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Abstract Second allogeneic stem cell transplantation (alloSCT2) is among the most effective treatments for acute myeloid leukemia (AML) relapse after first alloSCT (alloSCT1). Long-term EBMT registry data were used to provide large scale, up-to-date outcome results and to identify factors for improved outcome. Among 1540 recipients of alloSCT2, increasing age, better disease control and performance status before alloSCT2, more use of alternative donors and higher conditioning intensity represented important trends over time. Between the first (2000–2004) and last (2015–2019) period, two-year overall and leukemia-free survival (OS/LFS) increased considerably (OS: 22.5–35%, LFS: 14.5–24.5%). Cumulative relapse incidence (RI) decreased from 64% to 50.7%, whereas graft-versus-host disease and non-relapse mortality (NRM) remained unchanged. In multivariable analysis, later period of alloSCT2 was associated with improved OS/LFS (HR = 0.47/0.53) and reduced RI (HR = 0.44). Beyond, remission duration, disease stage and patient performance score were factors for OS, LFS, RI, and NRM. Myeloablative conditioning for alloSCT2 decreased RI without increasing NRM, leading to improved OS/LFS. Haploidentical or unrelated donors and older age were associated with higher NRM and inferior OS. In summary, outcome after alloSCT2 has continuously improved over the last two decades despite increasing patient age. The identified factors provide clues for the optimized implementation of alloSCT2.

Not available.

Abstract 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.

Secondary immunodeficiency (SID), acquired hypogammaglobinemia, is an immunodeficiency caused by different factors like diseases, medications, and/or nutrition disorders. Most patients with hematological malignancies (HM), namely chronic lymphocytic leukemia (CLL) and multiple myeloma (MM), experience such SID. These patients have a consistently high risk of infection throughout the disease course. Traditional chemotherapy and novel agents used to treat HM may further increase infection susceptibility. Immunoglobulin replacement therapy (IgRT) is an effective management option for SID. The prevalence of SID in the Middle East needs better documentation. Healthcare providers should consider and evaluate SID in patients at risk, monitor for infection occurrence, and treat accordingly (including initiating IgRT when indicated). A Delphi initiative was conducted by a consensus panel of 15 experts from the Middle East who have over 20 years of experience in actively managing patients with SID. The modified Delphi process was used, and 16 questions reached a consensus on managing SID patients with IgRT. In addition, the consensus panel of Middle East experts recommended real-world practice recommendations regarding initiating, dosing, and discontinuing IgRT in managing SID. This consensus recommendation aims to assist healthcare practitioners in the Middle East in evidence-based clinical decision-making for better management of SID.

Abstract We compared outcomes of adult patients with secondary acute myeloid leukemia (sAML) versus de novo AML after non-T-depleted haploidentical stem cell transplant (HaploSCT) with post-transplant cyclophosphamide (PTCy). Seventeen hundred and eleven AML patients (sAML-231, de novo-1480) in first complete remission transplanted from 2010 to 2021, were included. Patients with de novo AML were younger, median age 55.8 versus 60.8 years, p

Abstract 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.

Abstract Adult T cell leukemia/lymphoma (ATL) is an aggressive malignancy secondary to chronic infection with human T cell leukemia virus type 1 (HTLV-1). The viral oncoprotein Tax initiates T cell transformation through activation of critical cellular pathways, including NF-κB. Unexpectedly, Tax protein is not detectable in most ATL cells, in contrast to the HTLV-1 HBZ protein which antagonizes Tax effects. Here, we demonstrate that primary ATL cells from patients with acute or chronic ATL express very low levels of Tax mRNA and protein. Critically, survival of these primary ATL cells is dependent on continued Tax expression. Mechanistically, Tax extinction results in reversal of NF-κB activation, P53/PML activation and apoptosis. Tax drives interleukin-10 (IL-10) expression and recombinant IL-10 rescues the survival of tax-depleted primary ATL cells. These results demonstrate the critical role of continued Tax and IL-10 expression for the survival of primary ATL cells, highlighting their relevance as therapeutic targets.

Availability of haploidentical donors has broadened utilization of allogeneic hematopoietic cell transplantation (allo-HCT). Peripheral blood stem cells (PBSC) are being used with increased frequency in haploidentical allo-HCT. We evaluated extent of HLA disparity (2–3/8 versus 4/8 HLA antigen mismatches) on post-allograft outcomes when using T-cell replete PBSC from haploidentical donors for acute myeloid leukemia in first complete remission. Primary objectives entailed assessing cumulative incidence of grade 2–4 acute graft-versus-host disease (GVHD) and chronic GVHD (any grade). A total of 645 patients received a haploidentical allo-HCT from a donor with either 2–3 of 8 HLA antigen mismatches (n = 180) or with 4 of 8 HLA antigen mismatches (n = 465). Presence of 2–3 of 8 versus 4 of 8 HLA mismatches did not affect the incidence of acute GVHD (grade 2–4) and chronic GVHD (any grade). Overall survival (OS), leukemia-free survival (LFS) relapse incidence (RI), nonrelapse mortality and the composite endpoint of GVHD-free relapse-free survival were also similar among the groups. Pertaining to HLA-B leader matching effect, our analysis did not discern any difference in aforementioned post-allograft outcomes for this variable. However, in univariate analysis, absence of an antigen mismatch in HLA-DPB1 showed a trend for better OS. Notwithstanding inherent limitations associated with registry data, our results did not show an advantage of selecting a haploidentical donor with 2–3 of 8 HLA antigen mismatches over one with 4 of 8 HLA antigen mismatches when using PBSC as the cell source. Adverse cytogenetics remains a major adverse determinant of inferior OS and LFS and a higher RI. Using reduced-intensity conditioning yielded worse OS and LFS.

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.

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.

Abstract Multiple myeloma (MM) is a prevalent hematological malignancy. Resource-constrained settings such as the Middle East are particularly burdened by the increasing trends in MM morbidity and mortality in addition to challenges in the management of MM. It thus becomes necessary to identify and address debatable areas of current practice and gaps in the management of MM in the Middle East. With a special focus on the Lebanese situation, the first-line treatment of the very elderly (> 80 years old) is discussed, in addition to the impact of relapse type (biochemical or clinical relapse) on maintenance therapy, the choice of first relapse therapy in relation to maintenance therapy, and the role of MRD in the MM treatment landscape. The need for realistic management guidelines accounting for local resources and expertise, in addition to the reflection of drug accessibility and cost on clinical practice are recognized.

Abstract Myelodysplastic syndromes (MDS) are a heterogeneous clonal disease of myeloid neoplasms characterized by ineffective hematopoiesis, variable degree of cytopenias, and an increased risk of progression to acute myeloid leukemia (AML). Molecular and genetic characterization of MDS has led to a better understanding of the disease pathophysiology and is leading to the development of novel therapies. Targeted and immune therapies have shown promising results in different hematologic malignancies. However, their potential use in MDS is yet to be fully defined. Here, we review the most recent advances in therapeutic approaches in MDS, focusing on higher-risk disease. Allogeneic hematopoietic cell transplantation is beyond the scope of this article.

Abstract Background Mantle cell lymphoma is the rarest subtype of non-Hodgkin’s lymphoma. It can exhibit diverse extranodal manifestations. However, renal involvement is uncommon, and if it occurs, it usually only gets detected postmortem. There are several mechanisms by which mantle cell lymphoma can damage the kidneys. Renal failure is a potential complication, and prompt evaluation and diagnosis are critical steps to prevent long-term complications. Case presentation We present the case of a 75-year-old non-Hispanic White male with past medical history significant for hypertension and dyslipidemia, presenting with fever, weight loss, and night sweats. Work-up showed markedly elevated white blood cells, multiple enlarged lymph nodes, and a kidney mass. The patient was diagnosed with mantle cell lymphoma with kidney involvement confirmed with a kidney biopsy. His disease was positive for cyclin D1 overexpression despite t(11; 14) absence. The patient received six cycles of alternating vincristine, rituximab, cyclophosphamide, doxorubicin, and prednisone then dexamethasone, high-dose cytarabine, and oxaliplatin, after which he was maintained on ibrutinib and rituximab, with resolution of symptoms and disease regression. Conclusion We present a case of a rare presentation of Mantle cell lymphoma while describing the clinical presentation and diagnostic and treatment approaches. This case report can assist physicians in the clinical work-up and treatment of patients with similar diagnosis or presentation.

Abstract 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= .

Abstract The current standard of care model for newly diagnosed fit multiple myeloma (NDMM) patients is the sequential treatment of induction, high dose melphalan, autologous stem cell transplantation (ASCT), and maintenance. Adequate induction is required to achieve good disease control and induce deep response rates while minimizing toxicity as a bridge to transplant. Doublet induction regimens have greatly fallen out of favor, with current international guidelines favoring triplet or quadruplet induction regimens built around the backbone of the proteasome inhibitor bortezomib and dexamethasone (Vd). In fact, the updated 2021 European Haematology Association (EHA) and European Society for Medical Oncology (ESMO) clinical practice guidelines recommend the use of either lenalidomide-Vd (VRd), or daratumumab-thalidomide-Vd (Dara-VTd) as first-line options for transplant-eligible NDMM patients, and when not available, thalidomide-Vd (VTd) or cyclophosphamide-Vd (VCd) as acceptable alternatives. Quadruplet regimens featuring anti-CD38 monoclonal antibodies are extremely promising and remain heavily investigated, as is the incorporation of more recent proteasome inhibitors such as carfilzomib. This review will focus on induction therapies prior to ASCT examining the latest data and guidelines on triplet and quadruplet regimens.

Abstract Nucleophosmin‐1 (NPM1) mutations in acute myeloid leukemia (AML) confer a survival advantage in the absence of FLT3‐internal tandem duplication (FLT3‐ITD). Here, we investigated the main predictors of outcome after allogeneic hematopoietic stem cell transplantation (allo‐HCT). We identified 1572 adult (age ≥ 18 year) patients with NPM1‐mutated AML in first complete remission (CR1:78%) or second complete remission (CR2:22%) who were transplanted from matched sibling donors (30.8%) or unrelated donors (57.4%) between 2007 and 2019 at EBMT participating centers. Median follow‐up for survivors was 23.7 months. FLT3‐ITD was present in 69.3% of patients and 39.2% had detectable minimal/measurable residual disease (MRD) at transplant. In multivariate analysis, relapse incidence (RI) and leukemia‐free survival (LFS) were negatively affected by concomitant FLT3‐ITD mutation (HR 1.66 p = 0.0001, and HR 1.53, p

The treatment of acute myeloid leukemia (AML) has evolved over the past few years with the advent of next-generation sequencing. Targeted therapies alone or in combination with low-dose or high-intensity chemotherapy have improved the outcome of patients with AML treated in the frontline and relapsed/refractory settings. Despite these advances, allogeneic stem cell transplantation (allo-HCT) remains essential as consolidation therapy following frontline treatment in intermediate-and adverse-risk and relapsed/refractory disease. However, many patients relapse, with limited treatment options, hence the need for post-transplant strategies to mitigate relapse risk. Maintenance therapy following allo-HCT was developed for this specific purpose and can exploit either a direct anti-leukemia effect and/or enhance the bona fide graft-versus-leukemia effect without increasing the risk of graft-versus-host disease. In this paper, we summarize novel therapies for AML before, during, and after allo-HCT and review ongoing studies.

In this registry-based study, we compared outcomes of allogeneic hematopoietic cell transplantation (allo-HCT) in adult patients with acute lymphoblastic leukemia (ALL) transplanted in first complete remission (CR-1), following conditioning with total body irradiation (TBI) at a standard 12-Gray or at a lower 8-Gray total dose. Patients received fludarabine (flu) as the sole chemotherapy complementing TBI. Eight-Gray TBI/flu was used in 494 patients and 12-Gray TBI/flu in 145 patients. Eighty-eight (23.1%) and 36 (29%) of the patients had Ph-negative B-ALL, 222 (58.3%) and 53 (42.7%) had Ph-positive B-ALL, 71 (18.6%) and 35 (28.2%) T-ALL, respectively (P = 0.008). Patients treated with 8-Gray were older than ones received 12-Gray (median 55.7 versus 40.3 years, P < 0.0001) and were more frequently administered in vivo T-cell depletion (71% versus 40%, P

Objectives: Bacterial bloodstream infections (BSIs) with resistant pathogens in patients with haematological malignancies are rising due to increased use of novel chemotherapeutic agents and prophylactic antibiotics. Our goal was to understand the epidemiology and resistance patterns of bacterial pathogens in patients with haematological malignancies to help tailor empirical antibiotics and to limit resistance. Methods: This was a retrospective chart review looking at bacterial BSI episodes between 2007–2017 in patients previously diagnosed with haematological malignancy at a tertiary-care centre in Lebanon. Results: Among 165 hospitalised patients with haematological malignancy and bacterial BSI over 10 years, Gram-negative bacteria (GNB) caused 65.0% of all episodes, with the most common pathogens being Escherichia coli (45.6%), 79.6% of which were ESBL-producers, Pseudomonas aeruginosa (7.5%) and Acinetobacter baumannii (4.0%). The majority of the organisms (61.0%) were multidrug-resistant (MDR), with ANC < 100 neutrophils/μL (OR = 0.12, 95% CI 0.03–0.54) identified as an independent marker for increased multidrug resistance. The risk factors associated with increased mortality included recent use of amikacin (p

Outcomes of allogeneic hematopoietic cell transplantation (allo-HCT) for adult acute lymphoblastic leukemia (ALL) have improved over time. Studies have shown that total body irradiation (TBI) is the preferable type of myeloablative conditioning (MAC). However, outcomes based on central nervous system (CNS) involvement, namely CNS-positive versus CNS-negative, have not been compared. Here, we evaluated outcomes of 547 patients (CNS-positive = 96, CNS-negative = 451) who were allografted in the first complete remission (CR1) between 2009 and 2019. Primary endpoint was leukemia-free survival (LFS). Median follow-up was not different between the CNS-positive and CNS-negative groups (79 versus 67.2 months, P = 0.58). The CNS-positive group were younger (median age 31.3 versus 39.7 years, P = 0.004) and were allografted more recently (median year 2012 versus 2010, P = 0.003). In both groups, MAC was the preferred approach (82.3% versus 85.6%, P = 0.41). On multivariate analysis, the CNS-positive group had higher incidence of relapse (RI) (hazard ratio [HR] = 1.58 [95% confidence interval (CI) = 1.06-2.35], P = 0.025), but no adverse effect on LFS (HR = 1.38 [95% CI = 0.99-1.92], P = 0.057) or overall survival (OS) (HR = 1.28 [95% CI = 0.89-1.85], P = 0.18). A subgroup multivariate analysis limited to CNS-positive patients showed that a TBI-based MAC regimen resulted in better LFS (HR = 0.43 [95% CI = 0.22-0.83], P = 0.01) and OS (HR = 0.44 [95% CI = 0.21-0.92], P = 0.03) and lower RI (HR = 0.35 [95% CI = 0.15-0.79], P = 0.01). Another subgroup analysis in CNS-negative patients showed that MAC-TBI preparative regimens also showed a lower RI without a benefit in LFS or OS. While a MAC-TBI allo-HCT regimen may not be suitable to all, particularly for older patients with comorbidities, this approach should be considered for patients who are deemed fit and able to tolerate.

Abstract Hodgkin lymphoma is a highly curable disease. Although most patients achieve complete response following frontline therapy, key unmet clinical needs remain including relapsed/refractory disease, treatment-related morbidity, impaired quality of life and poor outcome in patients older than 60 years. The incorporation of novel therapies, including check point inhibitors and antibody–drug conjugates, into the frontline setting, sequential approaches, and further individualized treatment intensity may address these needs. We summarize the current treatment options for patients with classical Hodgkin lymphoma from frontline therapy to allogeneic hematopoietic stem cell transplantation and describe novel trials in the field.

The Human T-cell Leukemia virus type 1 (HTLV-1) causes an array of pathologies, the most aggressive of which is adult T-cell leukemia (ATL), a fatal blood malignancy with dismal prognosis. The progression of these diseases is partly ascribed to the failure of the immune system in controlling the spread of virally infected cells. HTLV-1 infected subjects, whether asymptomatic carriers or symptomatic patients are prone to opportunistic infections. An increasing body of literature emphasizes the interplay between HTLV-1, its associated pathologies, and the pivotal role of the host innate and adoptive immune system, in shaping the progression of HTLV-1 associated diseases and their response to therapy. In this review, we will describe the modalities adopted by the malignant ATL cells to subvert the host innate immune response with emphasis on the role of the two viral oncoproteins Tax and HBZ in this process. We will also provide a comprehensive overview on the function of innate immunity in the therapeutic response to chemotherapy, anti-viral or targeted therapies in the pre-clinical and clinical settings.

Abstract Amyloid light chain (AL) amyloidosis is among the more common and more severe of the amyloidoses usually involving the slow proliferation of a bone-marrow-residing plasma cell (PC) clone and the secretion of unstable immunoglobulin-free light chains (FLC) that infiltrate peripheral tissues and result in detrimental end-organ damage. Disease presentation is rather vague, and the hallmark of treatment is early diagnosis before irreversible end-organ damage. Once diagnosed, treatment decision is transplant-driven whereby ~20% of patients are eligible for autologous stem cell transplantation (ASCT) with or without bortezomib-based induction. In the setting of ASCT-ineligibility, bortezomib plays a central role in upfront treatment with the recent addition of daratumumab to the current emerging standard of care. In general, management of AL amyloidosis is aimed at achieving deep, durable responses with very close monitoring for early detection of relapse/refractory disease. This article provides a comprehensive review of the management of patients with AL amyloidosis including goals of therapy, current treatment guidelines in the setting of both ASCT-eligibility and ineligibility, treatment response monitoring recommendations, toxicity management, and treatment of relapse/refractory disease.

Abstract Background Adult T-cell leukemia-lymphoma (ATL) is an aggressive mature lymphoid proliferation associated with poor prognosis. Standard of care includes chemotherapy and/or the combination of zidovudine and interferon-alpha. However, most patients experience relapse less than 6 months after diagnosis. Allogeneic stem cell transplantation is the only curative treatment, but is only feasible in a minority of cases. We previously showed in a mouse model that Arsenic trioxide (As2O3) targets ATL leukemia initiating cells. Results As2O3 consolidation was given in 9 patients with ATL (lymphoma n = 4; acute n = 2; and indolent n = 3), who were in complete (n = 4) and partial (n = 3) remission, in stable (n = 1) and in progressive (n = 1) disease. Patients received up to 8 weeks of As2O3 at the dose of 0.15 mg/kg/day intravenously in combination with zidovudine and interferon-alpha. One patient in progression died rapidly. Of the remaining eight patients, three with indolent ATL subtype showed overall survivals of 48, 53 and 97 months, and duration of response to As2O3 of 22, 25 and 73 months. The other 5 patients with aggressive ATL subtype had median OS of 36 months and a median duration of response of 10 months. Side effects were mostly hematological and cutaneous (one grade 3) and reversible with dose reduction of AZT/IFN and/or As2O3 discontinuation. The virus integration analysis revealed the regression of the predominant malignant clone in one patient with a chronic subtype. Conclusion These results suggest that consolidation with As2O3 could be an option for patients with ATL in response after induction therapy and who are not eligible for allogeneic stem cell transplantation.

Treatment of non-Hodgkin lymphoma (NHL) in general has improved over the years with the emergence of the monoclonal antibodies (MAB) therapy. NHL is divided into B cell NHL and T cell NHL. Treatment of NHL was based on the subtype of NHL and its staging. NHL is divided into aggressive and indolent NHL (iNHL). Subtypes of iNHL include: Follicular lymphoma (FL), Marginal zone lymphoma (MZL), Chronic lymphocytic leukemia/small-cell lymphocytic lymphoma (CLL/SLL), Gastric mucosa-associated lymphoid tissue (MALT) lymphoma, Lymphoplasmacytic lymphoma, Waldenström macroglobulinemia, Nodal marginal zone lymphoma (NMZL), Splenic marginal zone lymphoma (SMZL). Chemotherapy was the main stay treatment of iNHL until the emergence of Rituximab, anti-CD20 MAB targeting CD-20 surface cell antigens that are present on B-cells lymphoma and not on precursor cells, mainly efficacious in B cell iNHL, It became the mainstay treatment in follicular lymphoma (FL) as a single agent modality or in combination with chemotherapy. The anti-CD20 Rituximab played an important role in the development of the treatment of iNHL to become FDA approved in 1997. It was also proven effective in multiple other types of lymphoma. MAB through targeting the cell surface antigen leads to a direct or immune mediated cytotoxicity. This carries few side effects, including allergic reactions. Other than that, a resistance mechanism to rituximab emerged by inducing a failure in the apoptosis mechanism. Alternative mechanisms of resistance included the presence of soluble antigens that could act by binding to the antibody present before the drug itself can bind the lymphoma cell. Thus, the interest in immunotherapy grew further to explore the possibility of conjugating an immune mediated drug to a radio-sensitizing agent in order to enhance the selectivity of the drug. Here came the development of 90Y-ibritumomab tiuxetan and 131I-tositumomab. After it, humanized anti-CD20 emerged ofatumumab, IMMU106 (veltuzumab) in 2005, and ocrelizumab which are considered as second generation anti-CD20 and 3rd generation anti-CD20 include AME-133v (ocaratuzumab), PRO131921 and GA101 (obinutuzumab). Also multiple other agents emerged targeting different surface cell antigens like CD52 (alemtuzumab), CD22 (unconjugated epratuzumab and calicheamicin conjugated CMC-544 [inotuzumab ozogamicin]), CD80 (galiximab), CD2 (MEDI-507 [siplizumab]), CD30 (SGN-30 and MDX-060 [iratumumab], Brentuximab vedotin), CD40 (SGN-40), and CD79b (Polatuzumab). Other agents include MAB targeting T-Cells like mogamulizumab, Denileukin Diftitox and BiTEs or bispecific T cell engagers like Mosunetuzumab, Glofitamab, and Epcoritamab. Moreover, further studies came up to evaluate the role of immunotherapy in combination chemotherapy as a pathway to evade the resistance mechanisms. Side effects of the treatment were mainly infusion related adverse reactions, myelosuppression in conjugated forms leading to immunosuppression and subsequently to infectious complications. Another important aspect in immunotherapy is the half-lives of the medication which is an important factor that can influence the evaluation of the response. The MAB treatment showed important benefit in the treatment of iNHL and it continuously shows how rapidly it can develop to provide optimum care and benefit to patients with iNHL.

Relapsed acute myeloid leukemia (AML) following allogeneic hematopoietic cell transplantation (allo-HCT) is an unfavorable event associated with a poor prognosis, particularly for patients with early relapses. It usually arises from resistant leukemic blasts that escaped both preparative chemotherapy regimen and the graft-versus-leukemia (GVL) effect. Independent from the choice of salvage treatment, only minority of patients can achieve durable remissions. In recent years, better understanding of the disease relapse biology post allo-HCT allowed the application of newer strategies that could induce higher rates of remission, and potential longer survival. Those strategies aim at optimizing drugs that have a direct anti-leukemia activity by targeting different oncogenic mutations, metabolism pathways or surface antigens, and concurrently enhancing the immune microenvironment to promote GVL effect. This review discusses the current treatment landscape of AML relapse post allo-HCT.

BackgroundThe Coronavirus Disease 2019 (COVID-19) was declared a pandemic by WHO in March 2020. The first case of COVID-19 was identified in Lebanon on the 21st of February 2020, amid a national economic crisis. As the numbers of cases increased, ICU admissions and mortality rose, which led hospitals across Lebanon to take certain safety measures to contain the virus. The Naef K. Basile Cancer Institute (NKBCI) at the American University of Beirut Medical Center handles oncology outpatient visits and outpatient treatment protocol infusions. The aim of this study is to evaluate the efficacy of the safety measures put forth by the NKBCI early in the pandemic.MethodsOncology patients are amongst the immunosuppressed population, who are at greatest risk of contracting COVID-19 and consequently suffering its complications. In this manuscript, we evaluated the precautionary measures implemented at the NKBCI of AUBMC from March 1st to May 31st of 2020, by surveying oncology patients on the telephone who had live and virtual appointments in both the oncology outpatient clinics and infusion unit. We conducted a prospective study of 670 oncology patients who had appointments at the NKBCI during this period and used their answers to draw responses about patient satisfaction towards those safety measures.ResultsOur results involved 387 responses of oncology patients who visited the NKBCI during the period of March 1st to May 31st of 2020. 99% of our respondents gave a rating of good to excellent with these new measures. The option of online consultation was given to 35% in the hematology group compared to 19% in those with solid tumors (p=0.001). From the total, 15% of patients opted for the telemedicine experience as a new implemented strategy to provide patient-centered medical care. Of this group of patients, 22% faced problems with connectivity and 19% faced problems with online payment.ConclusionNKBCI was competent in following the WHO guidelines in protecting the oncology patient population. Feedback collected from the surveys will be taken into account by the committee of the NKBCI to develop new safety measures that can better control viral spread while providing patient-centered medical care.

The role of histone mutations in leukemogenesis remains largely unexplored. In this study of AML, the authors show that histone mutations are early events that drive a more aggressive phenotype.

Severe aplastic anemia (SAA) is a hematological disease resulting in pancytopenia due to bone marrow failure. Treatment consists of immunosppressive therapy, or allo-SCT. Patients with aplastic anemia are predisposed to invasive fungal infections due to mucormycosis. Till now, syngeneic SCT in the context of active mucormycosis infection for patients with severe aplastic anemia is lacking in the literature.Here, we report a case of severe aplastic anemia with disseminated mucormycosis infection undergoing syngeneic transplant. Keywords: Mucormycosis, Severe aplastic anemia, Syngeneic transplantation

Retinoic acid (RA) was proposed to increase survival of chemotherapy- treated patients with nucleophosmin-1 (NPM-1c)-mutated acute myeloid leukemia. We reported that, ex vivo, RA triggers NPM-1c degradation, P53 activation and growth arrest. PML organizes domains that control senescence or proteolysis. Here, we demonstrate that PML is required to initiate RA-driven NPM-1c degradation, P53 activation and cell death. Mechanistically, RA enhances PML basal expression through inhibition of activated Pin1, prior to NPM-1c degradation. Such PML induction drives P53 activation, favoring blast response to chemotherapy or arsenic in vivo. This RA/PML/P53 cascade could mechanistically explain RA-facilitated chemotherapy response in patients with NPM-1c mutated acute myeloid leukemia.

Diffuse large B-cell lymphoma (DLBCL) is a biologically and clinically heterogeneous disease. Despite good responses to standard of care frontline chemoimmunotherapy, the prognosis of relapsed/refractory (R/R) patients remains obscured by the possible inadequate responses to salvage therapy, eligibility for autologous transplantation, age and comorbidities. Polatuzumab vedotin is an antibody-drug conjugate formed by a CD79b antibody conjugated to the highly cytotoxic agent monomethyl auristatin E by means of a cleavable linker. Following significant clinical efficacy in R/R DLBCL, polatuzumab vedotin was granted accelerated Food and Drug Administration (FDA) approval in combination with bendamustine plus rituximab for patients who have failed at least two prior therapies. Other clinical studies involving polatuzumab vedotin in combination with other therapy regimens are also under evaluation for previously untreated DLBCL patients. In this article, we review the different phases from the preclinical development of polatuzumab vedotin to studies leading to its first approval, and highlight the potential future roles of this molecule in the treatment landscape of DLBCL.

Adult T cell leukemia/lymphoma (ATL) is associated to chronic human T cell leukemia virus type 1 (HTLV-1) infection and carries a poor prognosis. Arsenic trioxide (AS) and interferon-alpha (IFNα) together selectively trigger Tax viral oncoprotein degradation and cure Tax-driven murine ATL. AS/IFNα/zidovudine treatment achieves a high response rate in patients with chronic ATL. Interleukin 10 (IL-10) is an immuno-suppressive cytokine whose expression is activated by Tax. Here we show that, in ATL, AS/IFNα-induced abrogation of leukemia initiating cell activity requires IL-10 expression shutoff. Loss of IL-10 secretion drives production of inflammatory cytokines by the microenvironment, followed by innate immunity-mediated clearance of Taxdriven leukemic cells. Accordingly, anti-IL-10 monoclonal antibodies significantly increased the efficiency of AS/IFNα therapy. These results emphasize the sequential targeting of malignant ATL cells and their immune microenvironment in leukemia initiating cell (LIC) eradication and provide a strong rational to test AS/IFNα/anti-IL10 combination in ATL.

Adult T cell leukemia (ATL) is an aggressive malignancy secondary to chronic infection by the human T-cell leukemia virus type 1 (HTLV-1) infection. Two viral proteins, Tax and HBZ, play central roles in ATL leukemogenesis. Tax expression transforms T cells in vitro and induces ATL-like disease in mice. Tax also induces a rough eye phenotype and increases hemocyte count in Drosophila melanogaster, indicative of transformation. Among multiple functions, Tax modulates the expression of the enhancer of zeste homolog 2 (EZH2), a methyltransferase of the Polycomb Repressive Complex 2 (PRC2), leading to H3K27me3-dependent reprogramming of around half of cellular genes. HBZ is a negative regulator of Tax-mediated viral transcription. HBZ effects on epigenetic signatures are underexplored. Here, we established an hbz transgenic fly model, and demonstrated that, unlike Tax, which induces NF-κB activation and enhanced PRC2 activity creating an activation loop, HBZ neither induces transformation nor NF-κB activation in vivo. However, overexpression of Tax or HBZ increases the PRC2 activity and both proteins directly interact with PRC2 complex core components. Importantly, overexpression of HBZ in tax transgenic flies prevents Tax-induced NF-κB or PRC2 activation and totally rescues Tax-induced transformation and senescence. Our results establish the in vivo antagonistic effect of HBZ on Tax-induced transformation and cellular effects. This study helps understanding long-term HTLV-1 persistence and cellular transformation and opens perspectives for new therapeutic strategies targeting the epigenetic machinery in ATL.

Background: The epidemiology and prevalence of the Human T-cell leukemia virus type-1 (HTLV-1) infection represent a recommended priority by global health agencies. An in-depth revision to update the status of this infection in countries including those of the Eastern Mediterranean Regional Office (EMRO) of the World Health Organization is hence required. Methods: Ninety-seven studies evaluating the HTLV-1 infection in low- and high-risk populations in EMRO countries were retrieved from the international electronic databases and were used to assess the epidemiological status of the infection in these countries. Results: Most epidemiologic reports were published from Iran, with more than 50% of Iranian prisoners and around 4% of healthy individuals reported to have the infection. In Egypt, a considerable prevalence of the virus spans around 1.11% of blood donors. Foci of HTLV-1 infection are also present in some countries and require a careful epidemiological evaluation. In the other EMRO countries, a lower prevalence that does not exceed 1% was reported. Conclusion: The epidemiology and prevalence of HTLV-1 in the EMRO countries require a tight revision and update. Published studies reveal a scarce distribution of the virus in the African countries of EMRO, while a lower prevalence is denoted in the Asian countries of EMRO, except in Iran, where the prevalence is high.

Relapse is the main cause of mortality in patients with acute myeloid leukemia (AML) after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Adverse cytogenetic or molecular risk factors, as well as refractory disease or persistent measurable residual disease (MRD) at the time of transplantation are associated with an increased risk of recurrence. Salvage therapy for AML relapse after allo-HSCT is often limited to chemotherapy, donor lymphocyte infusions and/or second transplants and is rarely successful. Effective post-transplant preventive intervention in high risk AML may be crucial. The most frequent and promising approach is the use of post-transplant maintenance with hypomethylating agents or with FLT3 tyrosine kinase inhibitors when the target is present. Moreover, IDH1/IDH2 inhibitors and BCL-2 inhibitors in combination with other strategies are promising approaches in the maintenance setting. Here we summarize the current knowledge about the preemptive and prophylactic use of pharmacologic agents after allo-HSCT to prevent relapse of AML.

The FMS-like tyrosine kinase 3 (FLT3) gene is mutated in 25-30% of patients with acute myeloid leukemia (AML). Because of the poor prognosis associated with FLT3-internal tandem duplication mutated AML, allogeneic hematopoietic stem-cell transplantation (SCT) was commonly performed in first complete remission. Remarkable progress has been made in frontline treatments with the incorporation of FLT3 inhibitors and the development of highly sensitive minimal/measurable residual disease assays. Similarly, recent progress in allogeneic hematopoietic SCT includes improvement of transplant techniques, the use of haploidentical donors in patients lacking an HLA matched donor, and the introduction of FLT3 inhibitors as post-transplant maintenance therapy. Nevertheless, current transplant strategies vary between centers and differ in terms of transplant indications based on the internal tandem duplication allelic ratio and concomitant nucleophos-min-1 mutation, as well as in terms of post-transplant maintenance/consolidation. This review generated by international leukemia or transplant experts, mostly from the European Society for Blood and Marrow Transplantation, attempts to develop a position statement on best approaches for allogeneic hematopoietic SCT for AML with FLT3-internal tandem duplication including indications for and modalities of such transplants and on the potential optimization of post-transplant maintenance with FLT inhibitors.

Adult T-cell leukemia-lymphoma (ATL) is a distinct mature T-cell malignancy caused by human T-cell leukemia/lymphotropic virus type I (HTLV-1) endemic in some areas in the world. HTLV-1 transmits through mother-to-child infection via breastfeeding, sexual intercourses, and blood transfusions. Early HTLV-1 infection, presumably through mother’s milk, is crucial in developing ATL. The estimated cumulative risk of the development of ATL in HTLV-1 carriers is a few percent after transmission from their mothers. The median age of ATL onset is about 70 in Japan and is now rising, whereas an overall mean age in the mid-forties is reported in other parts of the world. ATL is classified into four clinical subtypes (acute, lymphoma, chronic, and smoldering) defined by organ lesions and LDH/calcium values. In aggressive ATL (acute, lymphoma or unfavorable chronic types) and indolent ATL (favorable chronic or smoldering types), intensive chemotherapy followed by allogeneic hematopoietic stem cell transplantation and watchful waiting until disease progression has been recommended, respectively, in Japan. Based on a worldwide meta-analysis and multiple other retrospective studies, the antiviral combination of interferon alpha (IFN) and zidovudine (AZT) is recommended in many parts of the world in acute, chronic, and smoldering ATL whereas patients with the lymphoma subtype are treated with chemotherapy, either alone or combined with AZT/IFN. Several new agents have been approved for ATL by the Pharmaceutical and Medical Devices Agency (PMDA) after clinical trials, including an anti-CC chemokine receptor 4 monoclonal antibody, mogamulizumab; an immunomodulatory agent, lenalidomide; and an anti-CD30 antibody/drug conjugate, brentuximab vedotin.

Adult T cell leukemia-lymphoma (ATL) is an aggressive malignancy secondary to chronic infection with the human T cell leukemia virus type I (HTLV-I) retrovirus. ATL carries a dismal prognosis. ATL classifies into four subtypes (acute, lymphoma, chronic, and smoldering) which display different clinical features, prognosis and response to therapy, hence requiring different clinical management. Smoldering and chronic subtypes respond well to antiretroviral therapy using the combination of zidovudine (AZT) and interferon-alpha (IFN) with a significant prolongation of survival. Conversely, the watch and wait strategy or chemotherapy for these indolent subtypes allies with a poor long-term outcome. Acute ATL is associated with chemo-resistance and dismal prognosis. Lymphoma subtypes respond better to intensive chemotherapy but survival remains poor. Allogeneic hematopoietic stem cell transplantation (HSCT) results in long-term survival in roughly one third of transplanted patients but only a small percentage of patients can make it to transplant. Overall, current treatments of aggressive ATL are not satisfactory. Prognosis of refractory or relapsed patients is dismal with some encouraging results when using lenalidomide or mogamulizumab. To overcome resistance and prevent relapse, preclinical or pilot clinical studies using targeted therapies such as arsenic/IFN, monoclonal antibodies, epigenetic therapies are promising but warrant further clinical investigation. Anti-ATL vaccines including Tax peptide-pulsed dendritic cells, induced Tax-specific CTL responses in ATL patients. Finally, based on the progress in understanding the pathophysiology of ATL, and the risk-adapted treatment approaches to different ATL subtypes, treatment strategies of ATL should take into account the host immune responses and the host microenvironment including HTLV-1 infected non-malignant cells. Herein, we will provide a summary of novel treatments of ATL in vitro, in vivo, and in early clinical trials.

Chronic myeloid leukemia (CML) is caused by a balanced chromosomal translocation resulting in the formation of BCR-ABL1 fusion gene encoding a constitutively active BCR-ABL1 tyrosine kinase, which activates multiple signal transduction pathways leading to malignant transformation. Standard treatment of CML is based on tyrosine kinase inhibitors (TKI); however, some mutations have proven elusive particularly the T315I mutation. Drosophila melanogaster is an established in vivo model for human diseases including cancer. The targeted expression of chimeric human/fly and full human BCR-ABL1 in Drosophila eyes has been shown to result in detrimental effects. In this study, we expressed human BCR-ABL1p210 and the resistant BCR-ABL1p210/T315I fusion oncogenes in Drosophila eyes. Expression of BCR-ABL1p210/T315I resulted in a severe distortion of the ommatidial architecture of adult eyes with a more prominent rough eye phenotype compared to milder phenotypes in BCR-ABL1p210 reflecting a stronger oncogenic potential of the mutant. We then assessed the efficacy of the currently used TKI in BCR-ABL1p210 and BCR-ABL1p210/T315I expressing flies. Treatment of BCR-ABL1p210 expressing flies with potent kinase inhibitors (dasatinib and ponatinib) resulted in the rescue of ommatidial loss and the restoration of normal development. Taken together, we provide a CML tailored BCR-ABL1p210 and BCR-ABL1p210/T315I fly model which can be used to test new compounds with improved therapeutic indices.

Abstract Background Adult T-cell leukemia/lymphoma (ATL) is an aggressive malignancy secondary to chronic human T-cell lymphotropic virus 1 infection, triggered by the virally encoded oncoprotein Tax. The transforming activity and subcellular localization of Tax is strongly influenced by posttranslational modifications, among which ubiquitylation and SUMOylation have been identified as key regulators of the nuclear/cytoplasmic shuttling of Tax, as well as its ability to activate NF-κB signaling. Results Adding to the complex posttranslational modification landscape of Tax, we here demonstrate that Tax also interacts with the ubiquitin-related modifier 1 (Urm1). Conjugation of Urm1 to Tax results in a redistribution of Tax to the cytoplasm and major increase in the transcription of the NF-ĸB targets Rantes and interleukin-6. Utilizing a tax-transgenic Drosophila model, we show that the Urm1-dependent subcellular targeting of Tax is evolutionary conserved, and that the presence of Urm1 is strongly correlated with the transcriptional output of Diptericin, an antimicrobial peptide and established downstream target of NF-κB in flies. Conclusions These data put forward Urm1 as a novel Tax modifier that modulates its oncogenic activity and hence represents a potential novel target for developing new strategies for treating ATL.

BET inhibitors (BETi) including OTX015 (MK-8628) and JQ1 demonstrated antileukemic activity including NPM1c AML cells. Nevertheless, the biological consequences of BETi in NPM1c AML were not fully investigated. Even if of better prognosis AML patients with NPM1c may relapse and treatment remains difficult. Differentiation-based therapy by all trans retinoic acid (ATRA) combined with arsenic trioxide (ATO) demonstrated activity in NPM1c AML. We found that BETi, similar to ATO + ATRA, induced differentiation and apoptosis which was TP53 independent in the NPM1c cell line OCI-AML3 and primary cells. Furthermore, BETi induced proteasome-dependent degradation of NPM1c. BETi degraded NPM1c in the cytosol while BRD4 is degraded in the nucleus which suggests that restoration of the NPM1/BRD4 equilibrium in the nucleus of NPM1c cells is essential for the efficacy of BETi. While ATO + ATRA had significant biological activity in NPM1c IMS-M2 cell line, those cells were resistant to BETi. Gene profiling revealed that IMS-M2 cells probably resist to BETi by upregulation of LSC pathways independently of the downregulation of a core BET-responsive transcriptional program. ATO + ATRA downregulated a NPM1c specific HOX gene signature while anti-leukemic effects of BETi appear HOX gene independent. Our preclinical results encourage clinical testing of BETi in NPM1c AML patients.

Background: Invasive fungal infections (IFI) following allogeneic stem cell transplant (allo-HCT) are associated with high morbidity and mortality. Primary prophylaxis using voriconazole has been shown to decrease the incidence of IFI. Methods: We conducted a retrospective analysis at the Bone Marrow Transplant (BMT) unit of the American University of Beirut including 195 patients who underwent allo-HCT for hematological malignancies and received voriconazole as primary prophylaxis for IFI. The primary endpoints were based on the incidence of IFI at day 100 and day 180, and the secondary endpoint based on fungal-free survival. Results: For the study, 195 patients who underwent allo-HCT between January 2015 and March 2021 were included. The median age at transplant was 43 years. Of the patients, 63% were male, and the majority of patients were diagnosed with acute myeloid leukemia (AML) (60%). Voriconazole was given for a median of 90 days and was interrupted in 20 patients. The majority of IFI cases were probable invasive aspergillosis (8%). The incidence of IFI including proven, probable and possible IFI was 34%. The incidence of proven and probable IFI was 5% were 8%, respectively. The incidence of proven-probable (PP-IFI) was 5.1% at day 100 and 6.6% at day 180. The majority of PP-IFI cases were invasive aspergillosis (8%). A univariate analysis of patients, transplant characteristics and IFI showed a significant correlation between the type of donor, disease status before transplant, graft-versus-host disease prophylaxis used and incidence of IFI. Only disease status post-transplant showed a significant correlation with fungal-free survival in the multivariate analysis. Conclusion: Primary prophylaxis with voriconazole in allo-HCT is associated with a low incidence of IFI. More studies are required to compare various antifungal agents in this setting.

FMS-like tyrosine kinase 3 ( FLT3 ) mutations are one of the most frequently encountered genetic alterations in acute myeloid leukemia (AML), and are generally associated with unfavorable outcomes. Several tools are currently available to provide an accurate prognosis for patients with these mutations, including FLT3 mutation type (internal tandem duplication versus tyrosine kinase domain), mutation allelic ratio (high versus low), and concurrent nucleophosmin-1 ( NPM1 ) mutation, to help decide on optimal treatment. Recent advances in targeted therapies have paved the way for modern treatment strategies, such as the development of FLT3 kinase inhibitors. These novel drugs can be incorporated into any treatment component, including induction and consolidation, the relapse/refractory setting, bridging for transplant, salvage post-transplant, and as prophylactic long-term post-transplant maintenance. Many challenges remain though, such as their intolerability with high-dose chemotherapy in frail patients; whether their optimal use involves watchful waiting for molecular or hematologic relapse compared with prophylactic use as maintenance; and the exact role and indication for allogeneic stem cell transplantation, which arguably remains the only curative option for these high-risk patients.