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
Polina V. Kozhokar, Olesya V. Paina, Anastasia S. Borovkova, Anastasia S. Frolova, Zhemal Z. Rahmanova, Elena V. Semenova, Anna A. Osipova, Kirill A. Ekushov, Elena V. Babenko, Ludmila S. Zubarovskaya, Boris V. Afanasyev
Raisa Gorbacheva Memorial Research Institute of Pediatric Oncology, Hematology and Transplantation, Pavlov First Saint Petersburg State Medical University, St. Petersburg, Russia
Contact: Dr. Polina Kozhokar
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 1st clinical remission – 16 pts, in 2nd, 3rd 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 1st allo-HSCT was 148 days (31-1084), median time between 1st and 2nd 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 2nd 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.
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).
Second allo-HSCT is an effective treatment option of relapse after 1st allo-HSCT. The patients that achieved remission or even blast cytoreduction prior to 2nd allo-HSCT had improved outcome. Clinical manifestation of chronic GVHD can significantly improve the OS. RIC in 2nd allo-HSCT was comparable to MAC. Post transplant therapy is required to improve results after 2nd HSCT.
Hematopoietic stem cell transplantation, repeated, children, overall survival, clinical outcomes.