Rituximab for ALL Subset Improves Outcomes

Although the past 10 years has seen major improvements in outcomes for adults with acute lymphoblastic leukemia (ALL), targeted therapy holds the promise of even greater survival gains in certain disease subtypes.

Now, a multicenter, randomized trial shows that adding rituximab (Rituxan, Genentech) to standard chemotherapy significantly improves event-free survival in patients with CD20-positive, Philadelphia chromosome (Ph)–negative ALL.

The report was published online September 14 in the New England Journal of Medicine.

Sébastien Maury, MD, PhD, from the Institut Mondor de Recherche Biomédicale, Université Paris Est, Creteil, France, and colleagues report that after a median follow-up of 30 months, the estimated 2-year event-free survival rates were 65% for patients who received rituximab plus chemotherapy vs 52% for those who received chemotherapy alone (hazard ratio [HR], 0.66; P = .04). Events included failure of complete remission induction, relapse, and death.

"The results provide evidence of a beneficial effect of the addition of rituximab to chemotherapy in adults with CD20-positive, Ph-negative, B-cell precursor ALL," say the researchers. "A direct effect of rituximab, mediated by its binding to leukemic cells, is suggested by the more pronounced benefit observed in patients with higher levels of CD20 expression on their leukemic blasts."

Rituximab is a monoclonal antibody that targets CD20 surface antigens expressed by ALL blast cells. In earlier studies, use of rituximab led to significant improvement in patients with B cell non-Hodgkin's lymphoma, as well as Burkitt's mature B cell lymphoma or leukemia, the researchers note.

"I think that in the context of prior retrospective studies suggesting benefit from rituximab in CD20+ ALL, these results support the addition of rituximab as the standard of care for patients with ALL in which the blast cells express CD20," David P. Steensma, MD, told Medscape Medical News. Dr Steensma is associate professor of medicine at Harvard Medical School, Boston, Massachusetts, and was asked for comment.

The event-free survival benefit was mostly due to the lower relapse rates seen in patients receiving rituximab and didn't translate into significantly longer overall survival (HR, 0.70; P = .10). During the first remission, the cumulative incidence of death was similar between the two groups, Dr Maury and colleagues say.

"There are a lot of salvage options for patients with ALL," explained Dr Steensma, who is also an attending physician in hematologic oncology at the Dana-Farber Cancer Institute and attending physician in medicine at Brigham and Women's Hospital, Boston. "It's still beneficial to have improved event-free survival and fewer relapses."

In the Group for Research on Adult Acute Lymphoblastic Leukemia 2005 (GRAALL-2005) trial, 209 patients from 56 French and 9 Swiss centers were enrolled between May 2006 and April 2014. All were 18 to 59 years of age and had CD20-positive, Ph-negative ALL. The same median percentage (66%) of CD20-positive blasts was observed across both groups.

Patients were randomly assigned to chemotherapy with rituximab (105 patients) or chemotherapy alone (104 patients). A total of 16 to 18 intravenous infusions of rituximab were given during all treatment phases.

During the first complete remission, patients 55 years of age or younger were offered allogeneic hematopoietic stem cell transplantation.

"Although more patients in the rituximab group than in the control group underwent allogeneic stem-cell transplantation during the first remission, the reduced incidence of relapse and improvement in event-free survival cannot be clearly explained by a potential benefit of transplantation," say the investigators.

There was no significant difference between the two groups in the overall incidence of grade 3 or 4 adverse events. However, patients in the rituximab group experienced fewer allergic reactions to asparaginase, an unexpected finding.

Of the 16 patients who experienced severe allergic events, 15 were related to asparaginase. Only 2 of these patients were in the rituximab group, a finding that "suggests that a lot of those reactions to asparaginase are antibody mediated," Dr Steensma said.

Other surface antigens, such as CD19 and CD22, are showing promise in patients with relapsed or refractory ALL, Dr Maury and colleagues point out. These antigens may also be targeted by various antibodies or chimeric antigen receptor T cells and are expressed by ALL blasts more frequently than CD20.

More targeted agents are needed, Dr Steensma said. Some success has now been reported with inotuzumab ozogamicin (CMC-544, Pfizer), an antibody–drug conjugate against CD22, and with blinatumomab (Blincyto, Amgen), an anti-CD19 bispecific antibody that received US Food and Drug Administration approval last year, he noted.

"And of course CAR-T cells (anti-CD19 immunotherapy) are coming down the pike but the recent deaths on the Juno study emphasize that this therapy has risks," said Dr Steensma, referring to news from one developer.

This study was funded by the Paris Regional Clinical Research Office, the Programme Hospitalier de Recherche Clinique, the French Ministry of Health, Institut National du Cancer, and the Swiss State Secretariat for Education, Research, and Innovation. Dr Maury has disclosed no relevant financial relationships. Dr Steensma reports financial ties with many pharmaceutical companies, including Amgen, Astex, Boehringer Ingelheim, Celgene, Genoptix, Incyte, and MEI Pharma.

N Engl J Med. Published online September 14, 2016.


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