Where Does Clofarabine Fit in the Treatment of Patients With Acute Myeloid Leukemia?

Adding clofarabine – a second-generation 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 open-label, 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 clofarabine-enforced combination of induction chemotherapy.”

In this report from the HOVON-SAKK Cooperative Groups study, Dr. Löwenberg and 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/m2 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/m2 (via a 3-hour infusion on days 1, 2, and 3) and cytarabine 200 mg/m2 (via continuous infusion on days 1-7) with or without clofarabine 10 mg/m2 (via a 1-hour infusion on days 1-5)
  • cycle 2: amsacrine 120 mg/m2 (via 1-hour infusion on days 4, 5, and 6) and cytarabine 1,000 mg/m2 (administered intravenously for 3 hours twice daily on days 1-6) with or without clofarabine 10 mg/m2 (administered intravenously for 1 hour on days 1-5)

The authors noted that the 10 mg/m2 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/m2 experienced an increased rate of infections and other dose-limiting toxicities, compared with clofarabine 10 mg/m2. 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: 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).

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 intermediate-risk 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]

TABLE. Treatment-Related Outcomes
  Control Induction Therapy

(n=402)

Clofarabine Induction Therapy

(n=393)

OR/HR p Value
Complete remission (CR/CRi) 355

(88%)

352

(90%)

1.14

(95% CI 0.73-1.77)

0.57
   Early CR/CRi
(after cycle 1)
267

(66%)

298

(75%)

   Later CR/CRi
(after 2 cycles)
88

(22%)

59

(15%)

Early death (<30 days) 18

(4%)

21

(5%)

Death within 60 days 32

(8%)

33

(8%)

EFS at four years 35% 38% 0.90

(95% CI 0.75-1.07)

0.24
No CR 15% 13%
Relapse 38% 30%
Death 13% 29%
OS at four years 43% 44% 0.95

(95% CI 0.78-1.15)

0.57
RFS at four years 41% 44% 0.90

(95% CI 0.74-1.10)

0.32
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

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