A risk-stratified therapy for infants with acute lymphoblastic leukemia: a report from the JPLSG MLL-10 trial

Abstract

<jats:p>The prognosis of infants with acute lymphoblastic leukemia (ALL), particularly those with KMT2A gene rearrangement (KMT2A-r), is dismal. Continuous efforts have been made in Japan to investigate the role of stem cell transplantation (HSCT) for infants with KMT2A-r ALL, but improvement in outcomes was modest. In the Japanese Pediatric Leukemia/Lymphoma Study Group trial MLL-10 (registered at umin.ac.jp as UMIN000004801), infants with ALL were stratified into three risk groups (low-risk, LR; intermediate-risk, IR; high-risk, HR) according to KMT2A status, age, and presence of central nervous system leukemia. A modified Children's Oncology Group AALL0631 chemotherapy with addition of high-dose cytarabine in early intensification was introduced to KMT2A-r patients, and the option of HSCT was restricted to HR patients. The role of minimal residual disease (MRD) was also evaluated. Ninety eligible infants were stratified into LR (N=15), IR (N=19), or HR (N=56). The 3-year event-free survival (EFS) rate (standard error) for patients with KMT2A-r ALL (IR+HR) was 66.2% (5.6%) and 93.3% (6.4%) for those with KMT2A-g ALL (LR). The 3-year EFS rate was 94.4% (5.4%) for IR and 56.6% (6.8%) for HR patients. In multivariable analysis, female sex and MRD ≧0.01% at end of early consolidation were significant poor prognostic factors. Risk stratification and introduction of intensive chemotherapy in the current study were effective and able to eliminate HSCT for a subset of infants with KMT2A-r ALL. Early clearance of MRD seems to have translated into favorable outcomes and should be incorporated into risk stratifications in future trials.</jats:p>

A novel human fetal liver-derived model reveals that MLL-AF4 drives a distinct fetal gene expression program in infant ALL

“…Intriguingly, MLL-r childhood-ALL has an event-free survival (EFS) of 50-59% 3,4,11 compared to 19-45% in MLL-r infant-ALL 4,5 . This inferior outcome for MLL-r infant-ALL does not appear to be due to age-related differences in drug metabolism and/or toxicity since MLL wild-type ( MLL wt) infant-ALL has excellent EFS (74-93%) 7,12 . This suggests there may be intrinsic biological differences between MLL-r infant-ALL and MLL-r childhood-ALL blasts.…”

Intensive but tender care for infant ALL

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In this issue of Blood, Tomizawa et al report remarkably improved outcomes for 90 infants with acute lymphoblastic leukemia (ALL) by providing excellent supportive care while receiving intensive chemotherapy and the use of hematopoietic cell transplant (HCT) for specific high-risk groups. 1

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“…While the Interfant-06 and the COG AALL0631 studies used this combination at later phases of chemotherapy, 6,8 the MLL-10 protocol introduced it in the early consolidation phase for intermediateor high-risk patients. 1 Moreover, because of their different physiologic features compared with those of older children (eg, body composition, drug-plasma protein binding, and cytochrome p450 activity), infants often received reduced dosages of chemotherapy. In the MLL-10 study, more stringent criteria for age-based chemotherapy dose reduction were applied.…”

“…In the MLL-10 study, more stringent criteria for age-based chemotherapy dose reduction were applied. 1 These decisions could have resulted in better clearance of minimal residual disease at the end of the early consolidation phase, which proved to be the most important prognostic factor in the MLL-10 study. Remarkably, Tomizawa et al report no early deaths during induction or early consolidation, and only 2 deaths in complete remission in the later phase of their study.…”

“…Finally, the high-risk criteria used by the MLL-10 study (KMT2A rearrangement with either age ,6 months or central nervous system involvement [$5/mL WBC with ALL morphology]) were broader than those in the Interfant-06 study, resulting in 56 (62.2%) patients classified to have highrisk ALL. 1 HCT was performed in 43 patients, representing 87.8% of the 49 high-risk infants in remission and 47.8% of the entire cohort; 67.4% of the transplanted infants were alive in remission. In the Interfant-06 study, more stringent highrisk criteria were used, and there were many "early events" (n 5 54), resulting in only 76 (53.1%) of the 143 high-risk patients in remission and 111 (17.1%) of the entire cohort of 651 infants receiving HCT.…”