A standard nonmyeloablative transplant regimen for adults with sickle cell disease - are we there yet?

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) offers a curative option for individuals with sickle cell disease (SCD). In the last decade, there has been a growing list of reports, documenting >90% overall survival rate, acceptably low acute (20%) and chronic (10%) graft versus host disease (GvHD) and transplant related mortality (<10%) rates. These successes are most often seen after myeloablative,¹ reduced toxicity,² or reduced intensity³ HSCT using matched sibling donors in pediatric recipients. Active transplant regimens to improve outcomes using alternative donor sources are also ongoing, with a great deal of the attention directed toward pediatric recipients: matched unrelated, haploidentical donors, and unrelated cord blood.⁴

Much progress has been made for children, what about for adults? Our group recently reported transplant outcome in adults with SCD using a nonmyeloablative approach, modified from previous low dose TBI experience,⁵ with 300 cGy TBI, alemtuzumab 1mg/kg divided over 5 days, and immunosuppression with single agent sirolimus.⁶ We are elated that the success at our center is being replicated elsewhere and reported in this issue of BBMT. Specifically, this low toxicity approach was well tolerated in those with moderately high comorbidity scores; peri-transplant infection rates were low; all engrafted patients continued to have mixed chimerism; and mixed chimerism was stable off immunosuppression. Saraf and colleagues further reported that these successes can be applied with lower sirolimus levels (hence fewer sirolimus related adverse events) and donor-recipient ABO major incompatibility (alleviating some concerns about post transplant red cell aplasia from residual host B-lymphocytes/antibodies).⁷ Additionally, the quality of life by standard measures also improved.

It is easy to understate the importance of the report from Saraf et al, since it initially appears little more than a confirmatory study. Quite the contrary, it contributes greatly to the feasibility of allo-HSCT for this chronic but not-so-benign hemolytic disorder. Their corroborative report on the lack of GvHD is as intriguing as it is comforting, especially when unmanipulated G-CSF mobilized peripheral blood progenitor cells were used. Our results with no GvHD were previously met with many ‘raised eyebrows’ and skepticism. Now there is independent validation that this is real and can be achieved with resources available to most transplant centers. The mechanisms for this lack of GvHD include in vivo T cell depletion with alemtuzumab, induction of regulatory T cells, and persistent mixed chimerism. While these are being sorted out in the laboratory, the slower speed of donor T cell reconstitution (about 6 months or longer), and relatively less injury to skin and GI tract from the conditioning regimen, leading to less inflammatory cytokines, may be additional contributory factors.

This report also contributes to the change in momentum regarding whether allo-HSCT should be offered to adults with severe SCD. Now age alone is not an exclusion to this definitive treatment, nor are comorbid conditions in the kidneys (nephrotic syndrome and chronic kidney disease), lungs (pulmonary hypertension and mixed obstructive and restrictive lung diseases), and liver (iron overload, sickle congestion, with varying degree of fibrosis). Older and sicker patients can undergo this low toxicity regimen and have excellent outcomes as the younger and healthy ones have experienced. Additionally, busulfan, cyclophosphamide, and anti-thymocyte globulin (Bu-Cy-ATG) has been known for decades to be ‘the go to’ regimen in myeloablative HSCT in children, but there has not been such a regimen in adults until now. Based on the available data, alemtuzumab, 300 cGy TBI, and sirolimus (alem-300 TBI- siro) could be one, or is certainly an excellent candidate, for matched sibling donors.

There is a renewed interest in allo-HSCT for SCD and steady progress has been made. For adults or those with high comorbidity, patients and transplant physicians alike now have options with reasonable expectation for great outcome. Thus I believe we have arrived: allo-HSCT from matched sibling donors can be considered part of the standard of care in adults with SCD. Additionally, we have a regimen, alem-300 TBI-siro, with excellent clinical outcomes to be used alone or as a backbone for further modification. I am very hopeful that the same success with low toxicity can be extended to other institutions to offer this curative option to more adults.