Outcomes of immunological interventions for mixed chimerism following allogeneic stem cell transplantation in children with juvenile myelomonocytic leukemia

104

Section: Discussionsupporting

confidence: 42%

Section: Discussionmentioning

confidence: 99%

Analysis of risk factors influencing outcomes after cord blood transplantation in children with juvenile myelomonocytic leukemia: a EUROCORD, EBMT, EWOG-MDS, CIBMTR study

Locatelli

Crotta

Ruggeri

et al. 2013

104

“…Support to this hypothesis is given by the observation that withdrawal of immunosuppressive therapy in patients with incipient relapse of JMML can prevent the subsequent occurrence of overt relapse. [71][72][73] In view of these considerations, we recommend that JMML children with NF-1, somatic PTPN-11, or N-RAS mutations, age .4 years at time of diagnosis or with .20% of blasts at the time of HSCT, receive lowintensity GVHD prophylaxis with the aim of optimizing the GVL effect (Figure 2). In the absence of acute GVHD, prophylaxis should be discontinued between day 160 and 190 after HSCT.…”

Section: Org Frommentioning

confidence: 99%

How I treat juvenile myelomonocytic leukemia

Locatelli

Niemeyer

2015

201

251

Juvenile myelomonocytic leukemia (JMML) is a unique, aggressive hematopoietic disorder of infancy/early childhood caused by excessive proliferation of cells of monocytic and granulocytic lineages. Approximately 90% of patients carry either somatic or germline mutations of PTPN-11, K-RAS, N-RAS, CBL, or NF1 in their leukemic cells. These genetic aberrations are largely mutually exclusive and activate the Ras/mitogen-activated protein kinase pathway. Allogeneic hematopoietic stem cell transplantation (HSCT) remains the therapy of choice for most patients with JMML, curing more than 50% of affected children. We recommend that this option be promptly offered to any child with PTPN-11-, K-RAS-, or NF1-mutated JMML and to the majority of those with N-RAS mutations. Because children with CBL mutations and few of those with N-RAS mutations may have spontaneous resolution of hematologic abnormalities, the decision to proceed to transplantation in these patients must be weighed carefully. Disease recurrence remains the main cause of treatment failure after HSCT. A second allograft is recommended if overt JMML relapse occurs after transplantation. Recently, azacytidine, a hypomethylating agent, was reported to induce hematologic/molecular remissions in some children with JMML, and its role in both reducing leukemia burden before HSCT and in nontransplant settings requires further studies.

“…Once engraftment is established, the graft-versus-leukemia effect can potentially be harnessed via either rapid withdrawal of immunosuppression and/or donor lymphocyte infusions. 103 Advances in lineage-specific chimerism 104 and JMML mutationspecific MRD testing 97,105 can help guide the aggressiveness of the immunomodulation strategies. Finally, for those JMML patients who relapse after HSCT, recent data indicate that up to 50% of patients can be salvaged using a second HSCT with either the original or an alternative donor.…”

Section: Approaches To Hsctmentioning

confidence: 99%

“…Finally, for those JMML patients who relapse after HSCT, recent data indicate that up to 50% of patients can be salvaged using a second HSCT with either the original or an alternative donor. 4,103,106 Targeted therapy Although HSCT cures ;50% of JMML patients, significant morbidities and late effects in this young population have driven These pre-HSCT guidelines are provided for physician consideration. For personal use only.…”

Section: Approaches To Hsctmentioning

confidence: 99%

Bedside to bench in juvenile myelomonocytic leukemia: insights into leukemogenesis from a rare pediatric leukemia

Chang

Dvorak

Loh

2014

Juvenile myelomonocytic leukemia (JMML) is a typically aggressive myeloid neoplasm of childhood that is clinically characterized by overproduction of monocytic cells that can infiltrate organs, including the spleen, liver, gastrointestinal tract, and lung. JMML is categorized as an overlap myelodysplastic syndrome/myeloproliferative neoplasm (MDS/MPN) by the World Health Organization and also shares some clinical and molecular features with chronic myelomonocytic leukemia, a similar disease in adults. Although the current standard of care for patients with JMML relies on allogeneic hematopoietic stem cell transplant, relapse is the most frequent cause of treatment failure. Tremendous progress has been made in defining the genomic landscape of JMML. Insights from cancer predisposition syndromes have led to the discovery of nearly 90% of driver mutations in JMML, all of which thus far converge on the Ras signaling pathway. This has improved our ability to accurately diagnose patients, develop molecular markers to measure disease burden, and choose therapeutic agents to test in clinical trials. This review emphasizes recent advances in the field, including mapping of the genomic and epigenome landscape, insights from new and existing disease models, targeted therapeutics, and future directions.