Clinical, Cytogenetic and Immunophenotypic Spectra of Post-Transplant Relapse Following Allogeneic Hematopoietic Stem Cell Transplantation for Myelodysplastic Syndrome
Bibliographic record
Abstract
Introduction Allogeneic hematopoietic stem cell transplantation (HCT) is a curative therapy used to treat myelodysplastic syndrome (MDS). Relapse post-HCT confers poor outcomes and subsequent therapy is not standardized. Like acute myeloid leukemia (AML), several mechanisms are known to be involved in post-HCT relapse including clonal evolution in favor of chemotherapy-resistant clones and tumor immune escape. Systemic reviews are scarce in the MDS post-HCT relapse population. Accordingly, the present study aimed to investigate clinical, cytogenetic, and immunophenotypic (IP) spectra for MDS post-HCT relapse patients (pts), along with subsequent therapies, and clinical outcomes following post-HCT relapse. Patients and methods A retrospective study was conducted and found that 231 MDS pts received HCT between April 2010 and September 2022 at the Princess Margaret Cancer Centre (PMCC). The primary endpoint was overall survival (OS) following post-HCT relapse. Secondary endpoints explored time to relapse (TTR), relapse presentation (i.e., MDS or AML), clonal evolution (i.e., changes in cytogenetics or IP profiles), and therapeutic strategies delivered after relapse. Results Of the 231 MDS pts treated with HCT, 52 (23%) relapsed in a median of 4.5 months (range 0.9-59.8 months). Twenty-five (48%) pts relapsed with MDS (i.e., blast <20%), while 27 (52%) relapsed with AML (i.e., blast ≥20%) in the marrow. Fifteen (65%) pts showed cytogenetic changes at the time of post-HCT relapse. Eleven (48%) of which presented with more aggressive findings (i.e., additional structural abnormalities and monosomal karyotype). Ten of 17 (59%) pts presented with changes in their IP profile at post-HCT relapse, 7 (70%) of which relapsed with AML. Combined these findings give evidence of clonal evolution in favor of more aggressive malignant clones that are often responsible for post-HCT relapse. Treatment with hypomethylating agents (HMA) alone or in combination after post-HCT relapse increased OS to 5.6 months in comparison to those not receiving HMA of whom OS was 1.4 months (p=0.0003). Stratified by disease presentation cytogenetic clonal evolution was seen in 6/12 (50%) of the post-HCT MDS relapses, and 9/11 (82%) of the post-HCT AML relapses. Cytogenetic abnormalities at diagnosis and post-HCT relapse, respectively included in descending order: structural abnormalities (n=14/23, 61%; n=20/23, 87%), complex karyotype (n=12/23, 52%; 17/23, 74%), -5/del(5q) (n=11/23, 48%; n=10/23, 43%), -7/del(7q) (n=8/23, 35%; n=11/23, 48%), monosomy karyotype (n=8/23, 35%; n=11/23, 48%), -17 (n=3/23, 13%; n=5/23, 22%), der(5)/t(5;17) (n=2/23, 9%; n=5/23, 22%), -20 (n=2/23, 9%; n=3/23, 13%), and inv(3) (n=1/23, 4%, n=2/23, 9%). Seventeen pts had paired IP profiles available both prior to HCT and at post-HCT relapse, of which 10 (59%) had profile changes of at least 1 antigen. Seven of 10 (70%) pts that relapsed with AML post-HCT had IP expression changes, compared to 3/7 (42.9%) pts that relapsed with MDS post-HCT. Summarized IP findings include reduced expression of CD7 (n=2/6, 33%), altered expression of CD34 (n=3/15, 20%), altered expression of CD117 (n=3/14, 21%), and reduced expression of HLA DR (n=4/15, 27%). The presence of IP expression changes at post-HCT relapse suggests evidence of clonal evolution or immune escape as the mechanism behind the relapsed disease. Overall survival duration was 3.97 months; the 12-month OS rate was 20.0% (10.0-32.5%). Post-HCT relapse treatments included hypomethylating agents (HMA; n=13/46, 28%), HMA with donor lymphocyte infusion (DLI; n= 7/46, 15%), HMA with Venetoclax (VEN; n=7/46, 15%), chemotherapy (n=9/46, 19%), best supportive care (8/46, 17%) and second HCT (n=2/46, 4%). Patients that received HMA with or without DLI or VEN had a longer survival duration of 5.6 months (95% CI [3.4-13.2 months]) compared to those not receiving HMA 1.4 months (95% CI [0.6-0.39 months, p=0.0003]). The 12-month survival rate was also significantly in favor of pts that received HMA following post-HCT relapse (35.3% [95% CI 17.2-54.0%] vs 4.3% [95% CI 0.3-18.0%]). Conclusion Patients with MDS undergoing HCT may relapse with either MDS or AML. The relapsed disease often shows evidence of clonal evolution in its immunophenotype and/or cytogenetic profile toward a more aggressive disease. Approaches to post-HCT relapse remain heterogenous but HMA is beneficial.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.001 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.001 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.001 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".