pentostatin and Leukemia-Lymphoma--Adult-T-Cell

Adult T cell leukaemia-lymphoma (ATL) was first discovered and reported in Japan, where it has a high incidence in the south-west region. The first human retrovirus HTLV-I (human T-cell lymphotropic virus type I) is considered to be related to its aetiology. In ATL endemic areas, HTLV-I carriers form a fairly high percentage of the population, even among healthy individuals. ATL shows diverse clinical features. It can be divided into four subtypes: acute, chronic, smouldering and lymphoma type. ATL cells originate from the CD4-positive subset of peripheral T cells; they show a characteristic notch in the nucleus and a tendency to lobulation. ATL resists chemotherapy, and patients with acute and lymphoma types have a fairly poor prognosis. A definite diagnosis of ATL is made by documenting the presence of HTLV-I proviral DNA in the DNA of tumour cells. HTLV-I infection is caused by transmission of live lymphocytes via three routes (from mother to child, from males to females, and by transfusion). Familial occurrence of ATL is frequently seen. HTLV-I infection is seen in other countries, but its incidence is highest in Japan. Infection with HTLV-I is a direct cause of ATL. Furthermore, infection with this virus can indirectly cause many other diseases via the induction of immunodeficiency, such as chronic lung disease, opportunistic lung infection, cancer of other organs, monoclonal gammopathy, chronic renal failure, strongyloidiasis, non-specific dermatomycosis, HTLV-I-associated lymphadenitis, HTLV-I uveitis and HTLV-I-associated myelopathy-tropical spastic paraparesis (HAM/TSP).

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Caribbean Region; Female; Human T-lymphotropic virus 1; Humans; Hypercalcemia; Incidence; Japan; Leukemia-Lymphoma, Adult T-Cell; Lung Diseases; Male; Middle Aged; Neoplasms, Second Primary; Neoplastic Stem Cells; Pentostatin; Uveitis

Aggressive adult T-cell leukemia-lymphoma (ATL) generally has a very poor prognosis. Deoxycoformycin (DCF, pentostatin), an inhibitor of adenosine deaminase, has shown promising therapeutic efficacy for ATL. To develop a new effective therapy against aggressive ATL, we carried out a multicenter phase II study of DCF-containing combination chemotherapy. Sixty-two previously untreated patients with ATL (34, 21, and 7 patients with diseases of the acute, lymphoma, and unfavorable chronic types, respectively) were enrolled, but 2 were ineligible because they were judged to be favorable chronic types. A regimen of 1 mg/m2 vincristine intravenously on days 1 and 8, 40 mg/m2 doxorubicin intravenously on day 1, 100 mg/m2 etoposide intravenously on days 1 through 3, 40 mg/m2 prednisolone orally on days 1 and 2, and 5 mg/m2 DCF intravenously on days 8, 15, and 22 was administered every 28 days for 10 cycles unless disease progression or toxic complications occurred. Fifty-two percent of 60 eligible patients responded (95% confidence interval [CI], 38%-65%), with 17 patients (28%) achieving a complete response (CR) (95% CI, 17%-41%) and 14 achieving a partial response. The CR rate was inferior to those of both the previous Japan Clinical Oncology Group (JCOG) study (JCOG8701, 43%), a 9-drug combination chemotherapy of the second generation, and the subsequent JCOG9303 study (35%), a granulocyte colony-stimulating factor-supported, dose-intensified, 9-drug regimen. The median survival time of the 60 eligible patients in JCOG9109 was 7.4 months, and the estimated 2-year survival rate was 15.5%; these results were identical with those of JCOG8701 but inferior to those of JCOG9303. Grade 4 neutropenia and infection of grade 3 or greater were frequent (67% and 22%, respectively), and treatment-related death was observed in 4 patients (7%), septicemia in 2, and cytomegalovirus pneumonia in 2. We conclude that DCF-containing combination chemotherapy is not a promising regimen against aggressive ATL.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Carboplatin; Cyclophosphamide; Female; Humans; Japan; Leukemia-Lymphoma, Adult T-Cell; Male; Methotrexate; Middle Aged; Pentostatin; Remission Induction; Salvage Therapy; Societies, Medical; Survival Rate; Treatment Outcome; Vindesine

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

Treatment of adult T-cell leukemia (ATL) remains difficult. Alemtuzumab with or without nucleoside analogs such as pentostatin may provide a role in this setting. However, the associated immunosuppression is a concern in patients with viral-mediated disease.

Topics: Alemtuzumab; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antibodies, Neoplasm; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Enzyme Inhibitors; Female; Humans; Leukemia-Lymphoma, Adult T-Cell; Middle Aged; Pentostatin

Cases of adult T-cell leukemia (ATL) with aberrant phenotypes have a very poor prognosis. We report the development of acute type, CD 8 positive ATL in a carrier of hepatitis B virus (HBV). The patient was treated with a combination of lamivudine and chemotherapy and consequently had longer-term survival than those reported previously. A 64-year-old(corrected 65-year-old) man was referred to our hospital in January 2002 because of ascites and abdominal tumor. He was positive for anti-HTLV-1 antibody and HBV surface antigen. Generalized computed tomography demonstrated bilateral pleural effusion, abdominal mass, and massive ascites. Cytological examination of ascitis revealed numerous atypical lymphoid cells,which were positive for CD 2, CD 5, CD 8, and CD 25. Monoclonal integration of HTLV-1 provirus was detected by Southern blot analysis on DNA extracted from lymphoid cells. A diagnosis of acute type, CD 8 positive ATL was made. Lamivudine was administered for prevention of chemotherapy induced HBV reactivation. Subsequently, he was treated with 6 cycles of CHOP and went into remission. He maintained clinical remission during a follow-up of 13 months and then relapsed. Further salvage therapies were provided with a transient effect. He died of sepsis in February 2004. The overall survival time of this patient was 25 months. It is possible that lamivudine combined with chemotherapy may have had a therapeutic effect on ATL in this case.

Topics: Anti-HIV Agents; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Carrier State; CD8-Positive T-Lymphocytes; Cyclophosphamide; Doxorubicin; Drug Administration Schedule; Etoposide; Hepatitis B; HTLV-I Antibodies; Humans; Irinotecan; Lamivudine; Leukemia-Lymphoma, Adult T-Cell; Male; Middle Aged; Mitoxantrone; Nitrosourea Compounds; Pentostatin; Prednisone; Vincristine

This is a preliminary feasibility study to assess the pharmacokinetics and efficacy of pentostatin in a patient undergoing dialysis. Pentostatin is a safe and well-tolerated medication, but a dose reduction is required for patients with renal insufficiency. We present a patient with chronic adult T-cell leukemia, whose white blood cell count exceeded 100 X 10(9)/l, and end-stage renal disease, receiving long-term thrice-weekly dialysis. The initial treatment with oral cyclophosphamide or with oral etoposide resulted in no response. After informed consent was obtained, pentostatin (1, 2, or 3mg/m2) was administered. 1 or 2 hours after injection, the patient received hemodialysis over 4 hours to remove any of the drug remaining in his system. Plasma concentrations of pentostatin were calculated with the known pharmacokinetics parameters. The differential equations describing a 2-compartment open-infusion pharmacokinetic model were fitted to the measured concentration-time data. Tumor lysis syndrome occurred 4 days after the course of the highest dose (3mg/m2), and the patient achieved complete remission. Anorexia, graded as 2 according to the NCI-CTC classification system, occurred and continued for four weeks. Pentostatin therapy consisting of the decreased dose (2mg/m2) was then administered every other week and provided a transient partial response with mild anorexia. Consequently, pentostatin can be considered as one of the chemotherapeutic regimens available for a patient undergoing dialysis.

Topics: Antibiotics, Antineoplastic; Chronic Disease; Dose-Response Relationship, Drug; Feasibility Studies; Female; Humans; Kidney Failure, Chronic; Leukemia-Lymphoma, Adult T-Cell; Middle Aged; Models, Biological; Pentostatin; Remission Induction; Renal Dialysis

We describe the case of a 55-year-old man with adult T-cell leukemia/lymphoma (ATL) in first remission who underwent nonmyeloablative allogeneic peripheral blood stem cell transplantation with conditioning consisting of 4 courses of pentostatin and low-dose total body irradiation. Complete chimerism in peripheral blood was achieved on day 42 without severe myelosuppression. Concomitantly, the proviral DNA load for human T-cell leukemia virus I (HTLV-I) in peripheral blood mononuclear cells decreased below detectable limits and was still undetectable on day 270. This fact indicates that eradication of ATL cells is feasible by induction of an alloimmune response without high-dose chemoradiotherapy.

Topics: Adult; Hematopoietic Stem Cell Transplantation; Humans; Leukemia-Lymphoma, Adult T-Cell; Male; Middle Aged; Pentostatin; T-Lymphocytes, Cytotoxic; Transplantation Conditioning; Whole-Body Irradiation

We report a patient with a postoperative survival period of 6 years after the surgical excision of a cardiac malignant lymphoma. A 35-year-old woman underwent total excision of the tumor arising from the left ventricular outflow tract. After the operation, she was treated with chemotherapy for 6 months. She has been doing well thereafter without any medication. To date there is no evidence of recurrence.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Disease-Free Survival; Doxorubicin; Etoposide; Female; Heart Neoplasms; Humans; Leukemia-Lymphoma, Adult T-Cell; Pentostatin; Prednisolone; Vincristine

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

YK-176 is a newly isolated 2'-deoxycoformycin (DCF), a potent inhibitor of adenosine deaminase, produced by Aspergillus nidulans. In a cooperative phase I study, YK-176 was administered to 22 patients, comprising 18 with adult T-cell leukemia-lymphoma (ATL), two with cutaneous T-cell lymphoma (CTCL), one with lymphoblastic lymphoma of T-cell type and one with carcinoma of the uterine cervix. Doses of YK-176 ranged from 3.0 to 9.0 mg/m2 and were given intravenously for three consecutive days. General malaise, anorexia, nausea, vomiting and low grade fever were frequently encountered, but were transient and not dose-related. At all dose levels hematological toxicities were mild. Two of seven patients receiving 7.0 mg/m2 for three consecutive days developed hepatocellular enzyme elevations (grade 2) and one patient, proteinuria (grade 2). One of two patients given 9.0 mg/m2 for three consecutive days manifested a life-threatening (grade 4) disturbance of consciousness and dyspnea, presumably ascribable to the drug-related toxicity of YK-176. The results suggest that 7.0 mg/m2 i.v. for three consecutive days is the maximum acceptable dose of YK-176. Central nervous system, pulmonary and possibly renal toxicities appeared to be dose-limiting. Out of the 20 patients evaluable for therapeutic response, partial remissions were observed in four, three with ATL and one with CTCL, who received less than 7.0 mg/m2 for three consecutive days. We conclude that YK-176 is an active agent against ATL at doses that may not be associated with prohibitive toxicity. A starting dose of 5.0 mg/m2 for three consecutive days is recommended for further phase II studies on ATL.

Topics: Adult; Aged; Appetite; Drug Evaluation; Female; Humans; Leukemia-Lymphoma, Adult T-Cell; Male; Middle Aged; Nausea; Pentostatin; Remission Induction; Vomiting

Arabinosylguanine (araG) is a nucleoside analog that is rapidly converted by cells of the T lymphoid lineage to its corresponding arabinosylguanine nucleotide triphosphate, resulting in inhibition of DNA synthesis and selective in vitro toxicity to T lymphoblastoid cell lines as well as to freshly isolated leukemia cells from patients with T cell acute lymphoblastic leukemia. In this report, we demonstrate that araG is an effective agent to use for chemoseparation of malignant T lymphoblasts from human bone marrow. When freshly isolated human T leukemia cells or T lymphoblastoid cells were treated with 100 microM araG for 18 hr, up to 6 logs of clonogenic T cells could be eliminated without appreciable toxicity to the normal myeloid, erythroid, and megakaryocytoid clonal progenitor cells. We discuss the use of this agent in ex vivo elimination of residual malignant T cells from marrow of patients requiring myeloablative chemotherapy with autologous bone marrow rescue.

Topics: Antineoplastic Agents; Arabinonucleosides; Arabinonucleotides; Bone Marrow Purging; Cell Death; Cell Division; Cell Separation; Clone Cells; Erythroid Precursor Cells; Guanosine Triphosphate; Humans; Leukemia-Lymphoma, Adult T-Cell; Pentostatin; Precursor Cell Lymphoblastic Leukemia-Lymphoma; T-Lymphocytes; Tumor Cells, Cultured

Adult T-cell leukemia (ATL) was first discovered and reported in Japan, where it has a high incidence in the southwest region. The retrovirus HTLV-I (human T-cell lymphotropic virus type I) is considered to be related to its etiology. In ATL endemic areas, HTLV-I carriers are found at a fairly high percentage even among healthy individuals. ATL shows diverse clinical features. It can be divided into 5 types (acute type, chronic type, smoldering type, crisis type, and lymphoma type). ATL cells originate from the CD4-positive subset of peripheral T cells; they show a characteristic notch in the nucleus and a lobulation tendency. ATL resists chemotherapy, and patients with acute and lymphoma types have quite a poor prognosis. A definite diagnosis of ATL is made by documenting the presence of HTLV-I proviral DNA in the DNA of tumor cells. HTLV-I infection is caused by transmission of live lymphocytes via three routes (from mother to children, from males to females, and by transfusion). Familial occurrence of ATL is frequently seen. HTLV-I infection is also seen in other countries, but its incidence is highest in Japan. It is thus an urgent task for Japanese physicians to eliminate HTLV-I infection.

Topics: Antigens, Differentiation, T-Lymphocyte; Antineoplastic Agents; Coformycin; Female; HTLV-I Infections; Humans; Japan; Leukemia-Lymphoma, Adult T-Cell; Leukemia, T-Cell; Male; Pentostatin; Photochemotherapy

Topics: Antineoplastic Agents; Humans; Leukemia-Lymphoma, Adult T-Cell; Pentostatin; Photochemotherapy