Tisagenlecleucel Outcomes in Relapsed/Refractory Extramedullary ALL: A Pediatric Real World CAR Consortium Report.

Chimeric antigen receptor (CAR) T-cells have transformed the therapeutic options for relapsed/refractory (R/R) B-cell ALL. Data for CAR therapy in extramedullary (EM) involvement is limited. Retrospective data was abstracted from the Pediatric Real World CAR Consortium (PRWCC) of 184 infused patients from 15 US institutions. Response (CR) rate, overall survival (OS), relapse-free survival (RFS), and duration of B-cell aplasia (BCA) in patients referred for tisagenlecleucel with EM disease (both CNS3 and non-CNS EM) were compared to bone marrow (BM) only. Patients with CNS disease were further stratified for comparison. Outcomes are reported on 55 patients with EM disease prior to CAR (n=40 CNS3; n=15 non-CNS EM). The median age at infusion in CNS cohort was 10 years (range <1-25) and the non-CNS EM cohort was 13 years (2-26). In patients with CNS disease, 88% (35/40) achieved a CR, versus only 66% (10/15) with non-CNS EM disease. Patients with CNS disease (both with and without marrow involvement) had comparable 24-month OS outcomes to non-CNS EM or BM only (p=0.41). There was no difference in 12-month RFS between CNS, non-CNS EM, or BM only patients (p=0.92). No increased toxicity was seen with CNS or non-CNS EM disease (p=0.3). Active CNS disease at time of infusion did not impact outcomes. Isolated (iCNS) disease trended towards improved OS when compared to combined CNS and BM (p=0.12). R/R EM disease can be effectively treated with tisagenlecleucel with toxicity, relapse rates and survival rates comparable to patients with BM only. Outcomes for iCNS relapse are encouraging.

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Real-world outcomes of adult B-cell acute lymphocytic leukemia patients treated with blinatumomab

Blood Advances ◽

10.1182/bloodadvances.2019001381 ◽

2020 ◽

Vol 4 (10) ◽

pp. 2308-2316 ◽

Cited By ~ 2

Author(s):

Talha Badar ◽

Aniko Szabo ◽

Anjali Advani ◽

Martha Wadleigh ◽

Shukaib Arslan ◽

...

Keyword(s):

Clinical Trials ◽

Complete Remission ◽

B Cell ◽

Cell Transplantation ◽

Real World ◽

Hematopoietic Cell Transplantation ◽

Hematopoietic Cell ◽

Relapse Free Survival ◽

Free Survival ◽

Count Recovery

Abstract The availability and use of blinatumomab symbolizes a paradigm shift in the management of B-cell acute lymphoblastic leukemia (ALL). We conducted a retrospective multicenter cohort analysis of 239 ALL patients (227 relapsed refractory [RR], n = 227; minimal residual disease [MRD], n = 12) who received blinatumomab outside of clinical trials to evaluate safety and efficacy in the “real-world” setting. The median age of patients at blinatumomab initiation was 48 years (range, 18-85). Sixty-one (26%) patients had ≥3 prior therapies and 46 (19%) had allogeneic hematopoietic cell transplantation before blinatumomab. The response rate (complete remission/complete remission with incomplete count recovery) in patients with RR disease was 65% (47% MRD−). Among 12 patients who received blinatumomab for MRD, 9 (75%) patients achieved MRD negativity. In patients with RR disease, median relapse-free survival and overall survival (OS) after blinatumomab was 32 months and 12.7 months, respectively. Among patients who received blinatumomab for MRD, median relapse-free survival was not reached (54% MRD− at 2 years) and OS was 34.7 months. Grade ≥3 cytokine release syndrome, neurotoxicity, and hepatotoxicity were observed in 3%, 7%, and 10% of patients, respectively. Among patients who achieved complete remission/complete remission with incomplete count recovery, consolidation therapy with allogeneic hematopoietic cell transplantation retained favorable prognostic significance for OS (hazard ratio, 0.54; 95% confidence interval, 0.30-0.97; P = .04). In this largest “real-world” experience published to date, blinatumomab demonstrated responses comparable to those reported in clinical trials. The optimal sequencing of newer therapies in ALL requires further study.

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Evaluating Outcomes of Adult Patients with Acute Lymphoblastic Leukemia Treated on the GMALL Protocol

Blood ◽

10.1182/blood-2020-134771 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 28-29

Author(s):

Danielle Fredman ◽

Yulia Volchek ◽

Gabriel Heering ◽

Keren Shichrur ◽

Ronit Yerushalmi ◽

...

Keyword(s):

Overall Survival ◽

Research Funding ◽

Blood Donors ◽

Lymphoblastic Leukemia ◽

Survival Rates ◽

Disease Relapse ◽

Relapse Free Survival ◽

Free Survival ◽

Car T ◽

Matched Sibling

Background Chemotherapy based approaches still constitute an essential feature in the treatment paradigm of adult acute lymphoblastic leukemia (ALL). The German Multicenter Study Group (GMALL) is a well-established and commonly used protocol for ALL (Gökbuget 2012). Over the years evolving versions of the protocol have been developed with the aim of improving patient outcome (Apel 2014). In view of the recent advancements in the treatment of adult ALL we now analyzed our more recent data. Aims Assess the clinical outcomes of adult ALL patients treated on the GMALL protocol in real world settings, and establish prognostic parameters associated with long term survival and risk of relapse. Methods Retrospective analysis of all adult ALL patients who were treated with GMALL in our institution between the years 2008-2020. Demographic, clinical, cytogenetic, treatment, and transplant related data were collected using our institution's electronic medical records system. Baseline characteristics were evaluated by Fisher's exact test and Wilcoxon rank sum tests. Kaplan-Meier estimates were used to estimate overall survival (OS) and relapse-free survival (RFS). Hazard ratios and 95% confidence intervals were generated using a Cox proportional hazards model. Results The analysis comprised 81 evaluable patients with a median age of 36 years (range 18-73), 36% were adolescents and young adults (AYA). Forty-three were B-ALL (53%), 12 (15%) patients were Philadelphia chromosome positive ALL (Ph+ ALL), and 26 (32%) were T-ALL. Median duration of follow-up was 24.4 months (range 0.7-112.1 months), at the time of data analysis 51 patients (63.8%) were alive. Seventy patients (88%) attained a first remission (CR1) and 4 (5%) died during the first two induction phases. The 2-year and 5-year overall survival rates were 62% and 44%, respectively. Estimated 2-year and 5-year leukemia-free survival rates were 52% and 35%, respectively. Overall, disease relapse (31%), lethal infection (28%), and graft-versus-host disease (14%) accounted for most patient deaths. Of patients achieving CR1, 20 (29%) eventually relapsed after a median time of 9.8 months (range 1.1-69.3). Fifty-five patients (68%) underwent an allogeneic stem cell transplantation using matched sibling (47%), matched unrelated (31%), haploidentical (7%), partially mismatched (12%), and cord blood donors (3%). Of the 50 patients transplanted in CR1, 15 relapsed (30%) after a median time of 10.9 months (range 3.8-32.8). Multivariate analysis revealed that in terms of overall survival, increasing patient age was associated with inferior outcome [Hazard ratio (HR)=1.026, confidence interval (CI) 95%, 1.002-1.05, p=0.035) as was outcome for patients whose baseline cytogenetic analysis detected a higher number of clones (HR=2.69, CI 95%, 1.57-4.62, p=0.0002). T-ALL patients experienced longer survival compared with B-ALL (87 months versus 56 months, p=0.019) while patients transplanted using cord blood donors had inferior survival, 12.8 months, compared with matched sibling donors, 71.3 months, and fully matched unrelated donors, 73.4 months (p=0.001, and p=0.003, respectively). Relapse-free survival was significantly better in patients with T-ALL compared with B-ALL (90 months vs. 50 months, p=0.039), and in patients without t(12;21)(p13;q22) (75 months vs. 11.7 months, p=0.034). Gender, AYA status, extramedullary disease at diagnosis, initial white blood cell count, treatment delays, presence of MLL rearrangement, specific measurable residual disease modality used, GMALL risk category, and cytogenetic hyperdiploidy did not significantly impact on survival or disease relapse. Treatments for relapse following GMALL included blinatumomab (6), inotuzumab (3), nelarabine (3), and CAR-T (2). Conclusions While results are improving for patients treated on GMALL, a substantial patient segment still experiences relapse. It is conceivable that in the near future new novel therapeutic modalities for adult ALL involving the use of monoclonal antibodies and CAR-T cell therapy will help reduce relapse rates and further improve the current outcomes of patients treated on the GMALL protocol. Disclosures Avigdor: Takeda, Gilead, Pfizer: Consultancy, Honoraria; Janssen, BMS: Research Funding. Canaani:Abbvie: Consultancy, Honoraria, Research Funding.

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Reducing the initial number of rituximab maintenance-therapy infusions for ANCA-associated vasculitides: randomized-trial post-hoc analysis

Rheumatology ◽

10.1093/rheumatology/kez621 ◽

2020 ◽

Vol 59 (10) ◽

pp. 2970-2975

Author(s):

Pierre Charles ◽

Agnès Dechartres ◽

Benjamin Terrier ◽

Pascal Cohen ◽

Stanislas Faguer ◽

...

Keyword(s):

Survival Rates ◽

Group Differences ◽

Newly Diagnosed ◽

Relapse Free Survival ◽

Short Term ◽

Free Survival ◽

Remission Maintenance ◽

Post Hoc ◽

Relapse Rates ◽

Free Rate

Abstract Objective The randomized, controlled MAINRITSAN2 trial was designed to compare the capacity of an individually tailored therapy [randomization day 0 (D0)], with reinfusion only when CD19+ lymphocytes or ANCA had reappeared, or if the latter’s titre rose markedly, with that of five fixed-schedule 500-mg rituximab infusions [D0 + D14, then months (M) 6, 12 and 18] to maintain ANCA-associated vasculitis (AAV) remissions. Relapse rates did not differ at M28. This ancillary study was undertaken to evaluate the effect of omitting the D14 rituximab infusion on AAV relapse rates at M12. Methods MAINRITSAN2 trial data were subjected to post-hoc analyses of M3, M6, M9 and M12 relapse-free survival rates in each arm as primary end points. Exploratory subgroup analyses were run according to CYC or rituximab induction and newly diagnosed or relapsing AAV. Results At M3, M6, M9 and M12, respectively, among the 161 patients included, 79/80 (98.8%), 76/80 (95%), 74/80 (92.5%) and 73/80 (91.3%) from D0, and 80/81 (98.8%), 78/81 (96.3%), 76/81 (93.8%) and 76/81 (93.8%) from D0+D14 groups were alive and relapse-free. No between-group differences were observed. Results were not affected by CYC or rituximab induction, or newly diagnosed or relapsing AAV. Conclusions We were not able to detect a difference between the relapse-free survival rates for up to M12 for the D0 and D0+D14 rituximab-infusion groups, which could suggest that omitting the D14 rituximab remission-maintenance dose did not modify the short-term relapse-free rate. Nevertheless, results at M12 may also have been influenced by the rituximab-infusion strategies for both groups.

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Factors impacting disease-free survival in adult B cell B-ALL patients achieving MRD-negative CR after CD19 CAR-T cells.

Journal of Clinical Oncology ◽

10.1200/jco.2018.36.15_suppl.7005 ◽

2018 ◽

Vol 36 (15_suppl) ◽

pp. 7005-7005 ◽

Cited By ~ 1

Author(s):

Kevin Anthony Hay ◽

Jordan Gauthier ◽

Alexandre V. Hirayama ◽

Daniel Li ◽

Alyssa Sheih ◽

...

Keyword(s):

T Cells ◽

B Cell ◽

Disease Free Survival ◽

Free Survival ◽

Car T Cells ◽

Car T ◽

Disease Free

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CAR T cells with dual targeting of CD19 and CD22 in pediatric and young adult patients with relapsed or refractory B cell acute lymphoblastic leukemia: a phase 1 trial

Nature Medicine ◽

10.1038/s41591-021-01497-1 ◽

2021 ◽

Vol 27 (10) ◽

pp. 1797-1805

Author(s):

Shaun Cordoba ◽

Shimobi Onuoha ◽

Simon Thomas ◽

Daniela Soriano Pignataro ◽

Rachael Hough ◽

...

Keyword(s):

T Cells ◽

B Cell ◽

Lymphoblastic Leukemia ◽

Phase 1 ◽

Complete Response ◽

Free Survival ◽

Car T Cells ◽

Dual Targeting ◽

Car T ◽

Cell Acute Lymphoblastic Leukemia

AbstractChimeric antigen receptor (CAR) T cells targeting CD19 or CD22 have shown remarkable activity in B cell acute lymphoblastic leukemia (B-ALL). The major cause of treatment failure is antigen downregulation or loss. Dual antigen targeting could potentially prevent this, but the clinical safety and efficacy of CAR T cells targeting both CD19 and CD22 remain unclear. We conducted a phase 1 trial in pediatric and young adult patients with relapsed or refractory B-ALL (n = 15) to test AUTO3, autologous transduced T cells expressing both anti-CD19 and anti-CD22 CARs (AMELIA trial, EUDRA CT 2016-004680-39). The primary endpoints were the incidence of grade 3–5 toxicity in the dose-limiting toxicity period and the frequency of dose-limiting toxicities. Secondary endpoints included the rate of morphological remission (complete response or complete response with incomplete bone marrow recovery) with minimal residual disease-negative response, as well as the frequency and severity of adverse events, expansion and persistence of AUTO3, duration of B cell aplasia, and overall and event-free survival. The study endpoints were met. AUTO3 showed a favorable safety profile, with no dose-limiting toxicities or cases of AUTO3-related severe cytokine release syndrome or neurotoxicity reported. At 1 month after treatment the remission rate (that is, complete response or complete response with incomplete bone marrow recovery) was 86% (13 of 15 patients). The 1 year overall and event-free survival rates were 60% and 32%, respectively. Relapses were probably due to limited long-term AUTO3 persistence. Strategies to improve CAR T cell persistence are needed to fully realize the potential of dual targeting CAR T cell therapy in B-ALL.

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The Cerebroventricular Environment Reprograms Locally Infused CAR T Cells for Superior Activity Against Both CNS and Systemic B Cell Lymphoma

Blood ◽

10.1182/blood-2018-99-119335 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 965-965 ◽

Cited By ~ 1

Author(s):

Xiuli Wang ◽

Christian Huynh ◽

Ryan Urak ◽

Miriam Walter ◽

Lihong Weng ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

B Cell ◽

Research Funding ◽

Cns Lymphoma ◽

Cns Disease ◽

Car T Cells ◽

Car T Cell ◽

Car T ◽

Systemic Lymphoma

Abstract Central nervous system lymphoma (CNSL) is a lymphoid malignancy in which tumors from lymph tissue start in the brain, spinal cord, eyes, and/or meninges (primary CNSL) or present as a result of metastasis from initial systemic sites to the CNS (secondary CNSL). The incidence of primary CNS lymphoma has been increasing over the past 20 years. CNS lymphomas carry a worse prognosis than systemic lymphoma, and therefore, effective treatment is urgently needed for CNS disease. T cells that are genetically engineered with chimeric antigen receptors (CAR) targeting CD19 have broad applications in adoptive therapy of B cell malignancies and have shown tremendous potential in the treatment of systemic lymphoma. During the early phase of CD19-CAR T cell studies, most if not all protocols excluded patients with active CNS involvement. In all CD19-CAR T cell trials, T cell products are administrated intravenously. Systemic CD19-CAR T administration for ALL and DLBCL has resulted in complete remission of concurrent CNS disease. CD19-CAR T cell trafficking to the cerebrospinal fluid (CSF) is frequently reported; however, there has been no evidence thus far to indicate that CAR T cells in CSF are related to neurotoxicity. Therefore, an increasing number of CD19-CAR T cell trial protocols no longer exclude patients with active CNS lymphoma involvement. Based on the success of CD19-CAR T cell therapy in ALL and lymphoma, we aimed to translate this strategy toward a more effective therapy for CNS B cell disease. Methods and Results: Isolated naïve and central memory T cells were genetically modified with CD19-CAR lentivirus and expanded in vitro for 14 days. A mouse model with both CNS and systemic lymphoma in the same animal was established by simultaneously engrafting Daudi cells (human B cell lymphoma) intracranially and subcutaneously into NSG mice. We then administered 2x10^6 CD19-CAR T cells via two delivery routes: intracerebroventricular (i.c.v.) to bypass the blood-brain barrier and target tumor throughout the entire CNS, and intravenous injection (i.v.). We repeatedly observed that a single i.c.v. infusion was capable of completely eradicating CNS lymphoma and systemic lymphoma in all mice by day 14 post CAR T cell infusion and 100% of mice remained tumor free for 300 days until the termination of the experiment. In contrast, a single delivery of CD19-CAR T cells via i.v. infusion resulted in a noticeably delayed antitumor activity with complete remissions only observed approximately 40 days post CAR T cell treatment. Eventually, the tumors relapsed and all i.v. treated mice died before day 180 (Figure 1). T cell trafficking experiments demonstrated that i.c.v. CAR T cells are able to efficiently migrate to the periphery, home to systemic tumor locations, and dramatically expand outside the CNS. We were able to detect CAR T cells in the blood, bone marrow, and spleens of mice that received i.c.v. therapy at 300 days post CAR T cell treatment. These persisting T cells are CD4 dominant and express high levels of CD28 with a broad TCR repertoire. The persisting T cells also maintain anti-tumor functionality and are able to resist tumor re-challenge. Further mechanistic studies indicate that factors within the CSF are able to reprogram i.c.v. infused CAR T cells and upregulate genes that are related to memory function. In conclusion, our studies suggest that CAR T cells administrated via i.c.v. and nurtured by CSF exhibit better efficacy, expansion, and persistence, resulting in disease elimination. More interestingly, i.c.v. delivered CAR T cells efficiently traffic beyond the CNS to the periphery and completely eradicate systemic tumors in the same mouse. This study is the first to demonstrate that locally delivered CAR T cells are capable of efficiently treating both systemic lymphoma and concurrent CNS disease, which can lower the risk of cytokine release syndrome and avoid toxicities derived from lymphodepletion and systemic infusion of CAR T cells. Disclosures Wang: Mustang Therapeutics: Other: Licensing Agreement, Patents & Royalties, Research Funding. Budde:Mustang Therapeutics: Consultancy, Other: Licensing Agreement, Patents & Royalties, Research Funding. Brown:Mustang Therapeutics: Consultancy, Other: Licensing Agreement, Patents & Royalties, Research Funding. Forman:Mustang Therapeutics: Other: Licensing Agreement, Patents & Royalties, Research Funding.

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Új lehetőségek a refrakter és relabált Hodgkin-lymphomás betegek kezelésében

Orvosi Hetilap ◽

10.1556/650.2015.30260 ◽

2015 ◽

Vol 156 (45) ◽

pp. 1824-1833 ◽

Cited By ~ 1

Author(s):

Árpád Illés ◽

Ádám Jóna ◽

Zsófia Simon ◽

Miklós Udvardy ◽

Zsófia Miltényi

Keyword(s):

Stem Cell ◽

Hodgkin Lymphoma ◽

Treatment Options ◽

Survival Rates ◽

Relapse Free Survival ◽

Term Survival ◽

Free Survival ◽

Novel Treatment ◽

Refractory Hodgkin Lymphoma

Introduction: Hodgkin lymphoma is a curable lymphoma with an 80–90% long-term survival, however, 30% of the patients develop relapse. Only half of relapsed patients can be cured with autologous stem cell transplantation. Aim: The aim of the authors was to analyze survival rates and incidence of relapses among Hodgkin lymphoma patients who were treated between January 1, 1980 and December 31, 2014. Novel therapeutic options are also summarized. Method: Retrospective analysis of data was performed. Results: A total of 715 patients were treated (382 men and 333 women; median age at the time of diagnosis was 38 years). During the studied period the frequency of relapsed patients was reduced from 24.87% to 8.04%. The numbers of autologous stem cell transplantations was increased among refracter/relapsed patients, and 75% of the patients underwent transplantation since 2000. The 5-year overall survival improved significantly (between 1980 and 1989 64.4%, between 1990 and 1999 82.4%, between 2000 and 2009 88.4%, and between 2010 and 2014 87.1%). Relapse-free survival did not change significantly. Conclusions: During the study period treatment outcomes improved. For relapsed/refractory Hodgkin lymphoma patients novel treatment options may offer better chance for cure. Orv. Hetil., 2015, 156(45), 1824–1833.

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