Haplo-Identical Stem Cell Transpant Is a Feasible and Safe Treatment Option for Patients with Severe Thalassemia

Background Thalassemia-free survival after allogeneic stem cell transplant (allo-SCT) is typically at best 80-90% when matched related (MRD) or unrelated (MRD) donors are utilized. Unfortunately, the chance to find a suitable door is only in the range of 40-50%. Therefore, the use of haplo-identical donors has been investigated, but with mostly disappointing results. We hypothesized, that pretransplant iron depletion through chelation, followed by pharmacological pretransplant immunosuppression (PTIS) using two courses of pulse-dexamethasone (Dxm) and -fludarabine (Flu) would immunosuppress the patients sufficiently to consistently allow engraftment after a reduced-toxicity Flu-Busulfan (Bu) conditioning program, which in the mismatched/haplo-identical graft situation would be followed by post-transplant cyclophosphamide-based (post-Cy) GvHD prophylaxis.

Patients and Methods: Between January 2013 and July 2018, 78 patients (pts) with mostly severe, class 3, thalassemia underwent haplo-allo-SCT. Fifty five subjects were male and 23 were female. The median age was 12 years (range; 2-28). Forty six of 78 pts received stem cells from mother and 32 from father. Forty (51%) of 78 pts were high risk class 3. They initially received hydroxyurea 20 mg/kg/d for three months, together with chelation to decrease iron overload. All pts received two courses of PTIS with Flu 40 mg/m²/d and Dxm 25 mg/m²/d, both for 5 days (d-67 to d-63 and d-39 to d-35). After the PTIS, a reduced-toxicity conditioning (RTC) regimen consisting of thymoglobulin 1.5 mg/kg/d (d-11 to d-9), Flu 35 mg/m²/d i.v. (d-7 to d-2), each dose immediately followed by Bu 130 mg/m²once daily i.v. on d-7 to d-4, which after the first 32 pts was modified to pharmacologically-guided Bu to an average daily AUC of 4,500 µMol-min. GVHD prophylaxis with post-Cy, 50 mg/kg/d was given on d+3 and d+4, and on day+5 we started tacrolimus or sirolimus to be given for 6-12 months, in addition to mycophenolate mofetil, the latter quickly tapered after 2 months. T-cell replete peripheral blood stem cells were given to all patients, targeting a CD34+ cell-dose of 10 x 10⁶cells/kg (range, 7-16 x 10⁶).

Results: Seventy five of the 78 pts engrafted with full donor chimerism (100%) while 3 suffered graft failure. These 3 pts received a second transplant on day +30 with minimal added conditioning and additional PBSC after which two achieved full donor chimerism but later developed grade IV aGvHD and died, and one had autologous recovery and died later with pneumonia. Median time to neutrophil engraftment was 18 days (range; 14 -22). Fifteen pts developed aGVHD gr I, 5 grade II and 4 grade 3. Only two had extensive cGVHD. Median follow-up time is 16 months (range 6-63 mos). Seventy four of 78 pts survive thal-free and have sustained full donor chimerism (98-100%). One additional pt died of infectious complications. Two-year Event free survival (EFS) and overall survival (OS) are above 95%, and is not different from our results obtained with matched-related or -unrelated donors.

Conclusion: Haploidentical HSCT for high risk thalassemia patients is with our novel approach safe. The EFS rates among MRD, MUD and Haplo-HSCT recipients receiving this regimen, varied only in reference to the choice of matched vs mismatched donor is at least 95%, and we conclude that virtually every patient will now have the option of an allo-SCT regardless of donor compatibility. Therefore, we suggest that all thalassemia patients, even those with high risk class 3 features, should be offered allo-HSCT. However, this treatment program is not thalassemia-specific, but it is proof of principle for how to successfully transplant all patients with a genetic disease. The presence of an active or hyperactive immune system in such patients should not prevent their access to allogeneic SCT even if it is necessary to use an alternative donor.