Jorge Cortes, MD, Director of the Georgia Cancer Center, discusses five year follow-up results of the OPTIC clinical trial for chronic myeloid leukemia (CML).

CML is a myeloproliferative neoplasm characterized by the expression of the BCR-ABL1 fusion gene. It presents with neutrophilic leukocytosis. It can appear at any age, but it mostly affects middle aged and older individuals. Patients usually present with fatigue, weight loss, anemia, night sweats, and splenomegaly. Allogeneic stem cell transplantation and tyrosine kinase inhibitors are traditional lines of therapy for this condition.

The OPTIC clinical trial is a phase 2, randomized, open-label study evaluating the efficacy and safety of ponatinib in patients with CML. Ponatinib is a BCR-ABL1 tyrosine kinase inhibitor. Results from the five year follow-up were presented at the ASH 2024 meeting.

The primary endpoint of this study was 1% or less BCR-ABL1 at 12 months. Secondary endpoints included molecular response rates and safety outcomes. Across three randomized cohorts of 45 mg, 30 mg, and 15 mg once-daily, 283 patients were enrolled.

By five years, 60% of the 45 mg cohort, 41% of the 30 mg cohort, and 40% of the 15 mg cohort achieved 1% or less BCR-ABL1. Estimated progression free survival (PFS) rates were 63% in the 45 mg cohort, 57% in the 30 mg cohort, and 60% in the 15 mg cohort. Of patients whose dose was reduced to 15 mg after achievement of 1% or less BCR-ABL1, 29% in the 45 mg cohort and 23% in the 30 mg cohort lost response following reduction. However, following reescalation, 69% in the 45 mg cohort and 80% in the 30 mg cohort regained response.

Additionally, patients with a T315I mutation at baseline had higher MR2 rates by five years, comparable to those with no mutations at baseline. As of the data cutoff, 73 patients remained on ponatinib. The most common reasons for discontinuation of treatment included adverse events, lack of efficacy, and progressive disease. The most common grade three/four adverse events were thrombocytopenia, neutropenia, and hypertension.

0 0

Emma Searle, PhD, The Christie NHS Foundation Trust and University of Manchester, discusses bleximenib in combination with chemotherapy to treat patients with acute myeloid leukemia (AML).

AML is a group of neoplasms arising from precursor cells committed to the myeloid cell-line differentiation. AML is characterized by clonal expansion of myeloid blasts. Common symptoms include fever, pallor, anemia, hemorrhages and recurrent infections.

This clinical trial is a phase 1b, multicenter, dose-finding study. The purpose of this study was to evaluate the safety and efficacy of combination therapy bleximenib with intensive chemotherapy for AML. Bleximenib is a potent, selective menin-KMT2A complex inhibitor shown to have effects in NPM1-mutated or KMT2A-rearranged AML.

Twenty-two patients received bleximenib across dose levels in combination with intensive chemotherapy. In the study, 95% of patients experienced one or more treatment-emergent adverse event (AE). The most common AEs included diarrhea, thrombocytopenia, febrile neutropenia, pyrexia, anemia, and nausea. Only 18% of AEs were attributed to bleximenib alone. Further, 95% of patients experienced treatment-emergent AEs grade three or greater but only 14% being caused by bleximenib alone. No differentiation syndrome or dose-limiting toxicities occurred.

In those who achieved initial blast clearance, median time from day one of induction to platelet count recovery was 32 days. Additionally, the median time to neutrophil count recovery was 32 days.

Efficacy data was recorded in 14 patients, in which overall response rate was 93% (83% in patients with KMT2Ar AML and 100% in patients with NPM1m AML). The median time to complete response was 30 days.

1 0

Carolina Schinke, MD, University of Arkansas for Medical Sciences, discusses differences in clinical outcomes of black patients with multiple myeloma treated with talquetamab.

Multiple myeloma is a bone marrow-based plasma cell neoplasm characterized by a serum monoclonal protein and skeletal destruction with osteolytic lesions, pathological fractures, bone pain, hypercalcemia, and anemia.

The MonumenTAL-1 clinical trial (NCT03399799/NCT04634552) is a phase 1, first-in-human, open-label, dose escalation study evaluating talquetamab in patients with relapsed or refractory multiple myeloma. Talquetamab is a humanized GPRC5DxCD3 bispecific antibody approved for the treatment of multiple myeloma.

Black individuals have higher incidence and mortality in multiple myeloma but tend to be underrepresented in clinical trials. Preliminary analyses of talquetamab have hinted at differences in safety profile for black patients.

Patients in this study were split into two cohorts: 0.4 mg/kg weekly (QW) and 0.8 mg.kg biweekly (Q2W). In the Q2W cohort, a higher number of black patients had extramedullary disease than white patients.

While the clinical profile between black patients and white patients was generally consistent except for a few areas, results show the importance of evaluating demographic differences in patients in clinical trials.

0 0

Christopher Patriquin, MD, University of Toronto, discusses results of a clinical trial comparing combination C5 inhibitor therapy versus standard of care in patients with paroxysmal nocturnal hemoglobinuria (PNH).

PNH is a rare clonal hematopoietic stem cell disorder characterized by corpuscular hemolytic anemia, bone marrow failure and frequent thrombotic events.

The ACCESS-1 clinical trial is a phase 3, randomized, open-label study evaluating the safety and efficacy of pozelimab and cemdisiran (poze-cemdi) in patients with PNH. Poze-cemdi is a first-in-class combination therapy of an antibody and siRNA targeting C5. The combination therapy was compared to standard of care treatment ravulizumab, a complement C5 inhibitor.

The primary endpoint of cohort A in the study was percent change in lactate dehydrogenase (LDH) levels at 26 weeks. At the end of the study, 96% of patients treated with poze-cemdi achieved adequate LDH control compared to 80% with ravulizumab. 93% of patients achieved LDH normalization with poze-cemdi compared to 65% with ravulizumab. Patients treated with poze-cemdi experienced an 84% decrease in LDH from baseline at week 26 compared to 74% with ravulizumab. Additionally, the CH50 profile observed with poze-cemdi demonstrated complete and uninterrupted inhibition of terminal complement.

Additional data from the ACCESS-1 open-label extension following week 26 included a 95% achievement of LDH control in patients who switched from ravulizumab, compared to 68% that had adequate LDH control with ravulizumab. The safety profile of poze-cemdi was consistent with other approved C5 inhibitors.

0 0

Carsten Utoft Niemann, MD, PhD, Copenhagen University Hospital, discusses results from the GLOW clinical trial in chronic lymphocytic leukemia (CLL).

CLL is a rare cancer of the lymphocytes. Early signs and symptoms may include swollen lymph nodes, fatigue, weight loss, fever, night sweats and frequent infections. Over time, CLL may also spread to the lymph nodes and other organs, including the liver, spleen and lungs. The underlying cause is thought to be a combination of genetic and other unknown factors.

The GLOW clinical trial is a randomized, open-label, phase 3 study evaluating progression free survival (PFS) of ibrutinib plus venetoclax (Ibr+Ven) versus chlorambucil plus obinutuzumab (Clb+O) in patients with CLL.

Ibr+Ven was observed to prolong PFS with a rate of 59.9% and reduce the risk of progression or death by 73%. This is compared to a 17.8% PFS rate with Clb+O. Prolonged PFS rates with Ibr+Ven were independent of IGHV status.

Additionally, when compared to Clb+O, Ibr+Ven prolonged time to next treatment, reduced the need for second-line therapy, prolonged overall survival, reduced the relative risk of death by 54%, and prolonged time spent without toxicity or progression.

0 0

Elias Mai, MD, Heidelberg Myeloma Center, discusses the GMMG-HD7 clinical trial for patients with multiple myeloma.

Multiple myeloma is a bone marrow-based plasma cell neoplasm characterized by a serum monoclonal protein and skeletal destruction with osteolytic lesions, pathological fractures, bone pain, hypercalcemia, and anemia.

The GMMG-HD7 clinical trial is a randomized, phase 3 study evaluating the effect of isatuximab in induction therapy with lenalidomide/bortezomib/dexamethasone (RVd) and lenalidomide maintenance in patients with newly diagnosed multiple myeloma. Isatuximab is an anti-CD38 monoclonal antibody. 662 patients were enrolled in the trial.

Following a median follow up of 47 months, 179 PFS events occurred (time from first randomization to progression or death from any cause, whichever occurred first). Isa-RVd therapy was observed to significantly prolong PFS when compared to RVd, with three year PFS rates at 83% and 75%, respectively.

Additionally, similar results were seen in treatment with Isa-RVd followed by lenalidomide maintenance versus RVd induction followed by lenalidomide maintenance. Three year PFS rates were 84% and 73%, respectively. Overall survival rates were 88% for the Isa-RVd arm and 89% for the RVd arm.

0 0

Elias Jabbour, MD, MD Anderson Cancer Center, University of Texas, discusses results of a clinical trial evaluating bleximenib for patients with acute leukemia.

Acute myeloid leukemias are a group of neoplasms arising from precursor cells committed to the myeloid cell-line differentiation. All of them are characterized by clonal expansion of myeloid blasts. They manifest by fever, pallor, anemia, hemorrhages and recurrent infections.

A phase 1 clinical trial evaluated bleximenib dose optimization and safety and tolerability determination of RP2D in patients with relapsed/refractory acute leukemia patients with KMT2A and NPM1 alterations. Bleximenib is a potent, selective inhibitor of menin-KMT2A interaction

In the study, 121 patients in dose-escalation received oral bleximenib on a 28-day cycle with step-up dosing. Data was evaluated with three treatment dose subgroups including 45 mg twice daily, 90/100 mg BID, and 150 mg BID.

Treatment-related adverse events were present in 70 patients with the most common being differentiation syndrome, neutropenia, thrombocytopenia, and nausea. Overall response rate was 50% with the 90/100 mg BID group and 150 mg BID group and 39% in the 45 mg BID group. Composite complete response rates were 40% in both 90/100 mg and 150 mg groups while the 45 mg group was 23%. Overall response rates and composite complete response rates were similar between KMT2A and NPM1 patients.

For the 90/100 mg BID group, median time to first response was 30 days and median duration of response was 6.4 months. Additionally, this group resulted in reduced hematologic toxicity, optimized PD effect with MEIS1 reduction, and maximal efficacy.

1 0

Deeksha Vishwamitra, Janssen Research & Development, discusses an analysis of the TRIMM-2 clinical trial evaluating combination therapy of talquetamab + daratumab + pomalidomide (tal-DP) in patients with multiple myeloma.

Multiple myeloma is a bone marrow-based plasma cell neoplasm characterized by a serum monoclonal protein and skeletal destruction with osteolytic lesions, pathological fractures, bone pain, hypercalcemia, and anemia.

An analysis was conducted on immunologic pharmacodynamic profiles, correlatives of response, and associations with outcomes in patients treated with tal-DP from the TRIMM-2 clinical trial to look at the effects of this combination therapy. The TRIMM-2 clinical trial is a phase 1b study evaluating subcutaneous daratumumab regimens in combination with bispecific T-cell redirection antibodies for the treatment of patients with multiple myeloma.

Talquetamab is a bispecific antibody that has shown durable response in relapsed/refractory multiple myeloma. Teclistamab (tec) is the first approved B-cell maturation antigen x CD3 bispecific antibody for the treatment of relapsed/refractory multiple myeloma. Daratumumab (D) is a human monoclonal antibody that targets CD38, a protein overexpressed in multiple myeloma cells. Pomalidomide (P) is a thalidomide analogue that stimulates immune function and kills multiple myeloma cells. This combination is referred to as tal-DP.

Patients received tal 0.4 mg/kg weekly or 0.8 mg/kg biweekly with step-up dosing and approved schedules of D 1800 mg and P 2mg. Data from 77 patients was analyzed. Following treatment with tal-DP combination therapy, complementary pharmacodynamic effects were observed. These included the ability to induce T-cell margination, increase absolute T-cell recovery, expand effector memory T-cells, and decrease naive CD8 T-cells during initial cycles of treatment.
The addition of P further amplified these effects, leading to T-cell restimulation, reinduction of CD38 expression on CD8 T cells, and sustained activation of this subset. Notably, tal-DP reduced immunosuppressive CD38+ regulatory T-cells and rescued NK cells initially reduced by D treatment. Patients with prior bispecific antibody (BsAb) exposure, despite presenting more dysfunctional and exhausted baseline immune profiles, demonstrated enhanced CD8 T-cell expansion, NK-cell recovery, and T-cell activation compared to those without prior exposure.
Deeper responses to Tal-DP were associated with higher baseline CD8 T-cell counts, lower expression of activation and coinhibitory receptors, and improved progression-free survival (PFS) and duration of response (DOR). These patients showed earlier and greater recovery of CD8 T-cells and NK cells after P administration, correlating with longer PFS and DOR. In contrast, non-responders exhibited less sustained immune activation and recovery. Preliminary results from a parallel study on Teclistamab (Tec)-DP demonstrated similar findings.

1 0

Anita D’Souza, MD, Medical College of Wisconsin, discusses results from the MajesTEC-2 and TRIMM-2 clinical trials for combination therapy teclistamab + daratumumab + pomalidomide (tec-DP) in patients with multiple myeloma.

Multiple myeloma is a bone marrow-based plasma cell neoplasm characterized by a serum monoclonal protein and skeletal destruction with osteolytic lesions, pathological fractures, bone pain, hypercalcemia, and anemia.

The MajesTEC-2 clinical trial is a multi-arm phase 1b study evaluating the safety and tolerability of teclistamab with other anticancer therapies in patients with multiple myeloma.

The TRIMM-2 clinical trial is phase 1b study evaluating subcutaneous daratumumab regimens in combination with bispecific T-cell redirection antibodies for the treatment of patients with multiple myeloma.

Teclistamab is the first approved B-cell maturation antigen x CD3 bispecific antibody for the treatment of relapsed/refractory multiple myeloma. Daratumumab is a human monoclonal antibody that targets CD38, a protein overexpressed in multiple myeloma cells. Pomalidomide is a thalidomide analogue that stimulates immune function and kills multiple myeloma cells.


A total of 27 patients received weekly doses of teclisatamab (0.72, 0.75, or 1.5 mg/kg with step-up dosing) and approved schedules of daratumumab (1800 mg) and pomalidomide (2 or 4 mg; introduced following completion of step-up dosing).

Median follow-up was 25.8 months and median treatment duration of tec-DP was 12 months. The most common adverse events (AEs) in 50% or greater of patients included neutropenia, cough, and CRS. Grade three/four AEs in 15% or greater of patients included neutropenia, lymphopenia, anemia, COVID-19 pneumonia, and pneumonia. Infections occurred in 25 patients. Three patients discontinued treatment due to AEs and seven deaths occurred (one due to progressive disease and six due to infections).

Overall response rate was 88.5%, very good partial response or better rate was 84.6%, and complete response or better rate was 61.5%. Median time to first response was 0.95 months and median progression-free survival was 26.5 months.

Overall, tec-DP combination therapy showed favorable efficacy in patients with relapsed/refractory multiple myeloma. The frequency of infection emphasizes the importance of infection prophylaxis in these patients.

1 0