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Key Data From EHA 2021: A European Expert Perspective

Charles Craddock, CBE, FRCP (UK), FRCPath, DPhil, FMedSci

Academic Director, Centre for Clinical Haematology
Chair, UK NCRI AML Working Party
University Hospitals Birmingham
Director, Blood and Marrow Transplant Unit
Professor of Haemato-oncology
University Hospitals Birmingham NHS Foundation Trust, UK
Birmingham, United Kingdom


Prof. Charles Craddock, CBE, FRCP (UK), FRCPath, DPhil, FMedSci, has disclosed that he has received consulting/advisory fees from AbbVie, Astellas, Bristol-Myers Squibb, Daiichi Sankyo, Eurocept, Janssen, Jazz, Kite, Novartis, Pfizer, and Roche; fees for non-CME/CE services from AbbVie, Astellas, Bristol-Myers Squibb, Daiichi Sankyo, Eurocept, Janssen, Novartis, Pfizer, and Roche; funds for research support from Jazz and Kite.


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María-Victoria Mateos, MD, PhD

Associate Professor
Department of Hematology
University of Salamanca
Director, Myeloma Unit
Department of Hematology
University Hospital of Salamanca
Salamanca, Spain


Maria-Victoria Mateos, MD, PhD, has disclosed that she has received consulting/advisory fees from AbbVie, Adaptive, Amgen, Blue-bird bio, Celgene, GlaxoSmithKline, Janssen-Cilag, Pfizer, Regeneron, Roche/Genentech, and Takeda; funds for non-CME/CE services from AbbVie/Genentech, Adaptive, Amgen, Celgene, GlaxoSmithKline, Janssen-Cilag, Oncopeptides, Sanofi, and Takeda.


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Lydia Scarfò, MD

Assistant Professor
Internal Medicine
Università Vita-Salute San Raffaele
Consultant Hematologist
Strategic Research Program on CLL
Milan, Italy


Lydia Scarfò, MD, has disclosed that she has received consulting fees from AbbVie, AstraZeneca, and Janssen.


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Ali T. Taher, MD, PhD, FRCP

Professor of Medicine, Hematology and Oncology
Division of Hematology and Oncology
Department of Internal Medicine
American University of Beirut Medical Center
Beirut, Lebanon


Ali T. Taher, MD, PhD, FRCP, has disclosed that he has received consulting fees from Agios, Bristol-Myers Squibb/Celgene, Ionis, Novartis, and Vifor and funds for research support from Bristol-Myers Squibb/Celgene, Ionis, Novartis, and Vifor.


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Released: July 28, 2021

During the 2021 European Hematology Association (EHA) virtual annual meeting, important results from key clinical trials on blood disorders and hematologic malignancies were reported. Below, experts in hematology/oncology share their thoughts on key abstracts presented at the annual meeting.

β-Thalassemia
Ali T. Taher, MD, PhD:
BEYOND
My colleagues and I presented results from the randomized phase II BEYOND trial showing that in adults with non–transfusion-dependent β-thalassemia, 77.1% of those treated with the erythroid maturation agent luspatercept achieved a mean hemoglobin increase ≥1.0 g/dL over baseline vs 0% with placebo (P <.0001). Improvements in patient-reported quality of life outcomes (tiredness and weakness) correlated with this increase in hemoglobin. The safety profile of luspatercept was favorable, with no reported deaths, malignancies, or thromboembolic events. Given the increasing evidence for the detrimental effect of anemia in non–transfusion-dependent β-thalassemia, these findings represent a landmark achievement for a population lacking many treatment options.

BELIEVE
The phase III BELIEVE trial earlier demonstrated that luspatercept reduced red blood cell (RBC) transfusion burden in adults with β-thalassemia necessitating regular RBC transfusions. At the EHA 2021 virtual meeting, my colleagues and I presented an abstract evaluating the mean cumulative number of RBC transfusion units and visits among patients with low, medium, or high baseline RBC transfusion burden. We found that patients receiving luspatercept received fewer mean cumulative RBC transfusion units and had fewer visits through Week 48 across these levels of baseline RBC transfusion burden. Indeed, those responding to luspatercept continued to experience meaningful reductions through Week 120. These findings may help inform clinical practice and health policy decisions for patients with ꞵ-thalassemia. 

Acute Myeloid Leukemia (AML)
Professor Charles Craddock, CBE, FRCP (UK), FRCPath, DPhil, FMedSci:
QUAZAR AML‑001
In 2020, Wei and colleagues reported that oral azacitidine (CC‑486) significantly prolonged overall survival (OS) vs placebo in adults aged ≥55 years with de novo or secondary AML and intermediate-/poor-risk cytogenetics who achieved a complete response (CR) with intensive chemotherapy but were not candidates for stem cell transplant. At EHA 2021, Döhner and colleagues reported data for the effect of NPM1 and FLT3 mutation status at diagnosis on outcomes with oral azacitidine. They found that NPM1 status was prognostic for OS and relapse‑free survival and was predictive of a survival benefit with oral azacitidine. Of interest FLT3 ITD or TKD mutations conferred a negative prognosis with placebo but not with oral azacitidine, suggesting that oral azacitidine may overcome the adverse effects of FLT3 alterations. Finally, a multivariate analysis indicated independent prognostic influence of NPM1 and FLT3-ITD/TKD status in patients diagnosed with AML, and oral azacitidine significantly improved OS independent of NPM1 and FLT3 status (HR: 0.7236; P = .00297). These important data confirm the role of oral azacitidine maintenance therapy in adults with AML in remission after chemotherapy ineligible for transplant. The question now is whether oral azacitidine offers an improved survival advantage vs proceeding to transplant in those who are eligible.

V‑FAST
CPX-351, a liposomal encapsulation of cytarabine and daunorubicin, has previously been shown to prolong survival compared with conventional cytarabine and daunorubicin (7+3) induction chemotherapy in older adults with secondary AML, particularly in patients who proceeded to transplant. In separate studies venetoclax has been shown to be well tolerated and associated with encouraging clinical responses when combined with intensive chemotherapy. The abstract presented by Pullarkat and colleagues at EHA 2021 is building on the supportive data with cytarabine and idarubicin combined with venetoclax from the CAVEAT trial. V-FAST assessed in patients with newly diagnosed AML the tolerability of CPX‑351 when combined with the FLT3 inhibitor midostaurin in those with FLT3 alteration, the IDH2 inhibitor enasidenib in those with IDH2 mutation, or venetoclax in those with wild-type FLT3 and IDH2. Preliminary results presented at the meeting suggest acceptable tolerability and encouraging CR rates with these combinations, albeit in a very small number of patients. The key takeaway from V‑FAST is that these combinations appear to be tolerable, supporting both further research efforts and an ongoing randomized phase III trial comparing standard chemotherapy vs CPX-351 and/or gilteritinib in patients with newly diagnosed AML with or without FLT3 mutations (NCT04293562).

Chronic Lymphocytic Leukemia (CLL)
Lydia Scarfò, MD:
ALPINE
In the first interim analysis of this randomized phase III trial presented at EHA 2021, zanubrutinib demonstrated significantly superior overall response rate (ORR) vs ibrutinib (78.3 vs 62.5%, respectively; 2-sided P =.0006) and better tolerability profile in patients with relapsed/refractory CLL/small lymphocytic lymphoma. Of note, only 11.1% of patients discontinued zanubrutinib (7.8% due to adverse event) vs 24.0% discontinuing ibrutinib (13.0% due to adverse event). Although ORR is not the optimal primary endpoint for studies of BTK inhibitors─which can achieve durable disease control without deep responses─the improved 12-month progression-free survival (PFS) rate with zanubrutinib vs ibrutinib (94.9% vs 84.0%; HR: 0.40; 2-sided P = .0007) and the lower rate of any grade atrial fibrillation and flutter (2.5% vs 10.1%) appear promising and need to be confirmed with longer follow-up, as this analysis was conducted after a median follow-up of 15 months. 

GLOW
Kater and colleagues presented the primary analysis of the phase III GLOW trial, demonstrating that for older and/or unfit patients with treatment-naive CLL, fixed-duration treatment with ibrutinib + venetoclax significantly reduced the risk of progression or death by 78.4% vs chlorambucil + obinutuzumab (median PFS: not reached vs 21.0 months; P <.0001). In addition, a higher rate of undetectable minimal residual disease (uMRD) was achieved with ibrutinib + venetoclax, although the rates of uMRD in bone marrow (51.9%) and peripheral blood (54.7%) at 3 months after treatment discontinuation were lower than those reported in younger patients treated with fixed-duration ibrutinib + venetoclax in the CAPTIVATE trial. Of note, almost 1 out of 4 patients (22.6%) prematurely discontinued ibrutinib + venetoclax, primarily due to adverse event (10.4%). Results from GLOW support the feasibility and benefit of a chemotherapy-free, fixed-duration therapy vs standard chemoimmunotherapy in older and/or unfit patients.

Multiple Myeloma (MM)
Maria-Victoria Mateos, MD, PhD:
Phase II KarMMa Trial
Results from the ongoing phase II KarMMa trial led the European Medicines Agency to recommend conditional marketing authorization for idecabtagene vicleucel (ide-cel), a BCMA-directed CAR T-cell therapy, to treat adults with relapsed/refractory MM after ≥3 prior therapies, including an immunomodulatory agent, a proteasome inhibitor, and an anti─CD38 antibody, whose disease has worsened since their last therapy. At the EHA 2021 virtual meeting, Oriol and colleagues reported longer-term data on ide-cel at a dose of 150-450 x 106 CAR T-cells in 128 patients with heavily pretreated MM. Among all treated patients, the ORR was 73%, including 33% in CR/stringent CR; the median PFS and OS were 8.6 and 24.8 months, respectively. There was 1 death due to cytokine-release syndrome, which occurred at low grade (grade: 1 or 2) in most patients (78%); 18% experienced ≥1 neurotoxicity event, which were all grade ≤3. These results were consistent regardless of prior lines of therapy, and with previous reports on ide-cel, providing further evidence supporting its role as a treatment option for our patients with heavily pretreated MM.

Phase Ib/IIa of Iberdomide in MM
The cereblon-targeting agent iberdomide is under investigation in the ongoing multicohort phase Ib/IIa CC-220-MM-001 trial. At EHA 2021, Lonial and colleagues presented interim results for 3 cohorts of patients with relapsed/refractory MM receiving iberdomide + dexamethasone and either daratumumab, bortezomib, or carfilzomib. All 3 combinations were associated with activity (ORR: 45.9% to 56.0%) in this heavily pretreated population, including patients with disease refractory to immunomodulatory agents, daratumumab, and proteasome inhibitors. Any-grade neutropenia was common (range: 33.3% to 69.2%), particularly in the iberdomide, dexamethasone, and daratumumab cohort. The incidence of nonhematologic treatment-emergent adverse events was low, and most were low grade. The investigators identified the recommended phase 2 dose in the iberdomide/dexamethasone/daratumumab cohort and dose evaluation continues in the other cohorts. These combinations are of clinical interest, and we look forward to additional data being presented for these novel combinations.

Remember to visit the Clinical Care Options Web site to download a slideset summarizing the data from these studies and for more coverage of blood disorders and hematologic malignancies.

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