Early Phase Administration of Hematopoietic Stem Cell Transplantation to Prevent Early Relapse for Infants with Acute Lymphoblastic Leukemia and MLL Gene Rearrangement; a Report From the Japanese Pediatric Leukemia/Lymphoma Study Group (JPLSG) Trial MLL03

Infants with acute lymphoblastic leukemia (ALL) and MLL gene rearrangement (MLL-R) confer poor prognosis with approximately 40% probability of long term event-free survival (EFS). The major cause of treatment failure is leukemia relapse which usually occur very early after achieving the first remission (1CR). Prevention of early relapse is a key strategy to improve the outcome of MLL-R infants with ALL. On the basis of promising results in the previous MLL98 study with post-transplant EFS rate of 64.4% among the 29/44 patients transplanted in 1CR, we conducted a multi-center non-randomized trial for infants with MLL-R ALL to test an efficacy of intensive chemotherapy followed by early phase (≤ 4 months after achieving 1CR) hematopoietic stem cell transplantation (HSCT).

Infants with ALL aged less than 12 months were registered in JPLSG MLL03 study if MLL gene rearrangements were confirmed by Southern Blot analysis. After 7-day prednisolone monotherapy, all patients received induction therapy consisted of dexamethasone, vincristine, doxorubicin, cyclophosphamide, cytarabine, etoposide, and triple intrathecal injections, followed by two intensification courses including high-dose methotrexate and high-dose cytarabine. L-asparaginase was not included. If 1CR was achieved, HSCT either from HLA ≥5/6 phenotypically matched related donor or ≥4/6 matched unrelated cord blood donor was carried out. Conditioning regimen consisted of busulfan, which was dose-adjusted based on individual pharmacokinetics, etoposide, and cyclophosphamide.

A total of 63 infants with ALL and MLL-R were registered in MLL03 study between Feb/2004 and Jan/2009. Patient characteristics showed high proportion of young infants; 22 (35 %) aged 0 – 90 days, 21 (33 %) aged 91 – 180 days, and 20 (32 %) aged 181 days or higher. Remission status was evaluated after 2 chemotherapy courses; 49 achieved 1CR, 4 failed to achieve 1CR, and 3 died of infectious complications. Seven patients were removed from the study; 2 for lineage switch to myeloid leukemia, 1 for guardians' refusal, 2 for severe adverse events (AEs), and 2 for protocol violations. Grade 3 and 4 non-hematological AEs during induction phase, such as infections (73 %), tumor lysis syndrome (TLS, 40 %), and liver transaminase elevation (44 %) were relatively common, especially in young infants. Forty-four out of 49 cases who achieved remission were able to undergo HSCT in 1CR; 32 cases from unrelated cord blood and 11 cases from related donor (1 unknown). All the recipients achieved stable engraftment. Ten patients developed grade II – IV acute GVHD and 8 developed chronic GVHD (only 1 with extensive type). Most of the post-HSCT events were leukemia relapses (18 post-HSCT relapses), and two non-relapse death were observed; one of transfusion-related acute lung injury (TRALI) and one of sudden death for unknown cause. Finally, probability of EFS in 18 months was 54.5 % (95 % confidence interval [CI], 41.3 % – 66.0 %) and overall survival in 18 months was 80.8 % (95 % CI, 68.7 % - 88.6 %). Young age (< 90 days old) and CNS leukemia at diagnosis were poor prognostic factors.

The strategy of treating MLL-R ALL infants with intensive chemotherapy followed by early phase HSCT was feasible and prevention of early relapse was successful. However, significant improvement in EFS is unlikely compared with that of the previous MLL98 study. This may be due to, 1) high proportion of younger infants in the present study who are both high risk of relapse and severe treatment-related toxicities, 2) lack of sufficient intensity of pre-transplant chemotherapy in the present study to eradicate leukemia burden, and 3) limited efficacy of the strategy to treat MLL-R infant ALL with conventional chemotherapy and HSCT.

No relevant conflicts of interest to declare.