Therapy-Related Myeloid Leukemias Are Observed in Patients With Chronic Lymphocytic Leukemia After Treatment With Fludarabine and Chlorambucil: Results of an Intergroup Study, Cancer and Leukemia Group B 9011

Morrison, Vicki A.; Kanti, R.; Peterson, Bercedis L.; Kolitz, Jonathan E.; Elias, Laurence; Appelbaum, Frederick R.; Hines, John; Shepherd, Lois E.; Larson, Richard A.; Schiffer, Charles A.

doi:10.1200/jco.2002.08.128

Cited by 166 publications

(124 citation statements)

References 28 publications

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“…24,25 Despite potent myelosuppression, therapyrelated myeloid neoplasms secondary to fludarabine single-agent treatment is extremely rare, reported 0 in 174 (0%) and 1 in 188 (0.5%) in two studies conducted on chronic lymphocytic leukemia/small lymphocytic lymphoma patients who received fludarabine as initial therapy with a long-term followup. 26,27 However, the incidence of therapy-related myeloid neoplasms is significantly higher in the setting of fludarabine combination therapy. [13][14][15][16]26,28 It has been postulated that fludarabine inhibits DNA repair 29 and acts synergistically with DNA-damaging agents, such as cyclophosphomide.…”

Section: Therapy-related Myeloid Neoplasm Post Fcrmentioning

confidence: 99%

“…26,27 However, the incidence of therapy-related myeloid neoplasms is significantly higher in the setting of fludarabine combination therapy. [13][14][15][16]26,28 It has been postulated that fludarabine inhibits DNA repair 29 and acts synergistically with DNA-damaging agents, such as cyclophosphomide. As a result, genetically altered stem cells may escape DNA integrity check and gain survival advantage in the setting of genotoxic therapy.…”

Section: Therapy-related Myeloid Neoplasm Post Fcrmentioning

confidence: 99%

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Therapy-related myeloid neoplasms following fludarabine, cyclophosphamide, and rituximab (FCR) treatment in patients with chronic lymphocytic leukemia/small lymphocytic lymphoma

et al. 2012

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This study is focused on therapy-related myeloid neoplasms after the most promising frontline FCR (fludarabine, cyclophosphamide, and rituximab) therapy in previously untreated chronic lymphocytic leukemia patients. A total of 28 therapy-related myeloid neoplasm patients were identified, including 19 patients from 3 well-controlled FCR frontline trials (n ¼ 426 patients), giving an estimated frequency of 4.5% (1.9-8.3%) in a follow-up period of 44 months (range 5-122 months). Clinically, therapy-related myeloid neoplasms could emerge directly from 'prolonged myelosuppression' after FCR (10 patients), or after achieving complete hematological recovery (n ¼ 18). The overall latency was 35 months (range 3-118 months), with the former group of 23 months and the latter 42 months (Po0.001). In all, 10 cases presented as therapy-related acute myeloid leukemia and 18 as therapy-related myelodysplastic syndromes. Abnormal cytogenetics was present in 26 of 27 (96%) patients, with frequent chromosomes 5 and 7 abnormalities. The median survival was 7 months after therapy-related myeloid neoplasms. Our results indicate that the risk of therapy-related myeloid neoplasms secondary to frontline FCR therapy may not be as high as previously reported after removing the confounding factor of previous cytotoxic exposure, but this risk increased with older age and likely growth factor co-administration. Therapy-related myeloid neoplasms after FCR therapy shares clinicopathological features with therapy-related myeloid neoplasms secondary to other alkylating agents, but has a shorter latency interval indicating possible synergetic effects of the nucleotide analog fludarabine. The fact that therapy-related myeloid neoplasms can directly emerge from 'prolonged myelosuppression' warrants a bone marrow examination to rule out therapy-related myeloid neoplasms in this clinical setting.

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Section: Therapy-related Myeloid Neoplasm Post Fcrmentioning

confidence: 99%

Section: Therapy-related Myeloid Neoplasm Post Fcrmentioning

confidence: 99%

Therapy-related myeloid neoplasms following fludarabine, cyclophosphamide, and rituximab (FCR) treatment in patients with chronic lymphocytic leukemia/small lymphocytic lymphoma

et al. 2012

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“…1 Exposure to fludarabine may increase the risk of subsequent t-MDS/ AML. [2][3][4][5] Fludarabine is an effective treatment for follicular lymphoma (FL). In combination with mitoxantrone and dexamethasone as frontline therapy, fludarabine induced at least a PR in 96% of patients and a CR in 68%.…”

Section: Introductionmentioning

confidence: 99%

Fludarabine as a risk factor for poor stem cell harvest, treatment-related MDS and AML in follicular lymphoma patients after autologous hematopoietic cell transplantation

Waterman

Rybicki

Bolwell

et al. 2011

Bone Marrow Transplant

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Fludarabine is an effective treatment for follicular lymphoma (FL), but exposure to it negatively impacts stem cell mobilization and may increase the risk of subsequent myelodysplastic syndrome and acute myelogenous leukemia (t-MDS/AML). We hypothesized that the risk that fludarabine imparts to stem cell mobilization and t-MDS/AML would be affected by dose or timing. All patients with FL treated at Cleveland Clinic from 1991 to 2007 with autologous hematopoietic cell transplantation were evaluated. Recursive partitioning analysis was used to explore associations of fludarabine and mitoxantrone dose and timing with poor stem cell harvest and t-MDS/ AML. We identified 171 patients, of whom 52 previously received fludarabine. Patients exposed to fludarabine prior to auto-HCT were more likely to require 45 days of leukapheresis (Po0.001) and second stem cell mobilization (Po0.001), especially at a cumulative dose 4150 mg/m 2 . Univariable risk factors for t-MDS/AML included the number of chemotherapy regimens before auto-HCT, the need for 45 days of leukapheresis to collect CD34 þ cells and fludarabine exposure in a dosedependent manner, particularly when 4500 mg/m 2 . A cumulative dose of fludarabine 4150 mg/m 2 increases the risk for poor stem cell harvests and any exposure increases the risk of t-MDS/AML, with the greatest risk being at doses 4500 mg/m 2 .

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“…A recent analysis performed by Morrison et al 49 revealed another potential adverse effect associated with fludarabine. In patients with CLL, those investigators observed an increased incidence of secondary myelodysplastic syndromes (t-MDS) following treatment with fludarabine (either alone or in combination with chlorambucil).…”

Section: Toxicitymentioning

confidence: 99%

The role of fludarabine in the treatment of follicular and mantle cell lymphoma

Lenz

Hiddemann

Dreyling

2004

Cancer

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Therapy-Related Myeloid Leukemias Are Observed in Patients With Chronic Lymphocytic Leukemia After Treatment With Fludarabine and Chlorambucil: Results of an Intergroup Study, Cancer and Leukemia Group B 9011

Abstract: Our findings raise the possibility that alkylator-purine analog combination therapy may increase the risk of therapy-related myeloid malignancies, which is of particular relevance with regard to ongoing trials using these combination therapies.

Cited by 166 publications

References 28 publications

Therapy-related myeloid neoplasms following fludarabine, cyclophosphamide, and rituximab (FCR) treatment in patients with chronic lymphocytic leukemia/small lymphocytic lymphoma

Therapy-related myeloid neoplasms following fludarabine, cyclophosphamide, and rituximab (FCR) treatment in patients with chronic lymphocytic leukemia/small lymphocytic lymphoma

Fludarabine as a risk factor for poor stem cell harvest, treatment-related MDS and AML in follicular lymphoma patients after autologous hematopoietic cell transplantation

The role of fludarabine in the treatment of follicular and mantle cell lymphoma

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