Treatment of disease recurrence after allogeneic hematopoietic stem cell transplantation in children with juvenile myelomonocytic leukemia: A great challenge still to be won

T he last three decades have witnessed a dramatic improvement in the prognosis of many childhood cancers, some tumors, including retinoblastoma, Wilms tumor, Hodgkin disease, and acute lymphoblastic leukemia, having now an expected survival rate above 90% [1]. However, there are still some childhood cancers which have a dismal prognosis, especially when disease relapse occurs. Among them, there is no doubt that juvenile myelomonocytic leukemia (JMML) occupies a prominent position. JMML is a unique clonal hematopoietic disorder, typical of infancy and early childhood, that occurs with an estimated incidence of 1.2 cases per million; it is mainly characterized by hepato-splenomegaly and organ infiltration due to excessive proliferation of cells of the monocytic and granulocytic lineages [2]. Because of the rarity of the disease and the heterogeneous nature of the clinical manifestations, the diagnosis of JMML is frequently challenging for the average general practitioner/pediatrician and many children are diagnosed weeks or even months after the appearance of the first symptoms. Approximately, 90% of JMML patients harbor either somatic or germ-line mutations in genes coding for SHP-2, RAS, CBL, or NF1 proteins in their leukemic cells [3]. These genetic aberrations are largely mutually exclusive and all activate the Ras/mitogenactivated protein kinase (MAPK) signaling pathway, this resulting in hypersensitivity of JMML progenitors to granulocyte-macrophage colony-stimulating factor (GM-CSF). While some children with JMML (especially those with either Noonan syndrome or CBL mutations or specific RAS mutations) may experience spontaneous resolution or improvement of hematological abnormalities [4,5], the median survival time of patients who do not receive an allograft is only 10–12 months [2]. Thus, allogeneic hematopoietic stem cell transplantation (HSCT) remains the therapy of choice for the majority of patients. Indeed, allogeneic HSCT from either a histocompatible relative or from an HLA-matched/1-locus disparate unrelated donor has been demonstrated to be able to cure more than 50% of affected children [6–8]. Disease recurrence still remains the main cause of treatment failure, the relapse rate being as high as 40–50% [6–8]. Relapse occurs early, at a median of 2–4 months after transplantation and generally within the first year. The prognosis of children with JMML experiencing leukemia relapse after allogeneic HSCT remains unsatisfactory despite the fact that salvage therapy is employed. While donor lymphocyte infusion (DLI) was proved to be largely ineffective [9], a second allograft can rescue about one third of the patients [10]. In this issue of Pediatric Blood & Cancer, Inagaki et al. substantially confirm these data, since only one of the five patients given DLI obtained hematological remission, while 5 of the 11 children receiving a second allograft are alive and disease free. They also confirm other previously published data, namely that serial monitoring of quantitative chimerism identifies patients with increasing mixed chimerism as having the highest risk of relapse [11]. Immediate withdrawal of immunosuppressive therapy can lead to the eradication of the malignant cells re-growing/ persisting after the conditioning regimen used in preparation to the allograft, this finding highlighting that the graft-versusleukemia (GvL) plays an important role for a successful posttransplant outcome [11]. How can we further increase the proportion of children with JMML rescued after a relapse following HSCT? This crucial question involves more generally the issues of how to render both early detection of leukemia cell re-growth more effective and approaches of immunotherapy safer and more capable of eradicating the malignant clone. Concerning the first issue, allele-specific quantitative PCR approaches aimed at detecting mutation-specific clones have been reported to be a sensitive tool for identifying minimal residual disease, thus facilitating earlier withdrawal of immunosuppression [12]. While DLI is the treatment of choice for patients with Philadelphia-positive chronic myeloid leukemia relapsing after allogeneic HSCT, it resulted of limited efficacy in children with JMML. Moreover, DLI can be associated with the development of life-threatening acute or chronic graft-versus-host disease (GvHD). The biological/ immunological reasons why JMML recurrence has limited sensitivity to DLI remain obscure: the population doubling of the neoplastic cells could be too fast to allow donor immune cells to control leukemia re-growth, but we cannot exclude that mechanisms of immune escape peculiar of JMML cells contribute to disease progression. Further investigations in this area are more