Results of allogeneic hematopoietic stem cell transplantation for chronic myelogenous leukemia patients who failed tyrosine kinase inhibitors after developing BCR-ABL1 kinase domain mutations

Abstract

Hematopoietic stem cell transplantation (HSCT) is effective therapy for patients with chronic myelogenous leukemia (CML) but is now mostly indicated for patients who develop resistance to tyrosine kinase inhibitors (TKIs), which can be associated with point mutations in BCR-ABL1. We reviewed the outcomes of imatinib-resistant CML patients (chronic phase, n ‫؍‬ 34; accelerated phase [AP], n ‫؍‬ 9; and blast phase [BP], n ‫؍‬ 4) who underwent HSCT and had BCR-ABL1 sequencing. Mutations were found in 19 patients (40%); 15 of 19 had advanced CML (AP ؉ BP ؉ second chronic phase). Patients with mutations were more likely to transform to AP/BP at time of imatinib failure (69% vs 35%, P ‫؍‬ .03). Forty-two patients (89%) responded to HSCT: 32 (68%) had at least a major molecular response. The 2-year event-free survival was 36% and 58% (P ‫؍‬ .05) for the mutant and nonmutant groups, respectively; and the 2-year overall survival was 44% and 76% (P ‫؍‬ .02), respectively. HSCT is an important salvage option for TKI-resistant patients with or without BCR-ABL1 mutations. Patients with mutations were more likely to develop advanced disease and had worse outcomes after HSCT. HSCT should be considered early for patients deemed to have a low probability of responding to second-generation TKI. (Blood. 2011;117(13):3641-3647)

Chronic myeloid leukemia: 2014 update on diagnosis, monitoring, and management

“…However, alloSCT remains an important therapeutic option for CML-CP in the following situations: patients who fail at least 2 TKIs and potentially patients harboring the T315I mutation after a trial of ponatinib therapy [70].…”

“…At present, alloSCT is the only curative therapy for accelerated and BP CML: overall cure rates are in the range of 15-40% and 5-20%, respectively [37,70]. Patients with cytogenetic clonal evolution as the only AP criterion have a long-term event-free survival rate of about 60% [84].…”

An update on allogeneic hematopoietic progenitor cell transplantation for myeloproliferative neoplasms in the era of tyrosine kinase inhibitors

“…15 Allogeneic transplantation has been shown to be of benefit in patients who harbor BCR-ABL1 KD mutations, including the T315I mutation. 14,16 A retrospective analysis of patients transplanted with this mutation compared with a historical cohort showed that these patients appear to fare better with 2-year OS rates for chronic phase, accelerated phase, blast phase and Ph + ALL of 59%, 67%, 30% and 25%, respectively. 16,17 Only a few studies have analyzed transplant outcomes of patients who transformed to accelerated or blast phase.…”

“…12 In the original IRIS study, secondary resistance was deemed to occur at a rate of 4% annually, and was associated usually with a mutation in the BCR-ABL1 kinase domain. 6,13,14 Second-and third-generation TKIs have shown responses in patients with resistant mutations. 14,15 Recently, ponatinib has been approved for patients with T315I mutation based on a phase II study, which showed a 57% major cytogenetic response.…”

“…6,13,14 Second-and third-generation TKIs have shown responses in patients with resistant mutations. 14,15 Recently, ponatinib has been approved for patients with T315I mutation based on a phase II study, which showed a 57% major cytogenetic response. 15 Allogeneic transplantation has been shown to be of benefit in patients who harbor BCR-ABL1 KD mutations, including the T315I mutation.…”