pentostatin and Neutropenia

To examine the efficacy and safety of the combination of alemtuzumab and pentostatin in patients with T-cell neoplasms.. We treated 24 patients with a variety of T-cell leukemias and lymphomas with a combination of alemtuzumab 30 mg intravenously (IV) three times weekly for up to 3 months and pentostatin 4 mg/m(2) IV weekly for 4 weeks followed by alternate weekly administration for up to 6 months. Prophylactic antibiotics including antiviral, antifungal, and antibacterial agents were administered during the treatment and for 2 months after its completion.. The median age of patients was 57 years (range, 21 to 79 years). Eight patients were previously untreated, and 16 had a median of two prior therapies (range, one to six regimens). Thirteen patients responded to treatment (11 complete responses [CRs] and two partial responses), for an overall response rate of 54%. The median response duration was 19.5 months. Monoclonal T-cell receptor chain gene rearrangements were detected by polymerase chain reaction in bone marrow of 20 of 22 evaluable patients and became negative in five of seven evaluable patients in CR. Opportunistic infections caused by pathogens associated with severe T-cell dysfunction were common.. The combination of alemtuzumab and pentostatin is feasible and effective in T-cell neoplasms. Although infections, including cytomegalovirus reactivation, are a concern, they may be minimized with adequate prophylactic antibiotic therapy.

Topics: Adult; Aged; Alemtuzumab; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antibodies, Neoplasm; Antineoplastic Combined Chemotherapy Protocols; Drug Administration Schedule; Female; Humans; Leukemia, T-Cell; Lymphoma, T-Cell; Male; Middle Aged; Neutropenia; Pentostatin; Sepsis; Survival Analysis; Thrombocytopenia; Treatment Outcome; Young Adult

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

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

A 52-year-old woman presented to our clinic for investigation of agranulocytosis and mild lymphocytosis. A diagnosis of T-large granular lymphocyte leukemia was made, based on immunophenotyping findings of the peripheral blood lymphocytes (CD3, CD8, CD16, CD57). Flow cytometric analysis of TCR-Vbeta repertoire showed single Vbeta9 expression on peripheral T-cells. Clonality was also demonstrated with PCR analysis which revealed clonal rearrangement of TCRgamma-chain gene. Granulocyte-macrophage colony-stimulating factor (G-CSF) (G-CSF), cyclosporine, methylprednisolone and oral methotrexate failed to correct the neutropenia. Finally, treatment with 2-deoxycoformycin (DCF) was successful and resulted in complete correction of the neutrophil count. Flow cytometric analysis of TCR-Vbeta repertoire proved to be an effective method to assess the therapeutic response to various treatments and to evaluate residual disease.

Topics: Antibiotics, Antineoplastic; Antigens, CD; Female; Flow Cytometry; Genes, T-Cell Receptor beta; Humans; Immunoglobulin Variable Region; Immunophenotyping; Leukemia, Lymphoid; Leukemia, T-Cell; Middle Aged; Neutropenia; Pentostatin; Remission Induction

We report a case of CD8(+)/V beta 5.1(+) T-cell large granular lymphocyte leukemia (T-LGL leukemia) presenting with mild lymphocytosis, severe autoimmune neutropenia, thrombocytopenia, polyarthritis and recurrent infections with a chronic disease course. Immunophenotyping showed an expansion of CD3(+)/TCR alpha beta(+)/CD8(+bright)/CD11c(+)/CD57(-)/CD56(-) large granular lymphocytes with expression of the TCR-V beta 5.1 family. Southern blot analysis revealed a clonal rearrangement of the TCR beta-chain gene. Hematopoietic growth factors, high dose intravenous immunoglobulin and corticosteroids were of limited therapeutic benefit to correct the cytopenias. During the disease course, the patient developed a severe cutaneous leg ulcer and bilateral vascular mammary skin lesions. Treatment with 2-deoxycoformycin resulted in both clinical and hematological complete responses, including the resolution of vascular skin lesions. Combined immuno-staining with relevant T-cell associated and anti-TCR-V beta monoclonal antibodies proved to be a sensitive method to assess the therapeutic effect of 2-deoxycoformicin and to evaluate the residual disease.

Topics: Aged; Antibiotics, Antineoplastic; Arthritis, Rheumatoid; Breast; CD3 Complex; CD8 Antigens; Female; Gene Rearrangement, T-Lymphocyte; Humans; Immunophenotyping; Leg Ulcer; Leukemia, Lymphoid; Neutropenia; Pentostatin; Receptors, Antigen, T-Cell, alpha-beta; Thrombocytopenia

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

Purine analogs and alkylating agents are the most active drugs in the treatment of patients with chronic lymphocytic leukemia (CLL). Although fludarabine is the most widely tested purine analog in CLL, myelosuppression has limited its use in combination chemotherapy regimens. Because pentostatin (Nipent; SuperGen, San Ramon, CA), a related purine analog with proven activity in CLL, has less myelosuppression, we postulated that it would prove advantageous and could be more readily combined with alkylating agents. We are conducting a phase I/II trial of combination chemotherapy with pentostatin and cyclophosphamide for previously treated patients with CLL. Patients need to have Rai high-risk disease or "active" intermediate-risk disease. The treatment regimen consists of a fixed dose of pentostatin (4 mg/m2) combined with an increasing dose of cyclophosphamide. We plan to treat cohorts of three patients each at cyclophosphamide dose levels of 600, 900, 1,200, 1,500, and 2,000 mg/m2. Cycles will be repeated every 21 days. If unacceptable toxicity is encountered at one dose level, then three additional patients (total of six patients) will be accrued to that dose level before further dose escalations will be permitted. A second instance of unacceptable toxicity will close that dose level and identify the preceding level as the phase II dose. Additional patients will be accrued to the phase II dose level to better assess response. Supportive measures include the use of granulocyte colony-stimulating factor (5 microg/kg/d) to limit neutropenia. Sulfamethoxazole/trimethoprim will be given as prophylaxis against Pneumocystis carinii pneumonia and acyclovir will be administered as prophylaxis for herpes zoster. Response will be assessed according to standard criteria, and flow cytometry and fluorescent in situ hybridization will be used to assess for minimal residual disease in patients with trisomy 12.

Topics: Acyclovir; Anti-Infective Agents; Antibiotics, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Antiviral Agents; Chemoprevention; Chromosomes, Human, Pair 12; Clinical Trials, Phase I as Topic; Clinical Trials, Phase II as Topic; Cohort Studies; Cyclophosphamide; Dose-Response Relationship, Drug; Flow Cytometry; Granulocyte Colony-Stimulating Factor; Herpes Zoster; Humans; Immunosuppressive Agents; In Situ Hybridization, Fluorescence; Leukemia, Lymphocytic, Chronic, B-Cell; Neutropenia; Patient Selection; Pentostatin; Pneumonia, Pneumocystis; Remission Induction; Risk Factors; Trimethoprim, Sulfamethoxazole Drug Combination; Trisomy

The association of T-cell large granular lymphocyte (LGL) leukemia and rheumatoid arthritis is well described and it is now recognized that these patients and patients with Felty's syndrome represent different aspects of a single disease process. Most patients have rheumatoid arthritis at the time of diagnosis of LGL leukemia. This is the first detailed report of the development of rheumatoid arthritis after the diagnosis and treatment of LGL leukemia as well as the first report of rheumatoid arthritis that occurred in association with deoxycoformycin treatment. It is likely that the beneficial sustained normalization of neutrophil counts as a result of deoxycoformycin treatment played a significant role in the development of this complication. Hematological improvement occurred despite molecular genetic evidence of persistence of the abnormal T-cell clone. The role of the clonally expanded T cells in the pathogenesis of neutropenia and rheumatoid arthritis is discussed.

Topics: Antibiotics, Antineoplastic; Clinical Trials, Phase II as Topic; Clone Cells; Felty Syndrome; Gene Rearrangement, T-Lymphocyte; Genes, T-Cell Receptor; Histocompatibility Testing; HLA-DR4 Antigen; Humans; Leukemia, Lymphoid; Male; Middle Aged; Neutropenia; Pentostatin; Polymerase Chain Reaction

Myelodysplastic syndromes (MDS) have rarely been reported after treatment with nucleoside analogues, and mainly in patients who have also received alkylating agents. We report a patient who developed MDS (refractory anaemia with ring sideroblasts) after treatment with pentostatin (deoxycoformycin) alone.

Topics: Adenosine Deaminase Inhibitors; Aged; Anemia, Refractory; Antibiotics, Antineoplastic; Blood Transfusion; Bone Marrow; Combined Modality Therapy; Enzyme Inhibitors; Hematopoietic Stem Cells; Humans; Leukemia, Hairy Cell; Male; Neutropenia; Pentostatin; Remission Induction

Fifty patients with hairy cell leukemia were treated with pentostatin (2'-deoxycoformycin; dCF) for a median of 3 months; 32 (64%) patients achieved complete remission (CR), and 10 (20%) patients achieved partial remission (PR), for an overall response rate of 84%. After reaching maximal response, no maintenance therapy was administered. The median duration of follow-up is now 39 months, and only four of 32 patients in CR and two of 10 patients in PR have relapsed. dCF therapy produces durable long-term, disease-free survival in patients with hairy cell leukemia.

Topics: Humans; Leukemia, Hairy Cell; Neutropenia; Pentostatin; Recurrence; Remission Induction; Survival Rate; Time Factors