The ASH 2019 Annual Meeting & Exposition featured countless important sessions and lectures. It would be impossible to attend all the symposia, oral presentations, poster presentations, and special events. Below, we have selected some presentation highlights to supplement our coverage of the meeting.
Antibody-Drug Conjugate IMGN632 in AML
The investigational anti-CD123 antibody-drug conjugate IMGN632 showed encouraging preliminary safety and activity in patients with relapsed or refractory acute myelogenous leukemia (AML) or blastic plasmacytoid dendritic cell neoplasm in a phase I/Ib trial.1 In the study, response rates ranged from about 20% to 30% to single-agent IMGN632.
Overall, 13 of 71 patients with relapsed/refractory AML who received the antibody-drug conjugate at all dose levels in this phase I dose-escalation trial obtained a complete response with or without complete hematologic recovery. Additionally, two of nine patients with relapsed/refractory blastic plasmacytoid dendritic cell neoplasm obtained a complete response and one additional patient had a partial response. Responses were observed across various molecular and cytogenetic subgroups in AML (including post–stem-cell transplant relapses) and early in the course of treatment (after the first or second dose).
Toxicity was seen mainly at the higher doses of the compound. Infusion-related reactions were the most common treatment-related adverse events.
Naval G. Daver, MD
“This agent is generally well tolerated and can be given as an infusion on an outpatient basis. We don’t see any cytokine-release syndrome or capillary leak at this point in time. The main issue is infusion-related reactions, which are manageable with dexamethasone prophylaxis,” said lead author Naval G. Daver, MD, of The University of Texas MD Anderson Cancer Center, Houston.
CD123 is expressed in more than 90% of AML cases and almost universally in blastic plasmacytoid dendritic cell neoplasm. “CD123-directed therapy may be able to debulk and potentially eliminate the source of disease,” he explained. Although the response rate to single-agent therapy was encouraging, Dr. Daver said that if future studies pan out, the antibody-drug conjugate will probably be used in combination with other therapies including venetoclax and hypomethylating agents.
Patients enrolled in the phase I/Ib trial had CD123-positive relapsed or refractory AML (n = 85) or blastic plasmacytoid dendritic cell neoplasm (n = 10) and had received no more than three prior lines of therapy. The median age was 66 years (range = 33–83), almost half had adverse cytogenetics, and two-thirds had received prior intensive therapy, including 23% with prior allogeneic stem-cell transplantation.
The most common treatment-related adverse events observed with IMGN632 were infusion-related reactions (25%), nausea (11%), and febrile neutropenia (10%). Febrile neutropenia was the only grade ≥ 3 treatment-related adverse event that occurred in 10% of patients.
The phase I trial is continuing to enroll patients, including those with acute lymphocytic leukemia.
Enasidenib Plus Azacitidine in IDH2-Mutated AML
Enasidenib, an oral isocitrate dehydrogenase 2 (IDH2) inhibitor, significantly improved complete remission and overall response when added to azacitidine vs azacitidine alone in patients with newly diagnosed IDH2-mutated acute myeloid leukemia (AML), as reported in an interim analysis of an ongoing phase II trial designated as AG221-AML-005.2
At a median follow-up of 14 months, median event-free survival was 17.2 months in patients randomly assigned to receive enasidenib plus azacitidine vs 10.8 months in patients treated with azacitidine alone, said lead author Courtney D. DiNardo, MD, of The University of Texas MD Anderson Cancer Center, Houston.
“Responses [to enasidenib plus azacitidine] were observed in patients with RAS pathway co-mutations, which have been associated with resistance to enasidenib monotherapy.”— Courtney D. DiNardo, MD
Tweet this quote
At the time of the ASH analysis, there was no significant difference in overall survival between the two arms. However, Dr. DiNardo suggested that this could be partly attributable to the fact that 21% of patients in the azacitidine-alone arm received subsequent treatment with enasidenib monotherapy after discontinuation. An updated analysis with longer follow-up time is anticipated to be presented at the ASCO Annual Meeting in 2020.
IDH2 mutations are present in up to 19% of patients with AML and are often considered founder mutations that remain stable over the course of therapy. Enasidenib is already approved by the U.S. Food and Drug Administration for use as a single agent in adults with IDH2-mutant relapsed or refractory AML.
The phase II portion of the trial randomly assigned 101 patients with IDH2-mutant, newly diagnosed AML who were ineligible to receive intensive chemotherapy in a 2:1 ratio to receive either enasidenib plus azacitidine or azacitidine alone in 28-day cycles. All patients received subcutaneous azacitidine at 75 mg/m2/d for the first 7 days of each treatment cycle. Patients who were assigned to treatment with the combination also received continuous enasidenib at 100 mg once daily.
The median age was 75 years (range = 62–85). About 25% of patients had secondary AML. At baseline, about three-fourths of patients had an IDH2-R140 mutation and about one-fourth had IDH2-R172 mutation.
More than 80% of patients had intermediate-risk cytogenetics, but due to high-risk co-occurring mutations, the majority of patients were characterized as having ELN-adverse risk disease. However, “[There was] a notable underrepresentation of patients with either FLT3-ITD or NPM1 compared with expectations,” said Dr. DiNardo.
At the time of data cutoff (August 19, 2019), 94% of patients in the azacitidine-alone arm and 69% in the combination arm had discontinued therapy, most commonly for disease progression: 52% in the azacitidine-alone arm and 31% in the combination arm. Discontinuation due to adverse events was rare in both arms, at 6%.
The objective response rate was 71% in the combination arm vs 42% in the azacitidine-alone arm (P = .0064); complete response rates were 53% vs 12% (P = .0001), respectively. The time to first response was about 2 months in each arm, and the time to complete response was 5.5 months with enasidenib/azacitidine and 3.7 months with azacitidine alone. In responders, the median duration of response was 24.1 months with combination enasidenib/azacitidine and 12.1 months with azacitidine alone.
“Responses were observed in patients with RAS pathway co-mutations, which have been associated with resistance to enasidenib monotherapy,” Dr. DiNardo told listeners.
The 60-day mortality rates were 7% in the combination arm and 3% in the azacitidine-only arm, mostly related to disease progression. Two deaths were considered likely or possibly due to IDH differentiation syndrome.
The median overall survival of 22 months in each arm compares favorably with the historical median overall survival with azacitidine of about 10 months, Dr. DiNardo noted.
Novel Triplet Combo in CLL
The triplet of umbralisib, ublituximab, and venetoclax led to a complete remission rate of 44% in patients with relapsed or refractory chronic lymphocytic leukemia (CLL) in a phase I/II dose-escalation trial.3 After 12 cycles of treatment, the objective response rate was 100%, including a complete response rate of 44%. All patients were negative for minimal residual disease (MRD) in the peripheral blood, and 78% were MRD-negative in the bone marrow; 22% were MRD-intermediate (0.01% to 1.0%).
No disease progression was observed at a median follow-up of 6.4 months. Patients will continue to be followed for MRD status in the peripheral blood every 6 months.
Paul M. Barr, MD
Lead author Paul M. Barr, MD, of Wilmot Cancer Institute, University of Rochester, New York, said that the study has been expanded to evaluate the triplet combination in Richter’s transformation and mantle cell lymphoma. A large phase II study called ULTRA-V study has been mounted to explore the regimen further to gain regulatory approval.
Umbralisib is a dual PI3K-delta and CK1-epsilon inhibitor. Ublituximab is a glycoengineered CD20 inhibitor, and venetoclax is a BCL2 inhibitor. Preclinical study showed synergy for this combination.
Dr. Barr reported on 27 patients evaluable for safety and 23 for efficacy. The median age was 63 years, and 81.4% had an Eastern Cooperative Oncology Group (ECOG) performance status of 1. Ublituximab and umbralisib were given together as induction in the first three cycles before adding venetoclax to reduce the risk of tumor-lysis syndrome. Ublituximab was given only during the three-cycle induction period.
Consolidation with venetoclax and umbralisib was given during cycles 4 to 12. Patients with MRD-positive disease following consolidation were offered umbralisib monotherapy.
Following induction therapy, a mean 61% reduction in lymph node size from baseline was observed, with an overall response rate of 87%. By cycle 7, the overall response rate was 100%.
At the end of the consolidation period (cycle 12), the mean lymph node size had declined by 87%. Absolute lymphocyte count, which was a mean of 48,000 per μL at baseline, declined to 3,400 per μL by the end of cycle 6.
“Although it’s a relatively small cohort, there don’t seem to be any differences in treatment duration for those previously receiving Bruton’s tyrosine kinase inhibitors compared with the rest of the patients. No patients have had CLL progression, although it is a relatively short follow-up of only 6 months,” Dr. Barr stated.
No cases of tumor-lysis syndrome developed, and there were no reports of grade 3 or 4 liver enzyme abnormalities. The most common all-cause grade 3 or 4 adverse events occurring in more than 10% of patients were neutropenia (19%) and leukopenia (15%).
A 12-month analysis of the study is planned, and the phase II study continues to enroll participants, with a recruitment goal of 30. The ULTRA-V study plans to enroll 90 patients with treatment-naive and relapsed or refractory CLL.
Acalabrutinib Combination for Previously Untreated CLL
Benjamin L. Lampson, MD, PhD
The triplet acalabrutinib, venetoclax, and obinutuzumab appears to be safe and effective in previously untreated patients with chronic lymphocytic leukemia (CLL). Benjamin L. Lampson, MD, PhD, of the Dana-Farber Cancer Institute, Boston, and colleagues concluded that even preliminary data at early response evaluations appear to show favorable results, with a high proportion of complete responses and low toxicity rates.
The research team enrolled 37 previously untreated patients with CLL to receive the Bruton’s tyrosine kinase (BTK) inhibitor acalabrutinib, plus venetoclax and obinutuzumab. Overall, 23 patients (62%) had unmutated IgHV, 10 patients (27%) had TP53 disease, 10 patients (27%) had a del(11q) abnormality, and 7 patients (19%) had complex karyotypes.4
For the 24 patients who completed restaging at eight cycles, the overall response rate was 100%. Of those patients, 18 (75%) achieved a partial response, and 5 (25%) achieved a complete response. Undetectable minimal residual disease (MRD) in the peripheral blood was observed in 65% of patients, whereas half the patient population achieved undetectable MRD in the bone marrow. Among eight of the patients with TP53-aberrant disease, six patients achieved a partial response, two achieved a complete response, and three had undetectable MRD in the bone marrow. The most common severe adverse event was neutropenia (32%).
“Acalabrutinib, venetoclax, and obinutuzumab will also be studied head-to-head against chemoimmunotherapy and the acalabrutinib-plus-venetoclax doublet, in the phase III trial CL-311 (ClinicalTrials.gov identifier NCT03836261), which is currently enrolling,” the authors noted.
Daratumumab Increases Benefit of Carfilzomib/Dexamethasone in Myeloma
In patients with relapsed or refractory multiple myeloma, the addition of daratumumab to carfilzomib plus dexamethasone improved multiple outcomes, compared with carfilzomib/dexamethasone alone, in the international phase III CANDOR trial.1
Saad Z. Usmani, MD
“Overall, carfilzomib/dexamethasone/daratumumab was associated with a favorable benefit-risk profile and represents an efficacious new regimen for relapsed or refractory multiple myeloma, including lenalidomide-exposed and lenalidomide-refractory patients,” Saad Z. Usmani, MD, Chief of Plasma Cell Disorders at Levine Cancer Institute, Atrium Health, in Charlotte, reported.
In patients with relapsed or refractory multiple myeloma, the proteasome inhibitor carfilzomib and the anti-CD38 monoclonal antibody daratumumab are approved as single agents or as components of combination regimens. The triplet of carfilzomib, dexamethasone, and daratumumab (KdD) was shown to be efficacious and safe in patients with relapsed or refractory myeloma in the phase I MMY1001 study. This led to the phase III CANDOR trial, which compared KdD with carfilzomib and dexamethasone (Kd) alone in 466 patients with relapsed or refractory disease.
Dr. Usmani presented the primary analysis of CANDOR, which enrolled 466 patients with up to three prior lines of therapy and who achieved at least a partial response to at least one of those treatments. Of the 466 patients (median age = 64 years), 42.3% received prior lenalidomide-based regimens and 90.3% received previous bortezomib. One-third of patients were refractory to lenalidomide.
After a median follow-up of approximately 16 months, CANDOR met its primary endpoint. Median progression-free survival was not reached for the KdD arm and was 15.8 months for the Kd arm (HR = 0.63; P =.0014).
“KdD resulted in a significant progression-free survival benefit over Kd, with a 37% reduction in the risk of progression or death. The progression-free survival benefit of KdD was maintained across prespecified clinically important subgroups, particularly among lenalidomide-exposed and lenalidomide-refractory patients. Patients treated with KdD achieved deeper responses, with a nearly 10-times higher [MRD]-negative complete response rate than Kd-treated patients,” Dr. Usmani said.
DISCLOSURE: Dr. Daver has received research funding from Pfizer, BMS, Novartis, Daiichi Sankyo, Karyopharm, Incyte, AbbVie, Sunesis, Servier, Genentech, Nohla, Glycomimetics, Immunogen, Sobi, Astellas, Hanmi, and Forty Seven; has served in a consulting or advisory role for Pfizer, Novartis, BMS, Otsuka, Celgene, Incyte, Jazz, Karyopharm, Sunesis, Immunogen, AbbVie, Astellas, Daiichi Sankyo, and Agios; and has received honoraria from BMS, Jazz, Novartis, Incyte, Otsuka, Immunogen, Pfizer, Astellas, and AbbVie. Dr. DiNardo has served in a consulting or advisory role for AbbVie, Agios, Celgene, Daiichi Sankyo, and Notable Labs; and has received research funding from AbbVie, Agios, Celgene, and Daiichi Sankyo. Dr. Barr has served in a consulting or advisory role for AbbVie, AstraZeneca, Celgene, Genentech, Infinity Pharmaceuticals, Janssen, Merck, MorphoSys, Novartis, Pharmacyclics, Seattle Genetics, and TG Therapeutics; and. Dr. Lampson reported no conflicts of interest. Dr. Usmani reported financial relationships with AbbVie, SkylineDx, GSK, Seattle Genetics, Mundipharma, Takeda, Sanofi, Pharmacyclics, Merck, Janssen, Celgene, BMS, Array Biopharma, and Amgen.
REFERENCES
1. Daver NG, et al: Clinical profile of IMGN632 in relapsed/refractory AML or blastic plasmacytoid dendritic cell neoplasm. 2019 ASH Annual Meeting. Abstract 734. Presented December 9, 2019.
2. DiNardo CD, et al: Enasidenib plus azacitidine significantly improves complete remission and overall response compared with azacitidine alone newly diagnosed AML with isocitrate dehydrogenase 2 mutations. 2019 ASH Annual Meeting. Abstract 643. Presented December 9, 2019.
3. Barr PM, et al: A phase I/II study of umbralisib, ublituximab, and venetoclax in relapsed or refractory CLL. 2019 ASH Annual Meeting. Abstract 360. Presented December 8, 2019.
4. Lampson B, et al: Preliminary safety and efficacy results from a phase 2 study of acalabrutinib, venetoclax and obinutuzumab in previously untreated CLL. 2019 ASH Annual Meeting. Abstract 134. Presented December 8, 2019.
5. Usmani SZ, et al: Primary analysis results from the randomized, open-label, phase III study CANDOR (NCT03158688). 2019 ASH Annual Meeting & Exposition. Abstract LBA-6. Presented December 10, 2019.
