Efficacy of Autologous and Allogeneic Hematopoietic Cell Transplantation in Adults with Acute Promyelocytic Leukemia: Results of a Systematic Review and Meta-Analysis.

Despite therapeutic advances for acute promyelocytic leukemia (APL) with the emergence of all-trans retinoic acid, arsenic trioxide, and gemtuzumab-ozogamycin, approximately 10% of patients still experience disease relapse, typically occurring within 24 to 36 months following completion of front-line treatment. Traditionally, both allogeneic (allo) and autologous (auto) hematopoietic cell transplantation (HCT) have been considered reasonable treatment options for relapsed APL; however, no randomized controlled studies have been conducted comparing allo-HCT and auto-HCT in patients with relapsed APL. We performed a systematic review/meta-analysis to assess the totality of evidence pertaining to allo-HCT or auto-HCT in relapsed APL. Our search identified 1158 references, of which 23 met our inclusion criteria. While acknowledging the limitations of comparing these 2 treatment modalities indirectly, based on results from separate meta-analyses, it appears that pooled rates of event-free survival (71% versus 54%), progression-free survival (63% versus 43%), and overall survival (82% versus 58%) are higher after auto-HCT. This difference can be explained in part by the higher risk of pooled nonrelapse mortality (NRM) in patients undergoing allo-HCT (29% versus 5%), owing to inherent risks associated with this modality. In the absence of a randomized prospective clinical trial comparing allo-HCT and auto-HCT, our results show that both modalities are acceptable in patients with relapsed APL. The higher pooled NRM rate with allo-HCT is an important consideration when choosing this option. Additionally, the comparable pooled relapse rate for auto-HCT and allo-HCT (24% versus 23%) provides a rationale for evaluating post-HCT consolidative strategies to mitigate this risk.

Translational development of a novel BAFF-R CAR-T therapy targeting B-cell lymphoid malignancies.

Several CD19-targeting CAR-T cells are used to treat leukemias and lymphomas; however, relapsed and/or refractory (R/R) disease is still observed in a significant number of patients. Additionally, the success of CD19-CAR-T cell therapies is not uniform across hematological malignancies, particularly in chronic lymphocytic leukemia (CLL). In this study, we present the development of a novel CAR-T cell therapy targeting B-cell activating factor receptor (BAFF-R), a key regulator of B-cell proliferation and maturation. A new monoclonal antibody against BAFF-R was generated from a hybridoma clone and used to create a novel MC10029 CAR construct. Through a series of in vitro and in vivo models using the Nalm-6 cell line for leukemia and the Z138 cell line for lymphoma, we demonstrated the antigen-specific cytotoxicity of MC10029 CAR-T cells against tumor cells. Additionally, MC10029 CAR-T cells exhibited potent antitumor effects against CD19 knockout tumor cells, mimicking CD19-negative R/R disease. MC10029 CAR-T cells were specifically targeted to CLL, in which BAFF-R is nearly always expressed. The cytotoxicity of MC10029 CAR-T cells was first shown in the MEC-1 CLL cell line, before we turned our efforts to subject-derived samples. Using healthy donor-engineered MC10029 CAR-T cells against enriched primary tumor cells, followed by subject-derived MC10029 CAR-T cells against autologous tumor cells, we showed the efficacy of MC10029 CAR-T cells against CLL subject samples. With these robust data, we have advanced to the production of MC10029 CAR-T cells, using GMP lentivirus, and obtained an IND approval in preparation for a Phase 1 clinical trial.

Trends in utilization of stored cryopreserved autologous peripheral hematopoietic cells intended for a second (or beyond) autologous hematopoietic cell transplantation in patients with multiple myeloma: a single center experience.

Due to the advent of effective novel therapies for multiple myeloma (MM), the use of cryopreserved autologous peripheral blood hematopoietic cells (APBHC) for a salvage autologous transplant (auto-HCT) is in decline. We evaluated utilization trends and costs associated with cryopreserved APBHC in patients with MM. We retrospectively evaluated the clinicopathologic data from 440 patients with MM who underwent APBHC mobilization and collection at Mayo Clinic Florida between 2010 and 2019. Based on institution-specific charges as of May 2021, the cost of 1 session of APBHC collection/apheresis was $4,680 and the cost of 1 year of APBHC cryopreservation was $4,790 per patient. Out of 347 patients who had APBHC in cryopreservation, 5 (1.4%) underwent a salvage auto-HCT and 61% of patients had ≥1 excess collection sessions for APBHC that ultimately went unused. The median cost of excess collection sessions was $4,680 per patient (range, $4,680-$32,760) and the median total cost for excess collection sessions plus costs for storage was $23,840 per patient (range, $4,680-$85,450). The sum of costs of excess collection sessions was $2,077,920 and the sum of costs of cryopreservation was $5,812,665. Institutional policies regarding universal APBHC collection and long-term storage should be reevaluated in the era of novel therapeutics.

Management of CAR T-cell Related Toxicities: What did the Learning Curve Teach us so Far?

Chimeric antigen receptor T cell (CAR-T) therapy is an immunotherapy, which represents a therapeutic breakthrough in the treatment of B-cell malignancies and multiple myeloma. Since the first CAR T-cell approval in 2017, there have been five FDA approved CAR-T products, more approved disease indications for CAR-T therapy, and investigational trials launched for other cancers, including solid organ malignancies. CAR-T therapy possesses unique toxicities. Better understanding of these toxicities over time has helped in more efficient diagnosis, management, and treatment strategies. This review will focus on CAR-T-related toxicities including cytokine release syndrome, immune effector cell associated neurotoxicity syndrome (ICANS), cytokine release syndrome (CRS), and hemophagocytic lymphohistiocytosis (HLH)/ macrophage activation syndrome in terms of assessment, grading, and current management strategies. Additionally, this review will cover future directions and research on CAR-T-related toxicities.

Energy-Efficient Uplink Scheduling in Narrowband IoT.

This paper presents a detailed study of uplink scheduling in narrowband internet of things (NB-IoT) networks. As NB-IoT devices need a long battery lifetime, we aim to maximize energy efficiency while satisfying the main requirements for NB-IoT devices. Also, as the NB-IoT scheduling problem is divided into link adaptation problem and resource allocation problem, this paper investigates the correlation between these two problems. Accordingly, we propose two scheduling schemes: the joint scheduling scheme, where the two problems are combined as one optimization problem, and the successive scheduling scheme that manages each problem separately but successively. Each scheme aims to maximize energy efficiency while achieving reliable transmission, satisfying delay requirements, and guaranteeing resource allocation specifications. Also, we investigate the impact of the selected devices to be served on the total energy efficiency. Accordingly, we propose two device selection techniques to maximize the total energy efficiency. The first technique exhaustively searches for the optimal devices, while the second sorts the devices based on a proposed priority score. The simulation results compare the successive and the joint scheduling schemes. The results show that the joint scheme outperforms the successive scheme in terms of energy efficiency and the number of served devices but with higher complexity. Also, the results highlight the impact of each proposed selection technique on the scheduling schemes' performance.

Efficacy of a Second Allogeneic Hematopoietic Cell Transplant in Relapsed Acute Myeloid Leukemia: Results of a Systematic Review and Meta-Analysis.

Allogeneic hematopoietic cell transplantation (allo-HCT) remains the only known treatment modality that can offer the possibility of cure for acute myeloid leukemia (AML). Unfortunately, relapse and disease progression still occur in more than one third of cases even when patients are allografted in complete hematologic remission (CR). Treatment of AML relapsing after a first allo-HCT is particularly challenging. A second allo-HCT is offered to patients considered fit for the procedure, but reported outcomes have been conflicting. To perform a systematic review and meta-analysis to assess the totality of evidence on the role of a second allo-HCT in patients with AML, we performed a comprehensive literature search using PUBMED/MEDLINE and EMBASE on August 25, 2021, and extracted clinical outcome data relating to benefits (CR, overall survival [OS], and progression-free/disease-free survival [PFS/DFS]) and harms (acute and chronic graft-versus-host disease, non-relapse mortality [NRM], and relapse). The search identified 821 studies. Only 20 studies (n = 2772 patients) met our inclusion criteria. A second allo-HCT resulted in pooled CR, OS, PFS/DFS, NRM and relapse rates of 67%, 34%, 30%, 27%, and 51%, respectively. OS was 2-fold higher when the second allo-HCT was performed in CR (38% versus 17%) and 3-fold higher in patients who had a later relapse from the first allo-HCT (34% versus 10%). There was no apparent difference in pooled OS (hazard ratio = 1.01; 95% confidence interval, 0.78-1.31; P = .94) whether the same original donor or a different one was used. Notwithstanding several limitations apart from the high heterogeneity among included studies, this analysis shows that a second allo-HCT is a reasonable treatment option for relapsed AML. The procedure appears to be more effective when performed in CR and in patients who had a later relapse from the first allo-HCT. The high pooled relapse rates exceeding 50%, even when receiving the second allo-HCT in CR is worrisome and emphasizes the need to incorporate new therapies whether as post-transplantation maintenance or consolidation to mitigate relapse risk. This analysis was limited to patients receiving a second allo-HCT for the sole purpose of treating AML relapse. Accordingly, we caution against extrapolating these findings to other indications such as treatment of graft failure, poor graft function, or mixed donor chimerism.

Impact of Rituximab and Corticosteroids on Late Cytopenias Post-Chimeric Antigen Receptor T Cell Therapy.

Chimeric antigen receptor (CAR) T cell therapy represents a significant advancement in the treatment of patients with relapsed/refractory B cell lymphoid malignancies. Cytokine release syndrome and immune effector cell-associated neurotoxicity represent the most acute serious adverse events post CAR T cell therapy but the occurrence and persistence of cytopenias post CAR T cell therapy represent a significant adverse event and a management challenge. While most patients typically recover blood counts by 30 days, a significant subset of patients have persistent or late cytopenias beyond 30 days. Patients receiving CAR T cell are heavily pre-treated and the impact of prior therapies on late cytopenias is not well understood. In this study, we found an association between increased number of rituximab infusions and/or cumulative rituximab dose received prior to CAR T cell infusion and persistent anemia and thrombocytopenia at 90 and 180 days afterwards. An overall increased number of prior lines of therapy was also associated with persistent lymphopenia and anemia at 90 days while receiving a prior autologous hematopoietic cell transplant was associated with a greater risk of neutropenia and lymphopenia.

Bladder Myeloid Sarcoma with TP53 mutated Myelodysplastic Syndrome/Myeloproliferative Neoplasm Overlap syndrome: Response to Decitabine-Venetoclax regimen.

Myeloid sarcoma (MS) is a rare extramedullary blast proliferation of immature cells of myeloid origin. It is commonly associated with acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), or myeloproliferative neoplasm (MPN), and may precede, coincide with, or follow the diagnosis of a myeloid disorder. MS treatment is controversial, but AML induction like regimens is usually recommended. We present an unusual case of de novo TP53 mutated MDS/MPN overlap with bladder MS. Due to the high-risk nature of the disease, the patient was induced with decitabine and venetoclax combination therapy, resulting in complete remission. The response was further consolidated by an allogeneic hematopoietic stem cell transplantation.

Efficacy of Allogeneic Hematopoietic Cell Transplantation in Patients With Chronic Phase CML Resistant or Intolerant to Tyrosine Kinase Inhibitors.

Approximately 15-20% of chronic myeloid leukemia (CML) patients fail tyrosine kinase inhibitor (TKI) therapy secondary to resistance or intolerance. In the pre-TKI era, front-line allogeneic hematopoietic cell transplantation (allo- HCT) represented the standard approach for patients with chronic phase-CML (CP-CML) who were deemed fit to tolerate the procedure and had a human leukocyte antigen compatible donor available. Currently, CP-CML patients are eligible for allo-HCT only if they fail more than one TKI and/or are intolerant to the drug. We performed a systematic review/meta-analysis of the available literature to assess the evidence regarding allo-HCT efficacy in CP-CML patients. Data from eligible studies were extracted in relation to benefits (overall survival [OS], progression-free survival, disease-free survival [DFS], complete remission [CR], and molecular response [MR]) and harms (nonrelapse mortality [NRM], relapse, and acute and chronic graft-versus-host disease), and stratified by age into adult and pediatric groups. For adult allo-HCT recipients, the pooled OS, DFS, CR and, MR were 84% [95% confidence interval (CI) 59-99%], 66% (95% CI 59-73%), 56% (95% CI 30-80%), and 88% (95% CI 62-98%), respectively. Pooled NRM and relapse were 20% (95% CI 15-26%) and 19% (95% CI 10-28%), respectively. For the pediatric group, the OS rate was reported in one study and was 91% (95% CI 72-99%). Our results suggest that allo-HCT is an effective treatment for TKI-resistant or TKI-intolerant CP-CML. Post-transplant strategies are still needed to further mitigate the risk of relapse.

Driving Out Chronic Lymphocytic Leukemia With CAR T Cells.

Chronic lymphocytic leukemia (CLL) is the most prevalent leukemia in the Western hemisphere. The recent availability of novel targeted therapies, namely Bruton's tyrosine kinase, phosphoinositide-3 kinase, and BCL-2 inhibitors, have revolutionized the treatment algorithm for CLL but have not yet resulted in cure. Advances in the field of immuno-oncology and T cell engineering brought chimeric antigen receptor (CAR) T cell therapy from the laboratory to the clinic for treatment of B cell lymphoid malignancies and has improved the disease response and survival outcomes of various types of relapsed and/or refractory B cell lymphomas. While acknowledging that there are no approved CAR T cell therapies for CLL at this time, in this comprehensive review we explore novel targets for CAR T cell therapy in CLL and highlight the promising results of CAR T cell trials reported to date. Furthermore, we shed light on future areas of development, including multitarget CAR T cell products for this disease.

Omission of day +11 methotrexate dose and allogeneic hematopoietic cell transplantation outcomes: results of a systematic review/meta-analysis.

Allogeneic hematopoietic cell transplantation (allo-HCT) is potentially curative for patients with malignant and benign hematologic conditions. Graft-versus-host disease (GVHD) is a known complication of allo-HCT that results in significant morbidity and mortality. A common GVHD prophylaxis strategy combines a calcineurin inhibitor with methotrexate. When mucositis and organ toxicity develop, the day +11 dose is frequently omitted to limit further organ damage. The potential impact of this practice on allo-HCT outcomes is unclear as published data show conflicting results. Thus, we performed a systematic review/meta-analysis of the available literature to assess the impact of omitting day +11 methotrexate on allo-HCT recipients. Data were extracted in relation to benefits (overall survival [OS], progression-free survival [PFS]) and harms (acute and chronic GVHD, non-relapse mortality [NRM], and relapse). Pooled OS rate favored those who received day +11 methotrexate vs. those who did not (HR = 1.21; 95% CI = 1.02-1.43; p = 0.03). There was no significant difference in pooled rates of PFS (HR = 0.96; 95% CI = 0.60-1.52; p = 0.85), acute GVHD (HR = 1.03; 95% CI = 0.35-2.98; p = 0.96), chronic GVHD (HR = 0.83; 95% CI = 0.44-1.57; p = 0.57), NRM (HR = 0.86; 95% CI = 0.67-1.11; p = 0.25), and relapse (HR = 0.97; 95% CI = 0.75-1.26; p = 0.83) between the two groups. Large prospective multicenter studies are needed to better define the significance of day +11 methotrexate omission.

Medicine in Unplanned Mass Gatherings: A Qualitative Study of Health-Care Providers' Response and Recommendations to Beirut's Protests.

OBJECTIVE: This study aims at exploring the dynamics of health-care provision during recent unplanned public mass gatherings in Beirut, and how the health-care system adapts to mass movements in protests. METHODS: A qualitative study was conducted using semi-structured interviews with 12 health-care providers who volunteered at medical tents set during protests in Beirut, Lebanon. Responses were transcribed and coded. RESULTS: Three themes were noted: preparedness and logistics, encountered cases, and participants' proposed recommendations. In terms of preparedness and logistics, participants lacked knowledge of field medicine protocols and an organizational structure. They faced difficulties in securing equipment and advertising their services. Most encountered cases were physical injuries rather than mental health problems. The participants proposed both short-term recommendations, including advice on how to boost care provided, and long-term recommendations on structuring the health-care system to be better prepared. CONCLUSIONS: On-site health-care provision during unplanned mass gatherings is a vital need. We recommend forming a task force of health-care workers from various fields led by the Ministry of Public Health in every respective country to plan protocols, train personnel, and secure resources beforehand.

Lisocabtagene Maraleucel in Relapsed or Refractory Diffuse Large B Cell Lymphoma: What is the Evidence?

Lisocabtagene maraleucel (liso-cel) is an autologous CD19-directed chimeric antigen receptor (CAR) T cell product, with a CD3ζ activatory domain connected to 4-1BB costimulatory domain. Liso-cel, unlike the other two approved products-axicabtagene ciloleucel and tisagenlecleucel-is manufactured separately from CD4 and CD8 T cells and then administered as a sequential infusion of the two components at equal target doses. The approval of liso-cel was based on the results of Transcend NHL 001, a single-arm, open-label, multicenter, seamless design trial that enrolled 344 patients, of whom 269 received conforming liso-cel. The most common histology was diffuse large B cell lymphoma, not otherwise specified (DLBCL NOS; n = 137, 51%) followed by DLBCL transformed from indolent lymphomas (n = 78, 29%). Encouraging results were reported, yielding an objective response rate across all dose levels of 73% [complete remission (CR) = 53%], with an estimated duration of response at 1 year of 55% for all patients and 65% for those achieving a CR. The estimated 12-month overall survival was 58% for all patients and 86% for those achieving a CR. Cytokine release syndrome and neurological adverse events were reported in 42% and 30%, respectively. This review summarizes the evidence on the safety and effectiveness of liso-cel, resulting in its addition to the current treatment armamentarium of relapsed or refractory large B cell lymphoma.

Understanding the Etiology of Pancytopenias in the CAR T-Cell Therapy Setting: What We Know and What We Don't?

Chimeric antigen receptor T-cell (CAR T-cell) therapy represents an innovative and transformative therapy for patients with relapsed and/or refractory (R/R) hematological malignancies. CAR T-cell therapy was first approved in R/R diffuse large B-cell lymphoma (DLBCL) and acute lymphoblastic leukemia, today the use of CAR T-cell therapy has expanded to multiple myeloma and other lymphoma subtypes such as follicular and mantle cell lymphoma. It is also being explored in earlier lines of therapy in DLBCL. CAR T-cell therapy is associated with a unique toxicity profile and development of cytopenias post CAR T-cell therapy has been reported in all pivotal clinical trials and is now considered a related side effect. Here, we provide an in-depth evaluation of etiologies, consequences, and current management strategies for cytopenias following CAR T-cell therapy.

Endotoxin Triggers Tumor Initiation Events in Nontumorigenic Breast Epithelial Cells and Enhances Invasion-Related Phenotype in Pretumorigenic and Tumorigenic Breast Epithelial Cells.

Inflammation is associated with the development of several cancers, including breast cancer. However, the molecular mechanisms driving breast cancer initiation or enhancement by inflammation are yet to be deciphered. Hence, we opted to investigate the role of inflammation in initiating and enhancing tumor-like phenotypes in nontumorigenic, pretumorigenic, and tumorigenic breast epithelial cells. Noncytotoxic endotoxin (ET) concentrations capable of inducing an inflammatory phenotype were determined for the different cell lines. Results showed that short-term ET exposure upregulated matrix metalloproteinase-9 (MMP-9) activity in nontumorigenic mammary epithelial cells of mouse (SCp2) and human origins (HMT-3522 S1; S1) and upregulated inflammatory mediators including nitric oxide (NO) and interleukin 1-ß in tumorigenic human breast cells (MDA-MB-231), all in a dose-dependent manner. Long-term ET treatment, but not short-term, triggered the migration of SCp2 cells, and proliferation and migration of tumorigenic human breast cells MCF-7 and MDA-MB-231. Both short- and long-term ET exposures preferentially enhanced the invasion of pretumorigenic S1-connexin 43 knockout (Cx43-KO S1) cells compared to their nontumorigenic S1 counterparts. Moreover, both ET exposures disrupted lumen formation and apicolateral distribution of ß-catenin in 3D cultures of S1 cells. In conclusion, ET treatment at concentrations that elicited inflammatory phenotype triggered tumor initiation events in nontumorigenic and pretumorigenic breast cells, and increased tumorigenicity of breast cancer cells. Our findings highlight the role of inflammation in enhancing migration, invasion, and loss of normal 3D morphology and suggest that such inflammatory insults can "add injury" to pretumorigenic and tumorigenic breast epithelial cells.

Anti-CD19 chimeric antigen receptor T-cell therapy in B-cell lymphomas: current status and future directions.

AIMS: To review recent data and relevant of the role of anti-CD19 chimeric antigen receptor (CAR) T-cell therapy for B-cell non-Hodgkin lymphoma (NHL). METHODS: Review and compilation of the most recent and relevant data published in full text and abstract forms of anti-CD19 CAR T-cell therapy for B-cell NHL. RESULTS: Different anti-CD19 CAR T-cell therapy products have been tested and shown significant clinical activity across B-cell NHL patients. The objective responses in relapsed DLBCL, FL and MCL were 50-83%, 83-93% and 93%, respectively. CONCLUSIONS: Anti-CD19 CAR T-cell therapy is a viable option for poor risk refractory B-cell NHLs.

Cellular Therapies for Mantle Cell Lymphoma.

Mantle cell lymphoma (MCL) is a subtype of B cell non-Hodgkin lymphoma characterized by a heterogeneous clinical presentation. Patients who demonstrate an objective response to induction therapy(ies) and are eligible for intensive therapies are offered an autologous hematopoietic cell transplant (HCT) as front-line consolidation followed by rituximab maintenance. Allogeneic HCT is an option for younger and fit patients with high-risk disease or in patients who have relapsed after autologous HCT. Recent advances in T cell engineering brought chimeric antigen receptor T cell (CAR T) therapy from the bench to the bedside, with brexucabtagene autoleucel being the first CAR T product approved by the US Food and Drug Administration for use in relapsed/refractory MCL. In this comprehensive review, we summarize the literature on available cellular therapies for MCL and present a treatment algorithm that incorporates HCT, autologous or allogeneic, and CAR T therapies.

Systematic Review/Meta-Analysis on Efficacy of Allogeneic Hematopoietic Cell Transplantation in Sickle Cell Disease: An International Effort on Behalf of the Pediatric Diseases Working Party of European Society for Blood and Marrow Transplantation and the Sickle Cell Transplantation International Consortium.

Sickle cell disease (SCD) affects more than 300,000 children annually worldwide. Despite improved supportive care, long-term prognosis remains poor. Allogeneic hematopoietic cell transplantation (allo-HCT) is the sole validated curative option, resulting in sustained resolution of the clinical phenotype. The medical literature on allo-HCT for SCD is largely limited to children. Recent studies have evaluated allo-HCT efficacy in adults. Here, we conducted a systematic review/meta-analysis to assess the totality of evidence on the efficacy, or lack thereof, of allo-HCT in treating SCD. We performed a comprehensive literature search using PubMed/Medline, Embase, and Cochrane library databases on November 13, 2019. Four authors independently extracted data on clinical outcomes related to benefits (overall survival [OS] and disease-free survival [DFS]) and harms (acute graft-versus-host disease [aGVHD], chronic graft-versus-host disease [cGVHD], nonrelapse mortality [NRM], and graft failure [GF]). Our search identified a total of 1906 references. Only 33 studies (n= 2853 patients) met our inclusion criteria. We also performed a subset analysis by age. Analyses of all-age groups showed pooled rates of 96% for OS, 90% for DFS, 20% for aGVHD, 10% for cGVHD, 4% for NRM, and 5% for GF. In the pediatric population, pooled rates for OS, DFS, aGVHD, cGVHD, NRM, and GF were 97%, 91%, 26%, 11%, 5%, and 3%, respectively. In adults, pooled rates for OS, DFS, aGVHD, cGVHD, NRM, and GF were 98%, 90%, 7%, 1%, 0%, and 14%, respectively. Our data show that allo-HCT is safe and effective, yielding pooled OS rates exceeding 90%. The high GF rate of 14% in adults is concerning and emphasizes the need to evaluate new strategies.

Allogeneic hematopoietic cell transplantation is an effective treatment for patients with Richter syndrome: A systematic review and meta-analysis.

Efficacy of conventional chemoimmunotherapy is limited in patients with Richter syndrome (RS) with anticipated median overall survival (OS) of less than 10 months. Allogeneic hematopoietic cell transplantation (allo-HCT) is commonly offered as a consolidative treatment option in RS. To our knowledge, there are no randomized controlled studies that have compared allo-HCT against other therapies in RS; available allo-HCT data are limited to small case series from single-institution or registry studies. We performed a systematic review and meta-analysis to assess the totality of evidence regarding the efficacy (or lack thereof) of allo-HCT for RS. We extracted data on post-allograft outcomes related to benefits (overall response rate [ORR], complete remission [CR], OS, and progression-free survival [PFS]). For harms, data were extracted on non-relapse mortality (NRM) and relapse post-allografting. Our search strategy identified 240 studies, but only four studies (n = 72 patients) met our inclusion criteria. Pooled ORR, CR, OS, and PFS rates were 79%, 33%, 49%, and 30%, respectively. Pooled NRM and relapse rates were 24% and 28%, respectively. Results of this systematic review and meta-analysis indicate that allo-HCT yields encouraging OS in RS, thus remaining a reasonable treatment option in fit patients whose disease demonstrates a chemosensitive response to pre-transplant salvage therapies. Novel strategies are certainly needed to reduce the risk of relapse to further improve outcomes in these patients.

Real world experience of approved chimeric antigen receptor T-cell therapies outside of clinical trials.

Advances in the field of immuno-oncology brought chimeric antigen receptor T (CAR T) cell therapy from the bench to the bedside for treatment of relapsed and/or refractory B-cell lymphoid malignancies. Two CAR T products, namely axicabtagene ciloleucel and tisagenlecleucel, are commercially available and represent genetically engineered T cells expressing chimeric receptors for CD19. These CAR T-cell products have undoubtedly revolutionized the treatment of these diseases yielding impressive complete remission rates and improving survival. This review aims at assessing the published evidence pertaining to the efficacy of these two products in the real world practice as enrollment in clinical trials often follows stringent eligibility criteria and involves possible selection bias. Results of various observational analyses from patients treated in the real world setting show comparable results to those reported in clinical trials in terms of efficacy and toxicities. This is certainly noteworthy considering that many of these patients would have been considered ineligible to participate in clinical trials owing to their less than optimal performance scores, among other reasons. We believe that the prohibitive cost of these treatments poses a serious challenge to wider applicability in the less privileged populations throughout the world, especially in developing countries.