Three-Drug Combo 'Highly Effective' in Acute Myeloid Leukemia

Kate Johnson

March 31, 2020

A new combination of old drugs may be good news for patients with relapsed or refractory acute myeloid leukemia (AML).

By combining lower doses of clofarabine and cytarabine with mitoxantrone (CLAM), researchers found an apparent sweet spot, balancing efficacy with toxicity and achieving "unexpectedly" higher response rates than have been seen with previously tried clofarabine-containing regimens.

"CLAM was highly effective in bridging refractory/relapsed patients to allogeneic HSCT [hematopoietic stem cell transplant] and this was achieved without significant toxicity that compromised the procedure," report Yok-Lam Kwong, MD, and colleagues from the University of Hong Kong, China.

Rates of complete and sustained remission were also high, even among patients who did not undergo allogeneic HSCT, they note.

In addition, efficacy was "not apparently affected by high-risk karyotypes and genetic mutations," they add.

The findings come from a phase 2 study published on March 18 in Cancer Medicine.

CLAM Is Readily Available

"Treatment of refractory/relapsed AML has become more oriented toward targeting of individual gene mutations," note the authors, but they add that "in this era of molecular targeting, CLAM might still have a role to play.

"It offers the advantage of a highly effective regimen that is readily available," they continue. "It provides a median [duration of response] of 5 months, which is meaningful for organization of hematological stem cell transplant (HSCT). Delays associated with recruitment into clinical trials or sourcing of targeted drugs are obviated. Precious time is saved, so that patients can quickly be bridged to a potentially curative allogeneic HSCT."

Consideration of this new regimen is especially important in Asia, coauthor Harinder Gill, MD, told Medscape Medical News.

The new targeted therapies such as enasidinib, ivosidinib, gilteritinib, glasdegib, "to name a few, can hardly be made available to Asian countries," said Gill, who is also from the University of Hong Kong. "Whether this is marketing or commercially oriented is beyond our scope. It is important for the pharmaceutical companies to cover a wider scope and benefit patients. There is a huge unmet need in terms of sourcing targeting therapy in Asia."

Study Details

The phase 2 study included 52 adult AML patients (median age, 46 years) whose disease was either refractory to first-line induction with the 3+7 daunorubicin/cytarabine combination or who experienced relapse after 3+7 induction and high-dose cytarabine consolidation.

All patients received CLAM, which comprised clofarabine (30 mg/m2/d, days 1–5), cytarabine (750 mg/m2/d, days 1–5), and mitoxantrone (12 mg/m2/d, days 3–5).

Patients who achieved remission received up to two consolidation cycles of 50% CLAM; eligible patients were bridged to allogeneic HSCT.

The overall response rate after the first cycle of CLAM was 90.4% (complete remission [CR], 69.2%; CR with incomplete hematologic recovery [CRi], 21.2%).

Among the 22 CR/CRi patients who went on to receive allogeneic HSCT, 2-year overall survival (OS) was 65.8%, relapse-free survival (RFS) was 45.7%, and event-free survival (EFS) was 40.2%.

Among 25 patients did not receive allogeneic HSCT, seven patients remained in continuous CR after a median follow-up of 13 months, and 18 experienced relapse, with a "dismal" outcome, according to the authors.

Multivariate analyses showed that superior OS was associated with CR after CLAM (P = .005) and allogeneic HSCT (P = .005). Superior RFS and EFS were associated with allogeneic HSCT (P < .001).

"Remarkably, CR after CLAM and allogeneic HSCT resulted in 2-year OS of 84.3% and 90%, respectively," they report, adding that "karyotypic aberrations and genetic mutations did not influence responses or survivals."

Toxicity of the therapy was manageable, the main toxicity being hematologic.

"All cases developed grade 3 neutropenia, thrombocytopenia, and neutropenic fever requiring empirical antibiotics. However, with vigorous supportive care and G-CSF administration, none of these patients developed serious infective complications," they note.

Other nonhematologic toxicities were "mild and uncommon," they add. There was no treatment-related mortality, no patients were admitted to the intensive care unit, and there was no compromise of performance of allogeneic HSCT.

Coauthor Gill commented that a future randomized controlled trial of this CLAM regimen vs standard approaches in relapsed/refractory AML should also challenge the "3+7 induction in AML, especially in patients with intermediate and poor risk AML."

Cancer Med. Published online March 18, 2020. Full text

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