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PURPOSE: Axicabtagene ciloleucel (axi-cel) is an autologous CD19 chimeric antigen receptor (CAR) T-cell therapy that is approved for the treatment of relapsed or refractory large B-cell lymphoma. Little is known about the long-term survivorship after CAR T-cell therapy. METHODS: We previously reported the results of 298 patients who were leukapheresed with the intent to receive standard-of-care axi-cel (n = 275 infused) after two or more previous lines of therapy at a median follow-up of 12.9 months. Here, we report extended follow-up of this cohort to a median of 58 months, with a focus on late survivorship events. RESULTS: Among axi-cel-infused patients, progression-free survival at 5 years was 29% and overall survival (OS) at 5 years was 40%. The 5-year lymphoma-specific survival was 53% with infrequent late relapses. However, the 5-year nonrelapse mortality (NRM) was 16.2%, with over half of NRM events occurring beyond 2 years. Patients who were 60 years and older had a lower risk of relapse (P = .02), but a higher risk of NRM compared with patients younger than 60 years (NRM odds ratio, 4.5 [95% CI, 2.1 to 10.8]; P < .001). Late NRM was mainly due to infections and subsequent malignant neoplasms (SMNs). In total, SMNs occurred in 24 patients (9%), including therapy-related myeloid neoplasms (n = 15), solid tumors (n = 7), and unrelated lymphoid malignancies (n = 2). CONCLUSION: In the standard-of-care setting, axi-cel exhibits outcomes consistent with those reported in clinical trials, with sustained, durable responses observed at the 5-year time point. However, late infections and the development of SMN are key survivorship issues that reduce long-term survival after CAR T-cell therapy, particularly in the elderly.
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CD19-directed chimeric antigen receptor T-cell (CAR T) therapies, including axicabtagene ciloleucel (axi-cel), tisagenlecleucel (tisa-cel), and lisocabtagene maraleucel (liso-cel), have transformed the treatment landscape for B-cell non-Hodgkin lymphoma (NHL), showcasing significant efficacy but also highlighting toxicity risks such as cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). The FDA has mandated patients remain close to the treatment center for four weeks as part of a Risk Evaluation and Mitigation Strategy to monitor and manage these toxicities, which, while cautious, may add to cost of care, be burdensome for patients and their families, and present challenges related to patient access and socioeconomic disparities. This retrospective study across 9 centers involving 475 patients infused with axi-cel, tisa-cel, and liso-cel from 2018 to 2023, aims to assess CRS and ICANS onset and duration, as well as causes of non-relapse mortality (NRM) in real-world CAR T recipients. While differences were noted in the incidence and duration of CRS and ICANS between CAR T products, new-onset CRS and ICANS are exceedingly rare after two weeks following infusion (0% and 0.7% of patients, respectively). No new cases of CRS occurred after two weeks and a single case of new-onset ICANS occurred in the third week following infusion. NRM is driven by ICANS in the early follow-up period (1.1% until day 28), then by infection through three months post-infusion (1.2%). This study provides valuable insights into optimizing CAR T therapy monitoring and our findings may provide a framework to reduce physical and financial constraints for patients.
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BACKGROUND: Nivestym, a biosimilar granulocyte colony-stimulating factor (G-CSF) to the originator filgrastim (Neupogen), is now being used for the mobilization of peripheral blood stem cells (PBSC) in allogeneic hematopoietic stem cell transplantation (allo-HSCT). We aim to compare the efficacy of Nivestym and Neupogen for PBSC mobilization in healthy allogeneic donors. METHODS: We conducted a retrospective single-center study including 541 adult allo-HSCT donors receiving Nivestym (January 2013-July 2020), or Neupogen (July 2020-June 2023) for donor PBSC mobilization. Bivariate analysis was conducted using SPSS version 28. Statistical significance was determined at a p-value <.05. RESULTS: Our study included 541 allo-HSCT donors who received Neupogen (n = 345, 64%) or Nivestym (n = 196, 36%) for PBSC mobilization. The median age was 47 years (range 17-76). The median donor weight was 86 kg (95% confidence interval [CI]: 87-91). Donors receiving Neupogen had similar pre-G-CSF white blood cell count, CD34+ percentages, and circulating CD34+ count compared with donors receiving Nivestym. The Neupogen group had similar median PBSC product total neutrophil count, CD34+ percentage, absolute CD34+ count, and infused CD34+ dose compared with the Nivestym group. For donors aged 35 years or younger, the median CD34+ dose was higher in donors who received Neupogen compared with Nivestym (6.9 vs. 6.3 million cells/kg, p = .044). CONCLUSIONS: Nivestym demonstrated similar efficacy for PBSC mobilization compared with Neupogen among allo-HSCT donors. In donors aged 35 years or younger, a slightly lower PBSC product CD34+ count was noted with Nivestym compared with Neupogen.
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Biosimilares Farmacéuticos , Filgrastim , Movilización de Célula Madre Hematopoyética , Trasplante de Células Madre Hematopoyéticas , Células Madre de Sangre Periférica , Humanos , Filgrastim/uso terapéutico , Filgrastim/administración & dosificación , Filgrastim/farmacología , Adulto , Persona de Mediana Edad , Movilización de Célula Madre Hematopoyética/métodos , Masculino , Femenino , Estudios Retrospectivos , Anciano , Adolescente , Adulto Joven , Células Madre de Sangre Periférica/efectos de los fármacos , Trasplante Homólogo , Trasplante de Células Madre de Sangre PeriféricaRESUMEN
INTRODUCTION: Existing literature suggests that women are significantly underrepresented in the field of hematology-oncology. Women make up 35.6% of hematologists and data on females as site investigators for pivotal trials and authors in publications of pivotal trials in hematologic malignancies, specifically in the novel niche of Chimeric antigen receptor T cell (CAR-T), is sparse. METHODS: We examined the proportion of women in pivotal trials, screening a total of 2180 studies from PubMed using the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines. 2180 initially searched records were filtered by date (2017-2023) and clinical trial status, yielding 149 records. Following a manual review, we included 15 studies that led to the approval of or anticipated approval of CD19 and BCMA CAR-T therapies in lymphoid and plasma cell malignancies. We examined overall number of female authors, number of lead female authors, and ratio of all authors to female authors in the 15 trials, which were all high impact, cited on average 1314 times. RESULTS: Of the 436 authors assessed, 132 were female, correlating to 29.5% female authorship. The only study with female authorship >50% was ELIANA, a 2017 pediatric study. 7 of the 15 studies had female lead authors; notably, 6 out of 7 of these studies were published in 2021 or later. CONCLUSION: In conclusion, our data suggests gender iniquities for female investigators exist in the field of immune effector cell therapy. We suggest further investigation and strategies to decrease gendered authorship disparities.
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BCMA-directed chimeric antigen receptor T-cell (CAR T) therapies, including idecabtagene vicleucel (ide-cel) and ciltacabtagene autoleucel (cilta-cel), have transformed the treatment landscape for relapsed-refractory multiple myeloma (RRMM), offering remarkable efficacy with hallmark toxicity risks of cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). The FDA mandates a 4-week monitoring period at the treatment center as part of a Risk Evaluation and Mitigation Strategy (REMS) to monitor and manage these toxicities, which, while prudent, may add unnecessary challenges related to access and socioeconomic disparities. We sought to assess CRS and ICANS onset and duration, as well as causes of non-relapse mortality (NRM) in real-world BCMA CAR T recipients in order to better inform future changes to the monitoring guidelines for CAR T recipients. This is a retrospective study across four academic centers that examined 129 ide-cel and cilta-cel recipients that received CAR T cell infusions from May 2021 to June 2023. Infusion and toxicities were managed per institutional guidelines in accordance with previously published guidelines. While differences were noted in the incidence and duration of CRS/ ICANS between ide-cel and cilta-cel, late-onset CRS and ICANS were rare after 2 weeks following infusion (0% and 1.6%, respectively). NRM was driven by hemophagocytic lymphohistiocytosis and infections in the early follow-up period (1.1% until Day 29), then by infections through three months post-infusion (1.2%). Our findings suggest that 25% of patients had to relocate for 4 weeks due to distance from the treatment center. With the low risk of CRS and ICANS after 2 weeks, a flexible shorter monitoring period may be reasonable, emphasizing collaboration with referring oncologists to improve NRM.
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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.
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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
Idecabtagene vicleucel (Ide-cel) has demonstrated excellent efficacy and durable responses in patients with relapsed/refractory multiple myeloma (RRMM). However, the outcomes with ide-cel in patients with extramedullary disease (EMD) remain incompletely characterized. We included patients with RRMM treated with ide-cel between May 2021 and April 2023 across 11 US academic institutions. Visceral or soft tissue lesions non-contiguous from bone was classified as EMD. Time-to-event analyses were performed from date of ide-cel infusion. Among 351 patients, 84 (24%) had EMD prior to infusion. The median follow-up from ide-cel infusion was 18.2 months (95% CI: 17-19.3). The day 90 overall response rates (ORR) were 52% vs. 82% for the EMD and non-EMD cohorts, respectively (p < 0.001). The median progression-free survival (PFS) was 5.3 months (95% CI: 4.1-6.9) for the EMD cohort vs. 11.1 months (95% CI: 9.2-12.6; p < 0.0001) for the non-EMD cohort. In a multivariable analysis, EMD was an independent predictor of inferior PFS [hazard ratio 1.5 (1.1-2.2), p = 0.02]. The median overall survival was 14.8 months [95% CI: 9-Not reached (NR)] vs. 26.9 months (26.3 vs. NR, p = 0.006) for the EMD and non-EMD cohorts, respectively. Extramedullary disease represents an independent predictor of inferior day 90 ORR and PFS among patients treated with ide-cel.
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Mieloma Múltiple , Humanos , Mieloma Múltiple/tratamiento farmacológico , Masculino , Femenino , Persona de Mediana Edad , Anciano , Adulto , Anciano de 80 o más Años , Extractos de Tejidos/uso terapéutico , Resultado del Tratamiento , Productos Biológicos/uso terapéutico , Estudios Retrospectivos , Inmunoterapia Adoptiva/métodos , Supervivencia sin Progresión , Receptores Quiméricos de AntígenosRESUMEN
Chimeric antigen receptor T cell therapy (CAR-T) and bispecific T cell engagers (TCE) for multiple myeloma (MM) are readily available at many large US medical centers. However, many potentially eligible patients may not be referred to the specialized centers administering these therapies. Perspectives regarding potential barriers for MM cellular therapy from referring-center oncologists (ROs) versus treating-center oncologists (TOs) have not been reported previously. We conducted TACTUM-23, a survey of US oncologists who treat MM, to identify perceived barriers to these cellular therapies. This 24-question survey, which focused on demographics and perceived barriers to CAR-T and TCE, was conducted between June and August 2023. Of 247 oncologists, 37 (15%) completed the survey including 26 (70%) TOs who prescribed both CAR-T and TCEs, 4 (11%) TOs who only prescribed TCEs, and 7 (19%) ROs who referred patients. The top RO-stated barrier to CAR-T was financial toxicity, while the top TO-stated barrier to CAR-T was leukapheresis/ manufacturing slot availability. The top RO-stated barrier to TCE was financial toxicity, while the top TO-stated barrier to TCE was the hospitalization requirement. In conclusion, financial concerns are perceived by ROs to be the top barrier to both CAR-T and TCEs in myeloma. In contrast, TOs perceive logistical concerns to be the top barrier. Interventions to lower financial toxicity during these therapies, and outreach to raise awareness of such interventions among ROs, are needed alongside strategies to streamline manufacturing (for CAR-T) and monitoring.
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The presence of extramedullary disease (EMD) has been associated with poor outcomes in patients with relapsed-refractory multiple myeloma (RRMM). Herein, we report the outcomes of RRMM patients who were treated with standard-of-care (SOC) chimeric antigen receptor (CAR) T-cell therapy and had active extraosseous EMD before the infusion. Data were retrospectively collected from patients at three US institutions with the intent to receive SOC CAR T. Responses were assessed per the International Myeloma Working Group criteria. A total of 152 patients proceeded with infusion, of whom 47 (31%) had EMD (EMD group) and 105 (69%) did not (non-EMD group). Baseline patient characteristics were comparable between the two groups. The EMD group had a higher incidence of high-grade CRS, steroid and anakinra use, and thrombocytopenia on day +30 compared to the non-EMD group. In addition, the EMD group had an inferior overall response rate (58% vs 96%, p < 0.00001), median progression-free survival (PFS) (5.1 vs 12.4 months; p < 0.0001), and overall survival (OS) (12.2 vs 27.5 months; p = 0.00058) compared to the non-EMD group. We further subdivided the non-EMD patients into those with paramedullary disease (PMD-only group, n = 26 [17%]) and those with neither EMD nor PMD (bone marrow-contained group or BM-only group, n = 79 [52%]). Patients with PMD-only had similar median PFS (11.2 vs 13.6 months, p = 0.3798) and OS (not reached [NR] vs 27.5 months, p = 0.6446) compared to patients with BM-only disease. However, patients with EMD exhibited inferior median PFS (5.1 vs 13.6 months, p < 0.0001) and OS (12.2 vs 27.5, p = 0.0008) compared to patients in the BM-only group. Treatment with SOC CAR T yielded meaningful clinical outcomes in real-world RRMM patients with extraosseous EMD, though responses and survival outcomes were suboptimal compared to patients without EMD. The presence of only EMD but not PMD was associated with significantly worse survival outcomes following the CAR T infusion.
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Inmunoterapia Adoptiva , Mieloma Múltiple , Humanos , Mieloma Múltiple/terapia , Mieloma Múltiple/mortalidad , Masculino , Femenino , Persona de Mediana Edad , Anciano , Inmunoterapia Adoptiva/métodos , Estudios Retrospectivos , Receptores Quiméricos de Antígenos/uso terapéutico , Adulto , Resultado del Tratamiento , Nivel de Atención , Recurrencia Local de Neoplasia/terapiaRESUMEN
BACKGROUND: The optimal timing of vaccination with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines after cellular therapy is incompletely understood. The objectives of this study are to determine whether humoral and cellular responses after SARS-CoV-2 vaccination differ if initiated <4 months versus 4-12 months after cellular therapy. METHODS: We conducted a multicenter, prospective, observational study at 30 cancer centers in the United States. SARS-CoV-2 vaccination was administered as part of routine care. We obtained blood prior to and after vaccinations at up to 5 time points and tested for SARS-CoV-2 spike (anti-S) IgG in all participants and neutralizing antibodies for Wuhan D614G, Delta B.1.617.2, and Omicron B.1.1.529 strains, as well as SARS-CoV-2-specific T-cell receptors, in a subgroup. RESULTS: We enrolled 466 allogeneic hematopoietic cell transplantation (HCT) (n = 231), autologous HCT (n = 170), and chimeric antigen receptor T-cell (CAR-T-cell) therapy (n = 65) recipients between April 2021 and June 2022. Humoral and cellular responses did not significantly differ among participants initiating vaccinations <4 months versus 4-12 months after cellular therapy. Anti-S IgG ≥2500â U/mL was correlated with high neutralizing antibody titers and attained by the last time point in 70%, 69%, and 34% of allogeneic HCT, autologous HCT, and CAR-T-cell recipients, respectively. SARS-CoV-2-specific T-cell responses were attained in 57%, 83%, and 58%, respectively. Pre-cellular therapy SARS-CoV-2 infection or vaccination and baseline B-cell count were key predictors of post-cellular therapy immunity. CONCLUSIONS: These data support mRNA SARS-CoV-2 vaccination prior to, and reinitiation 3 to 4 months after, cellular therapies with allogeneic HCT, autologous HCT, and CAR-T-cell therapy.
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Anticuerpos Neutralizantes , Anticuerpos Antivirales , Vacunas contra la COVID-19 , COVID-19 , Trasplante de Células Madre Hematopoyéticas , SARS-CoV-2 , Humanos , Vacunas contra la COVID-19/inmunología , Vacunas contra la COVID-19/administración & dosificación , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Femenino , COVID-19/prevención & control , COVID-19/inmunología , SARS-CoV-2/inmunología , Adulto , Anticuerpos Antivirales/sangre , Anticuerpos Neutralizantes/sangre , Anciano , Vacunación , Inmunoterapia Adoptiva/métodos , Inmunoglobulina G/sangre , Receptores Quiméricos de Antígenos/inmunología , Glicoproteína de la Espiga del Coronavirus/inmunología , Estados UnidosRESUMEN
Chimeric antigen receptor T-cell (CAR T-cell) therapy has changed the paradigm of management of non-Hodgkin's lymphoma (NHL) and Multiple Myeloma. Infection complications have emerged as a concern that can arise in the setting of therapy and lead to morbidity and mortality. In this review, we classified infection complications into three categories, pre-infusion phase from the time pre- lymphodepletion (LD) up to day zero, early phase from day of infusion to day 30 post-infusion, and late phase after day 30 onwards. Infections arising in the pre-infusion phase are closely related to previous chemotherapy and bridging therapy. Infections arising in the early phase are more likely related to LD chemo and the expected brief period of grade 3-4 neutropenia. Infections arising in the late phase are particularly worrisome because they are associated with adverse risk features including prolonged neutropenia, dysregulation of humoral and adaptive immunity with lymphopenia, hypogammaglobinemia, and B cell aplasia. Bacterial, respiratory and other viral infections, protozoal and fungal infections can occur during this time . We recommend enhanced supportive care including prompt recognition and treatment of neutropenia with growth factor support, surveillance testing for specific viruses in the appropriate instance, management of hypogammaglobulinemia with repletion as appropriate and extended antimicrobial prophylaxis in those at higher risk (e.g. high dose steroid use and prolonged cytopenia). Finally, we recommend re-immunizing patients post CAR-T based on CDC and transplant guidelines.
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This systematic review aimed to evaluate the proportion of primary and secondary endpoints in hematopoietic stem cell transplant (HSCT) phase III randomized clinical trials (RCTs) and analyze their trends in time and study sponsorship status. The Chi-square test and logistic regression analyses were performed using SPSS version 28. A total of 147 HSCT phase III RCTs from 2006 to 2021 reported 197 primary and 600 secondary endpoints. Overall survival (OS, 17 %), progression-free survival (PFS, 15 %), graft versus host disease (GVHD, 8 %), event-free survival (EFS, 8 %), and organ function (8 %) were the most common primary endpoints. GVHD (12.3 %, n = 74), safety/toxicity/adverse events (11.8 %, n = 71), OS (11.5 %, n = 69), PFS (9.3 %, n = 56), and relapse rate (RR; 7.5 %, n = 45) were the most common secondary endpoints during 2006-2021. After 2013, an increase was noted in the use of PFS as a primary endpoint (12 %-18 %, p = 0.196), while the use of OS as a primary endpoint declined (20 %-13 %, p = 0.170). An increase was observed in using the secondary endpoints RR (5 %-10 %, p = 0.047) and NRM (3 %-6 %, p = 0.047). EFS was used more (14 % vs. 4 %, p = 0.012) than ORR (11 % vs. 2 %, p = 0.003) as a primary endpoint in pharmaceutical-compared to non-pharmaceutical-sponsored studies. As secondary endpoints, the use of EFS (4 % vs. 1 %, p = 0.013) and ORR (4 % vs. 1 %, p = 0.028) was higher, whereas that of organ systems/functions (1.5 % vs. 5.5 %, p = 0.022) and GVHD (6.5 % vs. 15 %, p = 0.002) was lower in pharmaceutical-compared to non-pharmaceutical sponsored studies. GVHD-free relapse-free survival was reported as a primary endpoint in 2 % of studies, while only 5 % reported quality of life as a secondary endpoint. We described commonly used endpoints in HSCT phase III RCTs and patterns in their use over time by funding source and study intervention category.
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Enfermedad Injerto contra Huésped , Trasplante de Células Madre Hematopoyéticas , Humanos , Ensayos Clínicos Fase III como Asunto , Enfermedad Injerto contra Huésped/etiología , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Preparaciones Farmacéuticas , Ensayos Clínicos Controlados Aleatorios como Asunto , Trasplante HomólogoRESUMEN
Vacuoles, E1 syndrome, X-linked, autoinflammatory, somatic (VEXAS) syndrome is a chronic inflammatory disorder that affects various organ systems. It is associated with hematologic malignancies and is generally refractory to therapies. Allogeneic hematopoietic stem cell transplantation (allo-HSCT) may be considered for selected patients. We report a case wherein systemic and hematological manifestations completely resolved in a patient with VEXAS and associated myelodysplastic syndrome (MDS), following the administration of fludarabine and cyclophosphamide as part of the preparation for allo-HSCT. We conducted a systematic literature review and included 86 patients with VEXAS syndrome and associated MDS. Most cases presented with musculoskeletal involvement (71%) and anemia (72%) with lower-risk MDS. Most patients responded to corticosteroids (CS) but had a recurrence of symptoms with CS taper and were refractory to other immunosuppressive agents. Hypomethylating agents and Janus kinase inhibitors achieved a complete response in some cases. Further research is needed to develop more effective treatment strategies.
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BACKGROUND: We aimed to investigate factors associated with cytomegalovirus (CMV) viremia and CMV disease and its impact on post-transplant outcomes including overall survival (OS) following allogeneic hematopoietic stem cell transplantation (Allo-SCT). METHODS: We conducted a single-center retrospective study including 452 Allo-SCT recipients (matched unrelated donor, MUD 61%; haploidentical, haplo 39%) from 2016 to 2021. Data were analyzed using SPSS v28. Descriptive (chi-square and t-test), Kaplan-Meier and regression analyses were conducted. RESULTS: The median age was 57 years. Sixty-one percent were males and 84.3% were Caucasians. CMV serostatus was positive in 59.1% of recipients. The median follow-up was 24.4 months. CMV viremia and CMV disease were observed in 181 (40%) and 32 (7%) patients, respectively. Among CMV seropositive recipients, 65% developed CMV viremia and 11% were noted to have CMV disease compared to 4% and 1% in seronegative recipients, respectively (p < 0.001). Patients with CMV disease had significantly lower OS than those without CMV disease (median 14.1 months vs. not reached, p = 0.024); however, OS was not associated with CMV viremia (median not reached in both groups, p = 0.640). Letermovir prophylaxis was used in 66% (n = 176/267) of CMV seropositive recipients, but no impact was observed on the incidence of CMV viremia or CMV disease and OS. CONCLUSIONS: CMV disease leads to significantly inferior survival after an allogeneic hematopoietic cell transplantation. Recipient CMV seropositive status was associated with the risk of CMV viremia and CMV disease, and this was not abrogated with the use of Letermovir prophylaxis.
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Infecciones por Citomegalovirus , Citomegalovirus , Trasplante de Células Madre Hematopoyéticas , Trasplante Homólogo , Activación Viral , Humanos , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Masculino , Persona de Mediana Edad , Femenino , Infecciones por Citomegalovirus/mortalidad , Estudios Retrospectivos , Citomegalovirus/fisiología , Adulto , Anciano , Estudios de Seguimiento , Adulto Joven , Viremia/epidemiología , Adolescente , Factores de Riesgo , PronósticoRESUMEN
ABSTRACT: The optimal management of patients with relapsed/refractory large B-cell lymphoma (LBCL) after disease progression or lack of response to second-line (2L) therapy remains unclear. Here, we report outcomes among patients who received subsequent antilymphoma therapy per investigator discretion separately by their randomized 2L arm in ZUMA-7, namely axicabtagene ciloleucel (axi-cel) vs standard of care (SOC). Progression-free survival (PFS) and overall survival (OS) were calculated from 3L therapy initiation. In the SOC arm, 127 of 179 randomized patients (71%) received 3L therapy. Median PFS among those who received 3L cellular immunotherapy (n = 68) vs those who did not (n = 59) was 6.3 vs 1.9 months, respectively; median OS was 16.3 vs 9.5 months, respectively. In the axi-cel arm, 84 of 180 randomized patients (47%) received 3L therapy. Median PFS among those who received 3L chemotherapy (n = 60) vs cellular immunotherapy (n = 8) was 1.7 vs 3.5 months, respectively; median OS was 8.1 months vs not reached, respectively. Of the 60 patients who received 3L chemotherapy, 10 underwent stem cell transplantation (SCT) after salvage chemotherapy. Median PFS was 11.5 vs 1.6 months, and median OS was 17.5 vs 7.2 months for those who did vs did not reach SCT, respectively. Eight patients received 3L cellular immunotherapy after 2L axi-cel. Of these, 6 patients received subsequent SCT in any line; all 6 were alive at data cutoff. These findings help inform subsequent treatment choices after 2L therapy failure for relapsed/refractory LBCL. The trial was registered at www.clinicaltrials.gov as #NCT03391466.
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Productos Biológicos , Linfoma de Células B Grandes Difuso , Nivel de Atención , Humanos , Productos Biológicos/uso terapéutico , Femenino , Masculino , Persona de Mediana Edad , Anciano , Linfoma de Células B Grandes Difuso/terapia , Linfoma de Células B Grandes Difuso/tratamiento farmacológico , Linfoma de Células B Grandes Difuso/mortalidad , Resultado del Tratamiento , Adulto , Receptores de Antígenos de Linfocitos T/uso terapéutico , Inmunoterapia Adoptiva/métodosRESUMEN
Background: The optimal timing of vaccination with SARS-CoV-2 vaccines after cellular therapy is incompletely understood. Objective: To describe humoral and cellular responses after SARS-CoV-2 vaccination initiated <4 months versus 4-12 months after cellular therapy. Design: Multicenter prospective observational study. Setting: 34 centers in the United States. Participants: 466 allogeneic hematopoietic cell transplant (HCT; n=231), autologous HCT (n=170), or chimeric antigen receptor T cell (CAR-T cell) therapy (n=65) recipients enrolled between April 2021 and June 2022. Interventions: SARS-CoV-2 vaccination as part of routine care. Measurements: We obtained blood prior to and after vaccinations at up to five time points and tested for SARS-CoV-2 spike (anti-S) IgG in all participants and neutralizing antibodies for Wuhan D614G, Delta B.1.617.2, and Omicron B.1.1.529 strains, as well as SARS-CoV-2-specific T cell receptors (TCRs), in a subgroup. Results: Anti-S IgG and neutralizing antibody responses increased with vaccination in HCT recipients irrespective of vaccine initiation timing but were unchanged in CAR-T cell recipients initiating vaccines within 4 months. Anti-S IgG ≥2,500 U/mL was correlated with high neutralizing antibody titers and attained by the last time point in 70%, 69%, and 34% of allogeneic HCT, autologous HCT, and CAR-T cell recipients, respectively. SARS-CoV-2-specific T cell responses were attained in 57%, 83%, and 58%, respectively. Humoral and cellular responses did not significantly differ among participants initiating vaccinations <4 months vs 4-12 months after cellular therapy. Pre-cellular therapy SARS-CoV-2 infection or vaccination were key predictors of post-cellular therapy anti-S IgG levels. Limitations: The majority of participants were adults and received mRNA vaccines. Conclusions: These data support starting mRNA SARS-CoV-2 vaccination three to four months after allogeneic HCT, autologous HCT, and CAR-T cell therapy. Funding: National Marrow Donor Program, Leukemia and Lymphoma Society, Multiple Myeloma Research Foundation, Novartis, LabCorp, American Society for Transplantation and Cellular Therapy, Adaptive Biotechnologies, and the National Institutes of Health.
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PURPOSE: Although chimeric antigen receptor T therapy (CAR-T) cells are an established therapy for relapsed/refractory multiple myeloma (RRMM), there are no established models predicting outcome to identify patients who may benefit the most from CAR-T. PATIENTS AND METHODS: This is an international retrospective observational study including patients with RRMM infused with currently available commercial or academically produced anti-B-cell maturation antigen (BCMA) CAR-T. We describe characteristics and outcomes in Europe (n = 136) and the United States (n = 133). Independent predictors of relapse/progression built a simple prediction model (Myeloma CAR-T Relapse [MyCARe] model) in the training cohort (Europe), which was externally validated (US cohort) and tested within patient- and treatment-specific subgroups. RESULTS: The overall response rate was 87% and comparable between both cohorts, and complete responses were seen in 48% (Europe) and 49% (the United States). The median time to relapse was 5 months, and early relapse <5 months from infusion showed poor survival across cohorts, with the 12-month overall survival of 30% (Europe) and 14% (the United States). The presence of extramedullary disease or plasma cell leukemia, lenalidomide-refractoriness, high-risk cytogenetics, and increased ferritin at the time of lymphodepletion were independent predictors of early relapse or progression. Each factor received one point, forming the three-tiered MyCARe model: scores 0-1 (low risk), scores 2-3 (intermediate risk), and a score of 4 (high risk). The MyCARe model was significantly associated with distinct 5-month incidence of relapse/progression (P < .001): 7% for low-risk, 27% for intermediate-risk, and 53% for high-risk groups. The model was validated in the US cohort and maintained prognostic utility for response, survival, and outcomes across subgroups. CONCLUSION: Outcomes of patients with RRMM after CAR-T are comparable between Europe and the United States. The MyCARe model may facilitate optimal timing of CAR-T cells in patient-specific subgroups.
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Antígeno de Maduración de Linfocitos B , Inmunoterapia Adoptiva , Mieloma Múltiple , Humanos , Mieloma Múltiple/terapia , Mieloma Múltiple/mortalidad , Mieloma Múltiple/inmunología , Persona de Mediana Edad , Masculino , Estudios Retrospectivos , Femenino , Anciano , Inmunoterapia Adoptiva/métodos , Antígeno de Maduración de Linfocitos B/inmunología , Estados Unidos , Adulto , Receptores Quiméricos de Antígenos/inmunología , Europa (Continente) , Resultado del Tratamiento , Recurrencia Local de Neoplasia/terapiaRESUMEN
We conducted a systematic review and meta-analysis to evaluate outcomes after allogeneic hematopoietic stem cell transplantation (Allo-HSCT) in TP53-mutated myelodysplastic syndromes (MDS). A literature search was performed on PubMed, Cochrane, Embase, and Clinicaltrials.gov. After screening 626 articles, eight studies were included. Data were extracted following the PRISMA guidelines and analyzed using the meta-package by Schwarzer et al. We analyzed 540 patients. The pooled median 3 (1-5) year overall survival was 21% (95% CI 0.08-0.37, I2=91%, n=540). The pooled relapse rate was 58.9% (95% CI 0.38-0.77, I2=93%, n=487) at a median of 1.75 (1-3) years. The pooled 4-year progression- free survival was 34.8% (95% CI 0.15-0.57, I2=72%, n=105). Outcomes of Allo-HSCT for TP53-mutated MDS patients remain poor, with 21% OS at three years; however, Allo-HSCT confers a survival advantage as compared to non-transplant palliative therapies. Our findings suggest the need to explore novel therapeutic agents in prospective clinical trials.
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Trasplante de Células Madre Hematopoyéticas , Síndromes Mielodisplásicos , Humanos , Estudios Prospectivos , Síndromes Mielodisplásicos/genética , Síndromes Mielodisplásicos/terapia , Supervivencia sin Progresión , Acondicionamiento Pretrasplante , Proteína p53 Supresora de Tumor/genéticaRESUMEN
ABSTRACT: Tisagenlecleucel is approved for adults with relapsed/refractory (r/r) follicular lymphoma (FL) in the third- or later-line setting. The primary analysis (median follow-up, 17 months) of the phase 2 ELARA trial reported high response rates and excellent safety profile in patients with extensively pretreated r/r FL. Here, we report longer-term efficacy, safety, pharmacokinetic, and exploratory biomarker analyses after median follow-up of 29 months (interquartile range, 22.2-37.7). As of 29 March 2022, 97 patients with r/r FL (grades 1-3A) received tisagenlecleucel infusion (0.6 × 108-6 × 108 chimeric antigen receptor-positive viable T cells). Bridging chemotherapy was allowed. Baseline clinical factors, tumor microenvironment, blood soluble factors, and circulating blood cells were correlated with clinical response. Cellular kinetics were assessed by quantitative polymerase chain reaction. Median progression-free survival (PFS), duration of response (DOR), and overall survival (OS) were not reached. Estimated 24-month PFS, DOR, and OS rates in all patients were 57.4% (95% confidence interval [CI], 46.2-67), 66.4% (95% CI, 54.3-76), and 87.7% (95% CI, 78.3-93.2), respectively. Complete response rate and overall response rate were 68.1% (95% CI, 57.7-77.3) and 86.2% (95% CI, 77.5-92.4), respectively. No new safety signals or treatment-related deaths were reported. Low levels of tumor-infiltrating LAG3+CD3+ exhausted T cells and higher baseline levels of naïve CD8+ T cells were associated with improved outcomes. Tisagenlecleucel continued to demonstrate highly durable efficacy and a favorable safety profile in this extended follow-up of 29 months in patients with r/r FL enrolled in ELARA. This trial was registered at www.clinicaltrials.gov as #NCT03568461.