Highlights From the American Society of Hematology Annual Meeting & Exposition

Key trial results that may soon shape clinical practice in hematology and oncology were presented at the 64th American Society of Hematology (ASH) Annual Meeting & Exposition in December 2022. Below are some of the highlights.

Mantle Cell Lymphoma

Results from the phase 3 TRIANGLE study (NCT02858258) demonstrated that the addition of ibrutinib (Imbruvica; Pharmacyclics, Janssen Biotech) to autologous stem cell transplant (ASCT) showed a superior failure-free survival (FFS) over ASCT alone in patients with mantle cell lymphoma (MCL). With a median follow-up of 31 months, the ibrutinib arm of the 3-arm study of 870 patients demonstrated a 3-year FFS of 88% vs 72% with ASCT alone.¹

The 3-arm study randomly assigned the 870 previously untreated patients 65 years or younger with stage 2 or higher MCL to induction chemoimmunotherapy and ASCT, induction chemoimmunotherapy plus ibrutinib and ASCT followed by 2 years of ibrutinib maintenance, or induction chemoimmunotherapy with ibrutinib followed by 2 years of ibrutinib maintenance. Following evidence of the benefit of rituximab (Rituxan; Genentech) as a maintenance therapy, the study protocol was updated to include rituximab maintenance in all arms of the trial.

Chronic Lymphocytic Leukemia

Four-year follow-up results from the phase 3 GLOW trial (NCT03462719) demonstrated a 79% reduction of progression/death with the fixed-dose combination of ibrutinib and venetoclax (Venclexta; AbbVie, Genentech) vs chemoimmunotherapy in the first line among older and/or unfit patients with chronic lymphocytic leukemia. Overall survival and progression-free survival advantages were seen in comparison with chlorambucil (Leukeran; Excella GmbH & Co) and obinutuzumab (Gazyva; Genentech). At 3.5 years, 74.8% of participants were alive and disease free in the ibrutinib and venetoclax arm vs 24.8% in the chlorambucil and obinutuzumab arm.²

Diffuse Large B-Cell Lymphoma

The question of whether a cure is on the horizon for diffuse large B-cell lymphoma (DLBCL) was present at ASH this year. For example, in a phase 2 trial (NCT03075696) that enrolled 155 patients with relapsed/refractory DLBCL, 154 received at least 1 dose of either obinutuzumab or glofitamab (RO7082859; Genentech Oncology), a T cell–engaging bispecific antibody targeting CD20 and CD3. The results demonstrated an 80% complete response rate at 24 months on fixed-duration glofitamab.³ The data cutoff was March 2022, so investigators hope to have another year’s data to support this response at the next ASH meeting in December 2023.³

Waldenström Macroglobulinemia

Data from a phase 2 trial (NCT04273139) presented by Dana-Farber Cancer Institute in Boston, Massachusetts, demonstrated that although a 100% overall response rate and a 93% major response were seen with the combination of venetoclax and ibrutinib for adult patients with Waldenström macroglobulinemia, a higher than expected 9% of patients experienced ventricular arrythmia, which caused the study to be halted.⁴

Multiple Myeloma

Talquetamab

Talquetamab (JNJ-64407564; Genmab/Janssen) is a first-in-class, off-the-shelf, T-cell–redirecting bispecific antibody targeting GPRC5D and CD3 receptors, making it a promising immunotherapy target for patients with multiple myeloma. Results from the phase 1/2 MonumenTAL-1 trials (NCT03399799/NCT04634552) demonstrated that 143 patients given a 0.4-mg/kg subcutaneous dose weekly had an overall response rate of 73%, with a very good partial response rate of 58% and a complete response rate of 29%. Additionally, the median time to response was 1.2 months (range, 0.2-5.0), and duration of response was 9.3 months (95% CI, 6.6-20.2; range, 1-23+).5 The participants all had more than 3 lines of prior treatment.⁵

Elranatamab

During a 10.4-month follow-up of the phase 2 MagnetisMM-3 trial (NCT04649359) assessing elranatamab (PF-06863135; Pfizer), an investigational B-cell maturation antigen (BCMA)-CD3–targeted bispecific T-cell engager antibody, the trial results demonstrated that patients with more than 3 prior lines of therapy showed a 61% overall response rate. Of these patients who responded to the therapy, 84% showed a probability of maintaining a response at 9 months.⁶

Teclistamab-cqyv

The phase 1b MajesTEC-2 study (NCT04722146) study investigated teclistamab-cqyv (Tecvayli; Janssen Biotech), a first-in-class BCMA-CD3–targeted bispecific T-cell engager antibody, in combination with daratumumab (Darzalex; Janssen Biotech) and lenalidomide (Revlimid; Celgene) for patients with multiple myeloma. The combination therapy provided 90.3% of participants who had 1 to 3 prior lines of treatment with a very good partial response and a manageable safety profile.⁷

Daratumumab

In the randomized phase 3 MAIA study (NCT02252172) assessing daratumumab plus dexamethasone (Decadron; Merck) and lenalidomide (D-Rd), D-Rd improved efficacy vs dexamethasone and lenalidomide alone in subgroups of patients younger than 75 years, younger than 70 years, and aged 70 to 74 years at a median follow-up of 64.5 months.⁷

Further, D-Rd showed clinically meaningful benefit across all end points, including progression-free survival, overall survival, overall response rate, and minimal residual disease negativity. These results, along with those presented previously by Saad Zafar Usmani, MD, at the American Society of Clinical Oncology’s annual meeting in 2019, support the frontline use of daratumumab-based combination regimens in patients with multiple myeloma who are younger than 75 years and those 75 years or older with transplant-ineligible, newly diagnosed multiple myeloma.^7,8

GC012F

GC012F (Gracell Biotechnologies) is a BCMA and CD19 dual-targeting chimeric antigen receptor (CAR) T-cell therapy developed on the novel FasTCAR-T enabling next-day manufacturing platform. In a singlearm phase 1 trial (NCT04935580) conducted in China, GC012F was found to shrink tumors in all 16 trial participants with transplant-eligible, newly diagnosed, high-risk multiple myeloma. Specifically, the trial results showed a very favorable safety profile, 100% overall response rate, and 100% minimal residual disease negativity.⁸

The presenters noted that these promising results warrant further assessment of GC012F for this patient population with a longer follow-up period. They noted the company is actively seeking a partner for a US-China study to evaluate the therapy in previously treated patients.⁸

Efgartigimod

Results from the phase 3 ADVANCE trial (NCT04188379) investigating intravenous efgartigimod (Vyvgart; argenx) in 131 patients with primary immune thrombocytopenia demonstrated that 51.2% in the efgartigimod arm met response criteria vs 20% in the placebo arm. Additionally, a sustained platelet count (PLT) response was reached in more patients treated with efgartigimod (21.8%; 17 of 78) than placebo (5.0%; 2 of 40; P = .0316) and 21.8% of patients met the primary end point of a PLT greater than 50 maintained from weeks 19 to 24 (vs 5% in the placebo arm).⁹

Further, efgartigimod showed an early PLT increase, higher sustained PLT response, and more weeks with PLT of 50 Å~ 109/L or greater, compared with placebo. Efgartigimod was also well tolerated with no new safety signals. In the phase 3 open-label ADVANCE+ extension trial (NCT04225156), long-term efficacy and safety data are being evaluated with a subcutaneous efgartigimod formulation that could potentially allow self-administration.⁹

Myelofibrosis

Data from 2 LIMBER studies were presented at ASH. The studies combined investigational agents with ruxolitinib (Jakafi; Incyte) to treat patients with myelofibrosis.¹⁰

Parsaclisib

Parsaclisib (INCB050465; Incyte) is an investigational novel oral inhibitor of PI3Kδ. Given daily to patients with a suboptimal response to ruxolitinib alone, the addition of parsaclisib in a phase 2 study (NCT02718300) resulted in a median change in spleen volume at week 12 of −1.6% (n = 28) in the once-daily/once-weekly cohort (QD/QW) vs −15.4% (n = 37) in the once-daily cohort (QD), and at week 24 was −2.5% (n = 20) and −19.3% (n = 29), respectively.¹⁰

Median percentage change in total symptom score (MFSAF-TSS, MPN-SAF-TSS) at week 12 was −14.0% (n = 21) in QD/QW and −32.8% (n = 24) in QD, and at week 24 was −10.0% (n = 16) and −44.4% (n = 18), respectively. Median percentage change in the MPN-SAFTSS total symptom score at week 12 was −19.2% (n = 20) in QD/QW and −39.8% (n = 30) in QD, and at week 24 was −43.3% (n = 15) and −60.8% (n = 26), respectively.¹⁰

These results demonstrate that patients with myelofibrosis having a suboptimal response to ruxolitinib alone experience improvement in symptoms and change in spleen volume with add-on parsaclisib. Further, the results showed that all daily dosing regimens had a greater efficacy than a daily/weekly dosing regimen. Additionally, the combination therapy was associated with limited grade 3/4 adverse events (AEs) and treatment-emergent AE (TEAE)–related discontinuations. Currently, there are phase 3 studies under way assessing 5-mg once-daily parsaclisib in combination with ruxolitinib-naïve patients and patients who have been previously treated with ruxolitinib.¹⁰

Zilurgisertib

Data from a phase 1/2 study (NCT04455841) investigating zilurgisertib (INCB000928; Incyte), a potent, selective ALK2 inhibitor, as a monotherapy or as a combination therapy with ruxolitinib in patients with anemia due to myelofibrosis were presented at ASH. Initial data showed a reduction in postdose hepcidin levels at all dose levels and observed improvements in anemia in the monotherapy and combination patient cohorts, suggesting the potential for therapeutic activity.¹⁰

The data from the trial also support once-daily dosing of zilurgisertib and continued dose escalation to achieve optimal exposure. Both the zilurgisertib as a monotherapy and in combination with ruxolitinib resulted in predominantly grade 1/2 TEAEs and no dose-limiting toxicities. Further, few TEAEs at grade 3 or higher were observed, although thrombocytopenia was observed in 2 patients with baseline grade 2 thrombocytopenia, and neutropenia was observed in 1 patient with baseline grade 2 neutropenia. However, no TEAEs led to drug discontinuation during the study.¹⁰

β-Thalassemia

In a study assessing betibeglogene autotemcel (beti-cel, Zynteglo; bluebird bio) to manage transfusion-dependent β-thalassemia, patients underwent autologous CD34+ hematopoietic stem and progenitor cell collection followed by pharmacokinetic-adjusted myeloablative busulfan conditioning and beti-cel infusion. Patients were followed for 2 years in the parent phase 1/2 (HGB-204, NCT01745120; HGB-205, NCT02151526) and phase 3 (HGB-207, NCT02906202; HGB-212, NCT03207009) studies. Patients then entered a 13-year long-term follow-up study (NCT02633943).⁹

In total, of the 63 patients who had received beti-cel and were followed for a median of 41.4 months (9.0-87.5) across the 4 parent studies and the long-term follow-up study, 49 patients (77.8%) achieved transfusion independence (not needing a transfusion at more than 1 year and maintaining hemoglobin greater than 9), and all 49 remained transfusion independent at 3-year follow-up.⁹

Additionally, a separate quality-of-life study was performed on these patients using the long-term follow-up study data. At 3-year follow-up, 93.8% of patients reported they were either working or looking for work (vs 68.8% prior to therapy) and 44.4% reported missing school due to illness vs 83.3% before therapy.⁹

Chronic Myelocytic Leukemia

Asciminib (Scemblix; Novartis), which is currently approved as a third-line treatment for chronic phase myelocytic leukemia, showed robust activity in the frontline setting in the phase 2 Australasian Leukaemia Lymphoma Group CML13 ASCEND-CML trial (NCT03578367). The trial results showed a 92% early molecular response rate at 3 months with a tolerable safety profile.¹¹

ABOUT THE AUTHOR

Douglas Braun, PharmD, CSP, RPh, is a senior pharmacy director at the American Oncology Network, LLC, in Naples, Florida.

REFERENCES

1. Fagerlie S. Ibrutinib outperforms ASCT in treatment-naive MCL. OBR Oncology. December 10, 2022. Accessed December 19, 2022. https://www.obroncology.com/article/ibrutinib-outperforms-asct-in-treatment-naive-mcl

2. New results from the phase 3 GLOW study of fixed-duration treatment with Imbruvica (ibrutinib) plus venetoclax demonstrate robust efficacy and sust ained response in older, unfit patients with previously untreated chronic lymphocytic leu kemia. News release. Janssen. December 10, 2022. Accessed December 19, 2022. https://www.janssen.com/new-results-phase-3-glow-study-fixed-duration-treatment-imbruvica-ibrutinib-plus-venetoclax

3. Bankhead C. Prolonged responses in DLBCL spark talk of a cure with bispecific antibody. MedPage Today. December 13, 2022. Accessed December 19, 2022. https://www.medpagetoday.com/meetingcoverage/ashhematology/102222

4. McDonald R. Frontline ibrutinib/venetoclax elicits responses in Waldenström macroglobulinemia, but has safety concerns. OncLive^®. December 11, 2022. Accessed December 19, 2022. https://www.onclive.com/view/frontline-ibrutinib-venetoclax-elicits-responses-in-waldenstr-mmacroglobulinemia-but-has-safety-concerns

5. Chari A, Touzeau C, Schinke C, et al. Talquetamab, a G protein-coupled receptor family C group 5 member D x CD3 bispecific antibody, in patients with relapsed/refractory multiple myeloma (RRMM): phase 1/2 results from MonumenTAL-1 clinically relevant abstract. December 10, 2022. Accessed December 19, 2022. https://ash.confex.com/ash/2022/webprogram/Paper159707.html

6. Pfizer presents updated favorable elranatamab data from pivotal phase 2 MagnetisMM-3 trial. News release. Pfizer. December 10, 2022. Accessed December 19, 2022. https://www.pfizer.com/news/press-release/press-release-detail/pfizer-presents-updated-favorable-elranatamab-data-pivotal

7. Janssen presents first data from MajesTEC-2 Trial of Tecvayli (teclistamab-cqyv) in combination with Darzalex Faspro (daratumumab and hyaluronidase-fihj) and lenalidomide in relapsed or refractory multiple myeloma. News release. Johnson & Johnson. December 10, 2022. Accessed December 19, 2022. https://www.jnj.com/janssen-presents-first-data-from-majestec-2-trial-of-tecvayli-teclistamab-cqyv-in-combination-with-darzalex-faspro-daratumumab-andhyaluronidase-fihj-and-lenalidomide-in-relapsed-or-refractory-multiple-myeloma

8. Liu A. ASH: in next BCMA myeloma race, Gracell dazzles with 100% response rate as Pfizer, BMS place their bets. Fierce Biotech. December 10, 2022. Accessed December 19, 2022. https://www.fiercebiotech.com/biotech/next-bcma-myeloma-race-gracell-dazzles-100-response-rate-pfizer-bms-and-more-place-their

9. Research highlights cutting-edge new treatments for blood disorders. News release. American Society of Hematology. December 10, 2022. Accessed December 19, 2022. https://www.hematology.org/newsroom/press-releases/2022/research-highlights-cutting-edge-new-treatments-for-blood-disorders

10. Incyte announces data from two LIMBER studies evaluating combination treatments in patients with myelofibrosis (MF) presented at ASH 2022. News release. Incyte. December 10, 2022. Accessed December 19, 2022. https://investor.incyte.com/news-releases/news-release-details/incyte-announces-data-two-limber-studies-evaluating-combination

11. Goodman J. Asciminib shows early promise as frontline therapy for CML-CP. Cancer Therapy Advisor. December 10, 2022. Accessed December 19, 2022. https://www.cancertherapyadvisor.com/home/news/conference-coverage/ash-2022/cml-cp-asciminib-early-promise-frontline-therapy/