Disease burden and conditioning regimens in ASCT1221, a randomized phase II trial in children with juvenile myelomonocytic leukemia: A Children's Oncology Group study

Dvorak, Christopher C.; Satwani, Prakash; Stieglitz, Elliot; Cairo, Mitchell S.; Dang, Ha; Pei, Qinglin; Gao, Yun; Wall, Donna A.; Mazor, Tali; Olshen, Adam B.; Parker, Joel S.; Kahwash, Samir B.; Hirsch, Betsy A.; Raimondi, Susana C.; Patel, Neil; Skeens, Micah; Cooper, Todd M.; Mehta, Parinda A.; Grupp, Stephan A.; Loh, Mignon L.

doi:10.1002/pbc.27034

Cited by 32 publications

(33 citation statements)

References 41 publications

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“…At the University of California San Francisco (UCSF) Benioff Children's Hospital, the institutional bias has been to treat JMML patients with moderately intense, well‐tolerated myeloid‐based chemotherapy to try and reduce disease burden prior to transplant. Data from a Children's Oncology Group transplantation study showed that pre‐HCT chemotherapy (performed at the discretion of the provider) did yield molecular remissions; however, the number of patients was small and the study not powered to address this question …”

Section: Introductionmentioning

confidence: 99%

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

Hecht

Meyer

Chehab

et al. 2019

Pediatric Blood & Cancer

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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.

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Section: Introductionmentioning

confidence: 99%

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

Hecht

Meyer

Chehab

et al. 2019

Pediatric Blood & Cancer

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Fusion driven JMML: a novel CCDC88C–FLT3 fusion responsive to sorafenib identified by RNA sequencing

et al. 2019

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To the Editor Juvenile myelomonocytic leukemia (JMML) is an aggressive myeloproliferative neoplasm of childhood with nearly half of all patients relapsing within 3 years [1,2]. More than 90% of JMML patients present with initiating mutations in NF1, KRAS, NRAS, RRAS, RRAS2, CBL, and PTPN11, all leading to hyperactivation of the Ras pathway [3]. Patients with additional molecular alterations including cytogenetic abnormalities, and in particular, point mutations in SETBP1 have inferior outcomes [4]. At present, hematopoietic stem cell transplantation (HSCT) is the only curative therapy, with the primary cause of death being relapse or progression to acute myeloid leukemia (AML) [5]. Recently, JMML patients who did not display Ras pathway mutations were found to have ALK and ROS1 fusions that were sensitive to ALK inhibition [6]. Given the poor overall survival of JMML patients even after intensive treatments such as HSCT, opportunities to implement precision medicine should be

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“…To demonstrate the platform’s potential utility in personalized medicine, a droplet digital PCR (ddPCR) assay that was previously designed for precision monitoring of a specific patient was replicated on the novel digital PCR platform. Juvenile myelomonocytic leukemia (JMML) is an aggressive myeloproliferative neoplasm of childhood with nearly half of all patients relapsing within three years 17,18 . A seven-week-old boy diagnosed with JMML was shown to have WT status for all known JMML mutations.…”

Section: Resultsmentioning

confidence: 99%

“…Given the novelty of this CCDC88C - FLT3 fusion, no commercial assays were available to identify fusion transcripts below the sensitivity of cytogenetics. As such, the oncologist designed a specific ddPCR assay to analyze the abundance of this CCDC88C - FLT3 fusion in peripheral blood RNA over serial time points 18 . This ddPCR-based method for monitoring the patient’s response to Sorafenib (Nexavar) enabled the patient to proceed safely to hematopoietic stem cell transplantation (HSCT) and eventually achieve a complete molecular remission.…”

Section: Resultsmentioning

confidence: 99%

Precision cancer monitoring using a novel, fully integrated, microfluidic array partitioning digital PCR platform

Dueck¹,

Lin²,

Zayac³

et al. 2019

Sci Rep

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A novel digital PCR (dPCR) platform combining off-the-shelf reagents, a micro-molded plastic microfluidic consumable with a fully integrated single dPCR instrument was developed to address the needs for routine clinical diagnostics. This new platform offers a simplified workflow that enables: rapid time-to-answer; low potential for cross contamination; minimal sample waste; all within a single integrated instrument. Here we showcase the capability of this fully integrated platform to detect and quantify non-small cell lung carcinoma (NSCLC) rare genetic mutants (EGFR T790M) with precision cell-free DNA (cfDNA) standards. Next, we validated the platform with an established chronic myeloid leukemia (CML) fusion gene (BCR-ABL1) assay down to 0.01% mutant allele frequency to highlight the platform’s utility for precision cancer monitoring. Thirdly, using a juvenile myelomonocytic leukemia (JMML) patient-specific assay we demonstrate the ability to precisely track an individual cancer patient’s response to therapy and show the patient’s achievement of complete molecular remission. These three applications highlight the flexibility and utility of this novel fully integrated dPCR platform that has the potential to transform personalized medicine for cancer recurrence monitoring.

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Disease burden and conditioning regimens in ASCT1221, a randomized phase II trial in children with juvenile myelomonocytic leukemia: A Children's Oncology Group study

Abstract: The regimen of Bu-Flu is inadequate to provide disease control in patients with JMML who present to HCT with large burdens of disease. Advances in molecular testing may allow better characterization of biologic risk, pre-HCT responses to chemotherapy, and post-HCT management.

Cited by 32 publications

References 41 publications

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

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

Fusion driven JMML: a novel CCDC88C–FLT3 fusion responsive to sorafenib identified by RNA sequencing

Precision cancer monitoring using a novel, fully integrated, microfluidic array partitioning digital PCR platform

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