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Blood, 1 October 2003, Vol. 102, No. 7, pp. 2315
PNAs for AML
The introduction of the purine nucleoside analogs (PNAs) including fludarabine, pentostatin, and cladribine, either alone or in combination with other agents, has produced durable remissions and cures of patients with the chronic lymphoproliferative disorders chronic lymphocytic leukemia and hairy cell leukemia.
These successes as well as preclinical studies suggested that the PNAs may also have a role in the treatment of acute myelogenous leukemia (AML). Synergistic interaction between the PNAs and the cytosine nucleoside analog, cytarabine, an active agent in AML, has also been demonstrated. Cladribine has been shown to produce a complete remission in 24% of newly diagnosed pediatric AML cases in a study by Krance et al.1 However, this activity was not duplicated in adults with AML in a study by Gordon et al2 where no complete remissions were achieved in 15 patients with relapsed or refractory AML and prolonged myelosuppression was noted. Fludarabine has been combined with cytarabine with or without the addition of granulocyte-colony stimulating factor (G-CSF) and/or an anthracycline, but retrospective studies have not clearly demonstrated an advantage of fludarabine-cytarabine regimens over traditional anthracycline-cytarabine combinations.3
Clofarabine (Cl-Fara-A, 2-chloro-2'-fluorodeoxy-9- -D-arabinofuranosyladenine) was synthesized over 10 years ago as a second-generation PNA to overcome some of the limitations and incorporate the best qualities of both fludarabine and cladribine. Clofarabine is structurally identical to cladribine except for the substitution of fluorine for a hydrogen atom at the C-2' position of the arabinofuranosyl moiety. A phase 1 study by Kantarjian et al4 of clofarabine established a phase 2 dose of 40 mg/m2 intravenously over 1 hour for 5 days for patients with acute leukemia. In this issue, Kantarjian and colleagues (page 2379) from MD Anderson Cancer Center report on a phase 2 trial of clofarabine in a group of 62 patients with relapsed and refractory AML (n = 31), myelodysplastic syndrome (MDS; n = 8), chronic myelogenous leukemia in blastic phase (CMLBP; n = 11), and acute lymphocytic leukemia (n = 12). Complete remissions were achieved in 20 patients (32%) and 9 patients had a complete remission without platelet recovery (CRp). In AML, higher responses were seen in patients with longer first complete remissions (7/8, 87%) and in patients in second or subsequent relapse (8/12, 67%). Responses were seen in 50% or more of patients with MDS and CMLBP but in only 2 of 12 patients with ALL. Severe but reversible liver dysfunction was noted in 15% to 25% of patients. The accumulation of clofarabine triphosphate in blast cells was greater in responding patients than nonresponders. This study suggested that clofarabine has significant activity in myeloid disorders. However, in contrast to these encouraging results, a recent multi-institutional trial of clofarabine by Foran et al5 produced only 1 CRp out of 29 evaluable patients.
In summary, the jury is still out on the ultimate role of PNAs in the therapy of AML in adults. Continued study of clofarabine and other PNAs in combination with other active agents should clarify their role in the treatment of patients with AML. Ultimately, to use a time-worn phrase, randomized trials will be required to definitively establish the role of these agents in AML treatment.
Mark R. Litzow
Mayo Clinic
References
- Krance RA, Hurwitz CA, Head DR, et al. Experience with 2-chlorodeoxyadenosine in previously untreated children with newly diagnosed acute myeloid leukemia and myelodysplastic diseases. J Clin Oncol. 2001;19: 2804-2811.[Abstract/Free Full Text]
- Gordon MS, Young ML, Tallman MS, et al. Phase II trial of 2-chlorodeoxyadenosine in patients with relapsed/refractory acute myeloid leukemia: a study of the Eastern Cooperative Oncology Group (ECOG), E5995. Leuk Res. 2000;24: 871-875.[Medline]
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- Estey EH, Thall PF, Cortes JE, et al. Comparison of idarubicin + ara-C-, fludarabine + ara-C-, and topotecan + ara-C-based regimens in treatment of newly diagnosed acute myeloid leukemia, refractory anemia with excess blasts in transformation, or refractory anemia with excess blasts. Blood. 2001;98: 3575-3583.[Abstract/Free Full Text]
- Kantarjian HM, Gandhi V, Kozuch P, et al. Phase I clinical and pharmacology study of clofarabine in patients with solid and hematologic cancers. J Clin Oncol. 2003;21: 1167-1173.[Abstract/Free Full Text]
- Foran JM, Faderl S, Wetzler M, et al. A phase II, open-label study of clofarabine in adult patients with refractory or relapsed acute myelogenous leukemia [abstract]. Proceedings ASCO. 2003;22: 587a.
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Related Article in Blood Online:
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Phase 2 clinical and pharmacologic study of clofarabine in patients with refractory or relapsed acute leukemia
- Hagop Kantarjian, Varsha Gandhi, Jorge Cortes, Srdan Verstovsek, Min Du, Guillermo Garcia-Manero, Francis Giles, Stefan Faderl, Susan O'Brien, Sima Jeha, Jan Davis, Zeev Shaked, Adam Craig, Michael Keating, William Plunkett, and Emil J Freireich
Blood 2003 102: 2379-2386.
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