Does FLT3 mutation impact survival after hematopoietic stem cell transplantation for acute myeloid leukemia? A Center for International Blood and Marrow Transplant Research (CIBMTR) analysis: Impact of FLT3 on OS Post-HCT for AML

BACKGROUND: Patients with FMS like tyrosine kinase 3 (FLT3)-mutated acute myeloid leukemia (AML) have a poor prognosis and are referred for early allogeneic hematopoietic stem cell transplantation (HCT). METHODS: Data from the Center for International Blood and Marrow Transplant Research (CIBMTR) were used to evaluate 511 adult patients with de novo AML who underwent HCT during 2008 through 2011 to determine whether FLT3 mutations had an impact on HCT outcomes. RESULTS: In total, 158 patients (31%) had FLT3 mutations. Univariate and multivariate analyses revealed an increased risk of relapse at 3 years in the FLT3 mutated group compared with the wild-type (WT) group (38% [95% confidence interval (CI), 30%-45%] vs 28% [95% CI, 24%-33%]; P = .04; relative risk, 1.60 [95% CI, 1.15-2.22]; P = .0048). However, FLT3 mutation status was not significantly associated with nonrelapse mortality, leukemia-free survival, or overall survival. Although more patients in the FLT3 mutated group died from relapsed primary disease compared with those in the WT group (60% vs 46%), the 3-year overall survival rate was comparable for the 2 groups (mutated group: 49%; 95% CI, 40%-57%; WT group: 55%, 95% CI, 50%-60%; P = .20). CONCLUSIONS: The current data indicate that FLT3 mutation status did not adversely impact overall survival after HCT, and about 50% of patients with this mutation who underwent HCT were long-term survivors. Cancer 2016;122:3005-3014. © 2016 American Cancer Society

Overview of approved CAR‐T therapies, ongoing clinical trials, and its impact on clinical practice

Abstract In recent years, we have seen rapid expansion of chimeric antigen receptor T‐cell (CAR‐T) therapies in multiple malignancies. CAR‐T therapy has profoundly altered the treatment landscape of non‐Hodgkin lymphoma, B‐cell acute lymphoblastic leukemia, and multiple myeloma. Currently available CD19 and B‐cell maturation antigen‐directed CAR‐T therapies have shown high overall response rate and durable remissions in patients who have failed standard therapies. Multiple studies are underway exploring the role of CAR‐T‐cell therapy as earlier line of treatment. In high‐grade B‐cell lymphoma, CD19 CAR‐T therapy may replace autologous hematopoietic cell transplantation as second line therapy in near future. CAR‐T‐cell therapy targeting novel tumor‐associated antigens will help expand utility of this treatment modality in other hematological malignancies. It may also help overcome limitations of currently approved CAR‐T‐cell therapies. In this review, we have provided an overview of currently approved CAR‐T therapies and upcoming clinical trials which may potentially impact the clinical practice

Time to Explore Preventive and Novel Therapies for Bronchiolitis Obliterans Syndrome after Allogeneic Hematopoietic Stem Cell Transplantation

Although allogeneic hematopoietic stem cell transplant (allo-HSCT) is performed to treat otherwise incurable and fatal diseases, transplantation itself can lead to life-threatening complications due to organ damage. Pulmonary complications remain a significant barrier to the success of allo-HSCT. Lung injury, a frequent complication after allo-HSCT, and noninfectious pulmonary deaths account for a significant proportion of non-relapse mortality. Bronchiolitis obliterans syndrome (BOS) is a common and potentially devastating complication. BOS is now considered a diagnostic criterion of chronic graft-versus-host-disease (cGVHD), and National Institutes of Health (NIH) consensus has been published to establish guidelines for diagnosis and monitoring of BOS. It usually occurs within the first 2 years but may develop as late as 5 years after transplantation. Recent prevalence estimates suggest that BOS is likely underdiagnosed, and when severe BOS does occur, current treatments have been largely ineffective. Prevention and effective novel approaches remain the primary tools in the clinician's arsenal in managing BOS. This article provides an overview of the currently available and novel strategies for BOS, and we also discuss specific preventive interventions to reduce severe BOS after allo-HSCT. Therapeutic trials continue to be needed for this orphan disease

2009

Acute myeloid leukemia is the most common indication for an allogeneic hematopoietic cell transplant. The introduction of reduced intensity conditioning has expanded the recipient pool for transplantation, which has importantly made transplant an option for the more commonly affected older age groups. Reduced intensity conditioning allogeneic transplantation is currently the standard of care for patients with intermediate or high-risk acute myeloid leukemia and is now most often employed in older patients and those with medical comorbidities. Despite being curative for a significant proportion of patients, post-transplant relapse remains a challenge in the reduced intensity conditioning setting. Herein we discuss the studies that demonstrate the feasibility of reduced intensity conditioning allogeneic transplants, compare the outcomes of reduced intensity conditioning versus chemotherapy and conventional myeloablative conditioning regimens, describe the optimal donor and stem cell source, and consider the impact of post-remission consolidation, comorbidities, center experience, and more intensive (reduced toxicity conditioning) regimens on outcomes. Additionally, we discuss the need for further prospective studies to optimize transplant outcomes. ABSTRACT as the backbone of most RIC regimens which also include either a reduced dose of an alkylating agent or a reduced dose of TBI. Fludarabine is generally well tolerated and synergizes well with alkylating agents to enhance inhibition of DNA repair mechanisms. 10 Multiple RIC regimens have been developed and described 23 McSweeney et al. described 45 patients with a median age of 56 years who had human leukocyte antigen (HLA)-identical sibling donors and relative contraindications to conventional conditioning for HCT. In these patients a conditioning regimen of TBI alone (200 cGy) produced a survival rate of >66% after a median follow-up of 417 days with a NRM rate of only 6.7%. The associated toxicities were mild, and over 50% of patients were able to have their transplant done completely in the outpatient setting. 23 This set the stage for future studies focusing on the potent immunological graft-versus-leukemia effect to induce cures as opposed to just on intensive pre-transplantation marrow ablative strategies. As the number of efficacious regimens grew, so did the number of patients for whom transplantation became a therapeutic option. Much enthusiasm has led to the widespread adoption of RIC HCT as a potentially curative option for older patients or those with comorbid disease, despite lack of supportive, prospective, randomized data. Nevertheless, studies have shown that age itself does not significantly affect outcomes, 24,25 and RIC regimens are tolerated well allowing transplants to be offered to patients up to the age of 70. McClune et al. reported a large retrospective study of the Center for International Blood and Marrow Transplant (CIBMTR) registry investigating outcomes of 1080 patients over the age of 40 and showed that neither age nor type of conditioning regimen had any impact on survival 25 Is reduced intensity conditioning better than standard chemotherapy? There are few studies that directly address the question of whether RIC HCT is better than standard chemotherapy. Mohty et al. reported a donor versus no donor comparison study that described the utility of RIC HCT in patients over the age of 50 years with high-risk AML in CR. This study included 95 patients of whom 35 (37%) with a sibling donor would go on to have a RIC HCT, while the remainder without a donor went on to receive standard chemotherapy. In their intention-to-treat analysis, the patients with donors who underwent RIC HCT with a regimen of fludarabine, busulfan, and anti-thymocyte globulin had a significantly higher 4-year leukemiafree survival (LFS) rate of 54% than the 30% in the no donor group (P=0.01). Overall survival (OS) was also improved (P=0.01), and in their multivariate analysis, the actual performance of a RIC HCT was the strongest predictor of improved LFS [relative risk (RR)=4.0; 95% confidence interval (CI): 1.7-9.6]. 26 Kurosawa et al. similarly compared a small series of patients who underwent RIC HCT between the ages of 50-70 and patients who underwent standard chemotherapy; the outcomes of the former were superior, with a reduced cumulative incidence of relapse (22% versus 62%), and improved LFS and OS. 27 Similarly, Russell et al. evaluated patients who were enrolled in the United Kingdom Medical Research Council AML15 (UK MRC AML15) trial and in their comparative analysis of patients who underwent RIC HCT versus standard chemotherapy alone, RIC transplantation significantly reduced the risk of relapse. However, there was no difference in OS at 5 years, and no evidence of benefit when stratified by risk groups. There was also significant hetero-S. Sengsayadeth et al. 860 haematologica | 2015; 100(7

CAR T cell therapy in solid tumors: A review of current clinical trials

Abstract Chimeric antigen receptor (CAR) T cell therapy has made tremendous strides in the arena of hematological malignancies with approved therapies in certain leukemias, lymphomas, and recently myeloma with overall highly favorable response rates. While numerous clinical studies are still ongoing for hematological malignancies, research is developing to translate the feasibility of CAR T therapy in solid organ malignancies. Unfortunately, the majority of diagnosed cancers are primarily solid tumors. Thus, a highly unmet clinical need for further research and development exists in this field. This review article highlights currently active clinical trials and a few pertinent preclinical studies involving CAR T cell therapy in solid tumors while briefly discussing study outcomes and potential key targets that may allow for the feasibility of this therapy option. Finally, we mention critical challenges existing in the solid tumor environment and discuss developing strategies that may potentially overcome the existing barriers to CAR T cell progress in solid tumors

Role of bridging therapy during chimeric antigen receptor T cell therapy

Abstract Chimeric antigen receptor (CAR) T‐cell therapy has been approved for use in several relapsed/refractory hematologic malignancies and has significantly improved outcomes for these diseases. A number of different CAR T products are now being used in clinical practice and have demonstrated excellent outcomes to those in clinical trials. However, increased real‐world use of CAR T therapy has uncovered a number of barriers that can lead to significant delays in treatment. As a result, bridging therapy has become a widely used tool to stabilize or debulk disease between leukapheresis and CAR T cell administration. Here we review the available data regarding bridging therapy, with a focus on patient selection, choice of therapy, timing of therapy, and potential pitfalls