Successful treatment of JMML relapsed after unrelated allogeneic transplant with cytoreduction followed by DLI and interferon-alpha: evidence for a graft-versus-leukemia effect in non-monosomy-7 JMML

Abstract

Summary:Relapse is the major cause of treatment failure after allogeneic transplantation of children with juvenile myelomonocytic leukemia (JMML), and the role of post-transplant immunomodulation is poorly understood. We report a 12-month-old child with JMML relapsed after unrelated marrow transplantation who received cytoreduction followed by donor lymphocyte infusion (DLI) with improvement, and after addition of interferon-alpha (IFN) achieved complete donor chimerism. He was weaned from IFN and has maintained complete remission for 19 months. This is the first published report of a patient with non-monosomy-7 JMML responding to post-transplant immunomodulation and suggests a role for DLI plus IFN in these patients. Juvenile myelomonocytic leukemia (JMML) is a rare pediatric malignancy, which presents in infancy or early childhood with myeloproliferative features and hepatosplenomegally. Monosomy-7 occurs in one-quarter of these patients, and although JMML with monosomy-7 may progress more slowly, long-term outcome is the same as non-monosomy-7 JMML (10-year overall survival 6%). 1 Hematopoietic cell transplantation has led to improved outcome, with reports of 2-to 4-year overall survival varying from 24% (NMDP) to 54% (Japanese data). 2,3 The major cause of failure is relapse, with rates as high as 58% at 2 years. 2 In spite of the well-documented efficacy of post transplant immunomodulation in other disorders, published work suggesting a graft-versus-leukemia (GVL) effect of post-transplant donor lymphocyte infusion (DLI) or intereferon in JMML is limited, and responding patients have all had monosomy-7 JMML. [4][5][6] We describe a patient who relapsed early after unrelated allogeneic bone marrow transplantation for non-monosomy-7 JMML in whom DLI induced a partial response, and the addition of interferon-alpha (IFN) likely contributed to attaining and sustaining a prolonged complete remission. This observation suggests a role for post-transplant immunotherapy approaches in non-monosomy-7 JMML. Clinical historyThe patient presented at age 6 months with hepatosplenomegally, thrombocytopenia, and GI bleeding. Initial WBC was 42.8  10 9 /l and marrow assessment showed JMML (based on the International JMML Working Group criteria). 1 Cytogenetics were normal. The patient underwent a splenectomy followed by two courses of cytoreductive chemotherapy with flu/ara-C (fludarabine 30 mg/m 2 /day  5 days and cytosine arabinoside 2 g/m 2 / day  5 days), resulting in pathologic complete remission.The patient then underwent allogeneic stem cell transplant utilizing a preparative regimen of TBI (total 1200 cGy), cyclophosphamide (60 mg/kg  2), and ATG (total 75 mg/kg). Bone marrow from a 6/6 matched unrelated donor was infused with a dose of 12  10 6 CD34 þ cells/kg. GVHD prophylaxis consisted of cyclosporin and short-course methotrexate. Stage 3 skin (overall grade II, Glucksberg) acute GVHD was noted just after engraftment, but resolved with topical therapy. Day þ 100 whole blood chimerism by VNTR analysis was 90% d...

Donor leukocyte infusion after hematopoietic stem cell transplantation in patients with juvenile myelomonocytic leukemia

“…Moreover, in all the three previously reported JMML patients successfully treated by DLI, the donor was an unrelated volunteer. [12][13][14] In contrast, in CML, there is no apparent major difference in efficacy of DLI in patients receiving lymphocytes from an HLAmatched sibling compared to a matched UD. 32,34,35 Modifications of the procedure will be needed for DLI from a matched sibling in JMML.…”

“…None of the eight patients who received a total T-cell dose o1 Â 10 7 /kg showed a sustained response. In the previously published reports detailed above, [12][13][14] the JMML patient given DLI from a mismatched UD responded to 1 Â 10 6 /kg T cells, the other two patients were given 1x10 7 /kg or 1x10 8 /kg T cells from a matched UD. Although we cannot draw definite conclusions due to the small number of patients, we suggest that at least 1 Â 10 7 /kg T cells are necessary for response to DLI in JMML, except for cases with HLA-mismatched donors.…”

“…Previous reports suggested a role of chemotherapy-induced cytoreduction or cytokine treatment with interferon-alpha along with DLI in JMML. 13,14 As none of the patients studied here received chemotherapy or splenectomy between last SCT and initiation of DLI, we cannot comment on the efficacy of this strategy in JMML. Like the use of cytokines, the role of cytoreduction with chemotherapy or novel drugs such as E21R 41 will have to be studied in well-designed clinical trials of cellular therapy in relapsed JMML.…”

“…In the literature, there are three other cases of successful therapy with DLI of relapsed JMML. [12][13][14] Two of the three patients had a normal karyotype, and one monosomy 7. Following chemotherapy (n ¼ 2) or splenectomy (n ¼ 1), DLI from the matched (n ¼ 2) or one HLA locus mismatched (n ¼ 1) UD were administered.…”

“…In JMML, the role of DLI for the management of recurrent disease remains uncertain; only a few relapsed patients successfully treated by DLI have been reported. [11][12][13][14] In this study, we summarize the experience with DLI in 21 children with JMML, enrolled in studies of the European Working Group of MDS in Childhood (EWOG-MDS), and relapsed after allogeneic HSCT.…”