Glofitamab, a Novel, Bivalent CD20-Targeting T-Cell–Engaging Bispecific Antibody, Induces Durable Complete Remissions in Relapsed or Refractory B-Cell Lymphoma: A Phase I Trial

Glofitamab; B-Cell Lymphoma; RelapsedGlofitamab; Linfoma de células B; RecaídaGlofitamab; Limfoma de cèl·lules B; RecaigudaPURPOSE Glofitamab is a T-cell–engaging bispecific antibody possessing a novel 2:1 structure with bivalency for CD20 on B cells and monovalency for CD3 on T cells. This phase I study evaluated glofitamab in relapsed or refractory (R/R) B-cell non-Hodgkin lymphoma (B-NHL). Data for single-agent glofitamab, with obinutuzumab pretreatment (Gpt) to reduce toxicity, are presented. METHODS Seven days before the first dose of glofitamab (0.005-30 mg), all patients received 1,000 mg Gpt. Dose-escalation steps were determined using a Bayesian continuous reassessment method with overdose control. Primary end points were safety, pharmacokinetics, and the maximum tolerated dose of glofitamab. RESULTS Following initial single-patient cohorts, 171 patients were treated within conventional multipatient cohorts and received at least one dose of glofitamab. This trial included heavily pretreated patients with R/R B-NHL; most were refractory to prior therapy (155; 90.6%) and had received a median of three prior therapies. One hundred and twenty-seven patients (74.3%) had diffuse large B-cell lymphoma, transformed follicular lymphoma, or other aggressive histology, and the remainder had indolent lymphoma subtypes. Five (2.9%) patients withdrew from treatment because of adverse events. Cytokine release syndrome occurred in 86 of 171 (50.3%) patients (grade 3 or 4: 3.5%); two (1.2%) patients experienced grade 3, transient immune effector cell–associated neurotoxicity syndrome-like symptoms. The overall response rate was 53.8% (complete response [CR], 36.8%) among all doses and 65.7% (CR, 57.1%) in those dosed at the recommended phase II dose. Of 63 patients with CR, 53 (84.1%) have ongoing CR with a maximum of 27.4 months observation. CONCLUSION In patients with predominantly refractory, aggressive B-NHL, glofitamab showed favorable activity with frequent and durable CRs and a predictable and manageable safety profile

The CAR-HEMATOTOX risk-stratifies patients for severe infections and disease progression after CD19 CAR-T in R/R LBCL

Hematologic neoplasms; Receptors; Chimeric antigenNeoplasias hematológicas; Receptores; Antígeno quiméricoNeoplàsies hematològiques; Receptors; Antigen quimèricBackground CD19-directed chimeric antigen receptor T-cell therapy (CAR-T) represents a promising treatment modality for an increasing number of B-cell malignancies. However, prolonged cytopenias and infections substantially contribute to the toxicity burden of CAR-T. The recently developed CAR-HEMATOTOX (HT) score—composed of five pre-lymphodepletion variables (eg, absolute neutrophil count, platelet count, hemoglobin, C-reactive protein, ferritin)—enables risk stratification of hematological toxicity. Methods In this multicenter retrospective analysis, we characterized early infection events (days 0–90) and clinical outcomes in 248 patients receiving standard-of-care CD19 CAR-T for relapsed/refractory large B-cell lymphoma. This included a derivation cohort (cohort A, 179 patients) and a second independent validation cohort (cohort B, 69 patients). Cumulative incidence curves were calculated for all-grade, grade ≥3, and specific infection subtypes. Clinical outcomes were studied via Kaplan-Meier estimates. Results In a multivariate analysis adjusted for other baseline features, the HT score identified patients at high risk for severe infections (adjusted HR 6.4, 95% CI 3.1 to 13.1). HThigh patients more frequently developed severe infections (40% vs 8%, p<0.0001)—particularly severe bacterial infections (27% vs 0.9%, p<0.0001). Additionally, multivariate analysis of post-CAR-T factors revealed that infection risk was increased by prolonged neutropenia (≥14 days) and corticosteroid use (≥9 days), and decreased with fluoroquinolone prophylaxis. Antibacterial prophylaxis significantly reduced the likelihood of severe bacterial infections in HThigh (16% vs 46%, p<0.001), but not HTlow patients (0% vs 2%, p=n.s.). Collectively, HThigh patients experienced worse median progression-free (3.4 vs 12.6 months) and overall survival (9.1 months vs not-reached), and were hospitalized longer (median 20 vs 16 days). Severe infections represented the most common cause of non-relapse mortality after CAR-T and were associated with poor survival outcomes. A trend toward increased non-relapse mortality in HThigh patients was observed (8.0% vs 3.7%, p=0.09). Conclusions These data demonstrate the utility of the HT score to risk-stratify patients for infectious complications and poor survival outcomes prior to CD19 CAR-T. High-risk patients likely benefit from anti-infective prophylaxis and should be closely monitored for potential infections and relapse.This work was supported by a Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) research grant provided within the Sonderforschungbereich SFB-TRR 388/1 2021-452881907, and DFG research grant 451580403 (to MS). The work was further supported by the Bavarian Elite Graduate Training Network (to MS), the Wilhelm-Sander Stiftung (to MS, project no. 20180871), the Else-Kröner-Fresenius Stiftung (to MS), and the Bavarian Center for Cancer Research (BZKF)

Real-world evidence of tisagenlecleucel for the treatment of relapsed or refractory large B-cell lymphoma

Recerca clínica del càncer; Càncer hematològic; Limfoma no HodgkinInvestigación clínica del cáncer; Cáncer hematológico; Linfoma no HodgkinClinical cancer research; Hematological cancer; Non-Hodgkin's lymphomaTisagenlecleucel (tisa-cel) is a second-generation autologous CD19-targeted chimeric antigen receptor (CAR) T-cell therapy approved for relapsed/refractory (R/R) large B-cell lymphoma (LBCL). The approval was based on the results of phase II JULIET trial, with a best overall response rate (ORR) and complete response (CR) rate in infused patients of 52% and 40%, respectively. We report outcomes with tisa-cel in the standard-of-care (SOC) setting for R/R LBCL. Data from all patients with R/R LBCL who underwent leukapheresis from December 2018 until June 2020 with the intent to receive SOC tisa-cel were retrospectively collected at 10 Spanish institutions. Toxicities were graded according to ASTCT criteria and responses were assessed as per Lugano 2014 classification. Of 91 patients who underwent leukapheresis, 75 (82%) received tisa-cel therapy. Grade 3 or higher cytokine release syndrome and neurotoxicity occurred in 5% and 1%, respectively; non-relapse mortality was 4%. Among the infused patients, best ORR and CR were 60% and 32%, respectively, with a median duration of response of 8.9 months. With a median follow-up of 14.1 months from CAR T-cell infusion, median progression-free survival and overall survival were 3 months and 10.7 months, respectively. At 12 months, patients in CR at first disease evaluation had a PFS of 87% and OS of 93%. Patients with an elevated lactate dehydrogenase showed a shorter PFS and OS on multivariate analysis. Treatment with tisa-cel for patients with relapsed/refractory LBCL in a European SOC setting showed a manageable safety profile and durable complete responses

Immunological and genetic kinetics from diagnosis to clinical progression in chronic lymphocytic leukemia

Progressió clínica; Evasió immuneProgresión clínica; Evasión inmuneClinical progression; Immune evasionBackground Mechanisms driving the progression of chronic lymphocytic leukemia (CLL) from its early stages are not fully understood. The acquisition of molecular changes at the time of progression has been observed in a small fraction of patients, suggesting that CLL progression is not mainly driven by dynamic clonal evolution. In order to shed light on mechanisms that lead to CLL progression, we investigated longitudinal changes in both the genetic and immunological scenarios. Methods We performed genetic and immunological longitudinal analysis using paired primary samples from untreated CLL patients that underwent clinical progression (sampling at diagnosis and progression) and from patients with stable disease (sampling at diagnosis and at long-term asymptomatic follow-up). Results Molecular analysis showed limited and non-recurrent molecular changes at progression, indicating that clonal evolution is not the main driver of clinical progression. Our analysis of the immune kinetics found an increasingly dysfunctional CD8+ T cell compartment in progressing patients that was not observed in those patients that remained asymptomatic. Specifically, terminally exhausted effector CD8+ T cells (T-betdim/−EomeshiPD1hi) accumulated, while the the co-expression of inhibitory receptors (PD1, CD244 and CD160) increased, along with an altered gene expression profile in T cells only in those patients that progressed. In addition, malignant cells from patients at clinical progression showed enhanced capacity to induce exhaustion-related markers in CD8+ T cells ex vivo mainly through a mechanism dependent on soluble factors including IL-10. Conclusions Altogether, we demonstrate that the interaction with the immune microenvironment plays a key role in clinical progression in CLL, thereby providing a rationale for the use of early immunotherapeutic intervention.This work was supported by the Instituto de Salud Carlos III, Fondo de Investigaciones Sanitarias (PI17/00950, M.C., PI18/01392, P.A. and PI17/00943, F.B.) and co-financed by the European Regional Development Fund (ERDF) and Fundación Asociación Española Contra el Cáncer (M.C. and P.A.), Gilead Fellowships (GLD16/00144, GLD18/00047, F.B.) and Fundació la Marató de TV3 (201905–30-31 F.B). S.B. is the recipient of a postdoctoral fellowship from Fundación Alfonso Martin Escudero. R.V-M. is supported by a Torres Quevedo fellowship from the Spanish Ministry of Science and Innovation (PTQ-16-08623). A.E-C. is funded by ISCIII/MINECO (PT17/0009/0019) which is co-funded by FEDER. M.C. holds a contract from Ministerio de Ciencia, Innovación y Universidades (RYC-2012-2018)

1 Prognostic factors and outcome of patients with lymphoproliferative disorders who receive treatment with chimeric antigen receptor T-cells

El mal pronòstic dels pacients amb limfoma difús de cèl·lules B grans en recaiguda o refractari ha millorat significativament des de la incorporació de la teràpia de cèl·lules T-CAR. Tot i aquests enormes avenços, aproximadament el 60% dels pacients infosos progressaran, cosa que s'associa amb una mitjana de supervivència aproximada de 6 mesos i taxes de resposta a les estratègies de rescat inferiors al 25%. Finalment, la teràpia amb limfòcits T-CAR no està exempta de toxicitat a curt i/o llarg termini que disminueix la supervivència d'alguns pacients. En conjunt, no hi ha dubte que una acurada selecció de pacients és clau per identificar quins candidats tenen una probabilitat més gran de beneficiar-se d'aquesta teràpia. Aquesta Tesi Doctoral està composta per tres estudis clínics que analitzen dades de vida real de les teràpies T-CAR axi-cel i tisa-cel. En tots ells es va observar un perfil de seguretat similar al dels assajos pivotals, encara que un ús més freqüent de tocilizumab i corticoides va conduir a una menor incidència de síndrome d'alliberament de citocines (SAC) i neurotoxicitat (NT) greus. Entre els productes, els pacients tractats amb axi-cel van presentar taxes més altes de SAC i NT que els receptors de tisa-cel, cosa que va portar a un major ús d'agents immunosupressors, hospitalització i infeccions. Els pacients amb LDH sèrica elevada, més de 2 línies de tractament prèvies o aquells amb mal estat general van presentar un risc més gran de SAC i/o NT greu. Pel que fa a l'eficàcia, les taxes de resposta i els resultats de supervivència van ser comparables als dels assaigs pivotals. No hi va haver diferències significatives en la supervivència entre tots dos productes a l'anàlisi per intenció de tractar modificat. Entre les característiques prèvies al tractament associades amb eficàcia, identifiquem que nivells elevats de LDH i volum metabòlic tumoral, juntament amb un estat general deteriorat, es van associar a una pitjor supervivència lliure de progressió. L'avaluació de resposta al mes post-infusió va predir els resultats de la teràpia T-CAR i va identificar els pacients en remissió parcial amb alt risc de progressió. En conclusió, els tres estudis que integren aquesta tesi doctoral van aconseguir identificar variables que, abans o després de la infusió de limfòcits T-CAR, són capaços de predir el resultat dels pacients que reben aquestes teràpies.El pronóstico sombrío de los pacientes con linfoma difuso de células B grandes en recaída o refractario ha mejorado significativamente desde la incorporación de la terapia de células T-CAR. A pesar de estos enormes avances, aproximadamente el 60% de los pacientes infundidos progresarán, lo que se asocia con una mediana de supervivencia aproximada de 6 meses y tasas de respuesta a las estrategias de rescate inferiores al 25%. Finalmente, la terapia con linfocitos T-CAR no está exenta de toxicidad a corto y/o largo plazo que disminuye la supervivencia de algunos pacientes. En conjunto, no cabe duda de que una cuidadosa selección de pacientes es clave para identificar qué candidatos tienen una mayor probabilidad de beneficiarse de esta terapia. Esta Tesis Doctoral está compuesta por tres estudios clínicos que analizan datos de vida real de las terapias T-CAR axi-cel y tisa-cel. En todos ellos se observó un perfil de seguridad similar al de los ensayos pivotales, aunque un mayor uso de tocilizumab y corticoides condujo a una menor incidencia de síndrome de liberación de citocinas (SLC) y neurotoxicidad (NT) graves. Entre los productos, los pacientes tratados con axi-cel presentaron tasas más altas de SLC y NT que los receptores de tisa-cel, lo que llevó a un mayor uso de agentes inmunosupresores, hospitalización e infecciones. Los pacientes con LDH sérica elevada, más de 2 líneas de tratamiento previas o aquellos con mal estado general presentaron un mayor riesgo de SLC y/o NT grave. En cuanto a la eficacia, las tasas de respuesta y los resultados de supervivencia fueron comparables a los de los ensayos pivotales. No hubo diferencias significativas en la supervivencia entre ambos productos en el análisis por intención de tratar modificado. Entre las características previas al tratamiento asociadas con eficacia, identificamos que niveles elevados de LDH y volumen metabólico tumoral, junto a un estado general deteriorado, se asociaron a una peor supervivencia libre de progresión. La evaluación de respuesta al mes post-infusión predijo los resultados de la terapia T-CAR e identificó a los pacientes en remisión parcial con alto riesgo de progresión. En conclusión, los tres estudios que integran esta tesis doctoral lograron identificar variables que, antes o después de la infusión de linfocitos T-CAR, son capaces de predecir el resultado de los pacientes que reciben estas terapias.The dismal prognosis of patients with relapsed/refractory large B-cell lymphoma has significantly improved since the advent of CAR T-cell therapy. Despite these enormous advances, approximately 60% of infused patients will eventually progress, which is associated with a median overall survival of 6 months and response rates to salvage strategies inferior to 25%. Finally, CAR T-cell therapy is not devoid of short and/or long-term toxicity that diminish the survival of some patients. Altogether, it is beyond doubt that a careful patient selection is key to identify which candidates have a higher chance of benefitting from CAR-T therapy. The Doctoral Thesis presented herein is composed by three clinical studies analyzing real-world data of axi-cel and tisa-cel CAR-T therapies. In all of them, a similar safety profile to the pivotal trials was observed, although a higher use of tocilizumab and steroids led to a lower incidence of severe CRS and ICANS. Among products, patients treated with axi-cel had higher rates of CRS and ICANS then tisa-cel recipients, leading to an increased use of immunosuppressive agents, hospital stay and infections. Patients with increased serum LDH, more than 2 prior lines of treatment or those harboring a poor PS presented an increased risk of severe CRS and/or ICANS. Regarding efficacy, the response rates and survival outcomes were comparable to the pivotal trials. There were no significant differences in survival between both products in the modified intention to treat analysis. Among pretreatment characteristics associated with efficacy, we identified high LDH levels, TMTV values and a poor PS to be associated with a worse PFS. The 1-month post-infusion assessment was predictive of CAR T-cell outcomes and identified patients in partial remission at high risk of disease progression. In conclusion, the three studies that represent the body of this doctoral thesis accomplished to identify variables that prior or after CAR-T infusion are able to predict the outcome of patients receiving these therapies

1 Prognostic factors and outcome of patients with lymphoproliferative disorders who receive treatment with chimeric antigen receptor T-cells

El mal pronòstic dels pacients amb limfoma difús de cèl·lules B grans en recaiguda o refractari ha millorat significativament des de la incorporació de la teràpia de cèl·lules T-CAR. Tot i aquests enormes avenços, aproximadament el 60% dels pacients infosos progressaran, cosa que s’associa amb una mitjana de supervivència aproximada de 6 mesos i taxes de resposta a les estratègies de rescat inferiors al 25%. Finalment, la teràpia amb limfòcits T-CAR no està exempta de toxicitat a curt i/o llarg termini que disminueix la supervivència d’alguns pacients. En conjunt, no hi ha dubte que una acurada selecció de pacients és clau per identificar quins candidats tenen una probabilitat més gran de beneficiar-se d’aquesta teràpia. Aquesta Tesi Doctoral està composta per tres estudis clínics que analitzen dades de vida real de les teràpies T-CAR axi-cel i tisa-cel. En tots ells es va observar un perfil de seguretat similar al dels assajos pivotals, encara que un ús més freqüent de tocilizumab i corticoides va conduir a una menor incidència de síndrome d’alliberament de citocines (SAC) i neurotoxicitat (NT) greus. Entre els productes, els pacients tractats amb axi-cel van presentar taxes més altes de SAC i NT que els receptors de tisa-cel, cosa que va portar a un major ús d’agents immunosupressors, hospitalització i infeccions. Els pacients amb LDH sèrica elevada, més de 2 línies de tractament prèvies o aquells amb mal estat general van presentar un risc més gran de SAC i/o NT greu. Pel que fa a l’eficàcia, les taxes de resposta i els resultats de supervivència van ser comparables als dels assaigs pivotals. No hi va haver diferències significatives en la supervivència entre tots dos productes a l’anàlisi per intenció de tractar modificat. Entre les característiques prèvies al tractament associades amb eficàcia, identifiquem que nivells elevats de LDH i volum metabòlic tumoral, juntament amb un estat general deteriorat, es van associar a una pitjor supervivència lliure de progressió. L’avaluació de resposta al mes post-infusió va predir els resultats de la teràpia T-CAR i va identificar els pacients en remissió parcial amb alt risc de progressió. En conclusió, els tres estudis que integren aquesta tesi doctoral van aconseguir identificar variables que, abans o després de la infusió de limfòcits T-CAR, són capaços de predir el resultat dels pacients que reben aquestes teràpies.El pronóstico sombrío de los pacientes con linfoma difuso de células B grandes en recaída o refractario ha mejorado significativamente desde la incorporación de la terapia de células T-CAR. A pesar de estos enormes avances, aproximadamente el 60% de los pacientes infundidos progresarán, lo que se asocia con una mediana de supervivencia aproximada de 6 meses y tasas de respuesta a las estrategias de rescate inferiores al 25%. Finalmente, la terapia con linfocitos T-CAR no está exenta de toxicidad a corto y/o largo plazo que disminuye la supervivencia de algunos pacientes. En conjunto, no cabe duda de que una cuidadosa selección de pacientes es clave para identificar qué candidatos tienen una mayor probabilidad de beneficiarse de esta terapia. Esta Tesis Doctoral está compuesta por tres estudios clínicos que analizan datos de vida real de las terapias T-CAR axi-cel y tisa-cel. En todos ellos se observó un perfil de seguridad similar al de los ensayos pivotales, aunque un mayor uso de tocilizumab y corticoides condujo a una menor incidencia de síndrome de liberación de citocinas (SLC) y neurotoxicidad (NT) graves. Entre los productos, los pacientes tratados con axi-cel presentaron tasas más altas de SLC y NT que los receptores de tisa-cel, lo que llevó a un mayor uso de agentes inmunosupresores, hospitalización e infecciones. Los pacientes con LDH sérica elevada, más de 2 líneas de tratamiento previas o aquellos con mal estado general presentaron un mayor riesgo de SLC y/o NT grave. En cuanto a la eficacia, las tasas de respuesta y los resultados de supervivencia fueron comparables a los de los ensayos pivotales. No hubo diferencias significativas en la supervivencia entre ambos productos en el análisis por intención de tratar modificado. Entre las características previas al tratamiento asociadas con eficacia, identificamos que niveles elevados de LDH y volumen metabólico tumoral, junto a un estado general deteriorado, se asociaron a una peor supervivencia libre de progresión. La evaluación de respuesta al mes post-infusión predijo los resultados de la terapia T-CAR e identificó a los pacientes en remisión parcial con alto riesgo de progresión. En conclusión, los tres estudios que integran esta tesis doctoral lograron identificar variables que, antes o después de la infusión de linfocitos T-CAR, son capaces de predecir el resultado de los pacientes que reciben estas terapias.The dismal prognosis of patients with relapsed/refractory large B-cell lymphoma has significantly improved since the advent of CAR T-cell therapy. Despite these enormous advances, approximately 60% of infused patients will eventually progress, which is associated with a median overall survival of 6 months and response rates to salvage strategies inferior to 25%. Finally, CAR T-cell therapy is not devoid of short and/or long-term toxicity that diminish the survival of some patients. Altogether, it is beyond doubt that a careful patient selection is key to identify which candidates have a higher chance of benefitting from CAR-T therapy. The Doctoral Thesis presented herein is composed by three clinical studies analyzing real-world data of axi-cel and tisa-cel CAR-T therapies. In all of them, a similar safety profile to the pivotal trials was observed, although a higher use of tocilizumab and steroids led to a lower incidence of severe CRS and ICANS. Among products, patients treated with axi-cel had higher rates of CRS and ICANS then tisa-cel recipients, leading to an increased use of immunosuppressive agents, hospital stay and infections. Patients with increased serum LDH, more than 2 prior lines of treatment or those harboring a poor PS presented an increased risk of severe CRS and/or ICANS. Regarding efficacy, the response rates and survival outcomes were comparable to the pivotal trials. There were no significant differences in survival between both products in the modified intention to treat analysis. Among pretreatment characteristics associated with efficacy, we identified high LDH levels, TMTV values and a poor PS to be associated with a worse PFS. The 1-month post-infusion assessment was predictive of CAR T-cell outcomes and identified patients in partial remission at high risk of disease progression. In conclusion, the three studies that represent the body of this doctoral thesis accomplished to identify variables that prior or after CAR-T infusion are able to predict the outcome of patients receiving these therapies.Universitat Autònoma de Barcelona. Programa de Doctorat en Medicin