Juvenile Myelomonocytic Leukemia: Molecular Pathogenesis Informs Current Approaches to Therapy and Hematopoietic Cell Transplantation

Abstract

Juvenile myelomonocytic leukemia (JMML) is a rare childhood leukemia that has historically been very difficult to confidently diagnose and treat. The majority of patients ultimately require allogeneic hematopoietic cell transplantation (HCT) for cure. Recent advances in the understanding of the pathogenesis of the disease now permit over 90% of patients to be molecularly characterized. Pre-HCT management of patients with JMML is currently symptom-driven. However, evaluation of potential high-risk clinical and molecular features will determine which patients could benefit from pre-HCT chemotherapy and/or local control of splenic disease. Furthermore, new techniques to quantify minimal residual disease burden will determine whether pre-HCT response to chemotherapy is beneficial for long-term disease-free survival. The optimal approach to HCT for JMML is unclear, with high relapse rates regardless of conditioning intensity. An ongoing clinical trial in the Children’s Oncology Group will test if less toxic approaches can be equally effective, thereby shifting the focus to post-HCT immunomanipulation strategies to achieve long-term disease control. Finally, our unraveling of the molecular basis of JMML is beginning to identify possible targets for selective therapeutic interventions, either pre- or post-HCT, an approach which may ultimately provide the best opportunity to improve outcomes for this aggressive disease.

Myeloablative BU, fludarabine, antithymocyte globulin and low-dose TBI in the treatment of juvenile myelomonocytic leukaemia with allogeneic haematopoietic cell transplantation

“…[1][2][3] With the exception of rare cases of spontaneous remission seen in children with specific molecular mutations, allogeneic haematopoietic SCT (HSCT) is the only curative therapy. Myeloablative conditioning is widely considered to be essential to eradicate leukaemic clones and to faciliate engraftment.…”

“…[1][2][3] Although allogeneic HSCT is the only curative option, relapse rates remain high (35%) and TRM is also unacceptably high (15%) with myeloablative conditioning. 4 Given that the highest rates of EFS in most series are around 50%, newer approaches are needed to lower rates of relapse and TRM.…”

“…1,[5][6][7] For diseases such as JMML with already high rates of TRM related to organ dysfunction and, at times, poor performance status at the time of HSCT, reduced toxicity of therapy is of great interest. 3,8 Such regimens retain myeloablation with drugs such as BU (generally considered myeloablative at total dosing ⩾ 10 mg/kg) while substituting other alkylating agents for less toxic chemotherapeutic agents that are immunosuppressive, but have been associated with lower rates of TRM and complications, such as sinusoidal obstructive syndrome (SOS). [7][8][9] Fludarabine has been commonly used as an immune suppressing substitute for CY with this goal in mind.…”

“…[7][8][9] Fludarabine has been commonly used as an immune suppressing substitute for CY with this goal in mind. 3 However, it has been suggested that reducedtoxicity regimens may not be sufficiently myeloablative to eradicate JMML clones and allow for engraftment, although some experts believe the GVL effect to be of greater importance. Debate regarding the intensity of conditioning required for curative HSCT in JMML is ongoing; during the development of the Children's Oncology Group JMML protocol ASCT1221, a myeloablative conditioning regimen was considered essential to maximise the potential for engraftment.…”

“…Debate regarding the intensity of conditioning required for curative HSCT in JMML is ongoing; during the development of the Children's Oncology Group JMML protocol ASCT1221, a myeloablative conditioning regimen was considered essential to maximise the potential for engraftment. 3 This study will compare the regimen with the best published results reported by the EWOG-MDS/EBMT consisting of BU, CY and melphalan conditioning to a BU/fludarabine approach. 4 The European group described an EFS and TRM of 52% and 13%, respectively, with the use of maximal dosing of alkylating agents.…”