Patients with Philadelphia-Positive Leukemia with BCR-ABL Kinase Mutations before Allogeneic Transplantation Predominantly Relapse with the Same Mutation

Abstract

Despite the successes of tyrosine kinase inhibitors (TKIs) in improving outcomes in patients with chronic myeloid leukemia (CML) and Philadelphia-positive acute lymphoblastic leukemia (Ph+ ALL), allogeneic hematopoietic stem cell transplantation (HSCT) continues to be an important and potentially curative option for selected patients with either disease. After HSCT, TKIs are increasingly being used to treat or prevent disease relapse, and practice patterns suggest that these TKIs are often chosen empirically without regard to pre-HSCT mutation status. We investigated whether ABL kinase domain mutations persist after transplantation, and thus whether pre-HSCT mutation status should inform the selection of post-HSCT TKIs in these patients. We retrospectively analyzed adults who underwent allogeneic HSCT for CML and Ph+ ALL at our institution between 2000 and 2010, and identified subjects who had detectable BCR-ABL transcripts by polymerase chain reaction (PCR), as well as available RNA for Sanger sequencing of the ABL kinase domain, in both the pre- and post-HSCT settings. In total, 95 CML and 20 Ph+ ALL patients with positive PCR transcripts were identified, of which 10 (10.5%) and 4 (20.0%), respectively, were found to have pre-HSCT ABL kinase mutations known to confer TKI resistance. In 9 (64.2%) of these 14 patients, the same kinase mutation was also detectable at an average time of 191 days post-HSCT. Seven (50.0%) of the 14 harboring mutations had relapsed/refractory disease by last follow-up, of which, in retrospect, 6 had received a predictably ineffective TKI within the first 100 days following transplant, based on our mutation analysis. These data support the idea that pre-existing mutations in the ABL kinase domain, frequently associated with resistance to TKIs and prevalent in a transplant population, are persistently detectable in the majority of patients after transplant. We propose that such resistance patterns should be considered when selecting TKIs in the post-HSCT setting, including clinical trials of post-HSCT TKI prophylaxis.

Next-generation sequencing for BCR-ABL1 kinase domain mutation testing in patients with chronic myeloid leukemia: a position paper

“…Furthermore, it has been shown that persistence of very low levels of residual disease ( BCR-ABL1 < 0.1% IS ) detectable up to 10 years post-transplant has less implication for relapse [43]. It has been suggested that pre-transplant mutation analysis should be considered when selecting a TKI for post-transplant prophylaxis, based on the observation that the majority of resistant mutations are still detectable after transplantation and that patients often relapse with these mutant clones despite receiving TKI therapy [44, 45].…”

Sequencing small genomic targets with high efficiency and extreme accuracy

“…An initial RT-PCR step with nested PCR was used to amplify exons 4 to 9 (codons 199 to 507) of the Abl kinase domain, and bidirectional Sanger sequencing of the PCR product was performed, as previously described 23 .…”

Use of tyrosine kinase inhibitors to prevent relapse after allogeneic hematopoietic stem cell transplantation for patients with Philadelphia chromosome–positive acute lymphoblastic leukemia: A position statement of the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation

“…Moreover, there are data indicating that Ph‐positive ALL patients with detectable BCR‐ABL transcripts and kinase domain mutations before alloHSCT relapse after transplantation with the same mutation. Egan et al analyzed ABL kinase domain mutations in patients with CML and Ph‐positive ALL who had detectable BCR‐ABL transcripts before alloHSCT. Pretransplant ABL kinase domain mutations were found in 14 patients, including 4 patients with Ph‐positive ALL.…”