Impact of Conditioning Intensity and Genomics on Relapse After Allogeneic Transplantation for Patients With Myelodysplastic Syndrome

Abstract

PURPOSE Patients with myelodysplastic syndrome (MDS) are at risk of relapse after allogeneic hematopoietic cell transplantation. The utility of ultra-deep genomic testing to predict and the impact of conditioning intensity to prevent MDS relapse are unknown. METHODS Targeted error-corrected DNA sequencing was performed on preconditioning blood samples from patients with MDS (n = 48) from the Blood and Marrow Transplant Clinical Trials Network 0901 phase III randomized clinical trial, which compared outcomes by allogeneic hematopoietic cell transplantation conditioning intensity in adult patients with < 5% marrow myeloblasts and no leukemic myeloblasts in blood on morphological analysis at the time of pretransplant assessment. Clinical end points (53-month median follow-up) included transplant-related mortality (TRM), relapse, relapse-free survival (RFS), and overall survival (OS). Of the 48 patients examined, 14 experienced TRM, 23 are relapse-free, and 11 relapsed, of which 7 died. RESULTS Using a previously described set of 10 gene regions, 42% of patients (n = 20) had mutations detectable before random assignment to reduced intensity conditioning (RIC) or myeloablative conditioning (MAC). Testing positive was associated with increased rates of relapse (3-year relapse, 40% v 11%; P = .022) and decreased OS (3-year OS, 55% v 79%, P = .045). In those testing positive, relapse rates were higher (3-year relapse, 75% v 17%; P = .003) and RFS was lower (3-year RFS, 13% v 49%; P = .003) in RIC versus MAC arms. Testing additional genes, including those associated with MDS, did not improve prognostication. CONCLUSION This study provides evidence that targeted DNA sequencing in patients with MDS before transplant can identify those with highest post-transplant relapse rates. In those testing positive, random assignment to MAC lowered but did not eliminate relapse risk.

Treosulfan compared with reduced‐intensity busulfan improves allogeneic hematopoietic cell transplantation outcomes of older acute myeloid leukemia and myelodysplastic syndrome patients: Final analysis of a prospective randomized trial

“…13 In brief, these include its open-label study design, missing implementation of minimal residual disease evaluation before and after HCT, as well as a common disease risk stratification for AML and MDS patients based on disease-specific risk categories, which were (and mostly still are) contemporary at the time of study design. 15,16,[26][27][28] These limitations, however, appear compensated by comparatively comprehensive and well-balanced study arms, accomplishment of prespecified rigorous efficacy boundaries, and a meaningful follow-up period.…”

Navigating the contested borders between myelodysplastic syndrome and acute myeloid leukemia

“…In patients without overt AML, there isn’t necessarily a penalty to deferring treatment ( 61 ), so providers should be patient and methodical, gathering more information over time if necessary, in defining the contours of the disease and in formulating the optimal treatment plan. Increasingly, measurable residual disease (MRD) is of interest for AML (and MDS, to a lesser extent) therapeutic optimization ( 62 – 64 ). This does requires an ongoing understand of the details of the sAML and what MDS-associated mutations were present prior to AML.…”

Is it the time to integrate novel sequencing technologies into clinical practice?

“…Determination of MRD status following treatment informs relapse risk, and thus, treatment planning such as the need for allogeneic stem cell transplantation in first remission [48,49] and the type of conditioning required prior to allogeneic stem cell transplant for CR MRDþ . It also provides an opportunity for detection of impending or early relapse and prompts intervention [50]. MRD testing for AML is currently performed by multiparameter flow cytometry (MFC) [51,52] or by molecular testing through quantitative or digital PCR or NGS.…”