Severe Cytokine Release Syndrome Is Associated with Impaired Hematopoietic Recovery after CD19-Targeted CAR-T Cell Therapy

Background Chimeric antigen receptor therapy (CAR-T) directed against CD19 has demonstrated efficacy in patients with relapsed/refractory (R/R) B-cell malignancies. Delayed hematopoietic recovery with grade 3/4 neutropenia and thrombocytopenia, requiring extended growth factor administration or transfusions, has been observed in patients undergoing CAR-T cell therapy, although the factors influencing recovery are poorly understood. In this study, we performed multivariable analyses to identify factors associated with hematopoietic recovery in patients undergoing CD19 CAR-T cell therapy. Methods We retrospectively analyzed 125 patients with R/R acute lymphoblastic leukemia (ALL), non-Hodgkin lymphoma (NHL), and chronic lymphocytic leukemia (CLL), treated with CD19-targeted CAR-T cells on a phase 1/2 clinical trial in our institution (NCT01865617). Patients receiving more than one CAR-T infusion were excluded. Criteria for neutropenia, thrombocytopenia, and recovery were defined as per the Center for International Blood and Marrow Transplant Research (CIBMTR) reporting guidelines: neutropenia, absolute neutrophil count (ANC) ≤ 500/mm3; thrombocytopenia, platelet (Plt) count ≤ 20 x 109/L; neutrophil recovery, ANC > 0.5 x 109/L for three consecutive laboratory values obtained on different days irrespective of growth factor administration; platelet recovery, Plt > 20 x 109/L for three consecutive values obtained on different days in the absence of platelet transfusion for seven days. For competing risk analysis, an event was defined as having achieved ANC or Plt recovery, with the following considered as competing events: death, new cytotoxic therapy, relapse with marrow involvement in the absence of ANC or platelet recovery. Patients who never met the CIBMTR criteria for neutropenia of thrombocytopenia were considered as having recovered at time = 0. To identify factors associated with impaired hematopoietic recovery after CD19 CAR-T cell therapy, patient-, disease- and CAR-T cell therapy-related variables were included in a multivariable Fine and Gray model prior to variable selection using LASSO penalization (Table 2 footnote). Results We included 125 patients (ALL, n=44; CLL, n=37; NHL, n=44) with a median age of 55 (range, 20-76). Patients were heavily pre-treated with a median of 4 prior therapies (range, 1-10); 31% had undergone prior autologous or allogeneic hematopoietic cell transplantation (HCT). Median ANC and Plt prior to lymphodepletion were 2 x 109/L (range 0-23) and 112 x 109/L, range 3-425), respectively. Patient and treatment characteristics are summarized in Table 1. ANC and Plt recovery after CD19 CAR-T cell therapy were observed in 91% (ALL, 86%; CLL, 92%; NHL, 95%) and 86% (ALL, 86%; CLL, 86%; NHL, 84%) of patients, respectively. Median time to ANC recovery was 9 days and the probability of ANC recovery at day 28, 60, and 90 was 80% (95%CI, 73-87), 86% (95%CI, 80-92) and 89% (95%CI, 83-94), respectively. The probability of platelet recovery on the day of CAR-T cell infusion was 55% (95%CI, 46-64); rising to 74% (95%CI, 67-82), 83% (95%CI, 76-90), and 84% (95%CI, 77-90) at day 28, 60, and 90, respectively. A competing event was always observed in patients without ANC or Plt recovery. In multivariable analysis, higher pre-lymphodepletion Plt count (HR=1.08 per 25 x 109/L increase, p=0.006) and higher peak CD8+ CAR-T cells in blood (HR=1.47 per log10 cells/µL increase, p<0.001) were associated with faster ANC recovery. ALL diagnosis and higher cytokine release syndrome (CRS) grade were associated with slower ANC recovery (CLL vs ALL, HR=1.60, p=0.02; NHL vs ALL, HR=2.07, p=0.007). Higher CRS grade was also associated with slower Plt recovery (HR=0.67 per grade increase, p<0.001). Higher pre-lymphodepletion platelet count and higher peak CD8+ CAR-T cell in blood were associated with faster platelet recovery (HR=1.08 per 25 x 109/L increase, p=0.001; HR=1.41 per log10 cells/µL increase, p<0.001). Of note, lymphodepletion intensity did not seem to affect hematopoietic recovery. Table 2 summarizes the results of the multivariable analysis. Figure 1 shows ANC and Plt recovery by CRS grade. Conclusion We identified CRS grade as independently associated with impaired hematopoietic recovery after CD19 CAR-T cell therapy. Our findings suggest that the prevention of CRS may improve hematopoietic recovery after CD19 CAR-T cell therapy. Figure Disclosures Hirayama: DAVA Oncology: Honoraria. Maloney:Celgene,Kite Pharma: Honoraria, Research Funding; BioLine RX, Gilead,Genentech,Novartis: Honoraria; Juno Therapeutics: Honoraria, Patents & Royalties: patients pending , Research Funding; A2 Biotherapeutics: Honoraria, Other: Stock options . Turtle:Caribou Biosciences: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Nektar Therapeutics: Other: Ad hoc advisory board member, Research Funding; Allogene: Other: Ad hoc advisory board member; Novartis: Other: Ad hoc advisory board member; Juno Therapeutics: Patents & Royalties: Co-inventor with staff from Juno Therapeutics; pending, Research Funding; Precision Biosciences: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Eureka Therapeutics: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; T-CURX: Membership on an entity's Board of Directors or advisory committees; Kite/Gilead: Other: Ad hoc advisory board member; Humanigen: Other: Ad hoc advisory board member.

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Impact of Lab Abnormalities at the Time of Progression in Patients Receiving CD19-Specific CAR T-Cell Therapy for Relapsed/Refractory Large B-Cell Lymphomas

Blood ◽

10.1182/blood-2019-124962 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 2889-2889

Author(s):

Ryan C. Lynch ◽

Victor A. Chow ◽

David G. Maloney ◽

Cameron J. Turtle ◽

Stephen D. Smith ◽

...

Keyword(s):

T Cell ◽

Cell Therapy ◽

Research Funding ◽

Ad Hoc ◽

Advisory Board ◽

Advisory Committees ◽

T Cell Therapy ◽

Car T Cell ◽

Car T Cell Therapy ◽

Car T

Introduction: CD19-specific chimeric antigen receptor (CAR) T-cell therapy is FDA approved in patients with relapsed or refractory large B-cell lymphomas. While 35-40% of patients may achieve a durable complete response (CR), the toxicity incurred with CAR-T therapy could impact the ability to receive subsequent treatment in those who progress after CAR-T infusion. Our prior data suggested that patients who experienced early progression had inferior overall survival. We now update our results and evaluate the impact of laboratory abnormalities and comorbidities at the time of progression on overall survival. Methods: Adults with large B-cell lymphomas who received CD19-specific CAR T-cells at the University of Washington/Seattle Cancer Care Alliance were included. Patients who received CAR T-cell therapy with additional concurrent protocol-specified therapy were excluded. Those who exhibited progressive disease (PD) or persistent lymphoma after CAR T-cell therapy were the focus of this study. We defined patients who progressed or received additional lymphoma directed therapy after last CAR-T cell infusion as early PD, with all other patients defined as late PD. We collected laboratory data closest to the date of progression. We defined an absolute neutrophil count < 1000, platelet count < 75K, Creatinine > upper limit of normal (ULN), INR > ULN, AST/ALT > 2.5x ULN, total bilirubin > ULN, and LDH > ULN as abnormal. Primary endpoint of this analysis was overall survival (OS) landmarked to date of progression. Secondary endpoints include sub-group analyses based on early PD as well as lab abnormalities at the time of progression. A multi-variate analysis with select baseline and progression variables was also performed. Results: We identified 66 patients who met the above criteria. Median follow up for the entire cohort is 30.4 months (range 0.1-64 months) by reverse KM method. Median time from last planned CAR infusion to progression was 43.5 days (range 11-658). Median OS of the entire cohort was 5.43 months (95% CI 3.75-12.2). 25 (38%) patients experienced early PD, which was associated with inferior OS (median 3.75 vs. 10.4 months, P=0.02). LDH > ULN at the time of progression defined a group with inferior outcomes (median OS 3.16 vs. 17.5 months, P<0.0001). Patients with at least one hematologic abnormality (ANC <1000 and/or platelets < 75K) had similar outcomes to those with higher values (median OS 4.18 vs 9.28 months, P=0.25). However, when we incorporated measurements of organ function, we found that patients with >1 indicator of hematologic and/or organ dysfunction (excluding LDH) at the time of progression had worse outcomes compared to those with one or fewer abnormalities (median OS 1.74 vs. 7.14 months, P=0.001). Multivariate analysis identified pre-CAR IPI score 4-5 (HR 6.33, 95% CI 1.97-20.36), LDH > ULN at progression (7.01, 95% CI 2.89-17.013), and abnormal creatinine at progression (5.32, 95% CI 1.71-16.53), as factors associated with increased risk of death. Conclusions: Patients with PD post CD19-specific CAR T-cell therapy, particularly those with early PD, elevated LDH, or renal failure experience extremely poor outcomes. These data can inform discussion of prognosis for patients who progress after CAR T-cell therapy and may predict which patients may benefit from additional anti-lymphoma therapy. Figure Disclosures Lynch: Johnson Graffe Keay Moniz & Wick LLP: Consultancy; Juno Therapeutics: Research Funding; Takeda Pharmaceuticals: Research Funding; T.G. Therapeutics: Research Funding; Incyte Corporation: Research Funding; Rhizen Pharmaceuticals S.A: Research Funding. Maloney:A2 Biotherapeutics: Honoraria, Other: Stock options ; Celgene,Kite Pharma: Honoraria, Research Funding; Juno Therapeutics: Honoraria, Patents & Royalties: patients pending , Research Funding; BioLine RX, Gilead,Genentech,Novartis: Honoraria. Turtle:Nektar Therapeutics: Other: Ad hoc advisory board member, Research Funding; Juno Therapeutics: Patents & Royalties: Co-inventor with staff from Juno Therapeutics; pending, Research Funding; Eureka Therapeutics: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Caribou Biosciences: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Novartis: Other: Ad hoc advisory board member; Precision Biosciences: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; T-CURX: Membership on an entity's Board of Directors or advisory committees; Allogene: Other: Ad hoc advisory board member; Kite/Gilead: Other: Ad hoc advisory board member; Humanigen: Other: Ad hoc advisory board member. Smith:Portola Pharmaceuticals: Research Funding; Pharmacyclics: Research Funding; Ignyta (spouse): Research Funding; Genentech: Research Funding; Denovo Biopharma: Research Funding; Ayala (spouse): Research Funding; Bristol-Myers Squibb (spouse): Research Funding; AstraZeneca: Membership on an entity's Board of Directors or advisory committees, Research Funding; Acerta Pharma BV: Research Funding; Merck Sharp & Dohme Corp: Consultancy, Research Funding; Seattle Genetics: Research Funding; Incyte Corporation: Research Funding. Shadman:TG Therapeutic: Research Funding; Mustang Bio: Research Funding; Atara Biotherapeutics: Consultancy; Pharmacyclics: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; Sunesis: Research Funding; Verastem: Consultancy; Astra Zeneca: Consultancy; ADC Therapeutics: Consultancy; Sound Biologics: Consultancy; Celgene: Research Funding; Gilead: Consultancy, Research Funding; BeiGene: Research Funding; Acerta Pharma: Research Funding. Ujjani:Pharmacyclics: Honoraria; Atara: Consultancy; Gilead: Consultancy; Genentech: Honoraria; Astrazeneca: Consultancy; AbbVie: Honoraria, Research Funding; PCYC: Research Funding. Cassaday:Amgen: Consultancy, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Incyte: Research Funding; Kite/Gilead: Research Funding; Merck: Research Funding; Seattle Genetics: Research Funding; Seattle Genetics: Other: Spouse's disclosure: employment, stock and other ownership interests. Till:Mustang Bio: Patents & Royalties, Research Funding. Shustov:Seattle Genetics, Inc.: Research Funding. Gopal:Seattle Genetics, Pfizer, Janssen, Gilead, Sanofi, Spectrum, Amgen, Aptevo, BRIM bio, Acerta, I-Mab-pharma, Takeda, Compliment, Asana Bio, and Incyte.: Consultancy; Seattle Genetics, Pfizer, Janssen, Gilead, Sanofi, Spectrum, Amgen, Aptevo, BRIM bio, Acerta, I-Mab-pharma, Takeda, Compliment, Asana Bio, and Incyte: Honoraria; Teva, Bristol-Myers Squibb, Merck, Takeda, Seattle Genetics, Pfizer, Janssen, Takeda, and Effector: Research Funding.

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Relapsed/Refractory Multiple Myeloma Patients. a Multicenter Retrospective Analysis of Eligibility Criteria for CAR-T Cell Therapy

Blood ◽

10.1182/blood-2021-149547 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 3755-3755

Author(s):

Francesca Fazio ◽

Alice Di Rocco ◽

Tommaso Za ◽

Valeria Tomarchio ◽

Angela Rago ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Cell Therapy ◽

Advisory Board ◽

T Cell Therapy ◽

Entire Cohort ◽

Car T Cells ◽

Car T Cell ◽

Car T Cell Therapy ◽

Car T

Abstract Background. The overall survival (OS) of multiple myeloma (MM) patients (pts) has improved over the years due to the introduction of several novel drugs, such as proteosome inhibitors (PI), immunomodulatory drugs (IMiDs) and, more recently, anti-CD38 monoclonal antibodies (moAb). Nevertheless, the majority of pts continues to relapse, and MM remains an incurable disease. To date, no standard of care has been established for relapsed/refractory (RR) MM pts who have been exposed to the main anti-myeloma drugs. Currently, these pts have a limited number of available treatment options and represent an unmet medical need. Moreover, the outcome of pts failing standard of care regimens, which is now defined as triple-refractory (including PI, IMiDs and moAb), is poor, with a median progression free survival (PFS) of 3-4 months and OS of 8-9 months. Novel therapeutic strategies with different mechanisms of action are warranted to overcome the natural occurrence of relapse or therapy resistance in RR MM pts. Immunotherapy, especially T-cell based approaches, represents the emerging therapeutic strategy for this subset of pts. Chimeric antigen receptor (CAR)-modified T cells are a promising new therapy approach for triple refractory RRMM. Different constructs and specific CAR-T targets are being studied, but BCMA-directed CAR-T cells have so far provided the most convincing evidence of activity, with one product (idecabtage vicleucel) recently approved by FDA. Aims. The primary endpoint of this observational and retrospective study was to define the clinical characteristics and outcome of a cohort of RR MM pts potentially eligible to CAR-T cell treatment according to the KarMMa trial criteria 1. Secondary endpoints were aimed at defining specific factors influencing CAR-T cell therapy eligibility and at identifying a real-life estimate of RRMM pts truly eligible for CAR-T cells. Methods and Results. This is a cohort analysis that used electronic REDCap, a data capture tool hosted at the Sapienza University, on RRMM pts managed between January 2018 and July 2021 at 4 Italian Centers of the Multiple Myeloma GIMEMA Lazio Group. At the time of data collection, 47 RRMM pts had underwent at least 3 prior therapy regimens; they had received a previous PI, IMiDs and a moAb and were considered refractory to the last regimen. The clinical characteristics are listed in Table 1. Median age was 68 years (43-86), 27 (61%) pts were >65 years; 27 (57%) were male. Of 47 pts, 33 (68%) were ECOG 0-1 and 14 (30%) were ECOG ³2; 21 pts (44%) were ISS III. The majority of pts, 28 (59%), had undergone an autologous stem cell transplantation; 31 pts (65%) had received 3 prior lines of therapy and 16 (34%) >3 prior lines of therapy. Thirty-seven (78%) were triple-refractory and 8 (17%) were penta-refractory. Based on the KarMMa trial criteria, 22/47 pts (47%) would be defined as eligible and 25 (53%) not eligible for CAR-T cell therapy. Specifically, 14 (30%) pts were not eligible because of an ECOG ³2, 24 (62%) had an organ dysfunction such as impaired renal function (eGFR <45 ml/min/1.73m 2), anemia and thrombocytopenia. Of the 25 pts considered ineligible for CAR-T cell therapy, 17 (68%) presented ≥2 ineligibility criteria. The entire cohort of 47 pts had a negative hepatitis and HIV serology, and no patient had previously undergone anti-BCMA therapy or an allogeneic stem cell transplantation. After a median follow-up of 34.7 months (mo) (0-53.8), the median OS for the entire cohort was 21.7 mo (95% CI: 14.2-36.9) (Fig. 1). The median OS was 30.7 mo (95%, CI: 14.21-NA) in eligible pts vs 16.2 mo (95%, CI: 6.28-NA) in non-eligible pts (p=0.002) (Fig.2). The median PFS of the entire cohort was 7.7 mo (95%, CI: 5.39-13.85) (Fig. 3) and the median PFS was 7.8 mo (95%, CI: 5.16-19.1) in eligible pts vs 6.5 mo (95%, CI: 3.36-NA) (p=0.513) in non-eligible pts (Fig.4). Conclusions. Despite the limits of a retrospective study and a limited cohort, our real-life analysis shows that heavily treated pts with RRMM are less likely to be eligible for CAR-T cell therapy. Considering the emergent role of quadruplet combined approaches for first-line therapy and given the therapeutic relevance of CAR-T cells for the management of RRMM pts previously exposed to PI, IMiDs and moAb, our data could help to better define pts who could benefit from CAR-T cells under the current indications, while waiting for an extension of this approach to earlier disease stages. 1. N Engl J Med 2021;384:705-16 Figure 1 Figure 1. Disclosures Fazio: Janseen: Honoraria. Caravita di Toritto: celgene: Other: travel expenses, Research Funding; Janseen: Other: travel expenses, Research Funding; amgen: Other: advisory board; takeda: Research Funding; GSK-SANOFI: Other: advisory board. Martelli: Gilead: Other: advisory board; Novartis: Other: advisory board. Petrucci: Janssen-Cilag: Honoraria, Other: Advisory Board; BMS: Honoraria, Other: Advisory Board; Takeda: Honoraria, Other: Advisory Board; Amgen: Honoraria, Other: Advisory Board; GSK: Honoraria, Other: Advisory Board; Karyopharm: Honoraria, Other: Advisory Board; Celgene: Honoraria, Other: Advisory Board.

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Factors Associated with Impaired Hematopoietic Recovery after CD19-Targeted CAR-T Cell Therapy

Biology of Blood and Marrow Transplantation ◽

10.1016/j.bbmt.2019.12.391 ◽

2020 ◽

Vol 26 (3) ◽

pp. S313

Author(s):

Krishna R. Juluri ◽

Alexandre V. Hirayama ◽

Erin Mullane ◽

Nancy Cleary ◽

Qian Wu ◽

...

Keyword(s):

T Cell ◽

Cell Therapy ◽

T Cell Therapy ◽

Factors Associated ◽

Car T Cell ◽

Hematopoietic Recovery ◽

Car T Cell Therapy ◽

Car T

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Characteristics of Patients with Relapsed/Refractory Burkitt Non-Hodgkin Lymphoma (NHL): Impact on the Feasibility of CAR-T Cell Therapy

Blood ◽

10.1182/blood-2019-131080 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 5352-5352

Author(s):

Sonia Fortin Gamero ◽

Yi Lin ◽

Saad S. Kenderian ◽

N. Nora Bennani ◽

Gita Thanarajasingam ◽

...

Keyword(s):

T Cell ◽

Cell Therapy ◽

Mayo Clinic ◽

Salvage Therapy ◽

Research Funding ◽

Advisory Board ◽

T Cell Therapy ◽

Car T Cell ◽

Car T Cell Therapy ◽

Car T

Background Burkitt NHL (BL) is a rare hematologic malignancy that occurs in younger adults and is highly curable with aggressive chemoimmunotherapy induction regimens. Unfortunately, patients that are refractory or relapse after these regimens fare poorly and treatment guidelines are not well established. The typical approach is with standard platinum-based salvage regimens; those who obtain a complete remission (CR) become eligible for autologous or allogeneic stem cell transplantation (SCT). Chimeric antigen receptor T (CAR-T) cell therapy and bispecific antibodies offer potential novel approaches for these patients, especially those who are unable to achieve remission in order to proceed with SCT; however, CAR-T therapy is not approved nor even tested in BL other than promising single case reports (Avigdor A, Bone Marrow Transplant. 2018 May 24). The goal of this study was to learn the clinical features and outcome of R/R BL in order to design a prospective strategy for novel therapy use in relapsed/refractory (R/R) BL patients. Methods We reviewed the Mayo Clinic Lymphoma database to find cases of BL diagnosed and treated between 1/1/2000 - 9/30/2018. Forty-two cases were identified and 32 (76%) entered CR and never relapsed; 10 (24%) did not respond or relapsed and are the focus of this report. Demographic, clinical response to treatment regimens, and long-term outcomes were extracted from the Mayo Clinic electronic medical record. Results The 10 patients with R/R BL had a median age of 41 years (range, 28-59); all had received aggressive chemoimmunotherapy induction regimens; 7 were primary refractory and 3 relapsed within 3 months (2-4) of achieving first CR. All 3 patients that relapsed did so in the central nervous system (CNS) despite receiving CNS prophylaxis with their induction therapy regimen. The response to salvage therapy was 30% (3/10) with 10% CR and 30% (3/10) proceeded to autologous SCT (no patients made it to allogenic SCT). The median progression free survival (PFS) and overall survival (OS) from diagnosis of all 10 patients was 4 months (1-9) and 70% (7/10) died within 6±4 months from date of relapse. The 3 patients with relapsed BL survived 7, 10, and17 months from date of relapse. The 3 patients who did survive to receive a SCT lived 2, 4, and 13 months from date of SCT. None of the 10 patients survived past 26 months from date of diagnosis. Conclusions Patients with R/R BL represent an uncommon and unique subset of aggressive NHL that require a new therapeutic approach such as CAR-T. Our study demonstrates the very poor outcome with traditional salvage therapies and the very short OS of these young, otherwise healthy patients. We recommend that these patients be considered as emergencies and referred promptly for novel therapies such as CAR-T trials at the very first sign of treatment failure. Waiting with the intent of attaining response to traditional therapies is futile. Insurance approval initiation and harvesting of T-cells should be rapidly performed, preferably prior to initiating salvage therapy, given the rapid clinical deterioration and demise of these patients. Disclosures Kenderian: Lentigen: Research Funding; Novartis: Patents & Royalties, Research Funding; Tolero: Research Funding; Humanigen: Other: Scientific advisory board , Patents & Royalties, Research Funding; Morphosys: Research Funding; Kite/Gilead: Research Funding. Bennani:Kite Pharma: Other: Advisory board; Bristol-Myers Squibb: Research Funding; Adicet Bio: Other: Advisory board; Adicet Bio: Other: Advisory board; Seattle Genetics: Other: Advisory board; Purdue Pharma: Other: Advisory board; Seattle Genetics: Other: Advisory board; Purdue Pharma: Other: Advisory board; Purdue Pharma: Other: Advisory board; Bristol-Myers Squibb: Research Funding; Adicet Bio: Other: Advisory board; Kite Pharma: Other: Advisory board; Kite Pharma: Other: Advisory board; Seattle Genetics: Other: Advisory board; Bristol-Myers Squibb: Research Funding. Nowakowski:Selvita: Membership on an entity's Board of Directors or advisory committees; NanoString: Research Funding; MorphoSys: Consultancy, Research Funding; Genentech, Inc.: Research Funding; F. Hoffmann-La Roche Ltd: Research Funding; Curis: Research Funding; Bayer: Consultancy, Research Funding; Celgene: Consultancy, Research Funding.

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