The outcomes of second allo-HSCT in a cohort of 50 pediatric patients with high-risk hematological malignancies lacking response or without engraftment after the allo-HSCT

Summary

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the standard of treatment in high risk hematological malignancies. Nevertheless, the relapse rates range from 10% to 70%. There are no optimal treatment options of the disease recurrence after allo-HSCT. Possible therapeutic options include reinduction chemotherapy, immuadoptive therapy (DLI), targeted therapy, immunotherapy (CAR-T) and second allo-HSCT. The presented study presents a retrospective single-center experience of second allo-HSCT in patients (pts) with refractory hematological diseases or graft failure in high-risk patients. The aims of this study were to evaluate the efficiency and factors affecting the outcome after second allo-HSCT in children that relapsed or had a graft failure after first allo-HSCT.

Materials and methods

We analyzed clinical outcomes in 50 children after second allo-HSCT with hematological malignancies: ALL – 24 pts, AML – 15 pts, MPL/MDS – 11 pts. First allo-HSCT was performed in 1^st clinical remission – 16 pts, in 2^nd, 3^rd and more remissions, in 18 pts; active disease, in 16 pts. Allo-HSCT was performed from MUD in 20 pts, MRD in 14 pts, haplo-donors in 14 pts, singeneic – 2 pts. Condition regimen was MAC in 34 pts, RIC in 16 pts. Median age at the time of the first allo-HSCT was 5 y.o. (1-18), median remission duration after 1^st allo-HSCT was 148 days (31-1084), median time between 1^st and 2^nd allo-HSCT was 7.3 month (1-48). Indications for the second allo-HSCT were relapse or progression of the disease in 36 pts, primary graft failure, in 11 pts, secondary graft rejection, in 2 pts, transplant hypofunction, in 1 case. Median age at second HSCT was 7 y.o. (1.0-20).The conditioning regimens prior to second allo-HSCT were RIC in 40 pts and MAC in 10 pts, included post-transplant cyclophosphamide on Days +3, +4 in 31 pts, ATG-based GVHD prophylaxis was used in 11 pts; combination Tx-based GVHD prophylaxis, in 38 pts; Sirolimus, in 31 pts, Cyclosporin A, in 7 pts; monothyerapy with calcineurin inhibitors, in 7 pts. The 2^nd allo-HSCT was performed from haploidentical donors in 44 pts (3 pts with the same haploidentical donor, as at in 1st allo-HSCT). In other pts: MUD (without donor substitution), in 4 pts; MRD (without donor substitution), in 2 pts. Different kinds of therapy prior to second HSCT were performed in 38 pts, 12 pts were transplanted in aplasia (transplant rejection/hypofunction). FLAG/BFM was administred in 24 pts; target therapy (hypomethylating agents/monoclonal antibodies), in 7 pts, combination of chemotherapy and targeted drugs was used in 7 pts. There was no clinical response in 16 pts, 10 pts achieved remission and cytoreduction of blasts (<20% blasts) was achieved in 12 pts. Thirty-one pts underwent post-transplant therapy: immunoadoptive therapy (DLI), 9 pts; maintenance therapy/HMA/MA, 13 pts; DLI + combined CT was performed in 9 pts.

Results

Forty-four patients achieved engraftment, with median neutrophil reconstitution time of 21 days (12-41). Clinical remission was achieved in 44 pts (88%). OS in the whole group was determined by Kaplan-Meier method as 48%; LFS was 60%. Median follow-up was 3.9 years. OS in ALL group was 46.2%; in AML group, 53.3%; in myeloproliferative disorders it was 44.4%. OS in patients with graft failure/rejection was 71.4% (14 pts). OS in pts with remission, 80%, and it 50% in cases of cytoreduction. Meanwhile, OS in pts who did not achieve remission or cytoreduction was 12% (p=0.05).There was no statistically significant impact of conditioning regimen upon OS, i.e., 50% vs 47% for MAC vs RIC, respectively (p=0.6). Donor type didn’t affect OS, with or without donor substitution (50% vs 47%, p=0.4). Impact of aGVHD grade II and III upon OS was marginal: 61%, vs overall survival in pts who didn’t have clinical manifistation of aGVHD, i.e., 21% (p=0.09). Mild and moderate chronic GVHD (cGVHD) was detected in 29 pts (65%). OS in pts with cGVHD significantly exceeded OS values in cases without cGVHD (72.4% vs 12.5%, p=0.000). Causes of death were as follows: relapse/progression, in 17 pts (65%); TRM, in 9 pts (20%). OS in patients with post transplant therapy: only DLI, 55.6%; usage of HMA, target therapy/maintenance therapy, 46.2%; combination of DLI+CT, 22.2%, as compared to patients without therapy (but with aGVHD incidence) 84.6%, p=0.08).

Conclusion

Second allo-HSCT is an effective treatment option of relapse after 1^st allo-HSCT. The patients that achieved remission or even blast cytoreduction prior to 2^nd allo-HSCT had improved outcome. Clinical manifestation of chronic GVHD can significantly improve the OS. RIC in 2^nd allo-HSCT was comparable to MAC. Post transplant therapy is required to improve results after 2^nd HSCT.

Keywords

Hematopoietic stem cell transplantation, repeated, children, overall survival, clinical outcomes.