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Hagop M Kantarjian - One of the best experts on this subject based on the ideXlab platform.
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Clofarabine in the treatment of myelodysplastic syndromes.
Expert opinion on investigational drugs, 2014Co-Authors: Jeffrey Bryan, Hagop M Kantarjian, Hillary Prescott, Elias JabbourAbstract:Introduction: Clofarabine is a second-generation purine nucleoside analog approved in 2004 for the treatment of pediatric patients with relapsed or refractory acute lymphocytic leukemia (ALL) following failure of at least two prior regimens. Clofarabine is a hybrid of fludarabine and cladribine, designed to overcome the pharmacologic limitations associated with its predecessors, while retaining their beneficial properties. In addition to providing a valuable treatment option for pediatric patients with ALL, Clofarabine alone and in combination with cytarabine (Ara-C) has demonstrated substantial activity against myelodysplastic syndrome (MDS), thus rendering this agent a potential therapeutic option for MDS. Areas covered: This review focuses on the pharmacology and clinical activity of Clofarabine in MDS, as well as its emerging role in the treatment of MDS. Publications in English were selected from the MEDLINE (PubMed) database, as well articles of interest from bibliographies and abstracts based on th...
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Clofarabine plus low dose cytarabine induction followed by Clofarabine plus low dose cytarabine alternating with decitabine consolidation in acute myeloid leukemia frontline therapy for older patients
Blood, 2013Co-Authors: Aziz Nazha, Guillermo Garciamanero, Alessandra Ferrajoli, Farhad Ravandi, Xuelin Huang, Hagop M Kantarjian, Xuemei Wang, Elias Jabbour, Tapan M Kadia, Marina KonoplevaAbstract:Background The outcome of elderly patients (pts) with acute myeloid leukemia (AML) treated with currently available therapies remains unsatisfactory. Clofarabine has single agent activity in AML. The combination of Clofarabine with low-dose cytarabine produced higher response rates with a comparable safety profile compared with single-agent Clofarabine. We previously reported a phase II study of Clofarabine + low dose cytarabine followed by prolonged consolidation with clorarabine + low dose cytarabine alternating with decitabine in elderly patients with newly diagnosed AML (Faderl, Cancer 2012). The complete remission (CR) rate was 58%. With median follow up of 31.2 months, the median overall survival (OS) was 12.7 months, and the median relapse free survival was 14.1months. The combination was well tolerated with induction mortality of 3% (Early Death <28 Days), 7% at 8-weeks. Here we report the result with a larger patient population and longer follow up. Material and Methods Pts were eligible if they were >/= 60 years of age with newly diagnosed AML (based on World Health Organization [WHO] criteria) or high-risk myelodysplastic syndrome (MDS; >/=10% blasts or >/= intermediate-2 by the International Prognostic Scoring System) with Eastern Cooperative Oncology Group (ECOG) performance status of 40%). Induction therapy consisted of Clofarabine 20 mg/m2 IV daily X 5 days (1-5) plus cytarabine 20 mg subcutaneously (SC) twice daily (BID) X10 days (1-10). All responses were defined as per IWG criteria (2003). Pts who did not achieve a CR could receive 1 re-induction cycle at the same dose after at least 28 days from C #1. Pts could receive up to 17 cycles of consolidation therapy. Consolidation was administered in blocks of 3 cycles where Clofarabine 20 mg/m2 IV daily X 3 days (1-3) plus cytarabine 20 mg SC BID X 7 days (1-7) alternated with decitabine 20 mg/m2IV X5 days (1-5). Consolidation cycles were repeated every 4 to 7 weeks depending on hematopoietic recovery. Results Between 10/21/08 and 10/17/2011, a total of 118 patients were enrolled. The clinical characteristics are summarized in [Table 1][1]. The overall response rate (ORR) was 68% (71 [60%] CR, 9 [8%] CRp/CRi). Twenty two (19%) pts required re-induction, 16 (73%) achieved a response (12 achieved CR, 2 CRp, and 2 CRi). Median number of cycles received was 3 (range, 1-19). With median follow up of 31.2 months (range, 9.5-53.9), the median OS was 11.1 (range, 0.2-53.9), EFS 7.7 (range, 0.2-49.5), and relapse-free survival (RFS) 15.9 months (range, 0.3-48.3). The median OS among the responders was 21.1 months (range, 1.3-53.9). Four-week mortality was 3% and 8-week mortality 8%. Adverse events were predominantly grade 2 or less and included (>/= 10%): elevated liver enzymes (53%), elevated bilirubin (42%), diarrhea (19%), nausea (81%), rash (54%), hand and foot syndrome (10%), and elevated creatinine (10%). Grade 3 or more toxicities included: elevated creatinine (3%), rash (2%), vomiting (1%), and hand and foot syndrome (1%). No unexpected toxicities were observed. View this table: Table 1 Patient characteristics Conclusion Clofarabine plus low-dose cytarabine followed by prolonged consolidation alternating with decitabine is an active regimen with an ORR of 73% in older patients with newly diagnosed AML and high risk MDS. The regimen was well tolerated with low induction mortality. A randomized trail to compare this combination to best available therapy is needed to further asses the role of this combination in the treatment paradigm of elderly patients with AML. Disclosures: Off Label Use: Clofarabine and decitabine use in AML. Faderl: Sanofi-Aventis: Consultancy, Membership on an entity’s Board of Directors or advisory committees, Research Funding. [1]: #T1
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Clofarabine does not negatively impact the outcomes of patients with acute myeloid leukemia undergoing allogeneic stem cell transplantation
Clinical Lymphoma Myeloma & Leukemia, 2013Co-Authors: Michael S Mathisen, Stefan Faderl, Guillermo Garciamanero, Farhad Ravandi, Gautam Borthakur, Hagop M Kantarjian, Elias Jabbour, Jorge E. Cortes, Alfonso QuintascardamaAbstract:Abstract Background Clofarabine is actively being investigated as a component of frontline chemotherapy for acute myeloid leukemia (AML). Hepatotoxicity is 1 of the primary adverse events associated with Clofarabine and can occasionally can include severe venoocclusive disease (VOD). Patients and Methods Many patients with AML undergo allogeneic stem cell transplantation (allo-SCT), a procedure that is also associated with hepatotoxicity. We identified AML patients undergoing allo-SCT and stratified them according to whether they received Clofarabine-containing (Clofarabine, idarubicin, and cytarabine [CIA]) or non–Clofarabine-containing cytarabine-based induction/consolidation chemotherapy (idarubicin and cytarabine [ara-C] [IA]). We compared both groups for differences in posttransplantation hepatotoxicity, VOD, and other transplantation outcomes. Forty-two patients were identified (20 receiving CIA and 22 receiving IA). Patient and transplant characteristics were similar. All patients receiving Clofarabine-based treatment received CIA within 2.5 months of their allo-SCT. Results There was no difference in the incidence of VOD in the 30 days after transplantation (0 CIA, 1 IA; P = 1.0). Rates of grade 3/4 hepatotoxicity also did not differ between groups. Acute graft-versus-host disease (GVHD), early relapse, and survival were also not significantly different. Conclusions We conclude that Clofarabine-containing chemotherapy does not adversely impact the outcome of allo-SCT. Specifically, it does not predispose patients to an increased risk of hepatotoxicity, VOD, GVHD, or relapse.
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advanced leukemia Clofarabine, a novel nucleoside analog, is active in pediatric patients with
2013Co-Authors: Mark Brandt, Varsha Gandhi, Sima Jeha, Hagop M Kantarjian, M. J. Keating, W. Plunkett, Ka Wah Chan, Lisa Mcdonald, Irma Ramirez, Renee MaddenAbstract:ABSTRACTBackground: Despite progress in leukemia therapy, most children who relapse have a dismal prognosis. New effective approaches are needed. We conducted a Phase I study of the novel nucleoside analog Clofarabine in pediatric patients with refractory and relapsed leukemia. Methods: Clofarabine was infused intravenously over one hour daily for 5 days. Six dose levels between 11.25 and 70 mg/m 2 /day for five days were studied in 25 patients. A modified 3 + 3 phase I design was followed with 30% dose escalation until the dose-limiting toxicity (DLT) was defined. Results: The maximum tolerated dose (MTD) was 52 mg/m 2 /day x five days. At the end of infusion at MTD, Clofarabine triphosphate levels in leukemia blasts varied between 6 and 19∝ M, which resulted in complete and sustained inhibition of DNA synthesis. The DLT was reversible hepatotoxicity and skin rash at 70 mg/m 2 /day x 5. Twenty-five patients were treated. Five patients achieved a complete remission (CR) and three had a partial remission (PR), for an overall response rate of 32%. Conclusions: Clofarabine is well tolerated and shows significant antileukemic activity in heavily pretreated children. Multicenter phase II trials in pediatric acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML) are ongoing. Key Words: leukemia; Clofarabine; AML; ALL; nucleoside analogFrom bloodjournal.hematologylibrary.org by guest on June 4, 2013. For personal use only.
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The role of Clofarabine in acute myeloid leukemia.
Leukemia & lymphoma, 2012Co-Authors: Hady Ghanem, Hagop M Kantarjian, Maro Ohanian, Elias JabbourAbstract:Clofarabine is a second-generation purine nucleoside analog that has been synthesized to overcome the limitations and incorporate the best qualities of fludarabine and cladribine. Clofarabine acts by inhibiting ribonucleotide reductase and DNA polymerase, thereby depleting the amount of intracellular deoxynucleoside triphosphates available for DNA replication. Compared to its precursors, Clofarabine has an increased resistance to deamination and phosphorolysis, and hence better stability as well as higher affinity to deoxycytidine kinase (dCyd), the rate-limiting step in nucleoside phosphorylation. Since the initiation of the first phase I study of Clofarabine in 1993 in patients with hematologic and solid malignancies, Clofarabine has demonstrated single-agent antitumor activity in adult acute leukemia, including acute myeloid leukemia (AML). Due to its unique properties of biochemical modulation when used in combination with other chemotherapy drugs, mainly cytarabine, combination regimens containing Clofarabine have been evaluated. A review of the English literature was performed that included original articles and related reviews from the MEDLINE (PubMed) database and from abstracts based on the publication of meeting materials. This review describes the development, pharmacology and clinical activity of Clofarabine, as well as its emerging role in the treatment of adult patients with AML and myelodysplastic syndrome.
Stefan Faderl - One of the best experts on this subject based on the ideXlab platform.
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Clinical Use of Clofarabine for Adults and Children with Leukemia
Chemotherapy for Leukemia, 2017Co-Authors: James K. Mccloskey, Stefan Faderl, Jamie L. Koprivnikar, Dirk Reinhardt, Nobuko HijiyaAbstract:Clofarabine is a second-generation nucleoside analogue designed to be more effective than precursor nucleoside analogues such as fludarabine and cladribine. Early clinical studies of Clofarabine demonstrated its activity in hematologic malignancies, and Clofarabine was approved by the United States Food and Drug Administration (FDA) for the treatment of relapsed and refractory pediatric acute lymphoblastic leukemia (ALL) in 2004. Clofarabine has significant efficacy in adults and children with hematologic malignancies including ALL, acute myeloid leukemia (AML), and myelodysplastic syndrome (MDS). The unique biochemical modulation properties of Clofarabine when used in combination with other established antileukemic drugs also make it an appealing agent for use in combination therapy with purine nucleoside analogues or DNA-damaging agents; these combinations have been tested in a number of studies in patients with ALL or AML. In this chapter, we review the development of Clofarabine, the rationale and history of its use in combination regimens, and the potential roles and toxicities of these regimens in the treatment of adult and pediatric leukemias. The use of Clofarabine in conditioning regimens prior to stem cell transplantation and for histiocytosis is also discussed.
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phase i and extension study of Clofarabine plus cyclophosphamide in patients with relapsed refractory acute lymphoblastic leukemia
Clinical Lymphoma Myeloma & Leukemia, 2014Co-Authors: Stefan Faderl, Alessandra Ferrajoli, Deborah A. Thomas, Farhad Ravandi, Gautam Borthakur, Jorge E. Cortes, Kumudha Balakrishnan, Susan Obrien, Jan A Burger, Tapan M KadiaAbstract:Abstract Background Clofarabine is a nucleoside analogue with activity in children with acute lymphoblastic leukemia (ALL). Based on the hypothesis that Clofarabine inhibits DNA repair after exposure to DNA-damaging agents, we designed a phase I and extension study to evaluate the combination of Clofarabine and cyclophosphamide in adult patients with relapsed/refractory ALL. Methods The continual reassessment method (CRM) was used to define the maximum tolerated dose (MTD). Results Fifty patients with a median age of 30 years (range, 21-72 years) were enrolled, 30 of whom were part of the phase I group. Clofarabine 40 mg/m 2 intravenously daily × 3 days and cyclophosphamide 200 mg/m 2 intravenously every 12 hours × 3 days were established as the MTDs. Dose limiting toxicity (DLT) included diarrhea, transaminase elevations, and skin rashes. The response rate of the whole study group was 14%, including 10% of patients who achieved complete remission (CR) or CR without platelet recovery (CRp). Three responses occurred in patients with primary refractory disease. Early mortality ( Conclusion The combination of Clofarabine plus cyclophosphamide at the doses used in this study in a group of heavily pretreated patients with ALL is only moderately effective. Other doses, alternative schedules, or a more favorable patient population may achieve better results.
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outcomes of patients with myelodysplatic syndrome and chronic myelomonocytic leukemia post Clofarabine failure
Therapeutic advances in hematology, 2014Co-Authors: Hady Ghanem, Stefan Faderl, Guillermo Garciamanero, Farhad Ravandi, Jorge E. Cortes, Naval G. Daver, Lakshmikanth Katragadda, Susan Obrien, Sherry Pierce, Tapan M KadiaAbstract:Background:The outcome of patients with myelodysplastic syndrome (MDS) and chronic myelomonocytic leukemia (CMML) post Clofarabine is unknown.Methods:We reviewed 109 patients with MDS or CMML with a median age of 67 years, treated with a Clofarabine-based chemotherapy as frontline (n = 38) or salvage (n = 71) therapy. A total of 58 (53%) patients received salvage therapy after Clofarabine failure: 13 allogeneic stem cell transplant (ASCT), 18 high-dose cytarabine-containing regimen, 10 hypomethylating agents and 17 investigational treatments.Results:Eight patients achieved complete remission (CR) and three had stable disease for an overall response rate of 19%. With a median follow-up of 3 months from Clofarabine failure, 12 patients (11%) remained alive, 5 remain in CR, 4 of them after ASCT. The median overall survival post Clofarabine failure was 4 months with a 1-year survival rate of 23%.Conclusions:This outcome is predictable, with patients with high-risk disease at the time of Clofarabine failure ha...
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Outcomes of patients with myelodysplatic syndrome and chronic myelomonocytic leukemia post Clofarabine failure
Therapeutic advances in hematology, 2014Co-Authors: Hady Ghanem, Stefan Faderl, Farhad Ravandi, Jorge E. Cortes, Susan O'brien, Naval G. Daver, Lakshmikanth Katragadda, Guillermo Garcia-manero, Sherry Pierce, Tapan M KadiaAbstract:The outcome of patients with myelodysplastic syndrome (MDS) and chronic myelomonocytic leukemia (CMML) post Clofarabine is unknown. We reviewed 109 patients with MDS or CMML with a median age of 67 years, treated with a Clofarabine-based chemotherapy as frontline (n = 38) or salvage (n = 71) therapy. A total of 58 (53%) patients received salvage therapy after Clofarabine failure: 13 allogeneic stem cell transplant (ASCT), 18 high-dose cytarabine-containing regimen, 10 hypomethylating agents and 17 investigational treatments. Eight patients achieved complete remission (CR) and three had stable disease for an overall response rate of 19%. With a median follow-up of 3 months from Clofarabine failure, 12 patients (11%) remained alive, 5 remain in CR, 4 of them after ASCT. The median overall survival post Clofarabine failure was 4 months with a 1-year survival rate of 23%. This outcome is predictable, with patients with high-risk disease at the time of Clofarabine failure having the worse survival. To date, patients with MDS continue to have a short survival after failure of all available therapies. Ultimately, patients who are candidates for additional treatments should be offered novel approaches. In conclusion, the outcome of patients with MDS and CMML post Clofarabine failure is poor. The pattern is similar to patients with MDS post hypomethylating agent failure and predictable using University of Texas M. D. Anderson Cancer Center global scoring system.
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Clofarabine does not negatively impact the outcomes of patients with acute myeloid leukemia undergoing allogeneic stem cell transplantation
Clinical Lymphoma Myeloma & Leukemia, 2013Co-Authors: Michael S Mathisen, Stefan Faderl, Guillermo Garciamanero, Farhad Ravandi, Gautam Borthakur, Hagop M Kantarjian, Elias Jabbour, Jorge E. Cortes, Alfonso QuintascardamaAbstract:Abstract Background Clofarabine is actively being investigated as a component of frontline chemotherapy for acute myeloid leukemia (AML). Hepatotoxicity is 1 of the primary adverse events associated with Clofarabine and can occasionally can include severe venoocclusive disease (VOD). Patients and Methods Many patients with AML undergo allogeneic stem cell transplantation (allo-SCT), a procedure that is also associated with hepatotoxicity. We identified AML patients undergoing allo-SCT and stratified them according to whether they received Clofarabine-containing (Clofarabine, idarubicin, and cytarabine [CIA]) or non–Clofarabine-containing cytarabine-based induction/consolidation chemotherapy (idarubicin and cytarabine [ara-C] [IA]). We compared both groups for differences in posttransplantation hepatotoxicity, VOD, and other transplantation outcomes. Forty-two patients were identified (20 receiving CIA and 22 receiving IA). Patient and transplant characteristics were similar. All patients receiving Clofarabine-based treatment received CIA within 2.5 months of their allo-SCT. Results There was no difference in the incidence of VOD in the 30 days after transplantation (0 CIA, 1 IA; P = 1.0). Rates of grade 3/4 hepatotoxicity also did not differ between groups. Acute graft-versus-host disease (GVHD), early relapse, and survival were also not significantly different. Conclusions We conclude that Clofarabine-containing chemotherapy does not adversely impact the outcome of allo-SCT. Specifically, it does not predispose patients to an increased risk of hepatotoxicity, VOD, GVHD, or relapse.
Elias Jabbour - One of the best experts on this subject based on the ideXlab platform.
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Clofarabine in the treatment of myelodysplastic syndromes.
Expert opinion on investigational drugs, 2014Co-Authors: Jeffrey Bryan, Hagop M Kantarjian, Hillary Prescott, Elias JabbourAbstract:Introduction: Clofarabine is a second-generation purine nucleoside analog approved in 2004 for the treatment of pediatric patients with relapsed or refractory acute lymphocytic leukemia (ALL) following failure of at least two prior regimens. Clofarabine is a hybrid of fludarabine and cladribine, designed to overcome the pharmacologic limitations associated with its predecessors, while retaining their beneficial properties. In addition to providing a valuable treatment option for pediatric patients with ALL, Clofarabine alone and in combination with cytarabine (Ara-C) has demonstrated substantial activity against myelodysplastic syndrome (MDS), thus rendering this agent a potential therapeutic option for MDS. Areas covered: This review focuses on the pharmacology and clinical activity of Clofarabine in MDS, as well as its emerging role in the treatment of MDS. Publications in English were selected from the MEDLINE (PubMed) database, as well articles of interest from bibliographies and abstracts based on th...
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Clofarabine plus low dose cytarabine induction followed by Clofarabine plus low dose cytarabine alternating with decitabine consolidation in acute myeloid leukemia frontline therapy for older patients
Blood, 2013Co-Authors: Aziz Nazha, Guillermo Garciamanero, Alessandra Ferrajoli, Farhad Ravandi, Xuelin Huang, Hagop M Kantarjian, Xuemei Wang, Elias Jabbour, Tapan M Kadia, Marina KonoplevaAbstract:Background The outcome of elderly patients (pts) with acute myeloid leukemia (AML) treated with currently available therapies remains unsatisfactory. Clofarabine has single agent activity in AML. The combination of Clofarabine with low-dose cytarabine produced higher response rates with a comparable safety profile compared with single-agent Clofarabine. We previously reported a phase II study of Clofarabine + low dose cytarabine followed by prolonged consolidation with clorarabine + low dose cytarabine alternating with decitabine in elderly patients with newly diagnosed AML (Faderl, Cancer 2012). The complete remission (CR) rate was 58%. With median follow up of 31.2 months, the median overall survival (OS) was 12.7 months, and the median relapse free survival was 14.1months. The combination was well tolerated with induction mortality of 3% (Early Death <28 Days), 7% at 8-weeks. Here we report the result with a larger patient population and longer follow up. Material and Methods Pts were eligible if they were >/= 60 years of age with newly diagnosed AML (based on World Health Organization [WHO] criteria) or high-risk myelodysplastic syndrome (MDS; >/=10% blasts or >/= intermediate-2 by the International Prognostic Scoring System) with Eastern Cooperative Oncology Group (ECOG) performance status of 40%). Induction therapy consisted of Clofarabine 20 mg/m2 IV daily X 5 days (1-5) plus cytarabine 20 mg subcutaneously (SC) twice daily (BID) X10 days (1-10). All responses were defined as per IWG criteria (2003). Pts who did not achieve a CR could receive 1 re-induction cycle at the same dose after at least 28 days from C #1. Pts could receive up to 17 cycles of consolidation therapy. Consolidation was administered in blocks of 3 cycles where Clofarabine 20 mg/m2 IV daily X 3 days (1-3) plus cytarabine 20 mg SC BID X 7 days (1-7) alternated with decitabine 20 mg/m2IV X5 days (1-5). Consolidation cycles were repeated every 4 to 7 weeks depending on hematopoietic recovery. Results Between 10/21/08 and 10/17/2011, a total of 118 patients were enrolled. The clinical characteristics are summarized in [Table 1][1]. The overall response rate (ORR) was 68% (71 [60%] CR, 9 [8%] CRp/CRi). Twenty two (19%) pts required re-induction, 16 (73%) achieved a response (12 achieved CR, 2 CRp, and 2 CRi). Median number of cycles received was 3 (range, 1-19). With median follow up of 31.2 months (range, 9.5-53.9), the median OS was 11.1 (range, 0.2-53.9), EFS 7.7 (range, 0.2-49.5), and relapse-free survival (RFS) 15.9 months (range, 0.3-48.3). The median OS among the responders was 21.1 months (range, 1.3-53.9). Four-week mortality was 3% and 8-week mortality 8%. Adverse events were predominantly grade 2 or less and included (>/= 10%): elevated liver enzymes (53%), elevated bilirubin (42%), diarrhea (19%), nausea (81%), rash (54%), hand and foot syndrome (10%), and elevated creatinine (10%). Grade 3 or more toxicities included: elevated creatinine (3%), rash (2%), vomiting (1%), and hand and foot syndrome (1%). No unexpected toxicities were observed. View this table: Table 1 Patient characteristics Conclusion Clofarabine plus low-dose cytarabine followed by prolonged consolidation alternating with decitabine is an active regimen with an ORR of 73% in older patients with newly diagnosed AML and high risk MDS. The regimen was well tolerated with low induction mortality. A randomized trail to compare this combination to best available therapy is needed to further asses the role of this combination in the treatment paradigm of elderly patients with AML. Disclosures: Off Label Use: Clofarabine and decitabine use in AML. Faderl: Sanofi-Aventis: Consultancy, Membership on an entity’s Board of Directors or advisory committees, Research Funding. [1]: #T1
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Clofarabine does not negatively impact the outcomes of patients with acute myeloid leukemia undergoing allogeneic stem cell transplantation
Clinical Lymphoma Myeloma & Leukemia, 2013Co-Authors: Michael S Mathisen, Stefan Faderl, Guillermo Garciamanero, Farhad Ravandi, Gautam Borthakur, Hagop M Kantarjian, Elias Jabbour, Jorge E. Cortes, Alfonso QuintascardamaAbstract:Abstract Background Clofarabine is actively being investigated as a component of frontline chemotherapy for acute myeloid leukemia (AML). Hepatotoxicity is 1 of the primary adverse events associated with Clofarabine and can occasionally can include severe venoocclusive disease (VOD). Patients and Methods Many patients with AML undergo allogeneic stem cell transplantation (allo-SCT), a procedure that is also associated with hepatotoxicity. We identified AML patients undergoing allo-SCT and stratified them according to whether they received Clofarabine-containing (Clofarabine, idarubicin, and cytarabine [CIA]) or non–Clofarabine-containing cytarabine-based induction/consolidation chemotherapy (idarubicin and cytarabine [ara-C] [IA]). We compared both groups for differences in posttransplantation hepatotoxicity, VOD, and other transplantation outcomes. Forty-two patients were identified (20 receiving CIA and 22 receiving IA). Patient and transplant characteristics were similar. All patients receiving Clofarabine-based treatment received CIA within 2.5 months of their allo-SCT. Results There was no difference in the incidence of VOD in the 30 days after transplantation (0 CIA, 1 IA; P = 1.0). Rates of grade 3/4 hepatotoxicity also did not differ between groups. Acute graft-versus-host disease (GVHD), early relapse, and survival were also not significantly different. Conclusions We conclude that Clofarabine-containing chemotherapy does not adversely impact the outcome of allo-SCT. Specifically, it does not predispose patients to an increased risk of hepatotoxicity, VOD, GVHD, or relapse.
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The role of Clofarabine in acute myeloid leukemia.
Leukemia & lymphoma, 2012Co-Authors: Hady Ghanem, Hagop M Kantarjian, Maro Ohanian, Elias JabbourAbstract:Clofarabine is a second-generation purine nucleoside analog that has been synthesized to overcome the limitations and incorporate the best qualities of fludarabine and cladribine. Clofarabine acts by inhibiting ribonucleotide reductase and DNA polymerase, thereby depleting the amount of intracellular deoxynucleoside triphosphates available for DNA replication. Compared to its precursors, Clofarabine has an increased resistance to deamination and phosphorolysis, and hence better stability as well as higher affinity to deoxycytidine kinase (dCyd), the rate-limiting step in nucleoside phosphorylation. Since the initiation of the first phase I study of Clofarabine in 1993 in patients with hematologic and solid malignancies, Clofarabine has demonstrated single-agent antitumor activity in adult acute leukemia, including acute myeloid leukemia (AML). Due to its unique properties of biochemical modulation when used in combination with other chemotherapy drugs, mainly cytarabine, combination regimens containing Clofarabine have been evaluated. A review of the English literature was performed that included original articles and related reviews from the MEDLINE (PubMed) database and from abstracts based on the publication of meeting materials. This review describes the development, pharmacology and clinical activity of Clofarabine, as well as its emerging role in the treatment of adult patients with AML and myelodysplastic syndrome.
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Clofarabine does not impact negatively the outcomes of patients with acute myeloid leukemia aml undergoing allogeneic stem cell transplantation and is not associated with higher liver toxicity rates compared with standard chemotherapy
Blood, 2011Co-Authors: Michael S Mathisen, Stefan Faderl, Guillermo Garciamanero, Farhad Ravandi, Gautam Borthakur, Hagop M Kantarjian, Elias Jabbour, Jorge E. Cortes, Alfonso QuintascardamaAbstract:Abstract 1489 Background: The purine nucleoside analog Clofarabine is currently being actively investigated at the M.D. Anderson Cancer Center (MDACC) in combination with idarubicin and cytarabine (CIA) as frontline therapy for younger patients with newly diagnosed acute myeloid leukemia (AML). Hepatotoxicity (i.e. elevation of transaminases and/or bilirubin) is one of the primary adverse events associated with Clofarabine and rare instances of severe hepatotoxicity as well as veno-occlusive disease (VOD) have been reported. Allogeneic stem cell transplant (allo-SCT) is indicated for younger AML patients with poor risk features (i.e. adverse cytogenetics, diploid karyotype with FLT3 mutations) in first complete remission (CR). Allo-SCT also places the patient at risk of liver toxicity and VOD. Therefore, we investigated whether pre-transplant Clofarabine-containing chemotherapy regimens adversely impacted the outcomes of younger patients with AML compared with those of patients pre-treated with non-Clofarabine containing chemotherapy. Methods: We conducted a retrospective review comparing patients who underwent allo-SCT after receiving CIA (Clofarabine 20 mg/m2 IV daily for 5 days, idarubicin 10 mg/m2 IV daily for 3 days, cytarabine 1,000 mg/m2 IV daily for 5 days) versus a non-Clofarabine containing chemotherapy regimen (IA, idarubicin 12 mg/m2 IV daily for 3 days, cytarabine 1,500 mg/m2 via IV continuous infusion over 24 hours daily for 4 days). Consolidation cycles contained the same agents given according to an attenuated schedule. Patients were all receiving CIA or IA as their frontline regimen for AML. Variables that were extracted from the medical record include age, number of cycles of chemotherapy, CR rate, allo-SCT in CR, stem cell source, conditioning regimen, engraftment day, incidence of VOD, incidence of acute hepatotoxicity post-transplant, incidence of graft versus host disease (GVHD), early death, and early relapse. Results: Overall, 42 younger patients with AML undergoing allo-SCT were identified (n = 20 CIA, n = 22 IA). Patient age in both groups was similar, and there were more females in the IA group. Other patient and transplant characteristics were comparable between cohorts. Most patients underwent a matched related donor or matched unrelated donor allo-SCT (CIA 80% versus IA 82%), and the majority received busulfan-fludarabine based conditioning (CIA 70% versus IA 82%). Two patients in each group received Clofarabine as part of their conditioning program. In general, there was not any appreciable difference in acute post-transplant hepatotoxicity or in the incidence of VOD ([table 1][1]). Moreover, early mortality, early relapse, and the incidence of GVHD were not increased in the pretransplant Clofarabine group compared to the IA group. View this table: Table 1. Outcomes of Patients Undergoing allo-SCT Conclusions: The use of Clofarabine does not appear to impact negatively the outcome of younger patients with AML undergoing allo-SCT. There does not appear to be an increased risk of delayed engraftment, hepatotoxicity, VOD, GvHD, early relapse, or early mortality among patients with AML undergoing allo-SCT who receive pretransplant Clofarabine. Disclosures: No relevant conflicts of interest to declare. [1]: #T1
Gautam Borthakur - One of the best experts on this subject based on the ideXlab platform.
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phase i and extension study of Clofarabine plus cyclophosphamide in patients with relapsed refractory acute lymphoblastic leukemia
Clinical Lymphoma Myeloma & Leukemia, 2014Co-Authors: Stefan Faderl, Alessandra Ferrajoli, Deborah A. Thomas, Farhad Ravandi, Gautam Borthakur, Jorge E. Cortes, Kumudha Balakrishnan, Susan Obrien, Jan A Burger, Tapan M KadiaAbstract:Abstract Background Clofarabine is a nucleoside analogue with activity in children with acute lymphoblastic leukemia (ALL). Based on the hypothesis that Clofarabine inhibits DNA repair after exposure to DNA-damaging agents, we designed a phase I and extension study to evaluate the combination of Clofarabine and cyclophosphamide in adult patients with relapsed/refractory ALL. Methods The continual reassessment method (CRM) was used to define the maximum tolerated dose (MTD). Results Fifty patients with a median age of 30 years (range, 21-72 years) were enrolled, 30 of whom were part of the phase I group. Clofarabine 40 mg/m 2 intravenously daily × 3 days and cyclophosphamide 200 mg/m 2 intravenously every 12 hours × 3 days were established as the MTDs. Dose limiting toxicity (DLT) included diarrhea, transaminase elevations, and skin rashes. The response rate of the whole study group was 14%, including 10% of patients who achieved complete remission (CR) or CR without platelet recovery (CRp). Three responses occurred in patients with primary refractory disease. Early mortality ( Conclusion The combination of Clofarabine plus cyclophosphamide at the doses used in this study in a group of heavily pretreated patients with ALL is only moderately effective. Other doses, alternative schedules, or a more favorable patient population may achieve better results.
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Clofarabine does not negatively impact the outcomes of patients with acute myeloid leukemia undergoing allogeneic stem cell transplantation
Clinical Lymphoma Myeloma & Leukemia, 2013Co-Authors: Michael S Mathisen, Stefan Faderl, Guillermo Garciamanero, Farhad Ravandi, Gautam Borthakur, Hagop M Kantarjian, Elias Jabbour, Jorge E. Cortes, Alfonso QuintascardamaAbstract:Abstract Background Clofarabine is actively being investigated as a component of frontline chemotherapy for acute myeloid leukemia (AML). Hepatotoxicity is 1 of the primary adverse events associated with Clofarabine and can occasionally can include severe venoocclusive disease (VOD). Patients and Methods Many patients with AML undergo allogeneic stem cell transplantation (allo-SCT), a procedure that is also associated with hepatotoxicity. We identified AML patients undergoing allo-SCT and stratified them according to whether they received Clofarabine-containing (Clofarabine, idarubicin, and cytarabine [CIA]) or non–Clofarabine-containing cytarabine-based induction/consolidation chemotherapy (idarubicin and cytarabine [ara-C] [IA]). We compared both groups for differences in posttransplantation hepatotoxicity, VOD, and other transplantation outcomes. Forty-two patients were identified (20 receiving CIA and 22 receiving IA). Patient and transplant characteristics were similar. All patients receiving Clofarabine-based treatment received CIA within 2.5 months of their allo-SCT. Results There was no difference in the incidence of VOD in the 30 days after transplantation (0 CIA, 1 IA; P = 1.0). Rates of grade 3/4 hepatotoxicity also did not differ between groups. Acute graft-versus-host disease (GVHD), early relapse, and survival were also not significantly different. Conclusions We conclude that Clofarabine-containing chemotherapy does not adversely impact the outcome of allo-SCT. Specifically, it does not predispose patients to an increased risk of hepatotoxicity, VOD, GVHD, or relapse.
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Clofarabine does not impact negatively the outcomes of patients with acute myeloid leukemia aml undergoing allogeneic stem cell transplantation and is not associated with higher liver toxicity rates compared with standard chemotherapy
Blood, 2011Co-Authors: Michael S Mathisen, Stefan Faderl, Guillermo Garciamanero, Farhad Ravandi, Gautam Borthakur, Hagop M Kantarjian, Elias Jabbour, Jorge E. Cortes, Alfonso QuintascardamaAbstract:Abstract 1489 Background: The purine nucleoside analog Clofarabine is currently being actively investigated at the M.D. Anderson Cancer Center (MDACC) in combination with idarubicin and cytarabine (CIA) as frontline therapy for younger patients with newly diagnosed acute myeloid leukemia (AML). Hepatotoxicity (i.e. elevation of transaminases and/or bilirubin) is one of the primary adverse events associated with Clofarabine and rare instances of severe hepatotoxicity as well as veno-occlusive disease (VOD) have been reported. Allogeneic stem cell transplant (allo-SCT) is indicated for younger AML patients with poor risk features (i.e. adverse cytogenetics, diploid karyotype with FLT3 mutations) in first complete remission (CR). Allo-SCT also places the patient at risk of liver toxicity and VOD. Therefore, we investigated whether pre-transplant Clofarabine-containing chemotherapy regimens adversely impacted the outcomes of younger patients with AML compared with those of patients pre-treated with non-Clofarabine containing chemotherapy. Methods: We conducted a retrospective review comparing patients who underwent allo-SCT after receiving CIA (Clofarabine 20 mg/m2 IV daily for 5 days, idarubicin 10 mg/m2 IV daily for 3 days, cytarabine 1,000 mg/m2 IV daily for 5 days) versus a non-Clofarabine containing chemotherapy regimen (IA, idarubicin 12 mg/m2 IV daily for 3 days, cytarabine 1,500 mg/m2 via IV continuous infusion over 24 hours daily for 4 days). Consolidation cycles contained the same agents given according to an attenuated schedule. Patients were all receiving CIA or IA as their frontline regimen for AML. Variables that were extracted from the medical record include age, number of cycles of chemotherapy, CR rate, allo-SCT in CR, stem cell source, conditioning regimen, engraftment day, incidence of VOD, incidence of acute hepatotoxicity post-transplant, incidence of graft versus host disease (GVHD), early death, and early relapse. Results: Overall, 42 younger patients with AML undergoing allo-SCT were identified (n = 20 CIA, n = 22 IA). Patient age in both groups was similar, and there were more females in the IA group. Other patient and transplant characteristics were comparable between cohorts. Most patients underwent a matched related donor or matched unrelated donor allo-SCT (CIA 80% versus IA 82%), and the majority received busulfan-fludarabine based conditioning (CIA 70% versus IA 82%). Two patients in each group received Clofarabine as part of their conditioning program. In general, there was not any appreciable difference in acute post-transplant hepatotoxicity or in the incidence of VOD ([table 1][1]). Moreover, early mortality, early relapse, and the incidence of GVHD were not increased in the pretransplant Clofarabine group compared to the IA group. View this table: Table 1. Outcomes of Patients Undergoing allo-SCT Conclusions: The use of Clofarabine does not appear to impact negatively the outcome of younger patients with AML undergoing allo-SCT. There does not appear to be an increased risk of delayed engraftment, hepatotoxicity, VOD, GvHD, early relapse, or early mortality among patients with AML undergoing allo-SCT who receive pretransplant Clofarabine. Disclosures: No relevant conflicts of interest to declare. [1]: #T1
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Clofarabine containing chemotherapy does not increase the risk of infectious complications in patients with newly diagnosed acute myeloid leukemia aml
Blood, 2011Co-Authors: Michael S Mathisen, Stefan Faderl, Guillermo Garciamanero, Farhad Ravandi, Gautam Borthakur, Hagop M Kantarjian, Elias Jabbour, Jorge E. Cortes, Alfonso QuintascardamaAbstract:Abstract 4256 Background: Clofarabine is a purine nucleoside analog currently approved for relapsed pediatric acute lymphoblastic leukemia (ALL). Its role is also being investigated in various other hematologic malignancies, including AML. While desirably myelosuppressive, Clofarabine is also lymphotoxic, which may impair cellular mediated immunity and result in higher rates of severe and/or atypical infections. Recently, an analysis of patients receiving Clofarabine as salvage therapy for AML revealed a potentially increased risk for “unconventional” infections (Knoebel RW, Leuk Res, 2011). At the M.D. Anderson Cancer Center (MDACC), Clofarabine has been tested as a component of multi-agent therapy for the frontline treatment of younger patients with AML. We hypothesized that Clofarabine may increase the infectious burden placed on these patients. Methods: We conducted a retrospective comparison of patients receiving Clofarabine containing chemotherapy (CIA: Clofarabine 20 mg/m 2 IV daily for 5 days, idarubicin 10 mg/m 2 IV daily for 3 days, cytarabine 1,000 mg/m 2 IV daily for 5 days) versus non-Clofarabine containing chemotherapy (IA: idarubicin 12 mg/m 2 IV daily for 3 days, cytarabine 1,500 mg/m 2 IV continuous infusion over 24 hours for 4 days) from 2007 – 2011. Consolidation cycles contained the same agents given according to an attenuated schedule. Variables extracted from the medical record included demographic data, number of cycles per patient, achievement of complete remission (CR), application of allogeneic stem cell transplant (allo-SCT), episodes of neutropenic fever, diagnosis of pneumonia, and diagnosis of atypical infections. Atypical infections were defined as viral infections, Pneumocystis Jirovecii, Nocardia, mycobacterial infections, Listeria, Legionella, Mucormycosis, or radiographic evidence of an atypical infection (REAI). Patients were followed until relapse, allo-SCT, or 6 months after the previous chemotherapy cycle. Results: 49 patients per group followed predominantly at MDACC throughout the duration of therapy were analyzed. Prophylactic antimicrobials prescribed after each chemotherapy cycle generally included valacyclovir, voriconazole, and an oral fluoroquinolone for all patients. The groups were well balanced in terms of age, therapy duration (2.7 cycles per patient on CIA versus 2.6 cycles per patient on IA), CR rate (CIA 73%, IA 71%), and predisposition to allo-SCT (CIA 49%, IA 45%). In the CIA group, 13 patients were diagnosed with pneumonia versus 15 patients in the IA group. Episodes of neutropenic fever per cycle also did not appear to differ between the groups (CIA 0.5, IA 0.62). Regarding atypical infections, there were 3 in the CIA cohort (1 Mucor, 2 REAI) versus 9 in the IA cohort (1 Mucor, 2 RSV, 6 REAI). Conclusions: Patients with AML treated in the frontline setting with Clofarabine-containing chemotherapy do not appear to be subjected to an increased infectious risk compared with other high-dose ara-C-containing chemotherapy. In addition, we did not observe a higher rate of atypical infections in the group treated with the CIA regimen. We further plan to evaluate our older population of patients as well as those patients who receive Clofarabine in the relapsed setting. Disclosures: No relevant conflicts of interest to declare.
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Clofarabine: emerging role in leukemias
Expert opinion on investigational drugs, 2009Co-Authors: Keeran Sampat, Hagop M Kantarjian, Gautam BorthakurAbstract:Clofarabine is a second-generation purine nucleoside analogue. It works mainly by inhibiting ribonucleotide reductase and incorporating into DNA. Clofarabine has shown efficacy in selected pediatric leukemias. It has also shown significant efficacy alone and in combination with other drugs in treating adult myeloid leukemias and high-risk myelodysplastic syndromes. Further, there is significant promise for Clofarabine in the treatment of older patients with acute myeloid leukemia who are unlikely to benefit from standard induction chemotherapy due to unfavorable baseline prognostic factors. An oral formulation of Clofarabine is also currently under development.
Sima Jeha - One of the best experts on this subject based on the ideXlab platform.
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advanced leukemia Clofarabine, a novel nucleoside analog, is active in pediatric patients with
2013Co-Authors: Mark Brandt, Varsha Gandhi, Sima Jeha, Hagop M Kantarjian, M. J. Keating, W. Plunkett, Ka Wah Chan, Lisa Mcdonald, Irma Ramirez, Renee MaddenAbstract:ABSTRACTBackground: Despite progress in leukemia therapy, most children who relapse have a dismal prognosis. New effective approaches are needed. We conducted a Phase I study of the novel nucleoside analog Clofarabine in pediatric patients with refractory and relapsed leukemia. Methods: Clofarabine was infused intravenously over one hour daily for 5 days. Six dose levels between 11.25 and 70 mg/m 2 /day for five days were studied in 25 patients. A modified 3 + 3 phase I design was followed with 30% dose escalation until the dose-limiting toxicity (DLT) was defined. Results: The maximum tolerated dose (MTD) was 52 mg/m 2 /day x five days. At the end of infusion at MTD, Clofarabine triphosphate levels in leukemia blasts varied between 6 and 19∝ M, which resulted in complete and sustained inhibition of DNA synthesis. The DLT was reversible hepatotoxicity and skin rash at 70 mg/m 2 /day x 5. Twenty-five patients were treated. Five patients achieved a complete remission (CR) and three had a partial remission (PR), for an overall response rate of 32%. Conclusions: Clofarabine is well tolerated and shows significant antileukemic activity in heavily pretreated children. Multicenter phase II trials in pediatric acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML) are ongoing. Key Words: leukemia; Clofarabine; AML; ALL; nucleoside analogFrom bloodjournal.hematologylibrary.org by guest on June 4, 2013. For personal use only.
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Clofarabine in refractory Langerhans cell histiocytosis.
Pediatric blood & cancer, 2008Co-Authors: Carlos Rodriguez-galindo, Michael Jeng, Phuong Khuu, M. Beth Mccarville, Sima JehaAbstract:Patients with multi-system Langerhans cell histiocytosis (LCH) who progress on frontline therapy have a dismal outcome. Responses to cladribine have been reported in relapsed LCH, but there are no well defined salvage regimens for LCH is refractory to therapy. The next generation deoxyadenosine analog, Clofarabine, has demonstrated activity in patients with leukemia that is refractory to salvage regimens, including other nucleotide congeners; however, no experience exist on the use of Clofarabine in LCH. In this report we describe significant single agent activity of Clofarabine in disseminated LCH refractory to salvage regimens, including cladribine.
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Clofarabine: past, present, and future.
Leukemia & lymphoma, 2007Co-Authors: Hagop M Kantarjian, Sima Jeha, Varsha Gandhi, Michael Wess, Stefan FaderlAbstract:Clofarabine is a good generation purine nucleoside analogue designed to overcome the limitations and to incorporate the best qualities of both cladribine and fludarabine. Clofarabine is thought to work via three mechanisms: inhibition of ribonucleotide reductase; incorporation to DNA; and induction of apoptosis. Given these mechanism of action, Clofarabine would be predicted to act synergistically with other chemotherapeutic agents such as other purine nucleoside analogues and DNA damaging or cross linking agents such as anthracyclines and platinum-based compounds. Intravenous Clofarabine showed significant efficacy in pediatric leukemias (specifically, acute lymphoblastic leukemia (ALL)) and, in 2004, it was approved by the United States Food and Drug Administration (FDA) for the treatment of pediatric relapsed/refractory ALL after at least two regimens. In adults, Clofarabine has shown significant efficacy in hematologic malignancies including acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) alone and in combinations. Ongoing and future studies will examine the use of Clofarabine in elderly patients with AML for whom standard regimens are too toxic, and in MDS intravenous and oral forms of the drug.
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phase ii study of Clofarabine in pediatric patients with refractory or relapsed acute lymphoblastic leukemia
Journal of Clinical Oncology, 2006Co-Authors: Sima Jeha, Paul S. Gaynon, Bassem I Razzouk, Michael Rytting, Susan R Rheingold, Edythe Albano, Richard Kadota, Lori Luchtmanjones, Lisa Bomgaars, Stewart GoldmanAbstract:Purpose To evaluate the efficacy and safety of Clofarabine, a novel deoxyadenosine analog, in pediatric patients with refractory or relapsed acute lymphoblastic leukemia (ALL). Patients and Methods In a phase II, open-label, multicenter study, 61 pediatric patients with refractory or relapsed ALL received Clofarabine 52 mg/m2 intravenously over 2 hours daily for 5 days, every 2 to 6 weeks. The median age was 12 years (range, 1 to 20 years), and the median number of prior regimens was three (range, two to six regimens). Results The response rate was 30%, consisting of seven complete remissions (CR), five CRs without platelet recovery (CRp), and six partial remissions. Remissions were durable enough to allow patients to proceed to hematopoietic stem-cell transplantation (HSCT) after Clofarabine. Median CR duration in patients who did not receive HSCT was 6 weeks, with four patients maintaining CR or CRp for 8 weeks or more (8+, 12, 37+, and 48 weeks) on Clofarabine therapy alone. The most common adverse eve...
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the role of Clofarabine in hematologic and solid malignancies development of a next generation nucleoside analog
Cancer, 2005Co-Authors: Stefan Faderl, William Plunkett, Varsha Gandhi, Michael J Keating, Sima Jeha, Hagop M KantarjianAbstract: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 1993, when, through efforts at The University of Texas M. D. Anderson Cancer Center, animal toxicology studies were conducted, and the first Phase I study was initiated in patients with hematologic and solid malignancies. Since then, Clofarabine has demonstrated single-agent antitumor activity in pediatric and adult acute leukemias. By way of its unique metabolic properties, Clofarabine also has lent itself to biochemical modulation strategies with other nucleoside analogs, such as cytarabine. Combinations of Clofarabine with cytarabine have been studied in acute leukemia and currently are being evaluated in untreated elderly patients with acute myeloid leukemia. Novel schedules are being explored in lymphoproliferative disorders and solid tumors. Clofarabine is a new nucleoside analog with considerable activity and an acceptable safety profile in acute leukemias.