EHA 2025 | Cytopenias & infections following cilta-cel in heavily pretreated patients with R/R multiple myeloma

Hello, everyone. My name is Dr Danai Dima, and I’m an assistant professor of hematology and medical oncology at the Fred Hutch Cancer Center of the University of Washington in Seattle. Today, I will be presenting our work that was presented at EHA in 2025 in Milan, Italy, with the title Cytopenias and Infections Following Ciltacabtagene autoleucel in Heavily Pretreated Relapsed or Refractory Multiple Myeloma. 

So a little bit of introduction here. So ciltacabtagene autoleucel or cilta-cel is a second-generation autologous BCMA-targeting CAR T-cell therapy that was approved for relapsed/refractory multiple myeloma in February of 2022 based on the results of the CARTITUDE-1 trial. So CARTITUDE-1 showed a 98% overall response rate, which is pretty impressive, and 83% CR rate, with a median progression-free survival of 34.9 months. So despite this very impressive efficacy, cilta-cel has been linked to some serious and potentially life-threatening toxicities. Cytopenias were the most common treatment-related adverse event in the CARTITUDE-1 trial, including neutropenia of grade 3 or more in 95% of patients, grade 3 or more anemia in 68% of patients, and grade 3 or more thrombocytopenia in 60% of patients, with most of those cytopenias improving to grade 2 or less by day 60. So cytopenias were commonly managed with growth factors and blood product transfusions in the trial. 

Infections were also common in the trial and were noted in more than 50% of the patients, with 20% of these infections being characterized as severe, and we had also a 4% of patients dying due to infections. Upper respiratory tract infections were the most common overall, and the most common severe infections were pneumonia and sepsis. Although infections and cytopenias are well-known complications related to myelosuppression, post-cilta-cel infusion, longitudinal data on duration and recovery of cytopenias in the real world are limited. 

So in this study, we evaluated cellular reconstitution infections and the requirement for supportive interventions in response to treatment-related cytopenias among patients who were treated with commercial cilta-cel before its recent approval in the second-line setting. The goal was to enhance our understanding of both short and long-term safety of cilta-cel, particularly for patients who would have been excluded from the clinical trial because of major comorbidities or severe cytopenias. And overall, we were hoping that this data will help optimize supportive care strategies and improve patient outcomes. 

Moving forward to the methods section, so this was a multi-institutional retrospective analysis that included patients from five US institutions. These patients received standard of care cilta-cel after four or more prior lines of therapy between May 11 of 2022 and May 30 of 2023. So cytopenia data were collected at apheresis, at lymphodepletion, and then at several time points after the infusion, including day 0, 7, 14, 21, 30, 90, and then at six months. Cytopenias were graded according to the common terminology criteria for adverse events and also with the ICAHT, the newer ICAHT score. Antimicrobial prophylaxis was provided to all patients per institutional guidelines. Overall, this differed a little bit between the centers, but they were similar to what has been published in terms of guidelines for antimicrobial strategies. So they were not identical, but they were basically similar across centers. 

So a little bit about the patient characteristics here. So the study included a total of 105 patients, all of whom underwent apheresis followed by lymphodepleting chemotherapy and cilta-cel infusion. The median time from apheresis to infusion was 69.5 days. All patients had received at least four prior lines of therapy. Among them, 73% were triple-class refractory and 84% had a history of autologous transplant. When gain of 1q was included as a high-risk cytogenetic feature, 72% of patients were classified as carrying high-risk cytogenetics. So lymphodepleting chemotherapy consisted mainly of standard of care FluCy in most of the patient cohort, and 45% of these patients, of the 105 patients, were deemed as ineligible for the CARTITUDE-1 trial. And last, the median follow-up of our subjects here was six months. 

Moving forward to a little bit of the cytopenia data. So those cytopenias were common at baseline with more than 80% of patients having any grade cytopenia at both apheresis in day minus five. Severe cytopenias, which means grade three or higher, were more commonly seen after, of course, the lymphodepletion. So cytopenias were more prevalent at day seven after the infusion with almost all patients experiencing any grade cytopenia and 69% of patients experiencing severe cytopenia. On day seven after cilta-cel, severe neutropenia and anemia had reached their peaks at 59% and 21% respectively. Grade three or more cytopenia of any kind persisted in 52% of patients at day 30 and the median platelet count was at the lowest at day 30. So while cytopenias generally improved over time, there were 13% of patients at day 90 and 14% of patients at day 180 that had prolonged severe neutropenia. 

Then we went ahead and we looked cytopenias based on the ICAHT grading, which is the newer grading for neutropenia severity, and we saw that 10% of patients experienced grade 3 or more early ICAHT in the first 30 days after the infusion, while only 3% of patients experienced grade 3 or higher late ICAHT after day 30. And we see here in this bar graph how cytopenias evolved over time. 

So then we went ahead and then we conducted univariable analysis to assess for risk factors for any cytopenia of grade 3 or higher at day 30 and 90. And what we found is at day 30, high risk of severe cytopenias of any kind was associated with the following parameters. First, extramedullary disease, high-risk cytogenetics, heavily pretreated patients with more than four prior lines of therapy, any great anemia or thromocytopenia at apheresis, high CAR-HEMATOTOX score, and tocilizumab use. At day 90, patients with severe cytopenias were more likely to be heavily pretreated with triple-class refractory disease and have any great thromocytopenia at apheresis. 

Moving forward to the supportive care, so a total of 68 patients received GCSF support with a median duration of 23.5 days and ending at a median of 32.5 days post-infusion. So neutrophilic recovery occurred at a median of 16.5 days following cilta-cel infusion. 38% of the patients received transfusional support at any time post-cilta-cel, mostly within the first 30 days. Transfusions after day 30 were needed in 15% of patients with red blood cells and 14% of patients with platelets. 10% of patients received TPO ongoing support for thrombocytopenia. Half of our cohort received IVIG. And almost 10% of our cohort received a stem cell boost. So all patients except one patient responded to the stem cell boost with a median time of hematologic recovery of 21 days. 

A little bit about infections. So we saw a total of 88 infections in 51 patients. 28 of the infections were severe and were reported in 15 patients. So early infections, which means infections within the first 30 days, were equally bacterial and viral. However, later infections between day 31 and 100 and after day 100 were mostly viral. There were a total of five fungal infections that were mostly thrush, so not severe, and they occurred within the first 30 days. Respiratory infections were the most common type of bacterial infections throughout the study. So in univariate analysis, we saw that ECOG performance status of two or more at lymphodepletion, higher maximum grade of CRS, steroid or anakinra use, and lower IgA levels at day 90 were associated with severe infections. And here we show the timing in this graph, the timing and the distribution of infections overall and severe infections and types of infections. 

So then we went ahead and compared the progression-free survival of patients based on current grading systems for CAR-T-related hematologic toxicity. There was no statistically significant difference in PFS when comparing patients based on the presence of grade 3 or higher cytopenia of any lineage by CTC-AE at day 30 or 90, early ICAHT or late ICAHT of any grade. Only the CAR-HEMATOTOX score was prognostic, showing significantly decreased PFS in patients with high score compared to patients with low score. So at the end of follow-up, 16 of our patients had expired. Of them, 38% died due to disease progression and the rest due to non-relapse mortality. Actually, the non-relapse mortality rate here was 9.5%, which is pretty notable. So the most common cause of non-relapse mortality was infection, and it constituted 31% of all deaths. 

And here we have our conclusions and take-home points. So in summary, cytopenias and infections are common long-term complications following the administration of standard-of-care cilta-cel. Severe grade 3 or higher cytopenias were most common in the first few weeks after cilta-cel, with two-thirds of patients experiencing severe cytopenias between days 7 and 14 post-infusion, but this improved in about half of the patients by day 30 and further improved in months 3 and 6 post-infusion. Treatment of cytopenias, of course, included growth factor support and blood transfusions. A significant proportion of deaths seen in our study were attributed to non-relapse mortality, particularly infections, emphasizing the critical need for enhanced supportive care strategies. So basically, as cilta-cel is increasingly used in earlier lines of therapy, optimizing supportive care protocols such as growth factor administration, IVIG, and infectious prophylaxis will be of critical importance in order to improve patient outcomes. And of course, management of this adverse event often requires close collaboration between CAR-T centers and local oncologists, which is huge because patients after day 30, they tend to go back to their local oncologist, so close collaboration will be critical.

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