The Outcome of Patients with Advanced Phase Chronic Myeloid Leukemia with and without Allogeneic Hemopoietic Stem Cell Transplantation

Introduction:

In spite of the widespread use of second- and third-generation tyrosine kinase inhibitors (TKIs) the prognosis of patients with advanced phase CML (accelerated phase (AP) or blast crisis (BC) ) is still dismal. The aim of this study was to compare outcomes in advanced phase CML cohorts based on whether or not these patients received allogeneic hemopoietic stem cell transplantation (allo-HSCT).

Patients and methods:

A total of 162 patients with AP/BC-CML with (allo-HSCT+TKIs, n=20/62,) or without (n=10/70, TKI) history of allo-HSCT were included in this retrospective study. All patients received allo-HSCT with a reduced-intensity conditioning regimen with fludarabine 180 mg/m² and busulfan 8-12 mg/kg or melphalan 140 mg/m². Forty-two patients received TKIs for post-transplant relapse prophylaxis. In the majority of cases dasatinib was used (n=36).

In the remaining 80 patients alloHSCT was not performed due to refusal for personal reasons or delay in referral to transplant center. They were included in TKI-group and were treated with chemotherapy+TKIs (60) or TKIs only (20). Eighty-one percent received second or third line TKIs. There were no significant differences in age, sex, comorbidity status, disease phase, and additional chromosomal aberrations incidence between allo-HSCT+TKI and TKI groups (Table 1).

Overall survival (OS) was defined as the time from the start of treatment (allo-HSCT/TKI, chemotherapy) to death, event-free survival (EFS) - as the time between commencement of treatment and loss of response or post-transplant relapse, death. Response was defined according to European Leukemia Net and National Comprehensive Cancer Network recommendations. All patients signed an informed consent for processing of personal data; the trial was approved by Pavlov University local ethical committee.

Results:

The median follow-up was 44 months (1-344). The engraftment was documented in 71 (86%) patients. The cumulative incidence of non-relapse mortality at day 100 and 1 year after allo-HSCT were 10% and 18%, respectively. Grade 2-4 acute graft versus host disease (GVHD) was documented in 21 (29%), grade 3-4 acute GVHD – 14 (20%), chronic GVHD – 18 (27%) including mild, moderate and severe form in 6 (9%), 8 (12%) and 4 (6%) patients, respectively. Two-year cumulative incidence of relapse was 39%. Twenty-four patients received donor lymphocyte infusions and TKIs after relapse, in 4 cases chemotherapy was added. In four cases only TKIs were administered to treat relapse. Nine patients achieved sustained complete molecular response (CMR), in 19 cases disease progression was documented.

The data on response was available for 71 patients in TKI group. Among patients with BC 36 (59%) patients did not respond to therapy, while complete hematological response (CHR), complete cytogenetic response (CCR) and CMR were achieved in 22 (34%), 1 (2%) and 2 (3%) cases, respectively. Nine patients (90%) without BC history achieved response to therapy (CHR 5, CCR 2, CMR 2), while 1 patient failed to respond. Sixty-nine patients died; all deaths were CML-related.

Four-year OS was 58% in allo-HSCT+TKIs versus 33% in TKI group (p=0.032) (Figure 1A). However, there was no significant difference in 4-year EFS between groups: 35% vs. 17% (p=0.5), accordingly. BC at the moment of allo-HSCT significantly worsened 4-year OS: 23% vs. 63% (p=0.007). The 4-year OS in patients transplanted in BC (n=10) was comparable to one in TKI group: 23% vs. 33% (p=0.3) (figure 1B).

Conclusions:

Allo-HSCT still has an advantage as potentially curative treatment for part of advanced phase CML patients even in the presence of new generation TKIs. Allo-HSCT in BC is associated with worse outcome. An earlier referral of these patients to the transplant center can improve the outcome of allo-HSCT and prognosis..