scholarly journals Outcomes with Chimeric Antigen Receptor T-Cell Therapy in Relapsed or Refractory Acute Myeloid Leukemia: A Systematic Review and Meta-Analysis

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 4825-4825
Author(s):  
Moazzam Shahzad ◽  
Sibgha Gull Chaudhary ◽  
Ali Hussain ◽  
Fatima Ali ◽  
Ayesha Khalid ◽  
...  

Abstract Background: Acute myeloid leukemia (AML) is a clonal hematologic malignancy that generally affects older adults. Despite achieving complete remission (CR) in over two-third of patients with initial induction therapy and subsequent allogeneic hematopoietic stem cell transplantation in intermediate-high risk patients, more than half of AML patients experience disease relapse. The prognosis of patients with relapsed/refractory AML (RR-AML) is often poor and treatment modalities are limited. Chimeric antigen receptor T cell (CAR-T) therapy has shown promising results in lymphoid malignancies and myeloma, and these are now being explored for the management of RR-AML. In this systematic review and meta-analysis, we aimed to investigate the outcomes of CAR-T therapy in RR-AML patients. Methods: Following the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines, a comprehensive literature search was conducted on three databases (PubMed, Cochrane Register of Controlled Trials, and Clinical trials.gov) using MeSH terms and keywords for "Leukemia, Myeloid, Acute" AND "Receptors, Chimeric Antigen" OR "adoptive immunotherapy" from the date of inception to April 2021. A total of 673 articles were screened and original studies reporting patients with RR-AML having CAR-T therapy as the only intervention were included while reviews, duplicate, and non-relevant articles were excluded. A total of 10 studies (8 clinical trials and 2 case reports) were included. The data for following outcomes were extracted: complete response (CR), partial response (PR), overall response rate (ORR), overall survival (OS), progression-free survival (PFS), stable disease (SD), progressive disease (PD), cytokine release syndrome (CRS) and neurotoxicity (NT). Quality evaluation was done using the NIH quality assessment tool. Inter-study variance was calculated using the Der Simonian-Laird Estimator. Proportions along with 95% confidence Interval (CI) were extracted to compute pooled analysis using the 'meta' package by Schwarzer et al. in the R programming language (version 4.16-2). Results: We identified 39 patients in 10 studies who received CAR-T therapy for RR-AML. Median age of patients was 35 (7.3-80) years and 59% (n=23) were male. The median follow-up time was 5 (0.7-23) months. (Table 1) Four patients had history of allogeneic hematopoietic stem cell transplant (HCT) prior to CAR-T therapy while subsequent HCT was performed in 5 patients. The pooled analysis showed a CR and ORR of 38.5% (95% CI 0.03-0.81, I 2 =66%, n=29) and 56% (CI 0.18-0.91, I 2=58%, n=29), respectively. Median duration of response was 5.5 (1-23) months. OS was reported from 1.9 months to 23 months. The pooled incidence of CRS and NT were 42.7% (95%CI 0.06-0.87, I 2=66%, n=28) and 1.3% (95% CI 0.00-0.16, I 2= 0%, n=21) respectively. Graft-versus-host disease (GVHD) was reported in 2 patients who had prior and subsequent HCT after CAR-T therapy; first patient developed grade IV GVHD in the setting of salvage therapy with donor lymphocyte infusions for relapsed disease 6 months' post CAR-T and 4 months post second allo-HCT while second patient received CAR-T as part of conditioning therapy and developed grade IV GVHD on day 32. Conclusion: CAR-T therapy has shown favorable results comparable to current salvage therapies for relapsed or refractory AML with an acceptable toxicity profile. However, there are several challenges including the heterogeneous biology of AML, lack of a targetable antigen expression on malignant cells, and immune escape and exhaustion. Future prospective studies with improved CAR-T constructs will hopefully improve the outcomes in this therapeutically challenging patient population. Figure 1 Figure 1. Disclosures Lin: AbbVie, Aptevo Therapeutics, Astellas Pharma, Bio-Path Holdings, Celgene, Celyad, Genentech-Roche, Gilead Sciences, Incyte, Jazz Pharmaceuticals, Novartis, Ono Pharmaceutical, Pfizer, Prescient Therapeutics, Seattle Genetics, Tolero, Trovagene: Research Funding. Abhyankar: Incyte/Therakos: Consultancy, Research Funding, Speakers Bureau. McGuirk: EcoR1 Capital: Consultancy; Juno Therapeutics: Consultancy, Honoraria, Research Funding; Pluristem Therapeutics: Research Funding; Bellicum Pharmaceuticals: Research Funding; Gamida Cell: Research Funding; Novartis: Research Funding; Astelllas Pharma: Research Funding; Kite/ Gilead: Consultancy, Honoraria, Other: travel accommodations, expense, Kite a Gilead company, Research Funding, Speakers Bureau; Fresenius Biotech: Research Funding; Novartis: Research Funding; Magenta Therapeutics: Consultancy, Honoraria, Research Funding; Allovir: Consultancy, Honoraria, Research Funding.

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 4410-4410
Author(s):  
Pranali Santhoshini Pachika ◽  
Moazzam Shahzad ◽  
Razwana Khanam ◽  
Adeel Masood ◽  
Zahoor Ahmed ◽  
...  

Abstract Background: Allogenic hematopoietic stem cell transplant (HSCT) is the potentially curative treatment in intermediate-high risk acute myeloid leukemia (AML). Relapse is the major cause of treatment failure and about 50% of AML patients relapse after the HSCT. Venetoclax is a B-cell lymphoma-2 (BCL-2) inhibitor that can restore activation of apoptosis in malignant cells. The FDA has approved venetoclax for the treatment of newly diagnosed adult AML patients unfit for intensive chemotherapy. We present a systemic review aimed to evaluate outcomes with venetoclax in patients with relapsed AML after HSCT. Methods: We performed a literature search on 3 databases (Pubmed, Cochrane, and Clinicaltrials.gov) following the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines using the Mesh terms "leukemia, myeloid, acute" OR "myelodysplastic syndromes" OR "hematopoietic stem cell transplantation" AND "venetoclax." After excluding duplicates and non-relevant articles, 161 studies including the case reports, review papers, and clinical trials were identified, and 7 studies were included in the analysis. Quality evaluation was done using the NIH quality assessment tool. Pooled analysis was done using the 'meta' package (Schwarzer et al, R programming language) and proportions with 95% confidence intervals (CI) were computed. The Inter-study heterogeneity among the studies was assessed using the Q statistic proposed by Cochrane and the I 2 index introduced by Higgins and Thompson. Results: Of 7 included studies, only 2 studies reported outcomes with the use of venetoclax in relapsed AML after HSCT and the rest of studies reported outcomes in all relapsed AML patients. (Table 1) Complete response (CR) with or without hematological recovery (CRi) was reported in 37% of patients (95% CI 24-52, I 2=75%, n=225). Morphologic leukemia free state (MLFS) was noted in 14% of patients (95% CI 0.08-0.22, I 2=31%, n=190) with an overall response rate (ORR) of 55% (95% CI 0.40-0.70, I 2=78%, n=220). Conclusion: Venetoclax has showed promising results in relapsed AML, but there is very limited data evaluating the role of venetoclax after HSCT in relapsed AML. Venetoclax is increasingly used off-label after HSCT in relapsed AML and our findings highlight the need for prospective studies to evaluate the safety and efficacy of venetoclax in this patient population. Figure 1 Figure 1. Disclosures Anwer: GlaxoSmithKline: Research Funding; BMS / Celgene: Honoraria, Research Funding; Allogene Therapeutics: Research Funding; Janssen pharmaceutical: Honoraria, Research Funding. Abhyankar: Incyte/Therakos: Consultancy, Research Funding, Speakers Bureau. McGuirk: Allovir: Consultancy, Honoraria, Research Funding; Juno Therapeutics: Consultancy, Honoraria, Research Funding; Magenta Therapeutics: Consultancy, Honoraria, Research Funding; EcoR1 Capital: Consultancy; Novartis: Research Funding; Bellicum Pharmaceuticals: Research Funding; Astelllas Pharma: Research Funding; Gamida Cell: Research Funding; Fresenius Biotech: Research Funding; Novartis: Research Funding; Kite/ Gilead: Consultancy, Honoraria, Other: travel accommodations, expense, Kite a Gilead company, Research Funding, Speakers Bureau; Pluristem Therapeutics: Research Funding.


2021 ◽  
Vol 11 ◽  
Author(s):  
Yanzhi Song ◽  
Zhichao Yin ◽  
Jie Ding ◽  
Tong Wu

BackgroundReduced intensity conditioning (RIC) before allogeneic hematopoietic stem cell transplantation (allo-HSCT) has been reported to have the same overall survival (OS) as myeloablative conditioning (MAC) for patients with acute myeloid leukemia (AML) in complete remission (CR) and myelodysplastic syndrome (MDS). However, results from different studies are conflicting. Therefore, we conducted a systematic review and meta-analysis guided by PRISMA 2009 to confirm the efficacy and safety of RIC vs. MAC for AML in CR and MDS.MethodsWe search PubMed, Web of Science, Embase, Cochrane central, clinical trial registries and related websites, major conference proceedings, and field-related journals from January 1, 1980, to July 1, 2020, for studies comparing RIC with MAC before the first allo-HSCT in patients with AML in CR or MDS. Only randomized controlled trials (RCTs) were included. OS was the primary endpoint and generic inverse variance method was used to combine hazard ratio (HR) and 95% CI.ResultsWe retrieved 7,770 records. Six RCTs with 1,413 participants (711 in RIC, 702 in MAC) were included. RIC had the same OS (HR = 0.95, 95% CI 0.64–1.4, p = 0.80) and cumulative incidence of relapse as MAC (HR = 1.18, 95% CI 0.88–1.59, p = 0.28). Furthermore, RIC significantly reduced non-relapse mortality more than total body irradiation/busulfan-based MAC (HR = 0.53, 95% CI 0.36–0.80, p = 0.002) and had similar long-term OS and graft failure as MAC.ConclusionRIC conditioning regimens are recommended as an adequate option of preparative treatment before allo-HSCT for patients with AML in CR or MDS.Systematic Review Registrationhttps://www.crd.york.ac.uk/PROSPERO/display_record.php?RecordID=185436.


2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e19014-e19014
Author(s):  
Syed Ather Hussain ◽  
Atif N khan ◽  
VENKATA S THAMMINENI ◽  
Muhammad Nauman Riaz ◽  
Moazzam Shahzad ◽  
...  

e19014 Background: Allogeneic hematopoietic stem cell transplantation (HSCT) is the only curative therapy for acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) but relapse and graft versus host disease (GVHD) remain the most common challenges. Donor lymphocyte infusion (DLI) is the infusion in which lymphocytes from the original stem cell donor are infused, after the transplant, to augment an anti-tumor response or to ensure that the donor stem cells remain engrafted. In this systematic review and meta-analysis, we focused at outcomes of preemptive DLI in AML and MDS. Methods: Following Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines (PRISMA) PubMed, CINAHL, Cochrane, and Clinical trials.gov were searched. We included 8 out of 214 articles, excluding duplicates and non-relevant articles. The quality of the included studies was evaluated using NIH quality assessment tool. Proportions along with 95% Confidence Interval (CI) were extracted to compute pooled analysis using the ‘meta’ package by Schwarzer et al. in the R programming language (version 4.16-2) to report the efficacy of preemptive DLI. We pooled the experimental arms results of the included trials using the inverse variance method and logit transformation. Between studies, the variance was calculated using Der Simonian-Laird Estimator. Results: We identified 222 patients who received preemptive DLI. Median age, time since transplant and DLI dose were 48 (32-58) years, 82 (7-160) days and 1.4 million cells/kg respectively. CR and PR were 43% (95%CI 0.14-0.78, I293%, n= 127) and 61% (95%CI 0.40-0.78, I262%, n= 81) respectively. After median follow up of 46 months, non-relapsed mortality (NRM) was 52% (95%CI 0.38-0.65, I249%, n = 121). OS was reported 72% (95%CI 0.62-0.80, I20%, n= 100). Acute and chronic GVHD incidence after DLI was 20% (95% CI 0.13-0.29, I24%, n= 105) and 25% (95% CI 0.08-0.56, I2=79%, n=101) respectively (Table). Conclusions: Preemptive DLI significantly improves OS with a low incidence of acute and chronic GVHD. However, NRM was seen in more than half of all the patients and prospective studies are needed to evaluate safety of preemptive DLI. Outcomes with preemptive DLI (n= 222).[Table: see text]


2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Qingya Cui ◽  
Chongsheng Qian ◽  
Nan Xu ◽  
Liqing Kang ◽  
Haiping Dai ◽  
...  

AbstractAllogeneic hematopoietic stem cell transplantation (allo-HSCT) is a potentially curative treatment for acute myeloid leukemia (AML). However, most patients experience relapse after allo-HSCT, with a poor prognosis, and treatment options are limited. The lack of an ideal targetable antigen is a major obstacle for treating patients with relapsed AML. CD38 is known to be expressed on most AML and myeloma cells, and its lack of expression on hematopoietic stem cells (HSCs) renders it a potential therapeutic target for relapsed AML. To investigate the clinical therapeutic efficacy and safety of CD38-targeted chimeric antigen receptor T (CAR-T-38) cells, we enrolled 6 AML patients who experienced relapse post-allo-HSCT (clinicaltrials.gov: NCT04351022). Prior to CAR-T-38 treatment, the blasts in the bone marrow of these patients exhibited a median of 95% (92–99%) CD38 positivity. Four weeks after the initial infusion of CAR-T-38 cells, four of six (66.7%) patients achieved complete remission (CR) or CR with incomplete count recovery (CRi); the median CR or CRi time was 191 (range 117–261) days. The cumulative relapse rate at 6 months was 50%. The median overall survival (OS) and leukemia-free survival (LFS) times were 7.9 and 6.4 months, respectively. One case relapsed 117 days after the first CAR-T-38 cell infusion, with remission achieved after the second CAR-T-38 cell infusion. All six patients experienced clinically manageable side effects. In addition, multiparameter flow cytometry (FCM) revealed that CAR-T-38 cells eliminated CD38 positive blasts without off-target effects on monocytes and lymphocytes. Although this prospective study has a limited number of cases and a relatively short follow-up time, our preliminary data highlight the clinical utility and safety of CAR-T-38 cell therapy in treating relapsed AML post-allo-HSCT.


Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 42-43
Author(s):  
Alexander E. Perl ◽  
Qiaoyang Lu ◽  
Alan Fan ◽  
Nahla Hasabou ◽  
Erhan Berrak ◽  
...  

Background: Gilteritinib is approved for patients (pts) with relapsed/refractory (R/R) FLT3-mutated acute myeloid leukemia (AML), based on findings from the phase 3 ADMIRAL trial (Perl AE, et al. N Engl J Med. 2019). A phase 3 trial, QuANTUM-R, demonstrated the benefit of quizartinib in pts with R/R AML with FLT3 internal tandem duplication (FLT3-ITD) mutations (Cortes JE, et al. Lancet Oncol. 2019). Although eligibility criteria across both studies were similar, QuANTUM-R was more stringent as to prior therapy intensity and remission duration, which potentially enriched for higher-risk pts. We sought to describe outcomes from ADMIRAL among pts who otherwise met eligibility for QuANTUM-R. Methods: In this post-hoc analysis, a subset of pts from ADMIRAL were matched with R/R FLT3-ITD+ AML pts from QuANTUM-R on the basis of baseline characteristics and prior treatment criteria. Matched pts were either refractory to initial anthracycline-based chemotherapy or had relapsed ≤6 mos after achieving composite complete remission (CRc) with an anthracycline-based regimen. Results: Overall, 218 pts with R/R FLT3-ITD+ AML in the ADMIRAL trial (gilteritinib, n=140; salvage chemotherapy [SC], n=78) were matched with the QuANTUM-R intention-to treat (ITT) population (N=367; quizartinib, n=245; SC, n=122). Proportions of pts preselected for high-intensity SC were 66% (n=143/218) in the matched ADMIRAL ITT population and 77% (n=281/367) in the QuANTUM-R ITT populations. Demographic and baseline characteristics of the matched ADMIRAL ITT population and QuANTUM-R ITT population were similar. Median durations of exposure to gilteritinib and quizartinib were 3.8 mos and 3.2 mos, respectively, and median number of treatment cycles received were five and four, respectively. Rates of hematopoietic stem cell transplantation (HSCT) were similar in pts treated with gilteritinib (35%; n=49/140) or quizartinib (32%; n=78/245), as were the proportions of pts who resumed gilteritinib (23%; n=32/140) or quizartinib (20%; n=48/245) therapy post-HSCT. Median overall survival (OS) in pts treated with gilteritinib or quizartinib was longer than that observed with SC. After a median follow-up of 17.4 mos, median OS was 10.2 mos with gilteritinib versus 5.6 mos with SC (hazard ratio [HR]=0.573 [95% CI: 0.403, 0.814]; one-sided nominal P=0.0008). After a median follow-up of 23.5 mos, median OS with quizartinib was 6.2 mos versus 4.7 mos with SC (HR=0.76 [95% CI: 0.58-0.98]; one-sided P=0.02). After censoring for HSCT, median OS was 9.3 mos with gilteritinib versus 5.5 mos with SC (HR=0.525 [95% CI: 0.356-0.775]; nominal one-sided P=0.0005), and 5.7 mos versus 4.6 mos with quizartinib versus SC, respectively (HR=0.79 [95% CI: 0.59, 1.05]; one-sided P=0.05). In both QuANTUM-R and matched ADMIRAL populations, the survival benefits of quizartinib and gilteritinib compared with SC were maintained across multiple subgroups, including high FLT3-ITD allelic ratio subsets. Compared with SC, high CRc rates were observed in pts treated with either gilteritinib (57%; n=80/140) or quizartinib (48%; n=118/245). The complete remission (CR) rate with gilteritinib was 23% (n=32/140), whereas the CR rate with quizartinib was 4% (n=10/245) (Table). Median time to achieve CRc was 1.8 mos with gilteritinib and 1.1 mos with quizartinib, median duration of CRc was 5.5 mos with gilteritinib and 2.8 mos with quizartinib. The safety profiles of gilteritinib and quizartinib were generally similar, though aspartate or alanine aminotransferase elevations (any grade) were more frequent with gilteritinib (41-44%) than quizartinib (≤13%), whereas neutropenia (14% vs 34%, respectively), fatigue (24% vs 39%, respectively), and prolonged QT intervals (9% vs 27%, respectively) were more frequent with quizartinib. Conclusions: In pts with R/R FLT3-ITD+ AML and similar baseline characteristics, both gilteritinib and quizartinib were generally well tolerated and associated with improved survival and treatment response compared with SC. Responses to gilteritinib and quizartinib, as measured by CRc, were similar; blood count recovery varied between the two FLT3 inhibitors. Although cross-study comparisons have substantial limitations, the findings suggest that while remission is achieved faster with quizartinib, response may be more durable and survival potentially longer with gilteritinib. Disclosures Perl: Syndax: Consultancy, Honoraria; Leukemia & Lymphoma Society, Beat AML: Consultancy; Novartis: Honoraria, Other, Research Funding; Agios: Consultancy, Honoraria, Other; Jazz: Honoraria, Other; FORMA Therapeutics: Consultancy, Honoraria, Other; Daiichi Sankyo: Consultancy, Honoraria, Other: Writing/editorial support, travel costs for meetings, Research Funding; FUJIFILM Pharmaceuticals USA, Inc: Research Funding; New Link Genetics: Honoraria, Other; Arog Pharmaceuticals Inc: Other: uncompensated consulting, travel costs for meetings; Actinium Pharmaceuticals Inc: Consultancy, Honoraria, Research Funding; Biomed Valley Discoveries: Research Funding; Astellas: Consultancy, Honoraria, Other: writing/editorial support, travel costs for meeting presentations related to study, Research Funding; Bayer HealthCare Pharmaceuticals: Research Funding; AbbVie Inc: Consultancy, Honoraria, Other, Research Funding; Takeda: Honoraria, Other: Travel costs for meeting; Loxo Oncology Inc, a wholly owned subsidiary of Eli Lilly & Company: Consultancy, Honoraria, Other. Lu:Astellas: Current Employment. Fan:Astellas Pharma: Current Employment. Hasabou:Astellas Pharma: Current Employment. Berrak:Astellas: Current Employment. Tiu:Eli Lilly & Company: Current equity holder in publicly-traded company, Ended employment in the past 24 months; Astellas Pharma Global Development: Current Employment.


2015 ◽  
Vol 25 (suppl_3) ◽  
Author(s):  
V Colamesta ◽  
M Breccia ◽  
S D’Aguanno ◽  
S Bruffa ◽  
C Cartoni ◽  
...  

2020 ◽  
Vol 14 (6) ◽  
pp. 701-710
Author(s):  
Bin Gu ◽  
Jianhong Chu ◽  
Depei Wu

AbstractChimeric antigen receptor T cell (CAR T) therapies have achieved unprecedented efficacy in B-cell tumors, prompting scientists and doctors to exploit this strategy to treat other tumor types. Acute myeloid leukemia (AML) is a group of heterogeneous myeloid malignancies. Relapse remains the main cause of treatment failure, especially for patients with intermediate or high risk stratification. Allogeneic hematopoietic stem cell transplantation could be an effective therapy because of the graft-versus-leukemia effect, which unfortunately puts the patient at risk of serious complications, such as graft-versus-host disease. Although the identification of an ideal target antigen for AML is challenging, CAR T therapy remains a highly promising strategy for AML patients, particularly for those who are ineligible to receive a transplantation or have positive minimal residual disease. In this review, we focus on the most recent and promising advances in CAR T therapies for AML.


Sign in / Sign up

Export Citation Format

Share Document