CLAM in R/R AML: High response rates, effective bridge to allo-HSCT

One cycle of clofarabine, cytarabine and mitoxantrone (CLAM) achieves an overall response rate (ORR) of >90 percent with a complete remission (CR) rate of nearly 70 percent in a phase II study of Hong Kong patients with refractory/relapsed acute myeloid leukaemia (R/R AML).

“For induction failures, salvage with other intensive regimens leads to a poor ORR of <40 percent,” commented the researchers. [Leukemia 2017;31:1306-1313]

The study included 26 men and 26 women (median age, 46 years) with AML, who were refractory to first-line 3 + 7 daunorubicin/cytarabine induction or relapsed following 3 + 7 induction and high-dose cytarabine consolidation. All patients completed the first cycle of clofarabine (30 mg/m²/d on days 1–5), cytarabine (750 mg/m²/d, days 1–5) and mitoxantrone (12 mg/m²/d, on days 3–5), achieving an ORR of 90.4 percent (CR, 69.2 percent; CR with incomplete haematological recovery [CRi], 21.2 percent). [Cancer Med 2020, doi: 10.1002/cam4.2865]

“In designing CLAM, we reduced the dose of clofarabine and cytarabine [normally used for R/R AML], with the objective of decreasing infection risks to facilitate subsequent allogeneic haematopoietic stem cell transplantation [allo-HSCT]. To maintain efficacy, we added mitoxantrone, which is active in refractory AML,” explained the researchers. [Curr Treat Options Oncol 2017;18:17]

The 2-year rates of overall survival (OS), relapse-free survival (RFS) and event-free survival (EFS) were 65.8 percent, 45.7 percent and 40.2 percent, respectively. Univariate and multivariate analyses showed that significantly superior OS was associated with CR after CLAM and allo-HSCT (p range, 0.005–0.02). “Remarkably, patients achieving CR after CLAM therapy had a 2-year OS rate of 84.3 percent, and patients receiving allo-HSCT had a 2-year OS rate of 90 percent, and RFS and EFS rates of 76.4 percent,” reported the researchers.

“Unexpectedly, CLAM was much more active, achieving results which were apparently superior to those of other clofarabine/cytarabine and clofarabine/mitoxantrone combinations,” noted the researchers. [Blood 2005;105:940-947; Br J Haematol 2011;155:182-189; J Clin Oncol 2012;30:2492-2499; Clin Lymphoma Myeloma Leuk 2015;15:41-46]

The median duration of response (DoR) for all responding patients was 5 months. The DoR was comparable between CR and CRi patients (5.5 months and 4 months, respectively; p=0.67). For CR/CRi patients undergoing allo-HSCT (n=22), the median DoR was 5.5 months, which was similar to the average DoR of 5 months achieved by patients not undergoing allo-HSCT (n=30; p=0.49). “A median DoR of 5 months is meaningful for organization of HSCT,” noted the researchers.

Of the 22 patients who underwent allo-HSCT, nine had the procedure immediately after CLAM reinduction and 13 after CLAM consolidation. While no treatment-related deaths occurred, acute and chronic graft-vs-host disease was observed in 11 patients and 7 patients, respectively. After a median follow-up of 21.5 months post-HSCT, there were three relapses.

“The main toxicity of CLAM was haematologic and all patients developed grade 3 neutropenia, thrombocytopenia, and neutropenic fever requiring empirical antibiotics,” reported the researchers. “However, toxicity was manageable and did not compromise subsequent allo-HSCT, which, when performed after CLAM-induced CR/CRi, resulted in excellent survival.”

“In this era of molecular targeting, CLAM offers the advantage of a highly effective and readily available regimen, which obviates the delays associated with recruitment into clinical trials or sourcing of targeted drugs. As precious time is saved, patients can quickly be bridged to potentially curative allo-HSCT,” concluded the researchers.