Younger Patients With ALL Could Bypass a Transplant

Mark R. Litzow, MD

The role of allogeneic transplant in the treatment of adult patients with acute lymphoblastic leukemia (ALL) is evolving as a result of new studies providing evidence of the efficacy of an improved chemotherapy regimen. Clinicians are now considering the risk-benefit analysis for individual patients based on the results of new clinical trials.

Mark R. Litzow, MD, a professor of Medicine in the Division of Hematology at the Mayo Clinic in Rochester, Minnesota, gave an overview of how best to assess ALL patients and decide whether a transplant is optimal during the 18th Annual International Congress on Hematologic Malignancies®: Focus on Leukemias, Lymphomas, and Myeloma. Physicians’ Education Resource®, LLC, hosted the conference on February 14-15 in New York City.

“The role of transplant in ALL has evolved with the recent evidence that utilization of pediatric intensive chemotherapy regimens in younger adult ALL patients results in improved outcomes compared with currently used adult combination chemotherapy regimens,” said Litzow. “This is one of the major advances in the treatment of ALL in the last 10 years.”

The rationale to test the efficacy of pediatric chemotherapy regimens stemmed from a 2008 study that showed that young adults and adolescents treated with a pediatric regimen through the Children’s Cancer Group had better outcomes compared with those patients with ALL of the same age but treated with adult chemotherapy regimens through the Cancer and Leukemia Group B (CALGB).¹ Among the most important differences between these two types of regimens are the much higher cumulative doses of nonmyelosuppressive drugs such as vincristine, corticosteroids, and asparaginase used in the pediatric compared with the adult chemotherapy regimens.

Support for applying pediatric regimens to the treatment of adult ALL is now based on several clinical trials that provided valuable information on the efficacy of these regimens in ALL as well as the types of patients who are most likely to benefit from these chemotherapy regimens.

A 2009 phase II trial in 212 patients aged 15 to 60 years compared the efficacy of a pediatric intensive protocol to treat ALL with adult regimens as well as with allogeneic stem-cell transplantation from a previous study.² The 2-year event-free survival was 56% in patients treated with pediatric regimens compared with 41% with adult regimens, including stem cell transplants (P = .0002). The overall survival was also improved from 54% to 66% with the pediatric regimen (P = .02). Litzow highlighted that these benefits, however, were not seen in those patients over 45 years of age, due to an excess of treatment-related toxicity and mortality in the older patients. The US Intergroup C10403 phase II study in adults up to the age of 40 years tested the efficacy of a pediatric regimen,³ he said, and has recently completed accrual. Results of this study are pending, according to Litzow.

Litzow also reviewed several meta-analyses of chemotherapy compared with transplant of patients with ALL. These analyses have so far provided somewhat surprising results: Standard-risk patients benefited from a transplant compared with chemotherapy in first complete remission, but for patients in the high-risk category, the benefit was not as clear.⁴ In a different meta-analysis, researchers concluded that transplant from a matched sibling donor improves survival only for younger patients in first remission, compared with adult chemotherapy regimens.⁵

Chemotherapy or Transplant? Practical Advice

Providing practical information on how to best manage patients with ALL who are currently in a first remission following chemotherapy, Litzow summarized how he makes decisions in his own practice.

“The data are not entirely clear on how to delineate and group our patients into the chemotherapy versus the transplant category,” said Litzow. With this caveat, Litzow suggests that patients up to the age of 35 to 40 years, should be enrolled in a pediatric intense regimen. “The results with pediatric regimens are encouraging enough that many of these younger patients are likely to not need transplant in first remission,” said Litzow. “Preferably, these patients should be treated on a clinical trial or through a referral to a colleague specializing in pediatrics.”

However, for those patients who are high risk, a transplant could be considered but, “Certainly many of those patients do not need a transplant and can be treated with chemotherapy,” said Litzow.

Those patients who are aged 35 years to 45 years fall into a gray area. These patients could benefit from a pediatric regimen but those with high-risk factors should be considered for a transplant. Patients between the ages of 45 and 55 years should be considered for a transplant, particularly one with a reduced intensity conditioning, which allows these older patients to better tolerate a transplant.⁶ Those patients over the age of 55 years should receive a chemotherapy regimen, according to Litzow, but can be considered for a reduced intensity conditioning regimen transplant on a selective basis.

Minimal residual disease (MRD) “is a potent prognostic predictor of outcome,” said Litzow. When there is evidence of residual leukemia, studies have shown, patients are more likely to relapse and have a poorer prognosis.

“Patients who have no detectable MRD at the end of their induction chemotherapy, or throughout the course of their chemotherapy, who are in morphologic remission, may not require a transplant during first remission, according to a new study,⁷” said Litzow. In contrast, those patients with evidence of MRD, even if they are in remission, are more likely to benefit from a transplant, although their outcomes may not be as good as those MRD-negative patients who do not receive a transplant.

Currently, two approaches for measuring MRD are flow cytometry, which assesses any aberrant antigen expression of the lymphoblast, and polymerase chain reaction (PCR), which analyzes the sequences of the T-cell receptor gene rearrangements in T-cell ALL and immunoglobulin gene rearrangements for B-cell ALL. PCR is slightly more sensitive but more labor intensive and individualized to the patient compared with flow cytometry, said Litzow, although both are valid approaches. Next-generation sequencing is currently being tested as a novel MRD assessment method and may become the standard laboratory technique for MRD evaluation in the next several years, said Litzow.

References

1. Stock W, La M, Sanford B, et al. What determines the outcomes for adolescents and young adults with acute lymphoblastic leukemia treated on cooperative group protocols? A comparison of Children’s Cancer Group and Cancer and Leukemia Group B studies [published online May 23, 2008]. Blood. 2008;112(5):1646-1654.
2. Huguet F, Leguay T, Raffoux E, et al. Pediatric-inspired therapy in adults with Philadelphia chromosome-negative acute lymphoblastic leukemia: the GRAALL-2003 study [published online January 5, 2009]. J Clin Oncol. 2009;27(6):911-918.
3. NIH Clinical Trials registry. www.ClinicalTrials.gov. NCT00558519.
4. Ram R, Gafter-Gvili A, Vidal L, et al. Management of adult patients with acute lymphoblastic leukemia in first complete remission: systematic review and meta-analysis. Cancer. 2010;116(14):3447-3457.
5. Gupta V, Richards S, Rowe J, et al. Allogeneic, but not autologous, hematopoietic cell transplantation improves survival only among younger adults with acute lymphoblastic leukemia in first remission: an individual patient data meta-analysis [published online November 19, 2012]. Blood. 2013;121(2):339-350.
6. Mohty M, Labopin M, Volin L, et al. Reduced-intensity versus conventional myeloablative conditioning allogeneic stem cell transplantation for patients with acute lymphoblastic leukemia: a retrospective study from the European Group for Blood and Marrow Transplantation [published online August 17, 2010]. Blood. 2010;116(22):4439-4443.
7. Dhédin D, Huynh A, Maury S, et al. Allogeneic Hematopoietic Stem Cell Transplantation (HSCT) in Adults With Philadelphia Chromosome (Ph)-Negative Acute Lymphoblastic Leukemia (ALL): results from the Group for Research on Adult ALL (GRAALL). Blood. 2013;122(21):abstr 552.