Carfilzomib, Dexamethasone, and Daratumumab Versus Carfilzomib and Dexamethasone for the Treatment of Patients with Relapsed or Refractory Multiple Myeloma (RRMM): Primary Analysis Results from the Randomized, Open-Label, Phase 3 Study Candor

Inhibition of Complement C1s with Sutimlimab in Patients with Cold Agglutinin Disease: Results from the Phase 3 Cardinal Study

The QUAZAR AML-001 Maintenance Trial: Results of a Phase III International, Randomized, Double-Blind, Placebo-Controlled Study of CC-486 (Oral Formulation of Azacitidine) in Patients with Acute Myeloid Leukemia in First Remission

Validation of BCL11A As Therapeutic Target in Sickle Cell Disease: Results from the Adult Cohort of a Pilot/Feasibility Gene Therapy Trial Inducing Sustained Expression of Fetal Hemoglobin Using Post-Transcriptional Gene Silencing

A Randomized Phase 3 Trial of Blinatumomab Vs. Chemotherapy As Post-Reinduction Therapy in High and Intermediate Risk First Relapse of B-ALL in Children and Adolescents/Young Adults Demonstrates Superior Efficacy and Tolerability of Blinatumomab

Primary Analysis Results from the Randomized, Open-Label, Phase 3 Study Candor

The use of lenalidomide (LEN) and bortezomib (BTZ) in newly diagnosed multiple myeloma (MM) patients (pts), along with continuous or maintenance therapy paradigm have improved survival outcomes. However, many pts progress while on these agents or discontinue them due to toxicity. There is a need for novel, efficacious, and tolerable regimens that can treat MM pts who are exposed or refractory to LEN or BTZ. The proteasome inhibitor carfilzomib and the anti-CD38 monoclonal antibody daratumumab have both been approved as single agents or as components of combination regimens for the treatment of RRMM. The combination of carfilzomib, dexamethasone, and daratumumab has been shown to be efficacious and safe in RRMM in the phase 1 study MMY1001 (Chari, Blood 2019). We present results from the primary analysis of CANDOR, a multicenter, phase 3, randomized study comparing carfilzomib, dexamethasone, and daratumumab (KdD) vs carfilzomib and dexamethasone (Kd) in RRMM pts.

Novelties on the treatment of non-Hodgkin lymphoma

Prof. Umberto Vitolo summarized several topics regarding lymphoma.

Inhibition of Complement C1s with Sutimlimab in Patients with Cold Agglutinin Disease: Results from the Phase 3 Cardinal Study

CAD is a rare autoimmune hemolytic anemia with an estimated prevalence of 16 per 1 million. Hemolysis is driven by activation of the classical complement pathway (CP), resulting in erythrocyte opsonization with predominant extravascular destruction and ensuing anemia. Patients with CAD have an increased early mortality and risk of thromboembolism. There are no approved treatments. Sutimlimab (formerly BIVV009) is a first-in-class humanized monoclonal anti-C1s antibody that selectively inhibits the C1 complex of complement, preventing CP activation, while leaving the alternative and lectin pathways intact. The objective of the Cardinal study (NCT03347396) is to assess efficacy and safety of sutimlimab in adults with CAD who have a recent history of transfusion.

The QUAZAR AML-001 Maintenance Trial: Results of a Phase III International, Randomized, Double-Blind, Placebo-Controlled Study of CC-486 (Oral Formulation of Azacitidine) in Patients with Acute Myeloid Leukemia in First Remission

Many older patients (pts) with AML respond to intensive induction chemotherapy (IC), but responses are often short-lived and overall survival (OS) is poor. The benefit of post-remission maintenance treatment (Tx) for pts with AML is unclear, as no therapy has shown to significantly improve OS. CC-486 is an oral hypomethylating agent that allows for prolonged drug exposure during each Tx cycle to sustain therapeutic activity. We hypothesized that prolonged Tx with CC-486 could be effective as post-remission maintenance in AML. Herein, we report the primary results of QUAZAR AML-001 (NCT01757535), a phase III international, randomized, double-blind, placebo (PBO)-controlled study evaluating CC-486 as maintenance therapy in pts aged ≥55 years with AML in first remission following IC.

Validation of BCL11A As Therapeutic Target in Sickle Cell Disease: Results from the Adult Cohort of a Pilot/Feasibility Gene Therapy Trial Inducing Sustained Expression of Fetal Hemoglobin Using Post-Transcriptional Gene Silencing

BCL11A regulates the fetal-adult hemoglobin switch by repressing expression at the gamma (γ)-globin locus (Sankaran et al., Science, 2008), and thus it represents an appealing therapeutic target for sickle cell disease (SCD). BCH-BB694 is a lentiviral vector (LVV) encoding a shRNA targeting BCL11A embedded in a microRNA scaffold (shmiR) allowing erythroid-specific knockdown to induce γ-globin expression and concomitantly and coordinately repress β-sickle globin expression (Brendel et al. JCI, 2016). In a pilot and feasibility gene therapy study we are evaluating the safety of infusion of BCH-BB694-transduced autologous CD34+ cells in patients with severe SCD. The study is an IND enabled and IRB approved open label, non-randomized, single center trial (NCT 03282656).

Clinical Impact of Ibrutinib with R-CHOP in Untreated Non-GCB DLBCL Co-Expressing BCL2 and MYC Genes in the Phase 3 Phoenix Trial

In the phase 3, double-blind, placebo (pbo)-controlled PHOENIX trial (NCT01855750), 838 patients (pts) with non-germinal center B-cell-like (non-GCB) diffuse large B-cell lymphoma (DLBCL) were randomized 1:1 to ibrutinib (IBR; 560 mg/day orally) + rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) or pbo + R-CHOP. IBR + R-CHOP did not improve event-free survival (EFS) in the intent-to-treat (ITT) non-GCB population (hazard ratio [HR] 0.934; 95% confidence interval [CI], 0.726-1.200). However, in an exploratory analysis, pts < 60 years benefited from the addition of IBR (HR 0.579; 95% CI, 0.380-0.881 for EFS), whereas pts ≥ 60 years did not (HR 1.228; 95% CI, 0.887-1.699 for EFS) due to increased toxicity and reduced R-CHOP exposure. Based on evidence that co-expression of BCL2 and MYC by immunohistochemistry (IHC) have a worse outcome with R-CHOP, we examined their clinical prognostic effect in the 2 arms of the PHOENIX trial.

Special Education Session on ASH Clinical Practice Guidelines on Venous Thromboembolism

VTE was selected as the first condition for which ASH would develop guidelines because it is a commonly encountered clinical concern for hematologists and for other medical specialties and disciplines, including emergency medicine, internal medicine, surgery, oncology, and pharmacology.

Novelties on the treatment of follicular lymphoma

Prof. Kai Hübel summarized several topics regarding follicular lymphoma. - Are there any new treatment priorities in first line follicular lymphoma beside immunochemotherapy? - Will there be a chance to replace chemotherapy by chemofree regimen in relapsed follicular lymphoma? - What would be the best approach to early relapse follicular lymphoma?

A Multicenter Study of Ibrutinib Resistance Development and Intervention with Venetoclax in Patients with Chronic Lymphocytic Leukemia

Ibrutinib (ibr) for the treatment of chronic lymphocytic leukemia (CLL) has improved progression-free survival (PFS) compared to other treatments, especially in high-risk patients (pts). However, resistance occurs and is associated with mutations in the drug binding target (BTK) and its immediate downstream target (PLCg2). These ibr resistance mutations (IRmut) are detectable months prior to developing progressive disease (PD) and predict clinical relapse. Prospectively determining the time from starting ibr to development of IRmut and from IRmut detection to PD will improve our understanding of how to manage these patients. Venetoclax (ven) is highly effective after ibr and decreases IRmut. Adding ven to ibr for ibr resistance is a rational choice as this combination is safe and effective in CLL. Adding an agent rather than stopping ibr avoids disease flare associated with ibr discontinuation. This phase 2 study was designed to follow CLL pts taking ibr and at high risk for resistance (observation cohort) and to test ven in combination with ibr for those who develop PD (intervention cohort). This will determine: the incidence of IRmut and PD in this population, the ORR with ibr/ven, and the ability of this combination to eliminate IRmut.

Evaluating Luspatercept Responders in the Phase 3, Randomized, Double-Blind, Placebo-Controlled BELIEVE Trial of Luspatercept in Adult Beta-Thalassemia Patients Who Require Regular Red Blood Cell Transfusions

β-thalassemia is an inherited hemoglobinopathy characterized by ineffective erythropoiesis and anemia. Luspatercept is a first-in-class erythroid maturation agent that binds to select TGF-β superfamily ligands to reduce aberrant Smad2/3 signaling and enhance late-stage erythropoiesis. We aim to evaluate in detail the number of response episodes, duration of clinical benefit, and safety in luspatercept responders during the phase 3 BELIEVE study (NCT02604433).

Treatment of multiple myeloma

Prof. Shaji Kumar speaks about several new studies presented, which are likly to lead the changes in the treatment paradigm on the next 2-5 years.

Phase II Trial of Ixazomib and Dexamethasone Versus Ixazomib, Dexamethasone and Lenalidomide, Randomized with NFKB2 Rearrangement. (Proteasome Inhibitor NFKB2 Rearrangement Driven Trial, PINR)

Proteasome inhibitors (PI) and immunomodulatory drugs have become the backbone of therapy for multiple myeloma (MM). The oral boron-containing selective and reversible proteasome inhibitor ixazomib has shown to induce deep and durable responses (Kumar RK et la, Blood 2016. 128(20):2415-2422). Triplets containing ixazomib, has shown to be more efficacious than doublet regimens in the relapse setting (Moreau P, et al. N Engl J Med 2016. 374:1621-1634).However, to date there is not companion diagnostics capable of predicting PI response. We have recently discovered that MM patients resistant to PI lack of the ankyrin (ANK) and death domain (DD) present in the 3'-end of NFKB2. Loss of NFKB2 3'end frequently resulted from a structural rearrangements. We found that NFKB2-ANK and -DD are crucial at initiating bortezomib's apoptotic signal by facilitating caspase-8 activation. Activation of this caspase resulted from NFKB2 interaction with FADD/caspase-8/p62 (unpublished data). Based on this findings, we design this study to examine the efficacy of NFKB2 break apart FISH to predict the response to the duplet ixazomib and dexamethasone (Id) vs ixazomib, lenalidomide and dexamethasone (IRd) in early relapse MM patients (1-3 lines of therapy).

Targeting Apoptosis in Myeloma

Prof. Wee-Joo Chng summarize the key points form the sessions on ASH 2019 on targeting apoptosis in Myeloma.

Lower Risk MDS – Transfusion Dependence

Cardiovascular disease (CVD) is an important cause of morbimortality in patients with low risk myelodysplastic syndrome (LR-MDS). Up to 70% of patients suffer cardiovascular events and heart disease is the second cause of death in this context. Cardiac damage etiology is complex and multifactorial in this group of patients. Iron overload cardiomyopathy (IOC) due to transfusion dependency is the most well identified factor in this setting, however other circumstances such as vascular aging, cardiac reserve reduction and high cardiac output related to chronic anemia, among others, play an important role in this population. Thus, despite its importance in MDS patients, prognostic cardiovascular predictive factors are not adequately identified, and cardiac monitoring in these patients is not sufficiently stablished. Therefore, our objectives were to determinate the prevalence and characterization of CVD in LR-MDS patients, to analyze their mortality and cardiovascular prognosis and to identify predictors of cardiovascular events or death (combined event, CE) in this setting.

Rivaroxaban for Treatment of Pediatric Venous Thromboembolism. an Einstein-Jr Phase 3 Dose-Exposure-Response EvaluationClinically Relevant Abstract

Recently, the randomized EINSTEIN-Jr study showed similar efficacy and safety for rivaroxaban and standard anticoagulation for treatment of pediatric venous thromboembolism (VTE). The rivaroxaban dosing strategy was established based on phase 1 and 2 data in children and through pharmacokinetic (PK) modeling.

RRMM and immunomodulators

Prof. Dominik Dytfeld speaks about the changes of the treatment of MM.