Lisocabtagene maraleucel (Breyanzi; liso-cel) demonstrated durable responses and a favorable safety profile in patients with relapsed/refractory large B-cell lymphoma, according to abstract findings from the phase 1 TRANSCEND NHL 001 trial (NCT02631044), which will be presented at the upcoming 2021 ASH Annual Meeting & Exposition.

As of the data cutoff on January 4, 2021, the objective response rate (ORR) per independent review committee was 73%, with a complete response (CR) rate of 53% in the efficacy-evaluable population (n = 257). The median duration of response (DOR) was 23.1 months (95% CI, 8.6–not reached), the median progression-free survival (PFS) was 6.8 months (95% CI, 3.3-12.7), and the median overall survival (OS) was 27.3 months (95% CI, 16.2-45.6).

The estimated 24-month rates of continued response, PFS, and OS were 49.5% (95% CI, 41.4%-57.0%), 40.6% (95% CI, 34.0%-47.2%), and 50.5% (95% CI, 44.1%-56.5%), respectively.

“CAR T cells are an FDA-approved option for certain types of lymphoma. At this year’s ASH meeting, we will present the 2-year follow up of the TRANSCEND NHL 001 trial, which evaluated the efficacy and safety of liso-cel, a CD19-directed CAR T-cell [therapy], in aggressive B-cell lymphoma,” said M. Lia Palomba, MD, senior study author and a medical oncologist at Memorial Sloan Kettering Cancer Center, in a statement to 

“Of the 270 patients who received liso-cel infusion, 73% had an objective response, and 53% [had] a CR. The median DOR was 23.1 months and the probability of PFS at 2 years was 40.6%. Importantly, liso-cel was safe, with only 2% of patients experiencing serious cytokine release syndrome [CRS] and 10% experiencing serious neurological toxicity,” added Palomba.

On February 5, 2021, the FDA approved liso-cel for the treatment of adult patients with certain types of large B-cell lymphoma who have not responded to, or who have relapsed after, at least 2 other types of systemic treatment.

The biologics license application for the anti–CD19-targeted CAR T-cell therapy was granted a priority review designation from the FDA in February 2020. The application was based on earlier findings from the multicenter phase 1 TRANSCEND NHL 001 trial, which showed an ORR of 73% and a CR rate of 53% in patients treated with liso-cel, with the time to first CR or partial response occurring at a median of 1 month.

In the extended follow-up analysis, 345 patients underwent leukapheresis. In the liso-cel–treated population (n = 270), the median age was 63 years (range, 18-86); 41% of patients were at least 65 years of age.

Histologies included diffuse large B-cell lymphoma not otherwise specified (de novo, 51%; transformed from indolent lymphoma, 29%), high-grade B-cell lymphoma (13%), primary mediastinal large B-cell lymphoma (6%), and follicular lymphoma grade 3B (1%). Seven patients (3%) had secondary central nervous system lymphoma.

Patients received a median of 3 prior lines of systemic therapy (range, 1-8) and 33% had prior autologous hematopoietic stem cell transplant (HSCT; prior allogeneic HSCT, 3%). Of all patients, 67% were refractory to chemotherapy, 45% had never achieved a CR, and 59% received bridging therapy.

As of the data cutoff, 268 patients had at least 24 months of follow-up, died, or withdrew from the study.

Additional findings indicated that during the 90-day treatment-emergent reporting period, 79% of patients in the liso-cel–treated population (n = 270) had grade 3 or greater treatment-emergent adverse effects (TRAEs); 45% had serious TEAEs.

Any-grade CRS and neurotoxicity occurred in 42% and 30% of patients, respectively (grade 3/4 CRS, 2%; grade 3/4 neurotoxicity, 10%). The median time to onset of CRS and neurotoxicity was 5 days (range, 1-14) and 9 days (range, 1-66), respectively.

Grade 3 or greater infections and laboratory-based prolonged cytopenia at day 29 occurred in 12% and 37% of patients, respectively. In the posttreatment emergent reporting period (day 91 to the end of the study), which included 17 patients who were retreated with liso-cel, 23% of patients in the liso-cel–treated population (n = 249) had grade 3 or greater AEs and 17% had serious AEs.

The most common grade 3 or greater AEs in the posttreatment emergent period were neutropenia (7%), anemia (6%), thrombocytopenia (4%), and febrile neutropenia (4%). Grade 3 or greater infections occurred in 5% of patients. In the posttreatment emergent period, 100 patients (37% of all patients) died, mostly due to disease progression (86% of all posttreatment emergent deaths; 32% of all patients).

Further results demonstrated that CAR T cells were present in peripheral blood for up to 4 years.

Abramson JS, Palomba ML, Gordon LI, et al. Two-year follow-up of Transcend NHL 001, a multicenter phase 1 study of lisocabtagene maraleucel (liso-cel) in relapsed or refractory (R/R) large b-cell lymphomas (LBCL). Presented at: 2021 ASH Annual Meeting & Exposition; December 9-14, 2021; virtual. Abstract 2840.

FDA approves new treatment for adults with relapsed or refractory large B-cell lymphoma. News release. FDA. February 5, 2021. Accessed November 19, 2021. http://prn.to/3aCkwBh.

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. Presented at: 2019 ASH Annual Meeting & Exposition; December 7-10, 2019; Orlando, FL. Abstract 241.

Articles

Lisocabtagene maraleucel demonstrated durable responses and a favorable safety profile in patients with relapsed/refractory large B-cell lymphoma. 

Lisocabtagene Maraleucel Displays Durable Remissions in Relapsed/Refractory LBCL

Lisocabtagene maraleucel (liso-cel) exhibited promising antitumor activity with low rates of grade 3 or higher cytokine release syndrome (CRS) and neurotoxicity in patients with relapsed/refractory mantle cell lymphoma (MCL), according to phase 1 results of the single-arm TRANSCEND NHL 001 trial that were presented during the 2020 ASH Annual Meeting and Exposition.

The objective response rate (ORR) among the 32 patients treated in the study was 84%, with a complete response (CR) rate of 66% at a median on-study follow-up of 5.9 months, lead study reported Maria Lia Palomba, MD, reported in a presentation during the virtual meeting.

The median time to first CR or partial response was 0.95 months.

“The median duration of response was not reached after a median follow-up of 3.9 months,” said Palomba, a hematologist/oncologist, Memorial Sloan Kettering Cancer Center. “A total of 6 patients have demonstrated a durable response over 1 year in this ongoing study. Importantly, responses were generally similar in patients with blastoid morphology and in patients who were resistant to ibrutinib [Imbruvica].”

Among the patients with Ki-67 level at 30% or higher, the ORR was 83% and the CR rate was 65%. Of those with blastoid morphology, the ORR and CR rates were 77% and 54%, respectively, and among patients with a 

 mutation, these rates were 100% and 57%, respectively.

Prognosis is poor in patients with MCL, with disease progression likely following receipt of a BTK inhibitor. The median overall survival with salvage therapy is typically 6 to 10 months.

 Liso-cell previously demonstrated an ORR of 73%, with a CR rate of 53%, among a subcohort of patients with relapsed/refractory large B-cell lymphoma who were enrolled on TRANSCEND NHL 001, in whom the rate of grade 3 or higher CRS was 2% and neurologic events occurred in 10% of these patients.

Liso-cel, a CD19-directed, 4-1BB CAR T-cell product, is administered as separate CD8+ and CD4+ T-cell components at equal target doses. “Importantly, the defined dose and CD8+/CD4+ ratio [of CAR T cells] may influence the incidence and severity of CRS and neurologic events,” she said.

At data cutoff, the relapsed/refractory MCL cohort consisted of 32 patients who, after lymphodepletion, were treated with liso-cel at 1 of 2 dose levels­—6 at dose level 1 (50 x 106 CAR T cells) and 26 at dose level 2 (100 x 106 CAR T cells). Administration of CAR T cells and monitoring were allowed in either the inpatient or outpatient setting. Bridging therapy was permitted and could include chemotherapy or radiotherapy. Eligible patients had at least 2 prior lines of therapy.

“After a protocol amendment, patients were required to have received a BTK inhibitor, an alkylating agent, and an anti-CD20 agent,” said Palomba.

The primary end points were adverse events (AEs), dose-limiting toxicities, and ORR by independent review committee per Lugano classification.

The median time to maximal liso-cel expansion was 10 days after infusion. “Liso-cel showed long-term persistence at 1 year in 67% of patients and at 2 years in 33% of patients with sufficient follow-up,” she said.

The median age was 67 years, 41% had blastoid morphology, 72% had documented Ki-67 at least 30%, and 22% had 

 mutations. Patients received a median of 3 prior lines of therapy, 81% had disease refractory to their most recent prior therapy, and 31% were refractory to prior ibrutinib.

Eighty-four percent had a grade 3 or higher treatment-emergent (TEAE), including anemia (38%), neutropenia (44%), and thrombocytopenia (31%). Prolonged grade 3 and higher cytopenias present at study day 29 were reported in 34% of patients.

Two grade-5 treatment-emergent adverse events occurred in 2 patients, both at dose level 2 and both were considered related to liso-cel: 1 patient experienced tumor lysis syndrome and 1 patient with cryptococcal meningoencephalitis died. There were no deaths related to CRS or neurologic events.

Grade 3 or higher CRS was reported in 1 patient (3%), with a median time to onset of 6 days and a median to resolution of 4 days. Grade 3 or higher neurologic events were reported in 4 (12.5%), with a median time to onset of 8 days and a median time to resolution of 4 days. For management of CRS and neurologic events, 12.5% of patients required both tocilizumab (Actemra) and corticosteroids, 12.5% required corticosteroids alone, and 6% tocilizumab only.

Enrollment into the study is ongoing at dose level 2 in the MCL cohort, said Palomba.

Palomba ML, Gordon LI, Siddiqi T, et al. Safety and preliminary efficacy in patients with relapsed/refractory mantle cell lymphoma receiving lisocabtagene maraleucel in Transcend NHL 001. Presented at: 2020 ASH Annual Meeting and Exposition; December 4-8, 2020; virtual. Abstract 118.

Martin P, Maddocks K, Leonard JP, et al. Postibrutinib outcomes in patients with mantle cell lymphoma. 

 2016;127:1559-1563. doi:10.1182/blood-2015-10-673145

Jain P, Kanagal-Shamanna R, Zhang S, et al. Long-term outcomes and mutation profiling of patients with mantle cell lymphoma (MCL) who discontinued ibrutinib. 

Epperla N, Hamadani M, Cashen AF, et al. Predictive factors and outcomes for ibrutinib therapy in relapsed/refractory mantle cell lymphoma-a "real world" study. Hematol Oncol. 2017;35:528-535. doi:10.1002/hon.2380.

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;396:839-852. doi: 10.1016/S0140-6736(20)31366-0

December 17, 2020 - Lisocabtagene maraleucel exhibited promising antitumor activity with low rates of grade 3 or higher cytokine release syndrome and neurotoxicity in patients with relapsed/refractory mantle cell lymphoma.

Liso-Cel Proves to Be Highly Active, Tolerable in Relapsed/Refractory MCL

Ciltacabtagene autoleucel (JNJ-68284528; cilta-cel) was found to elicit clinically meaningful improvements in health-related quality of life (HRQoL) in patients with relapsed/refractory multiple myeloma, and this benefit may become even more pronounced as responses to treatment* deepen over time, according to data from the CARTITUDE-1 study (NCT03548207) presented during the 

For 68 patients in the phase 2 portion of the trial, HRQoL was analyzed using 3 patient-reported instruments: the European Organisation for Research and Treatment of Cancer Quality-of-life Questionnaire Core 30 (EORTC QLQ-30), EORTC QLQ-MY20, and EQ-5D-5L visual analogue scale (VAS). These instruments assessed for global health status (GHS), functional scales, and symptom scales; emotional health status; and current health status, respectively.

There were clinically meaningful improvements observed for patients 100 days after their single infusion of cilta-cel. These improvements were seen with pain in 72% of 54 patients, fatigue in 54% of 52, physical functioning in 58% of 52, and GHS in 54% of 54 for the EORTC QLQ-C30. Out of 53 patients who completed the EORTC QLQ-MY20 assessment, 81% reported a meaningful improvement in being restless or agitated, 51% thought less about their illness, about dying (42%), and about their future health (32%).

“Multiple myeloma negatively affects health-related quality of life and further declines happen with each relapse,” Thomas Martin III, MD, from the University of California San Francisco, said in his presentation. “Because of this, quality of life is an important consideration in managing and evaluating new therapies.”

At 100 days post infusion, patients with a deeper treatment response showed a trend toward greater improvement in GHS, physical function, pain, and fatigue. For non-responders, scores were difficult to interpret since there were only 2 patients who did not respond to therapy. There was also 1 non-responder patient with progressive disease who was excluded due to lack of interviews, according to Martin. There was a similar trend toward improved patient-reported outcomes with deeper treatment response observed with the EQ-5D-5L VAS scores.

At day 7 post infusion, there was a worse score for improvement in physical function and GHS, then a gradual improvement over time, seen 1 to 2 months after infusion and continuing to day 212, which was the latest time point.

“Conversely, mean changes in pain and fatigue showed reduction over time, following initial worsening of fatigue at day 7. These reductions were observed through day 212, where patients reported levels of fatigue and pain that were below baseline values,” Martin explained.

Change in HRQoL was looked at from baseline and investigators assessed the percentage of those with clinically meaningful improvement. Completion rate of the questionnaires were high at baseline, at 92.6% (63/68). By day 212, completion rates were still relatively high with 67.9% (36/68) completing each questionnaire.

Limitations to this analysis of HRQoL included that the patient-reported outcomes were based on a relatively small sample size and the results were an exploratory and descriptive summary of these patients’ self-reported outcomes.
In the initial results of this phase 1b/2 trial, patients receiving the single infusion of cilta-cel following lymphodepletion chemotherapy demonstrated deep, durable responses, with an overall response rate of 96.9% (95% CI, 91.2%-99.4%), and 67% of patients experienced a stringent complete response.

Those who were penta-drug exposed made up 86.8% (59/68), meaning they received treatment with at least 2 proteasome inhibitors, 2 immunomodulatory drugs, and 1 anti-CD38 antibody; 88.2% (60/68) were triple-class refractory, and were refractory to at least 1 proteasome inhibitors, 1 immunomodulatory drug, and 1 anti-CD38 antibody; and patients who were penta-drug refractory to all 5 previous therapies made up 47.1% (32/68).

Eligibility for this trial included at least 3 prior lines of treatment or double-class refractory to a proteasome inhibitor, immunomodulatory drug, and/or an anti-CD38 antibody. They also had to have an ECOG performance status of 1 or more, measurable disease, and progressive multiple myeloma per International Myeloma Working Group criteria. There was a median of 6 prior therapies in this group of patients, a median age of 62 years, and 63.2% of patients were male.

“In summary, patients with heavily pretreated multiple myeloma reported rapid, clinically meaningful improvements in health-related quality of life after a single cilta-cel infusion. The improvement in physical function, general health status, pain, fatigue, and emotional status were consistent with clinical outcomes. We observed a trend toward greater improvements in patients with deeper clinical responses, which suggests patients may experience further quality-of-life improvements as their treatment response deepens over time,” Martin concluded.

Martin T, Lin Y, Agha M, et al. Health-Related Quality of Life in the Cartitude-1 Study of Ciltacabtagene Autoleucel for Relapsed/Refractory Multiple Myeloma. Poster presented at: 62nd American Society of Hematology Annual Meeting and Exhibition; December 5-8, 2020; Virtual. Abstract 2291. https://bit.ly/3a03gHx

Madduri D, Berdeja JG, Usmani SZ, et al. CARTITUDE-1: phase 1b/2 study of ciltacabtagene autoleucel, a B-cell maturation antigen–directed chimeric antigen receptor T cell therapy, in relapsed/refractory multiple myeloma. Presented at: 2020 ASH Annual Meeting and Exposition; December 5-8, 2020; Virtual. Abstract 177.

Ciltacabtagene autoleucel was found to elicit clinically meaningful improvements in health-related quality of life in patients with relapsed/refractory multiple myeloma, and this benefit may become even more pronounced as responses to treatment deepen over time, according to data from the CARTITUDE-1 study presented during the 2020 ASH Annual Meeting & Exposition.

Cilta-Cel Improves HRQoL in Relapsed/Refractory Multiple Myeloma

UCART22, an allogeneic off-the-shelf CD22-directed T-cell product, showed no unexpected toxicities at 2 dose levels and had early signs of activity in adult patients with relapsed/refractory CD22-positive B-cell acute lymphoblastic leukemia (ALL), according to results of the phase 1 BALLI-01 study (NCT04150497) that were presented during the 2020 ASH Annual Meeting.

In the dose-escalation and dose-expansion study, 2 patients at the 1 x 10

 cells/kg dose achieved a complete remission (CR) with incomplete hematologic recovery on day 28. One of these patients attained a minimal residual disease (MRD)–positive CR at day 42 followed by subsequent inotuzumab ozogamicin (Besponsa) and then transplant.

 cells/kg, experienced a significant bone marrow blast reduction at day 28, followed by disease progression.

No patients experienced dose-limiting toxicities (DLTs), immune effector cell–associated neurotoxicity syndrome (ICANS), graft-versus-host disease (GVHD), adverse effects (AE) of special interest (AESI), a UCART22-related AE that was grade 3 or higher, or a serious AE (SAE).

“UCART22 showed no unexpected toxicities at the doses of 1 x 10

 cells/kg with fludarabine and cyclophosphamide lymphodepletion,” lead study author Nitin Jain, MD, an assistant professor in the Department of Leukemia, The University of Texas MD Anderson Cancer Center, said in a virtual presentation during the meeting. “Host immune recovery was observed early, and the addition of alemtuzumab [Lemtrada] to fludarabine and cyclophosphamide lymphodepletion is currently being explored with the goal to achieve deeper and more sustained T-cell depletion and to promote expansion and persistence of UCART22.”

Standard treatment for adult patients with B-cell ALL includes multiagent chemotherapy with or without allogeneic stem cell transplant. However, 30% to 60% of patients with newly diagnosed B-cell ALL who achieve a CR will relapse, and the expected 5-year survival rate for those with relapsed/refractory disease is approximately 10%.

Previously, UCART19, when paired with lymphodepletion using fludarabine, cyclophosphamide, and alemtuzumab, was found to show efficacy in this patient population.

CD22 is an FDA-approved therapeutic target in B-cell ALL. UCART22 is an immediately available, standardized, manufactured agent with the ability to re-dose, and its CAR expression redirects T cells to tumor antigens, Jain explained.

Moreover, through its mechanism of action, 

 becomes disrupted using Transcription activator-like effector nucleases (Talen) technology to eliminate TCRαβ from cell surface and

reduce the risk of GVHD. CD52 is also disrupted with the use of Talen to eliminate sensitivity to lymphodepletion with alemtuzumab. Finally, there is a CD20 mimotope for rituximab (Rituxan) as a “safety switch,” Jain added.

 antitumor activity in immune-compromised mice that were engrafted with CD22-positive Burkitt lymphoma cells in a dose-dependent manner.

In the dose-escalation/dose-expansion BALLI-01 study, investigators are enrolling up to 30 patients in a modified Toxicity Probability Interval design. There are 3 cohorts, which have 2 to 4 patients on each cohort: 1 x 10

 cells/kg. The focus of the dose-escalation phase of the trial was to determine the maximum-tolerated dose (MTD) and the recommended phase 2 dose (RP2D) before heading into the dose-expansion portion of the trial.

To be eligible for enrollment, patients must have been between 18 and 70 years old, have acceptable organ function, an ECOG performance status of 0 or 1, at least 90% of B-cell ALL blast CD22 expression, and had previously received at least 1 standard chemotherapy regimen and at least 1 salvage regimen.

End points of the trial included safety and tolerability, MTD/R2PD, investigator-assessed response, immune reconstitution, and UCART22 expansion and persistence.

The lymphodepletion regimens were comprised of fludarabine (at 30 mg/m

 x 3 days); the study has since been amended to include the regimen of fludarabine (at 30 mg/m

 x 3 days), and alemtuzumab (20 mg/day x 3 days) and is currently enrolling patients.

Following screening, lymphodepletion, and UCART22 infusion, patients underwent an observation period for DLTs with a primary disease evaluation at 28 days; additional efficacy evaluations occurred at 56 days and 84 days. Patients were followed for 2 years and continued to be assessed for long-term follow-up.

As of July 1, 2020, 7 patients were screened, of which 1 patient failed and 6 were therefore enrolled on the study. One patient discontinued therapy before receiving UCART22 due to hypoxia from pneumonitis that was linked with lymphodepletion. Five patients were treated with UCART22 at dose level 1 (n = 3) and dose level 2 (n = 2).

The median age of participants was 24 years (range, 22-52), 3 of the 5 patients were male, and 3 had an ECOG performance status of 0. The median number of prior therapies was 3 (range, 2-6), and there were a median 35% bone marrow blasts (range, 10%-78%) prior to lymphodepletion.

Three patients had complex karyotype and 2 had diploid cytogenetics. One patient each had the following molecular abnormalities: 

. Only 1 patient had undergone haploidentical transplant. Four patients previously received prior CD19- or CD22-directed therapy, including blinatumomab (Blincyto), inotuzumab ozogamicin (Besponsa), and CD19-directed CAR T-cell therapy. At study entry, 3 patients had refractory disease and 2 patients had relapsed disease.

Grade 3 or higher treatment-emergent AEs (TEAEs), which were unrelated to study treatment, included hypokalemia, anemia, increased bilirubin, and acute hypoxic respiratory failure. Also not related to UCART22, 3 patients experienced 4 treatment-emergent SAEs: porta-hepatis hematoma, sepsis, bleeding, and sepsis in the context of disease progression. No treatment discontinuations due to a treatment-related TEAE were reported.

The patient who achieved a CR followed by transplant was a 22-year-old male who had undergone 2 prior treatments for B-cell ALL and received UCART22 at a dose of 1 x 10

 cells/kg. He did not experience CRS, ICANS, GVHD, nor a SAE, and all TEAEs were grade 1.

Jain also noted that host T-cell constitution was observed in all patients within the DLT observation period. UCART22 was also not detectable through flow cytometry or molecular analysis, the latter of which was at dose level 1 only.

Jain N, Roboz GJ, Konopleva M, et al. Preliminary results of BALLI-O1: a phase I study of UCART22 (allogeneic engineered T cells expressing anti-CD22 chimeric antigen receptor) in adult patients with relapsed/refractory anti-CD22+ B-cell acute lymphoblastic leukemia (NCT04150497). Presented at: 2020 ASH Annual Meeting and Exposition; December 4-8, 2020; Virtual. Abstract 163.

Benjamin R, Graham C, Yallop D, et al. Preliminary data on safety, cellular kinetics and anti-leukemic activity of UCART19, an allogeneic anti-CD19 CAR T-cell product, in a pool of adult and pediatric patients with high-risk CD19+ relapsed/refractory b-cell acute lymphoblastic leukemia. 

. 2018;132(suppl 1):896. doi:10.1182/blood-2018-99-111356

December 6, 2020 - UCART22, an allogeneic off-the-shelf CD22-directed T-cell product, showed no unexpected toxicities at 2 dose levels and had early signs of activity in adult patients with relapsed/refractory CD22-positive B-cell acute lymphoblastic leukemia.

Allogeneic Off-the-Shelf UCART22 Product Shows Early Activity, Tolerability in Relapsed/Refractory CD22+ B-Cell ALL

ALLO-715, an off-the-shelf chimeric antigen receptor (CAR) T-cell therapy that targets B-cell maturation antigen (BCMA), elicited responses in heavily pretreated patients with relapsed/refractory multiple myeloma in early findings from a first-in-human study presented at the 2020 ASH Meeting.

The therapy generated responses in 6 of 10 patients (60%), including a very good partial-plus response (VGPR+) in 4 patients (40%), who were treated with ALLO-715 at a dose of 320 x 10

 CAR cells plus a lymphodepleting regimen that included ALLO-647, an anti-CD52 monoclonal antibody, during the ongoing phase 1 UNIVERSAL study (NCT04093596).

The findings mark the first results for an allogeneic CAR therapy directed at BCMA, said lead study author Sham Mailankody, MBBS, a medical oncologist and investigator in the Cellular Therapeutics Center at Memorial Sloan Kettering Cancer Center in New York, New York. BCMA, which is highly expressed on plasma and multiple myeloma cells, has sparked intensive research interest.

“These results demonstrate the feasibility and safety of an off-the-shelf CAR T cell therapy for multiple myeloma. In this first report of an allogeneic BCMA CAR T-cell therapy, we show that nearly 90% of patients were treated within 5 days of enrollment and without needing any bridging therapy,” Mailankody said.

Allogeneic CAR therapy offers the potential for scalable manufacturing for on-demand treatment with shorter waiting times, which would overcome some of the logistical challenges posed by autologous CAR therapy, Mailankody said. The T cells needed for ALLO-715 are harvested from healthy donors and genetically engineered to express CARs aimed at specific cancer targets, according to Allogene Therapeutics, the company developing the therapy.

ALLO-715 includes a human-derived single-chain variable fragment anti-BCMA cell with a 4-1BB costimulatory domain. Mailankody said the “2 key attributes” of the construct are a knockout of CD52, which allows for selective lymphodepletion with ALLO-647 to prevent graft rejection without affecting the CAR T cells, and a knockout of the TRAC gene, which also minimizes the risk of graft-versus-host disease (GVHD).

The UNIVERSAL study, which is being conducted at 11 cancer centers in the United States, is recruiting patients with multiple myeloma who have received 3 or more prior therapies, including an immunomodulatory drug, a proteasome inhibitor, and an anti-CD38 agent, and are refractory to their last treatment. Participants must have an ECOG performance status score of 0 or 1.

The dose escalation portion of the study is testing ALLO-715 as a single infusion across 4 doses: 40, 160, 320, or 480 x 10

 CARs. Lymphodepletion regimens consist of fludarabine (F; 30 mg/m

/day) given on 3 days with ALLO-647 (A; 13-30 mg x 3 days; FCA) or cyclophosphamide plus ALLO-647 (CA).

Among the 35 patients enrolled at the time of the presentation, 4 became ineligible because of organ failure due to rapidly progressing disease. Of 31 patients in the safety population, the median age was 65 years (range, 46-76). Nearly half of the patients (48%) have high-risk cytogenetics and 23% had extramedullary disease. The efficacy population at data cutoff on October 30, 2020, comprised 26 patients across the 4 dosing levels, with a median follow-up of 3.2 months.

The overall response rate (ORR) varied across dosing cohorts and lymphodepleting regimens. No responses were observed among 3 patients each who received CARs at 40 x 10

 with FCA or 160 x 106 with CA, both with low-dose ALLO-647. The ORRs were 50% in 4 patients who received CARs at 160 x 10

 with low–ALLO-647 FCA; 33% in 3 at 480 x 10

 with low–ALLO-647 FCA; and 67% in 3 at 320 x 10

The most robust responses were seen among those who received ALLO-647 at 320 x10

. For this cohort, the ORR was 60% among 10 patients, including 3 of 6 who received CARs with low–ALLO-647 FCA and 3 of 4 who had the therapy with high–ALLO-647 FCA. Overall, 6 patients had a VGPR+, defined as stringent complete response, complete response, or VGPR. These included 1 at 160, 4 at 320, and 1 at 480 10 x 10

 CARs. Of the VGPR+ patients, 5 were negative for measurable residual disease. Additionally, 6 of 9 patients treated at the 320 or 480 x 10

Mailankody highlighted the experience of 1 participant, a 71-year-old man whose myeloma had progressed after undergoing 9 prior lines of therapy including autologous stem cell transplant and an experimental BCMA-targeted therapy. The patient received a conditioning regimen of FCA with low-dose ALLO-647 and ALLO-715 at 320 x 10

. He reached a VGPR on day 14 that deepened to a stringent complete response by day 28 that remains in effect at 6 months, while experiencing grade 1 cytokine release syndrome (CRS).

“The patient is clinically doing very well and is back at work,” Mailankody said.

Among 31 patients in the safety population, most adverse effects were of grade 1 or 2 severity. These included CRS in 14 patients (45%) and infusion-related reactions to ALLO-647 in 7 patients (23%). The use of drugs to manage CRS also was low, at 19% for tocilizumab and 10% for steroids.

All-grade infections were reported in 13 patients (42%), including grade 3 events in 4 (13%). One patient (3%) died from a presumed fungal pneumonia related to progressive disease and the CA conditioning regimen but unrelated to ALLO-715. There were no instances of neurotoxicity or GVHD.

“Notably, the fact that we did not see any GVHD is encouraging for an off-the-shelf allogeneic product,” Mailankody said.

In response to a question from a conference attendee, Mailankody said it is too soon to compare efficacy levels seen with this allogeneic CAR therapy with those observed with investigational autologous CARs, which have been under study for several years.

Moving forward, investigators are continuing to evaluate dosing levels for ALLO-715. UNIVERSAL is enrolling patients to the 480 x 10

 cohort, Mailankody said, adding that the appropriate dose likely would land between 320 and 480 x 10

Mailankody S, Matous JV, Liedtke M, et al. Universal: an allogeneic first-in-human study of the anti-Bcma ALLO-715 and the Anti-CD52 ALLO-647 in relapsed/refractory multiple myeloma. Presented at: 2020 American Society of Hematology Annual Meeting and Exposition. December 5-8, 2020; Virtual. Abstract 129. Accessed December 5, 2020. https://ash.confex.com/ash/2020/webprogram/Paper140641.html

Cho SF, Anderson KC, Tai YT. Targeting B cell maturation antigen (BCMA) in multiple myeloma: potential uses of BCMA-based immunotherapy. 

. 2019;9:1821. doi:10.3389/fimmu.2018.01821

AlloCAR T Therapy. Allogene Therapeutics. Accessed December 5, 2020. https://www.allogene.com/allocar-t-therapy

ALLO-715, an off-the-shelf chimeric antigen receptor T-cell therapy that targets B-cell maturation antigen, elicited responses in heavily pretreated patients with relapsed/refractory multiple myeloma in early findings from a first-in-human study presented at the 2020 ASH Meeting.

Off-the-Shelf CAR Therapy Shows Early Promise in Multiple Myeloma

Axicabtagene ciloleucel (axi-cel; Yescarta) demonstrated high rates of durable responses in patients with indolent non-Hodgkin lymphoma (NHL), according to extended follow-up results of the ZUMA-5 trial that were presented during the 

Results showed that, at a median follow-up of 17.5 months, the objective response rate (ORR) by independent radiology review committee (IRRC) was 92% (95% CI, 85%-97%), along with a complete response (CR) rate of 76% (95% CI, 67%-84%). The partial response (PR) rate was 16%; the stable disease (SD) was 3% and 5% of patients were undefined.

In patients with follicular lymphoma, the ORR was 94%, with a CR rate of 80%, and a PR rate of 14%. Four percent of patients had SD and 2% were undefined. In those with marginal zone lymphoma (MZL), the ORR was 85%, with a CR rate of 60%, and a PR rate of 25%; 0 patients had SD and 15% of patients were undefined.

“Axi-cel may be a highly promising therapeutic approach for patients with relapsed/refractory indolent NHL,” said lead study author Caron A. Jacobson, MD, MMSc, medical director of the Immune Effector Cell Therapy Program, and a senior physician and assistant professor of medicine, Harvard Medical School, Dana-Farber Cancer Institute. “Given the long natural history of these diseases, safety is of paramount importance. The safety profile was manageable and reversible and appeared to be at least similar to that of axi-cel in aggressive lymphomas. This may have implications for the possibility of outpatient therapy, and evaluation of this is planned.”

Patients with advanced-stage indolent NHL, including follicular lymphoma and MZL, frequently relapse on standard treatment; remission durations for these patients shorten with subsequent lines of therapy.

Axi-cel is an autologous anti-CD19 CAR T-cell therapy

 that is currently approved for the treatment of adult patients with relapsed/refractory large B-cell lymphoma following 2 or more lines of systemic treatment. The regulatory decision was based on findings from the ZUMA-1 trial, in which axi-cel elicited an ORR of 82% in the modified intent-to-treat population, along with a 58% CR rate.2

In the multicenter, single-arm, phase 2 ZUMA-5 trial (NCT03105336), investigators sought to evaluate axi-cel in 151 patients with relapsed/refractory indolent NHL, either follicular lymphoma or MZL, following 2 or more lines of therapy. Five patients could not be treated due to transformation to diffuse large B-cell lymphoma (DLBCL) via pretreatment biopsy (n = 1), ineligibility (n = 3), and death prior to infusion (n = 1). Therefore, a total 146 patients were treated as of the data cutoff and had either follicular lymphoma (n = 124) or MZL (n = 22). 

To be eligible for enrollment, patients needed to have relapsed/refractory follicular lymphoma in grades 1 to 3A or MZL that was nodal or extranodal. Patients must have received 2 or more prior lines of treatment that included an anti-CD20 monoclonal antibody plus an alkylating agent.

Conditioning regimens included 30 mg/m2 of intravenous (IV) fludarabine and 500 mg/m2 of IV cyclophosphamide on days –5, –4, and –3. Axi-cel was administered at 2 x 106 CAR+ cells/kg.

The primary end point of the trial was ORR, which was IRRC-assessed per Lugano classification. Secondary end points included IRRC-assessed CR rate, investigator-assessed ORR, duration of response (DOR), progression-free survival (PFS), overall survival (OS), adverse effects (AEs), and CAR T-cell and cytokine levels. The MZL cohort was exploratory, and all analyses for this cohort were descriptive in nature, Jacobson noted.

The efficacy analyses included 104 patients: those with follicular lymphoma who had at least 1 year of follow-up (n = 84), and patients with MZL with at least 4 weeks of follow-up (n = 20). The safety analysis included all 146 treated patients.

As of March 12, 2020, the median follow-up for the efficacy analysis was 17.5 months (range, 1.4-31.6). The median follow-up for the safety analysis was 15.1 months (range, 0.5-31.6). Axi-cel was manufactured for all 151 enrolled patients and was delivered to the study site a median 17 days following leukapheresis.

Overall, the median age was 61 years (range, 34-79), and 35% of patients were 65 years or older. Fifty-seven patients were male, and 38% had an ECOG performance status of 1. Most patients (86%) had stage III to IV disease, but less than half (47%) had a Follicular Lymphoma International Prognostic Index (FLIPI) score of 3 or lower, and 49% had high tumor bulk based on Groupe d'Etude des Lymphomes Folliculaire criteria.

The median number of prior therapies was 3 (range, 1-10), but 64% received 3 or more treatments; 29% had previously received a PI3K inhibitor. Sixty-eight percent of patients had refractory disease, and 55% had disease progression for more than 2 years from the first anti-CD20 monoclonal antibody–containing therapy. Twenty-three percent of patients underwent prior stem cell transplantation.

Results also showed that the median time to first response was 1 month (range, 0.8-3.1). Additionally, of 25 patients with follicular lymphoma who initially achieved a PR, 52% subsequently converted to a CR after a median 2.2 months (range, 1.9-11.2).

The response rate was consistent across key subgroups analyzed on the study, including age, sex, ECOG performance status, FLIPI score, high tumor burden, number of prior therapies, prior PI3K inhibition, prior autologous SCT, relapsed/refractory disease, progression of follicular lymphoma within 24 months from initiating first anti-CD20 monoclonal antibody–containing therapy, CD19 status, and corticosteroid and/or tocilizumab (Actemra) use.

At a median follow-up of 17.5 months, the estimated median DOR was not reached in the overall population, and the 12-month DOR rate was 71.7% (95% CI, 60.7-80.1).

In the follicular lymphoma cohort, which had a median follow-up of 12.1 months, the median DOR was not estimated and the 1-year DOR rate was 77.0%. Moreover, 64% percent of patients with follicular lymphoma had an ongoing response at data cutoff. Additionally, responses were ongoing in 78% of patients who achieved a CR and in 17% of patients with a PR.

In the MZL cohort, the median DOR was 10.6 months and the 1-year DOR rate was not estimated.

When the median DOR was calculated by best response, patients with follicular lymphoma who had a CR and PR had a median DOR of not estimated (NE) and 2.8 months, respectively; the 1-year DOR rates were 87.0% and 13.6%, respectively.

In the patients with MZL who achieved a CR and PR, the median DOR was 10.6 months and 8.1 months, respectively; the 1-year DOR rates were NE and 0%, respectively. However, Jacobson noted that the follow-up for the MZL cohort is much more limited, making these DOR data immature.

Moreover, further findings showed that the median PFS was NE (95% CI, 23.5

NE), and the 1-year PFS rate was 73.7%. In patients with follicular lymphoma, the median PFS was NE and the 12-month PS rate was 77.5%; in patients with MZL, the median PFS was 11.8 months and the 1-year PFS rate was 45.1%.

The median OS in all patients was NE, and the 1 year-OS rate was 92.9%. The median OS was NE and the 1-year OS rate was 92.8% in patients with follicular lymphoma; in patients with MZL, the median OS was NE and the 1-year OS rate was 92.9%.

Regarding safety, grade 3 or higher adverse effects occurred in 86% of patients, the most common of which were cytopenias (70%) and infections (16%). Three deaths were reported: 1 was related to axi-cel due to multisystem organ failure in the context of cytokine release syndrome (CRS; n = 1, day 7), while the other 2 were unrelated to study treatment and were due to aortic dissection (n = 1, day 399) and coccidioidomycosis (n = 1, day 327).

Overall, 82% of patients experienced any-grade CRS, and 7% had grade 3 or higher CRS. Ninety-six percent of patients experienced pyrexia and 41% had hypotension. Moreover, approximately half (49%), had their AEs managed with tocilizumab and 17% received corticosteroids. Grade 4/5 CRS occurred in 1 patient each, and no patients had ongoing CRS as of the cutoff date.

The median time to onset of CRS was 4 days (range, 1-15) and the median duration of events was 6 days (range, 1-27). Ninety-nine percent of patients, however, had resolved events.

The overall incidence of any-grade and grade 3 and higher neurologic events were 60% and 19%, respectively. Tremor and confusional state occurred in 52% and 40% of patients, respectively. To manage this AE, 36% of patients received corticosteroids and 6% were given tocilizumab. The median time to onset of neurologic events was 7 days, and the median duration of events was 14 days. Ninety-three percent of patients had resolved events.

When stratified by cohort, patients with MZL had higher rates of grade 3 or higher neurologic events versus those with follicular lymphoma, at 41% vs 15%, respectively.

Grade 4 neurologic events occurred in 3 patients, and no grade 5 events were reported. At the data cutoff date, events were ongoing in 6 patients, which included grade 1 memory impairment (n = 2), and grade 1 attention disturbance, intermittent paresthesia, and tremor (n = 1), and grade 2 facial paresthesia (n = 1).

Furthermore, the median time to peak of anti-CD19 CAR T-cell levels after the infusion of axi-cel was 9 days (range, 8-371). The CAR T-cell expansion by peak and area under the curve trended higher in patients with MZL. Seventy-eight percent of patients with evaluable samples had low levels of detectable CAR gene-marked cells at 1 year.

There was a trend toward higher CAR T-cell levels in patients with follicular lymphoma who had an ongoing response at 12 months, Jacobson added. Moreover, peak CAR T-cell levels were associated with grade 3 or higher CRS and neurologic events in patients with FL. Similar trends linked between CAR T-cell expansion and outcomes were seen in patients with MZL.

, in which 96 patients were evaluable for efficacy, the ORR was 93% (95% CI, 86-97) and the CR rate was 80% (95% CI, 71-88); the median time to first response was 1 month (range, 0.8-3.1).3 In patients with follicular lymphoma (n = 80), the ORR was 95% and the CR rate was 81%. In those with MZL (n = 16), the ORR was 81% and the CR rate was 75%.

In a press briefing during the meeting, Jacobson suggested that the biology of indolent NHL could be a reason for the higher efficacy rates and more tolerable safety profile with axi-cel compared with data in more aggressive lymphoma subtypes.

“It is the disease biology itself; we know that each of these lymphomas have unique microenvironments that may or may not make them more susceptible to immunologic killing,” Jacobson explained. “We know follicular lymphoma is a disease that can be cured by allogeneic stem cell transplant to a larger degree than what is seen with aggressive B-cell non-Hodgkin lymphomas. That may, in part, explain the efficacy.”

Additionally, Jacobson cited that the patients with MZL had slightly worse toxicity, replicative of patients with DLBCL.

“Their pretreatment inflammatory markers were elevated, or similarly, to DLBCL,” said Jacobson. “I think the disease itself is probably what dictates the toxicity profiles that we're seeing.”

Catherine Bollard, MD, MBChB, director of the Center for Cancer, and Immunology Director for the Program for Cell Enhancement and Technologies for Immunotherapy, Children’s National Research Institute, and moderator of the press briefing, commented on the longer ZUMA-5 findings.

“The work of Dr. Jacobson and colleagues is really very laudable. The longer the follow-up, the more robust the data, [we are then able] to really be able to draw some very effective comparisons than with historic [progression-free survival] and [disease-free survival] data, which will only really happen with the test of time,” said Bollard. “It's really exciting to see these data in the [indolent] lymphoma setting, and I actually would like to see it moved further up for the treatment of patients earlier in their disease process.”

Jacobson C, Chavez JC, Sehgal A, et al. Primary analysis of ZUMA-5: a phase 2 study of axicabtagene ciloleucel (axi-cel) in patients with relapsed/refractory indolent non-Hodgkin lymphoma. Presented at: 2020 ASH Annual Meeting & Exposition; December 4-8, 2020; Virtual. Abstract 700.

Locke FL, Ghobadi A, Jacobson CA, et al. Long-term safety and activity of axicabtagene ciloleucel in refractory large B-cell lymphoma (ZUMA-1): a single-arm, multicentre, phase 1-2 trial. 

. 2019;20:31-42. doi:10.1016/S1470-2045(18)30864-7

Jacobson CA, Chavez JC, Sehgal AR, et al. Interim analysis of ZUMA-5: A phase II study of axicabtagene ciloleucel (axi-cel) in patients (pts) with relapsed/refractory indolent non-Hodgkin lymphoma (R/R iNHL). 

. 2020;38(suppl 15):8008. doi:10.1200/JCO.2020.38.15_suppl.8008

December 5, 2020 - Axicabtagene ciloleucel demonstrated high rates of durable responses in patients with indolent non-Hodgkin lymphoma. 

Axi-Cel Elicits 92% ORR in Indolent Non-Hodgkin Lymphoma 

The CAR T-cell therapy axicabtagene ciloleucel (axi-cel; Yescarta) demonstrated long-term disease control with rapid responses and robust CAR T-cell expansion among patients with refractory large B-cell lymphoma (LBCL), according to findings from the 4-year analysis of the phase 1/2 ZUMA-1 trial, which were presented virtually during the 

The median 4-year overall survival (OS) was 25.8 months (95% CI, 12.8-not estimable) in the modified intention-to-treat (mITT) population (patients treated with axi-cel; n = 101), who had a median follow-up of 51.1 months. This translated to a 4-year OS rate of 44% by Kaplan-Meier estimation.

Among the entire enrolled patient population (ITT; n = 111), the median OS was 17.4 months, and the Kaplan-Meier estimated 4-year OS rate was 41%.

“Altogether, these findings support the hypothesis that persistence of functional CAR T cells is not necessary for deep and durable remissions in LBCL,” said lead study author Caron Jacobson, MD, a senior physician and medical director of the Immune Effector Cell Therapy Program at Dana-Farber Cancer Institute. “Importantly, the brief time between enrollment and objective response observed for the ITT population supports the speed, success, and reliability of manufacturing.”

, a CD19-directed CAR T-cell therapy, as a treatment for adult patients with relapsed/refractory non-Hodgkin lymphoma based on findings from the ZUMA-1 trial.

Results of the trial demonstrated an 82% objective response rate (ORR) and a complete response (CR) rate of 54%. After a median follow-up of 15.4 months, 42% of patients reported continued responses and 40% had continued CRs.2

The ZUMA-1 trial enrolled patients with refractory LBCL, including diffuse large B-cell lymphoma, primary mediastinal large B-cell lymphoma, and transformed follicular lymphoma. Patients had to have no response to their last chemotherapy or relapsed disease within 12 months of autologous stem cell transplant.

Following screening and leukapheresis, patients were given a conditioning chemotherapy regimen that consisted of 500 mg/m2 of cyclophosphamide and 30 mg/m2 of fludarabine for 3 days. Patients were hospitalized and given a single infusion of axi-cel at a dose of 2 x 106 CAR+ cells/kg. After a 7-day hospitalization period, the first tumor assessment occurred during follow up on day 28. The primary end point was ORR.

The updated data showed that evaluable patients who had available blood samples and were in ongoing response per institutional standard of care for at least 3 years (n = 21) had detectable B cells in blood at 3 years following CAR T-cell therapy infusion. Moreover, 67% of patients (n = 14) had detectable CAR gene-marked cells and polyclonal B cells in blood at 3 years.

Additionally, 91% of evaluable patients (n = 23) demonstrated polyclonal B-cell recovery. The median immunoglobulin kappa-lambda ratio was 1.6. The relative levels of key B-cell subsets, such as memory and naïve B-cell immunophenotypes, suggest reconstitution of the B-cell repertoire.

“Restoration of a polyclonal B-cell compartment and clearance of function CAR T cells [is] a key component of the long-term safety of CAR T-cell therapies,” said Jacobson, who is also an assistant professor of medicine at Harvard Medical School.

Regarding safety, no axi-cel–related secondary malignancies or cases of replication-competent retrovirus were reported at the 4-year cutoff date.

Furthermore, 59% (n = 66) of patients in the ITT population have died since study initiation. The primary causes of death include: progressive disease (n = 52; 47%), non-causal relationship events (n = 8; 7%), including myelodysplastic syndrome (n = 1) and cardiac arrest (n = 2), post-subsequent therapy events, including sepsis (n = 1), infection (n = 2), and pulmonary nocardiosis (n = 1), unknown event (n = 1), adverse effects (AEs; n = 5; 5%), including conditioning chemotherapy therapy–related tumor lysis syndrome (n = 1), non-causal relationship AEs (sepsis, n = 1; pulmonary embolism, n = 1), and axi-cel–related AEs (brain injury, n = 1; hemophagocytic lymphohistiocytosis/grade 5 cytokine release syndrome, n = 1), and secondary malignancy (n = 1; 1%).

Since the 2-year cutoff date, 8 patients died from progressive disease (n = 5) or secondary malignancy (n = 3). Notably, no new axi-cel–related serious AEs were reported, and 4 patients received intravenous immunoglobulin therapy.

Jacobson C, Locke FL, Ghobadi A, et al. Long-term survival and gradual recovery of B cells in patients with refractory large B cell lymphoma treated with axicabtagene ciloleucel. Presented at: 2020 ASH Annual Meeting; December 5-8, 2020; virtual. Abstract 1187.

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/NEJMoa1707447

December 5, 2020 - The CAR T-cell therapy axicabtagene ciloleucel demonstrated long-term disease control with rapid responses and robust CAR T-cell expansion among patients with refractory large B-cell lymphoma. 






