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.

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.

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.

Impact of disease burden on clinical outcomes of AML patients receiving allogeneic hematopoietic cell transplantation: a study from the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation.

Pre-transplant detectable measurable residual disease (MRD) is still associated with high risk of relapse and poor outcomes in acute myeloid leukemia (AML). We aimed at evaluating the impact of disease burden on prediction of relapse and survival in patients receiving allogeneic hematopoietic cell transplantation (allo-HCT) in first remission (CR1). We identified a total of 3202 adult AML patients, of these 1776 patients were in CR1 and MRD positive and 1426 patients were primary refractory at time of transplant. After a median follow-up of 24.4 months, non-relapse mortality and relapse rate were significantly higher in the primary refractory group compared to the CR1 MRD positive group (Hazards Ratio (HR) = 1.82 (95% CI: 1.47-2.24) p < 0.001 and HR = 1.54 (95% CI: 1.34-1.77), p < 0.001), respectively. Leukemia-free survival (LFS) and overall survival (OS) were significantly worse in the primary refractory group (HR = 1.61 (95% CI: 1.44-1.81), p < 0.001 and HR = 1.71 (95% CI: 1.51-1.94), p < 0.001, respectively). Our real-life data suggest that patients in CR1 and MRD positive at time of transplant could still be salvaged by allo-HCT with a 2-year OS of 63%, if negative MRD cannot be obtained and their outcomes are significantly better than patients transplanted with active disease.

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=. .

Relapse after allogeneic hematopoietic stem cell transplantation in acute myeloid leukemia: an overview of prevention and treatment.

Despite therapeutic progress in acute myeloid leukemia (AML), relapse post-allogeneic hematopoietic stem cell transplantation (allo-HSCT) remains a major challenge. Here, we aim to provide an overview of prevention and treatment of relapse in this population, including cell-based and pharmacologic options. Post-transplant maintenance therapy is used in patients who have undetectable measurable residual disease (MRD), while pre-emptive treatment is administered upon detection of MRD. Prompt transfusion of prophylactic donor lymphocyte infusion (DLI) was found to be effective in preventing relapse and overcoming the negative impact of detectable MRD. In addition, patients with persistent targetable mutations can benefit from targeted post-transplant pharmacological interventions. IDH inhibitors have shown promising results in relapsed/refractory AML. Hypomethylating agents, such as decitabine and azacitidine, have been studied in the post-allo-HSCT setting, both as pre-emptive and prophylactic. Venetoclax has been shown effective in combination with hypomethylating agents or low-dose cytarabine in patients with newly diagnosed AML, especially those unfit for intensive chemotherapy. FLT3 inhibitors, the topic of another section in this review series, have significantly improved survival in FLT-3-ITD mutant AML. The role of other cell-based therapies, including CAR-T cells, in AML is currently being investigated.

Mantle cell lymphoma negative for t(11,14) involving the kidneys: a case report.

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.

Pharmacologic Strategies for Post-Transplant Maintenance in Acute Myeloid Leukemia: It Is Time to Consider!

Patients with high-risk acute myeloid leukemia are offered allogeneic hematopoietic cell transplantation (allo-HCT) in first remission to reduce risk of relapse. However, disease recurrence remains the major reason of allo-HCT failure, occurring in around 35-45% of patients, and leading to dismal outcomes. Strategies to reduce the risk of relapse are greatly needed, especially in the early post-transplant phase where the graft-versus-leukemia (GVL) effect is not yet activated. Some practices include the use of myeloablative conditioning regimens, close monitoring of measurable residual disease and donor chimerism, rapid tapering of immunosuppression, and implementation of pre-emptive strategies as the use of donor lymphocyte infusion. However, it's time to consider prophylactic pharmacologic interventions post allo-HCT that aim at maintaining leukemic clones under control by both direct cytotoxic activity and by enhancing the GVL effect. In this current review, available data on drugs targeting epigenetic pathways like azacitidine, or actionable mutations like FLT3 and IDH1/2 inhibitors used as maintenance post allo-HCT, will be discussed.

20-Year Steady Increase in Survival of Adult Patients with Relapsed Philadelphia-Positive Acute Lymphoblastic Leukemia Post Allogeneic Hematopoietic Cell Transplantation.

PURPOSE: Relapse after allogeneic hematopoietic cell transplantation (allo-HCT) remains the first cause of transplant failure in patients with Philadelphia-positive (Ph+) acute lymphoblastic leukemia (ALL). In other hematologic malignancies, therapeutic advances resulted in significant improvement over time in survival of patients relapsing after transplant. EXPERIMENTAL DESIGN: We compared outcomes at European Society for Blood and Marrow Transplantation (EBMT) participating centers of 899 adult patients with Ph+ ALL who relapsed between 2000 and 2019 after allo-HCT performed in first complete remission. Median follow-up for alive patients was 56 months. RESULTS: Overall, 116 patients relapsed between 2000 and 2004, 225 between 2005 and 2009, 294 between 2010 and 2014, and 264 between 2015 and 2019. Patient and transplant characteristics were similar over the four time periods except for a progressive increase in unrelated donors, peripheral blood stem cells, reduced intensity conditioning, and in vivo T-cell depletion and a progressive decrease in total body irradiation. The 2-year overall survival (OS) after relapse increased from 27.8% for patients relapsing between 2000 and 2004 to 54.8% for 2015 and 2019 (P = 0.001). A second allo-HCT within 2 years after relapse was performed in 13.9% of patients resulting in a 2-year OS of 35.9%. In multivariate analysis, OS from relapse was positively affected by a longer time from transplant to relapse and the year of relapse. CONCLUSIONS: We observed a major progressive improvement in OS from posttransplant relapse for patients with Ph+ ALL over the years, likely multifactorial including transplant-related factors, posttransplant salvage, and improvement in supportive care. These large-scale real-world data can serve as a benchmark for future studies in this setting. See related commentary by Gale, p. 813.

The Use of Voriconazole as Primary Prophylaxis for Invasive Fungal Infections in Patients Undergoing Allogeneic Stem Cell Transplantation: A Single Center's Experience.

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.

Phase II study of single-agent nivolumab in patients with myelofibrosis.

Dysregulated JAK-STAT signaling in myelofibrosis induces pro-inflammatory cytokines, which suppresses T cell proliferation and differentiation, likely responsible for disease progression. The PD-1 pathway, found to be overexpressed in myeloid malignancies, has gained great interest as a therapeutic target, where a significant unmet need exists for novel therapeutic strategies. Preclinical models showed JAK2 mutant cells had higher expression of PD-L1; furthermore, JAK2 mutant xenografts treated with PD-1 inhibition had prolonged survival and reduction in JAK2 allele burden. We evaluated the efficacy and safety of single-agent nivolumab in 8 adult patients with myelofibrosis. Nivolumab was given at 3 mg/kg every 2 weeks for 8 doses, then every 12 weeks for up to 4 years, or until disease progression or toxicity. The median number of nivolumab doses received was 6 [range, 5-16 doses]. Five patients had stable disease including spleen size, total symptom score, and blood requirements for a median of 3.3 months [range, 2.3-15.2 months]. After a median follow-up of 57 months, two patients were still alive. The median overall survival was 6.1 months [range, 3.2-57.4 months]. Due to failure to meet the predetermined efficacy endpoint, the study was terminated early. Trial registration: Clinical trials.gov NCT: 02,421,354.

Safety and Efficacy of Replacing Vindesine with Vincristine in R-ACVBP Regimen for the Treatment of Large B Cell Lymphomas.

BACKGROUND: Intensified immunochemotherapy with rituximab, doxorubicin, cyclophosphamide, vindesine, bleomycin, and prednisone (R-ACVBP) improves outcomes in younger adults with diffuse large B-cell lymphomas (DLBCL) compared with R-CHOP. Due to vindesine unavailability, we assessed the safety and efficacy of replacing vindesine with vincristine in a modified R-ACVBP protocol (mR-ACVBP). METHODS: This is a retrospective study including all consecutive adult patients with newly diagnosed DLBCL who received first-line mR-ACVBP. Vindesine was replaced with vincristine 1.5 mg on days 1 and 5 of each cycle. Responders continued with published R-ACVBP consolidation. Patients with inadequate response on interim imaging were offered consolidative autologous stem cell transplantation. RESULTS: We identified 56 patients with DLBCL, with a median age of 41 years (range, 21-67). Thirty-seven (66%) patients had an age-adjusted International Prognostic Index of ≥ 2. Complete response was achieved in 41 (80%) patients and partial response in 6 (12%). The most common adverse events during induction were anemia (91%), febrile neutropenia (64%; grade 4 in 46%), thrombocytopenia (39%), and mucositis (21%). Peripheral neuropathy was encountered in 7 (12%) patients (grade 3; n = 1). Two deaths from septic shock were reported in patients with initial poor performance status. After a median follow-up of 17 months, the 2-year progression-free survival and overall survival rates were 86% and 87%, respectively. CONCLUSION: The replacement of vindesine with vincristine in mR-ACVBP seems feasible, with manageable adverse events and excellent 2-year progression-free survival. These data need validation in larger prospective trials.

Intrathecal methotrexate induced myelopathy, rare yet serious complication: A case report and review of the literature.

The regular administration of intrathecal chemotherapy has significantly reduced the risk of central nervous system leukemia in patients with acute lymphoblastic leukemia. We report the case of 28-year-old man who developed intrathecal methotrexate induced myelopathy; a rare but serious side effect of intrathecal chemotherapy. In the light of absent effective treatment strategies, description of the case, along with reviewing similar cases published in the literature will help shed a light on the possible pathophysiologic mechanisms behind this injury. To this date, there are no specific clinical, biochemical and imaging signs that would allow timely detection of intrathecal methotrexate induced myelopathy. This in turn is causing delayed treatment of this injury, resulting in significant morbidity and mortality.

Risk adapted therapeutic strategy in newly diagnosed acute myeloid leukemia: Refining the outcomes of ELN 2017 intermediate-risk patients.

INTRODUCTION: Despite advances in the treatment of acute myeloid leukemia (AML), cytotoxic chemotherapy remains the standard induction regimen. PATIENTS AND METHODS: In this single center retrospective study, we assessed outcomes of 99 consecutive adult AML patients treated with a risk-adapted strategy with a median follow-up of 35.5 months. RESULTS: We identified 24 (24 %), 55 (56 %) and 20 (20 %) patients classified as favorable-, intermediate-, and adverse- risk group respectively, according to the European LeukemiaNet (ELN) 2017 classification. Patients either received idarubicin and cytarabine induction chemotherapy with or without FLT3 inhibitors or hypomethylating agents based on age and comorbidity. The complete response (CR) rate was 76 % (82 % and 61 % in patients aged < 60 and ≥ 60, respectively). For the whole cohort, the 3-year overall survival (OS) was 53 %, being 62 % and 30 % in patients aged < 60 and ≥ 60, respectively. The 3-year leukemia-free survival (LFS) was 54 %, with 56 % and 45 % in patients aged < 60 and ≥ 60, respectively. The 3-year LFS were 58 %, 62 % and 25 % for patients within ELN favorable-, intermediate-, and adverse-risk groups respectively. Twenty-seven (36 %) out of 75 patients with intermediate- and adverse-risk disease underwent allogeneic hematopoietic cell transplantation (allo-HCT) in first CR with 92 % of them receiving post-transplant maintenance consisting of azacitidine in 19 (76 %) patients or sorafenib in 6 (24 %) patients. Of these patients younger than 60 years, the 3-year OS and LFS were 85 % and 69 %, respectively. CONCLUSION: These results indicate an improved OS for AML patients especially in intermediate-risk category who were treated with a total therapy consisting of induction chemotherapy followed by allo-HCT and post-transplant maintenance.

Post-Transplant Maintenance Therapy for Patients with Acute Myeloid Leukemia: Current Approaches and the Need for More Trials.

Relapse rates following allogeneic stem cell transplantation for acute myeloid leukemia remain unacceptably high and a major cause of death. Maintenance therapies post-transplant administered either to patients with impending relapse or at high risk of relapse could present a strategy to improve survival and overall outcomes. With the increasing use of molecular and genomic characterization of the disease, more novel therapies became available as maintenance strategies. These options were, however, hindered by excessive toxicities, mostly hematologic, especially with the use of myeloablative conditioning regimens. Several key questions have also emerged including the efficacy of these therapies, the duration of maintenance, as well as the potential modulation of the graft and the immune microenvironment. These issues are further complicated by the paucity of well-designed prospective randomized clinical trials evaluating these agents. Future directions in this field should include better risk stratification and patient selection based on assays of minimal residual disease, as well as the incorporation of novel targets and pathways of leukemogenesis. In this article, we highlight the current evidence behind the use of post-transplant maintenance therapy, the optimal patient and disease selection, as well as the challenges faced by these strategies in an area that remains quite controversial. We will focus on therapies targeting leukemia stem cells that directly or indirectly modulate the allografted immune microenvironment and augment the graft-versus-leukemia impact.

Phase 2 study of lenalidomide maintenance for patients with high-risk acute myeloid leukemia in remission.

BACKGROUND: New drug combinations have led to significant improvements in remission rates for patients with acute myeloid leukemia (AML). However, many patients with high-risk AML who respond to their initial treatment and are not candidates for allogeneic stem cell transplantation (ASCT) will eventually relapse with poor outcomes. METHODS: In this phase 2 trial, the efficacy of lenalidomide maintenance was evaluated in patients with high-risk AML who had achieved their first or second remission after induction chemotherapy and at least 1 consolidation cycle and who were not candidates for immediate ASCT. Lenalidomide was given orally at 10 to 20 mg daily on days 1 to 28 of a 28-day cycle for up to 24 cycles. RESULTS: A total of 28 patients were enrolled in this study with a median age of 61 years (range, 24-87 years). The median number of cycles was 8 (range, 1-24 cycles). Ten patients (36%) completed 24 months of maintenance treatment. With a median follow-up of 22.5 months (range, 2.6-55 months), 12 patients (43%) relapsed after a median of 3 months (range, 0.7-23 months). The median duration of remission for all patients was 18.7 months (range, 0.7-55.1 months). The 2-year overall survival and relapse-free survival rates from the time of enrollment were 63% and 50%, respectively. Overall, lenalidomide was well tolerated; serious adverse events of grade 3 or 4, including rash (n = 5), thrombocytopenia (n = 4), neutropenia (n = 4), and fatigue (n = 2), were observed in 13 patients (46%). CONCLUSIONS: Lenalidomide is a safe and feasible maintenance strategy in patients with high-risk AML who are not candidates for ASCT, and it has beneficial effects for patients with negative measurable residual disease.