Andrew Ip, MD, Hackensack Meridian Health’s John Theurer Cancer Center, Hackensack University Medical Center

Dr Ip on Reasons for Studying Real-World CAR T-Cell Therapy Outcomes in LBCL

“CAR T-cell [therapy] is now a curative option for second-line, third-line, or [later] LBCL. A lot of the trials [evaluating these agents] excluded certain patients, including very old or frail patients or [those with] different comorbidities. It’s always good to confirm these sort of rigorous trials with real-world data.”

Andrew Ip, MD, Hackensack Meridian Health’s John Theurer Cancer Center, Hackensack University Medical Center, discussed the rationale for conducting a retrospective real-world analysis of outcomes with CAR T-cell therapy in patients with large B-cell lymphoma (LBCL).

Although CAR T-cell therapy is a curative second- or later-line treatment option for many patients with LBCL, several clinical trials investigating this treatment class have excluded select patients who are elderly or have comorbidities, Ip began. Furthermore, real-world studies are often limited to sites within a single country, he explained. Therefore, it is important to confirm clinical trial findings in real-world, global patient populations, Ip asserted.

Ip and colleagues conducted a multinational comparative analysis of real-world outcomes with commercial CD19-directed CAR T-cell therapies in patients with LBCL.

This study included 501 patients from 4 centers in the United States and Israel who received commercial CAR T-cell products between April 2016 and January 2024. Patients who received tisagenlecleucel (Kymriah; n = 133) had inferior efficacy outcomes compared with those who received axicabtagene ciloleucel (axi-cel; Yescarta; n = 272) and lisocabtagene maraleucel (liso-cel; Breyanzi; n = 96). Additionally, patients who received liso-cel achieved higher overall response and complete response rates vs those who received axi-cel; however, the progression-free survival and overall survival rates were not significantly different between these populations. Moreover, liso-cel was associated with a more favorable toxicity profile compared with axi-cel. Findings were consistent between subanalyses of patients who received these CAR T-cell therapies in the second or later lines of treatment.

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Andrew Ip, MD, discusses the need for real-world studies investigating the efficacy and safety of CAR T-cell therapy in patients with LBCL.

Andrew Ip, MD, discusses the importance of making informed clinical decisions when selecting CAR T-cell therapy in older vs younger patients with LBCL.

Dr Ip on Real-World Data Informing CAR T-Cell Therapy Selection in LBCL

“For many of us in the community who are referring [patients to] or treating [patients] with CAR T-cell therapy, we're trying to give them the quickest option, even though we realize there might be some more risks of toxicity. That is something [we] should obviously take into account, and [these] data confirm that.”

Andrew Ip, MD, medical oncologist, Division of Lymphoma, Hematologic Malignancy, John Theurer Cancer Center, Hackensack University Medical Center, discusses the importance of making informed clinical decisions when selecting CAR T-cell therapy for older and frailer patients vs younger patients with large B-cell lymphoma (LBCL).

Findings from the real-world retrospective multicenter cohort study evaluating CAR T-cell therapy in patients with LBCL were presented at the 

Clinical trial data have previously indicated that the manufacturing for axicabtagene ciloleucel (axi-cel; Yescarta) can be more consistent and does not have as many out-of-specification failures, Ip details. This means that axi-cel could be available for administration before other CAR T-cell therapies, Ip adds.

In the real-world study, Ip says that there were more patients treated with axi-cel who had primary refractory disease and had an overall poorer performance status. Based on this finding, he emphasizes that this means patients in the real-world setting could be sicker and would require CAR T-cell therapy sooner. An important takeaway he notes is considering the risks of toxicity when referring or treating patients with CAR T-cell therapy, especially when it’s the quickest treatment option.

The study included 501 patients with LBCL from 4 centers in the U.S. and Israel between April 2016 and January 2024. Of note, 96 patients were treated with lisocabtagene maraleucel (liso-cel; Breyanzi), 133 with tisagenlecleucel (tisa-cel; Kymriah), and 272 with axi-cel. At a median follow-up of 19 months in the overall cohort, the complete response rates with liso-cel, tisa-cel, and axi-cel were 73%, 49%, and 61%, respectively (

 = .001). Partial response rates the same arms were 18%, 15% and 20%, respectively (

= .001). Median durations of CR were not reached (NR) for liso-cel (95% CI, NR-NR), 18 months for tisa-cel (95% CI, 7.4-NR), and 27 months for axi-cel (95% CI, 19-NR).

Regarding safety, lower rates of any-grade cytokine release syndrome (CRS) were observed in patients treated with liso-cel (55.1%) compared with tisa-cel (69.1%) and axi-cel (88.8%; 

 < .001). Liso-cel was also associated with lower rates of grade 2 or higher CRS (16.1% liso-cel; 31.3% tisa-cel; 42.8% axi-cel), any-grade immune effector cell-associated neurotoxicity syndrome (ICANS; 13.8%, 17.5%, and 37.9%; 

 < 0.001), and grade 2 or higher ICANS (6.2%; 9.9%, and 25.9%; 

Overall, differences in efficacy outcomes with liso-cel vs axi-cel were not statistically significant, although their safety profiles differed. However, he concludes that there is still selection bias, which could be inherent in real-world studies across the board.

Dr Ip on Comparative Findings Between CAR T-Cell Therapies in LBCL

“It was interesting, but also confirmatory, that liso-cel seemed to be safer in terms of cytokine release syndrome and neurotoxicity compared with [axi-cel and liso-cel]. I believe those are really the topline findings, so I'm very excited that we [have shared them] at the 2024 ASH Annual Meeting.”

Andrew Ip, MD, Lymphoma, Hematologic Malignancy, Hackensack University Medical Center, John Theurer Cancer Center, discusses comparative real-world outcomes with commercial CD19-directedCAR T-cell therapies in large B-cell lymphoma (LBCL). Notably, these findings were shared at the 

Ip states that he and his colleagues presented compelling findings from a collaborative study across 4centers, including one in Israel and several in the United States, such as Hackensack University Medical Center. The study encompassed 501 patients treated with 1 of the 3 CAR T-cell products that are approved for the treatment of patients with LBCL: tisagenlecleucel (tisa-cel; Kymriah), axicabtagene ciloleucel (axi-cel; Yescarta), and lisocabtagene maraleucel (liso-cel; Breyanzi), he reports. The focus was on evaluating the real-world efficacy and safety of these therapies, Ip shares.

One of the most notable findings, though largely confirmatory, highlights the comparative efficacy of these products in the second-line setting, he continues. Tisa-cel was found to be less effective than axi-cel and liso-cel, with lower progression-free survival and overall survival rates, Ip says. This finding aligns with previously understood data but provides additional validation for the use of CAR T-cell therapy in real-world clinical settings, he emphasizes.

In terms of safety, the findings were similarly confirmatory but just as important, Ip expands. Liso-cel was associated with a more favorable safety profile, including a lower incidence of cytokine release syndrome and neurotoxicity, compared with both axi-cel and tisa-cel, he shares. This safety profile reinforces the potential value of liso-cel for patients who may be at higher risk for developing these adverse effects, Ip concludes.

Andrew Ip, MD, discusses comparative real-world outcomes of commercial CD19-directed CAR T-cell therapies in large B-cell lymphoma.

Dr Ip on the Impact of BCMA Alternative Splicing in Lymphoma and Multiple Myeloma

Andrew Ip, MD, director, Hematologic Malignancies, John Theurer Cancer Center, discusses findings with alternative splicing of the 

 gene, which encodes BCMA. Ip and colleagues conducted a study to explore the potential of the presence of alternative splicing in BCMA transcripts through the sequencing of BCMA RNA in patients with lymphoma or multiple myeloma.

BCMA is a critical target for a variety of therapies, including CAR T cells, bispecific antibodies, and antibody-drug conjugates. This gene, expressed mainly on plasma cells and some B-cell malignancies, consists of 3 exons responsible for different domains of the protein.

The study investigated the presence of alternative splicing in BCMA RNA transcripts from 587 fresh bone marrow samples from patients with lymphoid/plasma cell neoplasms and 260 cell-free RNA (cfRNA) samples from the peripheral blood plasma of patients with lymphoma or multiple myeloma. RNA sequencing was performed using a hybrid capture-targeted RNA panel, with a focus on the 

Results revealed that 27% of the lymphoid/plasma cell samples exhibited alternative splicing involving the deletion of exon 2 (BCMA∆Ex2), and 6% of cfRNA samples showed BCMA∆Ex2. The median percentage of BCMA∆Ex2 transcripts was 0.7% in cellular samples compared with 9% in cfRNA samples. In cellular samples, there was a significant correlation between overall BCMA levels and BCMA∆Ex2 (R = 0.63; 

 < 0.0001). However, in cfRNA samples, no correlation was observed between BCMA levels and BCMA∆Ex2 (R = 0.21), although higher BCMA levels corresponded with slightly increased BCMA∆Ex2 levels (

Importantly, exon 3, typically detected in standard assays, was less frequently observed compared with other exons. Exon 2 was detected approximately 30% more, and exon 1 was detected approximately 20% more. Ip emphasizes that translating these data into clinical practice to better detect response and prognostic markers is a future direction for this research.

The study concluded that BCMA exon 2 skipping, which deletes the transmembrane domain, is prevalent in subsets of patients with multiple myeloma and lymphoma. This alteration could result in a cytoplasmic or secreted form of BCMA, contributing to increased cell turnover and possibly indicating more aggressive disease.

Ip notes that these findings underscore the need for further research to explore the clinical implications of BCMA exon 2 skipping on the effectiveness of antibody-based therapies and CAR T-cell treatments. Understanding these mechanisms could enhance the development of curative therapies and improve long-term remission rates in both myeloma and lymphoma, Ip concludes.

Andrew Ip, MD, discusses alternative splicing of the TNFRSF17 gene, which encodes BCMA, in patients with lymphoma or multiple myeloma.

Andrew Ip, MD, discusses the implications of using next-generation sequencing alongside machine learning in the diagnosis of hematologic malignancies.

Dr Ip on the Implications of NGS Plus Machine Learning for Diagnosing Hematologic Malignancies

Andrew Ip, MD, medical oncologist, John Theurer Cancer Center, Hackensack University Medical Center, discusses findings from a study assessing the feasibility of replacing flow cytometry analysis with next-generation sequencing (NGS) alongside machine learning to detect and diagnose hematologic malignancies, highlighting the clinical implications of this research.

, results from the study showed that the use of NGS to quantify RNA levels from 30 CD markers in combination with a machine learning algorithm may serve as a reliable and accurate screening method for differential diagnosis across various hematologic conditions. The study reported an area under the curve (AUC) consistently exceeding 90%, indicating a strong true positive rate with a 2% chance of false positivity. Notably, the data from this study were obtained from peripheral blood test samples.

The utilization of liquid biopsies has gained traction in recent years due to its ability to provide comprehensive information about cancer without the need for invasive tissue biopsies, Ip begins. This approach has been promising in hematologic malignancies, where NGS technologies can detect specific genetic alterations associated with various blood cancers, he notes.

Findings from this study build upon prior research, including a study published in the 

, which explored the feasibility of detecting acute myeloid leukemia (AML) using whole-exome sequencing, Ip states. The study found that whole-genome sequencing provided rapid and accurate genomic profiling in patients with AML or myelodysplastic syndrome, he reports.

Based on this study, Ip and his colleagues at the Genomics Testing Cooperative used a more targeted NGS panel focused on RNA and DNA mutations to assess the utility of NGS-based liquid biopsies across different hematologic conditions beyond AML, Ip says.

This research suggests that liquid biopsies using NGS and machine learning could improve the diagnosis and monitoring of hematologic neoplasms, Ip explains. By providing potentially more accurate, powerful, and automated methods of disease detection, this approach could enhance patient care, facilitate earlier interventions, and potentially reduce the need for more invasive diagnostic procedures like bone marrow biopsies or lymph node biopsies, Ip expands. Further research and validation will be needed to potentially integrate these technologies into routine clinical practice and optimize their utility across different hematologic cancers, Ip concludes.

Dr Ip on the Importance of NGS Testing in Hematologic Malignancies

Andrew Ip, MD, medical oncologist, John Theurer Cancer Center, Hackensack University Medical Center, discusses findings from a study on the use of next-generation sequencing (NGS) of flow cytometry CD markers and machine learning as a replacement to flow cytometry analysis for the diagnosis of hematologic neoplasms.

The focus of this study extended beyond the utilization of NGS CD1300 RNA and NGS CD300 DNA mutations, Ip begins. Collaboratively, investigators incorporated more conventional flow cytometry CD markers, a traditional method for detecting hematologic neoplasms, into the testing approach, he states. This involved the use of 30 CD markers in combination with the NGS platform from the genomics testing cooperative, Ip elucidates. The synergy of these 2 testing modalities significantly enhanced the power, sensitivity, specificity, and accuracy of the overall diagnostic process, he explains.

, Ip and other investigators presented data on this investigative approach. Ip presented results from a substantial dataset that necessitate the application of machine learning techniques and big data analyses in the diagnosis of hematologic malignancies. The primary outcome reported was the area under the curve (AUC), a metric that elucidates the true positive rate vs the false positive rate, Ip explains.

The true positive rate reflects the reliability of a positive test result, gauging the likelihood of it being a genuine positive or a potential false positive, Ip continues. In this study, across various hematologic conditions, such as acute myeloid leukemia, multiple myeloma, myelodysplastic syndromes, myeloproliferative neoplasms, and lymphomas, the AUC consistently exceeded 90%, he elucidates. In some instances, the AUC approached 98%, Ip notes. These findings indicate that a positive test result with a 90% confidence level corresponds with only a 2% chance of false positivity, he states. Such a high true positive rate signifies that the combination of NGS quantification and machine learning techniques denotes a potent screening modality, Ip concludes.

Andrew Ip, MD, discusses findings from a study on the use of next-generation sequencing of flow cytometry CD markers and machine learning as a replacement to flow cytometry analysis for the diagnosis of hematologic neoplasms.

Andrew Ip, MD, Hematologic Oncology, John Theurer Cancer Center, Hackensack University Medical Center, discusses carboplatin (Paraplatin), pemetrexed (Alimta), and pembrolizumab (Keytruda) as first-line therapy in recurrent/metastatic non–small cell lung cancer. 

In an ongoing analysis, investigators studied 523 patients treated at Hackensack University Medical Center and Memorial Sloan Kettering Cancer Center to determine outcomes with carboplatin, pemetrexed, and pembrolizumab, Ip says. At the time of analysis, the median overall survival for patients was 11 months, Ip adds. However, this is a stark contrast to what was expected based on a previous report of a 17-month overall survival benefit with the triplet, Ip concludes.

Andrew Ip, MD, discusses carboplatin, pemetrexed, and pembrolizumab as first-line therapy in recurrent/metastatic non–small cell lung cancer.  


Dr. Ip on the Utility of Carboplatin, Pemetrexed, and Pembrolizumab in Lung Adenocarcinoma

Andrew Ip, MD, chief, Outcomes and Value Care Division, member, Division of Lymphoma, John Theurer Cancer Center, Hackensack Meridian Health, discusses the use of targeted next-generation sequencing (NGS) in detecting chromosomal structural abnormalities in patients with myeloid neoplasms.

In a study of the reliability of targeted cell-free DNA (cfDNA) NGS in predicting chromosomal abnormalities in patients with myeloid neoplasms, Ip and colleagues found that liquid biopsy with targeted NGS is an accurate way to detect chromosomal structural abnormalities in myeloid neoplasms when compared with samples from bone marrow biopsies. When classified by prognostic classes, the investigators observed a 100% concordance in cytogenetic abnormalities between cfDNA NGS data and cytogenetic data.

This study looked at copy number variation, or cytogenetic differences, in the blood samples, with the goal of risk stratifying patients to understand whether peripheral blood tests can replace more invasive testing, Ip says. Findings showed that cfDNA-targeted NGS was sensitive enough to identify myeloid neoplasms and lymphoid neoplasms in many patients, Ip explains.

An important limitation of DNA mutation testing is that it doesn’t detect some rare isolated chromosomal abnormalities, Ip notes. In this study, for instance, deletion 5q, a mutation that does not appear on a broad NGS panel, was not detected with cfDNA-targeted NGS, Ip says. However, most patients being tested for myelodysplastic syndrome will have a molecular mutation profile that NGS testing can detect, Ip concludes.

Andrew Ip, MD, discusses the use of targeted next-generation sequencing in detecting chromosomal structural abnormalities in patients with myeloid neoplasms.

Andrew Ip, MD

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