Transplant No Help in Hypodiploid ALL

Stem-cell transplantation for children with hypodiploid acute lymphoblastic leukemia (ALL) did not not improve survival or prevent relapse and other clinical events as compared with chemotherapy alone, results of two retrospective analyses showed.

Patients who underwent transplantation after induction therapy had a 5-year event-free survival (EFS) and overall survival (OS) of 57.4% and 66.2%, respectively, as compared with 52.2% and 58.9% for patients treated with chemotherapy alone. Neither difference achieved statistical significance, according to a report from the Children’s Oncology Group (COG).

Pooled data from a multinational study showed a 5-year OS rate of 59% for children who had transplants and 51.5% for those who had chemotherapy alone, a difference that did not reach statistical significance. In particular, transplantation failed to improve outcomes in children who achieved negative minimal residual disease (MRD) status with induction therapy.

Both studies were reported in the Journal of Clinical Oncology.

“Consistent with previous reports, we confirm poor outcomes for patients with hypodiploidy,” said Jennifer L. McNeer, MD, of the University of Chicago, and co-authors of the report from the COG. “The only significant prognostic factor was EOI [end of induction] MRD, which underscores the importance of disease response in predicting outcomes. Hypodiploid patients with EOI MRD less than 0.01% had better outcomes, though still inferior compared with nonhypodiploid patients. For patients with MRD of 0.01% or greater, EFS and OS were dismal.”

“No subgroup significantly benefited from HSCT [hematopoietic stem-cell transplant], although trends toward improved outcomes were noted,” the researchers added. “It is possible that with more patients, subgroups that benefit from HSCT might be identified; however, taken together, our data strongly support alternative approaches for these patients.”

The author of an accompanying editorial found little positive news in either study.

“The articles … have called into question the role of HCT for pediatric patients with hypodiploid ALL,” wrote Michael J. Burke, MD, of the Medical College of Wisconsin in Milwaukee. “HCT may have been the standard treatment approach for these patients, but the reports … using MRD analysis at EOI to identify patients who had relatively good outcomes when they were treated with chemotherapy alone and not benefiting from HCT, argue against this.”

“Good treatment can sometimes overcome the prognostic importance of poor prognostic factors,” he added. “Unfortunately, it seems that HCT is not capable of achieving when it comes to hypodiploid ALL and persistent MRD.”

With risk-adapted therapy, 5-year OS for pediatric B-lymphoblastic leukemia exceeds 90%. Clinical factors, disease characteristics, and early response to therapy guide decision-making about the intensity of postinduction therapy, McNeer and co-authors noted.

Among unfavorable cytogenetic abnormalities, hypodiploidy occurs in fewer than 5% of patients with pediatric ALL. Hypodiploid leukemic clones have fewer than 46 chromosomes, the most common number being 45. Patients whose blasts harbor 44 or 45 chromosomes have significantly better outcomes as compared with patients whose blasts harbor fewer chromosomes, the authors continued.

Hypodiploid ALL has no uniform approach to treatment, but the poor prognosis associated with the feature lends support for intensified treatment, including HSCT. Nonetheless, the benefits of HSCT after first complete remission have remained unclear. McNeer and colleagues said they hoped to clarify the role of HSCT in hypodiploid pediatric ALL by reviewing outcomes among patients treated from 2003 to 2011 as part of the COG ALL03B1 study.

The analysis included 131 patients (the largest single cooperative group series reported to date), who had a median age of 10 and median chromosome number of 28. Induction therapy led to complete remission in 98.3% of the study group. As compared with other patients, those with hypodiploid ALL had a significantly lower rate of early response (72.8% vs 83.4%, P=0.03) and a higher incidence of EOI MRD ≥0.01% (32.2% vs 23.3%, P=0.019). Subsequently, 61 of the 131 patients underwent HSCT after achieving a first complete remission.

The 131 patients had a 5-year EFS of 52.2% and OS of 58.9%, as compared with 85.2% and 91.8% for patients with nonhypodiploid disease (P<0.001). The patients who underwent HSCT had numerically better ES and OS but not significantly better as compared with the patients who received only chemotherapy (P=0.62, P=0.32, respectively).

An analysis of outcomes by MRD status showed that patients who had EOI MRD <0.01% had 5-year EFS and OS of 63.7% and 73.2%, respectively, whereas EOI MRD ≥0.01% was associated with 5-year EFS and OS of 26.2% and 27.7%. HSCT did not improve EFS or OS, regardless of EOI MRD status.

Investigators in the multinational study of HSCT and hypodiploid ALL analyzed data in 306 patients treated from 1997 to 2013, a study population involving 16 cooperative study groups and single institutions. Of 272 evaluable patients, the 5-year EFS was 55.1% and OS was 61.2%. The 5-year EFS was 75% for patients with EOI MRD negativity and 74% for patients with high hypodiploidy, reported Ching-Hon Pui, MD, of St. Jude Children’s Research Hospital in Memphis, and co-authors.

The analysis of HSCT impact on outcomes excluded 40 patients with high hypodiploidy, who were not offered HSCT because of their more favorable outcome. The remaining 228 patients included 42 who underwent HSCT. The analysis showed a 5-year disease-free survival of 59.8% with HSCT and 53.0% for patients treated only with chemotherapy (P=0.47). The 5-year overall survival was 68.9% with HSCT and 57.7% without (P=0.21). HSCT did not improve outcomes regardless of MRD status.