Contributions
Abstract: S1568
Type: Oral Presentation
Presentation during EHA23: On Sunday, June 17, 2018 from 08:45 - 09:00
Location: Room K1
Background
Ig/TCR-based minimal residual disease (MRD) is a faithful marker of response to therapy and the strongest predictor of relapse in Ph-negative ALL. In adults with Ph+ ALL, MRD is commonly monitored by BCR-ABL1 transcript quantification although its prognostic significance is less clear. It has been shown that BCR-ABL1 rearrangement may be found in non-lymphoblastic cells in some of these patients.
Aims
We aimed to study the biological significance of BCR-ABL1 MRD in Ph+ ALL.
Methods
The study includes 57 adults with de novo Ph+ ALL enrolled in the ongoing GRAAPH-2014 trial. Bone marrow (BM) and peripheral blood (PB) follow-up (FU) samples were collected after each treatment cycle (first 4 time-points [TPs]) and during FU. MRD monitoring was performed by quantification of both BCR-ABL1 transcripts and Ig/TCR clonal rearrangements. BCR-ABL1 major molecular response (MMR) was defined as BCR-ABL1/ABL1 ratio <0.1%. We sequenced genomic fusions using capture and NGS of BCR and ABL1 introns and designed breakpoint-specific PCR systems to quantify BCR-ABL1 genomic fusion with the same methods as for Ig/TCR MRD. MRD levels between markers were compared using Spearman rank correlation (r). For a given FU sample, results were considered discrepant if more than one log10 difference or positivity/negativity discordance, taking account markers sensitivity.
Results
Quantification of genomic BCR-ABL1 and Ig/TCR MRD levels on 72 samples from 10 patients revealed poor correlation (r=0.51). This was related to discordant results from 2 patients who had repeatedly positive BCR-ABL1 samples while Ig/TCR MRD was undetectable, suggesting those patients had lymphoblast clearance but persistent clonal BCR-ABL1 hematopoiesis. By contrast, genomic and transcript BCR-ABL1 levels on the same FU samples were well correlated (r=0.80), showing that there was no disparity related to BCR-ABL1 transcriptional modulation. This prompted us to extend our study to the whole cohort by comparing BCR-ABL1 transcript and Ig/TCR MRD levels. We obtained data for 360 FU samples (BM=152; PB=208). Patients with at least 2 samples with discrepant BCR-ABL1 and Ig/TCR MRD levels were considered having divergent kinetics in relation with BCR-ABL1 clonal hematopoiesis. They represented a group of 27 patients (47%). As compared with remaining patients, this group showed unbalanced M/F sex ratio (2.9 vs 0.8, p=0.03), enrichment in major BCR-ABL1 breakpoint (M-bcr, 33% vs 7%, p=0.02) and less frequent IKZF1 intragenic deletions (48% vs 77%, p=0.03). As expected, those patients had less BCR-ABL1 MMR at TP2 in BM (54% vs 100%, p<0.001) and PB (39% vs 96%, p<0.001). By contrast, the prevalence of poor early Ig/TCR MRD was similar in the two groups (35% and 29%). At later TPs, patients with divergent kinetics mostly reached MMR in BM but maintained relatively high BCR-ABL1 levels in PB (MMR rate at TP4, 79% and 47% in BM and PB respectively).
Conclusion
A subgroup of adults with Ph+ ALL displays persistence of BCR-ABL1 detection during treatment which is not linked to poor lymphoblast clearance but to clonal hematopoiesis. This entity resembles CML, although mostly related to m-bcr breakpoint and without evidence of myeloproliferation. Its prognostic relevance will be evaluated in our ongoing GRAAPH-2014 trial. Yet, these observations have important implications as non-lymphoblastic persistent BCR-ABL1 hematopoiesis may not necessarily need treatment intensification nor indicate lymphoid antigen-directed therapies.
Session topic: 2. Acute lymphoblastic leukemia - Clinical
Keyword(s): Acute lymphoblastic leukemia, BCR-ABL, Ig and TCR gene rearrangement, Minimal residual disease (MRD)
Abstract: S1568
Type: Oral Presentation
Presentation during EHA23: On Sunday, June 17, 2018 from 08:45 - 09:00
Location: Room K1
Background
Ig/TCR-based minimal residual disease (MRD) is a faithful marker of response to therapy and the strongest predictor of relapse in Ph-negative ALL. In adults with Ph+ ALL, MRD is commonly monitored by BCR-ABL1 transcript quantification although its prognostic significance is less clear. It has been shown that BCR-ABL1 rearrangement may be found in non-lymphoblastic cells in some of these patients.
Aims
We aimed to study the biological significance of BCR-ABL1 MRD in Ph+ ALL.
Methods
The study includes 57 adults with de novo Ph+ ALL enrolled in the ongoing GRAAPH-2014 trial. Bone marrow (BM) and peripheral blood (PB) follow-up (FU) samples were collected after each treatment cycle (first 4 time-points [TPs]) and during FU. MRD monitoring was performed by quantification of both BCR-ABL1 transcripts and Ig/TCR clonal rearrangements. BCR-ABL1 major molecular response (MMR) was defined as BCR-ABL1/ABL1 ratio <0.1%. We sequenced genomic fusions using capture and NGS of BCR and ABL1 introns and designed breakpoint-specific PCR systems to quantify BCR-ABL1 genomic fusion with the same methods as for Ig/TCR MRD. MRD levels between markers were compared using Spearman rank correlation (r). For a given FU sample, results were considered discrepant if more than one log10 difference or positivity/negativity discordance, taking account markers sensitivity.
Results
Quantification of genomic BCR-ABL1 and Ig/TCR MRD levels on 72 samples from 10 patients revealed poor correlation (r=0.51). This was related to discordant results from 2 patients who had repeatedly positive BCR-ABL1 samples while Ig/TCR MRD was undetectable, suggesting those patients had lymphoblast clearance but persistent clonal BCR-ABL1 hematopoiesis. By contrast, genomic and transcript BCR-ABL1 levels on the same FU samples were well correlated (r=0.80), showing that there was no disparity related to BCR-ABL1 transcriptional modulation. This prompted us to extend our study to the whole cohort by comparing BCR-ABL1 transcript and Ig/TCR MRD levels. We obtained data for 360 FU samples (BM=152; PB=208). Patients with at least 2 samples with discrepant BCR-ABL1 and Ig/TCR MRD levels were considered having divergent kinetics in relation with BCR-ABL1 clonal hematopoiesis. They represented a group of 27 patients (47%). As compared with remaining patients, this group showed unbalanced M/F sex ratio (2.9 vs 0.8, p=0.03), enrichment in major BCR-ABL1 breakpoint (M-bcr, 33% vs 7%, p=0.02) and less frequent IKZF1 intragenic deletions (48% vs 77%, p=0.03). As expected, those patients had less BCR-ABL1 MMR at TP2 in BM (54% vs 100%, p<0.001) and PB (39% vs 96%, p<0.001). By contrast, the prevalence of poor early Ig/TCR MRD was similar in the two groups (35% and 29%). At later TPs, patients with divergent kinetics mostly reached MMR in BM but maintained relatively high BCR-ABL1 levels in PB (MMR rate at TP4, 79% and 47% in BM and PB respectively).
Conclusion
A subgroup of adults with Ph+ ALL displays persistence of BCR-ABL1 detection during treatment which is not linked to poor lymphoblast clearance but to clonal hematopoiesis. This entity resembles CML, although mostly related to m-bcr breakpoint and without evidence of myeloproliferation. Its prognostic relevance will be evaluated in our ongoing GRAAPH-2014 trial. Yet, these observations have important implications as non-lymphoblastic persistent BCR-ABL1 hematopoiesis may not necessarily need treatment intensification nor indicate lymphoid antigen-directed therapies.
Session topic: 2. Acute lymphoblastic leukemia - Clinical
Keyword(s): Acute lymphoblastic leukemia, BCR-ABL, Ig and TCR gene rearrangement, Minimal residual disease (MRD)