Hematology Experts Weigh In on Top Abstracts at 2018 ASH Annual Meeting

An estimated 30,000 hematology professionals descended on San Diego last week for the 2018 American Society of Hematology (ASH) Annual Meeting, held December 1-4 at the San Diego Convention Center. More than 5,000 abstracts were presented during the meeting, with a number of them demonstrating potential for a change in the standard of care across a variety of hematologic settings.

2018 ASH POLL: In what area do you think the most important data came from at#ASH18?

Tell us in the comments what abstracts you found most exciting. Tag colleagues to get their input, too! Stay tuned for the poll results and our final roundup!

#Lymsm#Leusm#mmsm#ASH2018

— Targeted Oncology (@TargetedOnc)December 4, 2018

Throughout the meeting, experts in attendance and watching remotely took to Twitter to share their thoughts on various abstracts with the conference hashtag. In a Twitter poll following the meeting,Targeted Oncologyfollowers voted on which areas they believed had the most exciting updates at this year’s meeting. Some of the biggest abstracts covered multiple myeloma, chronic lymphocytic leukemia (CLL), and non-Hodgkin lymphomas (NHL).While there had been a variety of encouraging data presented across various hematologic disease settings, CLL and multiple myeloma undoubtedly ruled the day, according to the poll results. As these topics heated up on Twitter, a few experts took a moment to discuss their thoughts withTargeted Oncology.There was still a big debate regarding which area had the top abstracts at the 2018 ASH Annual Meeting.

"There were a number of important updates and advances in NHL and Hodgkin lymphoma presented at the 2018 Annual ASH meeting," said Andrew M. Evens, DO, MSc, FACP, a professor of medicine at Rutgers Robert Wood Johnson Medical School. "This involved abstracts that continue to elucidate the efficacy and toxicity of CAR T-cell immunotherapy among clinical trial as well as non-clinical trial populations, which included patients that would have been excluded from the original pivotal studies."

One common agreement among hematology experts following the data reported at the meeting was that the spotlight shined on CAR T cells this year in a number of settings.

"I think we continue to see more follow-up [with CAR T cells] and we need to see more follow-up," said John P. Leonard, MD, associate dean for clinical research and Richard T. Silver Distinguished Professor of Hematology and Medical Oncology, Meyer Cancer Center, Weill Cornell Medicine and New York Presbyterian Hospital. "At this point, we are still working out with CAR T cells what are the durability of responses and how people do, but we saw a number of CAR T cell data at the ASH meeting."

“This was the year of BCMA immunotherapy,” noted Nina Shah, MD, associate professor of medicine at the University of California, San Francisco Helen Diller Comprehensive Cancer Center. “At least 7 BCMA CAR T cell abstracts were presented as was the first clinical data with BCMA-directed BiTe therapy.”

Anti-BCMA CAR T Cell Development Continues to Evolve for Multiple Myeloma

None of the BCMA-targeted CAR T-cell therapies have reached the FDA yet, but the data presented for these agents appeared promising. Each agent demonstrated its own efficacy and safety profile.

“This burst of clinical experience demonstrates that immunotherapy is rapidly becoming more integrated for the treatment of multiple myeloma,” Shah explained further. “I suspect that, before long, we will be moving some of these therapies to the up-front or consolidation settings.”

Two-Year Ixazomib Maintenance Delayed Progression in Newly Diagnoses Myeloma

In other exciting advances for the treatment landscape of multiple myeloma, findings from the phase III TOURMALINE-MM3 trial demonstrated a 39% improvement in progression-free survival (PFS) with a 2-year maintenance therapy of ixazomib in patients with multiple myeloma who had previously achieved a partial response with induction therapy of a proteasome inhibitor and/or an immunomodulatory agent following autologous stem cell transplant (ASCT). 

“The findings from the TOURMALINE trial demonstrate that ixazomib is a suitable agent for post-transplant maintenance for patients with newly diagnosed multiple myeloma,” said Navneet Majhail, MD, MS, director of the Blood and Marrow Transplant Program at the Cleveland Clinic. “Although the study did not compare ixazomib with our current standard of lenalidomide maintenance and the comparator arm was placebo, ixazomib can be considered for patients who either cannot tolerate or are poor candidates (eg, due to risk for secondary cancers) for lenalidomide maintenance.”

In 2015, the combination of ixazomib plus lenalidomide (Revlimid) and dexamethasone was approved by the FDA for the treatment of patients with multiple myeloma who have had at least 1 prior line of therapy. However, 29% of patients discontinue use of lenalidomide due to treatment-emergent adverse events. A once-weekly oral dose of ixazomib may be a better option with a more manageable safety profile.

Daratumumab With VRd Induced VGPR in 100% of Patients With Multiple Myeloma

The phase II Griffin trial was another study that appeared promising in the treatment landscape for multiple myeloma. In this study, the treatment regimen of daratumumab (Darzalex), bortezomib (Velcade), lenalidomide, and dexamethasone (VRd) was found superior to VRd in newly diagnosed patients who are eligible for high-dose therapy and autologous stem cell transplantation.

Peter Voorhees, MD, an investigator in the department of hematologic oncology & blood disorders, Levine Cancer Institute/Atrium Health, presented the data, noting that the regimen will be investigated further in a phase II study; enrollment for this trial closed in April, and data is expected to be available in 2019.

Following his report,Voorhees said, “This is potentially a regimen that could change practice in the future, and again, we hope that the randomized phase II study supports that.”  

Ibrutinib Significantly Improves PFS in Older Untreated Patients With CLL

In the realm of CLL, Jennifer A. Woyach, MD presented findings in which ibrutinib (Imbruvica) both as a monotherapy and in combination with rituximab (Rituxan) significantly improved PFS as a frontline therapy in older, previously untreated patients with CLL. In this study, the agent was compared to bendamustine plus rituximab (BR) regimen and will be investigated further in other combinations.

"This important phase III study demonstrates a clinically meaningul PFS benefit of ibrutinib over a current standard of care BR for the initial treatment of older CLL patients, which is most pronounced for patients with unmutated IGHV," Matthew S. Davids, MD, MMSc, associate director of the Center for Chronic Lymphocytic Leukemia at the Dana-Farber Cancer Institute, said after the meeting.

In the Alliance North American Intergroup Study A041202, PFS rates at the 24-month follow-up with ibrutinib were 87% as monotherapy, 88% with rituximab, and 74% in the combination with BR. Up until this trial, standard frontline chemoimmunotherapy regimens had not been compared to single-agent ibrutinib, although frontline ibrutinib monotherapy was approved in 2016 by the FDA for CLL and has been widely used in clinical practice.

"For patients with mutatedIGHV, the PFS benefit at time point is borderline, and given the lack of overall survival benefit with ibrutinib, one could still reasonably consider starting with BR in this subgroup, and then reserving ibrutinib or other novel agent-based therapies for the next line of therapy," Davids added. "Notably, this study also confirms in a phase III setting the prior observation that rituximab does not add any significant benefit to ibrutinib.”

Risk of Progression Significantly Reduced With Upfront Ibrutinib and Obinutuzumab in CLL/SLL

Ibrutinib was investigated further in the phase III iLLUMINATE (PSYC-1130) trial in combination with obinutuzumab (Gazyva) for patients with both CLL and small lymphocytic lymphoma (SLL).

Frontline use of ibrutinib plus obinutuzumab demonstrated a 77% reduction in risk of disease progression or death in patients with CLL and SLL, according to this trial. Compared to chlorambucil and obinutuzumab, the combination also reduced this risk by 85% in patients with high-risk CLL.

The ibrutinib/obinutuzumab combination was granted a priority review designation by the FDA in October 2018. Should this be approved, the regimen would be the first chemotherapy-free option available in the United States for the frontline treatment of patients with CLL and SLL.

Selinexor Combo Sees Activity in Heavily Pretreated Penta-Refractory Myeloma

Another combination with promising data was the STORM trial. According to part 2 of this study, over a quarter of patients with penta-refractory multiple myeloma responded to the combination of selinexor, an oral XPO1 inhibitor, plus low-dose dexamethasone. There was a median PFS of 3.7 months with an overall survival of 8.6 months in patients who had received at least 1 proteasome inhibitor, at least 1 immunomodulating drug, daratumumab, a glucocorticoid, and the patient’s last line of therapy.

This is the first investigational oral agent to show activity in this patient population. During his presentation of these data, Ajai Chari, MD, director of clinical research, multiple myeloma program, Mount Sinai School of Medicine, said, “Patients received a median of 7 prior therapies over 6.6 years. These patients have no known available therapies with clinical benefit.”

Triplet Regimen Could Replace Standard of Care for Transplant-Ineligible Myeloma

Another important trial in the field of multiple myeloma included the phase III MAIA study. The triplet regimen of daratumumab, lenalidomide, and dexamethasone (DRd) reduced risk of disease progression or death by 44% in patients with newly diagnosed disease who were not candidates for high-dose chemotherapy and ASCT.

After a median follow-up of 28 months, median PFS was not reached, compared to 31.9 months in the lenalidomide plus dexamethasone (Rd) arm of the trial. The PFS rate was 71% versus 56% in the DRd and Rd groups at 30 months, respectively.

An overall response rate of 93% was noted in the DRd arm, as compared to 81% with Rd. According to Thierry Facon, MD, of Claude Huriez Hospital in Lile, France, who presented these data, the results support DRd as a new standard of care for those patients who are ineligible for transplant.

Need for RBC Transfusion Reduced With Novel Agent for Low-Risk MDS-Related Anemia

Among other exciting presentations, Alan List, MD, reported the results from the phase III Medalist trial in which treatment with luspatercept significantly reduced red blood cell (RBC) transfusion dependence in more than half of the patients with anemia associated with low- to intermediate-risk myelodysplastic syndrome. The agent was also well tolerated in patients requiring regular RBC transfusions.

Of the patients treated with luspatercept, 37.9% experienced RBC transfusion independence (RBC-TI) for ≥8 weeks compared to 13.2% in the placebo arm. Furthermore, 28.1% of patients achieved RBC-TI for ≥12 weeks versus 7.9%, respectively.

Consistent OS Benefit Seen Across Patient Subgroups With Quizartinib in AML

In the QuANTUM-R trial, OS benefit was demonstrated with quizartinib, an FLT3 inhibitor, treatment for patients withFLT3-ITD-mutated acute myeloid leukemia compared to salvage chemotherapy. This agent also reduced risk of death by 24% in these patients after a frontline treatment with or without hematopoietic stem cell transplantation.

The median OS with this agent was 6.2 months at a median follow-up of 23.5 months as compared to 4.7 months with salvage chemotherapy. OS benefit was seen across several subgroups defined by response to prior therapies. Quizartinib will be explored further in the phase III QuANTUM-First study (NCT02668653).

Brentuximab Vedotin Demonstrates Survival Benefit Over CHOP in CD30+ PTCL

"Phase III results from the ECHELON-2 study were presented at ASH and contemporaneously published in theLancet [Oncology]for patients with untreated CD30-expressing peripheral T-cell lymphoma showing improved progression-free and overall survival using brentuximab vedotin (Adcetris) plus cyclophosphamide, doxorubicin, and prednisone (A+CHP) vs. cyclophosphamide, doxorubicin, oncovin and prednisone (CHOP)," Evens toldTargeted Oncology. "These data resulted in recent FDA approval this treatment platform."

The 3-year PFS rate for the brentuximab vedotin combination was 57.1% compared to 44% with CHOP. Additionally, this treatment regimen reduced risk of disease progression by 29% and risk of death by 34%.

In November 2018, brentuximab vedotin was approved for combination use with chemotherapy for frontline treatment of patients with CD30-expressing PTCL based on these data.

Significant PFS Benefit Seen With R2 Regimen in Indolent NHL

For patients with relapsed/refractory indolent NHL, the phase III AUGMENT trial found a significantly increased PFS rate with the addition of lenalidomide to rituximab compared to rituximab alone. After median follow-up of 28.3 months, median PFS was 39.4 months with the combination, named R², compared to 14.1 months with rituximab. There was also a 54% reduction in the risk of disease progression or death with R².

"Now that we can significantly improve the PFS and double the PFS while having a toxicity profile that is manageable, neutropenia being the most common adverse event, I think for many patients, the R²regimen, or lenalidomide/rituximab, will replace single-agent rituximab as a treatment option," Leonard concluded.

Overall, hematology experts were excited by the many abstracts presented at ASH this year. Find more on the data presented frommany other abstracts here.

"In addition, there were findings presented delineating the clinical activity of experimental targeted agents such as bi-specific B-cell antibodies, anti-body drug conjugates, and signaling pathway agents, (e.g., SYK/JAK inhibitor, etc)," Evens said ondata presented for relapsed/refractory patients with follicular lymphoma and diffuse large b-cell lymphoma (DLBCL), or transformed follicular lymphoma.

"Finally," Evens added, "there were several important abstract presentations examining the characteristics, prognostication and treatment outcomes for older lymphoma patients who are often underrepresented in clinical study results." Thisphase Ib/II trial in relapsed/refractory DLBCLdemonstrated OS was more than doubled with the addition of CD79b-targeted antibody—drug conjugate polatuzumab vedotin to BR.

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