Haploidentical TCRab Depleted Hematopoietic Cell Transplantation Leads To Rapid Immune Reconstitution and Promising Clinical Outcome In Adults
Authors: Haen Sebastian P. , Schumm Michael , Vogel Wichard , Faul Christoph , Handgretinger Rupert , Kanz Lothar , Bethge Wolfgang A. 
Published: October 2019

Immunomagnetic TCRab-depletion and reduced intensity conditioning (RIC) for haploidentical hematopoietic cell transplantation (HHCT) has been reported to result in improved immune reconstitution and clinical outcome in children. We here report the first clinical results in 10 adult patients. HHCT using TCRab-depleted grafts was performed in 7 men and 3 women (median age at transplantation 35 years, range 21-68 years). Patients were treated for ALL (n=1), AML (n=5), CLL (n=1), NHL (n=2) or SAA (n=1). Disease status prior transplantation was CR in two patients, minimal residual disease but cytologic CR in 1 patient, conditioning out of aplasia after salvage chemotherapie in 4 patients, and active disease in 3 patients. Haploidentical donors were parents (n=3), siblings (n=4) and children (n=3). Seven patients were treated with HHCT due to relapse after first (n=6) or second (n=1) allogeneic HCT. In 3 patients, HHCT was performed as primary transplantation. Conditioning regimen was myeloablative (12 Gy TBI/high dose cyclophosphamide) in 1 patient and reduced intensity conditioning (fludarabine/clofarabine, thiotepa, melphalan) in the remaining 9 patients. All conditioning regimens included ATG and mycophenolate mofetil as postgrafting immunosuppression until day +30. Patients received a median of 6.18 x 106 (range 3.4-20.4 x106) CD34+,5.92 x 106 (range 2.26-14.84) CD3+and 36.77 x 106 (range 15.75-51.84) CD56+ cells per kilogram body weight. TCRab-depletion of the grafts was a median of 4.5 logs with 0.38 104 TCRab+ CD3+ (range 0.06-1.17) cells per kilogram body weight in the graft. Median engraftment of neutrophils (&gt; 500/µl) and thrombocytes (&gt; 25.000/µl) occurred on days 12 (range day 8-15) and 14 (range day 10-23), respectively, with one patient not achieving thrombocyte engraftment until death. Patients were followed for a median of 276 days after HHCT (range 41-723 days). To date, 6 patients remain alive and in CR (60%). Four patients died due to viral infections (n=4, 40%) at a median of 92 days after HHCT (range 41-100 days) comprising adenovirus viremia, varicella zoster virus encephalitis, respiratory syncytial virus pneumonia and herpes simplex virus pneumonia. One patient also suffered from severe graft versus host disease (GvHD) of the liver. Acute GvHD ≥II occurred in a total of 5 patients with development of chronic GvHD not being observed. None of the patients experienced relapse of the underlying hematologic disease, the non-relapse mortality was 40%. Median overall and disease free survival were not reached during the observation period. Immune reconstitution was studied by flow cytometry at least every week for a median follow-up of 122 days after transplantation (range 25-558 days). Detailed information on immune reconstitution data is provided in the table. Median T cell (CD3+) engraftment (&gt; 200/µl) occurred on day 42 (range 21-397 days). Two patients did not reach &gt; 200/µl CD3+ cells until death. Engraftment of CD4+ T cells &gt; 200/µl was only achieved in 3 patients during the observation period. Our data indicate that in comparison to approaches applying CD34 selected or CD3/CD19 depleted grafts, depletion of TCRab T cells in HHCT might lead to more rapid immune reconstitution. A prospective study evaluating the role of TCRab depletion in HHCT in adults is presently ongoing.

Table Peripheral cell counts of leukocyte subsets. NK cells T cells T helper cells Cytotoxic T cells B cells CD56+ CD16+ CD3- CD3+ CD3+ CD4+ CD3+ CD8+ CD19+ Day 30 (median [/µl]) 435 28 3 12 1 range [/µl] 113-642 5-1,655 0-292 2-509 0-212 Day 60 (median [/µl]) 433 457 54 342 213 range [/µl] 188-504 1-1,367 0-175 0-368 0-556 Day 100 (median [/µl]) 319 74 9 39 82 range [/µl] 118-1,223 0-2,292 0-229 0-1,289 19-344 Peak (median [/µl]) 466 416 186 221 309 range [/µl] 134-2,650 5-4,529 3-787 2-4,029 1-3,065 Day Peak (median [day]) 52 62 59 62 63 range [days] 19-337 25-397 8-558 25-344 19-344

Disclosures:

No relevant conflicts of interest to declare.