NEW ORLEANS—A novel strategy to choose an alternative source of stem cells for hematopoietic stem cell transplantation (SCT) for children with acute leukemia speeds the process of finding a matching donor, reduces the risk of serious infections after transplant, and also extends survival. The results were reported here at the American Society of Hematology Annual Meeting (Abstract 157).
The new approach uses genetic modifications of haplo-identical (i.e., half-matched) stem cells prior to transplant. Transplants of haplo-identical blood-forming stem cells from a child's mother or father may be an effective option for patients in need of a transplant without a fully matched donor, said the study's lead author, Alice Bertaina, MD, of the Department of Pediatric Hematology/Oncology and Transfusion Medicine at Bambino Gesu Children's Hospital in Rome.
“We now have developed a strategy to permit all acute leukemia patients to have a prompt donor. Normally, patients have to wait for months for a match. Now we can find a donor in two weeks. In the past, less than 60 percent of patients survived with a fully matched donor. Now, in a high-risk population, we found three-quarters of patients have a leukemia-free survival with stem cells from only one relative.”
Treatment for children with acute leukemia has traditionally relied on hematopoietic stem cells that are matched for most parts of the human leukocyte antigen (HLA) complex. Half of the genes involved in the HLA complex are inherited from each parent, but only about 25 percent of patients have a sibling with the same pattern. The search for a fully matched, unrelated donor is often difficult and lengthy.
“T-cell depleted HLA-haploidentical hematopoietic stem cell transplantation is a suitable option for patients in need of an allograft who lack a HLA-matched donor. Although it offers the advantage of being immediately applicable to virtually all patients, so far, graft manipulation with removal of all T lymphocyte subsets and of natural killer cells has been associated with an increased risk of life-threatening infections, as well as, in some studies, of leukemia recurrence,” Bertaina said.
The team tested the effectiveness of manipulating half-matched donor stem cells in the laboratory before transplantation. Magnetic beads were used to selectively remove the alpha/beta-positive T cells and CD19-positive B cells from the donor graft, since those are more likely to trigger donor cells to attack recipient cells, resulting in graft-versus-host disease (GVHD). At the same time, the process preserved the healthy, mature, immune-active cells—natural killer cells and gamma/delta-positive T cells—that help prevent disease relapse and protect against infection.
A myeloablative regimen, containing total body irradiation in about two-thirds of cases, was given to all children, who also received anti-thymocyte globulin at 12 mg/kg over three days. Rituximab at 200 mg/m2 was administered the day before the procedure to further prevent lymphoproliferative disorders. No pharmacological GVHD prophylaxis was employed after transplantation.
A total of 50 patients with acute leukemia were treated with genetically engineered stem cells from one of their parents. All children were transplanted in morphological complete remission (CR)—about one-third in first CR, more than half in second CR, and the rest in more advanced CR.
All patients transplanted in first CR had either poor cytogenetic/molecular characteristics or high levels of minimal residual disease at the end of induction therapy.
After nearly three years of follow-up, transplants engrafted in 41 of the 50 patients, for a cumulative relapse rate of 19 percent. Two patients died—meaning that the rate of transplant-related mortality was four percent.
The estimated leukemia-free survival rate was 77 percent for all patients. Among acute lymphoblastic leukemia patients, the leukemia-free survival was about 80 percent, she said.
The cumulative incidence of GVHD was 26 percent, with no severe GVHD. None of the patients developed gut or liver acute GVHD, although 13 had skin-only GVHD of grades I and II. Only two patients developed skin-limited chronic GVHD, she noted.
One month after transplant, follow-up analyses showed that transplanted cells had persisted in the patients and demonstrated potential anti-leukemic activity, which continued to increase over time.
At a news conference at the meeting that highlighted “precision-medicine approaches for hard-to-treat blood disorders,” Bertaina said that the results—“which demonstrate that transplantation of selectively modified, half-matched donor stem cells has success rates equivalent to those of a fully matched transplant, preventing GVHD and reducing transplant-related death—help continue to establish the approach as a viable option for patients without a matched donor.
ALICE BERTAINA, MD
“This has the potential to make this lifesaving treatment more accessible to a much larger population of patients who may not have a perfect donor match,” she said.
At her presentation, she explained that a selective graft manipulation results in effective prevention of both acute and chronic GVHD, rapid recovery of neutrophil and platelet counts, and low treatment-related mortality.
“Although the median observation time is still limited, the lack of disease recurrence is encouraging.”
Optimize Recovery of Stem Cell Subsets
She added that the strategy could optimize the recovery of stem cell subsets in the early weeks after hematopoietic transplant and maximize immune-mediated viral and leukemia control with an acceptable risk of GVHD.
At a news conference, she noted that it made no difference whether a mother or father was the stem cell donor, although in the past, clinicians had observed an advantage using the mother's cells.
LAURENCE COOPER, MD
“What this does is widen the field of patients who can be transplanted. Presently, we can choose a donor from one of the parents. We have the advantage of choosing a haplo-identical relative,” Bertaina said.
In an interview, the moderator of the news conference, Laurence Cooper, MD, Professor of Pediatrics at the University of Texas MD Anderson Cancer Center, called the approach an example of the “modern age of HLA typing.”
“Previously, we used only HLA genetic differences in antigens to choose donors. Now we recognize through this type of work that we can use immune reconstitution of natural killer cells and T cells, and figure out which preferred donor has the ability to stimulate engraftment in the immune system.”
Cooper added that the strategy has two advantages: (1) it pushes technology forward in terms of efficacy by pulling out just the stem cells needed; and (2) it speeds finding an appropriate donor. He noted that patients often died during the time it took to search for a donor. “We no longer have to search through a massive registry to locate a donor,” he said. “Often, we can find a donor in the same room as the patient.”
In a video interview on the iPad edition of this issue with OT reporter Dan Keller conducted at the ASH meeting, OT Editorial Board member Michael Caligiuri, MD, Director of Ohio State University Comprehensive Cancer Center and CEO of the James Cancer Hospital and Solove Research Institute, describes the new James Cancer Hospital and discusses some of the innovations in the design and function—for example, including laboratories right on the patient floors. He also talks about the recently approved drug ibrutinib, which was developed in large part at OSU.
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