Molecular assessment of pretransplant chemotherapy in the treatment of juvenile myelomonocytic leukemia

Abstract

Background: Despite the intensity of hematopoietic stem cell transplantation (HCT), relapse remains the most common cause of death in juvenile myelomonocytic leukemia (JMML). In contrast to other leukemias where therapy is used to reduce leukemic burden prior to transplant, many patients with JMML proceed directly to HCT with active disease. The objective of this study was to elucidate whether pre-HCT therapy has an effect on the molecular burden of disease and how this affects outcome post-HCT.Procedure: Twenty-one patients with JMML who received pre-HCT therapy and were transplanted at UCSF were analyzed in this study. The mutant allele frequency of the driver mutation was assessed before and after pre-HCT therapy, using custom amplicon next-generation sequencing.Results: Of the 21 patients, seven patients (33%) responded to therapy with a significant reduction in their mutant allele frequency and were classified as molecular responders. Six of these patients received moderate-intensity chemotherapy, one patient received only azacitidine. The 5-year progression-free survival after HCT of molecular responders was 100% versus 61% for nonresponders (P = .12). Survival of molecular nonresponders was not improved by use of highintensity conditioning, but patients were salvaged if they experienced severe graft versus host disease. There were no baseline clinical characteristics that were associated with response to pre-HCT therapy. Conclusions:Despite the myelodysplastic nature of JMML, patients treated with pre-HCT therapy can achieve molecular remissions. These patients experienced a trend toward improved outcomes post-HCT. Importantly, molecular testing can be helpful to distinguish between responders and nonresponders and should become an integral part of clinical care.

Response to upfront azacitidine in juvenile myelomonocytic leukemia in the AZA-JMML-001 trial

“…In conclusion, although the long-term advantage of azacitidine therapy remains to be fully assessed, this prospective clinical trial has shown that azacitidine therapy prior to HSCT is a safe and efficacious option for patients with JMML. Whether response to upfront therapy like azacitidine or combination chemotherapy 24 is simply a biomarker for favorable disease or can effectively reduce post-HSCT JMML recurrence will have to be addressed in future clinical trials.…”

Molecular and phenotypic diversity of <I>CBL</I>-mutated juvenile myelomonocytic leukemia

“…Genomic DNA samples were sequenced using a custom amplicon-based sequencing approach (Paragon Genomics, Hayward, CA, USA) targeting 26 genes that are known to be recurrently mutated in JMML 18 (Supplementary Table 1 and Supplementary methods). A VAF of 0.05 (=5%) at diagnosis was required for reporting.…”

NUP98-NSD1 Driven MDS/MPN in Childhood Masquerading as JMML

“…With knowledge of the NUP98-NSD1 fusion, chemotherapy would have been continued until RT-PCR was negative, as achieving a molecular remission before transplant has been associated with improved outcomes in both JMML and AML. 19,20 In addition, it would have prompted use of a less intensive myeloablative conditioning regimen, which may have spared some of the patient's post-HCT toxicities. Lastly, this finding was of benefit by offering the ability to track the patient's disease status more accurately post-HCT using RT-PCR.…”

“…Abdominal ultrasound was negative for hepatosplenomegaly. Cytogenetic analysis showed a single abnormal cell with a 44,X,-X,del(9)(q13q22),-16 [1],46,XX [20] karyotype. FLT3-ITD, CEBPA, and NPM1 were tested using next generation sequencing and were all normal.…”