Anas Younes, MD
Potentially practice-changing abstracts in the field of hematologic malignancies are slated to be presented at the 2017 ASH Annual Meeting, being held December 9 to 12, 2017, in Atlanta, Georgia. The topline findings include advancements in chimeric antigen receptor (CAR) T-cell therapy, immunotherapy, and combination strategies, among others.
During OncLive News Network’s
“Pre-Conference Perspectives on Hematologic Malignancies,” key opinion leaders sat down to share their insight on the pivotal and highly anticipated abstracts across hematologic malignancies—including lymphoma, leukemia, and multiple myeloma—ahead of the annual meeting, and exactly how these findings could be implemented in and affect clinical practice.
Brentuximab vedotin (Adcetris) plus doxorubicin, vinblastine, dacarbazine (A+AVD) as frontline therapy demonstrates superior modified progression-free survival versus ABVD in patients with previously untreated stage III or IV Hodgkin lymphoma (hl): the phase III ECHELON-1 study (Abstract 6)
The unblinded, open-label, multicenter, phase III trial (NCT01712490) randomized patients with stage III or IV Hodgkin lymphoma 1:1 to receive A+AVD or ABVD intravenously in the frontline setting. Modified progression-free survival was the primary endpoint of ECHELON-1. The FDA granted brentuximab vedotin a breakthrough therapy designation for the first-line treatment of patients with classical Hodgkin lymphoma based on these findings in October 2017, and a supplemental new drug application has been filed with the FDA.
“Finally, we have the data [and it] will be presented at the plenary session at ASH. This is a randomized phase III trial comparing standard ABVD with the experimental arm, which is brentuximab plus AVD—no bleomycin. More than 1300 patients were randomized. The primary endpoint is met with about 5% different in progression-free survival (PFS) at 2 years. This is news for us for Hodgkin lymphoma,” said Anas Younes, MD, professor of medicine and chief of the Lymphoma Service at Memorial Sloan Kettering Cancer Center.
“It is going to be subjected to a lot of scrutiny on subsets and analysis of patients who may have a higher benefit than others. At face value, it is progress regardless of how you cut it. The field has been stable for more than 4 decades, so this is good news that we have something beyond ABVD. I would have liked [the benefit] to be more than 5%, but it provides an option for some patients.”
PET-based response after 2 cycles of brentuximab vedotin (Adcetris) in combination with AVD for first-line treatment of unfavorable early-stage Hodgkin lymphoma: first analysis of the primary endpoint of BREACH, a randomized phase II trial of LYSA-FIL-EORTC intergroup (Abstract 736)
BREACH is a randomized, multicenter phase II trial designed to evaluate the efficacy of brentuximab vedotin combined with AVD chemotherapy based on PET response after 2 cycles for previously untreated patients with unfavorable early-stage Hodgkin lymphoma (NCT02292979). Earlier results have showed that the combination demonstrated a promising efficacy with a favorable safety profile in a phase I trial for treatment-naïve patients. “The question is, ‘Can we bring brentuximab vedotin to early-stage patients?’” Younes asked. “This is trickier because early-stage patients do very well; it’s so difficult to find improvement beyond the 90% to 92% PFS with standard ABVD or plus radiation therapy. Therefore, the endpoint here was a PET-negative status and it is about 7% difference in PET negativity between ABVD versus AVD plus brentuximab. It’s too early to call. We need to look at the curves in the long term follow-up.”
R-DHA-oxaliplatin before autologous stem cell transplantation prolongs PFS and OS as compared to R-DHA-carboplatin and R-DHA-cisplatin in patients with mantle cell lymphoma (MCL), a subgroup analysis of the LyMa trial (Abstract 1496)
The LyMA trial is a prospective international randomized phase III trial that investigated maintenance therapy with rituximab (Rituxan) following autologous stem cell transplantation (ASCT) in previously untreated young patients with MCL (NCT00921414). In this analysis, researchers investigated the prognostic impact on PFS and overall survival (OS) of the nature of platinum salt used in the R-DHAP regimen.
“There are data that suggest that if [patients] fail ICE (ifosfamide, carboplatin, and etoposide), you can salvage them with R-DHAP…which is against what everyone thought,” said Younes. “The platinum agents may not be created equal, but this is not a platinum by itself—there are other things with these platinum compounds. It is interesting because they did not record or specify the type of platinum needed in the salvage regimen. This is practice changing—even though these are small numbers you have to give the patient the benefit of the doubt, and most of us would now use an oxaliplatin regimen in the frontline setting.”
John P. Leonard, MD, professor at Weill Cornell Medicine/NewYork-Presbyterian Hospital, commented, “I’d like to study it a little bit more, but it is certainly a reasonable thing. There is no big downside to using oxaliplatin in the big picture…so it’s certainly worth considering.”
Efficacy and safety of acalabrutinib monotherapy in patients with relapsed/refractory MCL in the phase II ACE-LY-004 study (Abstract 155)
John P. Leonard, MD
The phase II ACE-LY-004 study investigated monotherapy with the highly selective covalent BTK inhibitor acalabrutinib (Calquence) in patients with relapsed/refractory MCL. In October 2017, the FDA granted an accelerated approval to acalabrutinib as a treatment for adult patients with MCL following at least 1 prior therapy, which arrived several months ahead of expectations under the Prescription Drug User Fee Act.
“About 100 patients with relapsed MCL were treated with second-generation BTK inhibition, which is more selective, so we don’t expect it to be more effective because it binds to the same binding site as ibrutinib (Imbruvica),” Younes explained.
“We expect it to be safer with fewer side effects. At face value, you think this is more effective than ibrutinib because the complete response (CR) rate is higher, but one needs to be careful that they use different response criteria. If you compare them head to head, there is really not much of a difference. It certainly is an interesting agent that needs to be looked at with longer follow-up.”
Long-term follow-up ZUMA-1: a pivotal trial of axicabtagene ciloleucel (axi-cel; KTE-C19) in patients with refractory aggressive non-Hodgkin lymphoma (NHL; Abstract 578)
In October 2017, the FDA approved the CD19-directed CAR T-cell therapy axicabtagene ciloleucel (axi-cel; Yescarta) as a treatment for adults with relapsed or refractory NHL, making it the second CAR T-cell therapy approval this year and overall. This abstract includes the 1-year follow-up with a data cutoff of August 11, 2017 of the ZUMA-1 trial, which was the basis for the axi-cel approval in patients with refractory diffuse large B-cell lymphoma, transformed follicular lymphoma, or primary mediastinal large B-cell lymphoma.
“Everybody wants to see how many will remain in CR at 1 year because this is a good benchmark for patients with DLBCL,” said Younes, citing additional CAR T-cell studies at the meeting. “The other ones are interesting, but they still have short-term follow-up.”
Long-term follow-up of the PRIMA Study: half of patients receiving rituximab maintenance remain progression free at 10 years (Abstract 486)
The phase III PRIMA trial investigated the benefit of maintenance rituximab (Rituxan) for 2 years after patients with follicular lymphoma demonstrated responses to frontline R-CHOP induction regimens. Median 3- and 6-year follow-up results showed a significant improvement in patients who received the maintenance treatment over observation. At the 2017 ASH Annual Meeting, an additional 4 years of follow-up will be presented.
“Clearly, the data are a very nice 10-year follow-up and the median PFS is about 10 years; it’s remarkable,” commented Younes. “However, you have to put this into context because there is a parallel trial from Italy…which did not use maintenance with R-CHOP and also reported 10-year follow-up and was published in the [Journal of Clinical Oncology] with about a 10-year PFS. It is confusing for the average person. For now, I reserve the maintenance for select patients; my default is not to use maintenance for the majority of patients.”
Leonard added, “I agree. I would say I have talked about it with my patients but, in the absence of an OS benefit, the patient has a lot of flexibility. Some people want to push being able to stay in remission, while the others say ‘I’d rather take a break from coming in for therapy.’ The good news for patients is that they have a choice, which is certainly nice.”
Results from a phase I/II study of brentuximab vedotin in combination with nivolumab (Opdivo) in patients with relapsed or refractory Hodgkin lymphoma (Abstract 649)
Using 2 agents approved in the Hodgkin lymphoma landscape, a phase I/II trial is investigating the combination of brentuximab vedotin (Adcetris) and the PD-1 inhibitor nivolumab in patients with relapsed/refractory classical disease, an area said to be one of unmet medical need (NCT02572167). Adult patients enrolled progressed on frontline chemotherapy regimens.
“This abstract has been presented multiple times in the past,” Younes recalled. “These are merely updates with more patients and more follow-ups. It is very interesting because this is a chemotherapy-free regimen and just 2 drugs, so when you get to transplant, you’re probably in better shape [because you’re] not beaten up by chemotherapy. It’s very impressive. As you know, this doublet has been moved to a randomized trial in the posttransplant setting, which is seeking approval, so now the randomized trial is this doublet, compared to the standard brentuximab alone.” Younes
Safety and efficacy of atezolizumab (Tecentriq) in combination with obinutuzumab (Gazyva) and bendamustine in patients with previously untreated follicular lymphoma: an interim analysis (Abstract 481)
Interim findings of a cohort from a phase I/II study will be presented looking at the safety and efficacy of induction therapy with obinutuzumab and bendamustine plus the PD-L1 inhibitor atezolizumab, followed by maintenance treatment with obinutuzumab and atezolizumab in patients with treatment-naïve follicular lymphoma (NCT02596971). Previously, findings from the phase III GALLIUM trial demonstrated significant improvement with obinutuzumab in combination with bendamustine, thus the mechanistic effect of PD-L1 to the immune system could further improve responses.
“That’s where the field is heading right now, to incorporate these new agents that may not have overlapping toxicities with frontline regimens,” said Younes. “Atezolizumab is a PD-L1 antibody. I’m not interested in the concurrent administration, I’m interested in the adjuvant or maintenance setting because these agents may have a better chance of eradicating minimal residual disease (MRD) compared with a passive immune therapy like a CD23[-antibody].”
Initial treatment with lenalidomide (Revlimid) plus rituximab for mantle cell lymphoma: 5-year follow-up and correlative analysis from a multi-center phase II study (Abstract 154)
Previously, results of this phase II study had shown an overall response rate (ORR) of 92% and a CR rate of 64% in patients with MCL; the regimen was also found to be well tolerated (NCT01472562). The long-term findings will include 5 years of follow-up and an exploratory analysis of immunologic biomarkers and measurement of MRD.
“We are going to move away from chemotherapy gradually, and we’ll use less and less stem cell transplant upfront,” Younes explained. “That’s my prediction. It is very intriguing that you can achieve a 4-year PFS of 70%, and OS at 5 [years] is more than 80%. We used to think the median survival of patients was 7 years, so this is clearly a great option for patients.”
Ivosidenib (AG-120) in mutant IDH1 AML and advanced hematologic malignancies: results of a phase I dose escalation and expansion study (Abstract 725)
This is the first-in-human, phase I study of ivosidenib, a potent, selective, oral, small-molecule inhibitor of the mutant IDH1 protein in patients with IDH1
-mutant advanced hematologic malignancies, including relapsed/refractory acute myeloma leukemia (AML; NCT02074839). Data will include results from 4 expansion cohorts, which comprise a total of 258 patients. Researchers investigated safety, MTD, pharmacokinetics, and pharmacodynamics.
Alexander Perl, MD
“This, like enasidenib (Idhifa), is a drug that [researchers] were able to dose escalate from very low doses to very high doses,” explained Alexander Perl, MD, member of the Leukemia Program in the Abramson Cancer Center and an associate professor in the Division of Hematology/Oncology at the Perelman School of Medicine at the University of Pennsylvania.
“From 100 mg all the way up to 1200 mg, they found no obvious dose-limiting toxicity along the way and picked a median dose to move forward because they had a biomarker to say they were inhibiting the target of the drug and reducing this byproduct of the IDH2
mutation called 2HG. They do not see an obvious drug-associated toxicity profile at this dose, but they do see differentiation syndrome with this drug as they did with enasidenib. It looks very promising, and I know that this drug is poised to be submitted very soon to the FDA for review based on these data.
Leonard commented, “I’ve heard about some pretty impressive responses, but I’ve also heard of some that were relatively short-lived, so it sounds like there is more work to do.”
Phase I/II study of venetoclax (Venclexta) with low-dose cytarabine in treatment-naïve, elderly patients with AML unfit for intensive chemotherapy: 1-year outcomes (Abstract 890)
Long-term outcomes of this combination, including 1-year OS data and biomarker analyses will demonstrate the safety and preliminary efficacy of the combination, which was granted a breakthrough therapy designation by the FDA in July 2017 (NCT02287233). The agency’s decision was based on prior findings of this study presented at the 2017 European Hematology Association Annual Congress. These showed that the ORR was 61% with a CR rate of 21%, a CR with incomplete blood count recovery rate of 33%, and a partial remission rate of 7%.
“It looks like the addition of venetoclax to that background of low-intensity chemotherapy dramatically increases the response rate,” said Perl. “What is interesting about this abstract is not really the response rates—which you can do by adding more agents to low-dose cytarabine, but the durability of the response is what is much more important. There have been many drugs added to low-dose cytarabine that have had better responses, but no improvement in OS. This looks very promising because the 1-year survivals look very good.”
Preliminary results from a phase I study of gilteritinib in combination with induction and consolidation chemotherapy in subjects with newly diagnosed AML (Abstract 722)
Gilteritinib, a highly-selective oral FLT3/AXL inhibitor was investigated in patients with newly diagnosed AML in this open-label, dose-escalation and dose-expansion phase I study (NCT02236013). The safety and clinical activity of the agent was explored when combined with frontline 7+3 induction and high-dose cytarabine consolidation therapy, and when administered as single-agent maintenance therapy in subjects aged ≥18 years with newly diagnosed AML.
“This has substantial single-agent activity in relapsed/refractory patients added to 7+3 therapy, and this is the first time the data with that drug had been presented in a combination regimen,” Perl explained. “As you can see, we are still working out the optimal dosing, but it seems like we can go to the same doses that were active in single-agent therapy, which seems to be quite tolerable and also the response rates are really quite high. There is not enough follow-up on this study to say how well this is working in the long run, but there are median survivals of about 1 year on this study [in patients] who were treated and the response rates were more than 90%.”
Low relapse rate in younger patients ≤ 60 years old with newly diagnosed FLT3-mutated AML treated with crenolanib and cytarabine/anthracycline chemotherapy (Abstract 566)
Crenolanib is a potent type I FLT3 specific inhibitor, which can be safely administered at maximal doses in combination with 7+3 induction and high-dose cytarabine consolidation. Investigators will report the CR and relapse rates of patients younger than 60 years old with FLT3
-mutated AML who were treated with crenolanib plus standard induction chemotherapy. Results will be presented from 29 patients on the study.
“What you’re seeing again here is longer follow-up,” Perl said. “We don’t have a lot more information on response rates, but they are very high in frontline therapy. The big problem in particularly FLT3
mutant AML is relapse. This is very encouraging for early data.”
Preliminary results of a phase I study of flotetuzumab, a CD123 x CD3 Bispecific Dart protein, in patients with relapsed/refractory AML and myelodysplastic syndrome (MDS; Abstract 637)
In a phase I trial, flotetuzumab (MGD006/S80880), a novel T-cell redirecting bispecific DART protein is being explored in patients with relapsed/refractory AML and MDS. Results will include the safety profile, MTD and schedule, and preliminary antileukemic activity of flotetuzumab.
“They did see cytokine release syndrome (CRS) and they did also see responses, so they basically looked like they found a manageable way to give immunotherapy with a single agent here for relapsed/refractory patients, and that is very encouraging,” Perl explained. “It is a very small study in determining what the optimal dose is, and the follow-up is still limited but this is encouraging. Again, this is not the only drug in this realm.”
Role of allogeneic reduced intensity conditioning stem cell transplantation (RIC-SCT) in older patients with acute myeloid leukemia (AML): analysis of the ALFA-1200 study (Abstract 466)
Patients with AML who have intermediate- or adverse-risk genetics are candidates for allogeneic SCT in first complete remission. However, only a small subset of them undergoes SCT due to age, comorbidities, poor tolerance of prior therapy, inability to achieve CR, or early relapse. This study examines the benefit of RIC-SCT in older patients.
“What this study shows is basically the major benefit in older patients is still restricted to the most high-risk patients,” said Perl. “The most sizeable benefit was seen in the ELN-risk adverse group with not an obvious benefit for transplant, which is a little eye-opening, but I don’t know if it’s a definitive answer. This is likely a start for other groups to be reporting their experience with this.”
Curative strategy for high-risk smoldering myeloma (gem-cesar): carfilzomib (Kyprolis), lenalidomide (Revlimid) and dexamethasone (KRd) as induction followed by HDT-ASCT, consolidation with KRd and maintenance with Rd (Abstract 402)
This single-arm, phase II study evaluated the strategy of induction therapy with carfilzomib, lenalidomide, and dexamethasone followed by HDT-ASCT, consolidation therapy and then maintenance therapy with lenalidomide and dexamethasone for patients who have smoldering multiple myeloma who are at high risk of progression to multiple myeloma. Prior studies have shown that treatment with lenalidomide and dexamethasone early in a treatment course for these patients is likely to significantly improve PFS.
C. Ola Landgren, MD
“They only have a few patients who have completed all of the therapy, and so far the numbers look very familiar to the NCI study, but the key question will be long term,” shared C. Ola Landgren, MD, professor of medicine and chief of the Multiple Myeloma Service at Memorial Sloan Kettering Cancer Center. “Will there be a big difference if you add transplant or not in terms of efficacy? It’s too early, but this study will answer an important question: do you use the most aggressive treatment upfront?”
Daratumumab monotherapy for patients with intermediate or high-risk smoldering multiple myeloma: CENTAURUS, a randomized, open-label, multicenter phase II study (Abstract 510)
Although the monoclonal antibody daratumumab (Darzalex) is approved as a monotherapy and in combination with standard regimens for patients with relapsed/refractory multiple myeloma, this phase II study evaluated the agent in patients with high-risk smoldering multiple myeloma in an effort to delay symptomatic progression to multiple myeloma (NCT02316106).
“The study has 2 coprimary endpoints, one endpoint is CR rate at 6 months, and the other one is PFS at 12 months,” said Landgren. “According to the abstract, there is a PFS difference already at 12 months of follow-up in this patient population. Maybe we should start thinking about early treatment.”
Next-generation sequencing identifies smoldering multiple myeloma patients with a high risk of disease progression (Abstract 392)
The factors which are likely to cause patients with smoldering multiple myeloma or with monoclonal gammopathy of undetermined significance to progress to multiple myeloma have not been identified. Therefore, in this analysis, investigators used next-generation sequencing on clinically annotated samples of smoldering multiple myeloma at both the disease stage and at time of progression to determine what genetic factors may be associated with progression.
“This is an interesting study; they have close to 200 patients and have conducted whole-exome sequencing and whole-genome sequencing on a subset of patients,” Landgren discussed. “Really, the idea they have is to see whether you actually genetically can predict who is going to go into multiple myeloma. There is no study that, so far, has done that for us. This study doesn’t fully answer, but it provides a lot of new clues. It shows, for example, that mutational burden is higher in what we clinically refer to as high-risk smoldering myeloma.”
Minimal residual disease (MRD) in multiple myeloma: final analysis of the IFM2009 trial (Abstract 435)
In the prospective IFM2009 trial, researchers conducted immunoglobulin gene next-generation sequencing to quantitate MRD and to correlate with PFS and OS in 700 patients who received RVD induction followed by high-dose melphalan or observation. All patients then received 1 year of maintenance treatment with lenalidomide. Investigators assessed MRD using the clonoSeq kit by Adaptive Biotechnologies.
“What they had done was they stratified the data by response in the 2 arms, and they had preliminary data at that time showing that MRD negativity was achieved in both arms,” explained Landgren. “There were more people in the transplant arm than in the other arm, but if you were MRD negative, there was very similar PFS. That’s exactly what this new abstract is looking at. Now that we are taking it to the new level, they have new sequencing data. This is important; it really pushes the field [forward] even more.”
Effect of autologous hematopoietic stem cell transplant (aHSCT) on the development of second primary malignancies (SPM) in multiple myeloma patients (Abstract 332)
SPMs are a common development for patients with multiple myeloma; moreover, prior studies of patients who underwent aHSCT have calculated standardized incidence ratios versus the general population, but have not compared the cumulative incidence of SPMs among patients with myeloma undergoing aHSCT to those who do not. This is a direct comparison of the effect of aHSCT on the incidence of SPMs in patients with multiple myeloma.
“This looks into patients treated with and without transplant upfront and they look at 5 and 10 years of cumulative incidence,” Landgren said. “They show that at 5 and 10 years of follow-up, the cumulative incidence of secondary malignancies are 4% versus 7% in the nontransplant versus transplant patients. You double the rate of secondary malignancies in these patients. The particular increase is in the patients transplanted with regard to hematologic malignancies. That might be a reason for thinking about other therapies.”
Overall survival (OS) of patients with relapsed/refractory multiple myeloma (RRMM) treated with carfilzomib, lenalidomide, and dexamethasone (KRd) versus lenalidomide and dexamethasone (Rd): final analysis from the randomized phase III ASPIRE trial (Abstract 743)
Previously, ASPIRE demonstrated that the addition of carfilzomib to Rd is associated with a significant improvement in PFS compared with Rd alone in patients with RRMM, with a median PFS of 26.3 and 17.6 months, respectively. At the time of the PFS analysis, OS data were immature, but this planned final analysis of ASPIRE will include OS results.
“This is showing that the OS is significantly better with the 3-drug combination,” Landgren explained. “Previously, it was only for PFS; now, they show that the hazard ratio is 0.79. There is a 21% reduction in the risk of death, and the median OS is 48 versus 40.4 months.”
Daratumumab, lenalidomide, and dexamethasone (DRd) versus lenalidomide and dexamethasone (Rd) in relapsed or refractory multiple myeloma (RRMM): Updated efficacy and safety analysis of POLLUX (Abstract 739)
The pivotal phase III POLLUX trial was one of 2 studies that were the basis for the FDA approval of daratumumab in combination with lenalidomide and dexamethasone or bortezomib (Velcade) and dexamethasone for patients with relapsed multiple myeloma following at least 1 prior therapy in November 2016. When the prespecified interim analysis of POLLUX was presented at a median follow-up of 13.5 months, the triplet of daratumumab, lenalidomide, and dexamethasone was found to reduce the risk of disease progression or death by 63% and significantly improved the ORR versus Rd alone. This analysis will include updated efficacy and safety data in POLLUX based on longer follow-up.
“They do not have OS data, but they have extended follow-up and the follow-up goes, this time, up to 33 months,” Landgren said. “That previously was 18 months. It holds up, and none of the 2 arms have yet met the median for PFS. That is also a very interesting combination for sure.”
Durable clinical responses in heavily pretreated patients with relapsed/refractory multiple myeloma: updated results from a multicenter study of bb2121 anti-BCMA CAR T cell therapy (Abstract 740)
The CRB-401 study (NCT02658929) is a multicenter phase I dose escalation trial of bb2121 in patients with relapsed/refractory myeloma who have received more than 3 prior regimens, including a proteasome inhibitor and an immunomodulatory agent, or are double-refractory, and have more than 50% BCMA
expression on malignant cells. This study’s initial findings were the basis for the FDA granting a breakthrough therapy designation for this patient population in November 2017.
“Similar to what we heard from in the other disease areas, the numbers are relatively small and the follow-up time is restricted,” Landgren said. “There are ongoing clinical trials using different CAR T cells targeting BCMA
in myeloma. They all showed very similar findings that the therapy seems to work if you go into higher doses; bb2121 has less of [CRS] and, reportedly—numbers were so small—but there were some patients who were followed for up to 1 year that persisted in CR. It is exciting, but we need to see more data.”
To view the full "Pre-Conference Perspectices on Hematologic Malignancies" series, visit http://www.onclive.com/inside-oncology/pre-conference-heme2017.