Clofarabine in Clinical Haematology

Pharmacotherapy Angeline Taal 1 2011.09.30 14:25:24 +02'00' Clofarabine in clinical haematology

T. Lodewyck

Clofarabine is a second-generation nucleoside analogue which has been rationally developed with the aim to combine the therapeutic qualities and avoid the toxic limitations of fl udarabine and cladribine. Clofarabine has been reimbursed in Belgium for the treatment of paediatric patients up to the age of 21 years with relapsed or refractory Acute Lymphatic Leukaemia (ALL) after two or three preceding regimens respectively. Clinical effi cacy has also been demonstrated in newly diagnosed and advanced Acute Myoblastic Leukaemia (AML). The drug is currently being investigated in several randomised trials in AML and ALL and as part of the conditioning regimen prior to stem cell transplantation. This article fo- cuses on the pharmacology, toxicity and clinical effi cacy of clofarabine. (Belg J Hematol 2012;3:17-22)

Introduction Pharmacology: molecular structure Clofarabine is a second-generation nucleoside and mechanism of action analogue and is structurally related to fl udarabine Two features characterise the molecular structure and cladribine which are widely used in the of clofarabine [2-chloro-9-(2’-deoxy-2’-fl uoro-b-d- treatment of lymphoproliferative disorders.1 The arabinofuranosyl)-9H-purine-6-amine; Cl-F-ara-A; drug has been rationally designed in an attempt to CAFdA; 2-chloro-9-(2’-deoxy-2’-fl uoro-beta-D- combine the therapeutic qualities and overcome arabinofuranosyl)-adenine].1 As illustrated in Figure the toxic limitations of its congeners. Although 1, clofarabine has a chloro-atom at the 2-position developed in the 1980’s, there has been little of the adenine ring which confers resistance to interest in its development until 1993 when the degradation by intracellular adenosine deaminase. fi rst preclinical and animal studies were initiated at Halogenation at the 2-position of adenine is also MD Anderson Cancer Center. Human phase I trials the case for fl udarabine (fl uor-atom) and cladribine took off in 1998 and the drug was approved by (chloro-atom) which are equally resistant to the Food and Drug Administration (FDA) in 2004 deamination. However, in contrast to its congeners, for treatment of relapsed and refractory ALL in clofarabine has an additional fl uorine at the children and adolescents up to the age of 21 years. 2’-position of the ribose ring. This modifi cation Approval by the European Medicines Agency (EMA) renders the drug less susceptible to bacterial E. followed in 2006. Clofarabine has been reimbursed coli purine nucleoside phosphorylase in the gastro- in Belgium for patients ≤21 years with relapsed intestinal (GI) tract and increases its resistance to or refractory ALL having received two or three hydrolysis in acidic environments. Purine nucleoside preceding regimens respectively. This article reviews phosphorylase may cleave the glycosidic bond the pharmacology, toxicities and clinical effi cacy of between the ribose and purine ring of fl udarabine clofarabine. and cladribine. This may lead to the production By advertising in the Belgian Journal of Hematology (BJH) you’ll gain direct access to all key opinion leaders of a halogenated adenine which is a neurotoxic in Hematology and adherent fields in Belgium. Specialists using this educational journal on a daily basis for keeping up with the latest developments in their field. Reach out to our 850 readers and ensure daily prescription of your drug(s). Now place your order for a product advertisement, advertorial, insert or other promotional item, by contacting us by telephone or e-mail: Author: T. Lodewyck, MD, Department of Hematology, AZ Sint-Jan Brugge-Oostende AV, Ruddershove 10, 8000 Brugge, e-mail: [email protected]. ARiez iNteRNAtioNAl BV, telepHoNe: 0031-75-6429420 Confl ict of interest: The author has nothing to disclose and indicates no potential confl icts of interest. Key words: Clofarabine, acute leukaemia, nucleoside analogue. e-mAil: [email protected] oR ViSit: www.ARiez.com

Ariez international BV, Nieuweweg 108 A, 1531 AH Wormer, The Netherlands; P.O. Box 271, 1520 AG Wormerveer, Belgian Journal of Hematology Volume 3, Issue 1, March 2012 The Netherlands, tel: +31-75-6429420; fax: +31-75-6429421; web: www.ariez.com 17 Pharmacotherapy

derivative without antitumour effect. Substitution hand-foot syndrome are observed in a minority of a fl uorine at the 2’-position of the ribose moiety of patients. Signs and symptoms of a cytokine will eventually lead to a better stability in the GI release–like event in relation to the administration tract and less side-effects of clofarabine compared of clofarabine have been noticed in several patients. to the fi rst-generation nucleoside analogues. Symptoms included fever, chills, hypotension and Enhanced stability in the GI tract improves oral bio- respiratory distress. Whether this really constitutes availability and makes clofarabine an attractive drug a drug-induced cytokine release syndrome is not for oral use. Similar to other nucleoside analogues, certain since many patients concomitantly suffered clofarabine requires intracellular phosphorylation from sepsis or tumor lysis syndrome. Prophylactic to its triphosphate form by deoxycytidine kinase use of steroids prior to the infusion of clofarabine (dCyd kinase) to become active. Clofarabine may be considered for this purpose. Finally, renal exhibits greater affi nity to dCyd kinase and failure has been observed in a substantial (15- prolonged retention in leukaemic blasts compared 20%) proportion of elderly patients who received to fl udarabine and cladribine. While fl udarabine clofarabine.6,7 All these patients had concomitant preferably inhibits DNA polymerases, cladribine is sepsis or hypotension or use of nephrotoxic drugs primarily an inhibitor of ribonucleotide reductase that may have impaired renal function. However, a (RNR). Clofarabine inhibits both DNA polymerases direct nephrotoxic effect of clofarabine cannot be and RNR. This results in impaired DNA synthesis excluded. through inhibition of DNA elongation as well as depletion of deoxyribonucleotides. Furthermore, clofarabine shows activity in non-dividing cells and Clinical effi cacy cells with a low proliferation rate, probably through Acute lymphoblastic leukaemia disruption of mitochondria with release of pro- Children and adolescents apoptotic mitochondrial factors. The MTD of clofarabine for paediatric patients with relapsed and refractory acute leukaemia has been determined to be 52 mg/m² intravenously per day for Toxicity 5 days.2 DLTs occurred at 70mg/m². One patient had Phase I studies have defi ned the dose-limiting grade 4 hyperbilirubinaemia and grade 3 elevation toxicities (DLT) and maximum tolerated dose of transaminases, another patient experienced grade (MTD) of clofarabine for patients with acute 3 skin rash. A complete remission rate (CR) of 24% leukaemia.2,3 The MTD has been established at was observed in 17 heavily pretreated ALL patients. 40mg/m2 intravenous daily for 5 days in adults and One third of patients had undergone prior stem 52mg/m2 in children. Grade 3 and 4 elevations of cell transplantation. The remissions achieved with transaminases and bilirubin were dose-limiting in clofarabine were durable enough to allow several both paediatric and adult patients with advanced patients to proceed to stem cell transplantation. In leukaemia. Phase II studies confi rmed the 2002, a multicenter phase II study started enrolling occurrence of severe hepatotoxicity in 25% to 45% pediatric patients with relapsed or refractory ALL.3 of patients. Liver enzymes usually peak between days Median age was 12 years (range, 1 to 20 years). One 5- 7 and normalise by day 15.4,5 Apart from transient third of the 61 patients relapsed after earlier stem cell liver toxicity, most patients experience grade 3 to transplantation and the median number of previous 4 myelosuppression. Median time to neutrophil induction regimens was 3. An overall response rate (>500/µl) and platelet (>100000/µl) recovery (ORR) of 30% [20% CR/CR with incomplete platelet is approximately 28 days and thus comparable to recovery (CRp) and 10% partial remission (PR)] was what is expected following intensive chemotherapy achieved with a median of 2 cycles of clofarabine regimens. Febrile neutropaenia is frequent and at 52mg/m²/day for 5 days. These results led to occurs in up to 75% of patients. Gastro-intestinal FDA approval of clofarabine for patients aged 1-21 toxicities such as nausea, anorexia and diarrhea years who suffer from relapsed or refractory ALL are frequently observed but of limited severity and after at least two preceding regimens. One potential usually do not exceed grade 1 or 2. Skin rash and strategy to improve on these results is to combine

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clofarabine with other chemotherapeutic drugs. The most extensively studied drug combination in paediatric ALL is clofarabine with cyclophosphamide and etoposide. The rationale for this combination is that pretreatment with clofarabine might hamper repair of cyclophosphamide and etoposide induced DNA-damage and lead to increased apoptotic cell death. A phase I study determined the MTDs of clofarabine, cyclophosphamide and etoposide to be 40mg/m², 440mg/m² and 100mg/m² respectively, each daily for fi ve consecutive days. An ORR of 55% was observed in this study.8 Locatelli et al explored a slightly different dosage scheme. Twenty-fi ve patients with refractory or multiply relapsed ALL received clofarabine 40mg/m², cyclophosphamide Figure 1. Molecular structure of clofarabine. Clofarabine 400mg/m² and etoposide 150mg/m² for 5 days.9 has a chloro-atom at the 2-position of the adenine ring and This combination yielded a CR rate of 54% and a fl uorine at the 2’-position of the ribose ring. permitted half of the responding patients to proceed to stem cell transplantation. While 76% of B-ALL patients (n=17) responded, the response rate in AML. Kantarjian et al. reported on 31 patients with T-ALL (n=8) was only 12%. This combination AML in 1st or subsequent relapse.5 Clofarabine at regimen was well-tolerated with reversible liver 40mg/m² intravenously per day for 5 days yielded function abnormalities, profound myelosuppression an overall response rate of 55% (42% CR and 13% and febrile neutropaenia being the most common CRp). The majority (80%) of patients achieving CR toxicities. There were no treatment-related deaths. did so after 1 treatment cycle. A long duration of fi rst CR (≥12m) was associated with an improved Adults response rate of 87%. Encouraging responses were In contrast to childhood ALL, the experience as also observed in patients who received clofarabine well as the results with clofarabine in adult ALL as 2nd or subsequent salvage treatment. Interestingly, are limited. An ORR below 20% was noted in 25 CR rates were comparable for patients with poor- patients with advanced ALL treated with clofarabine risk cytogenetics and those without. Median 40mg/m² days 1-5 in phase I and II studies, almost duration of response was less than six months half the response rate observed in the paediatric and overall survival for the entire cohort was seven trials.3,5 Scarce but promising data are available from months. Promising results in relapsed/refractory phase I/II studies on the combination of clofarabine AML inspired several study groups to investigate and cyclophosphamide. Four out of 6 ALL patients single agent clofarabine as front-line treatment treated in a Phase I study of clofarabine followed by for patients who are not considered suitable for cyclophosphamide were responsive.10 A randomised intensive induction chemotherapy. In this setting, intergroup study of EORTC and HOVON (EORTC/ clofarabine has been studied at slightly lower doses HOVON 100 trial) in which several Belgian centres of 30mg/m² for fi ve days in induction and 20mg/ are participating, is currently investigating the value m² in consolidation. Two comparable phase II of clofarabine when applied during the prephase and studies conducted concurrently in the United States consolidation phase of intensive fi rst-line treatment (USA) and Europe have investigated single agent of adult ALL patients. clofarabine in newly diagnosed AML.6,7 Median age was 71 years. Rates of response and early death were very similar for both trials. An overall Acute myeloid leukaemia response rate (CR and CRp) of 47% and day 30 all- Phase II studies have evaluated the effi cacy of cause mortality below 10% were observed in both single agent clofarabine in refractory or relapsed studies. Moreover, these results compare favourably

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to outcomes after standard 3+7 induction study explored oral clofarabine in 32 patients with therapy in elderly patients with AML.11 Although previously treated high-risk MDS.18 Two thirds of similar with respect to haematologic toxicity and patients had received prior hypomethylating agents. incidence of infections, non-haematological side- Median age of patients was 70 years. The starting effects of clofarabine appear to be less severe and dose of clofarabine was 40mg/m² orally per day for 5 better tolerated. Currently, a randomised ECOG days. As the bioavailability of clofarabine is estimated trial is comparing clofarabine to the 3+7 regimen at 50%, this is approximately half the intravenous as fi rst-line treatment for elderly patients with dose of 40mg/m². However, this dose was found to AML. Furthermore, several randomised trials are be too toxic and dose de-escalations to 30mg/m² exploring clofarabine combinations versus intensive and even 20mg/m² were necessary, mainly because chemotherapy regimens in newly diagnosed AML. of protracted thrombocytopaenia or neutropaenia The most extensively studied combination in and infectious complications. Non-haematological AML is clofarabine with cytarabine.12-14 Preclinical toxicity was acceptable with gastro-intestinal and experiments have demonstrated that pretreatment cutaneous side-effects most frequently reported. with clofarabine increases the level of intracellular An ORR of 43% and CR rate of 25% was observed cytarabine-triphosphate in the leukaemic blasts.13 with a median of 2 treatment cycles. Clofarabine has A phase II study by Faderl et al. investigated the been evaluated as fi rst-line therapy for MDS. Faderl combination of clofarabine and cytarabine in newly et al. performed a randomised comparison between diagnosed AML.12 Sixty patients with a median intravenous clofarabine at 30mg/m² and clofarabine age of 61 years were treated with clofarabine plus low-dose cytarabine (20mg/m² subcutaneously 40mg/m² intravenously daily (day - 6) followed by for 14 days).19 The clofarabine combination was cytarabine 1g/m² (days 1-5) four hours later. An associated with signifi cantly higher CR rates (63% ORR of 60% (52% CR and 8% CRp) was observed versus 31%), less induction mortality (19% versus and four patients died during induction. Patients 31%) and improved EFS (7 months versus 1.7 reaching CR demonstrated a median remission months). Overall survival however did not differ duration and median OS of eight months and 23.5 between the two arms. months respectively. Other combinations including clofarabine and idarubicine with or without cytarabine as well as clofarabine in combination Non-Hodgkin lymphomas with daunorubicine and gemtuzumab ozogamycin The MTD of clofarabine for patients with have shown feasibility and effi cacy in phase I/ lymphomas has been determined to be 4mg/m² II trials.15,16 These clofarabine combinations are daily for fi ve days in the initial phase I study.3 DLT now being examined in several randomised trials was myelosuppression at higher doses. Nabhan et in young (e.g. HOVON 102) and elderly patients al. confi rmed the MTD of 4mg/m².20 In the phase II with newly diagnosed AML. Finally, the above- part of their study, 31 patients with refractory non- mentioned combination of clofarabine with cytarabine Hodgkin lymphomas received clofarabine 4mg/m². has been compared to single agent cytarabine as Twenty-four percent of patients failed after previous salvage treatment for relapsed or refractory AML in stem cell transplantation and 72% were rituximab- the CLASSIC I trial.17 Although a higher CR rate was refractory. An overall response rate of 42% (23% CR achieved in the experimental arm, the primary end- and 19% PR) with a median response duration of point of overall survival improvement was not reached. fi ve months was observed.

Myelodysplastic syndromes Stem cell transplantation A small number of studies have evaluated clofarabine Fludarabine is widely used in non-myeloablative in relapsed and newly diagnosed MDS. Out of conditioning regimens prior to allogeneic stem eight patients with relapsed MDS, four responded cell transplantation. A limited number of phase I/ to intravenous clofarabine 40mg/m² daily for ﬁ ve II studies have explored the safety and efﬁ cacy of days in the initial phase II study.5 A subsequent clofarabine as part of myeloablative as well as non-

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Key messages for clinical practice

1. Clofarabine is a second-generation nucleoside analogue which has been designed to combine the therapeutic qualities while avoiding the toxicities of ﬂ udarabine and cladribine.

2. The main side-effects are liver toxicity and myelosuppression.

3. Clofarabine is reimbursed in Belgium for treatment of patients ≤21 years with relapsed or refractory ALL.

4. Efﬁ cacy has also been demonstrated in newly diagnosed and advanced AML.

5. Randomised ﬁ rst-line studies in ALL and AML are ongoing.

myeloablative preparative regimens. Magenau et References al. examined increasing doses of clofarabine up 1. Ghanem H, Jabbour E, Faderl S, et al. Clofarabine in leukaemia. Expert Rev to 40mg/m² in combination with intravenous Hematol. 2010;3(1):15-22. busulphan prior to T-cell replete stem cell 2. Jeha S, Gandhi V, Chan KW, et al. Clofarabine, a novel nucleoside analog, is transplantation for non-remission haematologic active in pediatric patients with advanced leukaemia. Blood. 2004;103:784-9. malignancies, mainly refractory AML.21 The MTD 3. Kantarjian HM, Gandhi V, Kozuch P, et al. Phase I clinical and pharmacology of clofarabine was not reached. Forty-six patients study of clofarabine in patients with solid and hematologic cancers. J Clin with a median age of 53 years were included. All Oncol. 2003;21:1167-73. patients engrafted and 80% entered into remission 4. Jeha S, Gaynon PS, Razzouk BI, et al. Phase II study of clofarabine in after transplantation. Non-relapse mortality and pediatric patients with refractory or relapsed acute lymphoblastic leukaemia. J OS at 2 years from transplantation were 31% and Clin Oncol. 2006;24:1917-23. 28% respectively. This regimen was feasible with 5. Kantarjian H, Gandhi V, Cortes J, et al. Phase 2 clinical and pharmacologic grade 3 and 4 liver toxicity and mucositis being the study of clofarabine in patients with refractory or relapsed acute leukaemia. most common complications. Limited evidence is Blood. 2003;102:2379-86. available to suggest a role for clofarabine as part of 6. Kantarjian HM, Erba HP, Claxton D, et al. Phase II study of clofarabine the high-dose therapy prior to autologous stem cell monotherapy in previously untreated older adults with acute myeloid leukaemia transplantation.22 and unfavorable prognostic factors. J Clin Oncol. 2010;28:549-55. 7. Burnett AK, Russell NH, Kell J, et al. European development of clofarabine as treatment for older patients with acute myeloid leukaemia considered Conclusion unsuitable for intensive chemotherapy. J Clin Oncol. 2010;28:2389-95. Clofarabine has proven to be a valuable new 8. Hijiya N, Gaynon P, Barry E, et al. A multi-center phase I study of treatment modality for young and older patients clofarabine, etoposide and cyclophosphamide in combination in pediatric with acute leukaemia. The greatest benefi t at patients with refractory or relapsed acute leukaemia. Leukaemia. present is probably for children and young adults 2009;23:2259-64. with advanced leukaemia who are offered an 9. Locatelli F, Testi AM, Bernardo ME, et al. Clofarabine, cyclophosphamide and additional opportunity to proceed to allogeneic etoposide as single-course re-induction therapy for children with refractory/ stem cell transplantation in remission. The place multiple relapsed acute lymphoblastic leukaemia. Br J Haematol. 2009;147:371-8. of clofarabine in the fi rst-line treatment of acute 10. Karp JE, Ricklis RM, Balakrishnan K, et al. A phase 1 clinical-laboratory myeloid leukaemia and acute lymphoblastic study of clofarabine followed by cyclophosphamide for adults with refractory leukaemia still needs to be determined and will acute leukaemias. Blood. 2007;110:1762-9. hopefully be clarifi ed by several currently ongoing 11. Estey EH. How I treat older patients with AML. Blood 2000;96:1670-1673. randomised studies. 12. Faderl S, Gandhi V, O’Brien S, et al. Results of a phase 1-2 study of

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clofarabine in combination with cytarabine (ara-C) in relapsed and refractory 18. Faderl S, Garcia-Manero G, Estrov Z, et al. Oral clofarabine in the treatment acute leukaemias. Blood. 2005;105:940-7. of patients with higher-risk myelodysplastic syndrome. J Clin Oncol. 13. Gandhi V, Kantarjian H, Faderl S, et al. Pharmacokinetics and 2010;28:2755-60. pharmacodynamics of plasma clofarabine and cellular clofarabine triphosphate 19. Faderl S, Ravandi F, Huang X, et al. A randomised study of clofarabine in patients with acute leukaemias. Clin Cancer Res. 2003;9:6335-42. versus clofarabine plus low-dose cytarabine as front-line therapy for patients 14. Faderl S, Verstovsek S, Cortes J, et al. Clofarabine and cytarabine aged 60 years and older with acute myeloid leukaemia and high-risk combination as induction therapy for acute myeloid leukaemia (AML) in patients myelodysplastic syndrome. Blood. 2008;112:1638-45. 50 years of age or older. Blood. 2006;108:45-51. 20. Nabhan C, Davis N, Bitran JD, et al. Efﬁ cacy and safety of clofarabine in 15. Faderl S, Ferrajoli A, Wierda W, et al. Clofarabine combinations as acute relapsed and/or refractory non-Hodgkin lymphoma, including rituximab- myeloid leukaemia salvage therapy. Cancer. 2008;113:2090-6. refractory patients. Cancer. 2011;117:1490-7. 16. Burnett AK, Kell WJ, Hills RK, et al. The Feasibility of Combining 21. Magenau J, Tobai H, Pawarode A, et al. Clofarabine and busulfan conditioning Daunorubicin, Clofarabine and Gemtuzumab Ozogamicin Is Feasible and facilitates engraftment and provides signiﬁ cant anti-tumor activity in non- Effective. A Pilot Study. Blood (ASH Annual Meeting Abstracts), 2006;108:1950. remission hematologic malignancies. Blood. 2011 Aug 12. [Epub ahead of print] 17. Kantarjian H, Wetzler M, Rizzieri D, et al. Clofarabine Ara-C improves 22. Srivastava S, Jones D, Wood LL, et al. A phase I trial of high-dose clofarabine, response rates and event-free survival, not overall survival, in older patients with etoposide, and cyclophosphamide and autologous peripheral blood stem cell relapsed/refractory AML compared to Ara-C alone: updated CLASSIC I study transplantation in patients with primary refractory and relapsed and refractory results. EHA Annual Meeting Abstracts, 2011, Abstract 0470. non-Hodgkin lymphoma. Biol Blood Marrow Transplant. 2011;17:987-94.

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