Efficacy and safety of chimeric antigen receptor T-cell (CAR-T) therapy in hematologic malignancies: a living systematic review on comparative studies.

Background: Chimeric antigen receptor T-cell (CAR-T) cell therapies have been claimed to be curative in responsive patients. Nonetheless, response rates can vary according to different characteristics, and these therapies are associated with important adverse events such as cytokine release syndrome, neurologic adverse events, and B-cell aplasia. Objectives: This living systematic review aims to provide a timely, rigorous, and continuously updated synthesis of the evidence available on the role of CAR-T therapy for the treatment of patients with hematologic malignancies. Design: A systematic review with meta-analysis of randomized controlled trials (RCTs) and comparative non-randomized studies of interventions (NRSI), evaluating the effect of CAR-T therapy versus other active treatments, hematopoietic stem cell transplantation, standard of care (SoC) or any other intervention, was performed in patients with hematologic malignancies. The primary outcome is overall survival (OS). Certainty of the evidence was determined using the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach. Data sources and Methods: Searches were performed in the Epistemonikos database, which collates information from multiple sources to identify systematic reviews and their included primary studies, including Cochrane Database of Systematic Reviews, MEDLINE, EMBASE, CINAHL, PsycINFO, LILACS, DARE, HTA Database, Campbell database, JBI Database of Systematic Reviews and Implementation Reports, EPPI-Centre Evidence Library. A manual search was also carried out. We included the evidence published up to 1 July 2022. Results: We included the evidence published up to 1 July 2022. We considered 139 RCTs and 1725 NRSI as potentially eligible. Two RCTs (N = 681) comparing CAR-T therapy with SoC in patients with recurrent/relapsed (R/R) B-cell lymphoma were included. RCTs did not show statistical differences in OS, serious adverse events, or total adverse events with grade ⩾ 3. Higher complete response with substantial heterogeneity [risk ratio = 1.59; 95% confidence interval (CI) = (1.30-1.93); I 2 = 89%; 2 studies; 681 participants; very low certainty evidence] and higher progression-free survival [hazard ratio for progression or death = 0.49; 95% CI = (0.37-0.65); 1 study; 359 participants; moderate certainty evidence] were reported with CAR-T therapies. Nine NRSI (N = 540) in patients with T or B-cell acute lymphoblastic leukemia or R/R B-cell lymphoma were also included, providing secondary data. In general, the GRADE certainty of the evidence for main outcomes was mostly low or very low. Conclusion: So far, assuming important limitations in the level of certainty due to scarce and heterogenous comparative studies, CAR-T therapies have shown some benefit in terms of progression-free survival, but no overall survival, in patients with R/R B-cell lymphoma. Despite one-arm trials have already facilitated approval of CAR-T cell treatments, additional evidence from large comparative studies is still needed to better characterize the benefit-harm ratio of the use of CAR-T in a variety of patient populations with hematological malignancies. Registration: https://doi.org/10.12688/openreseurope.14390.1. PROSPERO/OSF Preregistration: 10.17605/OSF.IO/V6HDX.

Prevalence of Pure Red Cell Aplasia Following Major ABO-Incompatible Hematopoietic Stem Cell Transplantation.

Background: Pure red cell aplasia (PRCA) is one of the important complications in major ABO-incompatible allogeneic hematopoietic stem cell transplantation (HSCT). The established pathogenic factor of PRCA is the persistence of high anti-donor isohemagglutinins. As previously verified, the conditioning regimen and donor type were the factors associated with the development of PRCA in the small-sized studies. Currently, the prevalence, risk factors, and prognosis of PRCA are still worth studying to provide evidence. Methods: We conducted a prospective nested case-control study to determine the prevalence, donor-related factors, and the outcomes of PRCA following major ABO-incompatible transplantation. A total of 469 patients who underwent ABO-incompatible grafts were observed. Results: None of the patients were diagnosed with PRCA with minor or bidirectional ABO-incompatible HSCT. Thirteen of the187 patients (7%; 95% confidence interval [CI], 3.9%-11.9%) developed PRCA following major ABO-incompatible HSCT. Eleven of the 13 patients with PRCA recovered entirely. Donor type was an independent factor associated with post-HSCT PRCA (odds ratio [OR]=0.030; 95% CI, 0.003-0.321; P=0.004). The cumulative incidence rates of post-HSCT PRCA in the context of major ABO-incompatible HSCT were 0.8%, 13.1%, and 27.2% for the haploidentical donor (HID), unrelated donor, and matched related donor, respectively. No significant influence of PRCA on transplantation outcomes was observed.In conclusion, post-HSCT PRCA is a rare and less threatening complication in major ABO-incompatible HSCT. The majority of patients with PRCA could recover. Additionally, HIDs for recipients may have a low risk of post-HSCT PRCA. This trial was registered at www.chictr.org.cn (#ChiCTR2000041412).

Immune Reconstitution in the Aging Host: Opportunities for Mechanism-Based Therapy in Allogeneic Hematopoietic Cell Transplantation.

Older patients with hematologic malignancies are increasingly considered for allogeneic hematopoietic cell transplantation with encouraging outcomes. While aging-related thymic dysfunction remains a major obstacle to optimal and timely immune reconstitution post- transplantation, recent accumulating evidence has suggested that various aging hallmarks such as cellular senescence, inflamm-aging, and hematopoietic stem cell exhaustion, could also impact immune reconstitution post-transplantation in both thymic-dependent and independent manner. Here we review molecular and cellular aspects of immune senescence and immune rejuvenation related to allogeneic hematopoietic cell transplantation among older patients and discuss potential strategies for mechanism-based therapeutic intervention.

Recent Advances of Acute Kidney Injury in Hematopoietic Cell Transplantation.

Acute kidney injury (AKI) is a common complication of allogeneic hematopoietic cell transplantation (allo-HCT) and is associated with non-relapse mortality (NRM) and quality of life (QOL). Multiple factors may contribute to AKI during allo-HCT and are often present at the same time making it difficult to determine the cause of AKI in each patient. Nephrotoxic drugs, infections, thrombotic microangiopathy (TMA), and sinusoidal obstruction syndrome (SOS) are well described causes of AKI during allo-HCT. Acute graft-versus-host disease (aGVHD) is a major complication of allo-HCT that mainly targets the intestines, liver, and skin. However, recent studies suggest aGVHD may also attack the kidney and contribute to AKI following allo-HCT. For example, severe aGVHD is associated with AKI, suggesting a link between the two. In addition, animal models have shown donor immune cell infiltration and increased expression of inflammatory cytokines in recipient kidneys after allo-HCT. Therefore, aGVHD may also target the kidney and contribute to AKI following allo-HCT. Herein, we describe the etiology, diagnosis, risk factors, pathophysiology, prevention, and treatment of renal injury after allo-HCT. In addition, we highlight emerging evidence that aGVHD may contribute to the development of AKI after allo-HCT.

Allogeneic Stem Cell Transplantation for Acute Lymphoblastic Leukemia in Adolescents and Young Adults.

Hematologic stem cell transplantation (HSCT) is the most potent consolidation therapy for high-risk acute lymphoblastic leukemia (ALL), but their outcomes and complications in adolescent and young adult (AYA) patients remain unclear. We compared outcomes after HSCT for ALL among children (age 1 to 9 years; n = 607), adolescents (age 10 to 19 years; n = 783), and young adults (age 20 to 29 years old, n = 603), based on Japanese nationwide registry data. The 5-year overall survival (OS) rate among AYA patients was worse than that of children, at 64% (95% confidence interval [CI], 60% to 68%). In the AYA, the 5-year treatment-related mortality (TRM) after HSCT was 19% (95% CI, 16% to 22%), significantly higher than that in younger patients. The most common cause of TRM in the AYA was infection. The relapse rate was not different across the 3 age groups. When focusing on older adolescents (age 15 to 19 years), there was no difference in outcomes between those treated in pediatric centers and those treated in adult centers. In conclusion, the AYA had a greater risk of nonrelapse death than younger patients, and infection was the most common cause. Further optimization is required for HSCT in AYAs with ALL.

Outcome and Minimal Residual Disease Monitoring in Patients with t(16;21) Acute Myelogenous Leukemia Undergoing Allogeneic Hematopoietic Stem Cell Transplantation.

Patients with t(16;21) acute myelogenous leukemia (AML) who receive chemotherapy have poor outcomes. The treatment efficacy of allogeneic hematopoietic stem cell transplantation (allo-HSCT) must be identified, and the usefulness of minimal residual disease (MRD) monitoring requires evaluation. Fourteen consecutive patients with t(16;21) AML undergoing allo-HSCT at our institution were included in this study. Translocation liposarcoma- ETS-related gene (TLS-ERG) transcript levels were serially monitored for a median of 15 months (range, 3-51 months) after allo-HSCT. Eight patients relapsed, 7 patients died from relapse-related causes, and 1 patient died from a non-relapse-related cause. The 2-year cumulative incidence rates of relapse, disease-free survival, and overall survival after HSCT were 66.2%, 30.8%, and 46.2%, respectively. Of the 3 patients who received an HLA-matched sibling transplant, 2 relapsed, and 1 (33.3%) was in hematologic complete remission (CR) but died of nonrelapse mortality, whereas 5 of 11 patients (45.5%) who received haploidentical transplantation were in CR and were alive. Two of 6 patients with undetectable TLS-ERG at the time of allo-HSCT relapsed, at 14 and 15 months, and 3 of 4 PCR-positive patients relapsed, at a median of 10 months after HSCT. Four patients with continually low post-HSCT TLS-ERG levels (mostly <.01%) remained alive and in CR. The TLS-ERG levels of all 8 patients who relapsed were significantly increased before the relapse, exceeding 1.0% in all 7 patients who experienced hematologic relapse. In total, 7 patients received modified donor lymphocyte infusion (DLI), and 1 patient received IFN-α. All 7 patients with a TLS-ERG level >5.0% at the time of intervention experienced an increase or a brief decrease in TLS-ERG level, followed by an increase, and 6 relapsed, whereas the TLS-ERG level of 1 patient with a TLS-ERG level <1.0% at intervention decreased to undetectable. Therefore, t(16;21) AML is an indication for allo-HSCT. Among the HSCT recipients, 30.8% responded to treatment with CR. TLS-ERG transcript levels reflect MRD and might predict relapse and guide effective intervention.

Hematopoietic stem cell transplantation and cellular therapy.

Allogeneic stem cell transplantation is a form of immunotherapy that has increased the chances of survival for patients with relapsed leukemia and high risk leukemia in remission. The major obstacles are graft-vs-host disease (GVHD) involving vital organs and infections. A most efficacious prophylaxis of GVHD is by depleting of T cells from the graft. However, problems of T-depleted transplants are rejection, slow recovery of the immune system and high incidence of relapse of leukemia and myeloma. The major problem of allogeneic transplantation is the separation of a graft-vs-leukemia (GVL) effect from GVHD. This review will summarize the factors influencing GVHD, ways to exploit rapid advances in our knowledge of histocompatibility, chimerism and tolerance for fostering GVL over GVHD, and in particular the use of cellular therapies including donor lymphocyte infusions for disease control.

Emergence of linezolid- and vancomycin-resistant Enterococcus faecium in a department for hematologic stem cell transplantation.

BACKGROUND: Prevalence of vancomycin-resistant enterococci has increased in Germany. Here, we report the cluster of linezolid- and vancomycin-resistant Enterococcus faecium (LVRE) in a German department for hematologic stem cell transplantation (HSCT). METHODS: In this retrospective analysis we included all patients with LVRE in a university-based department for HSCT in 2014 and 2015. Patients chart reviews were used to investigate the epidemiology and clinical outcome. Available LVRE isolates underwent detailed microbiological characterization and genotyping by pulsed-field gel electrophoresis (PFGE). RESULTS: In total, 20 patients with LVRE were identified within the observed time period. All except two patients underwent allogeneic HSCT. Surveillance culture results from incoming patients and chart review revealed that 10 of 20 patients were colonized at hospital admission. Eight of 10 patients with in-hospital acquired LVRE had previous linezolid treatment. Analysis of spatio-temporal patterns showed no evidence for LVRE patient-to-patient or environment-to-patient transmission within the HSCT department. In five cases (25 %) LVRE bloodstream infection occurred. Nine LVRE isolates could be saved for characterization. Eight isolates carried vanA, one isolate vanB. PFGE analysis showed that four different LVRE clones were responsible for the cluster. One single genotype was present in six LVRE isolates whereupon the corresponding patients were all referred from the same hospital to the HSCT department. CONCLUSIONS: This is the first report demonstrating the emergence of LVRE in a German HSCT department. (L)VRE screening at patients' admission and appropriate infection control strategies were sufficient to prevent any transmission. Further studies in this predisposed patient collective are warranted.

Linezolid Induced Twice Pure Red Cell Aplasia in a Patient with Central Nervous System Infection after Allogeneic Stem Cell Transplantation.

Linezolid (LZD), severed as the first oxazolidinone antibiotic, was active against multidrug-resistant gram-positive strains. LZD can induce thrombocytopenia, anemia and leukocytopenia. Currently, reports on pure red cell aplasia (PRCA) cases induced by LZD are relatively rare (4-7). In this paper, we reported a patient with PRCA twice induced by LZD. A 37-year-old man was diagnosed with myelodysplatic syndrome (MDS) and underwent allo-HSCT from an unrelated donor with ABO blood type and leukocyte antigen (HLA)-matching. After HSCT for 2 years, the patient suffered from refractory fever and headache. He was first treated with empirical antifungal agent and antibiotics for central nervous system (CNS) infection, but then changed to LZD therapy for little effect. Twenty-eight days after LZD treatment, the symptom improved significantly but the hemoglobin declined to 70 g/L and the reticulocyte level was only 0.23%. The LZD therapy was stopped and the fever and headache symptoms reoccurred 1 week latter. Then, erythropoietin (EPO) and halved dosage of LZD were used for treatment. The CNS infection and the anemia symptom relieved gradually and the level of hemoglobin and reticulocyte declined again. After blood transfusion, the half dose of LZD was sustained without anaemia recovery. In summary, patients with anemia, myelosuppressants history or potential abnormal proliferation of T cells may suffer PRCA with long term LZD treatment. The monitoring of complete blood count and reticulocyte count were necessary during LZD therapy. If the clinical condition permits, LZD dosage reduction and blood transfusion should be considered.

Allogeneic Stem Cell Transplantation for Patients with T315I BCR-ABL Mutated Chronic Myeloid Leukemia.

Allogeneic stem cell transplantation (SCT) is currently the only curative treatment option for chronic myeloid leukemia (CML) patients with BCR-ABL T315I mutations. We report the outcome of SCT in 22 patients with T315I(+) CML, most (n = 16) from haploidentical family donors (HID-SCT). At the time the mutation was detected, 8 patients were in the chronic phase (CP), 7 in the accelerated phase (AP), and 7 in the blast phase (BP). At the time of SCT 7 were in the CP, 8 in the AP or returning to the CP post-AP (AP/AP-CPn), and 7 in the BP or returning to CP post-BP (BP/BP-CPn). The cumulative incidence of grades III to IV acute graft-versus-host disease was 9.1%. Chronic graft-versus-host disease was observed in 60.0% of patients, including 25.0% who suffered from severe disease. Four patients died of transplant-related complications at a median interval from SCT of 16.3 months. The estimated 2-year leukemia-free survival rate was 80.0%, 72.9%, and 0% in CP, AP/AP-CPn and BP/BP-CPn groups at the time of SCT, respectively. After a median follow-up of 17.3 months from SCT, 14 patients are alive, including 13 in complete molecular response and 1 with an extramedullary relapse. In conclusion, HID-SCT is a potentially curative treatment for T315I + CML patients. For patients in CP/AP, immediate SCT might result in promising survival. The outcome of patients in BP with T315I(+) mutation remains very poor.