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ASH Annual Meeting and Exposition

The addition of brentuximab vedotin (Adcetris) to standard 3-drug chemotherapy for patients with newly diagnosed, advanced-stage classical Hodgkin lymphoma (cHL) continued to outperform a 4-drug chemotherapy standard, according to 4-year follow-up data from the phase III ECHELON-1 trial presented at the 2019 ASH Annual Meeting.

In the multicenter, open-label trial, patients who received the the antibody-drug conjugate (ADC) brentuximab vedotin in addition to chemotherapy (A+AVD) had a statistically significant 31% reduction in the risk of disease progression or death after a median follow-up of 48.4 months. Progression-free survival (PFS) at 4 years was 81.7% (95% CI, 78.3-84.6) with the brentuximab vedotin combination versus 75.1% (95% CI, 71.4-78.4) with chemotherapy alone (ABVD).

The results mirrored those from the previously reported primary analysis at 2 years and an exploratory analysis of 3-year PFS, said Nancy Bartlett, MD, a medical oncologist at Siteman Cancer Center, and the and Koman Chair in Medical Oncology at the Washington University School of Medicine, in a poster presentation at the meeting.

“This PFS analysis at 4 years provides further support of a robust and durable benefit with A+AVD versus ABVD in the frontline treatment of patients with stage III/IV cHL,” added Bartlett. “Peripheral neuropathy continues to resolve and improve over time, with most patients experiencing complete resolution.

Although most patients with newly diagnosed advanced-stage cHL respond to up-front treatment with standard chemotherapy, about 30% will become refractory to or will subsequently relapse after frontline treatment. In the ECHELON-1 trial, 1,334 patients with newly diagnosed stage III or IV cHL were randomized to receive A+AVD (n = 664) or ABVD (n = 670) intravenously on days 1 and 15 of each 28-day cycle for up to 6 cycles.

The primary end point of the trial was modified PFS by independent radiologic review at 2 years. Results from the primary analysis showed a PFS of 82.1% (95% CI, 78.8-85.0) with A+AVD and 77.2% (95% CI, 73.7-80.4) with ABVD. The difference translated to a 23% reduction in the risk of progression or death (hazard ratio [HR], 0.77; 95% CI, 0.60-0.98; 

 PFS by investigator assessment was 84.2% with A+AVD and 78.0% with ABVD (HR, 0.70; 95% CI, 0.54-0.91; 

 An exploratory analysis of 3-year investigator-assessed PFS continued to demonstrate superiority for A+AVD (83.1% [95% CI, 79.9-85.9] vs 76.0% [95% CI, 72.4-79.2]; HR, 0.70; 95% CI, 0.55-0.90; 

At the 2019 ASH Annual Meeting, Bennett and colleagues reported findings from a posthoc analysis of 4-year PFS by investigator assessment. They also evaluated PFS by imaging status, age, and other key subgroups.

The updated analysis confirmed the superiority of A+AVD over ABVD, as well as the durability of treatment effect with A+AVD. The reduction in the HR remained statistically significant (HR, 0.691; 95% CI, 0.542-0.881; 

Furthermore, an extensive subgroup analysis showed a consistently lower risk of progression or death in patients treated with A+AVD. HRs ranged from 0.493 in North-American patients (95% CI, 0.319-0.764) to 0.827 in patients 60 years of age or older (95% CI, 0.496-1.379). Only Asian patients did not appear to benefit from the regimen (HR, 1.212; 95% CI, 0.616-2.387).

“The PFS for important subgroups, such as both stage III and stage IV disease, age, extranodal sites, and International Prognostic scores were generally consistent with the intention-to-treat population and numerically in favor of A+AVD, with overlapping confidence intervals,” the investigators noted.

The trial protocol included assessment by PET imaging after the second cycle of therapy (PET2). Imaging results showed that 89% of patients in the A+AVD arm and 86% of those in the ABVD arm had negative PET2 results; 7% and 9% of the patients had positive scans and PET2 status was unknown in the remaining patients. A PFS benefit favoring A+AVD was observed in all patients, independent of PET2 status.

Peripheral neuropathy was an adverse event of special interest in the trial. At the primary analysis, 67% of patients in the A+AVD arm and 43% of those in the ABVD arm had peripheral neuropathy.

 The 4-year follow-up analysis showed that peripheral neuropathy had resolved or improved in 83% (n = 365) of the A+AVD group and 84% (n = 240) of those in the ABVD group. Ongoing peripheral neuropathy at 4 years was grade 1/2 in most cases.

The median time to complete resolution of peripheral neuropathy was 30 weeks (range, 0-262 weeks) in the A+AVD arm and 15 weeks (range, 0-234 weeks) in the ABVD arm. The median time to improvement without complete resolution was 41 weeks (range, 8-205 weeks) with A+AVD and 12 weeks (range, 2-70 weeks) with ABVD.

“The PFS benefit for A+AVD is independent of PET2 status, disease stage, age, and IPS,” the investigators concluded. In [patients with] stage III and stage IV, A+AVD compares favorably to PET-adapted strategies without requiring a change of therapy based on PET2 status; [the regimen also] completely eliminates exposure to bleomycin.”

Bartlett NL, Straus DJ, Dlugosz-Danecka M, et al. Brentuximab vedotin with chemotherapy for stage 3/4 classical Hodgkin lymphoma (cHL): 4-year update of the Echeleon-1 study. Presented at: 2019 ASH Annual Meeting; December 7-10, 2019; Orlando, FL. Abstract 4026. bit.ly/34ru1Og.

Connors JM, Jurczak W, Straus DJ, et al. Brentuximab vedotin with chemotherapy for stage III or IV Hodgkin’s lymphoma. 

. 2018;378(4):331-344. doi: 10.1056/NEJMOa1708984.

Connors JM, Younes A, Gallamini A, et al. Brentuximab vedotin plus chemotherapy in patients with advanced-stage classical Hodgkin lymphoma (cHL): evaluation of modified progression-free survival (mPFS) and traditional PFS in the phase 3 ECHELON-1 study. 

. 2018;132(suppl 1):2904. doi: 10.1182/blood-2018-99-118828.

Chen RW, Ansell SM, Gallamini A, et al. Brentuximab vedotin with chemotherapy for stage III or IV Hodgkin lymphoma (HL): impact of cycle 2 PET result on modified progression-free survival (mPFS). 

. 2018;36(suppl 15; abstr 7539). doi: 10.1200/JCO.2018.36.15_suppl.7539.

Tomassetti S and Herrera AF. Update on the role of brentuximab vedotin in classical Hodgkin lymphoma. 

. 2018;9(9):261-272. doi: 10.1177/2040620718786833.

The addition of brentuximab vedotin to standard 3-drug chemotherapy for patients with newly diagnosed, advanced-stage classical Hodgkin lymphoma continued to outperform a 4-drug chemotherapy standard.

Brentuximab Vedotin Demonstrates Durable Long-Term PFS Benefit in Hodgkin Lymphoma

IMGN632, an investigational anti-CD123 antibody-drug conjugate (ADC), demonstrated preliminary activity in patients with relapsed/refractory acute myelogenous leukemia (AML) or blastic plasmacytoid dendritic cell neoplasm (BPDCN), according to results from a phase I/Ib trial presented at the 2019 ASH Annual Meeting.

Overall, 13 of 71 patients with AML who received the ADC in the trial obtained a complete response with or without complete hematologic recovery (CR/CRi). Additionally, 2 of 9 patients with BPDCN obtained a CR/CRi and 1 had a partial response. Responses were observed across the range of patient subsets represented in the study population. In most cases, responses occurred after the first or second dose of the drug.

The most common treatment-related adverse events (TRAEs) were infusion-related reactions, said Naval G. Daver, MD, of MD Anderson Cancer Center, in a presentation at the meeting. Furthermore, toxicity, in general, was limited to higher doses of the ADC.

“This agent is generally well tolerated and can be given as an infusion on an outpatient basis,” Daver said. “We don’t see cytokine release syndrome (CRS) at this point in time, and the main issue is infusion-related reactions, which are manageable with dexamethasone prophylaxis.

“I would say the response rate is in the 20% to 30% range [with IMGN632] as a single agent,” he added. “As we all know, the AML field is very competitive now, and I believe we will probably need to move forward with combination approaches. In BPDCN, [we have seen] good responses, even in [patients] who have had prior SL-401.”

CD123 is the alpha subunit of interleukin-3 receptor; it is expressed in more than 90% of AML cases, and almost universally in BPDCN.

  IL-3R/CD123 is a validated target in BPDCN, and CD123 expression is increased in AML blasts and leukemic stem cells as compared with normal hematopoietic stem and progenitor cells.

“CD123-directed therapy may be able to debulk and potentially eliminate the source of disease,” explained Daver. “CD123 is rapidly internalized, making it well suited for ADC-based therapeutic strategies.”

Preclinical studies of IMGN632 provided evidence of efficacy in AML, BPDCN, and B-cell acute lymphoblastic leukemia models. Laboratory studies also yielded evidence of increased antitumor activity with IMGN632 when used in combination with a variety of existing therapies for hematologic malignancies.

The primary objectives of the phase I study of IMGN632 were to establish the maximum-tolerated dose and determine the phase II dose and optimal dosing schedule for single-agent treatment in patients with relapsed/refractory AML and BPDCN. Secondary objectives were to determine the safety and tolerability of IMGN632 and to describe preliminary antileukemic activity as well as the pharmacokinetic profile of the agent in AML and BPDCN.

To be eligible for enrollment, patients had to have CD123-positive relapsed/refractory AML or BPDCN and have received no more than 3 prior lines of therapy. Intravenous doses of 0.015-0.045 mg/kg were evaluated in 2 dosing schedules: day 1 of a 3-week cycle and a fractionated schedule with dosing on days 1, 4, and 8 of a 3-week cycle.

Investigators enrolled a total of 95 patients; all but 10 patients had AML. The median age of the participants was 66 years (range, 33-83), almost half had adverse cytogenetics, two-thirds had received prior intensive therapy, including 23% with prior stem-cell transplantation.

The most common TRAEs observed with the ADC were infusion related reactions (25%), nausea (11%), and febrile neutropenia (10%). Febrile neutropenia was the only grade ≥3 TRAE that occurred in as many as 10% of patients.

The trial had a 30-day any cause mortality of 6%. Five deaths were considered unrelated to treatment; progressive disease occurred in 2 patients and 1 case each of lung infection, respiratory failure, and sepsis were reported. One potential treatment-related death involved an unknown cause.

The 13 responses observed in 71 evaluable patients with AML included patients with relapsed/refractory disease, those with relapsed/refractory de novo disease, those with adverse cytogenetics as defined by European LeukemiaNet criteria, and those with prior stem-cell transplantation.

The 3 responding patients with BPDCN had received SL-401, 2 also had prior intense chemotherapy and/or transplant, and all 3 had skin, PET, and bone marrow disease. In all 3 of these patients, bone marrow disease cleared from baseline 28%, 37%, 84%, to 0% blasts with IMNG632.

The trial resulted in a recommended phase II dose of 0.045 mg/kg, said Daver. Accrual to the trial continues, and enrollment has expanded to include patients with acute lymphocytic leukemia.

Furthermore, an ongoing phase Ib/II trial is evaluating IMGN632 in combination with azacytidine plus venetoclax (Venclexta). The ADC is also being examined as a frontline monotherapy for patients with minimal residual disease—positive AML.

Daver NG, Montesinos P, DeAngelo DJ, et al. Clinical profile of IMGN632, a novel CD123-targeting antibody-drug conjugate (ADC) in patients with relapsed refractory (R/R) acute myeloid leukemia (AML) or blastic plasmacytoid dendritic cell neoplasm (BPDCN). Presented at: 2019 ASH Annual Meeting; December 7-10, 2019; Orlando, FL. Abstract 734. bit.ly/38qt4ct.

Testa U, Pelosi E, Frankel A. CD 123 is a membrane biomarker and a therapeutic target in hematologic malignancies. 

. 2014;2(1):4. doi: 10.1186/2050-7771-2-4.

Ehninger A, Kramer M, Rölig C, et al. Distribution and levels of cell surface expression of CD33 and CD123 in acute myeloid leukemia. 

Kuruvilla VM, McCarthy R, Zhang Q, et al. IMGN632. A CD123-alkylating ADC bearing a DNA-alkylating IGN payload, combines effectively with azacitidine and venetoclax in vivo, prolonging survival in preclinical models of human acute myeloid leukemia (AML). Presented at: 2019 ASH Annual Meeting; December 7-10, 2019; Orlando, FL. Abstract 1375. bit.ly/2LHyhTs.

IMGN632, an investigational anti-CD123 antibody-drug conjugate, demonstrated preliminary activity in patients with relapsed/refractory acute myelogenous leukemia or blastic plasmacytoid dendritic cell neoplasm.

ADC Targeting CD123 Active in R/R AML and BPDCN

The investigational Bruton tyrosine kinase (BTK) inhibitor ARQ 531 demonstrated safety and clinical activity across a range of B-cell malignancies, a preliminary clinical trial showed.

Overall, 14 of 47 patients had partial responses (PRs) with ARQ 531, which targets the BTK-C481S mutation associated with resistance to ibrutinib (Imbruvica). An additional 10 patients had stable disease associated with tumor reduction of as much as 48%. Responses were observed in patients with chronic lymphocytic leukemia (CLL), Richter’s transformation (RT), diffuse large B-cell lymphoma (DLBCL), and follicular lymphoma (FL).

Across a range of doses as high as 75 mg QD, no dose-limiting toxicity occurred, and treatment with ARQ 531 was associated with a low frequency of toxicities. No atrial fibrillation or bleeding occurred, Jennifer Woyach, MD, an associate professor at The Ohio State University Comprehensive Cancer Center—James, said at the 2019 ASH Annual Meeting.

“You can definitely see that responses are very good,” Woyach told 

 in an interview at ASH. “This and other studies of other agents in this class have confirmed the efficacy of this class of drugs, the reversible BTK inhibitors.”

“For this study, two things really are striking,” continued Woyach, “One is that 89% of patients with [BTK C481S—mutated CLL] who were treated at the recommended phase II 65-mg dose responded. [Further], half of the people with Richter’s transformation responded, and Richter’s is a very unmet need in CLL, very difficult to treat. Seeing that kind of activity early on is really encouraging.”

Despite major advances in the treatment of B-cell malignancies, cases of primary and secondary resistance continue to emerge, are associated with poor outcomes, and have limited treatment options. Woyach said 80% to 85% of patients who progress on BTK inhibitor therapy do so because of emergence of the 

AMQ-531 is an orally available, reversible, dual inhibitor of wild-type and C481S-mutant BTK. The drug has demonstrated superiority over ibrutinib in mouse models of CLL and DLBCL and targets ibrutinib-resistant CLL, RT, and other B-cell malignancies, Woyach and colleagues noted in a poster presentation.

The presentation described results of a phase I dose-escalation trial involving patients with relapsed or refractory B-cell malignancies. The objectives were to evaluate the safety, pharmacology, and anticancer activity of ARQ-531 in patients with BTK-C481S resistance mutations.

The 47 patients enrolled in the study had a median age of 65, and men accounted for 85% of the total. The cohort comprised 29 patients with CLL/SLL, and 18 with B-cell non-Hodgkin lymphomas: 9 with RT, 3 with DLBCL, 4 with FL, and 1 each with mantle cell lymphoma and Waldenstrom macroglobulinemia (WM). They had received a median of 4 (range, 1-12) prior systemic regimens.

Investigators evaluated ARQ 531 doses ranging from ≤30 mg QD to 75 mg QD. The 13 patients who received the recommended phase II dose consisted of 5 patients with CLL, 7 with RT, and 1 with WM.

Eight of 9 patients with high-risk relapsed/refractory CLL achieved PRs with the 65-mg dose. Three of 6 patients with RT treated with the 65-mg dose also had PRs. The remaining 3 responses all occurred at ARQ 531 doses ≥45 mg. Three additional patients with RT were able to proceed with CAR T-cell therapy.

The 1 dose-limiting toxicity in the trial (grade 3 generalized rash) occurred in a patient with CLL treated with the 65-mg dose. The most common adverse events (AEs; all patients/grades) were hypertension (34%), back pain (32%), nausea (30%), fatigue (30%), rash (28%), constipation (28%), peripheral edema (26%), pyrexia (26%), headache (26%), diarrhea (23%), upper respiratory tract infection (23%), and cough (23%). The most common grade ≥3 AEs included decreased neutrophil count (19%), and decreased platelets, anemia, and hypertension (13% each).

Drug-related AEs were uncommon. Grade ≥3 drug-related AEs consisted of 6 cases (13%) of decreased neutrophil count, 2 (4%) cases of decreased platelets, and one case (2%) of rash.

With respect to pharmacokinetics, the 65-mg dose of ARQ 531 achieved a steady-state mean C

 exceeding 1 µM and plasma half-life of 56 hours. At the recommended phase II dose, ARQ 531 drives complete pBTK inhibition.

Woyach et al reported that ongoing clinical development of ARQ 531 includes phase II studies in relapsed/refractory CLL, RT, and multiple B-cell malignancies. Plans for trials of combination therapy and earlier lines of therapy are in development.

Woyach J, Stephens DM, Flinn IW, et al. Final results of phase 1, dose escalation study evaluating ARQ 531 in patients with relapsed or refractory B-cell lymphoid malignancies. Presented at: 2019 ASH Annual Meeting; December 7-10; Orlando, FL. Abstract 4298.

The investigational Bruton tyrosine kinase inhibitor ARQ 531 demonstrated safety and clinical activity across a range of B-cell malignancies.

Resistance-Targeting BTK Inhibitor ARQ 531 Active Across B-Cell Malignancies

More than three times as many patients with transplant-ineligible newly diagnosed multiple myeloma (NDMM) remained alive and progression free after >3 years when they received daratumumab (Darzalex) in addition to standard first-line therapy, according to updated safety and efficacy findings from the randomized ALCYONE study.

Patients treated with daratumumab plus bortezomib (Velcade), melphalan, and prednisone (D-VMP) had an estimated 42-month progression-free survival (PFS) of 48% compared with 14% for patients treated with VMP. The estimated overall survival (OS) was 75% and 62% for the D-VMP and VMP arms, respectively. The initial objective response rate of 91% at 16.5 months did not change after 40 months of follow-up.

The incidence of grade ≥3 treatment-emergent adverse events (TEAEs) was similar between treatment groups with the exception of higher rates of pneumonia (13.0% vs 4.2%) and hypertension (5.5% vs 1.7%) in the daratumumab arm. No new safety signals emerged with longer follow-up in the ALCYONE trial, as reported at the 2019 ASH Annual Meeting.

“D-VMP continued to demonstrate a significant PFS benefit versus VMP alone,” said Maria-Victoria Mateos, MD, of University Hospital of Salamanca in Spain. “Responses with D-VMP continued to deepen over time from the primary analysis, with improvements in rates of CR and MRD (minimum residual disease) negativity.”

“Patients with sustained MRD negativity had improved outcomes. Significantly more patients remained MRD negative for 12 months or longer with D-VMP.”

The multicenter global ALCYONE trial involved 706 patients with NDMM who were ineligible for stem-cell transplantation. They were randomized to 9 cycles of D-VMP (n = 350) followed by monthly daratumumab until disease progression or to 9 cycles of VMP without maintenance therapy. The primary endpoint was PFS.

The primary analysis after 16.5 months of follow-up showed that D-VMP reduced the risk of disease progression or death by 50% compared with VMP. Another analysis after 27.8 months of follow-up showed a PFS benefit of 57% in the D-VMP arm.

Dr. Mateos reported safety and efficacy results from ALCYONE after an additional 12 months of follow-up (40.1 total). As of data cutoff June 24, 2019 all patients in the VMP arm had discontinued or completed nine cycles of therapy. In the D-VMP arm 42% of patients continued to receive daratumumab monotherapy.

The update showed that the D-VMP arm still had almost a twofold greater median PFS (36.4 vs 19.3 months, HR 0.42, 95% CI 0.34-0.51; p<.0001). The objective response rate remained at 91% for the D-VMP arm, the same as at the primary analysis, and total response rate in the VMP arm was 74%, also unchanged from the original analysis.

The updated 91% total response rate with D-VMP included complete responses in 46% of patients (half of them stringent CR), VGPR of 27% and partial response (PR) in 18%. In contrast, VMP led to CR in 25% of patients (stringent in 8%), VGPR in 24%, and PR in 24%.

At the primary analysis, almost four times as many patients had MRD-negative status with D-VMP (22% vs 6%). After 40.1 months of follow up, the MRD-negative rate was 28% with D-VMP and 7% with VMP. D-VMP also led to higher rates of sustained MRD negativity. Both attainment of MRD negativity and persistence of negativity (≥12 months) were associated with improved PFS, said Mateos.

Patients assigned to D-VMP also had significantly prolonged PFS on subsequent therapy (PFS-2). The estimated 42-month PFS-2 was 68% with D-VMP and 50% with VMP, representing a 45% reduction in the hazard for progression or death (

 <.0001). The median time to subsequent therapy had yet to be reached in the D-VMP arm versus 25.9 months for the VMP arm, representing almost a 60% reduction in the hazard ratio (

“Based on the PFS2 results, longer survival outcomes are projected with other daratumumab-based regimens in the frontline setting,” said Dr. Mateos.

The 13% absolute difference in estimated 42-month OS represented a 40% reduction in the mortality hazard in favor of D-VMP (

=.0003). As with PFS, OS was significantly better for patients who attained MRD-negative status and sustained MRD negativity.

The rate of discontinuation associated with TEAEs was 6.9% with D-VMP and 9.3% with VMP. Invasive secondary primary malignancies occurred in 4.9% of patients in the daratumumab group versus 4.5% of patients randomized to VMP. Grade 5 (fatal) TEAEs occurred in 6.9% of the D-VMP arm and 5.6% of the VMP arm.

The most common TEAEs during daratumumab monotherapy were upper respiratory tract infection (URTI), bronchitis, viral URTI, cough, and diarrhea. The most common grade 3/4 TEAEs during maintenance were anemia and pneumonia.

Mateos MV, Cavo M, Bladé J, et al. Daratumumab plus bortezomib, melphalan, and prednisone versus bortezomib, melphalan, and prednisone in patients with transplant-ineligible newly diagnosed multiple myeloma: overall survival in Alcyone. Presented at: 2019 ASH Annual Meeting; December 7-10, 2019; Orlando, FL. Abstract 859. bit.ly/2E43gVJ.

More than three times as many patients with transplant-ineligible newly diagnosed multiple myeloma remained alive and progression free after >3 years when they received daratumumab (Darzalex) in addition to standard first-line therapy.

Large PFS Gain With Daratumumab in Transplant-Ineligible Myeloma

The anti-BCMA CAR T cell therapy bb21217 demonstrated high very good partial response (VGPR) or better rates in patients with heavily pretreated relapsed/refractory multiple myeloma, with minimal residual disease (MRD) negativity seen in most patients with confirmed responses, according to updated results from the phase I CRB-402 study presented at the 2019 ASH Annual Meeting.

The longest follow-up from the study (median 17.6 months) was available for patients receiving a 150 x 10

 dose of bb21217, which was the lowest dose explored in the study. In this cohort, the complete remission (CR) or stringent CR (sCR) rate was 33% and the VGPR rate was 50%, for an objective response rate (ORR) of 83%. All patients in this group were MRD-negative and the median duration of response was 11.1 months.

 dose cohort, the median duration of response is promising at 11.1 months. In the higher dose cohorts, follow up is short but there are no confirmed responders who have progressed," Jesus G. Berdeja, MD, from the Sarah cannon Research Institute, said during a presentation of the results. "The safety profile of bb21217 in this phase I study of relapsed/refractory multiple myeloma remains consistent with known toxicities of CAR T-cell therapies."

As part of the bb21217 manufacturing process, the CAR T-cell therapy bb2121 is cultured with the PI3 kinase inhibitor bb007 to enrich for T cells with a memory-like phenotype. In preclinical experiments, bb2121 and bb21217 both eliminated an initial tumor in mice; however, when rechallenged with a second tumor in the same mouse, only bb21217 prevented the tumor from growing without retreatment. Additionally, bb21217 also showed higher levels of CCR7 and CD27 compared with bb2121, suggesting higher levels of memory-like T cells, and bb21217 had lower levels of CD57, a marker of T cell exhaustion.

In the phase I study of bb21217, patients were treated with 150 x 10

(n = 6) CAR+ T cells in an initial dose escalation stage. An expansion cohort was opened to further explore the 300 x 10

 doses (n = 6), with the latter selected for further investigation. Lymphodepleting chemotherapy was given with fludarabine at 30 mg/m

 on days -5, -4, and -3 prior to infusion.

Across the study, 41 patients underwent leukapheresis, with 1 withdrawing and 2 receiving the infusion after the data cutoff. There was a 100% manufacturing success rate, although 3 patients were required to undergo remanufacturing prior to treatment. Patients were allowed to receive bridging therapy during the manufacturing process.

"[Time from leukapheresis to infusion] was about 4 to 5 weeks, which is standard for most of these targeted CAR T cells," said Berdeja. "Bridging therapy was left up to the individual investigator but I suspect that about half if not two-thirds of patients had bridging therapy."

The median age of patients enrolled in the study was 62 years (range, 33-74), and the median time since diagnosis was 5.5 years. Most patients had an ECOG performance status of 1 (63%) and an ISS stage of I (29%). A third of patients (34%) had high-risk cytogenetics and the median number of prior regimens received was 6 (range, 3-17). Ninety-five percent of patients had received prior proteasome inhibitors, IMiDs, and an anti-CD38 antibody. Eighty-two percent of patients had received 1 or more prior autologous stem cell transplants.

The median follow-up for patients in the 300 x 10

 doses was 4.0 and 3.3 months, respectively. At these early assessments, the ORR in the 300 x 10

 dose arm was 43%, which included a VGPR rate of 29% and a partial response (PR) rate of 14%. However, Berdeja warned that with the short follow up, these numbers were misleading, as some patients were not included in the analysis.

"Many of these patients had not reached 2 assessments to have a confirmed response and were left off the overall response for these percentages, especially for the 450 group," he said. "As is expected with CAR T cells, the responses will deepen over time."

 dose, the ORR was 57% and was composed of a PR rate of 14%, a VGPR rate of 29%, and an sCR/CR rate of 14%. None of the responding patients had progressed at the time of the data cutoff in September 2019.

The MRD-negative rate was 94% across the full study, with just 1 patient not achieving negative status at the assessment in the 300 x 10

 dose arm. At 6 months, CAR T cells continued to be detectable for 8 of 10 patients (80%). Although the numbers were small, at month 12 bb21217 was detectable in 2 of 4 patients (50%). Of the 2 patients with 18 months of follow up, both still had detectable levels of bb21217 (100%).

"bb21217 drug product is enriched for memory-like T cells, which are associated with robust CAR T cell expansion and less disease progression at month 6," said Berdeja. “Long-term CAR T-cell persistence was observed in 8 of 10 evaluable patients at month 6 and 2 of 2 at month 18.”

All-grade cytokine release syndrome (CRS) occurred in 66% of patients, most of which was grade 1 or 2 in severity; however, 1 patient had a grade 5 CRS event at the 450 x 10

 dose. The median time to onset of CRS was 3 days and the median duration of CRS was 4 days. Neurotoxicity occurred in 24% of patients. There were 2 grade 3 events and 1 grade 4 event, with the remainder being grade 1 or 2. The median time to neurotoxicity onset was 7 days.

Grade 3/4 treatment-emergent adverse events (AEs) included neutropenia (82%), leukopenia (55%), thrombocytopenia (55%), anemia (50%), lymphopenia (34%), hypophosphatemia (21%), infection (18%), hyponatremia (13%), and febrile neutropenia (11%). Half of patients had a serious AE (50%), and 95% had at least 1 grade 3/4 AE.

The expansion arm of the CRB-402 study continues to enroll participants for the 450 x 10

 dose of bb21217. The planned enrollment for the study is 74 patients (NCT03274219).

Berdeja JG, Alsina M, Shah N, et al. Updated results from an ongoing phase 1 clinical study of bb21217 anti-BCMA CAR T cell therapy. Presented at: 2019 ASH Annual Meeting; December 7-10, 2019; Orlando, FL. Abstract 927. bit.ly/35bET49.

The CAR T cell therapy bb21217 demonstrated high very good partial response or better rates in patients with heavily pretreated relapsed/refractory multiple myeloma.

Updated bb21217 Data Continue to Impress in Multiple Myeloma

A majority of adult patients with β-thalassemia who require regular red blood cell (RBC) transfusions experienced clinically meaningful and durable transfusion burden reduction associated with luspatercept (Reblozyl) in the phase III BELIEVE trial. There were no new safety signals. The incidence of adverse events (AE) was not associated with dose level, decreased over time, and did not affect treatment modification or continuation.

BELIEVE (NCT02604433) was a randomized, double-blind, study comparing luspatercept with placebo. Luspatercept is a first&#8209;in&#8209;class erythroid maturation agent binding select TGF-β superfamily ligands, reducing aberrant Smad2/3 signaling, and enhancing late-stage erythropoiesis.

This study enrolled adults with β-thalassemia or hemoglobin E/β&#8209;thalassemia (including compound β-thalassemia mutation and/or multiplication of α-globin genes), who required regular transfusions of 6—20 RBC units in the 24 weeks prior to random assignment, with no transfusion-free period >35 days. Patients were randomly assigned 2:1 to luspatercept (n = 224) 1.0 mg/kg (up to 1.25 mg/kg), or placebo (n = 112), subcutaneously every 3 weeks for ≥48 wks. Patients in both treatment arms received RBC transfusions to maintain baseline hemoglobin levels as well as iron chelation therapy.

The primary end point was reduction of RBC transfusion burden by ≥33% from baseline, with a reduction of ≥2 units in weeks 13-24 versus the 12 weeks prior to randomization. After study unblinding, patients assigned to the placebo arm were allowed to crossover to luspatercept treatment (92 of 109 patients treated with placebo; 84.4%). Results for the luspatercept arm include only patients initially assigned to luspatercept.

Assessments using a data cutoff of January 7, 2019 including the number of response episodes, duration of clinical benefit, and safety in patients who experienced a response to luspatercept, were presented in a poster by Vip Viprakasit, MD, DPhil, Siriraj Hospital, Mahidol University, Bangkok, Thailand during the 2019 American Society of Hematology Annual Meeting.

Response episodes were defined as reduction in RBC transfusion from baseline over any consecutive 24 weeks and assessed at a median follow-up of 64.1 weeks. Duration of clinical benefit, defined as the time of first response (≥33% reduction in RBC transfusion over any 24 weeks) to discontinuation due to any cause at that episode, was also assessed. The open-label portion of the trial could continue up to 5 years followed by post-treatment follow-up of up to 3 years. Median duration of treatment was 95.7 weeks (1.7-128.1 weeks) with luspatercept (223 of 224 patients enrolled were treated); and 74.7 weeks (8.9-104.0 weeks) with placebo.

The primary end point, reduction of RBC transfusion burden by ≥33% from baseline, with a reduction of ≥2 units in weeks 13-24, was reached in 21.4% of patients in the luspatercept arm, and in 4.5% of patients in the placebo arm. Reduction of RBC transfusion burden by ≥33% over any 12-week period was reached in 76.3% of patients in the luspatercept arm and 34.8% in the placebo arm (P <.0001) and over any 24-week period was reached in 45.1% of patients in the luspatercept arm, and in 2.7% of patients in the placebo arm (

In patients receiving luspatercept who experienced a response, 73.3% experienced ≥2 separate response periods during any 24-week interval. Overall, 4.9% of patients receiving luspatercept experienced multiple episodes of response, defined as having ≥1 non-overlapping durations of response during any 24-week interval. There were no changes in pre-transfusion hemoglobin levels from pre-transfusion level over any fixed 12-week period throughout the study.

The median duration of clinical benefit for those with a response to luspatercept as 76.3 weeks, with 17.4% of patients having an ongoing clinical benefit response through out the entire study period from the time of the first dose.

AEs more frequently associated with luspatercept versus placebo included bone pain (20.2% vs 8.3%), arthralgia (21.1% vs 14.7%), and dizziness (12.1% vs 4.6%). These were primarily transient, grade 1-2, and not associated with dose level, treatment modification, or discontinuation. Discontinuations due to AE occurred only in the luspatercept arm, and included 2 patients due to arthralgia and 1 due to bone pain. The incidence of new onset AE decreased over time during the study in the luspatercept arm.

Monitoring for safety outcomes is ongoing. An ongoing phase 2 study, BEYOND (NCT03342404) is determining the efficacy and safety of luspatercept in patients with non-transfusion-dependent β-thalassemia. A phase IIa study (NCT04143724) is ongoing to determine the safety and pharmacokinetics in pediatric patients with transfusion-dependent β-thalassemia.

Viprakasit V, Taher AT, Hermine O, et al. Evaluating luspatercept responders in the phase 3, randomized, double-blind, placebo-controlled BELIEVE trial of luspatercept in adult -thalassemia patients who require regular red blood cell transfusions. Presented at: American Society of Hematology Annual Meeting; December 7-10, 2019; Orlando, FL. Abstract 3545. https://ash.confex.com/ash/2019/webprogram/Paper122685.html.

A majority of adult patients with β-thalassemia who require regular red blood cell transfusions experienced clinically meaningful and durable transfusion burden reduction associated with luspatercept (Reblozyl).

Luspatercept Reduces Transfusion Burden in Transfusion-Dependent Patients With Beta-Thalassemia

REGN1979, a human anti-CD20 × anti-CD3 bispecific IgG4 antibody, demonstrated antitumor activity with an acceptable safety profile in heavily pretreated patients with relapsed/refractory (R/R) B-cell non-Hodgkin lymphoma (NHL).

Results from a phase I study presented at the 61st American Society of Hematology Annual Meeting and Exposition demonstrated an overall response rate (ORR) of 95.5% and a complete response (CR) rate of 77.3% among 22 patients in the study with R/R follicular lymphoma (FL) who were treated with ≥5 mg of REGN1979. Patients with R/R FL who were treated with ≥80 mg of REGN1979 had an ORR of 100%, according to Rajat Bannerji, MD, PhD, chief of hematologic malignancies at the Rutgers Cancer Institute of New Jersey, New Brunswick, who presented the findings.

In the R/R FL cohort, the median progression-free survival was 11.4 months (95% CI, 6.7-not evaluable). At data cutoff (September 3, 2019), 14 of 21 responses were ongoing, and 12 of 17 patients who had achieved a CR had ongoing CRs at the last tumor assessment. Median duration of follow-up in this group was 6.8 months.

In the subset of patients with R/R diffuse large B-cell lymphoma (DLBCL), dose-related responses were observed. With treatment at ≥80 mg of REGN1979, the ORR rate was 57.9% and the CR rate was 42.1%. At this dosage, the ORR was 71.4% in those patients not treated with prior chimeric antigen receptor (CAR) T-cell therapy (n = 7), which included all CRs. In those without prior CAR T-cell therapy, the ORR and CR rate were 50% and 25%, respectively. The responses appear durable, said Bannerji, as all CRs were ongoing at the last tumor assessment.

“Using this step-up dosing strategy, we were able to go to the maximum planned dose of the protocol without any dose-limiting toxicity,” he said.

At a median follow-up of 5.3 months, all 5 patients with R/R DLBCL without prior CAR T-cell therapy who responded to ≥80 mg of REGN1979 had ongoing responses at the last tumor assessment. In this subset of patients with R/R DLBCL who also had prior CAR T-cell therapy, the median follow-up was 2.6 months. Four out of 6 patients who responded had an ongoing response at the last tumor assessment, and all 3 with CRs maintained their CR at last tumor assessment.

In both of the above subsets of B-cell malignancies, baseline CD20 level did not predict response or nonresponse, but some progression may be associated with loss of CD20, said Bannerji. PD-L1 expression and PD-1—positive tumor infiltrating lymphocytes in malignant lymph node tissue increased following REGN1979 treatment. “This suggests that these bispecific [antibodies] may have some synergy with checkpoint inhibitors,” he said.

ORR and CR rates were 67% and 33% each, respectively, for enrolled patients with mantle cell lymphoma (MCL; n = 6) or marginal zone lymphoma (MZL; n = 6).

Eligible patients were those with R/R B-cell NHL who received prior CD20-directed therapy. Per study protocol, REGN1979 was administered over a 36-week period. Patients first received 12 weekly doses delivered intravenously followed by an every-2-week administration for a total of 12 doses.

A total of 110 patients were entered: 61 with DLBCL; 31 with grade 1 to 3a FL; 9 with MCL; 6 with MZL; and 3 with other B-cell malignancies, which could have included grade 3b FL or Waldenström macroglobulinemia. The median number of prior lines of therapy was 3. Eighty percent of patients were refractory to their most recent prior line of therapy and 15.5% had relapsed (data were missing for the other 4.5%).

At the analysis, 31 patients (28.2%) were continuing on the study; 10 (9.1%) had completed the study. Of the 69 patients who discontinued the study, 35 did so for progression or disease recurrence, 6 were due to physician decision, 5 were due to patient decision, 1 was because of an adverse event (AEs), 9 were for other reasons, and 13 had died.

The most common treatment-emergent AEs observed in all patients were pyrexia (80%), cytokine release syndrome (CRS; 59.1%), and chills (50.9%). The most common grade 3/4 AEs were anemia (21.8%), hypophosphatemia (19.1 %), lymphopenia (19.1 %), and neutropenia (19.1 %).

“Infusion-related reactions (IRRs) and CRS events occurred predominantly during weeks 1 through 3 and declined thereafter, without a dose-dependent increase in incidence or severity,” Bannerji said. No patient discontinued due to IRR or CRS.

Neurologic AEs were transient with none requiring treatment discontinuation. “We did not see any grade 4 or above adverse neurologic events,” he said. “The vast majority of neurologic AEs were grade 1 and 2.”

Six patients discontinued the study drug due to treatment-related AEs: 1 for grade 1 cytomegalovirus infection, 1 for grade 3 hemolysis, 1 for grade 3 fatigue, 2 for grade 3 pneumonia, and 1 for grade 3 toxoplasmosis. Two patients discontinued due to AEs unrelated to treatment. Infections/infestations were reported in 50% of patients; only 20% were grade 3/4 in severity with 2 deaths.

Fifteen patients died during the study, most often for progressive disease (n = 10; 1 with grade 5 multiorgan failure and 1 with grade 5 acute renal failure). Other causes of death were gastric perforation, cardiac arrest, lung infection, and pneumonia (1 each); 1 patient died of fungal pneumonia 7 months after discontinuing treatment.

After the data cutoff, a patient treated in the dose-expansion phase with MCL blastoid variant with bone marrow involvement and bulky disease developed CRS and died of tumor lysis syndrome. “At present, we halted enrollment in the expansion cohorts while a safety amendment is being put together,” he said.

The dose-escalation portion of the phase I trial is complete and expansion cohorts are expected to be re-opened. A global, multi-arm pivotal trial is under way.

Bannerji R, Allan JN, Arnason JE, et al. Clinical activity of REGN1979, a bispecific human, anti-CD20 x anti-CD3 antibody, in patients with relapsed/refractory (R/R) B-cell non-Hodgkin lymphoma (B-NHL). Blood. 2019;134(suppl 1;abstr 762) doi: 10.1182/blood-2019-122451.

REGN1979 demonstrated antitumor activity with an acceptable safety profile in heavily pretreated patients with relapsed/refractory B-cell non-Hodgkin lymphoma.

Bispecific Antibody Shows High Clinical Activity in Heavily Pretreated NHL

The addition of CP-0610, a selective and potent oral small molecule BET inhibitor, to ruxolitinib (Jakafi) in JAK inhibitor-naïve patients with myelofibrosis induced splenic and symptomatic responses as early as 12 weeks, according to preliminary data from a phase II study presented at the 2019 ASH Annual Meeting and Exposition, held December 7-10, in Orlando, Florida.

In the MANIFEST study, patients demonstrated splenic and symptomatic responses as early as 12 weeks, at which time 80% of patients had a spleen volume reduction (SVR) of ≥35% and 71.4% of patients had a total symptom score (TSS) improvement of ≥50%,

 reported Claire Harrison, MD. The combination was generally well tolerated; no adverse events led to study discontinuation.

“Whilst ruxolitinib, the first approved therapy for myelofibrosis, as shown in the COMFORT 1 study,

 delivers significant spleen volume and symptom improvement in approximately 40% of patients, the symptomatic improvement occurs in the setting of cytopenias in some agents, and additional agents with a different mechanism of action are postulated to be needed in order to deepen symptomatic responses and modify the disease in an unmet need patient population,” said Harrison, professor of hematology, Guy’s and St. Thomas’ Hospital, London, U.K.

BET proteins bind to acetylated histone lysine residues and function as co-activators of gene expression. They cooperate with the transcription factor NFκB to activate pro-inflammatory cytokine gene expression. CP-0610 downregulated pro-inflammatory cytokines in mouse models, and the combination of a BET inhibitor and ruxolitinib synergistically reduced splenomegaly, cytokine expression, bone marrow fibrosis, and the mutant allele burden.

Preliminary data from prior JAK inhibitor-treated patients in MANIFEST showed that CPI-0610 as monotherapy (arm 1) or “add on” to ruxolitinib (arm 2) was generally well-tolerated, and reduced spleen size, alleviated symptoms, improved levels of hemoglobin, and reduced transfusion burden, in patients with myelofibrosis, as well as suppressed proinflammatory cytokine and improved bone marrow fibrosis.

In her poster, Harrison presented preliminary data from arm 3 of MANIFEST, a global, multicenter, open-label study of CPI-0610 in combination with ruxolitinib in JAK inhibitor-naïve patients with myelofibrosis. Key eligibility criteria of arm 3 included a DIPSS risk ≥intermediate-2, ECOG performance status ≤2, platelet count ≥100 x 10

/L, peripheral blood blast count <10%, anemia (hemoglobin <10 g/dL), spleen volume ≥450 cm

/L without the assistance of granulocyte growth factors, and at least 2 symptoms measurable (score ≥3) or a TSS of ≥10.

As of October 17, 2019, 30 treatment-naïve patients were enrolled in arm 3, 15 (50%) of whom are on treatment for at least 12 weeks. Dose modification of ruxolitinib or CP-0610 was required in 40%. Some 53.3% had primary myelofibrosis, 10% had post polycythemia vera myelofibrosis, and 33.3% had post essential thrombocythemia myelofibrosis. At baseline, the median platelet count was 369.5 x 10

/L, the median spleen volume was 1,637 cm

, and the median TSS was 16. Fifty percent had high molecular risk mutations at baseline.

Patients were treated with CP-0610 at 125 mg on a 14-day on, 7-day off cycle, with a starting dosage of ruxolitinib, according to the baseline platelet count (10 mg twice daily with platelet count ≥100 x 10

/L; 15 mg twice daily if platelet count was >200 x 10

/L). Ruxolitinib dosage was increased by 5 mg twice daily per cycle from cycle 3, day 1 or thereafter, to a maximum dosage of 20 mg twice daily if upward dose titration criteria were met. CP-0610 dosage was increased from cycle 5, day 1 and thereafter by 25 mg once daily to a maximum dosage. All patients remain active on treatment for a median duration of 4 cycles (12 weeks).

“Encouraging early clinical activity is observed with this combination,” said Harrison. “Eighty percent of patients achieved a 35% reduction in spleen volume and 71% achieved a 50% reduction in TSS as early as 3 months after treatment.”

The median reduction in spleen volume at week 12 was 49.7%. Response was observed in patients considered to be high risk, including 86.7% of patients with DIPSS ≥int-2 and 80% of patients with hemoglobin <10 g/dL, and 53.3% of patients who were high molecular risk. The median change in TSS at week 12 was 60.3%.

In the 7 patients with elevated pro-inflammatory cytokines at baseline, median C-reactive protein (CRP) level was reduced by 57.1% and median interleukin (IL)-18 level was reduced by 85.7%. Normalization of CRP occurred in all 4 patients with abnormal CRP levels at baseline, and in 4 of 6 (66.7%) of patients with abnormal levels of IL-18 at baseline.

The benchmark for SVR for ruxolitinib alone at full dose in the JAK inhibitor-naïve population, per label, is 28.5 to 41.9%, noted Harrison.

Anemia occurred in 20% and thrombocytopenia in 16.7%. Thrombocytopenia was reversible and asymptomatic. Three patients had grade 3 anemia and 1 had grade 4 thrombocytopenia, which was the only grade 4 adverse event (AE) that required a 3-week dose interruption.

The most common nonhematologic AEs were diarrhea (26.7%), nausea (20%), constipation (20%), and mouth ulceration (20%), all of which were grade 1-2. There were no new or unexpected infections.

“Based on these preliminary data, this cohort has been expanded in the MANIFEST study and a phase 3 trial is being planned,” said Harrison.

Harrison C, Patriarca A, Mascarenhas J, et al. Preliminary report of MANIFEST, a phase 2 study of CPI-0610, a bromodomain and extraterminal domain inhibitor (BETi), in combination with ruxolitinib, in JAK inhibitor (JAKi) treatment naïve myelofibrosis patients. Presented at: 2019 ASH Annual Meeting; December 7-10, 2019; Orlando, FL. Abstract 4164.      

Verstovsek S, Mesa RA, Gotlib J,&#8239;et al. A double-blind, placebo-controlled trial of ruxolitinib for myelofibrosis. 

The addition of CP-0610 to ruxolitinib (Jakafi) in JAK inhibitor-naïve patients with myelofibrosis induced splenic and symptomatic responses as early as 12 weeks.

Addition of BET Inhibitor to Ruxolitinib Reduces Spleen Volume, Improves Symptoms in Myelofibrosis

The CD19-directed CAR T-cell therapy tisagenlecleucel (Kymriah) demonstrated similar real-world efficacy and safety findings to that of the pivotal JULIET trial in the treatment of adult patients with relapsed/refractory diffuse large B-cell lymphoma, according to an analysis of the PICTOR (CTL019B2401)/CIBMTR SC 17-08 registry presented at the 2019 ASH Annual Meeting.

Results showed that the best overall response rate (ORR) was 58%, which included a complete response (CR) rate of 40% and a partial response (PR) rate of 18%.  

The efficacy findings are overall comparable with the updated data from the phase II JULIET trial, which were published in the 

 earlier this year. Specifically, in JULIET, the ORR with the agent was 52%, with a CR rate of 40% and a PR rate of 12%.

“Tisagenlecleucel therapy real-world evidence confirms the efficacy data reported in the JULIET study,” Samantha M. Jaglowski, MD, associate professor in the Department of Internal Medicine, Ohio State University Comprehensive Cancer Center—James, said in a presentation during the conference. “Additionally, the safety profile [of the product] appears more favorable in the registry compared with the pivotal study.”

In May 2018, the FDA approved tisagenlecleucel for use in adult patients with relapsed/refractory large B-cell lymphoma—including DLBCL, high-grade B-cell lymphoma and DLBCL arising from follicular lymphoma&mdash;after ≥2 lines of systemic therapy.

The approval was based on earlier phase II JULIET findings, in which tisagenlecleucel reached an ORR of 50% (95% CI, 38%-62%) in adult patients with relapsed/refractory DLBCL.

 The CR rate was 32% and the PR rate was 18%; the median duration of response (DOR) had not yet been reached.

The Center for International Blood & Marrow Transplant Research (CIBMTR) Cellular Therapy (CT) Registry was created to capture long-term data from patients who have received CAR T-cell therapy. In September 2018, the CIBMTR and Novartis, the developer of tisagenlecleucel, created this post-marketing study of tisagenlecleucel in the real-world setting to collect long-term safety and efficacy data from patients receiving the CAR T-cell therapy.

The registry plans to follow patients with lymphoma (n = 1500) and acute lymphoblastic leukemia (n = 1000) who have been treated with tisagenlecleucel for 15 years; this includes patients receiving an out-of-specification (OOS) product. The first patient entered on the registry was infused in June 2018. Recommended visit assessments were pre-infusion, at months 3, 6, 12, and annually after infusion.

Efficacy and safety data were collected from patients with ≥3 months of follow-up. Additionally, cytokine release syndrome (CRS) as per the consensus American Society for Transplantation and Cellular Therapy criteria and neurotoxicity via the Immune Effector Cell—Associated Neurotoxicity Syndrome (ICANS) scale were reported. Tisagenlecleucel’s manufacturing product characteristics and cell product characterization by immunophenotyping were compared with clinical outcomes obtained in the registry. Investigators used descriptive summaries and univariate logistic regression analyses to evaluate the association of cells administered, cell viability, potency, transduction efficiency to overall response, CRS, and ICANS grade.

To date, 39 centers contributed findings for 116 patients with relapsed/refractory DLBCL through the registry. The efficacy data set included 80 patients, 75 of which were in a manufacturing set; safety data were available for 83 patients, 77 of which were in a manufacturing set. The total manufacturing set includes 102 patients.

The median age of the participants included in the analysis was 65 years (range, 15-89); in JULIET, Jaglowski noted that the median age was 56 years (range, 22-74). Sixty percent of patients were male and most patients were white (85.7%). Furthermore, 34.3%, 47.1%, 4.3%, and 14.3% of patients had an ECOG performance status of 0, 1, 2, and not reported, respectively. Forty-one percent of patients had double- or triple-hit lymphoma and 27% had transformed lymphoma; 32% and 61% of patients had refractory and relapsed disease, respectively. Twenty-four percent of patients had undergone prior autologous stem cell transplant; allogeneic stem cell transplant occurred in 4% of patients.

The CAR T-cell therapy tisagenlecleucel (Kymriah) showed similar real-world efficacy and safety findings to that of the JULIET trial in the treatment of adult patients with relapsed/refractory diffuse large B-cell lymphoma.