Fludarabine induced immune thrombocytopenia in a patient with CD5 positive B cell chronic lymphocytic leukemia (original) (raw)
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Blood, 1999
B-chronic lymphocytic leukemia (B-CLL) is characterized by the accumulation of long-lived CD5+ B lymphocytes. We have analyzed the effect in vitro of the combination of fludarabine with cyclophosphamide and/or mitoxantrone on cells from 20 B-CLL patients. Mafosfamide, the active form of cyclophosphamide in vitro, increased the cytotoxicity of fludarabine in all of the patients studied and produced a significant synergistic effect (P < .01) after 48 hours of incubation. The addition of mitoxantrone to this combination increased the cytotoxic effect in cells from 8 patients, but in the remaining 12 patients no significant increase was observed. The effect of fludarabine and mafosfamide was dose-dependent. Mafosfamide and fludarabine had a synergistic effect in inducing apoptosis of B-CLL cells as determined by DNA staining with propidium iodide and analysis of phosphatidylserine exposure. Mafosfamide significantly increased the apoptosis induced by fludarabine on CD19+ cells (P = ....
Fludarabine Combination Therapy for the Treatment of Chronic Lymphocytic Leukemia
Clinical Lymphoma, 2002
Fludarabine combination therapies have attained an increased popularity in the treatment of chronic lymphocytic leukemia (CLL). Among them, the combination of fludarabine/cyclophosphamide (FC) is by far the best regimen studied. Patients receiving FC at relapse show response rates (RRs) of 70%-94% with 11%-34% complete remission (CR) rates. In previously untreated patients with CLL, RRs of 64%-88% with 21%-46% CR rates were observed. The main side effects of FC are myelotoxicity and infections; most complications are reported as fever of unknown origin, infections of the upper respiratory tract, or herpes virus infection. There is probably a correlation between the higher dose of cyclophosphamide (> 750 mg/m 2 per treatment course) and an increase in the number of severe infectious complications. Similar results were reported regarding the RRs and side effects of the combination of fludarabine/epirubicin. The triple combination of fludarabine/cyclophosphamide/mitoxantrone and fludarabine combinations with anti-CD20 (rituximab) or anti-CD52 (Campath-1H) antibody, might be even be more promising, since a relevant number of complete molecular remissions are achieved with these drugs. The precise role of fludarabine combinations within the overall treatment strategy remains to be determined. Our current recommendation is to use these combinations at relapse, while their use in first-line therapy should be investigated in clinical protocols. It remains to be shown whether patients with CLL achieve improved overall survival with these combination chemotherapies.
Leukemia Lymphoma, 2010
Therapy related myelodysplastic syndrome (t-MDS) and secondary acute myeloid leukemia (AML) are seriously late complications of the use of alkylating agents, topoisomerase II inhibitors, and other chemotherapies. Deoxyribonucleic acid (DNA) damage that leads to chromosomal deletions or balanced translocations partly cause t-MDS. Deletions of chromosomes 5 and 7 are also commonly found in alkylator-associated MDS/AML. Over the last half decade, fludarabine has been widely used as frontline therapy for indolent B-cell lymphomas and chronic lymphocytic leukemia (CLL). The incidence of t-MDS/AML following fludarabine-based therapies is 0.5%, 3.5%, 9%, and 2% of patients receiving treatment with fludarabine alone, fludarabine plus chlorambucil, fludarabine combined with cyclophosphamide, and the combination of rituximab, fludarabine, and cyclophosphamide, respectively [1,2]. Nevertheless, the risk factor for fludarabine-induced t-MDS/AML has not been established. We therefore performed a retrospective study to analyze the predicting factors for t-MDS/AML in patients with B-cell lymphomas and CLL treated with fludarabinebased therapy.
Experimental Hematology, 2009
Objective. Fludarabine has been recognized as effective treatment in patients with follicular lymphoma (FL), but can induce myelotoxicity of unknown mechanism. Materials and Methods. Myelotoxicity was assessed by cultivation of two types of hematopoietic progenitor cells: colony-forming units granulocyte-macrophage (CFU-GM) and longterm culture-initiating cells (LTC-IC). Pretreatment amounts of CFU-GM and LTC-IC were correlated to age, gender, stage of disease, bone marrow involvement, and previous therapy. Posttreatment comparison of CFU-GM and LTC-IC was performed after different regimens of chemotherapy: fludarabine-based (FND ± R), procarbazine-based (COPP ± R), and CHOP(cyclophosphamide, doxorubicin, vincristine, prednisone) ± R(Rituximab). Results. One-hundred patients (median age 55 years; 21 patients relapsed) treated for FL were analyzed. The total number of progenitor hematopoietic cells in both types of cultures varied in wide ranges; for LTC-IC between 0 and 874 cells/mL with a median of 77.71 cells/mL and for CFU-GM between 0 and 531 3 10 2 cells/mL with a median of 30.58 3 10 2 cells/mL. Bone marrow involvement, gender, stage of disease, or previous therapy had no influence on LTC-IC and CFU-GM counts. We identified an increase in LTC-IC, but not CFU-GM, associated with age (p [ 0.01). Median figures for CFU-GM and LTC-IC were found to be significantly lower after FND ± R and COPP ± R than after CHOP ± R therapy, compared to baseline values (p ! 0.01). Conclusions. Fludarabine and procarbazine have a dramatic influence, especially on the most immature hematopoietic cells, mirrored in reduced numbers of LTC-IC. This finding is consistent with clinical observations (poor mobilization after fludarabine) and offers an insight into the mechanism of fludarabine-induced myelotoxicity. Ó
British Journal of Haematology, 2002
We evaluated the efficacy and toxicity of fludarabine combined with cyclophosphamide and mitoxantrone (FCM) in patients with relapsed or resistant chronic lymphocytic leukaemia (CLL). In total, 37 patients with recurrent or resistant CLL received FCM: fludarabine 25 mg/m 2 intravenously (IV), d 1-3; cyclophosphamide 200 mg/m 2 IV, d 1-3; and mitoxantrone 6 mg/m 2 IV, d 1, at 4-week intervals for up to six courses. Moreover, 23 patients received FCM with cyclophosphamide 600 mg/m 2 i.v. and mitoxantrone 8 mg/m 2 i.v. on d 1. In addition to clinical methods, response was assessed using cytofluorometric and molecular techniques. ÔIn vitroÕ sensitivity to the FCM regimen was also analysed in 20 samples. The median number of courses given was 3 (range: 1-6). Overall, 30 patients (50%) achieved complete response (CR), including 10 cases of negative minimal residual disease (MRD(-)) (17%), and 17 (28%) partial response (PR). The median duration of response was 19 months. ÔIn vitroÕ sensitivity also correlated with CR achievement (P ¼ 0AE04). Main toxicity consisted of neutropenia, infections (8% of courses), and nausea and vomiting. The treatment-related mortality was 5%. FCM did not hamper stem cell harvesting in patients who were candidates for autologous stem cell transplantation. FCM induced a high CR rate, including an important number of MRD(-), in patients with previously treated CLL.
Blood, 2002
Fludarabine can exacerbate idiopathic thrombocytopenia (ITP) in chronic lymphocytic leukemia (CLL). We report 3 CLL patients with refractory fludarabine-associated ITP who responded to rituximab. The patients had Rai stages III, III, and IV disease. Before fludarabine treatment, the platelet counts were 141 000/microL, 118 000/microL, and 70 000/microL. ITP developed within week 1 of cycle 3 in 2 patients and within week 2 of cycle 1 in 1 patient. Platelet count nadirs were 4000/microL, 1000/microL, and 2000/microL, respectively, and did not respond to treatment with steroids or intravenous immunoglobulin. Rituximab therapy (375 mg/m(2) per week for 4 weeks) was begun on days 18, 23, and 20 of ITP. Patient 1 achieved a platelet count of more than 50 000/microL at day 21 and more than 133 000/microL at day 28, patient 2 achieved a platelet count of more than 50 000/microL at day 4 and more than 150 000/microL at day 10, and patient 3 achieved a platelet count of more than 50 000/micr...
Biomedicine & Pharmacotherapy, 2011
Fludarabine combination chemotherapy achieves high response rates in chronic lymphocytic leukemia (CLL) and indolent lymphoma. The aim of this study was to investigate the incidence and characteristics of treatment-related myelodysplasia and acute myeloid leukemia (t-MDS/AML) after treatment with fludarabine in combination for lymphoproliferative disorders and identify risk factors for its development. In all, 176 patients treated with fludarabine combination were followed for a median of 41 months (range 6-125 months). In all, 19 cases of t-MDS/AML have been identified for an overall rate of 10.8%. Median overall survival post-t-MDS/AML diagnosis was 11 months. Patients developing t-MDS/AML included 11/54 with follicular lymphoma (FL) (crude rate 20.4%), 5/82 with CLL (6.1%) and 3/24 with Waldenstrom macroglobulinemia or marginal zone lymphoma (12.5%). Most patients had other cytotoxic treatments (median 4, range 0-7) but three with FL had fludarabine combination as their only line of treatment. Of the eleven patients (6.3%) who received mitoxantrone with their first fludarabine combination, four (36.4%) developed t-MDS/AML (P ¼ 0.007). There was a trend toward prior cytotoxic therapy increasing the risk for t-MDS/AML (P ¼ 0.067). Fludarabine combination chemotherapy is associated with a moderate risk of t-MDS/AML particularly when combined with mitoxantrone. This complication should be considered when evaluating the potential benefit of this treatment in lymphoproliferative disorders.