During the 2021 American Society of Hematology annual meeting (ASH 2021), important results from several key clinical trials in malignant and nonmalignant hematologic diseases will be reported. Below, experts have highlighted their most anticipated abstracts, which will be covered online as a part of CCO’s Independent Conference Coverage of ASH 2021. As ASH 2021 unfolds, remember to check the CCO website often for downloadable slidesets summarizing the data from these studies and more, and then again after the meeting for CME-certified online activities featuring expert analyses and perspectives on the clinical implications of the new data.

Top Picks: Acute and Chronic Leukemias
Eunice S. Wang, MD, and B. Douglas Smith, MD, have identified key studies for patients with leukemias at ASH 2021. In acute myeloid leukemia (AML), numerous studies are reporting results of venetoclax in combinations for patients with newly diagnosed or relapsed/refractory (R/R) AML, including interim results from a phase II trial of venetoclax plus decitabine in younger adult patients (<60 years of age) with newly diagnosed, European LeukemiaNet adverse-risk AML. Grenet and colleagues will report on the outcomes comparison from a multicenter retrospective study of CPX-351 vs hypomethylating agent plus venetoclax as frontline therapy in patients with AML. The abstract for that study indicates a favorable survival benefit favoring CPX-351 in the overall cohort and in clinically relevant subgroups. Yilmaz and colleagues will report on data from a study of quizartinib with decitabine and venetoclax in patients with FLT3-ITD–mutated AML showing activity in heavily pretreated and FLT3 inhibitor–exposed disease. Also, in FLT3-ITD–mutated AML, final response and survival endpoints will be presented from a multicenter phase Ib trial of venetoclax plus gilteritinib in R/R AML showing high rates of complete response plus complete responses with incomplete platelet recovery and FLT3 mutation clearance in most patients with prolonged survival. We will also see data from the phase III study of gilteritinib plus azacitidine vs azacitidine monotherapy for patients with AML and the FLT3 mutation ineligible for intensive induction therapy. Montesinos and colleagues will report data from the phase III AGILE trial, examining the safety and efficacy of the IDH1 inhibitor ivosidenib combined with azacitidine vs azacitidine plus placebo as first-line therapy in patients with AML and the IDH1 mutation.

In acute lymphoblastic leukemia (ALL), researchers will provide first results from the measurable residual disease–stratified, risk-adapted GMALL Trial 08/2013 in adults with newly diagnosed ALL/lymphoblastic lymphoma treated with multiple therapies.

Additional studies to watch in acute and chronic leukemias:

• Venetoclax in combination with hypomethylating agents in patients with AML and poor-risk cytogenetics (Abstract 224) 
• 48-week update results from phase III ASCEMBL evaluating safety and efficacy asciminib vs bosutinib in patients with chronic myeloid leukemia in chronic phase (Abstract 310)
• A phase Ib/II trial evaluating azacitidine with venetoclax and magrolimab triplet in 38 patients with newly diagnosed, older/unfit, or high-risk AML and in patients with R/R AML (Abstract 371)
• An analysis of low-dose (50 mg/day) vs standard-dose (100 mg/day) dasatinib as frontline therapy in patients with chronic myeloid leukemia in chronic phase (Abstract 631)

Top Picks: Lymphomas
John M. Burke, MD, and Peter Martin, MD, have selected numerous key studies in lymphomas to be presented at ASH 2021 with the potential to change the standard of care (SoC) for these diseases. For decades, R-CHOP has been the standard chemoimmunotherapy treatment for patients with advanced diffuse large B-cell lymphoma (DLBCL), and many attempts to improve upon R-CHOP have failed. The phase III POLARIX study is comparing polatuzumab vedotin with R-CHP (pola-R-CHP) vs R-CHOP in previously untreated DLBCL. Data from the abstract to be presented at ASH suggest an improvement in progression-free survival favoring pola-R-CHP with only modest changes in the toxicity profile, but no overall survival benefit was observed. According to the experts, the pola-R-CHP regimen will become a new standard option for patients with advanced DLBCL. Locke and colleagues will report the primary results from the phase III ZUMA-7 trial of axicabtagene ciloleucel CAR T-cell therapy vs SoC salvage chemotherapy and autologous stem cell transplant (ASCT) in patients with DLBCL who had relapsed within 12 months of initial chemoimmunotherapy and who were, therefore, at elevated risk of an unfavorable outcome from the latter approach. Data to be presented at ASH suggest improvement in the primary endpoint of event-free survival. The pivotal phase III TRANSFORM study, which has a similar design to that of ZUMA-7, is comparing the efficacy and safety of lisocabtagene maraleucel CAR T-cell therapy to SoC of chemoimmunotherapy followed by ASCT in patients with DLBCL who had relapsed within 12 months of initial chemoimmunotherapy. The abstract for that study also suggests improvement in event-free survival, progression-free survival, and complete response rate. Based on the encouraging results for these 2 large phase III studies of CAR T-cell therapy, experts are of the opinion that axicabtagene ciloleucel or lisocabtagene maraleucel therapy may become a new standard approach for patients whose DLBCL relapses within 1 year of their initial chemoimmunotherapy. Bishop and colleagues will report data from the phase III BELINDA trial of tisagenlecleucel CAR T-cell therapy vs SoC as second-line treatment in 322 patients with primary refractory or aggressive B-cell non-Hodgkin lymphoma who experienced progression within 12 months of first-line therapy.

In the setting of heavily pretreated follicular lymphoma (FL), Budde and colleagues will report promising results from a pivotal phase I/II study of mosunetuzumab, an anti-CD20 and anti-CD3 bispecific antibody used to redirect T-cells to eliminate malignant B-cells, in 90 patients with relapsed FL and a media of 3 previous therapies (range: 2-10). The abstract to be presented at ASH shows deep and durable remission rates with mosunetuzumab monotherapy, including in patients who had experienced disease progression within 24 months from start of initial therapy. Thieblemont and colleagues will present efficacy data from a phase II trial of tisagenlecleucel in 97 patients with R/R FL who had received at least 2 previous therapies or with disease relapse after ASCT. The abstract for that study reports a high (86%) and durable response rate in the 94 patients evaluable for the primary efficacy analysis. Finally, Lynch and colleagues will report on the efficacy and safety data from the phase II CITADEL-203 study of parsaclisib in 126 patients with R/R FL and at least 2 previous therapies.

Additional studies to watch in lymphomas: 

• First prospective data on measurable residual disease from phase III GLOW study: fixed-duration ibrutinib plus venetoclax vs chlorambucil plus obinutuzumab as frontline treatment for older or unfit patients with chronic lymphocytic lymphoma (CLL) (Abstract 70)
• Interim results from phase II SEQUOIA study of zanubrutinib vs bendamustine plus rituximab in patients with treatment-naive CLL/small lymphocytic lymphoma (Abstract 396)
• Initial results from the double-hit lymphoma cohort from the randomized phase II/III A051701 study of DA-EPOCH-R chemoimmunotherapy plus venetoclax (Abstract 523)
• Prospective multicenter phase study of next-generation immunosequencing assay for early detection of molecular relapse in 500 patients with DLBCL (Abstract 52)
• Primary analysis from the BTK inhibitor–naive cohort of phase II CITADEL-205 study in patients with R/R mantle cell lymphoma receiving parsaclisib monotherapy (Abstract 382)
• 2-year, postrandomization, disease-free survival results in the measurable residual disease cohort from phase II CAPTIVATE study evaluating first-line ibrutinib plus venetoclax for CLL (Abstract 68)
• Primary analysis results from the pivotal phase II study of valemetostat in Japanese patients with R/R adult T-cell leukemia/lymphoma (Abstract 303)
• 3-year follow-up from the phase III ASCEND study: acalabrutinib vs rituximab plus idelalisib or bendamustine in R/R CLL (Abstract 393)
• Characterization of BTK inhibitor–related adverse events from a head-to-head trial of acalabrutinib vs ibrutinib in 533 patients with previously treated CLL (Abstract 3721)

Top Picks: Multiple Myeloma
Shaji Kumar, MD, and Sagar Lonial, MD, have selected several exciting studies in multiple myeloma (MM) at ASH 2021. These include an update from the phase II GRIFFIN trial in newly diagnosed MM, which assessed first-line daratumumab plus VRd vs VRd alone followed by ASCT and maintenance therapy with either daratumumab plus lenalidomide or lenalidomide alone. These data will reinforce the initial conclusions and provide longer-term insight into the use of daratumumab/lenalidomide maintenance. We will also see results from the phase III GMMG-HD7 study of isatuximab plus VRd vs VRd alone in ASCT-eligible patients with newly diagnosed MM, with the primary endpoint of measurable residual disease negativity after induction therapy.

Also to be presented at the meeting are results from the Spanish GEM2014MAIN trial evaluating ixazomib plus Rd vs Rd maintenance in newly diagnosed MM. In addition, Kaufman and colleagues will report on the safety and preliminary efficacy from the expansion cohort of the phase I/II study of venetoclax plus daratumumab and dexamethasone vs daratumumab plus bortezomib and dexamethasone in patients with t(11;14) translocation R/R MM.

As in recent years, multiple studies will present data for anti-BCMA–targeted therapies including a phase I/II trial showing deep and durable responses with the bispecific antibody REGN5458. With the influx of potential anti-BCMA therapies available for patients with R/R MM, additional novel targets are also being explored. Data will be presented from the phase I MonumenTAL-1 trial of single-agent talquetamab, a bispecific antibody that binds to GPRC5D in R/R MM. Data from a phase I trial will be presented and will show a first glimpse of a novel CAR T-cell therapy targeting GPRC5D, MCARH109, for R/R MM. We will also see updated results from the phase I trial of cevostamab, a FcRH5xCD3 bispecific antibody, which has continued to show clinically meaningful activity for patients with R/R MM. Also to be presented at the meeting are results from the dose-expansion portion of the phase I/II study of iberdomide, a potent novel cereblon E3 ligase modulator, in combination with dexamethasone in patients with heavily pretreated, triple class–exposed R/R MM.

Additional studies to watch in MM: 

• Final overall survival results from the phase III BELLINI trial with venetoclax or placebo in combination with bortezomib/dexamethasone in R/R MM (Abstract 84)
• Updated results of the CARTITUDE-1 trial with ciltacabtagene autoleucel in R/R MM (Abstract 549)
• Updated results from phase I/II MajesTEC-1 with the bispecific antibody teclistamab in R/R MM (Abstract 896)
• First-in-human phase I trial of TNB-383B, an anti-BCMA and anti-CD3 T-cell–engaging bispecific antibody, in patients with R/R MM (Abstract 900)
• Open-label, single-center phase I/II trial of belantamab mafodotin in combination with Rd in transplant-ineligible MM (Abstract 2736)
• DREAMM-9 trial of belantamab mafodotin in combination with VRd (Abstract 2738)

Top Picks: Myelodysplastic Syndromes/Myeloproliferative Neoplasms
Amy E. DeZern, MD, MHS, and Srdan Verstovsek, MD, PhD, have identified several highly anticipated studies in myelodysplastic syndromes (MDS) and myeloproliferative neoplasms (MPNs) to be presented at ASH 2021. For MDS, Bernard and colleagues will present data on the molecular International Prognosis Scoring System that has been validated in 3675 patients with MDS. Of importance, this system incorporates molecular data formally for prognostication, which other MDS prognostic scoring systems have not. In addition, data will be presented from a phase Ib study of sabatolimab (MBG453), a novel immuno-myeloid therapy targeting TIM-3, plus hypomethylating agents in patients with very high–risk/high-risk MDS (N = 53) and newly diagnosed AML (N = 48). The abstract indicates that the combination of sabatolimab and hypomethylating agents is safe and effective with durable clinical responses seen in patients with very high–risk/high-risk MDS and newly diagnosed AML. We will also see data with CPX-351 (daunorubicin and cytarabine liposome for injection) in a phase I pilot study in transplant eligible, higher-risk patients with MDS (N = 19) and a phase II study in 31 patients with higher-risk MDS who were previously untreated with hypomethylating agents or chemotherapy and who were 70 years of age or younger. Finally, Sekeres and colleagues will report on the phase III PANTHER study of pevonedistat plus azacitidine vs azacitidine alone as first-line treatment in patients with higher-risk MDS/chronic myelomonocytic leukemia or AML with 20% to 30% marrow blasts.

In myelofibrosis, updated clinical and translational data will be presented from the phase II MANIFEST trial investigating pelabresib (CPI-0610) monotherapy in patients with advanced myelofibrosis who are intolerant/refractory to or ineligible for ruxolitinib and have a poor prognosis. In polycythemia vera (PV), Hoffman and colleagues will present data from a phase II trial of rusfertide (PTG-300) in 63 patients with PV who had at least 3 phlebotomies with or without concurrent cytoreductive therapy to maintain hematocrit <45% within the 24 week of treatment. Of importance, the primary goal of therapy for PV is to maintain hematocrit <45%, which is proven to decrease thrombotic risk and associated mortality in patients with PV. Data from this abstract indicate that, following initiation of rusfertide, therapeutic phlebotomy was essentially eliminated with hematocrit maintained consistently <45% with a reduction in red blood cell counts and an increase in mean corpuscular volume and mean corpuscular hemoglobin values. In myeloid/lymphoid neoplasms, Gotlib and colleagues will report data from the multicenter phase II FIGHT-203 trial of pemigatinib in adult patients with myeloid/lymphoid neoplasms, an 8p11 chromosomal abnormality, and at least 1 previous therapy. Of note, the abstract indicates a very high rate of complete and partial responses in this aggressive form of MPN.

Additional studies to watch in MDS/MPNs: 

• Safety and efficacy results from a phase II study of lenalidomide and eltrombopag as treatment for patients with low-risk or intermediate-risk MDS (Abstract 65)
• Study of molecular responses across mutational spectrum in treatment-naive patients with higher-risk MDS who received venetoclax plus azacitidine (Abstract 241)
• Study reporting outcomes for venetoclax in combination with hypomethylating agents in patients with higher-risk MDS (Abstract 536)

Top Picks: Nonmalignant Hematologic Disorders
Sujit Sheth, MD, and Mark A. Schroeder, MD, have identified key studies in hemoglobinopathies and graft-vs-host disease (GVHD) with the potential to change clinical practice. In hemophilia, highly anticipated results will be presented from a plenary session abstract from the multicenter phase III ATLAS-INH study of fitusiran, an investigational siRNA therapeutic targeting antithrombin, as prophylaxis in patients with hemophilia A or B (N = 57). Data from the abstract suggest that this study provides evidence to support an alternative, noncoagulation factor–based prophylactic treatment for patients with both FVIII and FIX inhibitors. There is currently one similar nonfactor–based treatment for FVIII deficiency—emicizumab—but no such approach for patients with FIX inhibitor patients. Moreover, the abstract reports good efficacy and a tolerable safety profile, without increased risk of thrombosis. In a related abstract, Srivastava and colleagues will present efficacy and safety data from the phase III ATLAS-A/B study of fitusiran prophylaxis vs on-demand treatment with factor concentrates in patients with hemophilia A or B without inhibitors. The study met its key primary endpoint of reducing annualized bleeding rate in the efficacy period (Day 29 after fitusiran first-dose up to Day 246), and secondary endpoints of reducing annualized spontaneous bleeding, annualized joint bleeding rate, and improved health-related quality of life in the treatment period. Experts comment that having additional options for the treatment of patients with hemophilia using FVIII and FIX inhibitors is a major step forward in advancing care. 

In sickle cell disease (SCD), we will see data from the phase I study of etavopivat, an allosteric activator of pyruvate kinase-R, reporting a reduction in markers of inflammation, hypercoagulability, and tissue hypoxia, and for the phase I study of mitapivat (AG-348) in adult patients with SCD reporting evidence of increased ATP, increased hemoglobin levels, and decreased markers of hemolysis, suggesting that the red cells in these individuals are turning over less rapidly. Both of these studies provide evidence to support the proposed mechanism of increasing pharmacokinetic activity in red cells in patients with SCD. The need for additional treatment options for patients with SCD, used alone or in combination for potential additive or synergistic effects, will advance care and potentially increase life expectancy for these individuals. 

Several new promising therapies for chronic and acute GVHD are advancing clinical development and are being reported at the ASH annual meeting. In chronic GVHD, Lee and colleagues will report on the safety and tolerability from a phase II of axatilimab, a CSF-1R humanized antibody, in 40 patients aged 6 years or older with active disease despite at least 2 prior lines of systemic therapy. The abstract for that study indicates an encouraging response rate of 66% in 25 of 38 patients evaluable for response. Koshy and colleagues report data from a phase II trial of abatacept, a recombinant fusion protein of CTLA-4 extra cellular domain linked to a modified Fc portion of human IgG1, in 39 patients with steroid-refractory chronic GVHD with multisystem involvement including skin, mouth, eyes, and gastrointestinal track. The abstract for that study also shows a promising response rate of 49% in 19 of 39 patients.

In paroxysmal nocturnal hematuria (PNH), Jang and colleagues will report on a phase II study of iptacopan (LN023), a novel, oral, selective, and potent first-in-class inhibitor of factor B, as monotherapy for patients with PNH. In a previous report, iptacopan was shown to effectively control intravascular and extravascular hemolysis, leading to rapid infusion-free improvement in hemoglobin levels in most patients treated. Data to be presented at ASH 2021 confirm those data and show that iptacopan leads to rapid and durable improvement in markers of hemolysis with a meaningful and sustainable clinical benefit based on improvement in hemoglobin. Data from this study support initiation of a phase III trial evaluating iptacopan as frontline therapy for patients with PNH. 

Additional studies to watch in nonmalignant hematologic disorders: 

• Initial safety and efficacy results from the phase II SOLACE-Kids trial of crizanlizumab, humanized monoclonal antibody that blocks P-selectin, in adolescents with SCD (Abstract 12)
• Phase II study of urinary-derived human chorionic gonadotropin/epidermal growth factor plus standard therapy for acute GVHD (Abstract 261)
• Secondary analysis of amphiregulin as a monitoring biomarker from 2 prospective clinical trials of urinary-derived human chorionic gonadotropin/epidermal growth factor for patients with steroid-refractory life-threatening acute GVHD treated (Abstract 256)

Remember to Check the CCO Website Often During and After ASH!
These are just a few of the interesting and important abstracts selected by our expert faculty from ASH 2021. Downloadable slideset summaries of these studies and more will be available on our website as the data are released. After the meeting, comprehensive analyses by our expert faculty members will explore the clinical implications of the data in CME-certified text-based modules.