Juvenile myelomonocytic leukemia (JMML) is an aggressive clonal malignancy and mixed myeloproliferative and myelodysplastic disorder. Although cure in most cases requires hematopoietic stem cell transplantation (HSCT), the major cause of treatment failure is relapse. However, in some cases, symptoms improve without treatment. We report a case of a patient with JMML who sustained remission after graft rejection of an unrelated bone marrow transplantation (UBMT).
An 18-month-old girl presented with marked splenomegaly and hemorrhagic diathesis. Laboratory blood tests revealed the following: white blood cell (WBC) count 12. 2 × 109/L, monocytes 22. 0%, hemoglobin 7. 6 g/dL, platelets 10. 0 × 109/L, and fetal hemoglobin 12. 8%. A bone marrow aspirate revealed a hypercellular marrow with mild dysplastic changes and 4. 4% blast cells. The BCR–ABL fusion gene was not detected. Following a diagnosis of JMML, she subsequently developed respiratory failure due to leukemic infiltration of the lungs, and was referred to our hospital. On admission, she developed severe thrombocytopenia due to splenic sequestration of platelets, and she needed frequent transfusions. She received chemotherapy with cytarabine and 6-mercaptopurine. Pulmonary leukemic infiltration improved, but transfusion frequency could not be reduced. After she had undergone splenectomy, platelet transfusion was not needed. When her clinical condition had improved, KRAS mutation was investigated by bone marrow aspiration, and the KRAS 13G>D mutation was detected. Five months after diagnosis, she was transplanted with major mismatch blood type, HLA-A 1-allele mismatch, from an unrelated female donor. The conditioning regimen consisted of busulfan (BU; 16 mg/kg), fludarabine (Flu; 120 mg/m2), and cyclophosphamide (CY; 120 mg/kg). Short-term methotrexate and tacrolimus (FK506) were administered for the prevention of graft-versus-host disease. The level of infused donor marrow cells was 1. 18 × 108/kg. Recovery of peripheral blood count was rapid, and no regimen-related toxicity was observed. Chimerism by short tandem repeat analysis of bone marrow mononuclear cells on day 28 after UBMT was 100% recipient type, indicating graft rejection with autologous hematopoietic cell recovery. FK506 was then discontinued. From day 48 after UBMT until the current day, WBC count has been almost 10. 0 × 109/L. Despite graft rejection, the KRAS 13G>D mutation was not detected by bone marrow aspiration on day 219, and her peripheral blood counts were normalized. Four years after diagnosis, the KRAS 13G>D mutation in the peripheral blood, nails, buccal mucosa, and hair was not detected, but the KRAS13G>D mutation was not. She has been managed without treatment and remained in complete remission for over 5 years since receiving UBMT.
In JMML patients with specific RAS mutations, spontaneous improvement in hematologic abnormalities has been reported. HSCT was needed in this case because the patient developed respiratory failure due to pulmonary infiltration of JMML cells. In JMML patients with gene mutation, JMML-specific gene mutations could not be detected after engraftment of HSCT. In contrast, most JMML cases relapse and need a second HSCT after rejection of the first. However, this patient's condition normalized after rejection of UBMT. Nowadays, minimal residual disease in JMML is analyzed by detection of JMML cell-specific gene mutations. The KRAS mutation can be detected in spontaneously regressed JMML following hematological improvement. We suggest that a myeloablative conditioning regimen including BU, Flu, and CY could eradicate JMML clones, and in some JMML cases, this could prevent the need for a second HSCT after rejection of the first.
No relevant conflicts of interest to declare.
Asterisk with author names denotes non-ASH members.