An Expert’s Guide to ASH 2020: A Preview of the Top Abstracts

During the 2020 ASH virtual annual meeting, important results from many 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 2020. As the ASH meeting unfolds, remember to check the CCO Web site 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: Chronic Lymphocytic Leukemia (CLL) and Lymphomas
John M. Burke, MD, and Jeff P. Sharman, MD, have identified several key studies in CLL and lymphomas to be presented at ASH 2020. The first is the phase III Unity-CLL study comparing umbralisib plus ublituximab (U²) vs obinutuzumab plus chlorambucil in patients with treatment-naive and relapsed/refractory (R/R) CLL—with a primary endpoint of PFS by independent review. Key findings from this trial will be presented, showing superior efficacy with U² compared with obinutuzumab plus chlorambucil in both treatment-naive and R/R CLL, and a more favorable safety profile for umbralisib compared with other PI3K inhibitors. This study is likely to lead to the FDA approval of both umbralisib and ublituximab for patients with CLL.

Another key finding in CLL/small lymphocytic lymphoma (SLL) will be presented from the measurable residual disease (MRD) cohort of the multicenter phase II CAPTIVATE study of frontline ibrutinib plus venetoclax. In this cohort, patients with confirmed undetectable MRD were randomized to receive additional treatment with ibrutinib or placebo, whereas those with detectable MRD were randomized to ibrutinib or ibrutinib/venetoclax; 1-year disease-free survival will be presented for the MRD cohort. The BRUIN study will report data for the next-generation, highly selective, noncovalent BTK inhibitor LOXO-305 in patients with heavily pretreated CLL/SLL, including those with a BTK inhibitor resistance mutation (BTK-C481).Preliminary efficacy and safety data from the phase I/II TRANSCEND CLL 004 study of lisocabtagene maraleucel in patients with R/R CLL/SLL with progression on, or prior exposure to, ibrutinib will be presented.

In the setting of heavily pretreated B-cell malignancies, Bannerji and colleagues will report on promising updated efficacy data for the phase I trial of odronextamab, a novel bispecific antibody targeting CD3 and CD20. The study is evaluating odronextamab doses ranging from < 5 mg to ≥ 80 mg in 127 patients with highly refractory non-Hodgkin lymphoma (NHL), including diffuse large B-cell lymphoma with or without previous CAR T-cell therapy. The abstract suggests significant single-agent activity in refractory NHL, with particularly high responses in patients with follicular lymphoma (FL).  Jacobson and colleagues will present data for the primary analysis of ZUMA-5, which evaluated axicabtagene in 146 patients with heavily pretreated R/R FL or marginal zone lymphomas (MZL). Finally, Zinzani and colleagues will be reporting on the final analysis of the phase II global Unity-NHL study of umbralisib in previously treated indolent NHL (MZL: ≥ 1 previous line, including anti-CD20 therapy; FL or SLL: ≥ 2 previous lines, including anti-CD20 and alkylator therapy).

Additional studies to watch in lymphoma:

• A 5-year update of MURANO: subset analysis of fixed-duration venetoclax plus rituximab in R/R CLL (Abstract 125)
• Safety and preliminary efficacy from TRANSCEND NHL 001 assessing lisocabtagene maraleucel in patients with R/R mantle cell lymphoma (Abstract 118)
• Phase II study of brentuximab vedotin alone or in combination in older patients with classical Hodgkin lymphoma (Abstract 471)
• A pooled analysis of cardiovascular events with acalabrutinib monotherapy in patients with CLL (Abstract 3146)

Top Picks: Leukemias
Eunice S. Wang, MD, and Jorge Cortes, MD, have identified key studies for patients with leukemias at ASH 2020. In newly diagnosed acute myeloid leukemia (AML), final results will be presented for the phase I study of gilteritinib plus 7+3 induction and high-dose cytarabine consolidation chemotherapy and as single-agent maintenance therapy. Health-related quality-of-life data will be reported from the phase III QUAZAR AML-001 study of hypomethylating agent CC-486 as maintenance therapy in 225 patients with AML and intermediate-risk or poor-risk cytogenetics. In addition, data from a phase I/II study of flotetuzumab in patients with AML and with primary induction failure and early relapse—a population with poor prognosis and high unmet medical need—will be presented.

In chronic myeloid leukemia (CML), Hochhaus and colleagues will present a highly anticipated late-breaking abstract on the phase III ASCEMBL study assessing safety and efficacy of the STAMP inhibitor asciminib vs bosutinib in 233 patients with chronic-phase CML. In acute lymphoblastic leukemia (ALL), the phase II study of blinatumomab and sequential high-dose chemotherapy in adults with Philadelphia chromosome–negative B-cell ALL evaluated the potential for decreasing the need for intensive chemotherapy in these patients. The abstract shows encouraging results, with 28 patients with active disease at study entry achieving CRs and 33 of 34 overall achieving MRD negativity.

Additional studies to watch in leukemia:

• 2 abstracts reporting on the efficacy, safety, and outcome by mutation status and line of therapy for ponatinib in patients with CML in chronic phase (Abstract 647 and Abstract 48)
• Safety and durable molecular responses in the phase I study of asciminib in chronic-phase CML with the T315I mutation (Abstract 650)
• Phase Ib results for the anti-CD47 monoclonal antibody magrolimab plus azacitidine in AML (Abstract 330)
• Efficacy and safety results from phase III QUAZAR AML-001 study using escalated 21-day dosing of CC-486 in patients with AML at risk of early relapse (Abstract 111)

Top Picks: Multiple Myeloma
Shaji Kumar, MD, and Sagar Lonial, MD, have selected several exciting studies in multiple myeloma (MM) at ASH 2020. These include updates from GRIFFIN and MAIA trials in newly diagnosed MM; the updates from the phase II GRIFFIN study (first-line daratumumab plus bortezomib/lenalidomide/dexamethasone [VRd] vs VRd alone in autologous stem cell transplantation [ASCT]–eligible patients) may reinforce the initial conclusions and provide insight into the use of daratumumab/lenalidomide maintenance, whereas the updates from the phase III MAIA trial (first-line daratumumab plus lenalidomide/dexamethasone [Rd] vs Rd alone in ASCT-ineligible patients) will include analysis of PFS2 and efficacy in patients with high-risk cytogenetics. Data from the phase III APOLLO study assessing SQ daratumumab plus pomalidomide/dexamethasone vs pomalidomide/dexamethasone in R/R MM will be presented, supporting the use of SQ daratumumab with pomalidomide/dexamethasone—possibly one of the most commonly used salvage regimens in MM. Multiple studies will present data for novel anti-BCMA–targeted therapies including an antibody–drug conjugate (MEDI2228), several bispecific antibodies (teclistamab, talquetamab, REGN5458, TNB-383B), a bispecific T-cell engager (AMG 701), and CAR T-cell therapies (ciltacabtagene autoleucel, CT053, P-BCMA-101).

Also to be presented at the meeting are the final analysis from the phase III TOURMALINE-MM2 study of ixazomib plus Rd vs Rd alone in newly diagnosed MM; the primary analysis of the phase I study of iberdomide, a potent novel cereblon E3 ligase modulator, in combination with either daratumumab and dexamethasone or bortezomib and dexamethasone in R/R MM; and part 1 of the phase I dose finding study of belantamab mafodotin with pomalidomide and dexamethasone in R/R MM.

Additional studies to watch in MM:

• Phase I/II study of once weekly selinexor, pomalidomide, and dexamethasone vs pomalidomide and dexamethasone alone in R/R MM (Abstract 726)
• First-in-human phase I study of allogeneic (off the shelf) anti-BCMA ALLO-715 and anti-CD52 CAR T-cell therapy in R/R MM (Abstract 129)

Top Picks: Myelodysplastic Syndromes (MDS)/Myeloproliferative Neoplasms (MPNs)
Amy E. DeZern, MD, MHS, and Srdan Verstovsek, MD, PhD, have identified some highly anticipated studies in MDS and MPNs, respectively, to be presented at ASH 2020. For MDS, the multicenter, phase II, biologic assignment BMTCTN1102 study is comparing reduced-intensity conditioning allogeneic hematopoietic cell transplantation vs hypomethylating therapy or best supportive care in 384 patients aged 50-75 years with higher-risk advanced MDS. The abstract for this study suggests a significant OS benefit at 3 years in the donor arm vs the no-donor arm. In addition, we will see data from the P-2001 study of pevonedistat plus azacitidine vs azacitidine alone in 67 patients with higher-risk MDS/chronic myelomonocytic leukemia (CMML) or low-blast AML from the intention-to-treat cohort (n = 120). The combination therapy increased the event-free survival and OS in these high-risk patients, and this study supported initiation of the ongoing confirmatory phase III PANTHER study in the same patient population. Another key study to be reported in CMML is the European Myelodysplastic Syndromes Cooperative Group randomized phase III DACOTA study comparing treatment with decitabine or hydroxyurea (HU) in 170 patients with proliferative CMML (WBC ≥ 13 x 10⁹/L).] In polycythemia vera (PV), long-term data will be presented from the phase III PROUD-PV/CONTINUATION-PV studies comparing ropeginterferon alpha-2b vs HU in patients with PV who were either cytoreduction naive or previously treated with HU for fewer than 3 years. The long-term clinical benefit of ropeginterferon, normalization of blood count in most patients, led to its approval in Europe for the treatment of PV without symptomatic splenomegaly, and it is currently under review by the FDA.  In myelofibrosis, 2 of the most clinically relevant studies reporting this year have the potential of becoming new standards of care for this disease. First, the phase II MANIFEST study evaluating the novel oral bromodomain and extraterminal domain protein inhibitor CPI-0610 in combination with ruxolitinib in JAK inhibitor–naive patients with myelofibrosis is reporting response rates that have not previously been seen with ruxolitinib alone for this disease. Results from MANIFEST led to initiation of the phase III MANIFEST-2 study comparing the combination of CPI-0610 plus ruxolitinib vs ruxolitinib alone in JAK inhibitor–naive patients. The second study in myelofibrosis is the phase II IMbark trial examining 2 dosing regimens of the telomerase inhibitor imetelstat in 107 patients with intermediate-2–risk or high-risk myelofibrosis and disease relapse or who are refractory to a JAK inhibitor. Of note, in addition to spleen and symptom responses, the abstract suggests an extension of survival—a major impact beyond symptom control.

Additional studies to watch in MDS/MPNs:

• Update from the phase II ACE-536-MF-001 study of luspatercept in 79 patients with myelofibrosis-associated anemia (Abstract 2992)
• Efficacy of roxadustat in transfusion-dependent very low-risk to intermediate-risk primary MDS (Abstract 1277)

Top Picks: Nonmalignant Hematologic Disorders
Hanny Al-Samkari, MD; Sujit Sheth, MD; and Mark A. Schroeder, MD, have identified key studies in autoimmune hematologic disorders, hemoglobinopathies, and graft-vs-host disease (GVHD), respectively, with the potential to change clinical practice. In immune thrombocytopenia (ITP), a significant milestone increasing the rate of long-term disease-free remission for patients with ITP will be presented. A late-breaking abstract for the multicenter, randomized FLIGHT study of mycophenolate plus steroids vs standard steroid treatment in 120 patients with ITP shows a higher rate of sustained long-term remission for the combination. Also in ITP, updated results will be presented from a phase I/II clinical trial of the oral, reversible, covalent BTK inhibitor rilzabrutinib (formerly PRN1008) in 32 patients with primary or secondary ITP (≥ 2 platelet counts < 30 x 10⁹/L in the 14 days prior to treatment initiation), including those with inadequate response to corticosteroids and/or thrombopoietin receptor agonists. Data from the abstract suggest that treatment with rilzabrutinib can lead to clinically significant platelet responses regardless of prior splenectomy or lack of response to previous therapy. In hemophilia, encouraging results will be presented from a late-breaking abstract of the open-label phase III HOPE-B study of single-dose etranacogene dezaparvovec gene therapy in an initial 54 adult patients with severe or moderate to severe hemophilia B, including patients with preexisting anticapsid-neutralizing antibodies. Based on the abstract, this study met its first coprimary endpoint of activity at 26 weeks, with patients discontinuing prophylaxis and reduction of bleeding episodes. In transfusion-dependent β-thalassemia (TDT) and sickle cell disease (SCD), we will see data from an abstract of the CLIMB THAL-111 and CLIMB SCD-121 studies of autologous CRISPR–CAS9-modified CD34+ hematopoietic stem and progenitor cells. Frangoul and colleagues will share available safety and efficacy results from all patients with ≥ 3 months of follow-up (N = 7; TDT, n = 5; SCD, n = 2), including positive fetal hemoglobin responses leading to transfusion cessation in patients with TDT. Several new promising therapies for chronic GVHD are advancing clinical development and are being reported at the ASH annual meeting. Anticipated results from the phase III REACH3 study of ruxolitinib, a JAK inhibitor, vs best available therapy in 329 patients with steroid refractory/dependent chronic GVHD will be presented.

The abstract for that study reports promising response rates seen with ruxolitinib vs best available therapy in steroid-dependent or refractory chronic GVHD. Finally, data for the phase I GRAVITAS-119 study of itacitinib with calcineurin inhibitor interventions as prophylaxis for GVHD showing acceptable safety and low rates of severe (grade 3/4) acute GVHD will be presented.

Additional studies to watch in nonmalignant hematologic disorders:

• Safety and tolerability results from the phase I, multiple ascending dose study of mitapivat (AG 348) in patients with SCD (Abstract 681)
• Top-line results from the open-label, randomized phase II study of once-daily or twice-daily belumosudil in patients with chronic GVHD and 2-5 prior lines of therapy (Abstract 353)
• Preliminary analysis of safety and efficacy from the phase I/II study of baricitinib in 20 patients with refractory chronic GVHD (Abstract 357)

Remember to Check the CCO Web Site Often During and After ASH!
These are just a few of the interesting and important abstracts selected by our expert faculty from ASH 2020. Downloadable slideset summaries of these studies and more will be available on our Web site 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.