Nichole Tucker

Axicabtagene ciloleucel (axi-cel; Yescarta) CAR T-cell therapy as first-line treatment for patients with high-risk large B-cell lymphoma (LBCL) produced encouraging responses, according to updated phase 2 ZUMA-12 (NCT03761056) data presented during the 

2022 Transplantation & Cellular Therapy Meetings

In 37 evaluable patients, the objective response rate (ORR) in the study was 89% (95% CI, 75%-97%) with complete responses (CRs) in 78%. Partial responses (PRs) were observed in 11% of the evaluable population, while 8% has stable disease (SD), and only 3 had progressive disease (PD).

Axi-cel is an autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy that already has FDA approval for the treatment of adults with relapsed or refractory LBCL and relapsed/refractory follicular lymphoma following at least 2 prior lines of therapy. ZUMA-12 is the first study to assess treatment with axi-cel in the first-line setting.

“Patients with high-risk large B cell lymphoma have poor outcomes, including lower response rates and poor overall survival. In addition, patients with early disease resistance as assessed by dynamic PET scan, after first-line chemoimmunotherapy have an increased risk of death,” said Sattva Neelapu, MD, professor, Department of Lymphoma/Myeloma, Division of Cancer Medicine, and deputy department chair, Department of Lymphoma/Myeloma, Division of Cancer Medicine, at The University of Texas MD Anderson Cancer Center, Houston, TX during a presentation at the 2022 Transplantation and Cellular Therapy Meetings.

Based on the unmet medical need for therapies to improve outcomes in high-risk LBCL, ZUMA-12 was created. The study is a phase 2, multicenter, open-label, single-arm study. At the 2022 TCT Meetings, Neepalu presented results on efficacy, safety, pharmacokinetics, and pharmacodynamics.

Per the study design, patients included in ZUMA-12 were those with high-grade B-cell lymphoma with 

 translocations or have an International Prognostic Index (IPI) score of ≥ 3. All patients must be 18 years of age or older with an ECOG performance score of 0 or 1, and their interim PET scan should show a Deauville score of 4 or 5 after 2 cycles of anti-CD20 mAb plus an anthracycline-containing regimen.

“Following enrollment and leukapheresis, patients could receive optional non-chemotherapy bridging, which could have included either corticosteroids or localized radiation. And once the product has been generated, they received standard [fludarabine] conditioning followed by a single infusion of axi-cel,” explained Neelapu about ZUMA-12 treatment.

The fludarabine conditioning was administered at 30 mg/m2 via intravenous (IV) infusion with cyclophosphamide 500 mg/m2 IV on days -5, -4, and -3. Axi-cel was administered at 2 x 106 CAR T cells/kg on day 0.

The primary end point of the ZUMA-12 study is CR rate assessed by investigators per Lugano 2014 classification. Secondary end points of the study include ORR, duration of response (DOR), event-free survival (EFS), progression-free survival (PFS), overall survival (OS), safety, and CAR T cells in blood and cytokine levels in serum.

Of the 42 patients enrolled, 40 were treated with condition chemotherapy and axi-cel. The patients had a median age of 61 years (range, 23-86), and were 68% male. In terms of disease characteristics, 95% of patients in the study has stage III or IV disease, 63% had an ECOG score of 1, and 100% had at least 1 prior systemic therapy. FISH testing assessed by investigator showed that 40% of patients had double- or triple-hit, and 25% were double- or triple-hit per central laboratory assessment. Also, the IPI score was ≥ 3 for 78% of patients, and 48% had a Deauville score of 4, while 53% had a Deauville score of 5.

The median follow-up for response in the evaluable population was 15.9 months (range, 6.0-26.7), with 62% of patients having been followed for ≥ 12 months. As of the data cutoff date, 73% of patients were having an ongoing response to axi-cel. The median time to response was 1.0-month (range, 0.9-6.8). Of the 11% who initially had a PR, 16% eventually converted to a PR. Moreover, 3% of those whose initial response was SD converted to a CR.

In the overall population (n = 40), the ORR was 90% (95% CI, 76%-97%) with a CR rate of 80% (95% CI, 64%-91%. Notably, CRs were consistent across all subgroup populations. The median DOR was not reached, but at month 12, the DOR rate was 80.8% (95% CI, 59.3%-91.6%).

All survival outcomes had not been reached by the time of data cut off. At 12 months, the EFS rate was 72.5% (95% CI, 53.1%-84.9), the PFS rate was 74.6% (95% CI, 54.8%-86.7%, and the OS rate was 90.6% (95% CI, 73.4%-96.9%).

Any-grade treatment-emergent adverse events (TEAEs) occurred in all 40 patients in the study of which, 85% were grade 3 or higher. The most common grade ≥ 3 axi-cel-related TEAEs were neutrophil count decrease (53%), white blood cell count decrease (43%), anemia (30%), encephalopathy (15%), and platelet count decrease (15%).

Serious TEAEs were observed in 45% of patients. In 68% of patients, grade ≥ 3 cytopenias occurred, and 15% experienced grade ≥ 3 infections. Twelve of patients died due to either PD (10%), COVID-19 (3%), or septic shock (3%).

Cytokine release syndrome (CRS) occurred in all patients in the study, but only 8% experienced grade 3 CRS. The most common CRS-related symptoms observed were pyrexia (100%), hypotension (30%), chills (25%), and hypoxia (23%).

“Tocilizumab was administered in 63% of outpatients and corticosteroids in 35% of the patients for management of CRS, only one patient required vasopressors,” noted Neelapu. “The median time to onset of CRS was four days and the median duration was 6 days. There were no grade 4 grade 5 CRS events and all CRS events resolved as of the data cut off.”

Neurologic events of any grade were observed in 73% of patients, and these events were grade 3 for 23% and grade 2 for 38%. The most common symptoms associated with neurologic events in the study were confusional state (28%), encephalopathy (25%), and tremor (25%).

Regarding neurologic events, Neelapu stated: “The median time to onset was 9 days and the median duration was 7 days. There were 2 grade 4 neurological events both due to encephalopathy and both resolved. There were no grade 5 neurological events noted. As of the data cut off, there's 1 patient who has an ongoing grade 1 tremor.”

Finally, ZUMA-12 results were compared with results from ZUMA-1 (NCT02348216), in which axi-cel was evaluated as third-line treatment for patients with LBCL.

“We observed a higher frequency of CCR7-positive, CD45RA-positive T cells in ZUMA-12 versus in ZUMA-1. Within the product, 35% of these T cells were of this phenotype on ZUMA-12 versus only 14% on ZUMA-1. And this was a phenotype that was previously associated with a favorable newer PK profile and better clinical efficacy,” said Neelapu.

The greater frequency of CCR7-positive, CD45RA-positive T cells observed in ZUMA-12 was associated with greater CAR T-cell expansion, which signals improved T-cell fitness in the first-line setting. Based on the collective findings, Neelapu et al., axi-cel may be beneficial to patients exposed to fewer prior therapies as well as those with high-risk LBCL.

Neelapu SS, Dickinson M, Munoz JL, et al. Primary analysis (PA) of Zuma-12: A phase 2 study of axicabtagene ciloleucel (Axi-Cel) as first-line therapy in patients (Pts) with high-risk large b-cell lymphoma (lbcl). Presented at. 2022 Transplantation and Cellular Therapy Meetings; April 23-26, 2022; Salt Lake City, UT. Abstract 12.

Articles

In 37 evaluable patients, the objective response rate in the study was 89% (95% CI, 75%-97%) with complete responses in 78%. 

Axi-cel as Frontline Therapy for High-Risk Large B-cell Lymphoma Produces Encouraging Responses

This content originally appeared on our sister site, 

 (ODD) to IASO Biotherapeutics' CT120 for the treatment of acute lymphoblastic leukemia.

"CT120 is the first dual-targeted CAR-T cell therapy. The ODD granted to CT120 demonstrates the FDA's recognition and expectation of the product. CT120 has obtained two investigation new drug approvals for B-cell non-Hodgkin lymphoma [B-NHL] and B-ALL in China, and the clinical trial for the treatment of B-NHL is going well, said Wen (Maxwell) Wang, MD, PhD, in the press release.

CT120 is a fully human CD19/CD22 dual-targeted chimeric antigen receptor (CAR)-T cell therapy. It reduces the Antibody-drug antibody effect and improves the viability of CAR-T cells by binding to tumor cells expressing CD19 and CD22. 

A single-armed, open-label, multicenter phase 1/2 study of CT120 for the treatment of patients with relapsed or refractory B-NHL. The study has a target enrollment of 125 patients who will be assessed for the coprimary end points of the incidence of dose-limiting toxicities and the incidence of adverse events in the phase 1 portion and overall response rate (ORR)at day 90 during phase 2. The secondary end points of the study include ORR, time to response, time to complete response, duration of response, progression-free survival, overall survival, the quantity of CAR copies in peripheral blood, the quantity of CAR T-cells level in peripheral blood, laboratory tests, vital signs, and physical examinations.

Posoleucel for Virus-Associated Hemorrhagic Cystitis Receives Orphan Drug Designation

To execute the study, investigators will conduct a leukapheresis to manufacture the CAR T cells.. The study protocol allowed for bridging therapy between peripheral blood mononuclear cell collection and lymphodepletion. Lymphodepletion with fludarabine and cyclophosphamide was performed for 3 consecutive days followed by 1 day of rest before receipt of CT120. Patients are infused with either 1.0 x 106 CAR-positive T cells/kg, 3.0 x 106 CAR-positive T cells/kg, or 6.0 x 106 CAR-positive T cells/kg.

Follow-up of patients in the study will go on for a minimum of 2 years after the final infusion of CT120. Long-term safety follow-up will continue for up to 15 years after the final infusion of CAR T cells in the study.

Patients are eligible to enroll given they are between the ages of 18 and 70 years old with pathologically confirmed B-NHL. Patients are also required to have at least 1 measurable lesion and a life expectancy of at least 12 weeks.

"The company is advancing the development of the product in China and United States. We look forward to the launch of this innovative therapy to cure more patients," said Wang, in the press release.

The ODD is expected to help with the development of CT120 in the United States.

1. IASO Biotheraputics’ CT120 granted orphan drug designation by the U.S. FDA. News release. IASO Biotheraputics. October 26, 2021. Accessed November 24, 2021. 


2. A phase 1/2 study of ct120 in patient with relapsed/refractory b-cell non-hodgkin's lymphoma. Clinicaltrials.gov. Accessed November 24, 2021. https://bit.ly/3HYnH5W

The cell therapy is approved for B-cell non-Hodgkin lymphoma and B-ALL in China.

CAR T-Cell Therapy gets Orphan Drug Designation for Acute Lymphoblastic Leukemia

The first patient with relapsed or refractory (r/r) large B-cell lymphoma (LBCL) has been dosed with efineptakin alfa (NT-17; NeoImmuneTech) in a phase 1b clinical trial following  treatment with the chimeric antigen receptor (CAR) T-cell therapy, tisagenlecleucel (Kymriah). 

"We have shown in multiple animal models that the addition of NT-I7 to CAR T cells substantially increased CAR T-cell proliferation, persistence, and target-specific tumor killing, resulting in significantly prolonged survival of the treated animals," said NgocDiep Le, MD, PhD, executive vice president, and chief medical officer, NeoImmuneTech, in the press release. "Now that we have begun dosing in this study, we look forward to evaluating the potential of NT-I7 therapy to prolong clinical response and survival for patients with r/r LBCL."

 for the treatment of adult patients with relapsed/refractory LBCL including diffuse large B-cell lymphoma (DLBCL), high-grade B-cell lymphoma, and DLBCL arising from follicular lymphoma—after 2 or more lines of systemic therapy. Efineptakin alfa is a long-acting human interleukin-17 (IL-17) agent, which enhances memory T-cell development to help patients maintain immune responses.

“While CAR-T cell therapies have revolutionized the way we treat multiple hematologic malignancies, the relapsed or refractory illness still impacts many patients with LBCL who are in need of additional treatment options. By advancing this Phase 1b study, we hope to pave the way for a new therapeutic solution that could enhance the clinical impact of Kymriah alone and ultimately improve patient outcomes,” said Hwan Yang, PhD, president, and chief executive officer, NeoImmuneTech, Inc, in the press release.

In the study, an estimated 57 patients will be enrolled and given efineptakin alfa via intramuscular injection 21 days after tisagenlecleucel. The primary end points of the study include safety/tolerability and determining the maximum tolerated dose and recommended phase 2 dose of the investigational drug. As secondary end points, the study is evaluating preliminary anti-tumor activity and the effect efineptakin alfa has on safety when administered after tisagenlecleucel infusion.2

To be eligible for inclusion, patients aged 18 years or older with r/r LBCL must have an ECOG performance status of 0 to 1, measurable disease, a life expectancy of at least 12 weeks, and adequate organ and marrow function. All patients enrolled must consent to biopsies.

Individuals are excluded from the study if they have grade ≥ 2/3 cytokine release syndrome (CRS) or immune effector cell-associated neurotoxicity syndrome (ICANS) after receiving

tisagenlecleucel, recent autoimmune disease history, central nervous system involvement, active and clinically relevant bacterial, fungal, viral, or TB infection, and other condition that may interfere with treatment. In terms of prior therapy, patients are ineligible to enroll if they received prior CD19-directed therapy, concurrent chemotherapy, or biologic or hormonal therapy for cancer treatment.

Two sites in California and Missouri are actively recruiting patients with r/r LBCL who were treated with tisagenlecleucel to receive efineptakin alfa in the study.

1. NeoImmuneTech announces first patient dosed in phase 1b study of NT-I7 (efineptakin alfa) and Kymriah® (tisagenlecleucel) in relapsed/refractory large b-cell lymphoma. News release. October 13, 2021. Accessed October 19, 2021.

https://bit.ly/2Z2lvbQ
2. A Study to evaluate the safety, tolerability and preliminary anti-tumor activity of NT-I7 (Efineptakin Alfa) post-tisagenlecleucel (Kymriah®) in relapsed/refractory large b-cell lymphoma subjects. Clinicaltrials.gov. Accessed October 19, 2021. https://bit.ly/3pjrzI2

New Treatment Post-Tisagenlecleucel Being Developed for Patients With LBC Lymphoma

 (RMAT) designation to  CTX110 (CRISPR Therapeutics), an allogeneic chimeric antigen receptor T-cell therapy that targets CD19-positive B-cell malignancies.

“This RMAT designation is based on the encouraging clinical data we have presented thus far, and it is an important milestone that recognizes the transformative potential of CTX110 for the treatment of hematological malignancies,” said Samarth Kulkarni, PhD, chief executive officer of CRISPR Therapeutics, in a press release. “We look forward to working closely with the FDA as we continue our efforts to bring this important new therapeutic modality to patients.”

The designation follows positive results reported with CTX110 from the large B-cell lymphoma (LBCL) cohort in the 

 (NCT04035434). In 26 patients with LBCL followed for at least 28 days, the objective response rate (ORR) was 58% with complete responses (CRs) in 38% of patients.

The 6-month CR rate in the LBCL cohort was 21% with the longest response having exceeded 18 months. Investigators noted, in a press release, that these responses were similar to what has been achieved in this population with CAR T-cell therapy.

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In terms of safety, there were no cases of grade 3 or higher cytokine release syndrome and rate of infection and immune effector cell-associated neurotoxicity syndrome were low.

The study is ongoing and aiming to enroll 143 patients with relapsed or refractory nonHodgkin lymphoma. The coprimary end points of the study include the incidence of adverse events and dose-limiting toxicities and ORR. Secondary end points explored in the study include duration of response, duration of clinical benefit, progression-free survival, overall survival, and ORR in the B-cell acute lymphoblastic leukemia population.

To be eligible for inclusion in the study, patients are required to be 18 years of age with NHL, or between the ages of 18 and 70 years with B-cell ALL. All patients must have an ECOG performance status of 0 or 1, adequate renal, liver, cardiac, and pulmonary organ function, and be using acceptable method of contraception throughout the study.

Patients who have been previously treated with gene therapy or genetically modified cell therapy are excluded from the study. The study also excludes individuals who recently underwent allogeneic hematopoetic stem cell transplant, have history of central nervous system involvement, or seizure disorder, have bacterial or viral infection, a previous or concurrent malignancy, received anti-cancer therapy within 15 days, have an immunodeficiency disorder, or are pregnant or breastfeeding.

Patients who meet the study criteria are being actively recruited at treatment centers in 15 states.

With a RMAT designation, clinical trial development and application reviews for CTX110 will be expedited by the FDA based on the drug’s potential to treat, modify, reverse, or cure a serious or life-threating disease or condition. 

1. CRISPR Therapeutics announces fda regenerative medicine advanced therapy (RMAT) designation granted to CTX110™ for the treatment of relapsed or refractory cd19+ b-cell malignancies. News release. CRISPR Therapeutics. November 22, 2021. Accessed November 23, 2021.


2. CRISPR Therapeutics reports positive results from its phase 1 CARBON trial of CTX110™ in relapsed or refractory cd19+ b-cell malignancies. News release. CRISPR Therapeutics. October 12, 2021. Accessed November 23, 2021.

In 26 patients with LBCL followed for at least 28 days, the objective response rate (ORR) was 58% with complete responses (CRs) in 38% of patients.

CD19+ B-Cell Malignancy Cell Therapy Receives RMAT Designation

Recently FDA-approved chimeric antigen receptor (CAR) T-cell therapies are being incorporated into the relapsed or refractory diffuse large 

B-cell lymphoma (DLBCL) treatment landscape

. These new treatment strategies are challenging the role of allogeneic hematopoietic stem cell transplant (allo-HCT) in the disease.

Mehdi Hamadani, MD, professor of medicine at the Medical College of Wisconsin in Wauwatosa, Wisconsin, and Bertram Glass, MD, chief physician of hematology and cell therapy at Helios Klinikum Berlin-Buch in Berlin, Germany, debated the question during the European Hematology Association (EHA) 2021 Virtual Congress.

Hamadani argued in favor of CAR T-cell therapy and Glass argued that there is still a role for allo-HCT in the treatment of patients with relapsed/refractory DLBCL.

“With patients in the United States, you have to ask the question of which clinical setting was typically allogeneic transplant considered. While that’s not the case for every single patient, allogeneic transplant was commonly considered in [patients with] aggressive lymphoma who relapsed after an autologous transplant and happened to then respond to the next line of therapy, and if they happen to be fit enough and young enough whenever a donor became available. That’s where allogeneic transplant was historically offered. During the debate, we asked if the historical option of allogeneic transplant is better than one option we have now, CAR T-cell therapies, and we looked at the pros and cons of both approaches,” Hamadani told 

CAR T-Cell Therapy From CRISPR Therapeutics Efficacious in CD19+ B-Cell Malignancies

CAR T-Cell Therapy for Relapsed/Refractory DLBCL

The presentation in favor of CAR T cells began with an explanation of how oncologists are currently using the agents in their practices.

“As of right now, patients who have failed 2 prior lines of therapy, and that includes patients with diffuse large B-cell lymphoma not otherwise specified, or patients with aggressive B-cell lymphoma with high-grade features, and diffuse large B-cell lymphoma transforming from indolent histology, CAR T-cell therapy using 1 of the 3 commercially available platforms directed against the CD19 antigen is currently a standard of care.”

The key question to evoke regarding the argument, according to Hamadani, is whether allo-HCT can outperform CAR T-cell use in any relevant clinical scenario.

In research co-authored by Hamadani and published in the 

, investigators utilized a prognostic tool to determine survival outcomes of patients who undergo allo-HCT alone. It was concluded from the study that adding novel cellular therapies to transplants can help reduce non-relapse mortality (NRM) and augment the graft-vs-lymphoma effect observed in patients with DLBCL.

Among adverse prognostic factors in 503 patients who underwent allo-HCT after disease progression/relapse following a prior autologous HCT (auto-HCT), 4 points were scored for having a Karnofsky performance score of <80, 5 points were given for chemoresistance, and 2 points were given to patients who went from auto-HCT to allo-HCT in less than 1 year.

Looking at the 3-year overall survival (OS) rate, the OS was 43% in patients with low-risk disease (0 points), 39% in those with intermediate-risk disease (2-5 points), 19% in those with high-risk disease (6-9 points), and 11% in the very high-risk population (11 points). Further, a comparison of CAR T-cell therapy to allo-HCT using the prognostic tool showed that the probability of progression-free survival (PFS) improvement was higher for CAR T-cell therapy vs allo-HCT. The probability of disease progression or relapse at 3 years was 38% (95% CI, 34%-43%).

A multivariate evaluation of chemoresistance before transplant and its impact on outcomes showed that patients with chemo-resistant disease had a higher risk of NRM (HR, 1.44; 95% CI, 1.04-2.00; 

 = .03). Those with chemo-resistant disease also had a higher risk of progression or relapse after allo-HCT (HR, 2.25; 95% CI, 1.51-3.36; 

 < .0001). Patients with a Karnofsky performance status <80 and chemo-resistant disease also had inferior OS outcomes compared with those without these features (HR, 1.86; 95% CI, 1.33-2.60; 

Based on this research, Hamadani explained a scenario in which CAR T-cell therapy would be more optimal for a patient than allo-HCT: “I’m not saying that every single 70- or 80-year-old can get CAR T-cell therapy. But it is a more feasible treatment for elderly patients. You can arguably give CAR T-cell therapy to less-fit patients, obviously not to a patient who is in active cardiac failure, but you have more wiggle room in terms of cardiac reserve, lung reserve, and hepatic reserve to give CAR T-cell therapies,” he explained. “There is no donor requirement for commercially available CAR T cells, so you don’t have to wait for a donor to be available. Today, these are some practical differences which make CAR T-cell therapy logistically easier.”

During his presentation, Hamadani further explained that looking at outcomes in patients with DLBCL over a 10-year period, allo-HCT has always been less active than auto-HCT, and better activity was shown once CAR T cells were introduced in 2017.

FIGURE. Activity of Transplant and CAR T-Cell Therapy in DLBCL in the United States

According to clinical trial results, axicabtagene ciloleucel (axi-cel; Yescarta), tisagenlecleucel (tisa-cel; Kymriah), and lisocabtagene maraleucel (liso-cel; Breyanzi) can all produce higher objective response rates (ORRs) in patients with relapsed/refractory aggressive non-Hodgkin lymphoma, including DLBCL. The ORR observed with axi-cel in the phase 2 ZUMA-1 trial (NCT02348216) of 101 patients was 82%, with a 54% complete response (CR) rate.

 With tisa-cel in the phase 2 JULIET trial (NCT02445248) of 111 patients, the ORR was 52%, with a CR rate of 40%.

 Finally, liso-cel achieved an ORR of 73%, with a CR rate of 53% in the phase 1 TRANSCEND-NHL-001 trial (NCT02631044) of 269 patients.

Toxicity with CAR T cells and allo-HCT can be of concern, Hamadani explained during the interview.

“The adverse event [AE] profile of CAR T-cell therapy and transplantation is different but there is obviously some overlap. The overlap is where you see common toxicities because of either transplant conditioning or lymphodepletion before CAR T-cell therapy. Both treatments can cause a patient’s blood counts to go down. So cytopenias happened with both, and the need for blood transfusions, nausea, vomiting, fatigue, and risk of infections exists with both therapies, but there are some toxicities that are very distinct. Reversible toxicities with CAR T-cell therapies are things like cytokine release syndrome where a patient develops fevers, trouble breathing, or hypotension,” Hamadani said.

Explaining that there is no one-size-fits-all approach to the treatment of DLBCL, Hamadani said: “These treatments are not mutually exclusive. In our experience, we have seen patients who got allo transplants, relapsed, and then were cured with CAR T-cell therapies. We have also seen patients who don’t benefit from either therapy. Finally, we have seen patients who have gotten CAR T-cell therapies, relapsed, and then went on to get an allo transplant and we’re long-term survivors following allo transplant.

The early years of utilizing allo-HCT showed that the strategy could achieve disease control, even in patients with very advanced disease.6 During the EHA presentation, Glass explained that the high remission rate observed with allo-HCT and its use in addition to CAR T-cell therapy could lead to optimal responses in patients.

“In one larger trial that has been run by my own group some years ago and published in 

, we applied allogeneic stem cell transplantation to patients with relapsed and refractory B- and T-cell lymphoma and the remission-free survival [rate] was in the range of 40%. There are also some analyses as well from the Center for International Blood and Marrow Transplant Research that show more or less the same thing,” Glass told 

In the randomized, open-label, phase 2 study (NCT00785330) conducted in Germany, 84 patients were randomized evenly to receive rituximab (Rituxan) or lymphoma-directed myeloablative conditioning with allo-HCT. The primary end points of the study were OS at 1 year after transplantation in all patients and the incidence of grade 2 to 4 acute graft-vs-host disease (GVHD) at 100 days in the rituximab and no rituximab groups, as reported by the treating physician. Secondary end points explored in the study included PFS in all patients, as well as time to progression, non-relapse mortality, the incidence of infectious complications, and the incidence and severity of chronic GVHD for rituximab compared with no rituximab in the intention-to-treat population.

At a median follow-up of 4.0 years (interquartile range, 2.5-5.6), the cumulative incidence of acute GVHD with lymphoma-directed myeloablative conditioning and allo-HCT was 42% (95% CI, 29%-59%), compared with 46% (95% CI, 32%-62%) in the rituximab arm (HR, 0.91; 95% CI, 0.52-1.60; 

 = .74). In all patients, the 1-year OS rate was 52% (95% CI, 41%-62%).

“Although we now have CAR T cells, my central argument would be that for the first allogeneic stem cell transplantation, it has been proven to be quite dangerous, but on the other hand, [it is] a very efficient method to treat relapse and chemorefractory aggressive B-cell lymphoma. The relapse rates in refractory and in relapsed patients is around 30 to 40 in many analyses, which included both retrospective and prospective studies,” Glass stated.

Glass explained that although allo-HCT is very effective at getting patients into remission, and although CAR T cells are an effective treatment option, their efficacy falls behind allo-HCT in this regard.

“On the other hand, the competitors, the CAR T cells, are also effective. However, if you look at the relapse rates, they are quite less effective towards the lymphoma. And then allogeneic stem cell transplant in context with high-dose chemotherapy can be because relapse rates or progression rates in most analyses of CAR T cells is around 60%. They are far less dangerous than allogeneic stem cell transplantation. So the treatment-related mortality with allo transplant is around 30% and with CAR T cells it is less than 5%. So the natural result in the end is not so far away from each other. Both can produce long-term remission-free survival in the range of 30% to 40%,” Glass said.

Another important factor that sets these treatment strategies apart is toxicity, as Glass noted, and although both strategies have their risks, one may be easier for oncologists to manage than the other. “The difference is that in one situation with CAR T cells, you don’t have to pay a high price in terms of toxicity, either acute or long term,” Glass said.

Further, considering the lower number of AEs that occur with CAR T cells, one strategy may be to use CAR T cells ahead of allo-HCT in patients with relapsed/refractory DLBCL.

“CAR T cells don’t solve the whole problem, and if patients fail from CAR T cells, it is one of the most valuable methods to apply allo-HCT to obtain long-term remissions in patients,” Glass said. “And therefore, I would say at the moment, before we have better CAR T cells and other methods like bispecific antibodies, allogeneic stem cell transplantation will keep its place for treatment of relapsed and refractory aggressive lymphoma.”

Bringing into thought Hamadani’s point of no one-size-fit- all approach, the use of both allo-HCT and CAR T-cell therapy in different treatment lines was a point he agreed with. “We don’t have data out to 3 years, 4 years, 5 years, but you can sequence these therapies,” he said. “And that was one of the messages that Dr Glass said, and I completely agree with it.”

1. Hamadani M, Glass B. CAR-T or allogeneic transplant for relapsed/refractory DLBCL? Presented at: European Society of Hematology 2021 Congress; June 9-17, 2021; virtual. Accessed June 11, 2021.
2. Fenske TS, Ahn KW, Graff TM, et al. Allogeneic transplantation provides durable remission in a subset of DLBCL patients relapsing after autologous transplantation.

. 2016;174(2):235-248. doi:10.1111/bjh.14046
3. Neelapu SS, Locke FL, Bartlett NL, et al. Axicabtagene ciloleucel CAR T-cell therapy in refractory large B-cell lymphoma. 

2017;377(26):2531-2544. doi:10.1056/NEJMoa17074474
4. Schuster SJ, Bishop MR, Tam CS, et al; JULIET Investigators. Tisagenlecleucel in adult relapsed or refractory diffuse large B-cell lymphoma. 

. 2019;380(1):45-56. doi:10.1056/NEJMoa1804980
5. Abramson JS, Palomba ML, Gordon LI, et al. Lisocabtagene maraleucel for patients with relapsed or refractory large B-cell lymphomas (TRANSCEND NHL 001): a multicentre seamless design study. 

. 2020;396(10254):839-852. doi:10.1016/S0140-6736(20)31366-0
6. Glass B, Hasenkamp J, Wulf G, et al; German High-Grade Lymphoma Study Group. Rituximab after lymphoma-directed conditioning and allogeneic stem-cell transplantation for relapsed and refractory aggressive non-Hodgkin lymphoma (DSHNHL R3): an open-label, randomised, phase 2 trial.

2014;15(6):757-766. doi:10.1016/S1470-2045(14)70161-5

Doctors debated the roles of allogeneic hematopoietic stem cell transplant and CAR T-cell therapy for the treatment of aggressive B-cell lymphoma.

The Roles of Stem Cell Transplant and CAR T-Cell Therapy in B-Cell Lymphoma

Multiple clinical trials have now evaluated the use of chimeric antigen receptor (CAR) T-cell therapies for the treatment of mantle cell lymphoma (MCL) and demonstrated that these treatments are a valuable addition to the treatment landscape and have improved efficacy outcomes.

The first FDA-approved CAR T-cell product for relapsed/refractory MCL was brexucabtagene autoleucel (formerly KTE-X19; Tecartus). This therapy was approved based on results from the phase 2 ZUMA-2 clinical trial. In the study, brexucabtagene autoleucel achieved durable remission in most of the patients treated and the toxicities experienced by patients were consistent with the know toxicities observed with other CAR T cells therapies.

Overall, 74 patients were enrolled in the study, and 71 were administered brexucabtagene autoleucel at 2 × 10

 CAR T cells per kilogram of body weight. Objective responses were achieved in 85% of patients with a CR rate of 59%. The treatment also had an estimated progression-free survival of 61%.

Other CAR T products are being studied as a treatment for relapsed/refractory MCL and are showing promise, including lisocabtagene maraleucel (lisocel; Breyanzi). The drug is already approved for the treatment of relapsed/refractory aggressive large B-cell lymphoma as of February 2021.

In an interview with Targeted Oncology™, Michael Wang, MD, professor in the Department of Lymphoma & Myeloma at the University of Texas MD Anderson Cancer Center, discussed the evolution of treatment in the MCL space specifically with the emergence of CAR T cells.

TARGETED ONCOLOGY™: Can you explain what it’s been like to treat MCL since last year’s approval of the first CAR T-cell therapy for this disease?

: During the SOHO Annual Meeting, my assignment was to talk about the CAR T-cell therapies in mantle cell carcinoma. I remember very clearly when the FDA approved brexucabtagene autoleucel on July 24, 2020. After that, we have been using this therapy to save patient’s lives ever since. There is a very intense usage of this product and it benefits our patients. We have treated over 30 patients since then and in the hospitals, there has increasing numbers every week and every month. For SOHO, we summarized our real-world data with brexucabtagene autoleucel in an abstract. This is from an ongoing project with multiple institutions such as the Mayo Clinic and Moffitt Cancer Center. So, the use of brexucabtagene autoleucel is high, and we will have much more real-world experience with this. This is an exciting time for our patients because this therapy could put patients with advanced mantle cell lymphoma into long-term remissions.

So far, have real-world outcomes with CAR T-cell therapy in relapsed/refractory MCL been similar to clinical trial outcomes?

Without any solid data, among the patients that have been treated at MD Anderson Cancer Center, we feel the efficacy is relatively the same. And of course, the study was conducted several years ago, even some 5 years ago and then we did not have so much therapy, knowledge or skills, or drug agents to combat cytokine release syndrome, neurotoxicity, and B-cell aplasia infections. Now, 5 years later, we have more agents, knowledge and comprehension on how to manage the toxicities. I feel that toxicity is much easier these days because we are better equipped. However, you can never let your guard down because CAR T-cell therapy is still relatively new, and the complications can still be life-threatening at times. While we enjoy our knowledge and skills to manage the disease, we continue to pay attention to patients’ symptoms and get them better. We not only want to protect them from toxicities but also get them into remission using CAR T cells.

This year, we also saw some excitement with liso-cel. Can you discuss the FDA approval of liso-cel and how it’s impacted treatment sense?

The liso-cel clinical trial were in large-cell lymphoma and mantle cell lymphoma. The large cell lymphoma trial has been reported to be very efficacious, and the deciding factor for toxicity is tolerable. During the last ASH meeting, M. Lia Palomba, MD, from Memorial Sloan Kettering Cancer Center, myself, and other colleagues reported the efficacy of liso-cel in relapsed mantle cell lymphoma from 32 patients. The overall response rate was 84% with a complete response rate of over 66%. We cannot compare trials across trial, but the efficacy of the brexucabtagene autoleucel can put us into the right context. The overall response rate of was 93% and the CR rate was 67%. So, you can see the CR rates between the 2 products in the 2 separate trials are relatively close. I really think the data on liso-cel relapse in relapsed/refractory mantle cell lymphoma shows good efficacy, and quite has been well-tolerated in relapsed/refractory mantle cell lymphoma. After the 32 patients, the trial is still ongoing and we are really looking forward to next presentation of data.

What advice can you give provide on the use of CAR T cells in MCL for community physicians who may still be using historic standards of care?

The clinical trials are conducted in the academic centers, and then the data is accumulated then FDA approved. Then those in the academic field will continue to use presentations to inform the community doctors on FDA-approved therapies. So, there's a lag time in getting information to the community, however, the lag time is improving.

Ever since the approval a little more than a year ago, I have started receiving referrals from the community oncologist for their patients and to be considered on CAR T-cell therapy. And so really, I think yes there are still oncologists using the older therapies, but I think the knowledge gap is closing very rapidly and everybody has heard about the CAR T cells. The MCL patient population is also very educated. So, I really think that with CAR T-cell therapies the efficacy and safety information will continue to spread and the usage of it will continue to rise. I think the future is bright.

With the agent that are coming down the pipeline, what clinical questions or challenges with treating MCL do you hope will be addressed?

In MCL, there are so many options, and with those options, how do know which therapy to use first. Also, how do you use the therapy later? We also need to know how do you design the whole strategy in a sequence? This all requires experience, knowledge, and skills and as well as good communication between the physicians and the patient. So those are the challenges in the future. But I think those are challenges that can be easily met.

1. Wang M, Munoz J, Goy A, et al. KTE-X19 CAR T-cell therapy in relapsed or refractory mantle-cell lymphoma.

. 2020; 382:1331-1342. doi: 10.1056/NEJMoa1914347
2. Abramson JS, Palomba ML, Gordon LI, et al. Pivotal safety and efficacy results from Transcend NHL 001, a multicenter phase 1 study of lisocabtagene maraleucel (liso-cel) in relapsed/refractory (R/R) large B cell lymphomas. 

. 2019;134(suppl 1):241. doi:10.1182/blood-2019-127508
3. FDA approves new treatment for adults with relapsed or refractory large-b-cell lymphoma. News release. February 5, 2021. Accessed September 22, 2021.

Michael Wang, MD, discussed the evolution of treatment in the MCL space specifically with the emergence of chimeric antigen receptor T cells.

Mantle Cell Lymphoma Treatment Landscape 1 Year After CAR T Approval

MD Anderson Cancer Center has announced that they are now offering caspase-9 (CaspaCIDe®), an inducible safety switch, as well as related technologies, and rimiducid for the use of patients receiving 

. The new offerings are a product of MD Anderson's license agreement with Bellicum Pharmaceuticals.

CaspaCIDe, which contains a CID-binding domain connected to the caspase-9 signaling domain, is activated with an infusion of rimiducid, causing selective apoptosis of the CaspaCIDe-containing cells. The safety switch is designed to address common adverse events (AEs) such as cytokine release syndrome (CRS) and neurotoxicity, and is still useful long after the initiation of a cellular therapy.

“The unique inducible caspase-9 technology covered by this agreement has the potential to reduce the risk of serious adverse events associated with cellular therapies and to improve patient outcomes,” said Katy Rezvani, MD, PhD, professor of Stem Cell Transplantation and Cellular Therapy at MD Anderson, in a press release. “We have successfully applied the technology to existing cell therapies, and we look forward to the potential future applications made possible by this agreement.”

Research shows that adoptive cell therapies (ACTs) lead to AEs that are more prevalent than AEs associated with radiation and chemotherapy, and the AEs from cellular therapies can last for several years. CRS, the most common toxicity, is observed with all ACTs and typically manifests as fever and chills to start. Immunosuppressive agents like glucocorticoids and anti-IL-6/IL-6 receptor antibodies are used to treat CRS, however experts still consider this AE to be a challenge in patients with cancer.

Recognizing and Managing AEs in CAR T-Cell Therapy

The use of chimeric antigen receptor (CAR) T-cell therapies, T-cell receptor engineering therapies (TCR-T) and tumor-infiltrating lymphocyte (TIL) therapy can cause neurotoxicity, which has clinical characteristics like confusion, delirium, expressive aphasia, obtundation, myoclonus, and seizure. This toxicity can be concurrent with CRS, making for a bigger treatment challenge. Other AEs related to the use of cellular therapies include off-target associated with both CAR T-cell therapy, and high dose IL-2–related toxicity associated with TILs.

In studies, the CaspaCIDe safety switch has demonstrated improvement of symptoms within rimiducid 24 hours. There are 45 clinical trials ongoing at MD Anderson that may be impacted by this license agreement. Currently, MD Anderson is the site for 12 clinical trials of chimeric antigen receptor T-cell therapies, 5 trials of T-cell receptor engineering therapies, 5 studies of tumor-infiltrating lymphocytes, and 23 trial of natural killer cell therapies.

“We are excited to expand our CaspaCIDe agreement with MD Anderson to include a broader set of programs to benefit cancer patients,” said Rick Fair, president and CEO of Bellicum Pharmaceuticals, in the press release. “We believe that our switch technology may enhance the benefit/risk profile of cell therapies. We intend to continue to pursue opportunities to expand its use via external collaborations with other leaders in the field.”

1. MD Anderson and Bellicum announce additional license agreement for use of CaspaCIDe® safety switch. News release. MD Anderson Cancer Center. September 1, 2021. Accessed September 3, 2021.

2. Jin Y, Dong Y, Zhang J, et al. The toxicity of cell therapy: Mechanism, manifestations, and challenges.

. 2021;41(5):659-667. doi: 10.1002/jat.4100

The new technologies were made available as a result of the licensing agreement between MD Anderson and Bellicum Pharmaceuticals.

MD Anderson to Offer Solutions to Cell Therapy AEs

Results of a recent retrospective review showcased that a number of factors, such as higher-grade cytokine release syndrome, immune effector cell-associated neurotoxicity syndrome, and higher peak C-reactive protein and ferritin, are associated with a lower rate of hemopoietic recovery in patients with hematologic malignancies who received CAR T-cell therapy, explained Craig Sauter, MD.

Following CAR T-cell therapy, patients with hematologic malignancies often develop cytopenia; however, there are limited data around the occurrence of cytopenia and the pathobiology that contributes to their onset. In an effort to shed light on this issue, investigators at Memorial Sloan Kettering Cancer Center (MSKCC) conducted a retrospective, real-world review of patients, providing the largest body of proof for hemopoietic recovery following CAR T-cell therapy and the factors that contribute to recovery.

The analysis included 115 adult patients who were given CAR T-cell therapy at MSKCC. The results of the analysis show that in 83 of those patients, that by 1 month, there was 61% hemoglobin recovery, 51% platelet improvement, 33% absolute neutrophil count (ANC) recovery, and 28% white blood cell count recovery. By 3 months, these percentages increased to 93%, 90%, 81%, and 59%, respectively.

Upon further examination, the investigators found that in cases where recovery of hemoglobin, platelets, ANC, and complete count values did not occur at 1 month in some patients, there was a statistically significant association with the type of CAR construct. Specifically, patients with higher-grade cytokine release syndrome, immune effector cell-associated neurotoxicity syndrome, and higher peak C-reactive protein and ferritin were less likely to recover.

The lack of hemoglobin recovery at 1 month was also found to be associated with lymphodepletion using high dose cyclophosphamide. The analysis showed that 58% of these patients recovered, whereas 42% do not (

 =.01). Acute lymphocytic leukemia diagnoses were also associated with no recovery of hemoglobin, as recoveries and non-recoveries were observed in 65% and 35% of patients, respectively (

Patients who received prior homologous stem cell transplantation (HCT) were less likely to have ANC recovery. The investigation showed that 87% did recover and 13% did not (

 = .004). Subjects who had received more than 3 prior lines of HCT were even less likely to have had ANC recovery (78% vs. 22%, 

In an interview with OncLive during the 2020 Transplantation & Cellular Therapy Meetings, Sauter, a hematologic oncologist and clinical director of the Adult Bone Marrow Transplant Service at Memorial Sloan Kettering Cancer Center, discussed the retrospective real-world review of patients with hematologic malignancies who developed cytopenia post-CAR T-cell therapy. He also made predictions about the role of CAR T cells in the future.

: What was the rationale for your retrospective review?

: This is an anecdotal observation in real-world patients. The FDA approval experience of CAR-modified T cells is that patients often are left with moderate to severe cytopenia for a prolonged period. This includes lymphopenia and occasional transfusion requirements going out weeks to months, for both platelets and red blood cells. If the patient failed their CAR T-cell therapy, this becomes a critical issue if patients need further therapy because if they progress, they will require further cytotoxic therapy with an adequate amount of hematopoietic reserve to be able to tolerate the CAR T-cell therapy. This is a key issue, and the pathophysiology of this is being investigated. Going forward, we hope to have more insight to circumnavigate this complication.

What is important for community oncologists to know about this analysis?

Be vigilant of cytopenia following CAR T-cell therapy, particularly around anti-microbial prophylaxis for viruses as well as other organisms such as fungi or Pneumocystis jiroveci pneumonia. Physicians should be more vigilant in patients who are profoundly lymphopenic.

How do you see the role of CAR T-cell therapy evolving in 10 years?

In diffuse large B-cell lymphoma, the randomized phase III studies like ZUMA-7 (NCT03391466), BELINDA (NCT03570892), and TRANSFORM (NCT03575351) are going to be key to answering the question of whether CAR T-cell therapy should be moved up to patients that fail rituximab (Rituxan), cyclophosphamide, doxorubicin, vincristine, prednisone (R-CHOP)-like chemotherapy and initial induction as opposed to requiring 2 lines of therapy, salvage therapy, or autologous transplant.

What issues still need to be addressed in this space?

We understand that the majority of patients are going to progress with their lymphoma following the administration of CAR-modified T cells. Enhancing efficacy, especially in patients with large tumor volume and tumor bulk [will be important]. With some of the products, toxicity mitigation is important. Being able to prospectively investigate strategies to mitigate toxicities as well as enhancing efficacy are going to be key to [improving treatment with CAR-modified T cells in the future].

What is the key takeaway from your presentation?

While this proof-of-concept and this therapy are exciting, the majority of patients are progressing after treatment with the presumed intent of cure. We have to improve upon efficacy.

Jain T, Knezevic A, Pennisi, M et al. Hematopoietic recovery following chimeric antigen receptor t cell (car t) therapy in hematological malignancies. Presented at: 2020 Transplantation & Cellular Therapy Meetings; February 19-23, 2020. Orlando, FL. Abstract 84. https://bit.ly/2V57Qg1.

Craig Sauter, MD, discusses results of a retrospective, real-world review of patients with hematologic malignancies who developed cytopenia post-CAR T-cell therapy.

Expert Highlights Contributing Elements to Hemopoietic Recovery From CAR T-Cell Therapy

Novel agents, including BTK and BCL-2 inhibitors have dramatically improved the treatment paradigm in mantle call lymphoma (MCL), explained Kieron Dunleavy, MD.

Researchers are now hoping to build on these advances by introducing CAR T-cell therapy into the MCL armamentarium. For example, the ongoing, phase II ZUMA-2 trial (NCT02601313) is evaluating the CD19-targeted CAR T-cell therapy axicabtagene ciloleucel (axi-cel; Yescarta) in patients with relapsed/refractory MCL. Following leukapheresis and manufacturing, patients will undergo conditional chemotherapy and then receive a single infusion of KTE-C19 cells at a dose of 0.5 x 10

, Dunleavy, professor of medicine, Director of the Lymphoma Program, Co-Director of the Microbial Oncology Program, GW Cancer Center, discussed the current treatment paradigm in MCL and the emerging potential for CAR T-cell therapy.

: Can you discuss the current approaches for MCL treatment?

: There are many approaches to this disease. One is deferring treatment and a so-called “watch-and-wait” approach. A proportion of newly diagnosed patients have very indolent disease and do not require aggressive approaches upfront. [Whether or not patients do need treatment] depends upon many different clinical and pathologic factors. Historically, more aggressive treatments have been given to patients under the age of 65, whereas less aggressive approaches are given to patients who are 65 and older. Most people who are diagnosed with MCL are in their 60s and 70s and therefore, they are frequently not eligible for very aggressive approaches.

Many experts advocate the use of high-dose therapy and autologous stem cell transplantation in younger patients. For older patients, less intensive approaches are typically used.

I would say that the treatment landscape of MCL is changing very dramatically because of the advent of a number of novel agents that are very effective in the relapsed/refractory setting in MCL, such as BTK inhibitors, BCL-2 inhibitors, and IMiDs (immunomodulatory drugs)—many new agents and approaches are being developed in this space.

Are there unresolved issues regarding these treatment approaches?

There is broad consensus that many patients with newly diagnosed MCL do not require immediate treatment. There is little consensus on what treatment should be used for patients who do need treatment. Novel agents are exciting in MCL as many classes of drugs have high efficacy in relapsed and refractory disease. An important question is what role these novel agents will have in the treatment of newly diagnosed patients.

There is much interest in a current National Cancer Institute (NCI) Inter-Group study that is looking at the role of autologous stem cell transplantation in patients who receive induction therapy for MCL and then are minimal residual disease (MRD) negative. That study will randomize patients to receive an autologous transplant versus getting maintenance therapy. The results of this study will help address this ongoing controversial question of which patients benefit from autologous transplantation. At the present time, for the treatment of younger patients with MCL, many physicians advocate for autologous translation while others do not.

What is the significance of the ongoing ZUMA-2 trial in MCL?

This trial involved administering anti-CD19 CAR T cells to patients with MCL. The first trial (ZUMA-1) was done in aggressive B-cell lymphoma, principally diffuse large B-cell lymphoma. Now, a number of patients have been accrued to the ZUMA-2 study.

At this point, we don't have long follow-up in patients who have been accrued. [Those results should be] very interesting. Long-term follow-up is needed to assess the effectiveness of this strategy in MCL given the indolent course of the disease.

How does the ZUMA-2 trial address the toxicity found in the ZUMA-1 trial?

In ZUMA-1, 2 of the major toxicities were cytokine release syndrome (CRS) and neurological toxicity. Given the very different biology of MCL, these toxicities may be different in terms of frequency and severity in ZUMA-2 and this will be interesting [to see] when the results of the trial are reported.

What challenges still exist with CAR T-cell therapy in MCL?

One important question is which patients with MCL can significantly benefit from this approach and will results be superior to other approaches in terms of long-term disease control? Second, how problematic will toxicities be in this population? CAR T-cell therapy for MCL has not been widely used, so we need a lot more experience with this approach, assuming the results of the ZUMA-2 and other similar studies are promising.

Much progress has been made in better understanding CAR T-cell efficacy and its toxicities. There now are widely accepted guidelines on how to approach and manage patients with CRS, for example.

Kieron Dunleavy, MD, discusses the current treatment paradigm in mantle call lymphoma and the emerging potential for CAR T-cell therapy.