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Nilotinib Plus Chemotherapy Yields Encouraging Results for Patients with Ph-Positive ALL

December 30, 2021

Nilotinib, when used in combination with multi-agent chemotherapy, achieved "deep" molecular responses similar or better than those achieved with imatinib in patients with Philadelphia-positive acute lymphocytic leukemia (Ph-ALL), according to results of a phase II trial recently published in Blood.

In a previous phase III, randomized clinical trial nilotinib – a highly selective BCR-ABL1 tyrosine kinase inhibitor (TKI) – helped patients with chronic myeloid leukemia achieve significantly higher rates of molecular response compared with imatinib, the authors of the current study, led by Dae-Young Kim, MD, PhD, wrote. Given this outcome, Dr. Kim, from the University of Ulsan College of Medicine in Seoul, Korea, and colleagues sought to evaluate the feasibility, efficacy, and safety of nilotinib plus multi-agent chemotherapy compared with imatinib in adult patients with Ph-ALL.

"Nilotinib achieved deeper molecular response [in the post-remission setting] than imatinib, and the adverse events were tolerable," Dr. Kim told ASH Clinical News. "We highly recommend the use of nilotinib as a first-line agent for the treatment of Philadelphia-positive ALL, if it is approved by the U.S. Food and Drug Administration."

Patients were eligible for inclusion in the multicenter, single-arm, prospective study if they were 15 years of age or older, were diagnosed with ALL or biphenotypic acute leukemia, and carried the Philadelphia chromosome.

All patients received induction chemotherapy (vincristine, daunorubicin, and prednisone) with nilotinib started eight days following induction therapy at a dose of 400 mg administered twice daily. Nilotinib therapy was continued until the start of allogeneic hematopoietic cell transplantation (alloHCT) or until the end of consolidation therapy. After achieving complete hematologic remission (CHR), patients received either five courses of consolidation followed by two-year maintenance therapy with nilotinib, or alloHCT. Minimal residual disease (MRD) was assessed at CHR and then every three months.

A total of 90 patients from 17 centers were included in the study, 82 of whom achieved CHR, for a CHR rate of 91 percent. Median time to CHR was 27 days (range, 13-72 days). Fifty-seven of these patients (70%) later went on to receive alloHCT; median time to alloHCT was 3.8 months after CHR (range, 1.4-8 months).

More than half of patients who achieved CHR also achieved complete molecular remission (CMR; 53%, or 48 patients), defined as a negative MRD when the BCR-ABL1/G6PDH ratio was <1×10-5. Cumulative rates of CMR were 86 percent among all patients and 94 percent among patients who achieved CHR. At two years, the rate of hematologic relapse-free survival (HRFS) was 72 percent among patients who achieved CHR; two-year molecular relapse-free survival rate was 63 percent among the 76 patients who achieved CMR.

The 57 patients who underwent alloHCT had a lower incidence of overt hematologic relapse than those who did not: 19 percent and 41 percent, respectively. In addition, patients receiving alloHCT had a significantly higher estimated two-year HRFS rates than non-recipients (78% vs. 49%; p=0.045). The two-year overall survival, however, was similar between those receiving alloHCT and those who did not (80% vs. 72%, respectively; p=0.227).

A significant portion of patients who failed to achieve a good molecular response (defined as a BCRABL1/G6PDH ratio of ≤1×10-3) at three months after HCR could be rescued successfully with alloHCT, Dr. Kim and investigators stressed, suggesting that alloHCT continued to play a significant role in treating Ph-positive ALL – even after the advent of potent TKIs.

Adverse events associated with nilotinib (including jaundice, gastrointestinal issues, serum lipase elevations, and pancreatitis) occurred mostly during the induction phase of therapy and were reversible with dose reduction or transient interruption of nilotinib. Most of the adverse events were tolerable, according to the researchers.

Because the study was not performed in a randomized, comparative fashion, the advantages of treatment with nilotinib over other TKIs were not definitively demonstrated. "Although the combination of nilotinib and chemotherapy was feasible," they noted, "the adverse events cannot be overlooked." Future studies should evaluate whether nilotinib – compared with other TKIs imatinib and dasinitib – improves the outcome of Ph-ALL by decreasing rates of hematologic relapse and the need for alloHCT, they added.

"Although the non-relapse mortality rate was relatively high, due to high doses of anthracycline and nilotinib during induction," Dr. Kim and authors concluded, "we found a high cumulative incidence of complete molecular response (negative MRD) and hematologic relapse-free survival rates, comparable to those reported previously with imatinib or dasatinib."


Kim DY, Joo YD, Lim SN, et al. Nilotinib combined with multi-agent chemotherapy for newly diagnosed Philadelphia-positive acute lymphoblastic leukemia. Blood. 2015 June 11. [Epub ahead of print].


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