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At the 2024 American Society of Hematology Annual Meeting & Exposition (ASH), a variety of promising therapies for the treatment of hematologic malignancies demonstrated significant efficacy and safety in real-world and clinical trial settings.

Here are some of the highlights from this year's meeting.

Real-World Data Supports Efficacy and Safety of Liso-cel in Second-Line LBCL Treatment

Real-world data from the Center for International Blood and Marrow Transplant Research (CIBMTR) Registry supports the efficacy and safety of lisocabtagene maraleucel (liso-cel; Breyanzi) as a second-line treatment for patients with relapsed/refractory large B-cell lymphoma.¹ In a cohort of 156 patients, the median progression-free survival (PFS) and overall survival (OS) were not reached (NR; 95% CI, NR-NR), with 6-month PFS rates of 61% (95% CI, 52%-69%) and OS rates of 87% (95% CI, 80%-92%). The objective response rate (ORR) was 84% (95% CI, 77%-89%), and the complete response (CR) rate was 70% (95% CI, 62%-77%).

These findings align with the pivotal TRANSFORM (NCT03575351) and PILOT (NCT03483103) trials, indicating that liso-cel produces similar outcomes in real-world settings. Notably, the data also showed high efficacy across various subgroups, including those with refractory disease and older patients.

Tisagenlecleucel Efficacy in R/R Follicular Lymphoma Sustained With 4-Year Update

Tisagenlecleucel (Kymriah) showed sustained clinical effectiveness and tolerability in patients with relapsed/refractory follicular lymphoma, including those in high-risk groups, according to a 4-year update from the pivotal phase 2 ELARA trial (NCT03568461).²

After a median follow-up of 53 months (range, 46-62), the median OS was not reached, with a 4-year OS rate of 79.3%. The median PFS was 53.3 months (95% CI, 18.2-not evaluable), and the 4-year PFS rates were 50.2% overall, rising to 66.1% for patients who achieved a CR. The CR rate was 69.1%.

Five-Year Follow-Up Confirms Zanubrutinib as a Frontline Option in CLL/SLL

Zanubrutinib (Brukinsa) led to sustained long-term efficacy benefits when compared with bendamustine plus rituximab (BR) in patients with treatment-naive chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL). These findings come from a 5-year follow-up from the phase 3 SEQUOIA trial (NCT03336333).³

In cohort 1 of the open-label trial, patients treated with zanubrutinib (n = 241) had significantly better PFS vs those treated with BR (n = 238), regardless of disease risk or the impact of COVID-19. Additionally, zanubrutinib demonstrated a higher ORR and a more favorable safety profile with fewer adverse events (AEs).

Ide-cel Leads to High Real-World Remission Rates in CNS Myeloma

Patients with relapsed/refractory multiple myeloma involving the central nervous system (CNS) treated with idecabtagene vicleucel (ide-cel, Abecma) had favorable responses and comparable outcomes to those with non-CNS multiple myeloma, according to a real-world analysis presented at the 2024 ASH Annual Meeting.⁴

In a cohort of 10 patients with confirmed CNS involvement and a median follow-up of 4.7 months, 7 patients (70%) experienced no CNS relapse after receiving ide-cel therapy. The estimated median PFS was 10.5 months, and the estimated median OS was 12.9 months.

D-VRd Increases MRD-Negativity Rate in Patients With Multiple Myeloma Not Receiving Transplant Up Front

An analysis of the phase 3 CEPHEUS trial (NCT03652064) showed that adding daratumumab (Darzalex) to the combination of bortezomib (Velcade), lenalidomide (Revlimid), and dexamethasone (VRd) improved minimal residual disease (MRD)-negativity rates among patients with transplant-ineligible or -deferred newly diagnosed multiple myeloma.⁵

The combination therapy also led to better PFS outcomes, regardless of whether patients were MRD-negative or MRD-positive. These findings support the incorporation of daratumumab into standard care for transplant-ineligible patients or those deferring transplant in the treatment of newly diagnosed multiple myeloma.

Selinexor With Ruxolitinib Continues to Demonstrate Efficacy in Myelofibrosis

Preliminary findings from the phase 2 SENTRY trial (NCT04562389) demonstrated that the combination of selinexor (Xpovio) plus ruxolitinib (Jakafi) in doses of 40 mg and 60 mg led to promising efficacy and a manageable safety profile in patients with myelofibrosis who had previously been treated with ruxolitinib.⁶

Regarding safety, the most common AEs of any grade were anemia and nausea (36.8%), followed by vomiting (23.7%). Grade 3 or 4 AEs included anemia (18.4%), thrombocytopenia (5.3%), and gastrointestinal symptoms such as nausea and vomiting (2.6%).

Zilovertamab Vedotin/R-CHP Elicits High Complete Response Rate in DLBCL

Zilovertamab vedotin added to cyclophosphamide, doxorubicin, prednisone, and rituximab (R-CHP) resulted in nearly all patients with previously untreated diffuse large B-cell lymphoma achieving a CR, according to findings from the phase 2 open-label WAVELINE-007 trial (NCT05406401). In the dose-escalation study, the overall ORR across all doses was 97.2%, with all responses being complete responses.⁷

At the recommended phase 2 dose (RP2D) of 1.75 mg/kg every 3 weeks, the ORR was 100%, entirely composed of CR. The median duration of response (DOR) was not yet reached in any group, but at 12 months, the DOR was 93.5% for all doses and 91.7% for the RP2D arm, suggesting robust and durable responses with the combination treatment.

Fixed-Duration Frontline Combo of Acalabrutinib and Venetoclax Delays Progression in CLL

Results from the phase 3 AMPLIFY trial (NCT03836261) showed that the all-oral, fixed-duration combination of acalabrutinib (Calquence) and venetoclax (Venclexta), with or without obinutuzumab (Gazyva), significantly reduced the risk of disease progression or death compared to standard-of-care chemoimmunotherapy in patients with treatment-naive chronic lymphocytic leukemia, regardless of IGHV mutational status.⁸

At a median follow-up of 40.8 months, the median PFS was not reached in both the acalabrutinib-venetoclax and acalabrutinib-venetoclax-obinutuzumab arms vs 47.6 months with the investigator’s choice of chemoimmunotherapy. The doublet regimen reduced the risk of disease progression or death by 35% (HR, 0.65; 95% CI, 0.49-0.87; P = 0.0038), and the triplet regimen led to a 58% reduction in risk (HR, 0.42; 95% CI, 0.30-0.59; P < .0001). Further, the 36-month PFS rates were 83.1% for acalabrutinib plus venetoclax and 76.5% for the triplet regimen, compared to 66.5% with standard chemoimmunotherapy.

Pelabresib Plus Ruxolitinib in JAK-Naive Myelofibrosis Maintains Benefit

The combination of pelabresib (CPI-0610) and ruxolitinib (Jakafi) continued to demonstrate significant benefits in reducing splenomegaly, symptoms, anemia, and bone marrow fibrosis in patients with JAK inhibitor–naive myelofibrosis, according to data from the MANIFEST-2 study (NCT04603495).⁹

After a median follow-up of 72 weeks, the primary end point of spleen volume reduction of 35% was maintained, with a 48-week response rate of 57.0% for the pelabresib and ruxolitinib combination vs 37.5% for ruxolitinib plus placebo. Improvement in total symptom score by at least 50% was observed in 45.3% of patients in the combination group vs 39.4% in the placebo group.

Navtemadlin Monotherapy Shows Safety, Efficacy in R/R Myelofibrosis

Navtemadlin monotherapy showed safety and efficacy in patients with myelofibrosis who were relapsed/refractory to JAK inhibitors, based on the global phase 3 BOREAS study (NCT03662126).¹⁰

Here, navtemadlin significantly outperformed best available therapy (BAT) in spleen volume reduction by 35% (SVR35) and total symptom score reductions of at least 50% (TSS50). At week 24, 15% of patients on navtemadlin achieved SVR35, compared with 5% on BAT, and 24% of navtemadlin patients achieved TSS50, vs 12% on BAT.

REFERENCES:

1. Bobillo MSO, Thiruvengadam SK, et al. Lee D, et al. Real-world (rw) outcomes of lisocabtagene maraleucel (liso-cel) as second-line (2L) therapy in patients (pts) with relapsed or refractory (r/r) large B-cell lymphoma (lbcl): first results from the Center for International Blood and Marrow Transplant Research (CIBMTR) Registry. Blood. 2024;144(suppl 1):470. doi:10.1182/blood-2024.199723

2. Thieblemont C, Dreyling M, Dickinson MJ, et al. Clinical Outcomes of Patients with High-Risk Relapsed/Refractory Follicular Lymphoma Treated with Tisagenlecleucel: Phase 2 ELARA 4-Year Update. Blood. 2024; 144 (suppl 1): 3034. doi:10.1182/blood-2024-201730

3. Shadman M, Munir T, Robak T, et al. Sustained superiority of zanubrutinib vs bendamustine + rituximab in treatment-naive chronic lymphocytic leukemia/small lymphocytic lymphoma: 5-year follow-up of cohort 1 from the SEQUOIA study. Blood. 2024;144(suppl 1):3249. doi:10.1182/blood-2024-194864

4. Maulhardt M, Berning P, Hanoun C, et al. Efficacy of idecabtagene vicleucel (ide-cel) in patients with relapsed/refractory multiple myeloma and prior central nervous system manifestation: a retrospective real-world analysis. Blood. 2024;144(suppl 1):4759. doi:10.1182/blood-2024-202467

5. Zweegman S, Facon T, Hungria V, et al. Phase 3 Randomized Study of Daratumumab (DARA) + Bortezomib, Lenalidomide and Dexamethasone (VRd) Versus Alone in Patients with Transplant-Ineligible Newly Diagnosed Multiple Myeloma or for Whom Transplant Is Not Planned As Initial Therapy: Analysis of Minimal Residual Disease in the Cepheus Trial. Presented at: 2024 ASH Annual Meeting; December 7-10, 2024; San Diego, California. Abstract 362.

6. Duan M, Ma L, Wu Q, et al. The efficacy and safety of selinexor in combination with ruxolitinib in ruxolitinib-treated myelofibrosis patients: the interim analysis of a prospective, open-label, multicenter, parallel-cohort, phase 2 study. Blood. 2024;144(suppl 1):1002-1002. doi.org/10.1182/blood-2024-201204

7. Ozcan M, Barca EG, Kim TM, et al. Waveline-007: Dose Escalation and Confirmation, and Efficacy Expansion Trial of Zilovertamab Vedotin in Combination with Cyclophosphamide, Doxorubicin, and Prednisone Plus Rituximab in Patients with Diffuse Large B Cell Lymphoma. Presented at: ASH 2023 Annual Meeting & Exposition. December 7-10; San Diego, CA. Abstract #578.

8. Brown JR, Seymour JF, Jurczak W, et al. Fixed-duration acalabrutinib plus venetoclax with or without obinutuzumab Versus chemoimmunotherapy for first-line treatment of chronic lymphocytic leukemia: interim analysis of the multicenter, open-label, randomized, phase 3 AMPLIFY trial. Blood. 2024;144(suppl 1):1009. doi:10.1182/blood-2024-200701

9. Mascarenhas JO, Grosicki S, Chraniuk D, et al. Updated Results from the Phase 3 Manifest-2 Study of Pelabresib in Combination with Ruxolitinib for Janus Kinase Inhibitor-Naïve Patients with Myelofibrosis. Blood. 2024;144(suppl 1):3178. doi:10.1182/blood-2024-193193

10. Mascarenhas JO, Popov VM, Mohan S, et al., Results from the Randomized, Multicenter, Global Phase 3 BOREAS Study: Navtemadlin Versus Best Available Therapy in JAK Inhibitor Relapsed/Refractory Myelofibrosis, Presented at: 2024 American Society of Hematology Annual Meeting; December 7-10, 2024; San Diego, California. Abstract 1000.