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Familial stem cell transplant improves outcomes in high-risk sickle cell disease
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SAN DIEGO — Myeloablative and haploidentical hematopoietic stem cell transplantation from parental donors that utilized CD34 enrichment and mononuclear cell addback significantly improved health-related quality of life and neurocognition of high-risk patients with sickle cell disease, according to a study presented at ASH Annual Meeting and Exposition.
The regimen conferred rapid hematological reconstitution, long-term stable white blood cell and red blood cell donor chimerism, stable to improved cardiac and pulmonary function, and low cumulative incidence of acute and chronic graft-versus-host disease.
“Basically, we are now at 3-year follow-up of this study, and there are no patients who have any signs of sickle cell disease and sickle symptoms, and they all off immunosuppressive therapy and are actually off all drugs,” Mitchell Cairo, MD, chief of pediatric hematology, oncology and stem cell transplantation; director of the children and adolescent cancer and blood diseases center; associate chairman of the department of pediatrics; and professor of pediatrics, medicine, pathology, microbiology and immunology, and cell biology and anatomy at New York Medical College, said during a press conference.
The only known cure for patients with sickle cell disease is an allogeneic HSCT from an HLA-matched sibling after myeloablative or reduced-toxicity conditioning.
However, that cure is only available to 15% of patients with sickle cell disease due to the rarity of HLA-matched siblings.
The analysis included 19 patients (male, n = 12; mean age, 13.1 years; standard error of mean [SEM], ± 1.2; range, 3.3-20) with sickle cell disease with one or more high-risk features — including cerebral vasculopathy, repetitive acute chest syndrome and vaso-occlusive crisis, and abnormal transcranial doppler requiring red blood cell transfusion — who underwent myeloablative and parental haploidentical HSCT. The regimen consisted of hydroxyurea, azathioprine, fludarabine, busulfan, cyclophosphamide, thiotepa, rabbit antithymocyte globulin, total lymphoid irradiation and peripheral blood stem cell transplant.
Based on the researchers’ previous data from pediatric matched unrelated donor recipients, the transplant regimen included CD34 enrichment (10 x 106 CD34/kg), mononuclear cell addback (2 x 105 CD3/kg) and tacrolimus acute GVHD prophylaxis for 100 days.
The study included 18 parental haploidentical donors (women, n = 15; mean age, 41.3 years; SEM ± 1.2; range 30-55).
The mean infused CD34-enriched peripheral blood stem cell was 10.94 x 106/kg (SEM, ± 0.4 x 106/kg) and mean mononuclear cell addback was 2 x 105 CD3/kg.
The median time to neutrophil engraftment was 9 days, and median time to platelet engraftment was 19 days.
At 1 year, the mean whole white blood cell mixed donor chimerism was 97.1% (SEM, ± 1.4) and red blood cell (CD71) mixed donor chimerism was 96.4% (SEM, ± 2).
Probability of EFS after 1 year was 90% (95% CI, 64-97).
Two years after haploidentical HSCT from parental donors, researchers reported pulmonary function tests and cardiac systolic fraction and tricuspid regurgitant jet velocity — a measure of pulmonary hypertension — appeared stable or improved.
Researchers observed no new overt or silent strokes and no new cerebral vasculopathy.
Patients underwent neurocognitive testing with DIVERGT screening at baseline and 2 years. They also underwent health-related quality-of-life testing with the age-appropriate CHRIS-General and CHRIs-HSCT tests at baseline and days 45, 100, 180, 365 and 730 post-HSCT.
Researchers found that intellectual functioning — including memory, language and executive function — were all stable or improved at 2 years. Also, processing speed (P < .026), emotional functioning (P < .03) and physical functioning (P < .01) each significantly improved.
The incidence of grade 2 to grade 4 acute GVHD was 6.2%, and 6.7% of patients experienced chronic GVHD.
“One patient developed chronic GVHD for a cumulative incidence of 6.7%,” Cairo said. “So, it’s not zero, and we will continue to look for ways to reduce that number to zero.”– by John DeRosier
Reference:
Cairo M, et al. Abstract 162. Presented at: ASH Annual Meeting and Exposition; Dec. 1-4, 2018; San Diego.
Disclosures : Cairo reports research funding from Janssen. Please see the abstract for all other authors’ relevant financial disclosures.
Perspective
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Ifeyinwa Osunkwo, MD, MPH
I am a firm believer that, if you have a disease as bad as sickle cell disease can be, you should be offered every potential opportunity to be cured. We had been limited with transplant because many patients didn’t have matched sibling donors. In some cases, siblings were not eligible to be a donor even if they were a match.
This approach opens up an entirely different opportunity for our patients. It is so exciting to see the results look so promising. We’re not just looking at a hundred days or a year after transplant, but rather 3 years later these patients continue to feel better and are more functional.
When I was in training, patients who underwent haploidentical transplant did not do well, and I remember seeing those patients in the ICU who were doing so poorly. When I read this abstract, I thought, ‘My gosh, this is so awesome.’ The toxicity level is so much less than we imagined. Many clinicians do not refer patients for haploidentical transplant because they remember how bad it was 15 or 20 years ago, so it is important that we get these data out there so everyone in the clinical community knows things have gotten better. It’s still not perfect, but it is light years ahead of where we were before.
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