Long-Term Efficacy and Safety of Allogeneic Hematopoietic Stem Cell Transplantation for Relapsed or Resistant Ph+ Acute B Lymphoblastic Leukemia That Cannot Get MRD- Remission after Multi-Line Treatment

Background The prognosis of PH positive (+) acute B lymphoblastic leukemia (B-ALL) has greatly improved after chemotherapy combined with tyrosine kinase inhibitors (TKIs). However, there are still a great many patients who get complete remission (CR), but minimal residue disease (MRD) cannot change to negative (-) after multi-line chemotherapy and TKIs, even after chimeric antigen receptor T (CART) cells, CD3/CD19 bispecific antibody and inotuzumab ozogamicin salvage treatment. For these patients, the relapse rate is more than 70% and we performed allogeneic (allo-) hematopoietic stem cell transplantation (HSCT) for them and showed an excellent long-term result of efficacy and safety. Here we report our results.

Methods We consecutively included 32 PH+-B-ALL patients with good performance status who got morphologic complete remission (CR), but MRD could not change to negative (-) after ≥4 courses of chemotherapy and ≥2 kinds of TKIs, or after chimeric antigen receptor T (CART) cells, CD3/CD19 bispecific antibody or inotuzumab ozogamicin salvage treatment and received allo-HSCT in our hospital between Jan 2018 and Jul 2024. Median age of included patients was 30 (2-61) years and the ratio of female to male was 11:21. 10 (31.3%) patients were BCR-ABL1 continuing positive after >4 courses of chemotherapy (2 were also flow cytometric +), 14 (43.8%) patients were BCR-ABL1+ after one course of CART (13 CD19-CART and 1 CD22-CART, 3 were also flow cytometric +), 5 (15.6%) patients were BCR-ABL1+ after at least two courses of CART (CD19 and CD22-CART), 3 (9.4%) patients did not get CR after two or three courses of CART and then received CD3/CD19 bispecific antibody or inotuzumab ozogamicin and got morphologic CR. 17 (53.1%) patients received graft from haplo-identical donors, 11 (34.4%) from matched (HLA 10/10 or 9/10 matched) unrelated donors and 4 (12.5%) from matched sibling donors. Five (15.6%) were 2^nd allo-HSCT. Myeloablative conditioning regimens were administered before HSCT with total body irradiation (fractionated, total 8~10 Gy) or busulfan (0.8mg/kg q6h x 3 days) /etoposide (200 mg/m² x 3 days) or thiotepa (5 mg/kg x 2 days) /fludarabine (30 mg/m² x 5 days) /Me-CCNU 250 mg/m² /rabbit anti-T-cell globulin (for haplo-identical and unrelated HSCT). Cyclosporine, mycophenolate mofetil and short-term methotrexate were employed to prevent acute (a) graft-versus-host disease (GVHD). Patients received maintenance regimens with TKIs based on whether T315I mutation was exist up to two years post-HSCT.

Results All the 32 patients achieved durable engraftment. The median follow-up time was 725.5 (50~1889) days. 25 patients were alive without leukemia detected and the two-year OS (overall survival) and LFS (leukemia-free survival) post-HSCT were 83.3% and 79.9%, respectively. There was no difference in OS and LFS for patients who had received CART or not (both P>0.05). Three patients (9.4%) relapsed, in which two died of relapse, and three patients (9.4%) died of transplantation-related events. Eight patients (25%) occurred serious infections, in which six were lung infection, one was intracranial infection and one was abdominal infection, and one died of infection. Nine patients (28.1%) developed I~II aGVHD and were cured after treatment. Four patients (12.5%) developed grade III~IV aGVHD, in which two died of aGVHD. Four patients (12.5%) had extensive chronic GVHD (cGVHD), two were obliterative bronchiolitis syndrome (BOS), one was arthrosclerosis, and one was multi-organ involved. They were relieved after combined immunosuppressive therapy. CMV and EBV reactivation were detected in nine (28.1%) and two (6.3%) patients, respectively, but no CMV or EBV disease developed. Four (12.5%) cases developed III/IV hemorrhagic cystitis. Two patients had human parvovirus B19 and one had adenovirus infection. One had human herpes virus 6 viremia. All of them resolved after anti-virus treatment.

Conclusion For these so heavily treated patients the OS and LFS reached to 83.3% and 79.9%, and the transplantation-related mortality was only 9.4%. Therefore, we conclude allo-HSCT is effective and safe for PH+-B-ALL patients who have gotten morphologic CR, but MRD cannot change to negative. In addition, it is demonstrated that for patients whose MRD cannot change to negative after both multi-line chemotherapy and CART treatment, allo-HSCT is also the potentially curative treatment regimen.