Investigators are using checkpoint inhibitors (CPIs) to treat aggressive hematologic malignancies in patients undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT) and in some patients with relapsed disease after allo-HSCT. CTLA-4 inhibitors and PD-1 inhibitors are 2 main types of CPIs, which work through activation of the immune system. On one hand, CPIs can achieve graft-versus-tumor effect, and on the other hand, there is a risk of graft-versus-host disease (GVHD). After a comprehensive literature review, we included data (n = 283) from 24 studies (11 original manuscripts and 13 case reports or case series) and evaluated the results to assess the safety and efficacy of CPI use in conjunction with allo-HSCT. Among the 283 patients, 107 received CPI before allo-HSCT, and 176 received CPI after allo-HSCT. The most common indication for CPI use was for Hodgkin lymphoma. The CPIs used in various studies included ipilimumab, nivolumab, and pembrolizumab. Among the patients exposed to CPI before allo-HSCT, 56% developed acute GVHD and 29% developed chronic GVHD. Investigators reported 20 deaths, 60% of which were GVHD-related. The overall mortality risk with GVHD is 11%. In this group, investigators noted an objective response rate (ORR) in 68% of patients, with complete remission (CR) in 47%, partial remission (PR) in 21%, and stable disease in 11%. Among the patients who received a CPI after allo-HSCT for disease relapse, 14% developed acute GVHD and 9% developed chronic GVHD. Investigators reported 40 deaths, 28% of which were GVHD-related. The mortality risk with GVHD is approximately 7%. Investigators reported ORR in 54% of patients, with CR in 33%, PR in 21%, and disease stabilization in 5%. After careful evaluation of collective data, we found that CPI use both before and after allo-HSCT can be highly effective, but exposure can lead to a significantly increased risk of GVHD-related morbidity and mortality in this patient population. Despite limited availability of data, there is need for extreme caution while making decisions regarding the use of CPIs. Detailed discussions and prospective well-designed clinical trials are needed to explore this issue further.

Blinatumomab and donor lymphocyte infusion (DLI) combination is a promising cancer therapy, whereby blinatumomab might achieve an initial reduction in leukemic-cell burden using T cells, and after tumor clearance, DLI can potentially stimulate the donor immune system to achieve longer lasting remission. Here, we present a 51-year-old female with mixed phenotype acute leukemia who had a hematologic relapse 3 months after she received total body irradiation-based myeloablative allogeneic hematopoietic stem cell transplantation from an unrelated human leukocyte antigen matched (10/10) donor and achieved complete remission with minimal residual disease negativity by multi-parameter flow cytometry using the combination of blinatumomab and DLI. To the best of our knowledge, this is the first report to describe the use of blinatumomab and DLI combination therapy in the treatment of B/myeloid mixed phenotype acute leukemia.

R-CHOP has been the standard of care for diffuse large B cell lymphoma (DLBCL), curing approximately 60% of patients for more than 2 decades. However, the optimal treatment of patients who are too frail to tolerate this regimen and/or are not candidates for anthracycline therapy continues to be debated. MInT and GELA trials established addition of rituximab to CHOP in DLBCL but excluded patients older than 80 years. Multiple regimens have been tried with varying success in the very elderly, including R-mini-CHOP, R-mini CEOP, R-split CHOP, pre-phase strategies, and R-GCVP. However, there has not been a randomized trial among these strategies. Although addition of novel agents including ibrutinib, brentuximab vedotin, lenalidomide, and many others on the horizon holds promise in this population, none have been tested in a randomized setting or have results awaited. There is also a lack of a validated and easy to use clinical tool in this population to predict patients who will not tolerate R-CHOP. Identifying patients who will not tolerate R-CHOP early with the help of tools like CGA, along with integrating biology-based treatment (ibrutinib, lenalidomide in activated B cell type DLBCL) is being investigated in this population.

Multiple Myeloma (MM) is primarily a disease of old age with a median age of sixty-nine years at diagnosis. The development of novel therapies for induction and use of autologous stem cell transplantation has resulted in improved clinical outcomes and better quality of life for MM patients. Elderly patients, comprising the majority of MM population, have a higher incidence of age-related comorbidities, frailty and organ dysfunction which complicates the coordination of treatment and limits the selection of therapies. Even in the era of multiple chemotherapeutic options, the clinical heterogeneity of the myeloma patients' demands personalized treatments which often require dose-adjustments or dose delays. The use of reduced-dose regimens and various comorbidity indices has improved clinical outcome and regimen tolerability in MM patients with renal, neurological and bone abnormalities. We focus on advancements in the treatment of multiple myeloma with the goal to guide clinicians towards patient-specific management.

Introduction: Chimeric antigen receptor t cells (CAR T) therapy is an innovative adoptive immunotherapy being used for the treatment of CD19+ive B cell hematological malignancies, especially B cell acute lymphoblastic leukemia (B-ALL), non-Hodgkin's lymphomas (NHL) and chronic lymphocytic Leukemia (CLL). This treatment holds the potential to be highly effective and potentially less toxic alternative to cytotoxic chemotherapy for patients with relapsed and refractory (R/R) disease.This therapeutic modality is associated with a variety of side effects which includes cytokine release syndrome (CRS), neurotoxicity, B cell aplasia, hypogammaglobulinemia and resultant high risk infections. There is paucity of data about infection related complications with CAR-T therapy. In this review, we focus on the infections associated with B cell targeting CART cell therapy for the treatment of hematological malignancies. Methods: We conducted a systematic review (following PRISMA guidelines) by completing a comprehensive PubMed, Cochrane Library and ClinicalTrials.gov search on May 15th2019. Our search strategy included using search and MeSH terms related to CAR T therapy, hematological malignancies, Infections, safety and mortality. We were able to identify 279 articles from PubMed, 26 from Cochrane, 5 from Clinical Trials.org and 7 from Web of Science. After screening we selected 13 prospective published trials (n=555) for data extraction. We manually extracted data and summarized our results. RESULTS: Total included trials were 13, and trial level data from 555 patient was summarized in Table 1. Commonly used targets were CD19 ( B cell malignancies), and BCMA (Multiple Myeloma). CAR T were used for the treatment of diseases B-cell acute lymphoblastic leukemia ( ALL), B cell NHL, CLL, and Multiple myeloma (MM). Out of the available data, the two most frequent infections were upper respiratory tract infections (RTI) and blood stream infections. Other infections observed were the lower RTI, urinary tract infections (UTI), clostridium difficile (C. Diff), meningitis, mucocutaneous herpes infections, cellulitis, mucormycosis, and aspergillosis. A Phase 1/2 trial (NCT00924326 / B-NHL / CD19 Target) demonstrated 43 cases of septicemia (23.2%), 4 cases of UTI (9.3%) and 1 case each of cellulitis (2.3%), opportunistic infections (2.3%), upper RTI and lower RTI (2.3%). Phase 1 trial (NCT01029366 / B lymphoma, leukemia / CD19 target / n=20) showed 3 cases (15%) of pneumonia, 1 case each of C Diff, Pseudomonas and salmonella (5%) infections. A Phase 2 trial (NCT02030834, B NHL, CD19 target, n=63) treated patients showed 34% patients experienced infection which included sepsis, UTI, upper and lower RTI, skin, small intestine and mucosal infections. A phase 1 trial ( NCT01840566, n=17, NHL, CD19 target) demonstrated cases of mucormycosis ( n=unknown) and 7 case of pneumonia (41.1%). In phase 2 trial (NCT02030847, B ALL, CD19, n=30) treated patients experienced cases of sepsis (10%), Pneumonia (6.7%) and 1 case each of oral Candidiasis, C Diff, influenza and meningitis (10%). A phase 1 trial (NCT01044069, n=53, RR ALL, CD19 target) showed incidence of 11 cases of blood stream infections (20.1%), 9 cases of upper RTI (16.9), 2 cases of UTI (3.8%), 2 cases of pneumonia (3.8%), 3 cases of pulmonary aspergillosis (5.7%) and a case of herpes infection (1.9). Phase 2 trial (NCT01747486, CLL, CD19, n=42) demonstrated 2 cases of sepsis (4.7%), 2 cases of influenza (4.7), 3 cases of upper respiratory tract infections (7.1%) and 2 cases of pneumonia (4.7%). NCT02215967, Phase 1 trial ( Multiple Myeloma, BCMA target, n=12) was associated with 3 cases of upper RTI (25%) and 1 case of UTI (8.3%). Table 2 summarizes additional ongoing CAR T cell trials. Conclusion: CAR T cell therapy is gaining popularity and its indications are expanding. Its complications need to be closely studied for potential infections amongst other side effects. Clinical trial results have likely under-reported infections associated with CAR-T therapy because of overlapping presentation with cytokine release syndrome (CRS), neurotoxicity and limited follow-up reported in the published trials. Additional studies with longer follow up duration are required to identify the true risk of infectious complications of CAR T therapy in patients with hematological malignancies. Real word data on CAr T patients can also reveal long term infectious complications. Disclosures Anwer: In-Cyte: Speakers Bureau; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees. OffLabel Disclosure: CAR-T therapy. We are summarizing infectious complications of CAR-T therapy and their projects under development.