Feasibility and Outcome of Haploidentical Hematopoietic Stem Cell Transplant with Post-Transplantation Cyclophosphamide in High-Risk Malignancies in Children

Allogeneic Hematopoietic Stem Cell Transplantation (HSCT) is an important curative therapy for children with high-risk leukemia; but, the lack of matched family donors represents a limiting factor in this group [1,2]. This issue is more relevant in regions with economic constraints or with a population which is not well represented in the international donor registries, both circumstances make access to unrelated cord blood units or bone marrow donors difficult. Haploidentical HSCT with post transplantation cyclophosphamide (Haplo-PTCy) is an alternative option for these patients; it is an effective and low-cost procedure that does not require any special technology for its implementation. 

In children, myeloablative conditioning regimens are the recommended option; however, they are associated with several toxicities such as growth retardation, infertility, increased of mortality and secondary malignancies; these complications can be decreased with the use of a Reduced Intensity Conditioning (RIC) regimen [3]. The anti-tumor effect of these regimens plus a low rate of toxic deaths produces an encouraging good overall survival [4-6]. In a survey done by the EBMT Pediatric Diseases and Complications and Quality of Life WP [6], near 40% of 161 centers from 30 different countries reported the use of an RIC regimen for treating malignant diseases with acceptable outcomes. Other study reported by Saglio [7] compared the outcomes of Haplo-PTCy from transplantation with unrelated HLA-Matched Donor (MUD) and HLA Mismatched Unrelated Donor (MMUD) in children; the Haplo HSCT was based on the non-myeloablative conditioning regimen reported by Luznik et al. [8], while the patients undergoing MUD and MMUD HSCT were transplanted using a myeloablative conditioning. There were not any differences in main outcomes among the groups. 

On the other hand, the use of Peripheral Blood Stem Cell Transplantation (PBSCT) has increased over the recent years, and now accounts for up to 32% of pediatric allogeneic hematopoietic cell transplantations [9]. A previous systematic review and meta-analysis comparing BMT and PBSCT for hematologic malignancies in adults concluded that Overall Survival (OS) and incidence of relapse were comparable between Bone Marrow Transplant (BMT) and PBSCT [10]. However, in the Haplo-PTCY setting the use of peripheral blood stem cells instead of bone marrow was associated with fewer relapses [11-13]. 

So, with the goal to decrease the toxicity but keeping a good antileukemic effect and a good engraftment rate, we decided to use in our Haplo-PTCy platform for transplanting children with high risk leukemia, a combination of an intermediate intensity regimen, instead of a truly non-myeloablative protocol as Johns Hopkins platform [14], and PBSC as the cellular source. 

Our results were recently published [15]. In short, the conditioning regimen used was a combination of fludarabine 160 mg/m2, split in four days, busulfan 8 to 12 mg/kg split in two days, or melphalan 100-140 mg/m2 in one day, plus total body irradiation 200-400 cGy.  All patients received PT-Cy 50 mg/kg/day on days +3 and +4. Starting on day +5 mycophenolate and cyclosporine were given for 2 and 6 months respectively. 

Forty-two patients less than 18 years of age with high-risk leukemia were transplanted; Twenty-six had Acute Lymphoblastic Leukemia (ALL), 13 acute myeloid leukemia, 2 juvenile myelomonocytic leukemia, and 1 blast crisis of chronic myeloid leukemia. Thirty three percent were in first remission (CR1), 50% in second (CR2), 14% in third (CR3), and 3% had refractory disease. Twenty one percent had positive Minimal Residual Disease (MRD) previous to transplant.  Neutrophil recovery occurred in 100% of 40 patients alive at day+30, transplant-related mortality at 1 year was 14%. The median follow-up for surviving patients was 45 months, the incidence of acute Graft-Versus-Host Disease (aGVHD) grade II-IV was 43%, while grade III-IV was 17%. The percent of patients with moderate-severe chronic Graft-Versus-Host Disease (cGVHD) was 29%. Overall survival (OS) and Event-Free Survival (EFS) at 36 months for the entire cohort were 56% and 46%, respectively, while for patients in first remission it was 71% and 58%, respectively. Regarding the 9 patients who underwent transplant with positive MRD, 44% were alive in remission at the moment of the report. 

In children there is a paucity of data regarding the outcomes of Haplo-PTCy; the majority of the studies included patients up to 21 years of age, have shorter follow-up periods, and report heterogeneous diseases  [16-19], which makes it difficult to conclude about which is the best conditioning regimen and the ideal cellular source in cases of high-risk acute leukemia. 

Ruggeri et al., [20] analyzed the outcomes of unmanipulated haploidentical transplantation using post-transplant cyclophosphamide in 180 pediatric patients with ALL; 69% of them were in CR1 or CR2, median age was 9 years, and the cellular source was PBSC in 36% of the transplants. The engraftment rate was near to 90%, the 100 days incidence of aGVHD II-IV was 28%, cGVHD at 2 years was 21,9% and the non-relapse mortality was 19%. The estimated 2-year EFS was 65%, 44% and 18,8% for patients transplanted in CR1, CR2 and CR3, respectively. In the multivariable analysis of patients in CR1 and CR2, disease status, age and use of PBSC were independent factors associated with decreased overall survival. 

Johns Hopkins group has reported its experience with Haplo-PTCY in children and young adults using non-myeloablative [14] and myeloablative [21] conditioning in patients with different malignancies. In both groups the cellular source was mainly BM, 40 patients were given a non-myeloablative protocol and 45% of them had high risk leukemias. The incidence of aGVHD grade II-IV was 33%, whereas the cGVHD was 24%, transplant-related mortality at 1 year was 13% and the 1-year actuarial overall and event-free survival were 56% and 43%, respectively. The group who received a myeloablative preparative regimen consisted of 96 children and adults, from 1 to 60 years, median age 42 years, and 66% of them had acute leukemia. There is not a clear discrimination between children and adults in the results, however the EFS at 1 and 3 years was 57 and 49%, whereas the incidence of Transplant-Related Mortality (TRM) at 1 year was 11%. In table 1 there is a summary of the main series using Haplo-PTCY in children. 

Table 1: Main series using Haplo-PTCY in children.

BM: Bone Marrow, PBSC: Peripheral Blood Stem Cell, ALL: Acute Lymphoblastic Leukemia, AML: Acute Myeloid Leukemia, MDS: Myelodysplastic Syndrome, HL: Hodgkin Lymphoma, NHL: Non-Hodgkin Lymphoma, MPAL: Mixed-Pediatric Acute Leukemia, CML: Chronic Myeloid Leukemia, RIC: Reduced-Intensity Conditioning, MAC: Myeloablative Conditioning, TBI: Total Body Irradiation, TRM: Transplant-Related Mortality, aGVHD: acute Graft-Versus-Host Disease, cGVHD: chronic Graft-Versus-Host Disease, EFS: Event-Free Survival, OS: Overall Survival. 

One of the problems with the use of Haplo-PTCY platform in children, is the incidence of acute and chronic GVHD; in our group it was of 43% and 29% [15], in the Ruggeri series [20] was 28% and 21.9%, and in the John Hopkins non myeloablative study [14] was 33% and 24%, respectively; this occurred despite most of the patients in the Ruggeri and Hopkins series were transplanted with bone marrow cells. Having this in mind, we make an amendment to our protocol: addition of anti-thymocyte globulin on days - 8 and -7, early introduction of cyclosporine before day +3, and harvesting of stem cells from the bone marrow [22]; we expect with these modifications, a reduction of acute and chronic GVHD. 

In conclusion, the use of Haplo- PTCy in children with high-risk leukemia offers a very good alternative to patients without a well-matched donor. This is especially relevant in areas with economic constraints where the access to unrelated donors or cord blood units is difficult. However, prospective trials with larger numbers of patients studying the intensity of the preparative regimen and the cellular source in pediatric patients with high-risk hematologic malignancies who undergo Haplo-PTCy are welcome.

Financial disclosure: There are no financial conflicts of interest to disclose.

Conflict of interest: There are no conflicts of interest to report.