Juvenile myelomonocytic leukemia (JMML) is a rare myeloproliferative disease characterized by monocytosis, hepatosplenomegaly, elevated HbF levels, and is often associated with abnormalities in the NF-1 gene. JMML is fatal unless treated with allogeneic BMT. Donor leukocyte infusions (DLI) or withdrawal of immunosuppression have been reported to be an effective therapy for recurrent JMML,1,2,3 which suggests that JMML may benefit from a graft-versus-leukemia (GVL) effect. We report a patient who relapsed following an unrelated donor BMT, who had a transient improvement in his JMML following DLI and ultimately required intensive chemotherapy and DLI to control his disease.
UPN 233 presented at 11 months of age with fever, hepatosplenomegaly and café au lait spots. Laboratory findings included a WBC 55 200/mm3 with 38% monocytes. His marrow had <2% blasts with normal cytogenetics. His peripheral blood exhibited spontaneous colony formation independent of GM-CSF and HbF level was 5%. Having met the international diagnostic criteria for JMML, he received induction therapy consisting of fludarabine and cytarabine, which did not affect his hepatosplenomegaly or monocytosis. After undergoing splenectomy, a BMT was performed using an unrelated bone marrow donor disparate at a single HLA-A locus. He received a preparative therapy consisting of 1200 cGy fractionated total body irradiation, thiotepa, cyclophosphamide, antithymocyte globulin and methylprednisolone. T-cell depletion was used for prevention of graft-versus-host disease (GVHD). Post transplant immunosuppression consisted of methylprednisolone given every other day from days +5 through +19. At the time of discharge, he had no organomegaly and peripheral blood showed 100% donor DNA. He did not develop GVHD and did well until hepatomegaly and a reduction in the percentage of donor DNA to 60% was noted at day +70 post BMT. By day +98, he was determined to have relapsed based on the development of hepatomegaly (liver palpable at the umbilicus), autologous reconstitution where his peripheral blood contained <10% donor DNA, and monocytosis (WBC=10 400/mm3 with 22% monocytes). As treatment for recurrent JMML, he received 2.5 × 10e5 CD3+ donor cells/kg without GVHD prophylaxis. He developed stage 3 skin GVHD 38 days post DLI, which was associated with a transient improvement in hepatomegaly and monocytosis and >90% donor DNA detected in his peripheral blood. GVHD was successfully treated with corticosteroids and cyclosporine A. By day +90 post DLI, hepatomegaly, leukocytosis and monocytosis returned (WBC=22 500/mm3 with 41% monocytes). On day +135 post DLI, he received cytarabine and mitoxantrone followed by consolidation with high-dose cytarabine4 and infusion of 9.0 × 10e5 CD3+ donor cells/kg. GVHD prophylaxis was not given. He developed grade 2 acute and extensive chronic GVHD that was treated with corticosteroids and cyclosporine A. He is currently 3 years post BMT and 18 months since discontinuing immunosuppressive therapy. He demonstrated 100% donor chimerism for the first year following the second DLI. His peripheral blood presently contains 40% donor DNA (which has remained stable for 2 years) and he does not have hepatomegaly. His WBC is 10 500/mm3 with 11% monocytes. His Lansky score is 100%. This case supports the presence of a GVL effect in JMML. Since our patient had only a temporary response to DLI (and acute GVHD) alone, we hypothesize that his sustained clinical remission resulted from acute and chronic GVHD along with chemotherapy-induced cytoreduction, and suggests a role for intensive chemotherapy along with DLI as treatment for JMML, which persists following DLI or withdrawal of immunosuppression.
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