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European Hematology Association (EHA)

“We [are trying] to simplify this and putting it all into one blueprint... putting all the components within a single construct really makes it easy for us. So, we're building kind of a similar blueprint, every time we build a cell therapy, we just might, from a modular perspective, switch in and out some of the components.”

Celyad Oncology is developing a number of allogeneic CAR T-cell therapies, including CYAD-211, which is currently being evaluated in the phase 1 IMMUNICY trial (NCT04613557). The company presented 

 from IMMUNICY at the European Hematology Association (EHA) 2021 Congress in June 2021 that showed dose-dependent engraftment up to dose level 3 of 300 x 106 cells per infusion. 

No graft-versus-host disease, dose-limiting toxicities, or CAR T-cell related encephalopathy syndromes have been reported to date. Two of the 5 evaluable patients achieved a partial response and CYAD-211 cells were detected by polymerase chain reaction-based methods in all 6 patients with evidence of a dose-dependent increase in cell engraftment.

 spoke with Filippo Petti, chief executive officer and chief financial officer, and Charles Morris, MBBS, chief medical officer, Celyad Oncology, about the positive data presented at EHA 2021. They also discussed how their modular platform to develop cell therapies can help them easily switch targets.

Celyad Oncology presents updates on allogeneic CAR T clinical candidates and shRNA-based preclinical concepts at research & development day. News release. Celyad Oncology. July 20, 2021. https://www.businesswire.com/news/home/20210720005854/en/Celyad-Oncology-Presents-Updates-on-Allogeneic-CAR-T-Clinical-Candidates-and-shRNA-based-Preclinical-Concepts-at-Research-Development-Day

The chief executive and chief medical officers of Celyad Oncology discussed their platform and positive data presented at EHA 2021. 

Using A Modular Approach to Develop Oncolytic Cell Therapies 

“There's not a lot of competition from the adoptive cell therapy perspective in targeting CD20. There are some newcomers, but the field has largely focused on CD19. The major competition we have is in terms of the target, but the world is a lot bigger than the CD20 target.”

MB-106, a CD20-targeted, autologous CAR T cell therapy, was shown to be efficacious for high-risk B-cell non-Hodgkin lymphomas (B-NHL) and chronic lymphocytic leukemia (CLL) in recent data presented by Mustang Bio at the European Hematology Association (EHA) 2021 Virtual Congress.

MB-106 treatment yielded an overall response rate (ORR) of 93% (14 of 15) and a complete rate (CR) of 67% (10 of 15). The ORR was 91% (10 of 11) and CR was 82% (9 of 11) in patients with follicular lymphoma. As of EHA 2021, all patients achieving CR remained in remission. CAR T persistence was seen in all dosages. The treatment had an acceptable safety profile, with cytokine release syndrome (CRS) occurring in 6 patients (40%): 3 cases of grade 1 and 3 cases of grade 2.

 spoke with Manuel Litchman, MD, president, chief executive officer, and director, Mustang Bio, to learn more about MB-106, the company’s lead program. He also discussed their second program, gene therapy for X-linked severe combined immunodeficiency (SCID) and research and upcoming studies with the SCID program.

Mustang Bio Announces Updated Interim Phase 1/2 Data for MB-106 CD20-Targeted CAR T in Patients with Relapsed or Refractory B-cell Non-Hodgkin Lymphomas and Chronic Lymphocytic Leukemia. NEws release. Mustang Bio. June 11, 2021. https://ir.mustangbio.com/News/news-details/2021/Mustang-Bio-Announces-Updated-Interim-Phase-12-Data-for-MB-106-CD20-Targeted-CAR-T-in-Patients-with-Relapsed-or-Refractory-B-cell-Non-Hodgkin-Lymphomas-and-Chronic-Lymphocytic-Leukemia/default.aspx

Manuel Litchman, MD, the president, chief executive officer, and director of Mustang Bio discussed the company’s lead and second program. 

CD20-Targeted Gene Therapy

“Our focus is on ex vivo lentiviral gene therapy of T cells to create CAR Ts and hemopoietic stem cells to address rare genetic diseases, and in particular X-linked severe combined immunodeficiency. So, we have 7 lentiviral gene therapy programs, 6 parties for a mixture of hematologic malignancies, and solid tumors, and our XSCID program.”

Mustang Bio recently announced positive data from the ongoing phase 1/2 trial of MB-106, a CD20-targeted, autologous CAR T cell therapy for high-risk B-cell non-Hodgkin lymphomas (B-NHL) and chronic lymphocytic leukemia (CLL), presented at the 

European Hematology Association (EHA) 2021 Virtual Congress.

Investigators saw an overall response rate (ORR) of 93% (n = 14/15) and a complete rate (CR) of 67% (10 of 15) with MB-106 treatment. The ORR was 91% (10 of 11) and CR was 82% (9 of 11) in patients with follicular lymphoma. As of EHA 2021, all patients achieving CR remained in remission. CAR T persistence was seen in all dosages. The treatment had an acceptable safety profile, with cytokine release syndrome (CRS) occurring in 6 patients (40%): 3 cases of grade 1 and 3 cases of grade 2.

spoke with Manuel Litchman, MD, president, chief executive officer, and director, Mustang Bio, to learn more about the company and its pipeline. He discussed the operations of their cell processing facility, trials the company is about to start in X-linked severe combined immunodeficiency, lymphoma and chronic lymphocytic leukemia, and a recently initiated trial in blastic plasmacytoid dendritic cell neoplasm. He also stressed the commitment that Mustang Bio has in treating solid tumors, which is reflected in its pipeline.

The president, chief executive officer, and director of Mustang Bio discussed the company’s pipeline. 

Investigating CAR T in Lymphoma, Leukemia, and Solid Tumors

After longer follow-up, ciltacabtagene autoleucel (cilta-cel) led to early, deep, and durable responses in patients with relapsed/refractory multiple myeloma (MM) with a manageable safety profile, according to updated results from the ciltacabtagene autoleucel CARTITUDE-1 trial (NCT03548207) presented at the 2021 European Hematology Association (EHA) Congress.

At the meeting, Saad Z. Usmani, MD, FACP, director of the Plasma Cell Disorder Program and director of clinical research in hematologic malignancies at Atrium Health, presented updated results from the phase 1b/2 trial with a median follow-up of 18 months.

Overall response rate (ORR) was 97.9%, including a 94.8% very good partial response (VGPR) or better. Moreover, the stringent complete response (sCR) rate was 80.4% and the partial response rate (PR) was 3.1%.

The median time to first response was 1 month (range, 0.9–10.7), with a time to best response of 2.6 months (range, 0.9-15.2). The median time to complete response or better (≥CR) was 2.6 months (range, 0.9-15.2). Duration of response was 21.8 months (95% CI, 21.8–not estimable [NE]), and median duration of response had not been reached in patients with sCR. The investigators estimated that 73% of responders had not progressed or died at 12 months.

Moreover, response rates were comparable across subgroups (range, 95%–100%), including number of prior lines of therapy, refractoriness, extramedullary plasmacytomas, and cytogenetic risk.

Of the 61 evaluable patients for minimal residual disease (MRD), 91.8% achieved MRD negativity at the 10-5 threshold, including 89.4% with ≥CR, compared with 57.7% and 43.3% of all patients, respectively. Median time to MRD negativity at 10-5 was 1 month (range, 0.8-7.7).

Among all patients, the 18-month progression-free survival (PFS) rate was 66.0% (95% CI, 54.9%-75.0%), and 75.9% (95% CI, 63.6%-84.5%) in those with sCR. Median PFS among all patients was 22.8 month (95% CI, 22.8 to NE) and was not reached in those with sCR.

Lastly, the 18-month overall survival (OS) rate in all patients was 80.9% (95% CI, 71.4%-87.6%).

The investigators did not identify any new safety signals with longer follow-up.

Cytokine release syndrome (CRS) occurred in 92 patients, of which the majority (94.6%) were grade 1/2 in severity. The median time to onset of CRS was 7 days (range, 1-12); however, the events resolved in 91 patients (98.9%) within 14 days of onset.

In addition, there was no new incidence of neurotoxicity with longer follow-up, and no additional movement and neurocognitive treatment-emergent adverse events (TRAEs).

No patient discontinued therapy due to manufacturing failure, while 1 patient received retreatment with cilta-cel.

In total, 21 patients died during the study, of which 10 were due to progressive disease, 6 from TRAEs as assessed by the study investigator, and 5 were from AEs unrelated to treatment.

Usmani noted that new patient management strategies have been implemented in the trial to prevent and reduce the incidence of neurotoxicity, including enhanced bridging therapy to reduce tumor burden, early and aggressive treatment of CRS and immune effector cell–associated neurotoxicity syndrome, and handwriting assessments and extended monitoring.

“Patient management strategies to prevent or reduce these AEs have been successfully implemented in new and ongoing cilta-cel studies,” the investigators wrote. “This is reliant on effective implementation of these patient management strategies.”

The study was designed to evaluate cilta-cel, a chimeric antigen receptor (CAR) T-cell therapy with 2 B-cell maturation antigen (BCMA)–targeting single-domain antibodies, in patients with relapsed/refractory MM who have been heavily pretreated.

Patients received a single cilta-cel infusion with a target dose of 0.75 × 106 CAR-positive viable T cells/kg and a median dose of 0.71 × 106 CAR-positive viable T cells/kg (range, 0.5–1.0 × 106 CAR+ viable T cells/kg) 5 to 7 days after lymphodepletion with 300 mg/m2 cyclophosphamide and 30 mg/m2 fludarabine daily for 3 days. Bridging therapy was permitted after apheresis.

The primary aims of the study were to evaluate safety, confirm the recommended phase 2 dose (RP2D), and evaluate efficacy.

Key eligibility criteria for patients included progressive MM per International Myeloma Working Group (IMWG) criteria; receipt of 3 or more prior therapies or double refractory disease to a proteasome inhibitor (PI) plus immunomodulatory drug (IMiD) and a PI, IMiD, and an anti-CD38 antibody therapy; measurable disease; and an ECOG performance status ≤1.

Of the 97 patients who received cilta-cel infusion, 76 were ongoing at the time of the data cut-off. In total, 73 patients received bridging therapy between apheresis and cilta-cel infusion.

The median time from receipt to release of product for cilta-cel was 29 days (range, 23-64).

Patients had a media age of 61 years (range, 43-78). The majority were male (58.8%). Patients had received a median of 6 prior lines of therapy (range, 3-18), with 87.6% who were triple-class refractory and 42.3% who were penta-drug refractory. Lastly, 99% of patients were refractory to their last line of therapy.

In a previous analysis at 12.4 months of follow-up, the ORR was 97%, with an sCR of 67%. In addition, 12-month PFS and OS were 77% and 89%, respectively.

Cilta-cel is being investigated in the ongoing phase 2 CARTITUDE-2 (NCT04133636) and phase 3 CARTITUDE-4 (NCT04181827) studies in earlier-line settings.

Usmani S, Berdeja J, Madduri D, et al. UPDATED CARTITUDE-1 RESULTS OF CILTACABTAGENE AUTOLEUCEL, A B-CELL MATURATION ANTIGEN–DIRECTED CHIMERIC ANTIGEN RECEPTOR T CELL THERAPY, IN RELAPSED/REFRACTORY MULTIPLE MYELOMA. Presented at: 2021 European Hematology Association Annual Meeting; June 9-17, 2021; Virtual; Abstract EP964.

At the 18-month follow-up, the CAR T-cell therapy led to early, deep, and durable responses with a manageable safety profile in patients with relapsed/refractory multiple myeloma.

Longer Follow-Up Shows Cilta-Cel Induces Deep, Durable Responses in Relapsed/Refractory MM

Chimeric antigen receptor (CAR) T-cell therapy has revolutionized treatment for some hematological malignancies, and there are hundreds of trials investigating CAR T-cell therapies in hematology and oncology. However, these therapies are complex to produce.

CAR-engineered natural killer (CAR NK) cells may be an alternative that compete with and complement CAR T-cell therapy, explained Ulrike Köhl, PhD, MD, professor of immune oncology and director of the Institute for Clinical Immunology at the University of Leipzig and director of the Fraunhofer Institute for Cellular Therapeutics and Immunology in Leipzig, Germany, during a plenary session at the European Hematology Association 2021 Virtual Congress.

For both CAR T cells and CAR NK cells, effector cells cannot recognize cancer cells to start killing, but transduction of the respective effector cells results in a new receptor that is upregulated on the surface and binds to the cancer cell. The benefits of CAR T-cell therapies in diseases like acute lymphocytic leukemia (ALL) and diffuse large B-cell lymphoma (DLBCL) has become well known. There are approximately 800 trials worldwide, Köhl said.

“But we are also aware that manufacturing of these autologous personalized CAR T cells is very complex,” she said. The process includes stimulation, transduction, expansion, and formulation. The average duration to manufacture CAR T cells is about 12 days, but it can take as long as 22 days.

Quality control is also challenging, and the CAR T-cell product can fail. Studies have shown that between 1% and 12% of patients, and possibly even up to 17% of patients, the product fails.

“What's the reason for that? These are heavily pretreated patients with a limited bone marrow function [and] less functional and exhausted T cells,” Köhl explained.

With NK cells, there is experience with allogeneic NK cell trials that show a good graft versus leukemia effect without graft-versus-host disease (GVHD), she said. A study of NK cell trials found that interleukin (IL)-2 stimulation led to improved NK cell cytotoxicity, but there was the disadvantage of tumor immune escape.

Köhl gave the example of a child with acute myeloid leukemia (AML) in an early relapse state, who reached complete remission 1 month after NK cell application. “Unfortunately, this did not last very long,” she said. “And this is due to tumor immune escape mechanism.”

Trials that redirected NK cells showed improved results. For instance, in ALL, donor NK cells activated with cytokines against ALL cells killed 70% of the leukemic cells, and when the NK cells were redirected, they could completely eliminate all of the ALL cells, according to Köhl.

Similar results were seen in AML, where activate NK cells had good activity against AML cells, but redirected CAR NK cells “killed much better.”

There is a growing interest in CAR NK cells. Worldwide, there were 20 trials in 2019: half were redirected against CD19 and the other half against different cancer epitopes. A year and a half later, there were 35 trials.

The first in-human trial in the United States led by Katy Rezvani, MD, PhD, at the University of Texas MD Anderson Cancer Center, tested CAR NK cells in patients with relapsed refractory B lymphoid malignancies redirected against CD19 and encoded with IL-15 for long-term persistence.

 In the 11 patients, there were good clinical outcomes: of the 8 patients who had a response, 7 had a complete remission.

Rezvani and her colleagues postulated that a single cord-blood unit could produce more than 100 doses of CAR NK cells with which to treat patients. In addition to the good response, there was no cytokine release syndrome, no neurotoxicity, and no GVHD.

Given the results seen with CAR NK cells, could they compete with CAR T-cell therapy? Köhl doesn’t think it’s that simple.

“We need both,” she said. “They clearly have also different roles,” with CAR NK cells possibly being used as a bridge to transplantation.

1. Liu E, Marin D, Banarjee P, et al. Use of CAR-transduced natural killer cells in CD19-positive lymphoid tumors. 

. 2020;382(6):545-553. doi:10.1056/NEJMoa1910607

New studies into chimeric antigen receptor (CAR)–engineered natural killer (NK) cells has shown promising results, explained Ulrike Köhl, PhD, MD, professor of immune oncology and director of the Institute for Clinical Immunology at the University of Leipzig in Germany.

The Role of CAR NK Cells: Competition or Compliment to CAR T-Cell Therapy?

Neurologic adverse effect (AEs) associated with CAR T-cell therapies like ciltacabtagene autoleucel (Cilta-cel or JNJ-68284528) can be managed without long-term lasting effects, as long as they are caught and treated promptly in patients with relapsed/refractory multiple myeloma, according to data from CARTITUDE-2 presented at the European Hematology Association 2021 Virtual Meeting.

“To date, more than 100 patients across the CARTITUDE study program have been dosed with cilta-cel. So when implemented, patient management strategies have reduced the incidence of neurotoxicity, including movement and neurocognitive events,” said Hermann Einsele, MD, FRCP, professor of internal medicine at the Julius Maximillians University of Würzburg in Germany, while presenting the study findings.

The open-label, phase 2, multicohort CARTITUDE-2 (NCT04133636) trial evaluated the efficacy and safety of cilta-cel in patients with myeloma. For the purpose of studying AEs, the researchers analyzed cohort A, which involved patients with myeloma that progressed after 1-3 lines of therapy, including a proteasome inhibitor and an immunomodulary drug.

Eligible patients were adults with measurable disease and ECOG performance status of 0 or 1. Their disease was refractory to lenalidomide (Revlimid) and was not previously treated with another BCMA-targeted drug.

Patients received cilta-cel (0.75×10 6 [range: 0.5–1.0×10 6] CAR+ viable T cells/kg) as a single infusion 5–7 days after the initiation of lymphodepletion (cyclophosphamide 300 mg/m2 + fludarabine 30 mg/m2 daily for 3 days).

“Patient management strategies included more effective bridging therapy to reduce baseline tumor burden, early aggressive treatment of [cytokine release syndrome] and [immune effector cell-associated neurotoxicity], as well as handwriting assessment for early detection of symptoms of neurotoxicity,” Einsele said. “These strategies have been successfully implemented across the CARTITUDE proves.”

At a median follow-up of 5.8 months (range, 2.5-9.8 months), 20 patients in cohort A received cilta-cell, and 4 (20%) experienced at least 1 neurotoxicity. Three patients had grade 1/2 immune effector cell-associated neurotoxicity (ICANS) alongside cytokine release syndrome. The median time to symptom onset was 8 days (range, 7-11), and, on average, symptoms lasted 2 days. Two patients received supportive measure for their ICANS, including levetiracetam and steroids.

There was 1 patient who experienced isolated grade 2 facial paralysis on day 29. The patient recovered 51 days later after being treated with dexamethasone for 28 days. Overall, there were no movement or neurocognitive disorders that were reported within Cohort A of the study.

“Importantly, none of the patients in the cohort A of the CARTITUDE study experienced other neurotoxicities that were seen in CARTITUDE-1,” Einsele said.

Einsele H, Parekh S, Madduri D, et al. Incidence, mitigation, and management of neurologic adverse events in the phase 2 CARTITUDE-2 study of ciltacabtagene autoleucel in patients with multiple myeloma. Presented at: 2021 European Hematology Association Congress. June 9-17, 2021. Virtual. Abstract EP1003.

Neurologic adverse effect associated with CAR T-cell therapies like ciltacabtagene autoleucel can be managed without long-term lasting effects, as long as they are caught and treated promptly in patients with relapsed/refractory multiple myeloma. 

Early Intervention For Neurotoxicity Can Improve Outcomes With Cilta-Cel in Relapsed/Refractory Multiple Myeloma

The CAR T-cell therapy brexucabtagene autoleucel (KTE-X19; Tecartus) demonstrated high rates of durable complete response (CR) with minimal residual disease (MRD) negativity in pediatric and adolescent patients with relapsed or refractory B-cell acute lymphoblastic leukemia (ALL), according to long-term data from the phase 1 portion of the ZUMA-4 trial (NCT02625480) presented in a poster at the 2021 European Hematologic Association (EHA) Congress.

Across doses of brexucabtagene autoleucel, patients with ALL who received prior blinatumomab (Blincyto; n = 8) treatment experienced a CR plus CR with incomplete hematologic recovery (CR/CRi) rate of 38%. All patients treated with prior allogeneic stem cell transplant (alloSCT; n = 6) had a CR/CRi rate of 86%. There was a CR in 1 patient who received prior inotuzumab ozogamicin (Besponsa). At a median follow-up of 36.1 months, 58% of treated patients (n = 14/24) were still alive and in continued follow-up as of the data cutoff.

"Treatment with KTE-X19 at the recommended phase 2 dose led to high complete remission rates, with the median overall survival not yet reached and a manageable safety profile," the authors, who were led by Alan S. Wayne, MD, of Children’s Hospital Los Angeles, USC Norris Comprehensive Cancer Center, wrote in their conclusions. "Phase 2 of ZUMA-4 is enrolling pediatric patients with relapsed/refractory B-ALL or non-Hodgkin lymphoma, including patients with minimal residual disease-positive disease and early relapse (<18 months) after first-line therapy."

Objectives of the trial were to determine safety and efficacy of brexucabtagene autoleucel in patients 21 years of age or younger with relapsed/refractory B-cell ALL or non-Hodgkin lymphoma. The primary end point of phase 1 was the incidence of dose-limiting toxicities (DLTs) with key secondary end points of CR/CRi rate, relapse-free survival (RFS), pharmacokinetics/pharmacodynamics, duration of response (DOR), and overall survival (OS).

All patients were screened prior to leukapheresis and were allowed to receive bridging therapy at the discretion of the treating investigators, either treatment complete 7 or more days prior to 5 half-lives before condition chemotherapy. Treatment consisted of a conditioning regimen of fludarabine at 25 mg/m

 on days –4 to –2 plus cyclophosphamide at 900 mg/m

 on day –2 followed by brexucabtagene autoleucel infusion at target doses of 1 × 10

At the data cut-off of September 9, 2020, the median follow-up was 36.1 months with 24 patients having received brexucabtagene autoleucel. The median time from leukapheresis to brexucabtagene autoleucel production was 14.0 days for all patients; leukapheresis to infusion time averaged 27.0 days.

 dose (n = 4) had a CR/CRi rate of 75%. In patients treated at the 1 × 10

, 40 mL (n = 9) doses, rates of CR/CRi were 64% and 67%, respectively. The rate of CR/CRi in the entire patient cohort was 67%. One patient in the 1 × 10

, 68 mL had a CR with partial hematologic recovery and 1 in the 1 × 10

, 40 mL group had hypoplastic/aplastic bone marrow. One patient in each of the 1 × 10

 dose groups had no response to treatment. Rates of MRD negativity in the 2 × 10

, 40 mL dose groups were 75%, 73%, and 78%, respectively.

Patients achieving CR/CRi (n = 16) went on to receive alloSCT in 87.5% of cases, with a median time to transplant of 2.3 months (range, 1.4-24.9). The median DOR in the 2 × 10

 dose group was 4.1 months (95%, not evaluable [NE]-NE). In the 1 × 10

, 40 mL dose groups, DOR was 10.7 months (95% CI, 7.2-14.2) and not reached (95% CI, NE-NE). DOR in 16 patients with a CR/CRi was 7.2 months (95% CI, 0.03-14.2).

, 40 mL dose group was not reached. In the 2 × 10

, 68 mL dose groups, median RFS was 5.2 months (95% CI, 0.03-5.2) and 9.1 months (95% CI, 0.03-17.8), respectively.

 dose group was 8.0 months (95%, 0.5-NE) and was not reached in either of the 1 × 10

 dose groups. The rate of OS at 24 months in the 1 × 10

, 40 mL dose group was 87.5% (95% CI, 38.7-98.1).

Peak CAR T-cell expansion were similar between doses but was greatest in the patients receiving brexucabtagene autoleucel at 2 × 10

 CAR-positive T cells. Patients with CR/CRi and those achieving MRD negativity tends to show the greatest expansion after infusion.

In terms of safety, no DLTs were observed in the 3 patients evaluable for DLT. Serious adverse effects (AEs) occurred in 71% of patients and 8 patients (33%) died on study. Deaths were attributed to disease progression in 6 participants and AEs other than grade 5 B-cell ALL in 2. The 2 grade 5 events were disseminated mucormycotic and Escherichia sepsis.

Notably, there were no reports of grade 4 or 5 cytokine release syndrome (CRS). In all patients, any CRS occurred in 88% and grade 3 CRS was seen in 33%. Three out of 4 patients treated at the 2 × 10

 dose had grade 3 CRS, with incidence rates below 30% seen in the 1 × 10

 dose groups. The median time to onset in the entire group was 5 days (range, 1-14) and was 2 days (range, 1-4) in the 2 × 10

 dose group. All events of CRS were resolved.

Neurologic events occurred in 67% of patients overall, with only 1 grade 4 event of brain edema reported in the 1 × 10

, 68 mL group. Grade 3 neurologic events occurred in 17% of patients overall and in 25% of those in the 2 × 10

 dose group. Two of the 16 neurologic events did not resolve by the time of death, 1 each from progressive disease and an AE unrelated to brexucabtagene autoleucel.

Patients with B-cell ALL were eligible for therapy with brexucabtagene autoleucel if they have 5% or more bone marrow blasts; had relapsed or refractory, Philadelphia chromosome–negative disease; adequate organ function; and a Lansky or Karnofsky performance status of 80% or greater. Prior treatment with blinatumomab required patients to have leukemic blasts with CD19 expression of 90% or more.

The phase 2 portion of the trial is currently enrolling patients with relapsed/refractory B-cell ALL with expanded inclusion criteria. brexucabtagene autoleucel is currently approved to treat adult patients with relapsed/refractory mantle cell lymphoma,

 with numerous clinical trials ongoing in other treatment settings.

Wayne AS, Huynh V, Hijiya N, et al. ZUMA-4 phase 1 long-term results: kte-x19 chimeric antigen receptor tcell therapy in pediatric/adolescent patients with relapsed/refractory B-cell acute lymphoblastic leukemia. Presented at: 2021 European Society of Hematology Congress; June 9-17, 2021. Virtual. Accessed June 11, 2021. https://bit.ly/3gti2bi

FDA approves brexucabtagene autoleucel for relapsed or refractory mantle cell lymphoma. FDA. July 24, 2020. Accessed June 11, 2021. https://bit.ly/3gHlK1d

Long-term efficacy assessment of brexucabtagene autoleucel demonstrated high rates of MRD negativity and CR rates in pediatric and adolescent patients with relapsed or refractory B-cell acute lymphoblastic leukemia. 


Brexucabtagene Autoleucel Safe, Efficacious as Therapy for Pediatric B-Cell ALL in ZUMA-4

Speakers sought to demystify cellular therapies in multiple myeloma (MM) at the European Hematology Association 2021 Virtual Congress.

Despite treatment advances, there is significant need for more effective agents in MM for patients who experience relapse on immunomodulatory drugs (IMiDs), proteasome inhibitors (PIs), and monoclonal antibodies, said Paula Rodriguez Otero, MD, a professor and clinician at the University of Navarra in Spain, who spoke about cellular therapies at the congress.

She discussed the promise of belantamab mafodotin, an antibody drug conjugate (ADC), bispecific T-cell engagers (BiTEs), and chimeric antigen receptor (CAR) T-cell infusions. 

Belantamab mafodotin has FDA and European Medicines Agency approval. In the pivotal DREAMM-2 phase 2 study (N = 97), among patients with 3 previous lines of treatment and refractory to PIs and IMiDs, the drug achieved an overall response rate (ORR) of 32% and a median duration of response of 11 months. Patients were treated with the approved 2.5 mg/kg dose.

With belantamab mafodotin, as with other ADC agents, “ocular toxicity is one of the major concerns,” Rodriguez Otero said. In DREAMM-2, keratopathy was observed in 72% of patients (n = 68) receiving the 2.5 mg/kg dose, median time to onset was 37 days, and median duration of the first event was 86.5 days, although “the good news” was that all patients recovered from keratopathy. 

“We need to understand and manage it well to get the best from this drug," Rodriguez Otero said, emphasizing the need for medical education on managing keratopathy with ADCs.

BiTEs have demonstrated encouraging efficacy and are poised to challenge the growing use of CAR T-cell therapies, although both BiTEs and CAR T-cell therapies share common toxicities, including cytokine release syndrome (CRS), neurotoxicity, and cytopenias. However, with BiTEs “this is less frequent, less severe, and confined to the first cycle of treatment,” she said.

“Responses are quick, generally by the first month, tend to deepen over time, and stay durable, so this platform of drugs is very interesting for the treatment of relapsed, refractory MM.”

BiTEs target the antigen BCMA on the myeloma cell and cause T-cell binding, leading to release of cytokines and cell destruction. For different BCMA-BiTEs under evaluation, efficacy rates have been “outstanding,” with ORRs from 26% to 80%, Rodriguez Otero said. “Responses are quick, generally by the first month, tend to deepen over time, and stay durable, so this platform of drugs is very interesting for the treatment of relapsed, refractory MM.”

All-grade CRS is present in 40% to 76% of patients across multiple BCMA-BiTEs currently under evaluation in clinical trials, including teclistamab, PF-3136, AMG701, and cevostamab. “Importantly, no or few patients developed grade 3 or higher CRS in these studies,” she said. Median onset is 1 to 2 days and median duration is also 1 to 2 days.

Compared with CAR T-cell therapy, neurotoxicity with BiTEs is mostly uncommon and mostly grade 1/2. Cytopenias are more common but short-lasting and manageable with growth factors, she said.

CAR T-cell therapy does show “outstanding efficacy” with a manageable adverse event profile, but toxicities are a concern, and further understanding is needed of macrophage activation syndrome (MAS) and hemophagocytic lymphohistiocytosis (HLH), both potentially fatal; however, patient and physician education can improve use of these therapies, Rodriquez Otero said.

She said 80% to 90% of patients treated with CAR T-cell therapy will develop CRS, although “the good news is that grade 3 or higher CRS is very uncommon.” As regards MAS/HLH, “it is clear that we need a better definition for these conditions and probably more guidance.”

Many treatments may be available for MM, but opinions differ on how these should be sequenced and in what combinations, said Joseph Mikhael, MD, a professor in the Translational Genomics Research Institute at City of Hope Cancer Center and chief medical officer for the International Myeloma Foundation.

Save the best for last is great for a movie, but it really doesn’t work in MM.

There are 2 schools of thought, he said. One is that MM should be treated aggressively early on to achieve deep, long-lasting remission; the other is that MM should be modulated by treating it much as you would hypertension. Neither is optimal, Mikhael said, although choosing the right course of treatment early on is critical because the survival curve angles downward as progressive lines of therapy add up. “Save the best for last is great for a movie, but it really doesn’t work in MM,” he said. “We want to bring our better therapies earlier and earlier in the disease course.”

He advised careful reflection and a strategy-based approach when initiating new treatment, given the large number of options. For early relapse in MM, he advised selection of therapies with mechanisms of action not previously used. At City of Hope, “If patients are progressing on lenalidomide maintenance, which is very common, it’s typical to not add another drug to it. We change classes.” He also advised use of triplets over doublets, citing growing trial evidence supporting this preference. 

The current choice for induction therapy tends to be a triplet combination, such as bortezomib-lenalidomide-dexamethasone, or carfilzomib-lenalidomide-dexamethasone (for transplant eligible patients), with lenalidomide maintenance. After first relapse, a monoclonal antibody is added to these agents if it’s not been used before. By third relapse, newer agents such as selinexor-dexamethasone, belantamab mafodotin, melphalan flufenamide, and CAR T-cell therapies are employed.

“We are going to see the greater introduction of quadruplets in front lines. We may even bring CAR T-cell therapy earlier [induction], and many of the things that are used in the third relapse plus lines are going to be brought earlier [first relapse],” he said.

Philippe Moreau, MD, of Chu Nantes-Hotel Dieu, France, said the value of combinations becomes clear when looking at the progression-free survival (PFS) times of older vs newer agents.

Daratumumab is an option for patients refractory to IMiDs and PIs, such as pomalidomide/dexamethasone and carfilzomib, but PFS times approximate 4 months, and for triple-class refractory patients, some of the newer agents don’t do much better: selinexor/dexamethasone, 3.7 months PFS; belantamab mafodotin, 2.9 months; and melfulfen, 4.2 months, Moreau said. “We have definitely better outcomes with the combination of these agents.”

However, recent studies of CAR T-cell therapies and BiTEs have demonstrated impressive outcomes and bear consideration, he said.

The pivotal KarMMa phase 2 study of FDA-approved CAR T-cell therapy idecabtagene vicleucel (ide-cel) enrolled patients refractory to 3 classes of agents (immunomodulatory, PIs, and anti-CD38 antibodies) including the last line of treatment.

, the ORR was 82% (n = 70). “That’s outstanding as compared to belantamab mafodotin in the same setting, as compared with selinexor, as compared with melflufen,” Moreau said. The PFS at the target dose was 12 months, but with a sharp drop-off. 

In 2022, there is potential for another CAR-T cell therapy approval: ciltacabtagene autoleucel (cilta-cel)

 In the LEGEND-2 study (N = 57), the median PFS was 20 months and the median overall survival was 36 months at a 25-month follow-up. CRS events were mostly grade 1 to 2.

“Potentially we should try to use CAR T-cell therapies earlier in the course of the disease, in less-advanced patients with a lower tumor burden as well."

In CARTITUDE-1, the ORR was 97.9% (N = 97) at the optimal cilta-cel dose, including an 80.4% complete response. “The median time to response was very quick. You can see a response in 1 month, in fact,” Moreau said. Median PFS was 18 months. “Potentially we should try to use CAR T-cell therapies earlier in the course of the disease, in less-advanced patients with a lower tumor burden as well."

Among BiTEs, teclistamab is promising with a manageable safety profile and subcutaneous administration. Also, the response rate according to recent findings was 65% (n = 40) at the optimal dose at a follow-up of 6.1 months, and this was in a triple refractory cohort.

Similarly, talquetamab has demonstrated a tolerable safety profile with subcutaneous administration, and an overall response rate was 70% (n = 30) in a recent study.

Comparing CAR T-cell therapies with BiTEs, Moreau noted the “off-the-shelf” value of BiTEs vs up to 2 months required for CAR T-cell development, as well as BiTEs’ subcutaneous administration vs CAR T cells’ intravenous administration, higher incidence of CRS with CAR T cells, and superior ORR with CAR T cells vs BiTEs (82%-98% vs 65%-70%).

Bispecific T-cell engagers and chimeric antigen receptor T-cell therapies seem destined to move into earlier lines of therapy for multiple myeloma (MM), speakers at the European Hematology Association 2021 Virtual Congress said.

Speakers Suggest Moving Newer Agents Into Earlier Lines in MM

Better outcomes were observed with ciltacabtagene autoleucel (cilta-cel) for patients with relapsed/refractory multiple myeloma when compared with conventional therapies in propensity score–matched analyses of the CARTITUDE-1 (NCT03548207) and MAMMOTH trials, according to data presented at the 2021 European Hematologic Association (EHA) Congress.

CARTITUDE-1 explored ciltacabtagene autoleucel whereas the treatments for patients in MAMMOTH included pomalidomide (34% of patients), anti-CD38 monoclonal antibody (24%), carfilzomib (19%), and cytotoxic chemotherapy (35%) as next therapy. After 1:1 propensity score matching, the study included 95 patients in the intent-to-treat population (ITT) and 69 patients in the modified ITT (mITT) population from both the CARTITUDE-1 and MAMMOTH trials.

The analysis found that the overall response rate (ORR) was 84% for the CARTITUDE-1 population compared with 28% in the MAMMOTH population (odds ratio [OR], 13.4; 95% CI, 6.6-27.3; 

“Our analysis provides evidence of better outcomes with cilta-cel compared with conventional treatments in patients with relapsed/refractory multiple myeloma who had received a proteasome inhibitor, an immunomodulatory drug (IMiD), and an anti-CD38 monoclonal antibody using propensity score matching,” Luciano Costa, MD, of the O’Neal Comprehensive Cancer Center at the University of Alabama at Birmingham, explained in his presentation of the data.

In MAMMOTH, which served as the comparative control group for CARTITUDE-1, patients who received a non–CAR T-cell subsequent therapy after becoming refractory to a proteasome inhibitor, IMiD, and anti-CD38 monoclonal antibody while also not having renal failure or meeting the criteria for plasma cell leukemia were in the ITT population. The mITT population included patients who also did not experience death or progression within 47 days from study inclusion to therapy initiation.

For CARTITUDE-1, the ITT population was defined as patients who underwent apheresis, while the mITT population consisted of patients who also received a cilta-cel infusion.

Survival data in the ITT populations were also significant for CAR T-cell therapy, with a 12-month progression-free survival (PFS) rate of 73% (95% CI, 64%-83%) for patients in the CARTITUDE-1 population and 12% (95% CI, 6%-21%) for patients in the MAMMOTH population. The 12-month overall survival (OS) rate followed suit, with rates of 83% (95% CI, 76%-91%) and 39% (95% CI, 30%-51%) in the CARTITUDE-1 and MAMMOTH populations, respectively.

The mITT analyses produced similar results to that of the ITT populations. The ORR for these patients was 96% in CARTITUDE-1 compared with 30% in MAMMOTH (OR, 50.3; 95% CI, 14.2-178.3; 

The 12-month PFS rate was 79% (95% CI, 69%-90%) in the CARTITUDE-1 population compared with 15% (95% CI, 7%-28%) in the MAMMOTH population (

 < .001). More, the 12-month OS rates were 88% (95% CI, 81%-96%) and 35% (95% CI, 24%-51%), respectively (

“In propensity score–matched analyses of ITT and mITT populations, ORR and 12-month PFS and OS rates were significantly higher in CARTITUDE-1 vs MAMMOTH,” wrote the investigators in their poster presentation of the data.

The CARTITUDE-1 trial treated patients with multiple myeloma who received 3 or more prior therapies or were double refractory to an IMiD and proteasome inhibitor, and who received a proteasome inhibitor, IMiD, and anti-CD38 monoclonal antibody. Eligible patients received a single cilta-cel infusion of 0.75 × 106 CAR-positive viable T cells/kg, which was given 5 to 7 days after starting lymphodepletion.

Eligible patients with multiple myeloma for the MAMMOTH study were previously treated for 4 or more weeks with an anti-CD38 monoclonal antibody regimen.

While the data are useful, the research team notes that study design differences between CARTITUDE-1 and MAMMOTH limit the results. Specifically, CARTITUDE-1 is a prospective clinical study, while MAMMOTH is retrospective and observational in design.

“In the absence of a direct comparator, however, this analysis indicates that cilta-cel outperforms currently available therapies for heavily pretreated patients with multiple myeloma,” concluded the investigators.

Costa LJ, Lin Y, Martin T, et al. Comparison of Ciltacabtagene Autoleucel Versus Conventional Treatment inPatients With Relapsed/Refractory Multiple Myeloma. Presented at: 2021 European Hematologic Association Congress; Virtual. June 9-17, 2021. Abstract EP990.

Treatment with the CAR T-cell therapy ciltacabtagene autoleucel significantly improved outcomes for patients with relapsed or refractory multiple myeloma when compared with conventional therapies.

Cilta-Cel Significantly Improved Response and Survival Over Conventional Therapy for R/R MM

Now that CAR T-cell therapies have exploded in the B-cell lymphoma paradigm, ongoing trials are dedicated to understanding whether this modality can be utilized after 1 prior line of treatment and whether it can be beneficial in patients who are ineligible for transplant, according to Nilanjan Ghosh MD, PhD.

Three randomized clinical trials—the phase 3 TRANSFORM study (NCT03575351), the phase 3 BELINDA study (NCT03570892), and the phase 3 ZUMA-7 study (NCT03391466)—are evaluating the efficacy of different CAR T-cell products following 1 line of prior treatment vs standard-of-care transplant. The primary end point of all these trials is event-free survival and the results are eagerly anticipated, according to Ghosh.

The open-label PILOT study (NCT03483103) is the first to examine the safety and efficacy of lisocabtagene maraleucel (liso-cel; Breyanzi) as a second-line treatment in patients with aggressive, relapsed/refractory large B-cell lymphoma not eligible for transplant. Results presented during 

2020 European Hematology Association Congress

 showed that the CAR T-cell therapy elicited a high objective response rate of 89% and all participants achieved an early objective response by day 30. The Kaplan-Meier–estimated probability of continued response at 3 months was 63% (95% CI, 37%-81%); at 6 month this rate was estimated to be 53% (95% CI, 25%-75%).

“This is not a phase 3 randomized study, but the results are very encouraging. [However], we do not have long-term data, so we will just have to wait and see how that pans out,” Ghosh said. “[Liso-cel] appears to be a very viable option. With most treatments in oncology, if something is very effective in [later lines], when you move it up, it will continue to be effective. The next step may be [to see whether] you could integrate it into frontline therapy, at least for high-risk patients. That is the future.”

 during an Institutional Perspective in Cancer webinar on CAR T-Cell Therapies, Ghosh, who is director of the Lymphoma Program and a physician with Levine Cancer Institute, Atrium Health, highlighted progress made with CAR T-cell therapies in B-cell lymphoma and some ongoing trials generating interest in the field.

: What are some of the key advances made with CAR T-cell therapies in B-cell lymphoma?

: Many new products have emerged in the B-cell lymphoma [paradigm]. The recent advances have been [primarily] in the cellular therapy space, specifically CAR T-cell therapy. Axicabtagene ciloleucel [axi-cel; Yescarta] has already been approved for diffuse large B-cell lymphoma [DLBCL] in the relapsed/refractory setting after 2 prior lines of therapy. Similarly, tisagenlecleucel [tisa-cel; Kymriah] and liso-cel were also approved for use in relapsed/refractory DLBCL and other aggressive [subtypes], such as primary mediastinal and high-grade B-cell lymphoma.

Very recently, axi-cel was also approved for follicular lymphoma after 2 prior lines of therapy, based on results from the ZUMA-5 study; that is really the first approval for a CAR T-cell therapy in [this disease]. The results of the study are fantastic—over 90% of patients responded [to treatment]. The follow-up [for the trial] is not that long, but the responses are quite durable.

We also know that in mantle cell lymphoma [MCL], we have an approval for the CAR T-cell therapy brexucabtagene autoleucel [Tecartus; formerly KTE-X19]. Liso-cel has good activity in that space, as well. In all CD19-expressing B-cell lymphomas, we are starting to see an expansion of CD19-targeted CAR T-cell products. The responses appear to be high in patients who have relapsed or refractory disease.

In aggressive B-cell lymphomas, we also have the advantage [of having longer follow-up], and we are seeing many durable responses. We are starting to see that in MCL, and time will tell how durable [this product] is in follicular lymphoma. Overall, there is going to be a significant uptick in the utilization of CAR T-cell therapies in B-cell lymphoma.

What trials are examining the use of this modality after 1 prior line of treatment in DLBCL?

[One important question is], is it appropriate to use CAR T-cell therapy at that point or [should we] do salvage therapy followed by transplant? That is being tested in 3 large studies with 3 different types of CAR T-cell products: the phase 3 TRANSFORM study, the phase 3 BELINDA study, and the phase 3 ZUMA-7 study. In these trials, the control arm is autologous transplant, and the experimental arm is CAR T-cell therapy. The results of [these trials] have not read out yet, so we will have to wait and see.

The PILOT trial is examining whether CAR T-cell therapy can be offered to patients who are not candidates for transplant. Could you speak to this research and the findings reported thus far?

In the PILOT study, liso-cel was tested after 1 line of therapy. [This trial enrolled] patients who are primary refractory to frontline therapy or who have relapsed after frontline therapy. For that study, [investigators] looked at patients who were not great candidates for transplant. [Patients] only needed to meet 1 of the criteria [outlined]. Patients could be aged 70 [years] or older, or [have] a performance status of 2; they could have impaired pulmonary function where their diffusion lung capacity for carbon monoxide could be 60% or lower, or their cardiac function could be impaired to some extent. Their renal function could be impaired, but they needed to still have creatinine clearance above 30 mL/min.

If they had any of these criteria, they could have enrolled on the study and have [received] liso-cel as their second-line therapy. This study has completed accrual, but the [most recently] presented results were revealed at the2020 European Hematology Association Congress. [Results indicated] a very nice response rate [with the CAR T-cell therapy]; we saw an 89% overall response rate, with a 56% complete response [CR] rate. Also, some partial responses converted into CRs. Mostly, the CRs appear to be durable. The [rates of] cytokine release syndrome [CRS] and neurotoxicity are very low, as has been the story with liso-cel. [The product] has clearly demonstrated very good activity in the second-line setting.

What questions need to be addressed with long-term data from this trial?

The main thing [that we want to see from] the long-term data is the durability of the response [achieved with these products]. Fortunately, we know from many of the CAR T-cell therapy studies that patients who [achieve a CR] and maintain that CR maybe for the first 3 or 6 months seem to continue to be in long-term remission for years. We do not have 5- or 10-year data, but it does appear that the curves plateau after the first 6 months, or, at the most, 1 year. In some cases, [this can happen] maybe even at 3 months. Fortunately, if the read out is quick, and you get a sense of how many patients are in a CR at 6 months, that may give you an idea about the durability of the response. Of course, 3 years or 5 years is when you actually prove your hypothesis; however, if you go by what has been seen, we can get a good idea [of whether these] patients are going to do well in the long run.

In terms of toxicity, most [effects occur] early. For example, CRS and neurotoxicity occur early [on in treatment], and they do not seem to linger over a long period of time. What may linger is hypogammaglobulinemia; that may persist for a long time. Cytopenias sometimes persist for longer than what people may expect. Outside of those [effects], there is a need to follow patients who receive CAR T-cell therapy over a long period of time because they are receiving genetically-modified T cells. [We need to watch for] any long-term effects, like secondary malignancies and others.

Lisocabtagene maraleucel (JCAR017) as second-line therapy (TRANSCEND-PILOT-017006). ClinicalTrials.gov. Updated February 8, 2021. Accessed April 7, 2021. https://clinicaltrials.gov/ct2/show/NCT03483103

Nilanjan Ghosh MD, PhD, highlights progress made with CAR T-cell therapies in B-cell lymphoma and some ongoing trials generating interest in the field.

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