Results of a phase 1-2 study of clofarabine in combination with cytarabine (ara-C) in relapsed and refractory acute leukemias

Faderl, Stefan; Gandhi, Varsha; O’Brien, Susan; Bonate, Peter L.; Cortes, Jorge; Estey, Elihu H.; Beran, Miloslav; Wierda, William G.; Garcia‐Manero, Guillermo; Ferrajoli, Alessandra; Estrov, Zeev; Giles, Francis J.; Du, Min; Kwari, Monica; Keating, Michael J.; Plunkett, William; Kantarjian, Hagop M.

doi:10.1182/blood-2004-05-1933

Cited by 206 publications

(165 citation statements)

References 28 publications

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“…Ten of these patients achieved CR1 after cycle 3 of induction chemotherapy. Cycle 4 induction chemotherapy was administered to two patients and both received the combination of clofarabine and ARA-C [13]. Both patients achieved CR1 after cycle 4 of induction chemotherapy.…”

Section: Patient Characteristicsmentioning

confidence: 99%

Inferior outcome after allogeneic transplant in first remission in high‐risk AML patients who required more than two cycles of induction therapy

Lim

Raptis

et al. 2015

American J Hematol

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While some patients with high-risk acute myeloid leukemia (AML) require one or two cycles of induction chemotherapy to achieve a complete remission (CR), others require more than two cycles. We examined the outcomes of patients with high-risk AML who received allogeneic HPC transplant in CR1. Forty five consecutive high-risk AML patients in CR1 were included. All 45 patients had adverse cytogenetics, FLT 3 mutations, or secondary AML. Group A patients (n 5 33) received one or two cycles, and Group B (n 5 12) three or more cycles of induction chemotherapy. The patients were comparable in age, sex, white cell count at presentation, and time from diagnosis and from last chemotherapy to transplant. The 100-day mortality rate was higher in Group B patients (50% vs. 9%, P 5 0.006). They had a higher non-relapse mortality (33% vs. 6%, P 5 0.035) and a longer length of hospital stay from the day of stem cell infusion (median 21 vs. 20, P 5 0.02; third quartile 22 vs. 28, P 5 0.02). There was also a trend toward inferior event-free survival and overall survival. High-risk AML patients undergoing allogeneic transplant in CR1 after three or more cycles of induction chemotherapy have an inferior outcome and higher mortality when compared to those who only needed one or two cycles of induction chemotherapy. Novel strategies are needed to reduce the transplant-related mortality in high-risk AML patients needing more than two cycles of induction chemotherapy prior to allogeneic transplant in CR1.

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Section: Patient Characteristicsmentioning

confidence: 99%

Inferior outcome after allogeneic transplant in first remission in high‐risk AML patients who required more than two cycles of induction therapy

Lim

Raptis

et al. 2015

American J Hematol

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“…3 Although novel agents such as Flt3 inhibitors and farnesyl transferase inhibitors are currently being investigated, the allogeneic BM SCT has been shown to deliver a sustained graft-vstumour effect against chemotherapy-resistant leukaemic stem cell clones. [4][5][6][7] The benefit of this reduced relapse risk is often negated by significant non-relapse mortality, the major causes being GVHD, infection and diffuse alveolar damage. 4,8 Reduced-intensity conditioning (RIC) regimens have been developed that allow stable engraftment and low non-relapse mortality allowing allografting to be feasible in older patients.…”

Section: Introductionmentioning

confidence: 99%

Alemtuzumab markedly reduces chronic GVHD without affecting overall survival in reduced-intensity conditioning sibling allo-SCT for adults with AML

Malladi

Peniket

Littlewood

et al. 2008

Bone Marrow Transplant

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By retrospective analysis of 88 patients from the British Society of Blood and Marrow Transplantation registry, we investigated the effect of in vivo T-cell depletion in HLA-identical sibling reduced-intensity conditioning (RIC) allografts for adult AML by comparing patients who received alemtuzumab with those without alemtuzumab conditioning. Both groups were equivalent for age, sex, karyotype and disease status at transplant. With a median follow-up of 27 months (3-72 months) and 48 months (7-72 months), the 2-and 5-year overall survival, with or without alemtuzumab, is 60 and 60% (P ¼ 0.80) and 61 and 53%, respectively (P ¼ 0.85). The 2-year nonrelapse mortality is 12% with alemtuzumab, and 17% without alemtuzumab (P ¼ 0.49). The 2-year relapse rate is 35% with alemtuzumab compared with 19% without alemtuzumab (P ¼ 0.28). Grades II-IV acute GVHD occurred in 22% (8/37) without alemtuzumab compared with 14% (7/51) given alemtuzumab (P ¼ 0.25). Extensive chronic GVHD occurred in 47% (14/30) not given alemtuzumab compared with 4% (2/45) who were given alemtuzumab (P ¼ 0.001). Among evaluable patients, the risk of infections was higher in those treated with alemtuzumab compared with those not treated with alemtuzumab (79 vs 57%, respectively, P ¼ 0.02). In conclusion, alemtuzumab has a beneficial effect by reducing chronic GVHD without affecting overall survival. Further studies are warranted before alemtuzumab can be recommended as standard in RIC allografts for AML.

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“…The first study of clofarabine plus cytarabine was designed as a combined Phase I and II study in adults with acute leukemias and high-risk MDS who either were in first recurrence or who were primary refractory to the respective induction regimen. 41 The cytarabine dose of 1 g/m 2 per day intravenously on Days 2-5 remained constant; clofarabine was dose escalated during the Phase I part starting at 15 mg/m 2 intravenously daily on Days 2-6 and proceeding through dose levels of 22.5 mg/m 2 , 30.0 mg/m 2 , and 40.0 mg/m 2 . Because no DLTs occurred during the Phase I component, an ara-C dose of 1 g/m 2 and a clofarabine dose of 40 mg/m 2 were recommended for Phase II studies.…”

Section: Development Of Clofarabine In Acute Leukemias and Myelodysplmentioning

confidence: 99%

The role of clofarabine in hematologic and solid malignancies—Development of a next‐generation nucleoside analog

Faderl

Gandhi

Keating

et al. 2005

Cancer

Self Cite

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Clofarabine is a new-generation nucleoside analog that has been synthesized to combine the most favorable pharmacokinetic properties of its congeners fludarabine and cladribine. In addition to inhibition of DNA polymerases and DNA synthesis, clofarabine acts as a strong inhibitor of ribonucleotide reductase (RnR), an enzyme involved in regulating intracellular deoxynucleotide pools, and has a high affinity to the enzyme deoxycytidine kinase (dCyd), the rate-limiting step in nucleoside phosphorylation.A review of the English literature was performed that included original articles and related reviews from the MEDLINE (PubMed) data base and from abstracts based on the publication of meeting materials.Although it was synthesized early in the 1980s, the development of clofarabine was stalled until

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Results of a phase 1-2 study of clofarabine in combination with cytarabine (ara-C) in relapsed and refractory acute leukemias

Cited by 206 publications

References 28 publications

Inferior outcome after allogeneic transplant in first remission in high‐risk AML patients who required more than two cycles of induction therapy

Inferior outcome after allogeneic transplant in first remission in high‐risk AML patients who required more than two cycles of induction therapy

Alemtuzumab markedly reduces chronic GVHD without affecting overall survival in reduced-intensity conditioning sibling allo-SCT for adults with AML

The role of clofarabine in hematologic and solid malignancies—Development of a next‐generation nucleoside analog

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