TY - JOUR
AU - Kanate, Abraham, S
AB - Abstract Purpose A delayed-onset effect of clofarabine in the treatment of an adult patient with acute myeloid leukemia (AML) is reported. Summary A 44-year-old African-American man with pancytopenia was transferred to an academic medical center for evaluation. His medical history included bipolar depression, gynecomastia, and HIV infection (diagnosed 5 years prior) for which he was being treated with atazanavir, emtricitabine-tenofovir, and ritonavir. He was diagnosed with AML with 60% myeloblasts found during bone marrow biopsy. He had primary refractory disease after induction chemotherapy treatment. His disease was refractory to subsequent therapy with high-dose cytarabine and then etoposide and mitoxantrone. The patient then underwent treatment with granulocyte-colony stimulating factor-primed clofarabine and cytarabine (G-CLAC). At blood count recovery, he was diagnosed with refractory disease, with 17% blasts in peripheral blood and was subsequently discharged home on hospice 38 days after G-CLAC and 19 days after the last dose of filgrastim. He arrived at the outpatient clinic 79 days after G-CLAC chemotherapy with significantly improved blood counts. Two weeks later, a bone marrow biopsy confirmed complete remission with incomplete hematologic recovery. Conclusion A patient with relapsed AML achieved a delayed response to clofarabine at least 38 days after treatment. acute myeloid leukemia, clofarabine, delayed-onset, refractory disease, remission KEY POINTS Clofarabine-based regimens have been shown to be effective for treatment of relapsed or refractory acute myeloid leukemia (AML). To our knowledge, this is the first case of a delayed-onset effect of clofarabine after documented refractory disease to be reported in the literature. Patients with AML who are treated with clofarabine may exhibit a delayed-onset remission. Clofarabine is a second-generation purine nucleoside analog.1 It was synthesized to combine the best components of fludarabine and cladribine while overcoming some of the resistance mechanisms associated with these agents. Clofarabine works by inhibiting ribonucleotide reductase and DNA polymerase, depleting the amount of intracellular deoxynucleoside triphosphates available for DNA replication. Compared with fludarabine or cladribine, clofarabine has an increased resistance to deamination and phosphorolysis. It also displays a higher affinity to deoxycytidine kinase, the rate-limiting step in nucleoside phosphorylation. Clofarabine has substantial activity in patients with acute myeloid leukemia (AML) and is a commonly utilized agent in the relapsed and refractory settings. It can be used as a single agent,1,2 or in combination with other chemotherapy agents (e.g. cytarabine)3–9 with complete remission (CR) rates reported in the range of 21–61%.1–8 It should be noted that the first case of a delayed-onset effect was reported in a previous clofarabine study, as 1 patient entered CR 7 weeks after the start of chemotherapy.6 We report the case of a patient having a delayed response occurring at least 38 days after clofarabine treatment. Case report A 44-year-old African-American man with a medical history of bipolar disorder, gynecomastia, and HIV infection (diagnosed 5 years prior) receiving highly active antiretroviral therapy of unknown duration, sought treatment for generalized weakness at an outside facility. Blood counts showed pancytopenia. Considering the possibility of antiretroviral-induced cytopenia, medications including oral atazanavir, emtricitabine-tenofovir, and ritonavir were held for over a week with no improvement in blood counts. A bone marrow biopsy (BMB) performed at the referring facility suggested AML. He was transferred to our facility for further evaluation and management. On admission to our facility, his absolute CD4 count was 324 cells/µL, CD4:CD8 ratio was 0.5, and viral load was 115,000 copies/mL. Peripheral blood showed pancytopenia with a white blood cell (WBC) count of 2.4 x103/µL with 16% neutrophils and 9% blasts, hemoglobin concentration of 11.5 g/dL; and platelet count of 77 x103/µL. Uric acid, renal, and hepatic laboratory test values were within normal limits. The patient’s lactate dehydrogenase concentration was slightly elevated (306 IU/L), and his fibrinogen concentration was 759 mg/dL. A BMB performed at our facility shortly after his admission revealed a hypercellular marrow (approximately 98% cellularity) with 60% myeloblasts. Flow cytometry revealed that the blasts were positive for CD34 (dim), CD13, CD33 (very dim), CD117, HLA-DR, and myeloperoxidase, confirming the diagnosis of AML. Cytogenetic analysis demonstrated a complex karyotype consisting of trisomy 8, in addition to a second cell line with ring chromosome 18 and additional chromosomes 6 and 13. The patient received induction chemotherapy with 1 cycle of cytarabine (100 mg/m2 i.v. daily for 7 days) and idarubicin (12 mg/m2 i.v. daily for 3 days) shortly after diagnosis. While a BMB performed 14 days after the start of chemotherapy showed aplasia and no increase in blasts, the patient had 4% blasts on marrow analysis approximately 2 months later after blood count recovery (day 64). At that time, the patient's absolute CD4 count was 404 cells/µL and viral load was 36 copies/mL. The patient received 2 cycles of high-dose cytarabine (3 g/m2 i.v. every 12 hours for 6 doses) consolidation chemotherapy over the next 3 months. A BMB performed the month following chemotherapy revealed a hypercellular marrow with 9% blasts (Figure 1, panels A and B). At that time, the patient’s absolute CD4 count was 819 cells/µL and viral load was undetectable. The patient then received reinduction chemotherapy with etoposide (100 mg/m2 i.v. daily for 5 days) and mitoxantrone (10 mg/m2 i.v. daily for 5 days), but unfortunately still had persistent AML with 13% blasts on BMB. Two months later, the patient’s absolute CD4 count was 197 cells/µL and viral load was undetectable. The patient then underwent reinduction chemotherapy with granulocyte-colony stimulating factor-primed clofarabine (25 mg/m2 i.v. daily for 5 days) and cytarabine (2 g/m2 i.v. daily for 5 days) (G-CLAC). The last dose of filgrastim was administered 20 days after the start of the second round of reinduction chemotherapy. At blood count recovery 33 days after start of chemotherapy, the patient was diagnosed with disease refractory to clofarabine with a WBC count of 5.7 × 103/µL, 17% blasts, and flow cytometry-confirmed refractory disease. The patient’s WBC count peaked at 9.6 × 103/µL with 33% blasts in peripheral blood by day 38. The patient was discharged home on hospice 19 days after the last dose of filgrastim. Figure 1. View largeDownload slide Before clofarabine therapy (panel A), the bone marrow showed refractory disease with 9% blasts by aspirate differential (500x). In panel B, the corresponding core biopsy shows limited maturation with numerous immature cells (400x). After blood count recovery (93 days post-clofarabine administration), the bone marrow aspirate (panel C) showed trilineage maturation with no increase in blasts (500x). The corresponding core biopsy (panel D) is hypercellular with complete, progressive maturation and no increase in immature cells (400x). Figure 1. View largeDownload slide Before clofarabine therapy (panel A), the bone marrow showed refractory disease with 9% blasts by aspirate differential (500x). In panel B, the corresponding core biopsy shows limited maturation with numerous immature cells (400x). After blood count recovery (93 days post-clofarabine administration), the bone marrow aspirate (panel C) showed trilineage maturation with no increase in blasts (500x). The corresponding core biopsy (panel D) is hypercellular with complete, progressive maturation and no increase in immature cells (400x). The patient presented to the outpatient clinic 79 days after G-CLAC with significantly improved blood counts (WBC count of 12.3 × 103/µL with 44% neutrophils and 3% blasts, hemoglobin concentration of 16.5 g/dL, and platelet count of 15 × 103/µL). He was scheduled for a repeat BMB to assess disease status, at which time his WBC count was 8.2 × 103/µL with 35% neutrophils and 0% blasts, hemoglobin concentration was 15.9 g/dL, and platelet count of 23 × 103/µL. A BMB revealed hypercellular marrow (approximately 90% cellularity) with no increase in blasts or blast foci (Figure 1, panels C and D). Both CD34 immunohistochemistries performed on the core biopsy and flow cytometry showed no increase in blasts. It was determined that the patient had CR with incomplete hematologic recovery (CRi). The following month, the patient received 1 cycle of G-CLAC consolidation chemotherapy (clofarabine 20 mg/m2 i.v. daily for 5 days and cytarabine 1 g/m2 i.v. daily for 5 days). Lack of a suitable related or alternative donor limited the ability to proceed to allogeneic hematopoietic cell transplantation. One month after consolidation therapy, a BMB revealed relapsed disease with increased blasts (12% by aspirate differential) which was confirmed by flow cytometry. The peripheral blood smear revealed 4% circulating blasts. The patient subsequently received palliative decitabine therapy without response. Five months after the BMB, the patient died at home. Discussion To our knowledge, this is the first case of a delayed-onset effect of clofarabine after documented refractory disease to be reported in the literature, and only the second report of a delayed-onset effect of clofarabine. The response occurred at least 38 days after clofarabine treatment. Patients in previous studies had a prolonged time until documentation of remission, but this was likely in the setting of prolonged pancytopenia.2,6 In patients receiving G-CLAC for relapsed or refractory AML, a bone marrow analysis on day 14 is unreliable, as patients who have more than 5% blasts at day 14 may achieve CR at day 21 without additional treatment. The CR plus CRi rate with G-CLAC is 61%, and the CR rate is 46%, with 54% of patients subsequently undergoing allogeneic hematopoietic cell transplantation. The median time to neutrophil recovery after G-CLAC induction therapy is 21 days.6 It is unknown why this delayed effect occurred, and prior clofarabine studies have not provided a rationale regarding this phenomenon. Clofarabine causes a prolonged suppression of DNA synthesis and has prolonged intracellular retention in leukemia cells, but this would not account for such a delayed effect.10 Patients infected with HIV have a 2-fold increased risk of developing AML compared with the general population, but have comparable rates of CR with conventional treatment. Patients with a CD4 count exceeding 200 cells/µL at the time of AML diagnosis have improved survival. In addition, HIV-infected patients who enter CR have a similar duration of neutropenia as do AML patients without HIV.11,12 Although rare, this case demonstrates the potential for patients with AML to derive benefit from clofarabine later than anticipated. Clinicians should be cognizant of the unlikely, yet possible, occurrence of delayed-onset remission with clofarabine. Conclusion A patient with relapsed AML achieved a delayed response to clofarabine occurring at least 38 days after treatment. Disclosures The authors have declared no potential conflict of interest. References 1. Kantarjian H , Gandhi V , Cortes J et al. Phase 2 clinical and pharmacologic study of clofarabine in patients with refractory or relapsed acute leukemia . Blood. 2003 ; 102 : 2379 – 86 . Google Scholar Crossref Search ADS PubMed 2. Burnett AK , Russell NH , Hunter AE et al. Clofarabine doubles the response rate in older patients with acute myeloid leukemia but does not improve survival . Blood. 2013 ; 122 : 1384 – 94 . Google Scholar Crossref Search ADS PubMed 3. Faderl S , Wetzler M , Rizzieri D et al. Clofarabine plus cytarabine compared with cytarabine alone in older patients with relapsed or refractory acute myelogenous leukemia: results from the CLASSIC I trial . J Clin Oncol. 2012 ; 30 : 2492 – 9 . Google Scholar Crossref Search ADS PubMed 4. Buchholz S , Dammann E , Stadler M et al. Cytoreductive treatment with clofarabine/ara-C combined with reduced-intensity conditioning and allogeneic stem cell transplantation in patients with high-risk, relapsed, or refractory acute myeloid leukemia and advanced myelodysplastic syndrome . Eur J Haematol. 2012 ; 88 : 52 – 60 . Google Scholar Crossref Search ADS PubMed 5. Scappini B , Gianfaldoni G , Caracciolo F et al. Cytarabine and clofarabine after high-dose cytarabine in relapsed or refractory AML patients . Am J Hematol. 2012 ; 87 : 1047 – 51 . Google Scholar Crossref Search ADS PubMed 6. Becker PS , Kantarjian HM , Appelbaum FR et al. Clofarabine with high dose cytarabine and granulocyte colony-stimulating factor (G-CSF) priming for relapsed and refractory acute myeloid leukaemia . Br J Haematol. 2011 ; 155 : 182 – 9 . Google Scholar Crossref Search ADS PubMed 7. Naqvi K , Ravandi F , Kantarjian H et al. Phase II study of the combination of clofarabine plus idarubicin and cytarabine (CIA) in patients with relapsed/refractory acute myeloid leukemia (AML) . Blood . 2010 ; 116 :abstract 1061. 8. Faderl S , Borthakur G , Ravandi F et al. Results of a randomized phase 2 study of clofarabine plus cytarabine (CA) vs clofarabine plus idarubicin (CI) vs clofarabine, idarubicin, plus cytarabine (CIA) as salvage therapy in acute myeloid leukemia (AML) . Blood. 2008 ; 112 : a964 . Google Scholar Crossref Search ADS 9. Amadori S , Stasi R , Martelli AM et al. Temsirolimus, an mTOR inhibitor, in combination with lower-dose clofarabine as salvage therapy for older patients with acute myeloid leukaemia: results of a phase II GIMEMA study (AML-1107) . Br J Haematol. 2012 ; 156 : 205 – 12 . Google Scholar Crossref Search ADS PubMed 10. Xie KC , Plunkett W . Deoxynucleotide pool depletion and sustained inhibition of ribonucleotide reductase and DNA synthesis after treatment of human lymphoblastoid cells with 2-chloro-9-(2-deoxy-2-fluoro-beta-D-arabinofuranosyl) adenine . Cancer Res. 1996 ; 56 : 3030 – 7 . Google Scholar PubMed 11. Sutton L , Guénel P , Tanguy ML et al. Acute myeloid leukaemia in human immunodeficiency virus-infected adults: epidemiology, treatment feasibility and outcome . Br J Haematol. 2001 ; 112 : 900 – 8 . Google Scholar Crossref Search ADS PubMed 12. Aboulafia DM , Meneses M , Ginsberg S et al. Acute myeloid leukemia in patients infected with HIV-1 . AIDS. 2002 ; 16 : 865 – 76 . Google Scholar Crossref Search ADS PubMed © American Society of Health-System Pharmacists 2019. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com. This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model)
TI - Delayed-onset effect of clofarabine in the treatment of an adult patient with acute myeloid leukemia
JO - American Journal of Health-System Pharmacy
DO - 10.1093/ajhp/zxy055
DA - 2019-02-21
UR - https://www.deepdyve.com/lp/oxford-university-press/delayed-onset-effect-of-clofarabine-in-the-treatment-of-an-adult-ymUb04lyZ0
SP - 349
VL - 76
IS - 6
DP - DeepDyve
ER -