pentostatin and Opportunistic-Infections

Patients with hairy cell leukaemia (HCL) have highly favourable outcomes after purine analogue therapy. However, most patients subsequently relapse and require re-treatment. A minority of patients develop purine analogue-refractory disease. Targeted therapies have improved outcomes for such patients. Recently, the BRAF V600E mutation was identified in most patients with classical HCL, resulting in constitutive mitogen-activated protein kinase pathway activation; impressive responses are achieved in heavily pre-treated patients with BRAF inhibition. The CD22-targeted immunoconjugate moxetumomab pasudotox and BTK inhibitor ibrutinib also achieve responses in relapsed and refractory patients. HCL variant and the IGHV4-34 molecular variant of HCL lack BRAF mutation and have inferior outcomes with standard purine analogue therapy. The addition of rituximab to purine analogues achieves very high rates of minimal residual disease-negative complete remission and improves outcomes for patients with HCL variant. Given the rarity of HCL, optimal integration of novel therapies into treatment algorithms will require well-designed, collaborative studies.

Topics: Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Cladribine; Diagnosis, Differential; Humans; Immunologic Factors; Interferon-alpha; Leukemia, Hairy Cell; Mutation; Opportunistic Infections; Pentostatin; Proto-Oncogene Proteins B-raf; Purine Nucleosides; Rituximab; Social Support; Splenectomy; Treatment Outcome

Pentostatin (Nipent; SuperGen, San Ramon, CA) is a safe and well-tolerated medication but, like all chemotherapeutic agents, it may be associated with some toxicity. The toxicity seen with pentostatin is dose and schedule dependent and can be minimized by appropriate dosing. The dose of pentostatin should never exceed 4 mg/m2. A dose reduction is required for patients with renal insufficiency. Renal and neurological toxicities may occur, yet are uncommon with appropriate dosing. Nausea and vomiting also occur; however, they are usually controlled with antiemetic therapy. Like the other purine nucleoside analogs, pentostatin is an immunosuppressive drug that may increase the risk of infection, especially with opportunistic organisms. Prophylactic antibiotics should be considered when treating patients with pentostatin.

Topics: Antibiotic Prophylaxis; Antibiotics, Antineoplastic; Antiemetics; Dose-Response Relationship, Drug; Drug Administration Schedule; Humans; Immunosuppressive Agents; Kidney; Nausea; Nervous System; Opportunistic Infections; Pentostatin; Vomiting

Both recombinant interferon alpha and deoxycoformycin (dCF) are effective in the treatment of hairy cell leukaemia. In an attempt to reduce the complications from dCF therapy, a pilot study of the Eastern Cooperative Oncology Group (ECOG) first treated patients with interferon to improve peripheral blood cell counts before dCF treatment began. Thirty-four patients were treated for 3 months with recombinant interferon alpha-2a (rIFN alpha-2a), 3 x 10(6) IU subcutaneously three times a week for 3 months, and then by dCF, 4 mg/m2 intravenously every 2 weeks for a maximum of 12 months. The overall response rate was 94% (32/34); 76% of patients (26/34) had complete response (CR) (90% confidence interval, 62-88%) and 18% (6/34) partial response. One patient was found to have a Mycobacterium avium infection while receiving rIFN alpha-2a. Without specific antimycobacterial therapy and with continued administration of rIFN alpha-2a and dCF, the infection resolved and he achieved CR. Three patients had culture-negative febrile episodes during the dCF phase of treatment. Non-disseminated herpes zoster developed in four patients, but three of the episodes occurred only after treatment was discontinued. Sequential administration of rIFN alpha-2a and dCF resulted in fewer infections (P = 0.027) than in ECOG's previous study of dCF used alone. Two patients died, one of combined hairy cell leukaemia and non-Hodgkin's lymphoma of intermediate histologic type 17 months after entry into the study and the other of cardiac arrest 20 months after entry. Thirty-two patients were alive with a median follow-up of 21 months (range 13-31 months). This combination produces durable CRs with a low incidence of infection.

Topics: Adult; Aged; Blood Cell Count; Combined Modality Therapy; Drug Evaluation; Female; Humans; Interferon alpha-2; Interferon-alpha; Leukemia, Hairy Cell; Male; Middle Aged; Opportunistic Infections; Pentostatin; Recombinant Proteins

Between March 1992 and August 1993, thirty patients with hairy cell leukemia (HCL) were treated in a single institution with 2-chlorodeoxyadenosine (2-CdA) for one course (N=27) or two courses at six month interval (N=3). Sixteen patients were previously untreated, 14 had been treated with alpha interferon (alpha IFN) (N=5), alpha IFN and splenectomy (N=8) and splenectomy, alpha IFN and Deoxycoformycin (N=1). Overall results in 29 evaluable patients were: 25 CR (86%), 3 PR (10%), one failure. The three PR patients relapsed after 18, 24 months and five years. Two were retreated successfully. Two CR patients relapsed after five years. Careful clinical survey, sequential bone marrow biopsies (BMB) with DBA44 immunostaining for assessment of response and detection of residual disease and serially evaluation of lymphocyte subsets counts were performed. Results of bone marrow biopsies study show 1) a progressive reduction in hairy cell infiltration during the first six months after therapy and not after that indicating that the best moment for the evaluation of response may be the sixth month, 2) the persistence of a very small number of DBA44+ cells (80% of BMB). There was a correlation between the presence of > 5% DBA44 positive cells on 6th month BMB and relapse. 60% had an absolute CD4+ lymphocyte count less than 0.2 10(9)/l at least on one examination after treatment. CD4+ lymphocyte level persisted less than baseline level in 8/18 patients tested after four and/or five years. Lymphopenia was less marked in splenectomized patients: 7/7 splenectomized patients tested have recovered a CD4+ lymphocyte count equal to pretherapy level compared to 3/11 non splenectomized patients (p: 0.004). Three opportunistic infections were observed early (first 6 months) after 2CdA therapy: pneumocystis pneumonia, retinitis due to toxoplasma in the patient who failed and legionella pneumonia in a patient retreated after relapse. Two patients developed a second carcinoma 6 and 12 months after therapy. Five patients died, three from a cause unrelated to HCL, one from HCL and one from infection while in second CR. At five years, overall survival is 83% and progression free survival is 66%. Our study shows 1) long-lasting response in the majority of patients after 2-CdA, 2) a correlation between persistent minimal residual disease detected with DBA44 immunostaining and occurrence of relapse and 3) a profound and persistent CD4+ lymphopenia more marked in non splenectomized patie

Topics: Adult; Aged; Aged, 80 and over; Antimetabolites, Antineoplastic; Bone Marrow; CD4 Lymphocyte Count; Cladribine; Combined Modality Therapy; Disease Progression; Disease-Free Survival; Female; Follow-Up Studies; Humans; Infections; Interferon-alpha; Leukemia, Hairy Cell; Male; Middle Aged; Neoplasm, Residual; Neoplasms, Second Primary; Opportunistic Infections; Pentostatin; Remission Induction; Splenectomy; Survival Rate