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Highlights From ASH 2019 Included New Data in Leukemia, Lymphoma, Myeloma, and Myelodysplastic Syndromes


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The 2019 American Society of Hematology (ASH) Annual Meeting & Exposition featured a cornucopia of sessions. It was impossible to attend all the lectures, symposia, oral presentations, poster presentations, and special events because many were concurrent. Below, we have selected some presentation highlights to supplement our regular coverage of the meeting. We hope you find them of interest.

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 myeloid 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 or 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 or 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.

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

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 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 years), 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 recommended phase II dose of IMGN632 was 0.045 mg/kg. 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 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.

Courtney D. DiNardo, MD

Courtney D. DiNardo, MD

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 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 with 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 years). 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 European LeukemiaNet (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 of treatment 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 rate was 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 comutations, 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-alone 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

Paul M. Barr, MD

Lead author Paul M. Barr, MD, of Wilmot Cancer Institute, University of Rochester, New York, said 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 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 anti-CD20 antibody, 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/μL at baseline, declined to 3,400/μL by the end of cycle 6.

“Although it’s a relatively small cohort, there doesn’t seem to be any difference 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 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.

Pretreatment ctDNA Correlated With ­Outcomes in Aggressive Lymphoma

Studies investigating aggressive diseases such as diffuse large B-cell lymphoma can be particularly affected by selection bias, since clinical urgency and the need for therapy may not allow the requisite extensive screening and consent processes. Diagnosis-to-treatment interval has been proposed as a novel metric to capture this phenomenon; a short diagnosis-to-treatment interval has also been associated with adverse outcomes. The current study assessed whether pretreatment levels of circulating tumor DNA (ctDNA) are associated with a shorter diagnosis-to-treatment interval and may constitute an objective measure of clinical urgency.4

The investigators quantified pretreatment ctDNA levels in plasma from 255 patients with aggressive B-cell lymphomas. Levels of ctDNA were measured, and pretreatment values were correlated with diagnosis-to-treatment interval, clinical factors, and treatment outcomes. A shorter diagnosis-to-treatment interval was associated with higher ctDNA levels, and both diagnosis-to-treatment interval and ctDNA levels were associated with treatment outcomes.

Hazard ratios (HRs) for event-free survival were 1.9 for diagnosis-to-treatment interval ≤ 14 days vs > 14 days (P = .006) and 2.6 for high vs low ctDNA (P < .001). In the multivariate analysis, ctDNA level predicted event-free survival independent of diagnosis-to-treatment interval, metabolic tumor volume, and International Prognostic Index (IPI). In fact, diagnosis-to-treatment interval proved to be the only factor significantly associated with event-free survival (HR = 1.6; P = .002), according to Stefan Alig, MD, of Stanford University.

Stefan Alig, MD

Stefan Alig, MD

“Shorter [diagnosis-to-treatment interval] is associated with higher pretreatment ctDNA levels in patients with aggressive B-cell lymphomas. When compared to established factors (IPI, metabolic tumor volume), pretreatment ctDNA levels appear to best predict clinical outcomes,” he said. “This suggests that quantification of ctDNA better reflects disease burden and treatment urgency than existing clinical biomarkers. Pretreatment ctDNA level may therefore be a valuable metric for disease aggressiveness of patients included in clinical trials and may help identify studies suffering from selection bias. This may be particularly useful for noncontrolled phase I/II single-arm trials but also for stratification in randomized trials.”

Ixazomib for High-Risk Smoldering Myeloma

The combination of ixazomib, lenalidomide, and dexamethasone was an effective and well-tolerated intervention in high-risk smoldering myeloma, producing responses in 94% of patients, in a phase II study reported by Mark Bustoros, MD, of Dana-Farber Cancer Institute and Harvard Medical School, Boston.5

Mark Bustoros, MD

Mark Bustoros, MD

In the study, 61 patients met eligibility for high-risk smoldering myeloma, which carries a 50% risk of disease progression within 2 years. Treatment was nine cycles of induction with ixazomib (4 mg) on days 1, 8, and 15, in combination with lenalidomide (25 mg) on days 1 to 21 and dexamethasone on days 1, 8, 15, and 22. The induction phase was followed by ixazomib (4 mg) and lenalidomide (15 mg) maintenance for another 15 cycles. The analysis was conducted on 48 patients who completed at least one cycle of therapy (45 received ≥ 4 cycles). Patients were followed for a median of 15 months.

Treatment was well tolerated. The only grade ≥ 3 adverse events reported by more than 5% of patients were hypertension (6.2%) and hypophosphatemia (8.3%). One grade 4 event (neutropenia) occurred.

The overall response rate was 93.8%, with 31% being stringent complete responses and 19% being very good partial responses. MRD was evaluated in 13 patients, of whom 9 (69%) were found to be MRD-negative.

“Seventy percent of patients who were complete responders were MRD-negative, and with continued treatment, responses deepened. After a median 15 months of follow-up, we saw no progression to symptomatic myeloma and no biologic progression,” said Dr. Bustoros. As an intervention for high-risk smoldering disease, this regimen may be a “moderate approach” between use of an immunomodulatory drug alone and more intense regimens that involve stem cell transplant, he suggested.

Lenalidomide Plus Epoetin Alfa in Myelodysplastic Syndrome

The E2905 Intergroup phase III trial (a study of the ECOG-ACRIN Cancer Research Group) evaluated the use of lenalidomide plus epoetin alfa in individuals with lower-risk myelodysplastic syndrome (MDS) refractory to epoetin alfa.6 The final analysis showed that lenalidomide could restore sensitivity to epoetin alfa in patients with refractory, lower-risk MDS without deletion 5q (non-del[5q]) and yield significantly higher rates of erythroid response than lenalidomide alone.

“Modulation of erythropoietin responsiveness by lenalidomide led to a longer, clinically meaningful duration of response, with a median major erythroid response duration approaching 2 years, compared to 13 months with lenalidomide monotherapy. The results support the use of combined lenalidomide and epoetin alfa in this population,” said Alan List, MD, of Moffitt Cancer Center, Tampa, Florida.

Alan List, MD

Alan List, MD

E2905 enrolled 205 patients (n = 195 evaluated) with low to intermediate-1 disease by the International Prognostic Scoring System (IPSS), failure on erythropoietin-stimulating agents, or low response profile and hemoglobin < 9.5 g/dL. Patients were randomly assigned to lenalidomide at 10 mg/d for 21 days every 4 weeks or lenalidomide plus epoetin alfa at 60,000 units weekly.

The primary endpoint, major erythroid response, was achieved by 28.3% with the combination vs 11.5% with lenalidomide alone (P = .004). The overall erythroid response (major and minor) was 51.9% with lenalidomide plus epoetin alfa and 40% with lenalidomide, which was not significantly different (P = .30). Mean peak hemoglobin and rise in hemoglobin were also similar between the arms—approximately 13 g/dL and 5 g/dL, respectively.

Mean major erythroid response duration (interval between the documented date of major erythroid response and next transfusion, or reduction in hemoglobin ≥ 2 g/dL) was estimated to be 23.6 months with the combination and 13.0 months with lenalidomide. In the multivariate model for major erythroid response, treatment (lenalidomide/epoetin alfa vs lenalidomide) was the only independent predictor (P = .01). The combination treatment was safe, with no increased risk of thromboembolic events or frequency of progression to AML, Dr. List reported. ν

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 has received institutional research funding from AstraZeneca and Pharmacyclics. Dr. Alig reported no conflicts of interest. Dr. Bustoros has received honoraria from Dava Oncology and Takeda and has served in a consulting or advisory role for Takeda. Dr. List has received honoraria from Aileron, Celgene, and Cellular Biomedical Group; has served in a consulting or advisory role for Acceleron Pharma, Aileron Therapeutics, Amphivena, Celgene, and Cellular Biomedicine Group; has received research funding from Celgene; and has been reimbursed for travel, accommodations, or other expenses by CBMG and Celgene.

REFERENCES

1. Daver NG, Montesinos P, DeAngelo DJ, et al: Clinical profile of IMGN632, a novel CD123-targeting antibody-drug conjugate in patients with relapsed/refractory acute myeloid leukemia or blastic plasmacytoid dendritic cell neoplasm. 2019 ASH Annual Meeting. Abstract 734. Presented December 9, 2019.

2. DiNardo CD, Schuh AC, Stein EM, et al: Enasidenib plus azacitidine significantly improves complete remission and overall response compared with azacitidine alone in patients with newly diagnosed acute myeloid leukemia with isocitrate dehydrogenase 2 mutations: Interim phase II results from an ongoing, randomized study. 2019 ASH Annual Meeting. Abstract 643. Presented December 9, 2019.

3. Barr PM, Hill BT, Ma S, et al: A phase I/II study of umbralisib, ublituximab, and venetoclax in patients with relapsed or refractory chronic lymphocytic leukemia (CLL). 2019 ASH Annual Meeting. Abstract 360. Presented December 8, 2019.

4. Alig S, Macaulay C, Kurtz DM, et al: Short diagnosis-to-treatment interval is associated with higher levels of circulating tumor DNA in aggressive B-cell non-Hodgkin lymphoma. 2019 ASH Annual Meeting. Abstract 491. Presented December 8, 2019.

5. Bustoros M, Nadeem O, Sperling AS, et al: Phase II trial of the combination of ixazomib, lenalidomide, and dexamethasone in high-risk smoldering multiple myeloma. 2019 ASH Annual Meeting. Abstract 580. Presented December 9, 2019.

6. List AF, Sun Z, Verma A, et al: Combined treatment with lenalidomide and epoetin alfa leads to durable responses in patients with epo-refractory, lower risk, non-deletion 5q[del(5q)] MDS: Final results of the E2905 Intergroup phase III study—an ECOG/ACRIN Cancer Research Group Study, Grant CA180820, and the National Cancer Institute of the National Institutes of Health. 2019 ASH Annual Meeting. Abstract 842. Presented December 9, 2019.


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