Background Acute Myeloid Leukemia (AML) and Myelodysplastic Syndrome (MDS) are two closely related blood cancers that are more frequent in older adults. AML is the most common type of adult acute leukemia, and MDS is characterized by ineffective blood cell production and abnormalities in the bone marrow and blood. Both can be resistant to treatment, often due to dysfunction in the process of apoptosis, the body’s natural mechanism for cell death. Venetoclax, an orally-administered medication that selectively targets the BCL-2 protein, has shown promise in enhancing treatment sensitivity in some hematological malignancies by reducing the apoptotic threshold. This review aims to evaluate the effectiveness of venetoclax in treating AML and MDS, as well as potential mechanisms of resistance to the medication. Methods A literature search was conducted utilizing PUBMED to capture all relevant research articles on the use of venetoclax as a therapy for both diseases. The MeSH terms “acute myeloid leukemia”, “myelodysplastic syndrome” and “venetoclax” were searched. Furthermore, Clinicaltrials.gov was accessed to ensure the inclusion of all ongoing clinical trials. Results Although Venetoclax showed modest results as a single-agent therapy in AML, venetoclax-based combination therapies? mainly with hypomethylating agents or low-dose cytarabine? yielded significantly positive results. Preliminary results oN the use of venetoclax-based combination therapy with HMA, mainly azacitidine, in unfit high-risk MDS also yielded optimistic results. Identification of mutations for which various drugs have been approved has spurred active investigation of venetoclax in combination trials. Conclusion Venetoclax-based combination therapies have been shown to induce rapid responses and increase overall survival in AML patients unfit for intensive chemotherapy. These therapies are also yielding positive preliminary results in high-risk MDS patients in phase I trials. Resistance to venetoclax and drug-related toxicity are two main obstacles that need to be overcome to reap the full benefits of this therapy.
Background: Clofarabine (Clo) is an immunosuppressive purine analog that may have better anti-leukemic activity than fludarabine (Flu) in the conditioning regimen for allogeneic stem cell transplant (allo-SCT) for acute leukemia patients. The addition of total body irradiation (TBI) to conditioning regimens has been widely investigated. However, the use of single agent Clo in combination with intermediate doses of TBI ranging from 4-8 Gy has not been studied yet. Objective: This study aims to identify the outcome of patients with high-risk hematological malignancies who underwent allo-SCT from different donor types and received Clo and TBI (4-8 Gy) as a conditioning regimen. Methods: This is a double center, observational, retrospective study of patients with high-risk hematological malignancies diagnosed from 2012 to 2021, treated at the American University of Beirut Medical Center in Beirut (AUBMC), Lebanon, and Saint-Antoine Hospital (SA) in Paris, France. Data regarding patient baseline characteristics, disease-related factors, and transplant outcomes including graft-versus-host disease (GVHD), Non-relapse mortality (NRM), progression-free survival (PFS), and overall survival (OS), were collected. Results: We identified 24 high-risk patients with a median age at transplant of 37 years (range 22-78). Of these, 15 patients (63%) were males, 8 patients (33%) had acute myeloid leukemia (AML), 3 patients (13%) had myelodysplastic syndrome (MDS), and 12 patients (50%) had acute lymphoblastic leukemia (ALL), and 1 patient had B-lymphoblastic lymphoma (B-ALL) (4%). At the time of the transplant, only 15 patients (63%) were in complete remission (CR). Nine patients (38%) received transplants from a matched related donor(MRD), 9 patients (38%) from a haploidentical related donor(haplo), 4 patients (17%) from a matched unrelated donor(MUD), and 2 patients (8%) from an unrelated cord blood donor (UCB). All patients received Clo. For TBI, 21 patients (88%) received a total dose of 4 Gy, and 3 (12%) received 8 Gy. Sixteen patients (67%) received anti-thymocyte globulin(ATG). After a median follow-up of 40 months, the cumulative incidences of grade II-III acute GVHD, grade IV acute GVHD, and chronic GVHD were 50%, 4%, and 8%, respectively. NRM at 100 days, and 1 year after transplant was 4% and 25%, respectively. 17% of the patients had a relapse or progression of the disease by the end of the study. The 2-year PFS and OS were 50% and 56%, respectively. The median PFS and OS were not reached. Conclusions: Clo/TBI (4-8 Gy) as a conditioning regimen for allo-SCT in high-risk patients confers disease control with an acceptable toxicity profile.
This letter describes the experience of the American University of Beirut Medical Center in Lebanon with haploidentical stem cell transplant (haplo-SCT) for hematological malignancies in adult patients. Haplo-SCT made it possible through universal and rapid donor availability for most of the adult patients with leukemia or lymphoma not only in the Middle East but also globally. Moreover, the use of post-transplant cyclophosphamide (PTCy) and reduced intensity conditioning (RIC) regimens when indicated improved the outcome and decreased the toxicity of haploidentical stem cell transplant.RIC regimens also allowed its use in the elderly population. Patients from throughout the Middle East come to our center, the American university of Beirut Medical Center, to receive this transformative type of stem cell transplant. In this paper, we discuss the results of haplo-SCT with PTCy done on adult patients with hematological malignancies in our center from 2015 to 2021. The results are encouraging and show that haplo-SCT should be considered more often in the Middle Eastern countries. The subgroup analysis showed the importance of achieving complete remission of the disease prior to transplant to improve outcomes in our center. There is a paucity of literature on the outcomes of haplo-SCT in the Middle East which may contribute to the limited number of centers that offer this type of SCT. Herein, we aim to fill this gap in the hopes of encouraging the implementation of this potentially curative modality of treatment to a larger extent in the Middle East.
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