Pediatric-inspired Post-remission Chemotherapy Superior to Stem Cell Transplantation for Young Adults with ALL

Study results from ASH 2019 shed light on treatment

A pediatric-inspired post-remission chemotherapy regimen is more effective than myeloablative allogeneic hematopoietic cell transplantation (HCT) in treating adolescents and young adults (AYAs) with Ph-negative acute lymphoblastic leukemia (ALL) in first complete remission, new research shows.

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The chemotherapy regimen produced better survival outcomes and reduced the occurrence of relapse.

The findings, presented at the 2019 American Society of Hematology (ASH) annual meeting, are a follow-up to a study published earlier in 2019 that found an intensified pediatric initial chemotherapy regimen for AYAs with ALL was tolerable, effective and improved survival rates compared to historical controls treated with an adult chemotherapy regimen.

Taken together, the results add significant insight into the treatment of AYAs with ALL, says hematologist Anjali Advani, MD, the Director of Cleveland Clinic Cancer Center’s Inpatient Leukemia Program. Dr. Advani is a co-author of both studies. She served on the ASH conference’s education committee and co-chaired the session that addressed ALL.

CALGB 10403: Testing a pediatric-inspired regimen

ALL treatment regimens for adults and children differ in intensity and componentry. Older adolescents and young adults with ALL who are treated with adult regimens have had historically worse outcomes than pediatric patients. Although complete remission rates are high (>90%) in both groups, overall survival (OS) rates in children are 80 to 90%, compared to only 30-40 % in adults.

That suggests differences in therapy, not just differences in age and biology, may affect outcomes.

To further explore possible explanations for the survival disparities, Dr. Advani and her colleagues from multiple cancer centers undertook a cooperative group trial, Cancer and Leukemia Group B (CALGB) 10403.

“CALGB 10403 investigated whether AYAs could tolerate an intensive pediatric regimen and whether such a regimen would improve survival rates,” says Dr. Advani.

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CALGB 10403 enrolled 295 patients with new diagnoses of precursor B- or T-cell ALL. Participants’ ages ranged from 17 to 39. The patients came from three U.S. cooperative groups — CALGB, the Eastern Cooperative Oncology Group and the Southwest Oncology Group (SWOG). Dr. Advani was the SWOG’s principal investigator.

CALGB 10403’s treatment regimen replicated the treatment used in one arm of the randomized COG AALL0232 trial, with escalating doses of Capizzi methotrexate without leucovorin rescue, followed by PEG asparaginase.

Two hundred sixty-three participants achieved remission. Median disease-free survival (DFS) was 81.7 months (95% confidence interval [CI], 58.4 months-not reached), and three-year DFS was 66% (95% CI, 60%-72%). Both rates were significantly higher than in historical controls (median DFS 34 months [95% CI, 28-50 months]); 3-year DFS 48% [95% CI, 41%-55%]).

“The 10403 study demonstrated that treating AYAs with an intensive pediatric regimen provides better outcomes,” Dr. Advani says. “Such treatment can be managed by adult oncologists who have expertise with pediatric regimens.”

Comparing results: HCT versus pediatric-inspired regimen

For AYA ALL patients who achieve complete remission, the ideal post-remission therapy is not clear. With the exception of patients in a few high-risk subsets, most participants in CALGB 10403 did not receive an allogeneic HCT.

The follow-up study presented at ASH that Dr. Advani co-authored retrospectively reviewed the outcomes of AYAs with Ph-negative ALL who were treated with HCT in their first complete remission and compared them with the outcomes of participants in CALGB 10403 who received pediatric-inspired chemotherapy.

“Our hypothesis was that post-remission therapy with the pediatric-inspired regimen would yield superior outcomes to allogeneic HCT,” says Dr. Advani.

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The post-remission chemotherapy recipients in CALGB 10403 were compared with a contemporary matched AYA cohort from the database of the Center for International Blood and Marrow Transplant Research who had undergone myeloablative allogeneic HCT.

The review included patients aged 16-39 with Ph-negative ALL in their first complete remission who underwent HCT from a matched sibling/relative or unrelated donor using peripheral blood or bone marrow stem cells between November 2002 and August 2012. Outcomes for these patients were compared to OS, DFS, relapse and non-relapse mortality (NRM) of patients receiving post-remission pediatric-inspired chemotherapy in the CALGB 10403 study.

The chemotherapy recipients had superior OS (p<0.0001), DFS (p=0.0011), and NRM (p<0.001) compared to patients who received allogeneic HCT. Multivariate analysis showed that receiving allogeneic HCT was associated with inferior OS (hazard ratio [HR] 1.99, 95% CI 1.5-2.65, p <0.001), inferior DFS (HR 1.51, 95% CI 1.17-1.94, p<0.002), and increased NRM (HR 3.93, 95% CI 2.53-6.10, p <0.001). Late relapse was more likely with the chemotherapy regimen; early relapse was more likely with allogeneic HCT.

Summing up

“Our conclusion was that post-remission therapy with a pediatric-inspired chemotherapy regimen as used in CALGB 10403 was superior to treating with allogeneic HCT,” says Dr. Advani. “In AYAs with newly diagnosed Ph-negative B- and T-cell ALL, the OS, DFS and NRM were better using the CALGB protocol versus the HCT protocol.”

The new study findings do not provide information about the impact of minimum residual disease (MRD) at first complete remission, or whether high-risk genetics such as Ph-like ALL have an impact on the effectiveness of the pediatric-inspired regimen versus allogeneic HCT.

“Patients who are MRD-positive, who have other high-risk cytogenetic features, or are Ph-like, might have improved outcomes with a transplant,” says Dr. Advani. “Further research is needed to evaluate this question.”