pentostatin and Lymphopenia

It has been widely demonstrated that one single 7-day course continuous infusion (c.i.) 2-chlorodeoxyadenosine (2-CdA) at a dose of 0.1 mg/kg daily is dramatically effective in inducing high and prolonged complete remission (CR) rates in patients with hairy-cell leukemia (HCL). However, 2-CdA administration often results in severe neutropenia and lymphocytopenia both responsible for the infectious complications observed in these patients. We previously reported preliminary data regarding the effectiveness and toxicity of a modified protocol of 2-CdA administration (0.15 mg/kg 2 hours infusion once a week for 6 courses) in 25 HCL patients. This treatment schedule produced a similar overall response rate compared to standard 2-CdA regimen and appeared to be followed by a lower incidence of infectious episodes. In the present study we report response rate and toxicity of weekly 2CdA administration in a larger cohort of patients and with a longer follow-up.. In a group of HCL patients with a pronounced decrease in neutrophils count (< 1 x 10(9)/L), we modified the standard protocol (0.1 mg/kg daily x 7 days c.i.) by administering 2-CdA at a dose of 0.15 mg/kg 2 hours infusion once a week for 6 courses. Thirty HCL patients, 24 males and 6 females with a median age of 56 years (range 37-76), entered into this protocol. Seventeen out of 30 patients were at diagnosis while the remaining 13 had been previously treated with alpha-interferon (alpha-IFN) (7), or 2-CdA (4) or deoxycoformycin (DCF) (2).. Overall, 22/30 (73%) patients achieved CR and 8 (27%) partial remission (PR) with a median duration of response at the time of writing of 35 months, ranging from 6 to 58 months. Five patients (1 CR and 4 PR) have so far progressed. The treatment was very well tolerated. Five out of 30 patients (16%) developed severe neutropenia (neutrophils < 0.5 x 10(9)/L) and only in two of them we did register an infectious complication which required treatment with systemic antibiotics and granulocyte colony-stimulating factor (G-CSF).. In conclusion, we confirm that weekly administration of 2-CdA at a dose of 0.15 mg/kg for 6 courses appears to be very effective in HCL inducing a high CR rate, similar to that observed with daily c.i. administration. CR durability and relapse/progression rates are also comparable to standard 2-CdA schedule. Moreover this new regimen seems to be safer in pancytopenic patients, markedly reducing life-threatening infectious complications.

Topics: Adult; Aged; Antimetabolites, Antineoplastic; Cladribine; Disease Progression; Drug Administration Schedule; Female; Follow-Up Studies; Humans; Infection Control; Interferon-alpha; Leukemia, Hairy Cell; Lymphopenia; Male; Middle Aged; Neutropenia; Pentostatin; Remission Induction; Treatment Outcome

In a canine model of dog leukocyte antigen (DLA)-identical nonmyeloablative marrow transplantation including postgrafting immunosuppression with cyclosporine (CSP) and mycophenolate mofetil (MMF), engraftment was only transient with 100 cGy total body irradiation (TBI) conditioning, indicating suboptimal pretransplant immunosuppression. In contrast, grafts after 200 cGy TBI were durable in 11/12 recipients. We hypothesized that addition of pentostatin before transplantation could, in part, substitute for 100 cGy TBI. Pharmacokinetic studies showed pentostatin significantly inhibited adenosine deaminase in canine lymphocytes. Eight dogs were conditioned with 6x4 mg/m pentostatin and 100 cGy TBI, whereas two dogs received 3x4 mg/m pentostatin plus 100 cGy TBI. All were given MMF/CSP posttransplant. All showed initial engraftment; four remained stable mixed chimeras for >32 weeks. The median duration of engraftment was 13 (range 9 to >39) weeks, which was significantly longer than in six historical controls conditioned with 100 cGy TBI alone (median 10, range 3-12 weeks) (P=0.01).

Topics: Adenosine Deaminase Inhibitors; Animals; Bone Marrow Transplantation; Cyclosporine; Dogs; Graft Survival; Immunosuppressive Agents; Lymphopenia; Mycophenolic Acid; Pentostatin; Transplantation Chimera; Transplantation Conditioning; Transplantation, Homologous; Whole-Body Irradiation

Topics: Adenine; Adenosine Deaminase; Adenosine Deaminase Inhibitors; Cell Survival; Cells, Cultured; Coformycin; Deoxyadenosines; Humans; Interphase; Leukemia; Lymphopenia; Nucleoside Deaminases; Pentostatin; Purines; Ribonucleosides; T-Lymphocytes

Topics: Adenosine Deaminase; Animals; Brain Edema; Coformycin; Dogs; Graft Survival; Lymphopenia; Pentostatin; Ribonucleosides; Skin Transplantation; Thrombocytopenia; Time Factors

2'-Deoxycoformycin (2'-dCF), a tight-binding inhibitor of adenosine deaminase, was administered to 26 pediatric patients with acute lymphoblastic leukemia in a Phase I study. Doses ranged from 0.25 to 1.0 mg/kg given i.v. for 3 consecutive days. Common toxicity included nausea, vomiting, diarrhea, hepatocellular enzyme elevations, and conjunctivitis. Lymphopenia occurred in all patients. The most serious adverse effects were acute tubular necrosis and central nervous system toxicity, which appeared to be dose related. In addition, two patients given the 0.75-mg/kg dose developed severe hepatic toxicity, although this could not be ascribed definitively to 2'-dCF. Antitumor activity was observed in eight patients, two of whom experienced a complete remission. Inhibition of lymphoblast adenosine deaminase activity was noted in the majority of cases and was observed at all doses. Antileukemic activity occurred at doses of 2'-dCF which were not associated with limiting toxicities. These results suggest that 2'-dCF is active against acute lymphoblastic leukemia and that a starting dose of 0.5 mg/kg/day be utilized in Phase II studies.

Topics: Adenosine Deaminase Inhibitors; Adolescent; Adult; Child; Child, Preschool; Coformycin; Drug Administration Schedule; Drug Evaluation; Female; Humans; Leukemia, Lymphoid; Liver; Lymphopenia; Male; Nausea; Pentostatin; Prognosis; Ribonucleosides; Vomiting

Topics: Adenosine Deaminase; Animals; Body Weight; Coformycin; Immunosuppressive Agents; Lymph Nodes; Lymphocyte Activation; Lymphopenia; Male; Mice; Mice, Inbred C57BL; Mitogens; Organ Size; Pentostatin; Ribonucleosides; Spleen; Thymus Gland