LY-04. Allogeneic hematopoietic stem cell transplantation in patients with relapsed or refractory mantle cell lymphoma

Summary

Introduction

The main reason for chemoresistance in patients with MCL is the presence of mutations in the TP53 gene (10-20%). Among other factors, the presence of mutations in the genes MLL2, NOTCH1/2, CDKN2A/B, ATM, translocation in the gene c-Myc, etc. is also considered. The clinical course of R/R forms of MCL is characterized by aggressive morphology, the presence of complex karyotype, “reverse” growth in size tumors in the inter-course interval, and the absence of CR and MRD-negativity at the time of completion of therapy. Allo-HCT is the only method that is able to overcome chemoresistance and achieve CR in this group of patients. Our aim was to estimate the efficacy of allogeneic HCT in patients with relapsed or refractory MCL.

Materials and methods

In this study, we analyzed 6 patients with MCL who had received allogeneic HCT between October 2016 and June 2020. Four patients had a primary-refractory disease, of which 3 cases revealed mutations in the TP53 gene. Two patients developed a relapse 6 and 24 months after auto-HCT. The median age of patients is 47 (42-63) years, M:W= 4:2. Blastoid morphology and complex karyotype were found in 4 and 6 patients, respectively. Deletion of 17p chromosome was detected in 3 patients, and in all cases in combination with TP53 gene mutation. One patient from the TP53 + group had the t c-Myc gene. In one case, in addition to t (11; 14) (q13; q32), t (3; 22) (q27; q11) and t (14; 18) (q32; q21) were identified. All patients underwent NGS, and mutations were identified: №1 – TP53, CDKN2C, NOTCH2; №2 – TP53, NOTCH1, CDKN2A/B, MLL2; №3 – TP53, WHSC1, MLL2, ATM, CHEK1; №4 – CDKN2A/B, CDKN2C, ATM, BCOR, BRCA2; №5 – CHEK2, ATM, ATR, FANCF, GATA2, BTG2; №6 – BCL2, BCOR, MEF2B, ASXL1, RICTOR, CREBBP, FOXO1, EZH2, IRF1, TET2.

Results

In the course of their disease, four patients received a combination of different chemotherapy and target therapy schedules including R-BAC/R-HA, R-EPOCH, platinum-based courses, mNHL-BFM-90, ibrutinib, lenalidomide, venetoclax and Obinutuzumab; one out of 4 patients had received prior autologous HCT. However, CR and MRB negativity were not achieved. Two patients underwent therapy according to the “MCL-2016” protocol, which included 4 courses of the R-BAC/R-HA rotating program with auto-HCT and maintenance therapy with rituximab for 2 years. After 6 and 24 months, a relapse of the disease was noted. Before allo-HCT, 1 patient had been treated with ibrutinib in combination with palbocyclib, and another patient – mNHL-BFM-90 with venetoclax. Stem cells from peripheral blood were used as a transplant source in 5 cases and bone marrow in 1 patient. Three patients had an HLA-identical unrelated donor, two patients had haploidentical related donors and the remaining 1 patient had a mismatched unrelated donor (9/10). Reduced-intensity conditioning (RIC) consisted of fludarabine + busulfan (n=4) and fludarabine+melphalan+treosulfan in 2 patients. For GvHD prophylaxis, the patients received ATG+CSA+MMF+MTX (n=1), ATG+PTCy+CSA+MMF+MTX (n=1), ATG+PTCy+CSA+MMF (n=2), PTCy+CSA+MMF (n=2). All patients developed acute graft-versus-host disease (skin, grade II (n=3); skin + intestine, grade III-IV (n=3). To date, four pts remain in complete remission and demonstrate full donor cell chimerism. One patient developed cGVHD of mucous membranes, moderate degree, being refractory to glucocorticosteroids. Against the background of prolonged IST cGVHD, the patient developed a relapse of MCL for + 16 months after allo-HCT. Currently, therapy is underway with ibrutinib, venetoclax and palbociclib. One patient died 3 months after allogeneic HCT due to infectious complications. Primary graft hypofunction was documented in one case 42 days after allogeneic HCT.

Conclusion

Performing allo-HCT allows a cure in the group of R/R patients, even in the presence of a mutation in the TP53 gene, although it is associated with a high risk of severe complications. Prolonged IST may explain the development of MCL relapse after allo-HCT. Considering the aggressive course of R/R MCL, in the context of a lack of time to search for a donor, performing allo-HCT from haploidentical donors with Cy prophylaxis in the post-transplant period is the optimal approach.

Keywords

Mantle cell lymphoma, allo-HCT, TP53 mutation.