Haploidentical Stem Cell Transplantation with Post-Transplantation Cyclophosphamide for High Risk Acute Pediatric Leukemia. Promising Results Using a Protocol with Peripheral Blood and a Medium Intensity Conditioning

Introduction: T cell replete haploidentical stem cell transplantation with post-transplantation cyclophosphamide (PTCy) has shown encouraging results for the treatment of hematologic malignancies, its main advantage is that almost every patient will have a donor in a timely manner. However this technique has been explored mainly in adults and using bone marrow as a cellular source. Here we present our experience using T cell replete haploidentical peripheral blood stem cell transplantation (TCR-Haplo-PBSCT) with PTCy in 21 pediatric patients whit high-risk acute leukemia

Methods and Patients: Donors were mobilized with filgrastim 5 mg/kg/BID for five days, the PBSC were collected with one large volume apheresis procedure. The conditioning consisted of fludarabine 30 mg/m2 /day for 5 days, oral busulfan 4-8 mg/kg/split in 1-2 days and, one day before transplant, total body irradiation 400 cGy divided in two fractions (Flu Bu TBI) or fludarabine 150 mgs/m2 split in 5 days, melphalan 100-140 mgs/m2, one day and TBI 200-400 cGy on day - 1 (Flu Mel TBI). All patients were given PTCy 50 mg/kg/day on D+3 and D+4, followed by ciclosporin and mycophenolate starting on day + 5. In all cases filgrastim was administered after transplant beginning on d + 6

After a signed informed consent, 21 patients who needed an urgent transplant, were allografted; median age was 11  years (range 1-16), 10 were girls, the diagnosis were: acute lymphoblastic leukemia 11 patients, acute myeloid leukemia 9, and blastic phase of chronic myeloid leukemia one. 19% were in first remission (CR1), 43% in second (CR2), and 39% in third or with refractory disease(CR3).

Results:

17 patients were given Flu Bu TBI conditioning while 4 received Flu Mel TBI combination

All the donors shared 4 out of 8 alleles with the recipient; in 62% of the cases the donor was the Mother in 19% the Father and in other 19% one sibling.  A median of  16 million of CD34+ cells/kg was infused. The engraftment rate was 100%, median time to achieve 500 neutrophil or more was 15 days (range 14-20), 1 patient out of 21 died without platelet recovery, the remaining had a self- sustained platelet count of 20.000 or more at a median of 14 days (range 10-21). Chimerism at day + 100 was available in 19 cases; all of them had full donor hematopoiesis.

The median follow-up is 11 months (range 3-28), the cumulative incidence of graft versus host disease (GVHD) acute grade II-IV and chronic extensive  was 23.8% and 25% respectively. Six patients have died, the causes were; pneumonia (n:1) and relapse of leukemia( n:5).

In table 1 is presented the overall survival (OS) and event free survival (EFS) for the whole group and discriminated according remission

	Whole group	CR1	CR2	CR3
OS month 12	77.4% ± 10	100%	100%	47.3% ± 18.8
EFS month 12	71.5% ± 10.9	100%	100%	43.8% ± 18.8
OS month 24	69.6% ± 11.6	100%	80% ± 17.9	47.3% ± 18.8
EFS month 24	63.6% ± 12.3	100%	83% *22 months	21.9% ±18.1

Conclusion: The use of TCR-Haplo-PBSCT with PTCy and a medium intensity conditioning for treating pediatric high risk acute leukemia is promising; it is associated with very good engraftment rate, low transplantation related mortality and an acceptable incidence of GVHD despite the use of peripheral blood.

This protocol produces a remarkable leukemia free survival rate, especially in patients in CR1 and CR2. This approach could be a good alternative for children with high-risk leukemia and without suitable matched donors. It deserve further studies