RESUMEN
We evaluated patients with relapsed multiple myeloma with renal impairment (RI) treated with standard of care idecabtagene vicleucel (ide-cel), as outcomes with chimeric antigen receptor (CAR) T-cell therapy are unknown in this population. RI was defined as creatinine clearance (CrCl) <50 mL/min. CrCl of <30 mL/min or dialysis dependence were defined as severe RI. The study cohort included 214 patients, 28 (13%) patients with RI, including 11 patients severe RI (dialysis, N=1). Patients with RI were older, more likely to be female and had higher likelihood of having Revised International Staging System stage 3 disease. Rates and severity of cytokine release syndrome (89% vs. 84%, grade ≥3: 7% vs. 2%) and immune effector cell-associated neurotoxicity syndrome (23% vs. 20%) were similar in patients with and without RI, respectively. Patients with RI had higher incidence of short-term grade ≥3 cytopenias, although cytopenias were similar by 3 months following CAR T-cell therapy. Renal function did not worsen after CAR T-cell therapy in patients with RI. Response rates (93% vs. 82%) and survival outcomes (median progression-free survival: 9 vs. 8 months; P=0.26) were comparable in patients with and without RI, respectively. Treatment with ide-cel is feasible in patients with RI, with a comparable safety and efficacy profile as patients without RI, with notable exception of higher short-term high-grade cytopenias.
Asunto(s)
Citopenia , Mieloma Múltiple , Neoplasias de Células Plasmáticas , Receptores Quiméricos de Antígenos , Insuficiencia Renal , Humanos , Femenino , Masculino , Mieloma Múltiple/complicaciones , Mieloma Múltiple/terapia , Inmunoterapia Adoptiva/efectos adversos , Tratamiento Basado en Trasplante de Células y TejidosRESUMEN
While response rates and survival outcomes have been very promising for idecabtagene vicleucel (ide-cel), a proportion of patients do not respond or relapse early after this B-cell maturation antigen (BCMA) targeted CAR T-cell therapy. Understanding the characteristics of these patients is important for patient selection and development of novel strategies to improve outcomes. We evaluated factors associated with early progression (progression or death due to myeloma ≤ 3 months after CAR T infusion) in patients treated with standard of care ide-cel at 11 US academic centers. Among 211 patients that received ide-cel, 43 patients had a progressive event ≤ 3 months of infusion. Patients with a history of extramedullary disease, prior BCMA targeted therapy, elevated ferritin at lymphodepletion, use of bridging therapy, Hispanic ethnicity, plasma cell leukemia and t(4;14) were more likely to progress ≤ 3 months of infusion (p < 0.05). Of these risk factors for early progression identified in univariate analyses, history of extramedullary disease, prior BCMA targeted therapy, elevated ferritin at lymphodepletion, plasma cell leukemia, and t(4;14) were associated with worse progression-free survival (PFS) in multivariable analysis. Presence of three or more of these factors had a significant negative impact on PFS (p < 0.001; median PFS for ≥ 3 factors, 3.2 months vs. 0 factors, 14.1 months). This study helps identify patients at high risk of early progression after CAR T who may benefit from specific interventions pre and post CAR T to improve outcomes.
RESUMEN
Despite a well-established risk of chronic kidney disease (CKD) after allogeneic hematopoietic cell transplant (allo-HCT), the benefits of using nephrotoxic anti-infective agents to treat serious peritransplant infections often outweigh this risk. While there is no consensus on the optimal management of post-allo-HCT human herpes virus 6 (HHV6) reactivation, the nephrotoxic drug foscarnet is often used, although its long-term impact on renal function has not been established. We retrospectively reviewed 987 adult patients who underwent transplantation between 2002 and 2016, of whom 45.3% (n = 447) were exposed to foscarnet. The most frequent indications for foscarnet treatment were cytomegalovirus (n = 257, 57.5%) and HHV6 (n = 139, 31.1%). In the first 3 months post-transplant, patients exposed versus unexposed had similar rates of acute kidney injury and acute kidney failure (defined as 3 times baseline creatinine or <75% baseline estimated glomerular filtration rate [eGFR], 61.6% versus 58.7%, P = .42 and 28.1% versus 26.6%, P = .64, respectively). There was no difference in the eGFR at 3 months (P = .36), but patients treated with foscarnet had significantly lower median eGFRs (mL/min/1.73 m2) at 6 months (69.3, interquartile range [IQR] 51.4 to 92.8 versus 77.4, IQR 57.3 to 99.3; P = .009) and 12 months (67.8, IQR 52.7 to 85.0 versus 80.7, IQR 63.1 to 102.0; P < .001), respectively. There was also a significant difference in the decline in eGFR from baseline to 12 months (median 32.8, IQR 14.6 to 53.2 versus 21.9, IQR 6.4 to 37.4; P < .001), irrespective of the duration of foscarnet treatment. Multivariate analysis revealed that patients treated with foscarnet were more likely to experience a >30% decrease in eGFR from baseline to 12 months compared to those who were not (odds ratio, 2.30; 95% CI, 1.40 to 3.78; P = .001). We conclude that foscarnet use following allo-HCT had a profound impact on long-term renal function independent of other transplant-related factors.
Asunto(s)
Foscarnet , Trasplante de Células Madre Hematopoyéticas , Adulto , Foscarnet/uso terapéutico , Tasa de Filtración Glomerular , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Humanos , Estudios Retrospectivos , Trasplante HomólogoRESUMEN
Immune checkpoint inhibitors (ICPis) are a novel class of immunotherapeutic agents that have revolutionized the treatment of cancer; however, these drugs can also cause a unique spectrum of autoimmune toxicity. Autoimmune hemolytic anemia (AIHA) is a rare, but often severe, complication of ICPis. We identified 14 patients from nine institutions across the United States who developed ICPi-AIHA. The median interval from ICPi initiation to development of AIHA was 55 days (interquartile range [IQR], 22-110 days). Results from the direct antiglobulin test (DAT) were available for 13 of 14 patients: 8 patients (62%) had a positive DAT and 5 (38%) had a negative DAT. The median pretreatment and nadir hemoglobin concentrations were 11.8 g/dL (IQR, 10.2-12.9 g/dL) and 6.3 g/dL (IQR, 6.1-8.0 g/dL), respectively. Four patients (29%) had a preexisting lymphoproliferative disorder, and two (14%) had a positive DAT prior to initiation of ICPi therapy. All patients were treated with glucocorticoids, with three requiring additional immunosuppressive therapy. Complete and partial recoveries of hemoglobin were achieved in 12 (86%) and 2 (14%) patients, respectively. Seven patients (50%) were rechallenged with ICPis, and one (14%) developed recurrent AIHA. Clinical and laboratory features of ICPi-AIHA were similar in DAT positive and negative patients. ICPi-AIHA shares many clinical features with primary AIHA; however, a unique aspect of ICPi-AIHA is a high incidence of DAT negativity. Glucocorticoids are an effective first-line treatment in the majority of patients with ICPi-AIHA, and most patients who are rechallenged with an ICPi do not appear to develop recurrence of AIHA.
Asunto(s)
Anemia Hemolítica Autoinmune , Hemoglobinas/metabolismo , Terapia de Inmunosupresión , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Anemia Hemolítica Autoinmune/sangre , Anemia Hemolítica Autoinmune/terapia , Femenino , Glucocorticoides , Humanos , Masculino , Persona de Mediana EdadRESUMEN
Chimeric antigen receptor (CAR) T cell therapies have dramatically improved treatment outcomes for patients with relapsed or refractory B-cell acute lymphoblastic leukemia, large B-cell lymphoma, follicular lymphoma, mantle cell lymphoma, and multiple myeloma. Despite unprecedented efficacy, treatment with CAR T cell therapies can cause a multitude of adverse effects which require monitoring and management at specialized centers and contribute to morbidity and non-relapse mortality. Such toxicities include cytokine release syndrome, immune effector cell-associated neurotoxicity syndrome, neurotoxicity distinct from ICANS, immune effector cell-associated hemophagocytic lymphohistiocytosis-like syndrome, and immune effector cell-associated hematotoxicity that can lead to prolonged cytopenias and infectious complications. This review will discuss the current understanding of the underlying pathophysiologic mechanisms and provide guidelines for the grading and management of such toxicities.
RESUMEN
The safety and efficacy of CAR T-cell therapy is not well described in older patients, a population that has higher frailty and co-morbidities. In this multicenter retrospective study, we evaluated clinical outcomes along with frailty and geriatric characteristics such as comorbidities, polypharmacy, falls, neuropathy, organ dysfunction, and performance status in younger (<65 years) versus older (≥65 years) patients who received commercial idecabtagene vicleucel (ide-cel). A total of 156 patients (n=75, ≥65 years) were infused with ide-cel by data cut-off. In older patients (median age: 69 years, range: 65-83 years; 66.7% frail; 77.3% did not meet KarMMa eligibility criteria), with a median follow-up duration of 14.2 months, best overall response rate (ORR) was 86.7%, which was comparable to pivotal KarMMa study results (ORR: 73%). Median progression-free survival (PFS) and overall survival (OS) in older patients were 9.1 months and 26.5 months, respectively. Grade 3 or higher cytokine-release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) were observed in 1% and 4% of older patients, respectively. Compared to younger patients, the older patients had significantly higher prevalence of frailty, geriatric characteristics such as polypharmacy (5+ drugs; 97%), 4+ comorbidities (69%), and organ dysfunction (35%) (p<0.05). The safety and efficacy of ide-cel therapy were similar in younger and older patients. Frailty and geriatric characteristics such as polypharmacy, comorbidities, and organ dysfunction in older patients did not confer an inferior overall outcome.
RESUMEN
ABSTRACT: Idecabtagene vicleucel (ide-cel) was the first chimeric antigen receptor T-cell therapy to gain US Food and Drug Administration approval for patients with relapsed/refractory multiple myeloma (RRMM). The clinical outcomes of standard of care (SOC) ide-cel in racially and ethnically diverse populations have been understudied. This study pooled data from 207 patients with RRMM (28% patients of racial and ethnic minority groups) treated with SOC ide-cel across 11 institutions to examine racial and ethnic differences in the incidence of toxicities and adverse events, response to ide-cel, and survival. This study included 22 (11%) Hispanic, 36 (17%) non-Hispanic Black, and 149 (72%) non-Hispanic White patients with RRMM. Compared with Hispanic and non-Hispanic White patients, non-Hispanic Black patients had higher median levels of C-reactive protein (1.0, 0.8, and 3.5 mg/dL, respectively; P = .02) and baseline ferritin (362.0 vs 307.0 vs 680.5, respectively; P = .08) and were more likely to develop cytokine release syndrome (77%, 85%, and 97%, respectively; P = .04). Although best overall response rate was lower among Hispanic patients (59%) than among non-Hispanic Black (86%) and White patients (86%; P = .01), there were no racial and ethnic differences in progression-free or overall survival. We provide, to our knowledge, the first and largest investigation of clinical outcomes of SOC ide-cel by race and ethnicity. Despite differences in safety and response to ide-cel, our findings encourage the use of ide-cel in all patients with RRMM. These findings should be confirmed in larger samples of diverse patients with RRMM, with longer follow-up time.
Asunto(s)
Mieloma Múltiple , Neoplasias de Células Plasmáticas , Estados Unidos , Humanos , Mieloma Múltiple/terapia , Inmunoterapia Adoptiva/efectos adversos , Etnicidad , Grupos MinoritariosRESUMEN
Idecabtagene vicleucel (ide-cel) has shown impressive efficacy in relapsed/refractory multiple myeloma (RRMM). This study aimed to investigate the impact of absolute lymphocyte count (ALC) on the survival outcomes of RRMM patients treated with standard of care (SOC) ide-cel. Data were collected retrospectively from 11 institutions in the U.S. Impact of ALC parameters including pre-apheresis (pre-A), pre-lymphodepletion (pre-LD), absolute and percent difference from pre-A to pre-LD on clinical outcomes after ide-cel were examined using survival analysis. A new ALC profile was created based on univariate analysis that comprises 3 groups: normal (≥1 × 109/L) pre-LD ALC (LDN), low (<1 × 109/L) pre-LD ALC (LDL) + percent reduction <37.5 (%RL), and LDL ALC + percent reduction ≥37.5 (%RH). A total of 214 SOC ide-cel recipients were included in this analysis. The median patient age was 64 years (interquartile range [IQR], 57 to 69 years), median number of prior therapies was 6 (IQR, 5 to 9), and median duration of follow-up was 5.4 months (IQR, 2.1 to 8.3 months). Most patients had both low pre-A ALC (75.3%) and pre-LD ALC (77.2%), and the reduction from pre-A to pre-LD (median, .65 to .55 × 109/L) was statistically significant. Univariate analysis showed that the LDL + %RH group had significantly worse progression-free survival (PFS) and overall survival (OS) compared to the LDL + %RL and LDN ALC groups (6-month PFS: 40% versus 67.6% and 60.9%; 6-month OS: 69.5% versus 87% and 94.3%). In multivariable analysis, after adjusting for age, performance status, cytogenetic risk, use of bridging therapy, and extramedullary disease, PFS did not maintain its statistical significance; however, OS remained significantly worse for LDL + %RH group compared to the LDN ALC group (hazard ratio [HR], 4.3; 95% confidence interval [CI], 1.1 to 17), but the difference between the LDL + %RH versus %RL groups was not statistically significant (HR, 1.7; 95% CI, .8 to 4.0). Our findings indicate that low pre-LD ALC with high %R from pre-A to pre-LD was associated with inferior survival outcomes, particularly OS, in patients who received SOC ide-cel.
Asunto(s)
Mieloma Múltiple , Humanos , Mieloma Múltiple/terapia , Mieloma Múltiple/mortalidad , Mieloma Múltiple/inmunología , Persona de Mediana Edad , Masculino , Femenino , Anciano , Recuento de Linfocitos , Estudios Retrospectivos , Resultado del Tratamiento , Extractos de Tejidos/uso terapéutico , Vacunas contra el Cáncer/uso terapéutico , Estados Unidos/epidemiología , Inmunoterapia/métodos , Receptores Quiméricos de AntígenosRESUMEN
PURPOSE: Idecabtagene vicleucel (ide-cel) is an autologous B-cell maturation antigen-directed chimeric antigen receptor T-cell therapy approved for relapsed/refractory multiple myeloma (RRMM) on the basis of the phase II pivotal KarMMa trial, which demonstrated best overall and ≥ complete response rates of 73% and 33%, respectively. We report clinical outcomes with standard-of-care (SOC) ide-cel under the commercial Food and Drug Administration label. METHODS: Data were retrospectively collected from patients with RRMM who underwent leukapheresis as of February 28, 2022, at 11 US institutions with intent to receive SOC ide-cel. Toxicities were graded per American Society for Transplantation and Cellular Therapy guidelines and managed according to each institution's policies. Responses were graded on the basis of the International Myeloma Working Group response criteria. RESULTS: One hundred fifty-nine of 196 leukapheresed patients received ide-cel by data cutoff. One hundred twenty (75%) infused patients would have been ineligible for participation in the KarMMa clinical trial because of comorbidities at the time of leukapheresis. Any grade and grade ≥ 3 cytokine release syndrome and neurotoxicity occurred in 82/3% and 18/6%, respectively. Best overall and ≥ complete response rates were 84% and 42%, respectively. At a median follow-up of 6.1 months from chimeric antigen receptor T infusion, the median progression-free survival was 8.5 months (95% CI, 6.5 to not reached) and the median overall survival was 12.5 months (95% CI, 11.3 to not reached). Patients with previous exposure to B-cell maturation antigen-targeted therapy, high-risk cytogenetics, Eastern Cooperative Oncology Group performance status ≥ 2 at lymphodepletion, and younger age had inferior progression-free survival on multivariable analysis. CONCLUSION: The safety and efficacy of ide-cel in patients with RRMM in the SOC setting were comparable with those in the phase II pivotal KarMMa trial despite most patients (75%) not meeting trial eligibility criteria.
Asunto(s)
Mieloma Múltiple , Receptores Quiméricos de Antígenos , Humanos , Antígeno de Maduración de Linfocitos B , Estudios Retrospectivos , Inmunoterapia Adoptiva , Síndrome de Liberación de CitoquinasRESUMEN
Most patients with multiple myeloma experience disease relapse after treatment with a B-cell maturation antigen-targeted therapy (BCMA-TT), and data describing outcomes for patients treated with sequential BCMA-TT are limited. We analyzed clinical outcomes for patients infused with standard-of-care idecabtagene vicleucel, an anti-BCMA chimeric antigen receptor (CAR) T-cell therapy, at 11 US medical centers. A total of 50 patients with prior BCMA-TT exposure (38 antibody-drug conjugate, 7 bispecific, 5 CAR T) and 153 patients with no prior BCMA-TT were infused with ide-cel, with a median follow-up duration of 4.5 and 6.0 months, respectively. Safety outcomes between cohorts were comparable. The prior BCMA-TT cohort had a lower overall response rate (74% versus 88%; p = 0.021), median duration of response (7.4 versus 9.6 months; p = 0.03), and median progression-free survival (3.2 months versus 9.0 months; p = 0.0002) compared to the cohort without prior BCMA-TT. All five patients who received a prior anti-BCMA CAR T responded to ide-cel, and survival outcomes were best for this subgroup. In conclusion, treatment with ide-cel yielded meaningful clinical responses in real-world patients exposed to a prior BCMA-TT, though response rates and durability were suboptimal compared to those not treated with a prior BCMA-TT.
Asunto(s)
Antígeno de Maduración de Linfocitos B , Inmunoterapia Adoptiva , Mieloma Múltiple , Receptores Quiméricos de Antígenos , Humanos , Mieloma Múltiple/terapia , Antígeno de Maduración de Linfocitos B/antagonistas & inhibidores , Inmunoterapia Adoptiva/métodos , Receptores Quiméricos de Antígenos/uso terapéutico , Masculino , Femenino , Adulto , Persona de Mediana Edad , Anciano , Resultado del TratamientoRESUMEN
ABSTRACT: Antibody-drug conjugates (ADCs) have emerged as a treatment option for patients with relapsed/refractory multiple myeloma with the regulatory approval of the first-in-class B-cell maturation antigen (BCMA) ADC belantamab mafodotin. Other BCMA and non-BCMA ADCs are currently in clinical development. Whereas ADCs allow antigen-specific delivery of a chemomoiety to myeloma cells, on-target and off-target effects related to antigen target, antibody, linker, and chemomoiety can also limit these approaches. We review the clinical development of belantamab mafodotin and ongoing efforts to enhance its efficacy while mitigating ocular toxicity. The landscape of other ADCs being evaluated clinically in patients with multiple myeloma will also be reviewed.