Following the 2020 ASH Annual Meeting, a number of hematology experts shared their insights on the most important data presented during the meeting with Targeted Oncology.
The 2020 American Society of Hematology (ASH) Annual Meeting was hosted virtually to disseminate the latest information and data from clinical trials across hematologic malignancies despite the challenges brought on by the coronavirus disease 2019 (COVID-19) pandemic. As 2020 has been a challenging year with new travel restrictions, social distancing requirements, and researchers around the world diverting their efforts to this viral infection, this year’s meeting justly focused on COVID-19 as it relates to patients with blood cancers.
“During this all-time horrible pandemic year, research was slowed down and, in some cases, shut down, but what we saw was a rallying of labs around the world, using new safety procedures and clinical trials with our brave patients and families enrolling to trials,” Naveen Pemmaraju, MD, associate professor, Department of Leukemia, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, told Targeted Oncology. “The debate in our field, which is very personal to me as a treating physician, is how do we treat our patients with intensive chemotherapy during COVID-19? How do they follow-up safely to the clinic, and what about complex procedures, like bone marrow stem cell transplant or CAR [chimeric antigen receptor] T-cell infusions?”
These questions, among others that have been raised in hematology over the past year, were addressed during the meeting, with Anthony S. Fauci, MD, director of the National Institute of Allergy and Infectious Diseases, kicking off the meeting with a discussion on the most current information regarding the pandemic and the effects it has had on the hematologic field. A few days after the conclusion of the meeting, the FDA granted an Emergency Use Authorization to the first vaccine for the prevention of COVID-19, which is an encouraging next step in the field and warrants excitement for both patients and physicians in the hematology field.
“COVID-19 certainly impacted both clinical practice and clinical research,” Alexey V. Danilov, MD, PhD, associate professor of medicine at the Oregon Health & Science University, said to Targeted Oncology in an interview. “However, 1 question or problem that hasn't been solved is the problem of cancer, unfortunately. In many ways, what has happened with us is we learned to adjust to the new environment, and at this point, I'm confident to say that I feel very comfortable bringing in patients to our clinics, offering clinical trials to them, and offering innovative treatment approaches. That has to continue, and I'm certainly optimistic about the newest data coming from the vaccine trials for COVID-19, so we are already hopeful that this will change for the better very soon.”
According to findings from the ASH Research Collaborative (RC) COVID-19 Registry, patients with hematologic malignancies who are infected with COVID-19 at greater risk for poor outcomes from the virus were identified, and the mortality risk was potentially even greated among patients who were older, had more severe infection, a poorer prognosis, or who decided to forego intensive therapy. The ASH RC COVID-19 Registry for Hematology is a global reference tool and was developed early on during the pandemic, aiming to make available to the public information on patients who have a hematologic malignancy and are infected with COVID-19 or are experiencing a post–COVID-19 complications.1
Although this update and others regarding COVID-19 were important at this year’s meeting, the main focus was on advances and hypothesis-generation data observed in various blood cancers across clinical trials and other analyses. In particular, there were preliminary data shared from early clinical trials demonstrating promise with several novel therapies.
In a Twitter poll, Targeted Oncology asked hematologists what area appeared to have the most significant and practice-changing data at this year’s meeting. Multiple myeloma drew the most votes, while leukemias also generated a lot of attention as well. Lymphomas and myeloproliferative neoplasms (MPNs) also drew some attention at this meeting, but the bulk of this year’s excitement appeared to come from early clinical trials for novel therapeutic strategies, such as bispecific antibodies or new CAR strategies.
“I think this was certainly a year where therapy with bispecific antibodies stood front and center in this meeting. There were many presentations using a different variety of bispecific antibodies in diffuse large B-cell lymphoma [DLBCL] and other malignancies with great success in the relapsed/refractory setting. We had heard some good CAR T cell stories with impressive results shown in CAR T cells in follicular lymphoma, and there also was a very impressive presentation of some novel agents in mantle cell lymphoma [MCL],” Danilov told Targeted Oncology.
“The key takeaway is that the multiple myeloma landscape is really changing. There is so much that's coming in with the CARs and with the different bispecifics,” Deepu Madduri, MD, assistant professor at Mount Sinai Hospital, told Targeted Oncology. “Before you know it, we're going to get different targets other than BCMA for CAR T, so we know that we're fighting hard to find a cure for our patients, and maybe we're getting closer each year with the new targets that are available.”
Findings from the phase 3 APOLLO study (NCT03180736) showed a higher rate of complete responses (CRs) with subcutaneous daratumumab (Darzalex) added to pomalidomide (Pomalyst) and dexamethasone (D-Pd) compared with pomalidomide and dexamethasone alone (Pd) in patients with relapsed or refractory multiple myeloma who had received at least 1 prior therapy.
The CR rate was 25% with the triplet and minimal residual disease (MRD)-negativity was observed in 9% versus a 4% CR rate and 2% MRD-negativity with the doublet. The median progression-free survival (PFS) with the addition of subcutaneous daratumumab was 12.4 months versus 6.9 months without, resulting in a 37% reduction in the risk of progression or death. The risk for death was also reduced by 9% with added daratumumab, although survival data were still immature at the time of data cut-off.
CAR T-cell therapy appeared promising in the phase 1b/2 CARTITUDE-1 study (NCT03548207) with a significant response rate and manageable safety profile observed with the recommended phase 2 dose of ciltacabtagene autoleucel (cilta-cel; JNJ-68284528).
The objective response rate (ORR) with the second-generation BCMA-directed CAR T-cell therapy was 96.9% in patients with heavily pretreated relapsed/refractory multiple myeloma, with stringent CRs in 67% of patients. The 1-year PFS rate was 76.6% and was 84.5% in those who achieved a stringent CR. The agent also demonstrated a manageable safety profile with mild cases of cytokine release syndrome and neurotoxicity.
Clinical activity and a good safety profile were observed in the ongoing phase 1/2 DREAMM-6 clinical trial (NCT03544821) with the combination of belantamab mafodotin (belamaf; Blenrep), bortezomib (Velcade), and dexamethasone in patients with relapsed or refractory multiple myeloma.
These preliminary findings demonstrated an ORR of 78% (95% CI, 52.4%-93.6%) with very good partial responses (PRs) in 50% of patients and PRs in 28%. The clinical benefit rate was 83% (95% CI, 58.6%-96.4%). The ORR was 75% among those with prior exposure to bortezomib and 67% for those with prior exposure to daratumumab, and the clinical benefit rates were 81% and 67%, respectively.
In addition, a post-hoc analysis of the DREAMM-2 study (NCT0352678) also demonstrated deep and durable responses with no notable alterations in the safety profile as treatment of heavily pretreated relapsed/refractory multiple myeloma who received at least 7 prior lines of therapy.
An ongoing phase 1 dose-escalation study (NCT03275103) demonstrated high clinical activity and manageable safety with the first-of-its-kind FcRH5xCD3 bispecific antibody cevostamab (BFCR4350A) in a difficult-to-treat population of patients with multiple myeloma.
Cevostamab induced an ORR of 53% as treatment of patients with heavily pretreated relapsed/refractory multiple myeloma who received active doses of the therapy. Among 34 patients who received the target doses of 20 mg or higher, 18 had responded to therapy, of which 32% had a very good PR or better and 18% achieved a CR or better. An even higher ORR of 61% was observed with higher dose levels, including 90 mg or 132 mg.
“In chronic lymphocytic leukemia [CLL], specifically, there was a 5-year update of the MURANO study, which, in my view, is just another nail in the coffin of chemoimmunotherapy in the relapsed/refractory setting,” said Danilov. “[We saw] dramatic improvements in PFS with venetoclax [Venclexta] plus rituximab [Rituxan] versus bendamustine plus rituximab.”
The MURANO study (NCT02005471) demonstrated sustained PFS and OS at 5 years in patients with relapsed/refractory CLL who were treated with the combination of venetoclax plus rituximab compared with bendamustine plus rituximab. The median PFS with the combination was 53.6 months (95% CI, 48.4-57) compared with 17 months in the control arm (95% CI, 15.5-21.7), and the 5-year OS estimates were 82.1% (95% CI, 76.4%-87.8%) and 62.2% (95% CI, 54.8%-69.6%), respectively.
Early findings for an investigational allogeneic off-the-shelf CD22-directed therapy, UCART22, demonstrated clinical activity as treatment of adult patients with relapsed/refractory CD22-positive B-cell acute lymphoblastic leukemia (ALL) in the phase 1 dose-escalation/expansion BALL1-01 clinical trial. Two patients achieved a CR with incomplete hematologic recovery on day 28 at the 1 x 105 cells/kg dose level. No dose-limiting toxicities, immune effector cell-associated neurotoxicity syndrome, graft-versus-host disease (GVHD), adverse events (AEs) of special interest, UCART22-related AEs of grade 3 or higher, nor serious AEs were observed.
Asciminib (ABL001) led to a major molecular response rate of 25.5% at 24 weeks, which was almost double the rate with bosutinib of 13.2% in patients with chronic-phase chronic myeloid leukemia (CP-CML) who have received at least 2 prior tyrosine kinase inhibitors (TKIs) in the phase 3 ASCEMBL study. The first-in-class STAMP inhibitor had a rate of complete cytogenetic response of 40.8% at 24 weeks versus 24.2% with bosutinib. The rate of AEs was similar between the 2 arms, but the rate of treatment discontinuation due to AEs was significantly higher in the control arm.
A real-world analysis also demonstrated positive safety and efficacy with asciminib in patients with CML who had no alternatives in clinical practice, and these findings demonstrated particular efficacy observed among those with prior TKI intolerance and those who achieved prior complete cytogenetic response.
The phase 3 UNITY-CLL clinical trial (NCT02612311) demonstrated synergistic activity with the combination of CD20-targeting ublituximab (TGTX-1101) plus PI3K-targeting umbralisib (TGR-1202; U2) as treatment of patients with CLL, irrespective of prior treatment. The combination regimen also had a favorable safety profile.
The median PFS in the intention-to-treat population was 31.9 months (95% CI, 28.2-35.8) with U2 compared with 17.9 months (95% CI, 16.1-22.6) with standard-of-care chemoimmunotherapy (HR, 0.546; 95% CI, 0.413-0.720; P < .0001). Among the treatment-naïve population, the median PFS was 38.5 months (95% CI, 33.2-not evaluable) with U2 versus 26.1 months (95% CI, 19.4-33.1) in the control arm, in which patients received obinutuzumab (Gazyva) plus chlorambucil (HR, 0.601; 95% CI, 0.415-0.869; P < .01).
Two clinical trials, including the pivotal single-arm phase 2 PACE study (NCT01207440) and the multicenter randomized phase 2 OPTIC study (NCT02467270), of ponatinib (Iclusig) demonstrated high response rates and robust survival outcomes in patients with CP-CML who failed prior therapy with a second-generation TKI.
In the PACE trial, 270 patients with resistant or intolerant CP-CML had deep and durable responses to ponatinib, and in the OPTIC study, response-based dosing of ponatinib appeared clinically safe in 93 patients with highly resistant CP-CML. At 2 years, the PFS rates were 67% in the PACE trial and 81% in the OPTIC trial, and OS rates were 85% and 93%, respectively. The efficacy of this therapy was observed regardless of mutational status in both studies.
“There were a lot of nice abstracts and presentations. There were no large pivotal phase 3 trials in lymphoma at the ASH meeting, but I would say a multitude of good phase 2 work and other retrospective real-world work in DLBCL. We, of course, saw a lot of continued updates on CAR T-cell therapy,” Andrew M. Evens, DO, MSc, director of the Lymphoma Program and associate director for Clinical Services at the Rutgers Cancer Institute of New Jersey, told Targeted Oncology.
In an analysis of the phase 2 ZUMA-5 trial (NCT03105336) of the CAR T-cell therapy axicabtagene ciloleucel (axi-cel; Yescarta) in patients with relapsed/refractory indolent non-Hodgkin lymphomas (NHLs), a response rate of 92% was observed by independent radiology review committee.
“As we know, so far, the current CD19 CAR T-cell therapy is FDA approved in lymphoma, only in DLBCL, so this ZUMA-5 study was a phase 2 study of axi-cel in patients with relapsed/refractory indolent NHL,” said Evens. “In a sentence, it was extremely active, with an ORR of over 90% and a CR rate over 70%.”
CRs were reported in 76% and PRs in 16% overall. For patients with follicular lymphoma (FL) specifically, the response rate was 94%, with CRs in 80% and PRs in 14%. The marginal zone lymphoma population had a response rate of 85% with CRs in 60% and PRs in 25%.
“The bulk of patients [had] follicular lymphoma, and similar to DLBCL, patients who achieved a CR and had a better duration of response [did] much better. In other words, if you achieve only a PR or even less, the duration of response was much less,” Evens said.
The ongoing phase 1/1b clinical trial demonstrated that a fixed duration of the CD20xCD3 bispecific antibody mosunetuzumab induced high, durable, and consistent responses as treatment of patients with FL across subgroups.
The ORR among patients with FL was 67.7% with a 51.6% CR rate and 16.1% PR rate. The ORR was significantly higher among those who were refractory to a PI3K inhibitor at 92.3%, which included an 84.6% CR rate and 7.7% PR rate. The safety profile was acceptable with low grade 2 cytokine release syndrome (CRS), and no grade 3 CRS events occurring, in patients with previously-treated disease.
Longer follow-up of a phase 1 study showed promising antitumor activity with the novel CD20 x CD3 bispecific antibody odronextamab (REGN1979), as well as an acceptable safety profile in patients with heavily pretreated relapsed/refractory NHL, including those who have had prior CAR T-cell therapy.
In this difficult-to-treat population, the ORR was 33%, with a CR rate of 21%. The CRs appeared durable with 100% still ongoing, and 1 patient has maintained an ongoing CR for 20 months. Among patients with relapsed/refractory DLBCL who had not received prior CAR T, the ORR was 55%, all of which were CRs and 83% durable, and among those with relapsed/refractory FL, the ORR was 90% with a 70% CR rate, which appeared durable (81%).
The CD20 x CD3 bispecific IgM antibody IGM-2323 induced tumor shrinkage in 9 of 14 patients with CD20-positive relapsed/refractory NHL in a phase 1 dose-escalation study (NCT04082936).
The agent appeared well tolerated with no dose-limiting toxicities and no neurotoxicity. The study included 10 patients with FL or marginal zone lymphoma and 6 patients with DLBCL or MCL. Overall, 9 (64.2%) patients had evidence of tumor size reduction. No grade 3 treatment-emergent AEs were observed, and the most common grade 2 events included hypophosphatemia (25%) and infusion-related reactions (19%).
The phase 1 NP3019 study (NCT03075696) demonstrated a significant rate of CRs in patients with relapsed/refractory NHL who were treated with glofitamab (RG6026), and the safety profile appeared manageable with mostly low-grade CRS events observed.
The ORR was 51.4% with 36.2% CRs when glofitamab was given at ≥10 mg in fixed-dose cohorts, and the ORR was 66.7% with 50.0% CRs in patients with indolent NHL compared with 49.4% and 34.1%, respectively, among those with aggressive NHL. The most common AEs related to treatment included CRS, neutropenia, pyrexia, and thrombocytopenia.
A study demonstrated that certain driver mutations for MPNs can be traced back to when they were acquired as early as in utero. The study comprised a cohort of 10 patients with MPNs, and each patient’s peripheral blood and bone marrow samples were grown into single cell—derived hematopoietic colonies that underwent whole-genome sequencing. The driver mutations were evaluated for appearance patterns across each colony, reflecting the relative development of the mutation in each patient.
“This study is elucidating a new dogma, a new mechanism that shows that JAK2 V617F and DNMT3Amutations in patients with MPNs later on in life may have [been] picked up in utero shortly after birth. This is a huge game-changing finding,” said Pemmaraju. “This is an important abstract.”
One area of interest at the ASH Annual Meeting for patients with MPNs was the add-on or add-back strategy, according to Pemmaraju. “This is where you keep your JAK inhibitor, ruxolitinib [Jakafi] for example, and then you add in the second agent, a new agent. I presented data on ruxolitinib plus navitoclax, showing early encouraging data there in an ongoing phase 2, and then my colleagues presented data sets with ruxolitinib plus a bromodomain inhibitor. That is also showing not only encouraging data in the relapsed setting or suboptimal setting, but also they've moved that agent into the frontline.”
In this phase 2 clinical trial, the addition of the BCL1/BCL-XL inhibitor navitoclax to ruxolitinib improved spleen volume and total symptom score as treatment of patients with myelofibrosis (MF) who no longer benefited from prior ruxolitinib therapy. The improvements were clinically meaningful and independent of the presence of high-molecular-risk mutations or high numbers of total gene mutations at baseline.
“There are brand new agents that go beyond JAK inhibition that stand alone as a monotherapy in clinical trials, and 1 of those notable agents was imetelstat, the telomerase inhibitor,” Pemmaraju said. “This trial showed a potential signal for OS improvement.”
The higher dose of imetelstat demonstrated better OS, spleen response, and symptom response as treatment of patients with MF who relapsed after or are refractory to JAK inhibition, according to the findings from the phase 2 IMbark study (MYF2001; NCT0246086). This randomized study evaluated 2 doses of the intravenous therapy at 4.7 mg/kg and 9.4 mg/kg every 3 weeks.
Ruxolitinib demonstrated a high response rate as treatment of adult and pediatric patients with chronic GVHD compared with best available therapy in the phase 3 REACH3 trial (NCT03112603), as well as a substantially greater improvement in failure-free survival.
The response rate was 49.7% versus 25.6% with best available therapy (odds ratio, 2.99; 95% CI, 1.86-4.80; P < .0001). CRs were achieved in 6.7% of patients treated with ruxolitinib, and PRs in 43.0%. The median failure-free survival was not reached in the ruxolitinib arm versus 5.7 months with best available therapy. The JAK inhibitor also induced greater improvements in symptoms.
CD123-Targeting ADC IMGN-632 Demonstrates Encouraging Findings in Rare Blood Cancer
In terms of other hematologic malignancies, promising data were observed for the treatment of patients with blastic plasmacytoid dendritic cell neoplasm (BPDCN) with the novel agent IMGN632. This ongoing study, which represents the largest-to-date prospective group of uniformly treated patients with relapsed/refractory BPDCN, induced a favorable safety profile with limited grade 3 or higher treatment-emergent AEs, no treatment-related discontinuations or deaths, and 0% 30-day mortality.2
"This is a new CD123-targeting agent, which has actually recently received FDA Breakthrough Therapy designation for patients with relapsed/refractory BPDCN,” said Pemmaraju. “These were very encouraging data in this data set. We have 28 patients treated with relapsed/refractory BPDCN, showing an ORR of 29%, and the drug appears to be showing us a very early signal for both a nice safety profile as well as efficacy that we have to keep following."
In October 2020, IMGN632 received a Breakthrough Therapy designation from the FDA for the potential treatment of patients with relapsed/refractory BPDCN. This study is particularly encouraging for this patient population as BPDCN is a rare hematologic malignancy that is in need of new treatment options, much like other rarer diseases that were presented on during the 2020 ASH Annual Meeting.
“What this research reminds us is that no matter how rare or challenging of a disease or blood cancer, it just gives hope that there are folks all around the world who are trying to focus on even the most rare of rare blood cancers. We're trying to find clinical breakthroughs there, so I actually think that's actually very exciting,” Pemmaraju concluded.
1.ASH RC Data Hub COVID-19 Registry for Hematology. ASH Research Collaborative. Accessed December 15, 2020. https://bit.ly/2JFRIy3.
2. Pemmaraju N, Martinelli G, Todisco E, et al. Clinical Profile of IMGN632, a Novel CD123-Targeting Antibody-Drug Conjugate (ADC), in Patients with Relapsed/Refractory (R/R) Blastic Plasmacytoid Dendritic Cell Neoplasm (BPDCN). Presented at: 2020 ASH Annual Meeting & Exposition; December 5-8, 2020; Virtual. Abstract 167.