A rare Philadelphia story in AML: Outcomes with allogenic SCT for BCR-ABL1-positive AML patients

The Philadelphia chromosome corresponding to the BCR-ABL rearrangement is the cytogenic hallmark of chronic myelogenous leukemia. However, it is a rare entity in Acute Myeloid Leukemia (AML), only occurring in approximately 0.5–3% of patients, and corresponds with a poor prognosis according to the 2017 European Leukemia Net risk stratification.^1,2

Vladimir Lj Lazarevic from Skåne University Hospital, Lund, Sweden, et al., on behalf of the European Society for Blood and Transplantation (EMBT), retrospectively studied the outcomes of patients with BCR-ABL1-positive AML who underwent Allogenic Stem Cell Transplantation (allo-SCT) and also aimed to elucidate the impact of Tyrosine Kinase Inhibitor (TKIs) treatment in this group of patients. The results of the study were published in American Journal of Hematology on 3^rd October 2017.

Using the EMBT registry, Lazarevic et al. identified 57 adult patients (median age = 48 years; range, 19–67) with BCR-ABL1-positive AML who underwent allo-SCT between 2000–2013 at EMBT centers. Forty patients were treated with TKIs (imatinib, 31/40) before allo-SCT.

Prior to allo-SCT, 48 patients were in First Complete Remission (CR1) and the remaining nine patients had advanced stage disease. Additionally, Minimal Residual Disease (MRD) negativity (BCR-ABL1 ratio < 10⁴) was achieved in 36% (14/40) of patients with available MRD information prior to transplant. The median follow-up of the study was 6.3 years.

The key findings were:

• MRD negativity was achieved in 61.5% (16/26) patients who were MRD positive at allo-SCT
• Graft versus Host Disease (GvHD)
  • Grade II–IV acute GvHD; 28.5%
  • Chronic GvHD (cGvHD); 24.9%
  • Extensive cGvHD; 21.4%
• Outcomes of patients who underwent SCT in CR1 at 5 years
  • Overall Survival; 59.4%
  • Leukemia Free Survival (LFS); 46.5%
  • Graft-versus Host free relapse free survival (GRFS); 34.9%
  • Relapse Incidence (RI); 36.4%
  • Non-Relapse Mortality; 15.9%
• Younger age (< 50 years) was associated with reduced RI and longer LFS
• MRD negative status prior to allo-SCT associated with improved GRFS

In summary, the authors describe this as the “largest cohort of patients with BCR-ABL1-positive AML who underwent allo-SCT with a prolonged follow-up”. The authors discussed that in spite of the poor prognosis indicated for BCR-ABL1-positive AML, the results of their study suggests a favorable outcome for this group of patients in CR1. Hence, demonstrating that there is a “high probability of potential benefit provided by the addition of TKI to standard chemotherapy” prior to allo-SCT in this group of patients.

Key limitations of this study include its retrospective nature, small sample and selection bias. Lazarevic et al. concluded by stating that the findings of their study demonstrates that the “outcomes of patients with BCR-ABL1-positive AML receiving allo-SCT in CR is encouraging” particularly in younger patients thus “reflecting the possible synergy between TKIs and graft versus leukemia effect”.  They further added that the optimal management of BCR-ABL1-positive AML patients is not fully understood yet.

Abstract

The aim of the study was to assess the role of allogeneic stem cell transplantation (SCT) in patients diagnosed with BCR-ABL1-positive acute myeloid leukemia (AML). Fifty-seven patients (median age, 48 years, range: 19-67) with BCR-ABL1 positive AML undergoing SCT were identified. The majority of the patients (70%) received a TKI before the transplant. At SCT 48 patients were in CR (45 in CR1), while 9 patients were transplanted in a more advanced stage of the disease. MRD was negative (BCR-ABL1/ABL<104) at time of SCT in 36.1% (14/40). After SCT, 16 (61.5%) out of 26 patients with MRD positive at transplantation reached MRD negativity. After a median follow-up of 6.3 years (0.7-14.2), NRM, RI, LFS, OS, and GRFS at 5 years were 18.1%, 37%, 44.2%, 53.8%, and 32.1%, respectively. The cumulative incidence of acute GvHD grade II-IV was 16.4%, incidence of chronic GvHD 24.9%, and of extensive cGvHD 21.4%, respectively. In patients who received SCT in CR1, 5-yr NRM, RI, LFS, OS, and GRFS were 15.9%, 36.4%, 46.5%, 59.4%, and 34.9%, respectively. Univariate analysis showed that age (<50 vs. ≥50 years) was associated with RI (5-yr: 22.7 vs. 50%), LFS (5-yr: 61.9 vs. 31.8%), and GRFS (5-yr: 52.4 vs. 18.2%), whereas MRD-negative status before SCT was associated with an improved GRFS (38.9 vs. 16.7%). We conclude that the outcome of patients <50 years of age with BCR-ABL1-positive AML receiving allogeneic SCT in CR is relatively favorable, possibly reflecting the beneficial effect of the use of TKI.