Allogeneic Transplants No Benefit in Hypodiploid ALL

Liam Davenport

January 25, 2019

Children with hypodiploid acute lymphoblastic leukemia (ALL) should not undergo allogeneic hematopoietic cell transplantation in a bid to beat their poor prognosis as it does nothing to improve outcomes, urge US clinicians.

Ching-Hon Pui, MD, Department of Oncology, St. Jude Children’s Research Hospital in Memphis, Tennessee, and colleagues looked at data on more than 300 hypodiploid ALL patients treated over a 16-year period.

They found that, overall, event-free survival at 5 years was just over 55%, while 5-year overall survival was a little more than 61%.

While factors such as no minimal residual disease (MRD) at the end of induction; disease chromosomal number; and MRD-directed treatment were linked to improved outcomes, allogeneic transplantation conferred no survival benefit over chemotherapy alone.

The research, published online in the Journal of Clinical Oncology January 18, drew the same conclusion even when looking at patients with no MRD.

Speaking to Medscape Medical News, Pui explained that while the study revealed that, statistically, there was no benefit with allogeneic transplantation in any patient subgroup, "it doesn’t totally exclude the usefulness of transplantation."

However, Pui added that he, personally, does not like performing transplants in these patients, noting that it would have "to significantly improve outcome by a large margin before I would recommend that to my patients."

The transplantation process involves these patients undergoing irradiation (in preparation for receiving the transplant), and this places them at lifelong risk of developing a second cancer, Pui said.

Noting that their results are similar to those from other study groups, Pui believes that allogeneic transplantation has traditionally been used in hypodiploid ALL because "the patients have a poor outcome."

"As you can see, even in this study, only about half of the patients had long-term survival," he said, adding, "In everybody’s mind, transplant is the most intensive treatment."

Pui said that he and his coauthors have experience dealing with hypodiploid patients "so we think deeper, but most others think: 'OK, hypodiploidy, a very bad outcome.' "

"The first knee-jerk reaction is: Oh, let’s consider transplantation."

Pui emphasized that these latest results mean "we now know we have to rethink therapy, to think carefully about long-term survival…and quality of life.

This is why I want to caution the doctor who is taking care of leukemia: Don’t use a knee-jerk response to recommend transplant."

Don’t use a knee-jerk response to recommend transplant. Dr Ching-Hon Pui

Although there have been improvements in outcomes for childhood ALL in general, those for hypodiploid ALL with 44 or fewer chromosomes have remained poor.

However, recent studies have offered hope, with MRD levels during induction and consolidation treatment identified as having prognostic and therapeutic implications, with the potential for guiding treatment.

To investigate further, the researchers conducted a retrospective analysis of 272 patients with hypodiploid ALL aged up to 21 years, enrolled on the protocols of 16 cooperative study groups or single institutions between 1997 and 2013.

All patients were enrolled in intensive protocols, with 47 receiving allogeneic transplantation. The median age was 9.8 years.

Forty patients, including five who underwent allogeneic transplantation, had high hypodiploidy with 44 chromosomes.

Negative MRD, defined as <10-4, was identified in 87 of 161 evaluable patients, while 25 had an MRD between 10-4 and 10-3 and 49 had an MRD of ≥10-3.

Four patients died during remission induction, with the remaining 268 achieving complete remission.

During a median follow-up of 6.6 years, 90 patients experienced relapse, and 24 died at a median time of 8 months following first remission. At the last evaluation, 150 patients remained in continuous complete remission.

The team calculates that 5-year event-free survival was 55.1%, and 5-year overall survival was 61.2%.

After relapse, survival was very poor, at a 2-year survival of 12%.

On univariate analysis, negative MRD status was associated with a more favorable outcome, at a 5-year event-free survival of 75%.

Similarly, high hypodiploidy with 44 chromosomes was associated with a 5-year event-free survival of 74%, while MRD-stratified treatment protocols were linked to a 5-year event-free survival of 62%.

To determine the impact of transplantation on survival, the team excluded the 40 patients with high hypodiploidy with 44 chromosomes, as they are not offered this treatment.

The team determined that adjusted 5-year disease-free survival was not significantly different between the 186 patients treated with chemotherapy alone and the 42 who received transplantation, at 53% vs 59.8% (P = .47).

There was also no difference in adjusted five-year overall survival rates between the two groups, at 57.7% and 68.9%, respectively (P = .21).

The researchers also found no significant difference between chemotherapy alone and transplantation in terms of in 5-year event-free survival in MRD negative patients (P = .81) and those with an MRD-positive status (P = .29).

While survival was, overall, relatively poor, Pui pointed out that none of the patients were given chimeric antigen receptor (CAR)–modified T cells or blinatumomab (Blincyto, Amgen), which may be promising therapeutic options in the future.

"We hope that, one day, we will improve outcomes," he said "There are more therapies available, and FDA [Food and Drug Administration] approved, so why not try to use those to improve outcomes in this group of patients?"

The study was supported by National Cancer Institute grants, Bloodwise, and American Lebanese and Syrian Associated Charities. Pui disclosed receiving honoraria from Amgen and Bristol-Myers Squibb, serves or has served in a consulting or advisory role for Novartis, and has received travel/ accommodations/expenses from Amgen and Sanofi. Other coauthors have also disclosed relationships with pharmaceutical companies.  

J Clin Oncol. Published online January 18, 2019. Abstract

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