ASH Clinical News February 2017 New | Page 23

CLINICAL NEWS

Adding clofarabine – a secondgeneration nucleoside analogue – to a standard induction regimen reduced the risk of relapse for patients with newly diagnosed acute myeloid leukemia ( AML ), but did not improve survival , compared with induction therapy alone , according to results of an openlabel , randomized , phase III study published in Blood . The drug did improve survival in a subset of patients with intermediate-risk AML but without NPM1 and FLT3-ITD gene mutations , though .

“ The results of the study show the additive anti-leukemic effect of clofarabine on top of an anthracycline-cytarabine-based remission-induction program : More early complete remissions ( CRs ) were accomplished , and the probability of relapse was substantially reduced ,” lead author Bob Löwenberg , MD , PhD , Editor-in-Chief of Blood and professor of hematology at Erasmus University Medical Center in Rotterdam in the Netherlands , told ASH Clinical News . “ However , the results also reveal an enhanced level of toxicity of the clofarabineenforced combination of induction chemotherapy .”

In this report from the HOVON-SAKK Cooperative Groups study , Dr . Löwenberg and

TABLE 2 . Treatment-Related Outcomes

Complete remission ( CR / CRi )

Early CR / CRi ( after cycle 1 )

Later CR / CRi ( after 2 cycles )

Control Induction Therapy ( n = 402 )

355 ( 88 %)

267 ( 66 %)

88 ( 22 %)

Early death (< 30 days ) 18 ( 4 %)

Death within 60 days 32 ( 8 %) authors prospectively evaluated the efficacy and safety of two induction regimens with or without clofarabine as an adjunct therapy in 795 patients newly diagnosed with AML ( n = 715 ) or higher-risk myelodysplastic syndromes ( n = 80 ; median age for all patients = 55 years ; range = 18-65 years ).

Patients were enrolled between February 25 , 2010 , and September 28 , 2013 , and were eligible for inclusion if they had an International Prognostic Scoring System of ≥1.5 and a World Health Organization performance status of ≤2 .

Patients were randomized to receive a standard 7 + 3 regimen of idarubicin plus cytarabine ( cycle 1 ) and amsacrine plus cytarabine ( cycle 2 ) with or without clofarabine 10 mg / m 2 on days one through five of each treatment cycle . A total of 402 patients received standard induction therapy alone , and 393 patients received induction plus clofarabine , in the following regimens :

• cycle 1 : idarubicin 12 mg / m 2 ( via a 3-hour infusion on days 1 , 2 , and 3 ) and cytarabine 200 mg / m 2 ( via continuous infusion on days 1-7 ) with or without clofarabine 10 mg / m 2 ( via a 1-hour infusion on days 1-5 )

Clofarabine Induction Therapy ( n = 393 )

352 ( 90 %)

298 ( 75 %)

59 ( 15 %)

21 ( 5 %)

33 ( 8 %)

OR / HR

1.14 ( 95 % CI 0.73-1.77 )

−

−

−

− p Value

Relapse 44 % 35 % − − Death 15 % 22 % − −

OR = odds ratio ; HR = hazard ratio ; CRi = complete remission with incomplete hematologic recovery ; EFS = event-free survival ; OS = overall survival ; RFS = relapse-free survival

• cycle 2 : amsacrine 120 mg / m 2 ( via 1-hour infusion on days 4 , 5 , and 6 ) and cytarabine 1,000 mg / m 2 ( administered intravenously for 3 hours twice daily on days 1-6 ) with or without clofarabine 10 mg / m 2 ( administered intravenously for 1 hour on days 1-5 )

The authors noted that the 10 mg / m 2 dose of clofarabine was used for the phase III portion of this study after results from the dose-finding run-in phase ( August to November 2010 ) found that patients treated with clofarabine 15 mg / m 2 experienced an increased rate of infections and other dose-limiting toxicities , compared with clofarabine 10 mg / m 2 . After cycle 2 , patients in CR or CR with incomplete hematologic recovery ( CRi ) went on to receive consolidation with additional chemotherapy with mitoxantrone-etoposide ( cycle 3 ; n = 206 ; 26 %), autologous hematopoietic cell transplantation ( HCT ) following busulfan plus cyclophosphamide ( n = 66 ; 8 %), or allogeneic HCT ( n = 331 ; 42 %).

At the four-year follow-up time point , there was no difference in event-free survival ( EFS ; primary endpoint ) or overall survival ( OS ) for those who received clofarabine versus those who did not ( 38 % vs . 35 % [ p = 0.024 ] for EFS ; 43 % vs . 44 % [ p = 0.57 ] for OS ). However , in a subgroup analysis , the addition of clofarabine improved EFS and OS for two groups of patients :

• Those with European-Leukemia- Net 2010 intermediate-risk AML :

0.57

−

−

−

−

0.32

26 % vs . 40 % ( p = 0.002 ) for EFS ; 29 % vs . 50 % ( p < 0.001 ) for OS

• Those with intermediate-risk AML and NPM1 wild-type / FLT3 without ITD mutations : 18 % vs . 40 % ( p < 0.001 ) for EFS and 22 % vs . 49 % ( p < 0.001 ) for OS

Rates of CR and CRi also were similar between the control and clofarabine groups ( 85 % vs . 84 % and 4 % vs . 5 %, respectively ), although more patients in the clofarabine groups achieved early CRs ( occurring after cycle 1 ; 66 % vs . 75 %; p value not reported ).

In the control group , 148 patients relapsed and 216 died ( including 48 deaths during the first CR ), compared with 114 relapses and 198 deaths ( including 66 deaths during the first CR ) for those treated with clofarabine ( TABLE 2 ).

Patients who received clofarabine experienced more grade 3 / 4 adverse events ( AEs ) and more infections after cycles 1 and 2 , the authors reported . Although time to neutrophil or platelet recovery did not differ between groups after cycle 1 , recovery was delayed in patients receiving clofarabine after cycle 2 .

In addition , compared with control patients , patients receiving clofarabine spent more nights in the hospital after cycle 2 ( 32 vs . 28 days ; p value not reported ) and cycle 3 ( median = 56 vs . 52 days ; p value not reported ). In addition , more patients who received induction therapy without clofarabine were able to proceed to consolidation therapy , compared with the clofarabine-treated group ( 48 and 22 patients , respectively ; p value not reported ).

“ Ultimately , survival was not significantly better for the clofarabine treatment regimen , based on the similarities in outcomes , but increased AEs , associated with clofarabine ,” Dr . Löwenberg told ASH Clinical News . However , he continued , “ it appears that clofarabine markedly improves survival in the subset of intermediaterisk AML , and the promise of clofarabine seems greatest in [ such patients ].”

The authors noted the integration of clofarabine therapy “ on top of an already quite intensive chemotherapy schedule ” as a potential limitation of the study , as it may have increased toxicities . In addition , the study was not blinded to clofarabine treatment . Future studies should evaluate whether different dosing of clofarabine ( or the backbone therapies ) could circumvent the added toxicity .

REFERENCE

Löwenberg B , Pabst T , Maertens J , et al . Therapeutic value of clofarabine in younger and middle aged ( 18-65 years ) adults with newly diagnosed AML . Blood . 2017 January 3 . [ Epub ahead of print ]

ASHClinicalNews . org ASH Clinical News

21