Prognostic factors impacting post-transplant outcomes in adult T-cell acute lymphoblastic leukemia: a registry-based study by the EBMT acute leukemia working party.

T-cell acute lymphoblastic leukemia (T-ALL) predominantly affects individuals in late childhood and young adulthood. Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a curative modality particularly in the setting of poor risk genetics and/or persistent minimal residual disease. Limited studies have directly explored the impact of patient- and transplant-related factors on post-transplant outcomes in T-ALL. Using a large dataset from the European Society for Blood and Marrow Transplantation registry, we identified 1907 adult T-ALL patients (70% male) who underwent their first allo-HSCT in first complete remission (CR1) from matched sibling donors (MSD; 45%), unrelated donors (UD; 43%) or haploidentical donors (12%) between 2010 and 2021. The median age at transplant was 33.4 years (18.1-75). The median follow up was 2.9 years. Most patients underwent total body irradiation (TBI)-based myeloablative conditioning (69%). The 2-year overall survival (OS) was 69.4%, and leukemia -free survival (LFS) was 62.1%. In multivariate analysis, advanced age at transplant negatively affected LFS (for each 10-year increment, HR = 1.11, p = 0.004), GVHD-free, relapse-free survival (GRFS) (HR = 1.06, p = 0.04), OS (HR = 1.12, p = 0.002), and non-relapse mortality (NRM) (HR = 1.23, p < 0.001). More recent years of allo-HSCT were associated with improved GFRS (For each 3-year increment, HR = 0.89, p < 0.001), OS (HR = 0.9, p = 0.02), and decreased NRM (HR = 0.82, p = 0.008). TBI improved LFS. (HR = 0.79, p = 0.02), GRFS (HR = 0.83, p = 0.04), and relapse incidence (RI) (HR = 0.65, p < 0.001). Female-to-male transplant negatively affected GRFS (HR = 1.21, p = 0.02) and OS (HR = 1.23, p = 0.048). In vivo T-cell depletion significantly improved GFRS (HR = 0.74, p < 0.001). This large study identified prognostic factors, such as age at transplant conditioning regimen, in influencing post-transplant in adult T-ALL patients undergoing allo-HSCT. Importantly, a significant improvement over time was noted. These findings hold great promise for new adapted treatment strategies and can serve as a benchmark for future studies in that setting.

Philadelphia-chromosome positive acute lymphoblastic leukemia: ten frequently asked questions.

Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) constitutes a distinctive cytogenetic entity associated with challenging outcomes, particularly in adult patients. Current upfront chemotherapy-tyrosine kinase inhibitor (TKI)-based therapies include first, second and third-generation TKIs that have revolutionized patient outcomes including molecular remission and overall survival. Chemotherapy-free regimens such as blinatumomab-dasatinib or blinatumomab-ponatinib offer exciting possibilities, yet challenges arise, particularly in preventing central nervous system relapse. Monitoring measurable residual disease is now a cornerstone particularly using next-generation sequencing (NGS)-Clonoseq for accurate assessment. Controversy regarding the ability to omit consolidation with allogeneic stem cell transplantation, specifically for patients achieving early molecular remission, is related to the excellent survival achieved with novel combinations in the upfront setting, however challenged by the lower disease control when transplant is utilized beyond first remission. Post-transplant maintenance introduces new dilemmas: the optimal TKI, dosing, and duration of therapy are open questions. Meanwhile, a myriad of new combinations and cellular therapies are used for relapsed Ph+ ALL, prompting us to unravel the optimal sequencing of these promising regimen. In this review, we delve into the breakthroughs and controversies in Ph+ ALL with ten commonly asked questions.

A rare case of IgA lambda multiple myeloma in a 32-year-old woman with t(14;16) translocation associated with kidney injury and non-albumin proteinuria.

BACKGROUND: Multiple myeloma (MM) is a malignant disorder characterized by monoclonal differentiated plasma cells. While it is more commonly diagnosed in elderly individuals, it can also affect younger populations, though with a lower incidence. CASE PRESENTATION: Here, we present the case of a 32-year-old woman diagnosed with IgA lambda MM. She presented with fatigue, nausea, acute kidney injury (AKI) with a rapid increase in creatinine, and anemia. A kidney biopsy was done to rule out a rapidly progressive glomerular disease and a diagnosis was thus reached. A genetic workup revealed t(14;16) translocation and an extra copy of TP53. The patient received aggressive intravenous steroids and intravenous fluid resuscitation, resulting in an improvement in renal function. Treatment with daratumumab in combination with bortezomib, thalidomide, and dexamethasone was initiated and well tolerated. Despite the generally poor prognosis of IgA MM, our case emphasizes the importance of considering MM in young patients with unexplained kidney injury. CONCLUSION: Early recognition and prompt intervention are essential in managing MM patients, especially in those with high-risk cytogenetic abnormalities. This case serves as a reminder for clinicians to maintain a high index of suspicion for MM, even in younger populations, when presented with unexplained kidney injury.

Bi- and Tri-specific antibodies in non-Hodgkin lymphoma: current data and perspectives.

Bispecific antibodies (BsAbs) are a new group of targeted therapies that are revolutionizing the treatment landscape of B-cell non-Hodgkin's lymphoma (B-NHL). In the relapsed/refractory setting, salvage chemotherapy and autologous stem cell transplantation are capable of curing 50% of patients, whereas the other half will have a dismal outcome with a median overall survival of less than 12 months. This unmet need reinforced the importance of innovative therapies like the BsAbs and CAR-T cell therapies. In this review, we delve into BsAbs in B-NHL from the preclinical development to clinical data in both refractory and frontline settings, and then discuss future perspectives.

[Vaccination of allogeneic haematopoietic stem cell transplant recipients: Guidelines from the Francophone Society of Bone Marrow Transplantation and Cellular Therapy (SFGM-TC)]. / Mise à jour du calendrier vaccinal après allogreffe de cellules souches hématopoïétiques : recommandations de la Société francophone de greffe de moelle et de thérapie cellulaire (SFGM-TC).

During immune reconstitution following allogeneic haematopoietic stem cell transplantation (allo-HSCT), (re)vaccination of allo-HSCT recipients is recommended. Herein, we propose an update of practical recommendations regarding vaccination of allo-HSCT recipients. These recommendations, based on data from the literature, national and international guidelines and the consensus of the participants when no formally proven data are available, were elaborated during the workshop of practice harmonization organized by the Francophone Society of Bone Marrow Transplantation and Cellular Therapy (SFGM-TC) in Lille in September 2022.

Improved Posttransplant Outcomes in Recent Years for AML Patients with FLT3-ITD and Wild-type NPM1: A Report from the EBMT Acute Leukemia Working Party.

PURPOSE: Allogeneic hematopoietic cell transplantation (allo-HCT) is recommended in first complete remission (CR1) in patients with acute myeloid leukemia (AML) harboring FMS-like tyrosine kinase 3-internal tandem duplication (FLT3-ITD). We assessed changes over time in transplant characteristics and outcomes in patients with AML age 60 years and younger with a FLT3-ITD. EXPERIMENTAL DESIGN: We identified 1,827 adult patients with AML (median age 49 years, range 18-60) with FLT3-ITD and intermediate karyotype, allografted between 2012 and 2021 in CR1. RESULTS: NPM1 was mutated in 72% of patients. We compared changes over time in 688 patients transplanted between 2012 and 2016, and 1,139 patients transplanted between 2017 and 2021. For patients with wild-type NPM1, the 2-year leukemia-free survival (LFS) and overall survival (OS) significantly improved over time from 54% to 64% (HR = 0.67; P = 0.011) and from 63% to 71% (HR = 0.66; P = 0.021), respectively. Allo-HCT in recent years significantly reduced the cumulative incidence of relapse (CIR). For patients with NPM1 mutation, no significant changes over time were noted. CONCLUSIONS: In patients with AML with FLT3-ITD and wild-type NPM1, we noticed a significant decrease over time in the CIR and improvement of LFS and OS, likely reflecting the efficacy of FLT-3 inhibitors, including when used as posttransplant maintenance, in this high-risk setting. On the contrary, no significant change over time was noticed in outcomes of patients harboring a FLT3 and NPM1 mutation.

Systemic Mastocytosis: A Mimicker of Reactive Arthritis.

Objectives: Illustration of a case of systemic mastocytosis mimicking reactive arthritis in the absence of an infectious etiology. Methods: Review of the patient's medical records. Results: We report a case of systemic mastocytosis relapse, presenting with pancytopenia accompanied by knee monoarthritis, cystitis, and bilateral conjunctivitis occurring simultaneously at the same time interval within 2-4 days, mimicking reactive arthritis in the absence of an infectious etiology. Conclusion: Our case demonstrated reactive arthritis features (triad of urethritis, conjunctivitis, and arthritis) without an infectious trigger but rather a relapse of mastocytosis. We should think outside the box when faced with such a clinical scenario in the absence of an infectious etiology. Paraneoplastic reactive arthritis is to be considered after excluding an underlying infection.

Novel strategies to prevent and overcome relapse after allogeneic hematopoietic cell transplantation in acute lymphoblastic leukemia.

The outcome of B-cell acute lymphoblastic leukemia (B-ALL) has improved over time with the incorporation of multi-agent chemotherapy in the treatment landscape as well as the recent approval of immunotherapeutic agents allowing a larger proportion of patients to undergo allogeneic hematopoietic cell transplantation (allo-HCT) which is still considered a potential curative approach. However, relapse post-transplant is still occurring and constitutes a common cause of treatment failure in B-ALL. The present review aims to discuss the novel strategies and therapies used to prevent and overcome relapse post allo-HCT in patients with ALL, focusing on the role of tyrosine kinase inhibitors in Philadelphia chromosome positive B-ALL, the role of innovative agents such as blinatumomab and inotuzumab ozogamicin, and finally the role of cellular therapy.

Cardiac toxicities in multiple myeloma: an updated and a deeper look into the effect of different medications and novel therapies.

With the continuous improvement in survival of cancer patients, including those with multiple myeloma, related to the novel treatment agents and therapeutic approaches, the probability for patients to develop cardiovascular disease has significantly increased, especially in elderly patients and those with additional risk factors. Multiple myeloma is indeed a disease of the elderly population and so these patients are, solely by age, at an increased risk of cardiovascular disease. Risk factors for these events can be patient-, disease- and/or therapy-related, and they have been shown to adversely impact survival. Cardiovascular events affect around 7.5% of patients with multiple myeloma and the risk for different toxicities has considerably varied across trials depending on patients' characteristics and treatment utilized. High grade cardiac toxicity has been reported with immunomodulatory drugs (odds ratio [OR] around 2), proteasome inhibitors (OR 1.67-2.68 depending on the specific agent, and generally higher with carfilzomib), as well as other agents. Cardiac arrhythmias have also been reported with various therapies and drug interaction plays a significant role in that setting. Comprehensive cardiac evaluation before, during and after various anti-myeloma therapy is recommended and the incorporation of surveillance strategies allows early detection and management resulting in improved outcomes of these patients. Multidisciplinary interaction including hematologists and cardio-oncologists is critical for optimal patient care.

Venetoclax: A New Partner in the Novel Treatment Era for Acute Myeloid Leukemia and Myelodysplastic Syndrome.

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.

Clofarabine and total body irradiation (TBI) as conditioning regimen for allogeneic stem cell transplantation in high-risk acute leukemia patients: a two-center retrospective cohort study.

Clofarabine (Clo) is an immunosuppressive purine analog that may have better anti-leukemic activity than fludarabine (Flu). 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 to 8 Gy has not been studied yet. This study 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 (SAH) in Paris, France. It aims to identify the outcome of patients with high-risk hematological malignancies who underwent allogeneic stem cell transplant (allo-SCT) and received Clo and TBI (4-8 Gy) before transplant. 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. We identified 24 high-risk patients diagnosed with a hematological malignancy. The median age at transplant was 37 years (range 22-78). At the time of the transplant, only 15 patients (63%) were in complete remission (CR). All patients received Clo/TBI (4-8 Gy). 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 66 and 68 months respectively. As a conclusion, Clo/TBI (4-8 Gy) as a conditioning regimen for allo-SCT in high-risk patients confers disease control with an acceptable toxicity profile.

Strategic priorities for hematopoietic stem cell transplantation in the EMRO region.

The World Health Organization-designated Eastern Mediterranean region (EMRO) consists of 22 countries in North Africa and Western Asia with a collective population of over 679 million. The area comprises some of the wealthiest countries per capita income and some of the poorest. The population structure is also unique and contrasts with western countries, with a much younger population. The region sits in the heart of the thalassemia belt. Many countries have a significant prevalence of sickle cell disease, and cancer is on the rise in the region. Therefore, the strategic priorities for the growth and development of hematopoietic stem cell transplantation (HSCT) differ from country to country based on resources, healthcare challenges, and prevalent infrastructure. Thirty-one reporting teams to the Eastern Mediterranean Blood and Marrow Transplantation Group have active HSCT programs in 12 countries; allogeneic transplants outnumber autologous transplants, and the proportion of allotransplants for non-malignant conditions is higher in the EMRO region than in Western Europe and North America. The vast majority (99%) of allotransplants are from matched related donors. Matched unrelated donors and other alternate donor transplants are underutilized. The chance of finding a matched related donor for allografts is higher, with a significant chance of finding matched donors among non-sibling related donors. Reasons for relatively lower rates of transplants compared with other countries are multifactorial. Capacity building, development of newer centers, innovative funding, and better utilization of information technology are required to make transplantation as an accessible modality to more patients. Cost-effectiveness and cost-containment, regulation, and ensuring quality will all be priorities in planning HSCT development in the region.

Thiotepa, busulfan and fludarabine conditioning-regimen is a promising approach for older adult patients with acute lymphoblastic leukemia treated with allogeneic stem cell transplantation.

For acute lymphoblastic leukemia (ALL) patients, total body irradiation (TBI)- based conditioning regimens are the first choice specially in young population. However, several studies have shown an equivalence in clinical outcomes with thiotepa-based conditioning regimen. We performed a retrospective study to evaluate the outcome of adult ALL patients who received allogeneic hematopoietic stem cell transplantation (allo-HCT) with a thiotepa-busulfan-fludarabine (TBF) myeloablative conditioning regimen with reduced toxicity. Fifty-five patients received a TBF regimen. The median age of the patients was 51 years (range, 17 to 72.4). Most patients had a diagnosis of B-ALL (93%) with 7% having T-ALL. Two - and 5-year overall survival was 73.2% and 64%, respectively. At 2 years, leukemia-free survival and GVHD-free, relapse-free survival were 59.5% and 57.6%, and at 5 years, 53.4% and 51.8%, respectively. The 5-year non-relapse mortality was 15%. The day 180 cumulative incidence (CI) of grade II-IV acute GVHD and grade III-IV acute GVHD were 38.2% and 5.5%, respectively. At 2 years, the CI of chronic GVHD and extensive chronic GVHD was 16.9% and 1.9%, respectively. Our study results do suggest that using TBF as the conditioning regimen in adult ALL patients is a promising option with acceptable toxicity.

Haploidentical stem cell transplantation with post-transplant cyclophosphamide challenges and outcome from a tertiary care center in Lebanon.

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.

Safety and Efficacy of Elective Switch from Nilotinib to Imatinib in Newly Diagnosed Chronic Phase Chronic Myeloid Leukemia.

The treatment of newly diagnosed chronic phase chronic myeloid leukemia (CML) with nilotinib has resulted in a higher rate of major molecular (MMR) and complete cytogenetic response (CCyR) at 12 months compared to imatinib but at a higher cumulative cost and increased risk of serious adverse events. To maintain long-term efficacy and minimize both toxicity and costs, we aimed at evaluating in a prospective single-center trial the efficacy and safety of a response-directed switch from nilotinib to imatinib after 12 months in patients newly diagnosed with chronic phase CML. Thirteen adult patients were enrolled. Twelve patients started on nilotinib 300 mg twice daily. Eleven patients completed one year of nilotinib and were switched to imatinib 400 mg daily as per protocol. At 3 months, all patients achieved a complete hematologic response, with 7 (58%) patients had early molecular response. At 12 months, all patients achieved CCyR, of whom 5 (42%) and 4 (33%) patients achieved MMR and MR4.5, respectively. Three (27%) patients switched back to nilotinib after 18, 24, and 51 months respectively: 1 patient because of loss of CCyR after 18 months, and 2 patients because of imatinib intolerance. At last follow-up, all patients (n = 12) were alive and in MMR, 6 (50%) of them in continuous MR4.5. These findings suggest that response directed switch from nilotinib to imatinib at 12 months is capable of maintaining long-term response, with manageable side effects. This approach warrants further exploration with larger prospective trials. Clinical trial registration: Clinicaltrials.gov identifier: NCT01316250, https://clinicaltrials.gov/ct2/results?cond=&term=NCT01316250&cntry=&state=&city=&dist=. .