The Hematologist

May-June 2019, Volume 16, Issue 3

Hematopoietic Stem Cell Transplantation: Not Always a Panacea for Leukemia Patients With Unfavorable Outcome

David T. Teachey, MD Associate Professor of Pediatrics
Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA

Published on: April 26, 2019

McNeer JL, Devidas M, Dai Y, et al. Hematopoietic stem cell transplantation does not improve the poor outcome of children with hypodiploid acute lymphoblastic leukemia: a report from Children's Oncology Group. J Clin Oncol. 2019;37:780-789.

Most children and young adults with acute lymphoblastic leukemia (ALL) are cured. Nevertheless, the outcome remains poor for patients with relapsed and refractory disease, as well as for patients with certain high-risk biologic features. Infants with KMT2A-rearranged ALL for example, do very poorly with current therapies, as cure rates have not improved throughout the past 30 years.1 Patients with t(17;19) and hypodiploid ALL also have poor survival.2 Most children with ALL do not require hematopoietic stem cell transplantation (HSCT) for cure. Historically, decisions to transplant or not transplant in children with ALL have been based on arbitrary lines in the sand with most centers and expert groups advocating for transplantation in first complete remission (CR1) if event-free survival (EFS) is predicted to be approximately 50 percent or less with chemotherapy alone.3 While it is rational to use an alternate approach such as HSCT in patients who fare poorly with chemotherapy alone, the decision to transplant should be based on whether or not HSCT can improve cure rates.

Dr. Jennifer L. McNeer and colleagues report data on 131 children with hypodiploid B-ALL who were treated on Children’s Oncology Group (COG) protocols, AALL0031, AALL0331, or AALL0232 between 2003 and 2011. Patients treated on AALL0331 received a “three-drug” four-week remission induction regimen with vincristine, dexamethasone, and asparaginase, as well as intrathecal chemotherapy. Patients on AALL0331 and AALL0232 received a “four-drug” induction regimen that also included an anthracycline. All patients were enrolled on a companion biology study, AALL03B1. After induction, patients underwent flow-cytometry–based minimal-residual disease (MRD) testing at one of two centralized laboratories.

Of 8,522 patients enrolled on AALL03B1, 131 (1.5%) had hypodiploid ALL, defined as having less than 44 chromosomes or a DNA index less than 0.81. Fifty-five, 47, and three patients had 25 to 29, 30 to 39, and 40 to 43 chromosomes, respectively. Twenty-six patients had masked hypodiploidy. Patients with hypodiploid ALL are often subdivided into different groups because the degree of aneuploidy is associated with prognosis and disease biology. In 2013, Dr. Linda Holmfeldt and colleagues published seminal work performing genomic profiling of 124 patients with hypodiploid ALL and found that patients with 32 to 39 chromosomes frequently have alterations in RB1 (41%), IKZF2 (53%), or TP53 (91.2%).4 Importantly, TP53 alterations were germline in approximately 50 percent of cases. In contrast, patients with 24 to 31 chromosomes frequently have alterations in receptor tyrosine kinase and RAS signaling (71%) and IKZF3 (13%).

Of the 131 patients with hypodiploid ALL, HSCT data were available for 113: 61 patients underwent HSCT in CR1, and 52 did not. The investigators found no statistically significant difference in EFS or overall survival (OS) comparing those who underwent transplant with those who did not (5-year EFS, 56.4% +/– 7.3% vs. 48.8% +/– 7.8% [p = 0.62] and 5-year OS, 65.6% +/– 6.9% vs. 53.8% +/– 7.8% [p=0.32], respectively). Unlike patients without hypodiploid ALL, where the National Cancer Institute (NCI) risk group predicts outcome, the outcomes for NCI high-risk (HR; WBC ≥ 50,000/mm3 or age ≥ 10 years) and NCI standard-risk (SR; WBC < 50,000/mm3 and age < 10 years) patients were not different. Patients with end-of-induction MRD less than 0.01 percent had outcomes superior to those with MRD 0.01 percent or greater. Strikingly, subanalyses demonstrated no statistically significant improvement in outcome with HSCT (EFS or OS) in patients with MRD lower than 0.01 percent (5-year EFS, 66.3% +/– 7.9% [HSCT] vs. 60.3 +/– 9.2% [no HSCT]; p=0.7) or MRD 0.01 percent or greater (5-year EFS, 29.4% +/– 14.3% [HSCT] vs. 16.7% +/– 10.8% [no HSCT]; p = 0.67; Figure). HSCT did not affect outcome in the NCI HR or NCI SR groups. The overall sample size was small, and subgroup analyses only included a few patients in each group. Yet, no group was identified that benefited from HSCT.

Similar results also were published recently by the Ponte di Legno Group.5 Dr. Ching-Hon Pui and colleagues reported outcomes from 306 patients with hypodiploid ALL from 16 cooperative groups who were treated between 1997 and 2013. They also found that patients with negative-end induction MRD had better outcomes than those with positive MRD; however, HSCT did not improve outcomes in the overall cohort or in patients with positive or negative MRD. The authors noted that the total number of patients who underwent transplantation was low (n = 42), and as with the prior study, this retrospective study was likely underpowered for many of the subanalyses.

Outcomes for matched-sibling donor, unrelated donor, and haploidentical transplantation for children with leukemia are similar using modern protocols and supportive care.6 Thus, the decision to transplant in 2019 is often agnostic to donor status and is typically based on whether or not a child with ALL is expected to have poor outcomes with chemotherapy alone. The benefit of transplantation primarily derives from the graft-versus-leukemia (GVL) effect, where donor T and NK cells eliminate leukemic blasts.7 Arguably, not all types of ALL will derive the same benefit from GVL as some biologic ALL subtypes are likely more sensitive to immune surveillance than others. In theory, there are patients with ALL with good prognosis with chemotherapy alone who might have even better prognosis with HSCT. In contrast, as demonstrated by Dr. McNeer and colleagues and by Dr. Pui and colleagues, poor response to chemotherapy does not equate to benefit from transplantation. As HSCT has significant risks and long-term morbidities, it is crucial to determine which patients with ALL have the potential to benefit from transplantation and to not make transplant decisions based entirely on poor response to chemotherapy. For patients with hypodiploid ALL and positive MRD at end induction, new therapies such as immunotherapies, or biologically based therapies such as BCL-2 inhibitors are needed.8


  1. Brown P, Pieters R, Biondi A. How I treat infant leukemia. Blood. 2019;133:205-214.
  2. Teachey DT, Pui CH. Comparative features and outcomes between paediatric T-cell and B-cell acute lymphoblastic leukaemia. Lancet Oncol. 2019;20:e142-154.
  3. Merli P, Algeri M, Del Bufalo F, et al. Hematopoietic stem cell transplantation in pediatric acute lymphoblastic leukemia. Curr Hematol Malig Rep. 2019; doi: 10.1007/s11899-019-00502-2. [Epub ahead of print].
  4. Holmfeldt L, Wei L, Diaz-Flores E, et al. The genomic landscape of hypodiploid acute lymphoblastic leukemia. Nat Genet. 2013;45:242-252.
  5. Pui CH, Rebora P, Schrappe M, et al. Outcome of children with hypodiploid acute lymphoblastic leukemia: a retrospective multinational study. J Clin Oncol. 2019:JCO1800822. [Epub ahead of print].
  6. Leung W, Campana D, Yang J, et al. High success rate of hematopoietic cell transplantation regardless of donor source in children with very high-risk leukemia. Blood. 2011;118:223-230.
  7. Yshurun M, Weisdorf D, Rowe JM, et al. The impact of the graft-versus-leukemia effect on survival in acute lymphoblastic leukemia. Blood Adv. 2019;3:670-680.
  8. Diaz-Flores E, Comeaux EQ, Kim KL, et al. BCL-2 is a therapeutic target for hypodiploid B-lineage acute lymphoblastic leukemia. Cancer Res. 2019; doi: 10.1158/0008-5472.CAN-18-0236. [Epub ahead of print].

Conflict of Interests

Dr. Teachey indicated no relevant conflicts of interest. back to top