Ashling Wahner

Some pediatric patients with B-ALL may benefit from a novel CAR-T cell therapy, according to a presentation at the 2024 ASH Annual Meeting.

Children with relapsed or refractory B-cell acute lymphoblastic leukemia (B-ALL) demonstrated high remission rates after treatment with a novel bicistronic CD19/CD22-directed CAR-T cell therapy.

The treatment also generated durable responses and was shown to be safe among these patients, including those with isolated or combined extramedullary relapsed disease, according to updated data from a phase 2 trial presented at the 

At a median follow-up of 13.9 months, the one-year event-free survival (EFS) rate was 75.5%, and the one-year overall survival (OS) rate was 93.5% among patients enrolled and treated with bicistronic CD19/CD22-directed CAR-T cell therapy (343 patients). 

Bicistronic CD19/CD22 CAR-T cell therapy: a specific type of CAR-T cell therapy that targets two proteins on B-cell leukemia cells: CD19 and CD22.

Event-free survival (EFS): the length of time after treatment that a patient lives without the cancer returning or worsening.

Overall survival (OS): the length of time a patient lives after being diagnosed with cancer, regardless of their disease status, until death of any cause.

Cytokine release syndrome (CRS): when the body releases too many cytokines into the bloodstream and overreacts to an infection or injury. This is a serious condition.

Complete remission (CR): when patients fully respond to treatment, meaning they no longer show signs or symptoms of cancer.

Minimal residual disease negativity: minimal residual disease means a small amount of cancer cells may remain in the body after treatment. Negativity refers to having no traces of cancer in the body after treatment.

Following CAR-T cell expansion, the one-year EFS rates among patients who underwent bridging bone marrow transplant (38 patients) versus those who did not (280 patients) were 89.7% versus 76.8%, respectively. The respective one-year OS rates were 95.8% versus 95.2%.

“After CAR-T cell therapy, we have found that the one-year EFS [rate] is higher [with] CAR-T cell treatment plus bone marrow transplant than CAR-T cell treatment alone, [although the] one-year OS [rates were] very similar between these two [populations],” presenting author Dr. Hua Zhang, vice president and chief scientific officer at SPH Biotherapeutics (HK), Limited, stated in an oral presentation of the data during a virtual press briefing.

Most patients developed cytokine release syndrome (CRS); those with lower-grade CRS had better one-year EFS outcomes than those with higher-grade CRS. Among the 172 patients with grade 1 or 2 (mild or moderate) CRS, the one-year EFS rate was 80.9%. The one-year EFS rate for the 145 patients with grade 3 or 4 (severe or life-threatening) CRS was 69.9%.

In the presentation, Zhang added that “in this study, we found the severity of CRS was not related to the study dose range of infused cells, whereas it was highly correlated with disease burden and CAR-T cell viability.”

Complete Responses to CAR-T Cell Therapy in Pediatric B-ALL

Following treatment, complete remission (CR) to treatment was achieved across all patients in the isolated extramedullary relapse cohort. In the refractory, isolated, combined hematologic relapse cohort, all but one patient with isolated bone marrow relapse achieved a CR. This patient died before their evaluation.

A total of 13 and 228 patients in the isolated bone marrow and bone marrow plus testes relapse subgroups, respectively, underwent subsequent transplantation according to protocol criteria. Notably, 25 additional patients in the isolated bone marrow subgroup underwent transplantation according to parental request.

Based on these results, a phase 1 study of the regimen is underway. Investigators on the study plan to enroll 12 to 18 patients in the study.

Previously reported data from this phase 2 trial showed that co-administration of CD19- and CD22-directed CAR-T cell therapy produced relatively durable EFS rates and a high CR rate among 225 children with relapsed or refractory B-ALL or those at a high risk of hematologic or extramedullary relapse. CR was achieved in 99% of patients (194 patients), all of whom achieved minimal residual disease negativity. 

The 12-month EFS rates were 69.2%, 95% and 68.6%for patients treated for hematologic relapse without consolidative allogeneic hematopoietic cell transplantation (allo-HSCT; 116 patients), isolated testicular relapse (two patients) and isolated central nervous system (CNS) relapse (10 patients), respectively.

Accordingly, investigators developed a bicistronic CD19/CD20-directed CAR-T cell therapy to enhance EFS, OS and safety outcomes for patients with relapsed or refractory B-ALL, regardless of prior exposure to consolidative allo-HSCT after CAR-T cell therapy

“Safety and efficacy of bicistronic CD19/CD22 CAR T cell therapy in childhood B cell acute lymphoblastic leukemia” by Dr. X. Wan, et al. Presented at the 2024 ASH Annual Meeting.

For more news on cancer updates, research and education, don’t forget to 

subscribe to CURE®’s newsletters here.

Articles

A novel bicistronic CD19/CD22-directed CAR-T cell therapy has shown promising results in children with relapsed or refractory B-cell acute lymphoblastic leukemia (B-ALL), achieving high remission rates and durable responses. The phase 2 trial reported a one-year event-free survival (EFS) rate of 75.5% and an overall survival (OS) rate of 93.5%. The therapy was effective across various relapse types, with cytokine release syndrome (CRS) severity correlating with disease burden. A phase 1 study is underway to further explore this treatment's potential.

Treatment with bicistronic CD19/CD22 CAR-T cell therapy has shown event-free survival improvements in children with relapsed or refractory B-ALL.

CAR-T Cell Therapy Shows EFS Benefit in Pediatric Leukemia Subset

Blincyto plus chemotherapy significantly improved disease-free survival rates compared to chemotherapy alone in pediatric patients with standard-risk B-ALL.

In pediatric patients with newly diagnosed standard-risk B-cell acute lymphoblastic leukemia (B-ALL), adding Blincyto (blinatumomab) to chemotherapy significantly improved 3-year disease-free survival (DFS) rates compared with chemotherapy alone.

Patients eligible for the treatment combination are at average or high risk for relapse, according to findings from the interim analysis of the Children’s Oncology Group Study AALL1731, presented during a press briefing ahead of the 

At a median follow-up of 2.5 years, the three-year DFS rate in the overall population of 1,440 patients was 96% with Blincyto plus chemotherapy versus 87.9% with chemotherapy alone. In the standard risk-average population, these respective rates were 97.5% (417 patients) and 90.2% (418 patients). In the standard risk-high population, respective rates were 94.1% (301 patients) and 84.8% (304 patients).

Additionally, Blincyto plus chemotherapy reduced rates of bone marrow relapse versus chemotherapy alone in the overall population, as well as in the standard risk-average and standard risk-high populations. Patients who received Blincyto also had a numerically lower cumulative incidence of central nervous system (CNS) relapses versus those who received chemotherapy alone.

Disease-free survival (DFS): time after treatment when patients no long show signs or symptoms of cancer.

Cytogenetic: the study of chromosome changes via tissue, blood or bone marrow testing.

End-of-induction (EOI): the end of a phase of treatment.

Minimal residual disease (MRD): small traces of cancer left in the body after cancer treatment.

Cytokine release syndrome (CRS): abnormal amounts of cytokines released into the bloodstream, which can become very serious.

Overall survival: time patients live, regardless of disease status, until death of any cause.

“The improvement in DFS was secondary to a significant reduction in bone marrow relapses,” lead study author Dr. Rachel E. Rau, stated in a presentation of the data. “We did not see similar reduction in the [rarer] event of an isolated CNS relapse. This finding was not surprising, given [Blincyto’s] known limited activity in the CNS.”

Rau is an associate professor of pediatrics at the University of Washington and a pediatric hematologist-oncologist at Seattle Children’s Hospital in Washington.

DFS and Safety of Blincyto Plus Chemotherapy in Pediatric B-ALL

A subset analysis in prognostically relevant patient subsets showed that the addition of Blincyto significantly improved DFS outcomes versus chemotherapy alone, regardless of patient sex, most races/ethnicities, cytogenetic risk and end-of-induction bone marrow minimal residual disease (MRD) levels.

“[These findings indicate] that, to an extent, Blincyto neutralizes many of the known or prognostic features of B-ALL,” Rau explained.

Regarding safety, Blincyto target toxicities reported in 624 patients in the first cycle of treatment included cytokine release syndrome (CRS), seizure and encephalopathy (brain disease that alters brain function). Blincyto target toxicities reported in 552 patients during the second cycle of treatment included CRS and seizure. No encephalopathy was reported during the second cycle of Blincyto. 

In the standard risk-average population, higher rates of grade 3 (severe) or higher infectious toxicities were seen in the Blincyto group of 351 patients versus the chemotherapy alone group of 376 patients, including febrile neutropenia (low blood cell count and a fever), sepsis (body’s overreaction to an infection) and catheter-related infections (flexible tube inserted into bladder) and other infections.

“Most of the differences in the rates [of sepsis and catheter-related infections] were attributable to increased events in the chemotherapy blocks that followed [Blincyto] therapy,” Rau said.

In the standard risk–high population, higher rates of grade 3 or higher febrile neutropenia, sepsis and catheter-related infections were also seen in the Blincyto group versus the chemotherapy alone group. However, the rate of other infections was higher in the chemotherapy alone group (37.9%) versus the Blincyto group (35.2%). No differences in grade 4 or 5 (life-threatening to fatal) side effects were observed between the randomized trial groups.

No deaths were reported during Blincyto cycles, and no deaths were attributed to Blincyto in randomly assigned patients.

“Overall, our results demonstrate that Blincyto added to chemotherapy represents a new treatment standard for most patients with NCI standard-risk B-ALL,” Rau said.

In AALL1731, groups A and C enrolled standard risk-average patients and standard risk-high patients, respectively, to receive chemotherapy alone. Groups B and D enrolled standard risk-average patients and standard risk­-high patients, respectively, to receive standard consolidation chemotherapy followed by the first cycle of Blincyto, the second cycle of Blincyto and maintenance chemotherapy.

Overall, clinical, demographic and disease characteristics were balanced across the two risk categories. The median age of patients was 4.3 years old and the majority of patients were boys (52.6%). Hispanic patients comprised 25.8% of the population, and 5.6% of patients were non-Hispanic Black.

“Our standard risk-favorable patients are known to have an excellent survival with standard chemotherapy alone, and thus they were nonrandomly assigned to standard treatment,” Rau added.

Patients classified as standard risk-high were further arranged according to MRD status at the end of the consolidation phase per flow cytometric analysis of bone marrow.

The trial’s primary objective was DFS and other key exploratory objectives included the duration of overall survival, relapse and safety. The data cutoff for the current analysis was June 30, 2024.

 by the Food and Drug Administration for the treatment of adult and pediatric patients at least 1 month of age with CD19-positive, Ph-negative, B-ALL in the consolidation phase, regardless of MRD status.

“Blinatumomab added to chemotherapy improves disease-free survival in newly diagnosed NCI standard risk pediatric B-acute lymphoblastic leukemia: results from the randomized Children’s Oncology Group” by Dr. S. Gupta, et al. 

Adding Blincyto (blinatumomab) to chemotherapy in pediatric patients with standard-risk B-cell acute lymphoblastic leukemia (B-ALL) significantly enhances 3-year disease-free survival (DFS) rates compared to chemotherapy alone. The Children’s Oncology Group Study AALL1731 interim analysis showed improved DFS across various risk populations, with notable reductions in bone marrow relapse. Blincyto's safety profile includes cytokine release syndrome and infections, with no deaths attributed to the drug. These findings suggest Blincyto plus chemotherapy as a new treatment standard for most NCI standard-risk B-ALL patients.

Pediatric patients with standard-risk B-ALL demonstrated significantly improved disease-free survival with Blincyto plus chemotherapy versus chemotherapy alone.

Blincyto With Chemo May Improve Disease-Free Survival in Pediatric B-ALL

Magrolimab plus docetaxel improved outcomes in patients with metastatic NSCLC and high CD47 expression, according to a study.

Improved outcomes were seen with magrolimab plus docetaxel in patients with metastatic non-small cell lung cancer (NSCLC) who had higher CD47 expressions, according to a presentation on the phase 2 ELEVATELung&UC trial at the 2024 Society for Immunotherapy of Cancer (SITC) Annual Meeting.

Magrolimab is a type of monoclonal antibody that targets CD47 by binding to it, according to the National Cancer Institute. When the drug binds to CD47, it helps destroy the cancer cells directly. In the study, magrolimab was combined with docetaxel, a type of chemotherapy. 

The study included 31 patients with metastatic NSCLC who previously received treatment in the second- or later-line setting. Researchers found that patients with NSCLC with confirmed partial responses (PRs) or complete responses (CRs) to magrolimab plus docetaxel had higher baseline levels of CD47 expression.

Among patients with CD47 expression on more than 50% of tumor cells, the median progression-free survival (PFS) was 8.9 months versus 2.6 months for those with baseline CD47 expression below 50%. The median PFS in the NSCLC population treated with magrolimab plus docetaxel was 5.4 months.

Higher CD47 expression: a marker in some cancers, such as NSCLC, that helps determine survival outcomes. Higher CD47 expression is associated with poorer survival outcomes.

Partial responses (PRs): shrinkage in patients’ tumors after treatment.

Complete responses (CRs): disappearance of tumors after treatment.

Progression-free survival (PFS): time patients live without their cancer worsening or spreading.

ECOG performance score: measures patients’ independence when performing daily tasks. A score of 0 means full independence and 4 means full dependence on others. 

Overall responses: percentage of patients in the study who had a partial or complete response to treatment.

Stable disease (SD): the disease has not gotten worse or better with treatment.

Progressive disease (PD): disease that has worsened or spread after treatment.

“Despite a limited sample size, the correlation between CD47 expression and better outcome in both [ELEVATELung&UC] and in Tempus real-world data of patients treated with chemotherapy and/or [immunotherapy] suggests a positive prognostic role for CD47 in metastatic NSCLC,” lead study author Nick van Buuren, of Gilead Sciences and coauthors, wrote in a poster of the data.

Among the 31 patients with metastatic NSCLC in the study who received treatment (intent-to-treat population; ITT), the median age was 65 years. Most patients were male (77.4%), White (90.3%), had stage 4 disease (96.8%), had an ECOG performance score of 1 at baseline (54.8%) and were former smokers (58.1%). The best overall responses to magrolimab plus docetaxel in this population included CR or PR (19.4%), stable disease (SD; 38.7%) and progressive disease (PD; 16.1%).

The biomarker-evaluable population was a subset of 24 patients with stage 4 NSCLC who had reportable baseline CD47 results. The patient characteristics and best overall response rates reflected those observed in the ITT population. In this population, the median age was 64 years. Most patients were male (75%), White (87.5%), had an ECOG performance score of 1 at baseline (62.5%) and were former smokers (50%). Best overall responses to magrolimab plus docetaxel in this population included CR or PR (20.8%), SD (37.5%) and PD (12.5%).

The ELEVATE-Lung&UC trial evaluated the safety, tolerability and effectiveness of magrolimab plus docetaxel in patients with metastatic NSCLC, metastatic small cell lung cancer and metastatic bladder cancer.

Patients with mNSCLC must have received one or two prior lines of platinum-based chemotherapy, a checkpoint inhibitor or both.

Patients received magrolimab at a priming dose of 1 milligram per kilogram (mg/kg) on cycle one day one, followed by a weekly dose of 30 mg/kg from cycle one day eight to cycle two day 15. After, patients received a maintenance dose of 60 mg/kg every three weeks from cycle three day one onward. Docetaxel was given at 75 mg per square meter every three weeks.

In February 2024, Gilead announced a global pause in enrollment to studies investigating magrolimab in patients with solid tumors, including ELEVATELung&UC, to review the risk-benefit profile of magrolimab across the trials. The FDA subsequently requested a partial clinical hold on these trials.

Gilead later decided to terminate the ELEVATELung&UC trial.

“Biomarker analysis of magrolimab plus docetaxel in patients from ELEVATE-Lung and UC, a phase 2 multicohort study” by Nick van Buuren, et al., 2024 SITC Annual Meeting.

For more news on cancer updates, research, and education, don’t forget to 

The ELEVATELung&UC trial demonstrated improved outcomes in metastatic NSCLC patients with high CD47 expression treated with magrolimab plus docetaxel. Magrolimab, a monoclonal antibody targeting CD47, showed enhanced efficacy in patients with over 50% CD47 expression, achieving a median PFS of 8.9 months compared to 2.6 months in those with lower expression. Despite promising results, the trial was terminated following a global pause and FDA partial clinical hold due to safety concerns. The study highlighted CD47's potential prognostic role in metastatic NSCLC.

Patients with metastatic non-small cell lung cancer and high CD47 expression showed improved responses to treatment with magrolimab plus docetaxel. 

Magrolimab-Chemo Combo Improves Responses in Metastatic NSCLC

PD-L1 expression levels were found to predict improved outcomes with Opdivo and Yervoy in patients with ccRCC, while high KIM-1 levels were associated with worse outcomes.

PD-L1 expression levels were found to be predictive of improved outcomes with Opdivo (nivolumab) and the CTLA-4 inhibitor Yervoy (ipilimumab) in patients with clear cell renal cell carcinoma (ccRCC), whereas high KIM-1 expression led to worse outcomes in this patient population with Opdivo alone or with Yervoy, according to findings from the phase 3 CheckMate 914 trial presented at the 2024 SITC Annual Meeting.

Data showed that high KIM-1 levels were associated with worse disease-free survival (DFS) with Opdivo monotherapy versus placebo in patients with ccRCC, as well as a trend toward poor DFS with Opdivo and Yervoy, suggesting that micro-metastatic disease releases KIM-1 into the circulation, as well as that serum KIM-1 is a potential minimally invasive biomarker for resected RCC recurrence. However, KIM-1 levels were not found to be predictive of response to Opdivo alone or with Yervoy versus placebo.

When DFS was evaluated across study groups stratified by patients with PD-L1 expression lower than 1% (663 patients) and 1% or higher (87 patients), results showed that PD-L1 expression was determined to be predictive of response to Opdivo and Yervoy. Higher baseline PD-L1 levels were significantly associated with better DFS, showing consistency with results from the phase 3 KEYNOTE-564 trial of adjuvant Keytruda (pembrolizumab) in patients with RCC.

However, patients who had higher fibroblast levels within the tumor microenvironment had shorter DFS with Opdivo plus Yervoy compared with Opdivo alone.

Disease-free survival (DFS): the length of time a patient remains free of cancer or disease after treatment.

Overall survival (OS): the length of time a patient survives after being diagnosed.

Tumor microenvironment: the surrounding area of a tumor

Immune checkpoint inhibitors: they help the immune system recognize and attack cancer cells.

Biomarkers: indicators that can signal a condition or the effect of treatment.

“In the adjuvant setting, tumor PD-L1 expression is potentially predictive of favorable [Opdivo] plus [Yervoy] outcome, while high circulating KIM-1 levels are prognostic of worse clinical outcomes,” co-first study authors Sai Vikram Vemula, precision medicine/biomarker lead of immuno oncology at Bristol Myers Squibb, and Dr. Wenxin (Vincent) Xu, an assistant professor of medicine at Harvard Medical School/Dana-Farber Cancer Institute in Boston, Massachusetts, wrote alongside coinvestigators in a poster presented during the meeting. “Patients with PD-L1 expression may be enriched with immune cell populations, contributing to better immunotherapy response.”

Rationale and Design of This Biomarker Analysis

An unmet need exists for predictive biomarkers for immune checkpoint inhibitors in the treatment of patients with ccRCC. Prior data from part A of the CheckMate 914 trial showed that PD-L1 expression and serum KIM-1 levels are independently associated with treatment effect from Opdivo combined with Yervoy versus placebo in patients with localized ccRCC.

In the analysis presented at the 2024 SITC Annual Meeting, investigators further evaluated the role of PD-L1 and KIM-1 for association with Opdivo alone and with Yervoy in part B of the CheckMate 914 trial; they also explored a novel human-interpretable image feature–based platform to characterize the cell and tissue composition from hematoxylin and eosin whole-slide images. This was to assess the platform’s potential to identify novel prognostic and predictive biomarkers for immunotherapy response in RCC.

Part B of CheckMate 914 comprised 825 patients with RCC with predominant clear cell histology. Patients could not have any clinical or radiological evidence of residual disease or distant metastases after nephrectomy.

The median follow-up was 27 months. Additional results showed that serum KIM-1 levels were linked with age and nephrectomy status. Higher levels of KIM-1 were more commonly reported in those who were older than 65 years of age and had undergone partial nephrectomy.

Investigators also explored the association of on-treatment changes in KIM-1 with response to Opdivo alone and with Yervoy. Results showed that on-treatment increase in circulating KIM-1 was linked with shorter DFS, suggesting that KIM-1 could be an early predictor for response to single-agent Opdivo and Opdivo plus Yervoy in this setting.

Furthermore, patients with PD-L1 expression levels of 1% or higher had higher levels of macrophages, lymphocytes and neutrophils, which are all types of white blood cells, indicating a potentially inflamed tumor microenvironment; endothelial cell levels were also lower in this subgroup.

The primary end point was DFS for Opdivo versus placebo, and secondary end points were DFS for Opdivo versus Opdivo/Yervoy, overall survival (OS) for Opdivo versus placebo, OS for Opdivo versus Opdivo/Yervoy and safety.

The authors concluded that these observations should be explored in further clinical trials.

"Integrative biomarkers analysis from the Phase 3 CheckMate 914 trial of nivolumab plus ipilimumab or nivolumab versus placebo for adjuvant clear cell renal cell carcinoma (ccRCC)" by Dr. Vemula SV, et al., presented at: 2024 SITC Annual Meeting; November 6-10, 2024; Houston, TX.

"Overall survival with adjuvant pembrolizumab in renal-cell carcinoma" by Dr. Choueiri TK, et al., 

"Adjuvant nivolumab plus ipilimumab versus placebo for localized renal cell carcinoma after nephrectomy (CheckMate 914): a double-blind, randomised, phase 3 trial" by Dr. Motzer RJ, et al., 

PD-L1 expression levels are predictive of improved outcomes with nivolumab and ipilimumab in clear cell renal cell carcinoma (ccRCC), while high KIM-1 expression correlates with worse outcomes. The CheckMate 914 trial revealed that high KIM-1 levels are linked to poor disease-free survival (DFS) with nivolumab, suggesting KIM-1 as a potential biomarker for RCC recurrence. PD-L1 expression is associated with better DFS, consistent with previous trials. High fibroblast levels in the tumor microenvironment correlate with shorter DFS when treated with nivolumab and ipilimumab.

PD-L1 expression was found to predict better outcomes with Opdivo and Yervoy in patients with ccRCC, while high KIM-1 levels were linked to worse outcomes.

Ashling Wahner

CAR-T Cell Therapy Shows EFS Benefit in Pediatric Leukemia Subset

Blincyto With Chemo May Improve Disease-Free Survival in Pediatric B-ALL

Magrolimab-Chemo Combo Improves Responses in Metastatic NSCLC

PD-L1, KIM-1 Levels May Predict Kidney Cancer Response to Opdivo, Yervoy

Latest News