November 2022 Clinical Case of the Month
Title: Maintenance Therapy Post Allogeneic Stem Cell Transplantation in Acute T-Cell Lymphoblastic Leukemia
Submitted by: Ali Atoui, MD
Hematology-Oncology Fellow
American University of Beirut Medical Center
Beirut, Lebanon
Physicians expert perspective: Ali Bazarbachi, MD, PhD
Professor of Medicine, Hematology and Oncology
Director, Bone Marrow Transplantation Program
American University of Beirut, Medical Center
Beirut, Lebanon
A 32-year-old man was diagnosed with mature type T-cell lymphoblastic leukemia (T-ALL) in April 2017. He received the HyperCVAD [1] regimen for 8 cycles followed by maintenance therapy with vincristine, methotrexate and 6-mercaptopurine and prednisone for 2 years. In February 2020, the patient presented for thrombocytopenia for which bone marrow aspirate showed relapsed disease. He received the augmented BFM induction regimen [2] after which he achieved a second complete remission. The patient continued the augmented BFM consolidation for 2 months and was referred for transplant. He underwent allogeneic stem cell transplant from matched-related donor in April 2020 using conditioning with clofarabine 30 mg/m2/day for day -4 to day -2, total body irradiation 4 Gy in 2 fractions on day -1 and thymoglobulin 2.5 mg/kg on day -2. He received cyclosporine and mycophenolate mofetil as graft-versus-host disease prophylaxis. Disease evaluation at day 30 post-transplant showed no evidence of leukemia by morphology and flow cytometry, negative molecular studies for TCR rearrangement, diploid cytogenetics and 99% donor chimerism.
Which of the following is the most appropriate post-transplant systemic maintenance therapy?
A. No post-transplant maintenance therapy
B. Donor Lymphocyte Infusion (DLI)
C. Hypomethylating agents
D. Hypomethylating agents in combination with a BCL-2 inhibitor (venetoclax)
Expert Perspective by Ali Bazarbachi
Relapsed/Refractory (R/R) T-ALL is an aggressive disease which carries a dismal outcome with around 10% survival at 5 years [3]. Although allogeneic stem cell transplant has shown benefit in this population, around 40% of recipients relapse with the greatest risk being in the first year post allo-HSCT [4]. Post-transplant prophylactic maintenance in such high-risk disease is one potential therapeutic option to decrease the risk of relapse, especially with the few available additional salvage therapies in this setting. This maintenance strategy has been well established in Philadelphia positive ALL using tyrosine kinase inhibitors or in acute myeloid leukemia (AML) using FLT3 inhibitors or hypomethylating agents [5]. However, to date, the is no robust data to support the use of post-transplant maintenance in T-ALL.
Donor Lymphocyte Infusion (DLI) use as prophylaxis to enhance graft versus leukemia effect was mostly investigated in patients with AML and myelodysplasia. Although the cumulative incidence of relapse was significantly higher in the non-DLI group compared to DLI group, the efficacy of preemptive or prophylactic DLI use post-transplant is limited due to the risk of severe GHVD [6].
T-ALL is a genetically heterogeneous disease in which hypermethylation is associated with poor prognosis [7]. Multiple studies have shown that hypermethylation of tumor suppressor genes is frequent in T-ALL, thus providing rationale for the possible use of hypomethylating agents as maintenance therapy to prevent relapses [8]. Post-transplant decitabine in ALL was investigated in a Chinese prospective trial which showed no relapses in 7 patients with T-ALL [9].
Although the efficacy of the BCL-2 inhibitor venetoclax was demonstrated in early T cell precursor ALL, there is no data to date about its use as maintenance post-transplant. The combination of venetolcax and decitabine has shown efficacy in a case report of relapsed T-ALL who underwent transplant in second complete remission [10]. Promising results were recently reported with the use of venetoclax and azacytidine as post-transplant maintenance therapy in high-risk T-ALL [11].
Despite the absence of large studies or guidelines supporting the use of hypomethylating agents and BCL-2 inhibitors as post-transplant maintenance in T-ALL, this treatment modality may be considered given the very high of relapse of this disease when transplanted beyond first remission, and the limited salvage therapies available thereafter. Further prospective trials are needed to support these findings. Indeed, this patient received post-transplant maintenance therapy with venetoclax and low dose azacytidine and achieved a long lasting complete remission, that is still ongoing after more than 30 months post-transplant.
Correct Answer – A or D
References:
- Kantarjian, H.M., et al., Results of treatment with hyper-CVAD, a dose-intensive regimen, in adult acute lymphocytic leukemia. J Clin Oncol, 2000. 18(3): p. 547-61.
- Stary, J., et al., Intensive chemotherapy for childhood acute lymphoblastic leukemia: results of the randomized intercontinental trial ALL IC-BFM 2002. J Clin Oncol, 2014. 32(3): p. 174-84.
- Pui, C.H., M.V. Relling, and J.R. Downing, Acute lymphoblastic leukemia. N Engl J Med, 2004. 350(15): p. 1535-48.
- Barrett, A.J. and M. Battiwalla, Relapse after allogeneic stem cell transplantation. Expert Rev Hematol, 2010. 3(4): p. 429-41.
- Bazarbachi, A., et al., Sorafenib improves survival of FLT3-mutated acute myeloid leukemia in relapse after allogeneic stem cell transplantation: a report of the EBMT Acute Leukemia Working Party. Haematologica, 2019. 104(9): p. e398-e401.
- Krishnamurthy, P., et al., Outcome of donor lymphocyte infusion after T cell-depleted allogeneic hematopoietic stem cell transplantation for acute myelogenous leukemia and myelodysplastic syndromes. Biol Blood Marrow Transplant, 2013. 19(4): p. 562-8.
- Touzart, A., et al., Epigenetic analysis of patients with T-ALL identifies poor outcomes and a hypomethylating agent-responsive subgroup. Sci Transl Med, 2021. 13(595).
- Peirs, S., et al., Epigenetics in T-cell acute lymphoblastic leukemia. Immunol Rev, 2015. 263(1): p. 50-67.
- Liu, J., et al., Maintenance Treatment With Low-Dose Decitabine After Allogeneic Hematopoietic Cell Transplantation in Patients With Adult Acute Lymphoblastic Leukemia. Front Oncol, 2021. 11: p. 710545.
- Rahmat, L.T., et al., Venetoclax in Combination with Decitabine for Relapsed T-Cell Acute Lymphoblastic Leukemia after Allogeneic Hematopoietic Cell Transplant. Case Rep Hematol, 2018. 2018: p. 6092646.
- Hassan et al. Azacytadine in Combination with Venetolcax Maintenance Post Transplant in Acute T-Lymphoblastic Leukemia. Clinical Hematology International, In Press.
Future Clinical Case of the Month
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