell lymphoma (CTCL), comprising mycosis fungoides and Sezary syndrome, 13, and large granular lymphocytic leukaemia, four. Two-thirds of patients were refractory to previous therapy, which included four drug combinations. DCF was given intravenously at 4 mg m-2 weekly for the first 4 weeks and then every 2 weeks until maximal response. Toxicity was very low with only one death resulting from prolonged neutropenia. Overall response rates, partial (PR) and complete. (CR), were 38%, with variations according to diagnosis. Best responses, 54%, were seen in CTCL but limited to Sezary patients, one CR, six PR, whilst none of the mycosis fungoides responded. Responses in T-PLL were recorded in 48% including three CR (of 8-12 months' duration unmaintained) and 12 PR. Fifteen per cent of responses were seen in ATLL. The only ATLL responders - two CR, one PR - were those patients who received combination chemotherapy prior to DCF, with reduction of tumour bulk but short of PR. When results were analysed according to membrane phenotypes it was apparent that responses were seen mainly in cases with CD4+, CD8- T cells -22 of 47 (47%) - contrasting with only three of 19 (16%) with other T-cell phenotypes. We conclude that DCF is a useful therapy for the treatment of T-cell leukaemias, in particular Sezary syndrome and T-PLL, and should play a part in strategies to improve the natural history of this group of lymphoid malignancies.

Topics: Adult; Aged; Aged, 80 and over; Female; Humans; Leukemia-Lymphoma, Adult T-Cell; Leukemia, Lymphoid; Leukemia, Prolymphocytic; Leukemia, T-Cell; Lymphoma, T-Cell, Cutaneous; Male; Middle Aged; Mycosis Fungoides; Pentostatin; Sezary Syndrome

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

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

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

Topics: Alemtuzumab; Aminopterin; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bortezomib; Clinical Trials as Topic; Deoxycytidine; Depsipeptides; Diphtheria Toxin; Disease Progression; Doxorubicin; Electrons; Gemcitabine; Humans; Hydroxamic Acids; Immunotherapy; Incidence; Interleukin-2; Lenalidomide; Lymphoma, T-Cell; Mycosis Fungoides; Pentostatin; Photopheresis; Polyethylene Glycols; Randomized Controlled Trials as Topic; Recombinant Fusion Proteins; Retinoids; Sezary Syndrome; Stem Cell Transplantation; Thalidomide; United States; Vorinostat

Topics: Antineoplastic Combined Chemotherapy Protocols; Bexarotene; Cyclophosphamide; Humans; Mycosis Fungoides; Pentostatin; Sezary Syndrome; Skin Neoplasms; Tetrahydronaphthalenes; Treatment Outcome

Mycosis fungoides (MF) and Sezary syndrome (SS) are the most common forms of cutaneous T-cell lymphoma (CTCL). Various topical and systemic therapeutic alternatives are available, but there is no standard or definite curative treatment regimen. When making a decision about the appropriate treatment modality, the age and compliance of the patient, stage of the disease, treatment accessibility, and previous treatment history should be considered.. To determine the therapeutic response of patients with MF and SS to different treatment modalities. Patients were evaluated with respect to their clinical and demographic features.. One hundred and thirteen patients diagnosed clinically and dermatopathologically with MF and SS between March 1984 and June 2001 were included in the study.. Of the 113 patients studied, 110 had a diagnosis of MF and three had a diagnosis of SS; 101 patients (89.4%) were diagnosed with early stage (IA, IB, IIA) and 12 (10.6%) with late stage (IIB, III, IVA, IVB) disease. The age at diagnosis varied between 12 and 81 years (mean, 45.6+/-15.8 years). Fifty-five (48.7%) patients were male and 58 (51.3%) were female. The duration of the skin lesions varied between 1.5 months and 32 years (mean, 6.1 years). Psoralen plus UVA (PUVA) was the most commonly used initial treatment modality in early stage disease (91%), with a complete remission (CR) rate of 80.4%. With PUVA+interferon-alpha (INF-alpha) treatment, CR was 57% in the early stages and 33.3% in the late stages. For late stage disease, systemic therapies, such as pentostatin, gemcitabine, and fludarabine, alone or in combination with INF-alpha, were preferred. Of the 113 patients, eight (7% of the total and 57.1% of the advanced stage cases) died of MF; 21.4% of the late stage patients showed partial remission and 14.2% showed CR. None of the patients diagnosed with early stage disease died of MF, but two (1.9%) progressed to late stage disease.. PUVA and PUVA+INF-alpha are effective treatment modalities, especially for early stage MF. Once the disease has progressed, both MF and SS are very resistant to treatment regimens, including chemotherapeutic agents. It is important to diagnose and treat these diseases, especially MF, in the early stages for lasting remission.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Child; Deoxycytidine; Female; Gemcitabine; Humans; Interferon-alpha; Male; Middle Aged; Mycosis Fungoides; Neoplasm Staging; Pentostatin; PUVA Therapy; Sezary Syndrome; Treatment Outcome

We report a case of Sezary syndrome with two abnormal CD4+ T-cell populations detected in the peripheral blood by flow cytometry immunophenotyping and DNA cell content, suggesting a biclonal T-cell lymphoproliferative disorder. Despite these findings, molecular analysis of the T-cell receptor genes was consistent with a monoclonal T-cell proliferation, supporting the existence of intraclonal diversity rather than a true biclonal disease. The patient achieved a transient response with 2-deoxycoformycin, with a selective decrease of the larger/hyperploid T-cell population; later on, an increased representation of this T-cell population was observed concomitantly with clinical relapse.

Topics: Aged; Antibiotics, Antineoplastic; CD4-Positive T-Lymphocytes; Cell Division; Flow Cytometry; Humans; Immunophenotyping; Male; Pentostatin; Phenotype; Sezary Syndrome; Skin Neoplasms; T-Lymphocyte Subsets

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

Cutaneous T-cell lymphoma (CTCL) comprises a constellation of diseases of malignant clonal T lymphocytes that present initially in the skin. Since biochemical studies of pentostatin suggested that T cells are more sensitive to the effects of inhibition of adenosine deaminase by purine analogs, early studies with pentostatin were conducted in patients with refractory T-cell neoplasms. Durable responses were reported in several patients on phase I studies. Of 94 CTCL patients treated on five phase II studies with single-agent pentostatin, the overall response rate was 40%, with a 7% complete response rate; the median time to progression ranged from 1.3 to 8.3 months. There was a trend toward improved response in patients with diffuse erythroderma or plaque disease. A phase II study combining pentostatin with intermittent high-dose interferon-alpha demonstrated a 41% overall response rate, with two complete responses, both in patients with Sézary syndrome and diffuse erythroderma Toxicities have been tolerable at doses of 4 to 5 mg/m2 administered weekly or for 3 consecutive days, with grade 3-4 hematologic toxicity in 31 patients, renal insufficiency in seven, nausea in 17, and conjunctivitis in three. In summary, pentostatin has demonstrated impressive activity in patients with advanced and refractory CTCL. Additional studies using pentostatin in earlier-stage CTCL or in combination with other active agents in advanced disease are warranted.

Topics: Adenosine Deaminase Inhibitors; Antibiotics, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Clinical Trials, Phase I as Topic; Clinical Trials, Phase II as Topic; Disease Progression; Enzyme Inhibitors; Humans; Immunosuppressive Agents; Interferon-alpha; Lymphoma, T-Cell, Cutaneous; Pentostatin; Remission Induction; Sezary Syndrome; Skin Neoplasms; T-Lymphocytes

We present a case of a patient who developed all manifestations of thrombotic thrombocytopenic purpura-hemolytic uremic syndrome (TTP-HUS) acutely following treatment of cutaneous T-cell lymphoma (CTCL, Sezary syndrome) with deoxycoformycin (pentostatin). Symptoms and signs included severe thrombocytopenia and microangiopathic hemolytic anemia; hallucinations, confusion and disorientation; oliguric acute renal failure requiring hemodialysis; and fever. No other etiology for these symptoms and signs was present. Complete recovery followed treatment for one month with plasma exchange and glucocorticoids. During the succeeding 20 months she has remained well and her CTCL remains stable on no further treatment. This case and two previously published cases suggest that acute and severe TTP-HUS may be a dose-dependent toxicity of deoxycoformycin (pentostatin).

Topics: Enzyme Inhibitors; Female; Glucocorticoids; Hemolytic-Uremic Syndrome; Humans; Middle Aged; Pentostatin; Plasma Exchange; Purpura, Thrombotic Thrombocytopenic; Sezary Syndrome

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

A 65-year-old man was evaluated for pancytopenia in March 1979, and found to have hairy cell leukemia (HCL). Treatment with splenectomy and subsequently interferon produced temporary remissions. In July 1985, the patient began intravenous deoxycoformycin (DCF) therapy, and after 1 year complete peripheral blood and bone marrow remission was achieved. Fourteen months after cessation of therapy, the patient developed a skin rash and was found to have cutaneous T-cell lymphoma and Sezary syndrome. Morphologic study of the hairy cells (HC) in the peripheral blood at presentation and the Sezary cells was distinct by light and electron microscopic study. Immunophenotyping of peripheral blood mononuclear cells showed clearly that the HC were of B-cell origin (CD20+, sIg+), whereas the lymphoid population at second presentation was T-cell (CD3+, CD4+, HLA-DR-). Clonal rearrangement of T-cell antigen receptor beta-chain gene was detected by Southern analysis of the Sezary cell population, whereas immunoglobulin heavy and light chain genes remained in germ line configuration. This is the first case of Sezary syndrome developing in a patient previously treated for HCL where studies have confirmed distinct B-cell and T-cell origin of the two neoplasms. The authors suggest that treatment and disease-related immunosuppression are possible etiologic factors in the development of this second lymphoid neoplasm.

Topics: Aged; Blotting, Southern; Gene Rearrangement, beta-Chain T-Cell Antigen Receptor; Genes, Immunoglobulin; Humans; Immunophenotyping; Leukemia, Hairy Cell; Male; Neoplasms, Multiple Primary; Pentostatin; Remission Induction; Sezary Syndrome; Skin Neoplasms; T-Lymphocytes, Helper-Inducer

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

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

Knowledge of the vital role of the purine degradative enzyme adenosine deaminase (ADA) in the differentiation of T and B lymphocytes has stimulated interest in the pharmacologic inhibition of ADA as specific cytotoxic therapy for lymphoproliferative diseases. 2'-Deoxycoformycin (DCF) is a tight-binding ADA-inhibitor and has shown activity in T and B cell neoplasms. In this phase-II study, the efficacy and toxicity of DCF in chronic T and B cell neoplasms is investigated. We report the preliminary results of treatment in 27 patients (8 with Sézary syndrome, 11 with B-chronic lymphocytic leukemia (CLL), and 8 with hairy cell leukemia (HCL)), who were refractory to conventional therapy. DCF was applied at a dosage of 4 mg/m2 weekly x 3, then 4 mg/m2 every other week x 3. Three of the 8 patients with Sézary syndrome and 3 of the 11 patients with B-CLL attained a partial remission. One complete and 7 partial remissions have been achieved thus far in the 8 patients with HCL refractory to interferon alpha treatment. Other than nausea in 10 patients (mainly grade 1 and 2), transient skin rash in 4 patients and Herpes infections in 4 patients (mainly grade 2), no other major toxicities were observed. Thus DCF is highly active in hairy cell leukemia that did not respond to interferon alpha, and shows moderate activity in refractory Sézary syndrome and B-CLL.

Topics: Antineoplastic Agents; B-Lymphocytes; Coformycin; Drug Evaluation; Humans; Leukemia; Leukemia, Hairy Cell; Leukemia, Lymphoid; Lymphoma; Pentostatin; Ribonucleosides; Sezary Syndrome; Skin Neoplasms; T-Lymphocytes

The adenosine deaminase inhibitor deoxycoformycin was used in low doses to treat 19 patients with clinically aggressive T cell malignancy with a mature membrane phenotype. The patients comprised eight with prolymphocytic leukaemia, two with chronic lymphocytic leukaemia, four with adult T cell leukaemia-lymphoma, three with Sézary syndrome, and two with T cell lymphoma. Two thirds of the patients had been resistant or minimally responsive to combination chemotherapy. Complete remission was obtained in five patients (two with prolymphocytic leukaemia and one each with chronic lymphocytic leukaemia, adult T cell leukaemia-lymphoma, and Sézary syndrome) and partial remission in two others. Unmaintained complete remission lasting more than one year was seen in three patients. Responses were obtained only in patients with CD4+,CD8-membrane markers (seven out of 10), and no responses were recorded in any of the nine patients with a different phenotype. In this series remission appeared to correlate with the membrane phenotype of the neoplastic cell and not with the cytopathological diagnosis. Future studies should establish the biochemical basis for the greater sensitivity of CD4+ lymphoid cells to deoxycoformycin.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Cell Membrane; Coformycin; Cyclophosphamide; Deltaretrovirus Infections; Doxorubicin; Female; Follow-Up Studies; Humans; Leukemia; Leukemia, Lymphoid; Lymphoma; Male; Middle Aged; Pentostatin; Phenotype; Prednisone; Prognosis; Ribonucleosides; Sezary Syndrome; T-Lymphocytes; Vincristine

Topics: Antineoplastic Agents; Coformycin; Drug Evaluation; Humans; Leukemia, Lymphoid; Pentostatin; Ribonucleosides; Sezary Syndrome

Hereditary deficiency of the enzyme adenosie deaminase (adenosine aminohydrolase, EC 3.5.4.4) results in an immunodeficiency syndrome characterized by a marked reduction in circulating lymphocytes. We have administered 2'-deoxycoformycin, a potent inhibitor of adenosine deaminase, to a patient with a lymphoproliferative malignancy. The clinical consequences of pharmacologic inhibition of adenosine deaminase activity included an abrupt decrease in the lymphocyte count, abnormalities of renal and hepatic function, and hemolytic anemia. The plasma concentrations of adenosine and deoxyadenosine rose to peak values of 13 microM and 5 microM, respectively, and erythrocyte dATP levels increased to 110 pmol/10(6) cells over 9 days. There was a corresponding decrease in erythrocyte ATP levels from 128 to < 6 pmol/10(6) cells. A similar profound reductin in ATP occurred in the erythrocytes of a second patient. The rapid and unexpected depletion of ATP associated with dATP accumulation may account, at least in part, for the toxicity associated with 2'-deoxycoformycin administration. The inverse relationship of ATP and dATP raises major questions about the control of energy metabolism in erythrocytes.

Topics: Adenosine; Adenosine Deaminase Inhibitors; Adenosine Triphosphate; Aged; Coformycin; Deoxyadenine Nucleotides; Deoxyadenosines; Erythrocytes; Humans; Nucleoside Deaminases; Pentostatin; Ribonucleosides; Sezary Syndrome