Development of T-cell Acute Lymphoblastic Leukemia in a Patient in Very Long Lasting Complete Remission of Juvenile Myelomonocytic Leukemia

Abstract

Juvenile myelomonocytic leukemia (JMML) occurs with an incidence of 1.2 per million children a year, and represents 18% to 30% of all myelodysplastic (MDS) and myeloproliferative (MPS) disorders in the age group below 15, being by far the most common MDS/MPS in children younger than 4 years. The only therapeutic approach which results in a definitive cure of patients with JMML is myeloablative chemo-therapy/radio-therapy, followed by allogeneic hematopoietic cell transplantation. Few cases of transformation of JMML in acute lymphoblastic leukemia have been reported. We describe a child with JMML diagnosed at the age of 4 months in whom complete remission was achieved with 13-cis retinoic acid and cytosine-arabinoside and was sustained for 7 years with no maintenance therapy. Ninety-eight months after the diagnosis of JMML was established, overt T-cell leukemia developed. Treatment with acute lymphoblastic leukemia (ALL)-directed chemotherapy induced complete restoration of normal hemopoiesis, but testicular involvement persisted. The patient died after transplantation with unrelated cord blood. This case suggests that JMML is a true stem cell disorder and that stem cell transplantation should be considered, even in patients with a very favorable clinical course.

Hematopoietic-restricted Ptpn11E76K reveals indolent MPN progression in mice

“…Our T-cell findings have notable parallels in JMML patients. Occasionally, these children acquire T-ALL either concurrently with their MPN or after the resolution of their myeloid disease [ 18 , 34 – 36 ]. Our observation of decreased naïve peripheral T cells and increased thymic precursors may provide a mechanistic explanation for this association.…”

JMML and RALD (Ras-associated autoimmune leukoproliferative disorder): common genetic etiology yet clinically distinct entities

“…11 Others have reported long-term survival of JMML patients without the need for chemotherapy treatment or bone marrow transplant, and relief of symptoms by using immunosuppressive agents such as sirolimus, suggesting indolent autoinflammatory disease. 27,[35][36][37][38] Niemeyer et al 39 reported that 65% of JMML patients had hypergammaglobulinemia, and 22% had signs of autoimmunity, which are also features of RALD. Interestingly, although PTPN11 mutations result in constitutive activation of the RAS signaling pathway and are common in JMML 17,22 and Noonan syndrome, so far we have not identified PTPN11 mutations in any of the patients being evaluated for RALD.…”

“…Given that RALD and its clinical overlap with JMML are likely underrecognized, some patients diagnosed with JMML may have an indolent disease more consistent with RALD. JMML patients have occasionally been reported to undergo spontaneous regression of proliferative myelomonocytic disease 27,[35][36][37] with persistence of autoimmune disease, B lymphocytosis, and RAS-mutated clones. 35 RAS activation can indeed alter selection patterns of autoreactive B cells and antibody production leading to autoimmune manifestations.…”

Concurrent juvenile myelomonocytic leukemia and T‐lymphoblastic lymphoma with a shared missense mutation in NRAS

“…Single cases of B‐ and T‐lymphoblastic leukemia/lymphoma occurring after remission of JMML, and JMML occurring after remission of B‐lymphoblastic leukemia have been reported in the literature, as summarized in Table . These cases pose intriguing questions regarding a possible clonal relationship between JMML and lymphoblastic leukemia arising in the same patient or whether the two events simply occur by chance.…”