The B-cell receptor (BCR) inhibitors ibrutinib (Imbruvica) and idelalisib (Zydelig) have revolutionized the treatment of chronic lymphocytic leukemia (CLL); however, “There are still a significant number of patients who will relapse after those therapies or discontinue because they’re intolerant,” said Jeffrey Jones, MD.

At the 2016 ASH Annual Meeting, Jones presented findings from a phase II study demonstrating high response rates with the BCL-2 inhibitor venetoclax (Venclexta) among patients with CLL who had progressed, relapsed, or were refractory to ibrutinib (n = 43), idelalisib (n = 21), or both agents (n = 4). The overall response rate with venetoclax was 67%, including 70% of patients previously treated with ibrutinib and 62% treated with idelalisib.

: Can you discuss the design of the study?

 at ASH, Jones, an assistant professor of Internal Medicine in the Division of Hematology at The Ohio State University, discussed the promising early data for venetoclax in CLL after progression on BCR-pathway inhibitors, as well as the next steps with the research.

: One of the things that happens in clinical medicine is new advances, no matter how great they are, often create new clinical situations and new unmet medical needs. That's happened in CLL medicine with the addition of kinase inhibitor therapy—although it is remarkably effective for the majority of patients, there are still a significant number of patients who will relapse after those therapies or discontinue because they're intolerant.

The new drug venetoclax, an oral inhibitor BCL-2, was recently approved here in the United States for treatment of CLL with deletion 17p relapsing after at least one prior therapy. That drug has a unique mechanism distinct from ibrutinib or idelalisib that makes it interesting to assess in the context of treatment failure after those drugs.

This trial was a phase II study of single-agent venetoclax in 2 parallel cohorts of patients. One was a group of patients progressing after or during treatment with ibrutinib. The second cohort of patients was progressing after or during treatment with idelalisib. In fact, the majority of patients, about 43 patients, treated in the ibrutinib arm progressed during ibrutinib treatment. On the other hand, the majority of patients treated in the idelalisib arm were treated after discontinuing ibrutinib for reasons of toxicity or tolerance. Slightly different groups of patients.

Overall, venetoclax was highly effective in both groups of patients. In the ibrutinib arm where patients had been in treatment longer, the overall response rate was 70%; it was 62% in the arm after prior treatment with idelalisib. That compares favorably with prior studies of single-agent venetoclax in relapsed/refractory CLL, many of whom had never been exposed to a kinase inhibitor.

One concern that's arisen as venetoclax is moved into the clinic is the need to better understand its toxicity profile. In some earlier studies of venetoclax, there were cases of hyperacute tumor lysis syndrome that required urgent intervention in order to manage. Modifications were made in prophylactic measures and a careful dose ramp-up schedule that was employed in the trial we're speaking about.

Is there a reason you wanted to look at venetoclax specifically?

What will the findings of this study mean for patients?

What are the next steps for this research?

With that, there were only 2 cases of biochemical tumor lysis reported in this trial between both groups of patients. Neither of those cases required urgent medical intervention like hemodialysis. The remainder of the toxicity was consistent with what had been reported in the past—chiefly hematologic, mostly neutropenia and thrombocytopenia, but not associated with a higher incidence of infection beyond what might expected in a group of relapsed and refractory CLL patients.

Retrospective data that has been presented previously and is being updated at this meeting suggests that older drugs like chemotherapy and single-agent monoclonal antibodies achieve suboptimal responses in this setting, with overall response rates no higher than 30% in patients progressing after 1 or both kinase inhibitors. Looking for drugs that have a novel mechanism of action and have a favorable safety profile is what really generates interest in general. Venetoclax is a drug like that with a distinct mechanism of action, favorable safety profile, and excellent single-agent activity, making it chief among the available drugs that are in advanced stages of clinical development. Plus, since it's an oral agent, it doesn't require hospitalization in most patients for care. There's no clinic visits for infusions. It improves patient acceptability.

As kinase inhibitors move beyond academic practice and become more widely adapted in the community, there's going to be a growing group of patients exposed to those drugs and unfortunately a larger group of patients whose disease will progress after treatment with those drugs. This is really the first prospective study in this emerging group of patients that demonstrates there is an effective option with a favorable risk benefit ration. I think this immediately suggests that the first best choice for patients, and particularly those progressing after ibrutinib who don't have access to investigational therapies, is this treatment with venetoclax.

We're presenting data on the first group of patients that was accrued to the trial. There are just over 60 patients. A larger group of patients has been treated in an expansion cohort after treatment with one or both of the kinase inhibitors. What we're really interested to understand is how durable these first responses will be. Are there some patients who are prone to early relapse? If so, can we identify who those patients are to think about other strategies for them, maybe combination strategies or early referral to transplant or CAR T-cell therapy? Among the patients who achieved durable responses, is there some indicator where the responses are sufficiently deep so they might be able to discontinue therapy in the future?

Overall, many people are interested in thinking about these drugs given concurrently rather than sequentially, as was done in this trial. Is there a way of giving ibrutinib with venetoclax as a way of preventing the clinical situation we're describing, which is a high-risk patient with disease progressing because of acquired resistance [to one of those drugs]? Many of our great successes in oncology have come with combination therapies using drugs with nonoverlapping mechanisms of action and nonoverlapping toxicity profiles. That's the next step as we move forward with the novel targeted agents.

Jones J, Choi MY, Mato AR, et al. Venetoclax (VEN) monotherapy for patients with chronic lymphocytic leukemia (CLL) who relapsed after or were refractory to ibrutinib or idelalisib. Presented at: 2016 ASH Annual Meeting; December 3-6, 2016; San Diego, CA. Abstract 637.

Articles

Jeffrey Jones, MD, discusses promising early data for venetoclax in chronic lymphocytic leukemia after progression on BCR-pathway inhibitors, as well as the next steps with the research.

Expert Discusses Value of Venetoclax After BCR Inhibition in CLL

Lenalidomide (Revlimid) as a maintenance treatment for patients with newly diagnosed symptomatic multiple myeloma demonstrated encouraging phase III findings in the Myeloma X1 trial, which were presented at the 2016 ASH Annual Meeting.

In the multicenter, open-label, randomized, UK study, 1550 patients were randomized to receive maintenance lenalidomide or observation following maximum response or at 100 days after transplant.

Results showed that the lenalidomide maintenance therapy arm was associated with a 55% reduction in the risk of progression or death compared with the no maintenance arm (HR, 0.45; 95% CI, 0.39-0.52; 

 <.0001). The median progression-free survival (PFS) was 37 versus 19 months for lenalidomide maintenance and no maintenance, respectively.

: Can you provide some background on this maintenance study?

 during the meeting, lead study author Graham Jackson, MD, professor, consultant hematologist, Newcastle Hospital, provides an overview of the study and the impact of maintenance therapy with lenalidomide on the landscape of multiple myeloma.

: The Myeloma XI trial that we presented is a large phase III study conducted in over 100 centers in the UK. We recruited more than 4000 patients to the trial in its entirety. The data being presented are about lenalidomide maintenance, and examining patients who went through their treatment and responded. They were randomized on a 1:1 basis between lenalidomide maintenance and no maintenance treatment.

The findings of this study, in about 850 patients, is that lenalidomide—throughout all patient populations&mdash;increased the number of people staying in remission. The PFS across the whole cohort increased by about 22 months and, for the transplant-eligible patients, by nearly 28 months.

What is the main takeaway from this study?

Even for the older population, the PFS increased by over 12 months. All patients, of all ages, benefited from the lenalidomide maintenance. The results really confirm the data that have been put together looking at the meta-analysis of lenalidomide maintenance. Our results really nicely integrate with this, showing that lenalidomide maintenance is now the standard of care for patients with myeloma in their first response.

There is now a huge body of evidence across a large number of patients. There were 857 patients in our study who went on to receive lenalidomide maintenance. We have shown that it is safe, deliverable, and really prolongs remissions. It prolongs the remission of patients who are in a transplant-eligible group. It also prolongs the remission in those patients who are older, frailer, and are not eligible for transplant. It's an across-the-board benefit.

How was the adverse-event profile in this study?

We have shown it’s safe. There were some questions about the instance of secondary malignancies in this group of patients, but we have also shown that this incidence of second primary malignancies is really not as significant as we first thought.

Some main adverse events from lenalidomide maintenance are around hematological toxicity. The most common grade 3/4 toxicity was neutropenia. We didn't see a lot of infection and, on the whole, most patients seemed to tolerate the treatment very well. Of course, with lenalidomide maintenance, you can adjust the dose so the patient stays on the therapy without having to come off the drug because of toxicity.

Is there anything else that was presented at the 2016 ASH Annual Meeting that you found exciting?

What are some of the challenges in myeloma that you would like to see addressed in the next few years?

One of the interesting pieces of data we are looking at shows that, if patients stay on maintenance longer, they benefit more. We saw that patients who came off the study early because of toxicity generally relapsed quicker than patients who managed to stay on the drug. Obviously, there are a number of reasons why that might be; however, it does speak to the possibility that prolonged maintenance is important.

The next steps are that are we are going to look at overall survival (OS). The meta-analysis would suggest that patients who are on lenalidomide maintenance gain an advantage not only in PFS but also in OS. The data suggest that it might be as long as 2 years. We should have a readout on that data very soon. Hopefully, we can confirm that, not only is there a PFS advantage from lenalidomide maintenance across a large group of patients in the study, but there is a survival advantage, too.

This has been a really exciting meeting, in terms of the myeloma data. The daratumumab (Darzalex) combinations continue to be exciting. We've seen the POLLUX data presented by Philippe Moreau, MD. Those data look really stunning. The researchers looked at minimal residual disease in those populations and showed that they can achieve some really deep responses. It looked like they were doing really well. That's exciting.

There are many challenges we still face in multiple myeloma. The number one challenge is the fact that we are still not curing all the patients. We do very well with patients who respond and have low-risk disease. Clearly, there is a lot of focus on patients with the highest-risk disease—the patients who go through their treatments very quickly and only respond transiently. With that group, there is a clearer unmet need, even now.

Also, patients become refractory to a number of different therapies. We've seen a very nice piece of data called the STORM study about selinexor (KPT-330) in that group of patients. That study looks interesting. There are more novel agents coming, which is exciting.

Jackson GH, Davies FE, Pawlyn C, et al. Lenalidomide is a highly effective maintenance therapy in myeloma patients of all ages; results of the phase III Myeloma XI study. Presented at: 2016 ASH Annual Meeting; December 3-6, 2016; San Diego, CA. Abstract 1143.

Lenalidomide as a maintenance treatment for patients with newly diagnosed symptomatic multiple myeloma demonstrated encouraging phase III findings in the Myeloma X1 trial, which were presented at the 2016 ASH Annual Meeting.

Expert Touts Value of Lenalidomide Maintenance in Myeloma

Since the FDA approval of nivolumab (Opdivo) in May 2016, researchers continue to explore the agent as well as its fellow PD-1 inhibitor, pembrolizumab (Keytruda), in various treatment settings for patients with Hodgkin lymphoma.

In 12-month follow-up results of the phase II CheckMate-205 trial presented at the 2016 ASH Annual Meeting,

 patients with classical Hodgkin lymphoma (cHL) who received brentuximab vedotin (Adcetris) after autologous hematopoietic stem cell transplantation (AHSCT) treated with nivolumab had an overall response rate (ORR) of 67.5%, with a duration of response of 13.1 months (95% CI, 8.7-NA). The median progression-free survival was 14.8 months.

Results from a separate CheckMate-205 cohort supported the FDA’s approval of nivolumab for patients with cHL who relapse or progress after AHSCT and posttransplantation brentuximab vedotin.

In December 2016, the FDA granted a priority review to a supplemental biologics license application for pembrolizumab as a treatment for patients with refractory cHL or those who have relapsed after ≥3 lines of therapy. This is based on findings from the phase II KEYNOTE-087 and phase Ib KEYNOTE-013 trials, which evaluated pembrolizumab for the proposed indication in the application.

: Can you provide a recap of your talk on Hodgkin lymphoma?

In an interview, David J. Straus, MD, an internist and hematologic oncologist at Memorial Sloan Kettering Cancer Center, provides an overview on recent findings and future directions in Hodgkin lymphoma. Straus spoke on these topics during the 2016 

 State of the Science Summit on Hematologic Malignancies.

: The first portion was on overall results in a rare type of Hodgkin lymphoma, nodular lymphocyte-predominant Hodgkin lymphoma, which is about 5% of Hodgkin lymphoma. It is different biologically, as well as clinically, from cHL in that it is a lymphoma with a mature B-cell phenotype. It also has a behavior with an excellent prognosis, but late recurrences—somewhat akin to low-grade B-cell non-Hodgkin lymphoma (NHL). This is a disease where there is no evidence of a decreased survival at diagnosis. Also, there are little data to suggest that any treatment affects the overall outcome.

This was a look at patients who relapse after initial treatment on various studies of the German Hodgkin Study Group, which puts a lot of patients on treatment. They had various protocols that they use for cHL. They ended up with 99 patients who relapsed after their initial treatment. They did not include patients who transformed to an aggressive NHL, which is the clearest indication for treatment.

The bottom line was that everybody did great. They used various treatments, including autologous transplant. The survivals were close to 90% to 100% for whatever they did. In these 99 patients, they only had 10 deaths, 5 of which were due to nodular lymphocyte-predominant Hodgkin lymphoma and 5 due to treatment, including 3 secondary malignancies, 1 infection, and 1 pulmonary failure.

The other 3 abstracts I covered pertained to the use of checkpoint inhibitors. Two of them had really been tested extensively and involved the PD-1 inhibitors pembrolizumab and nivolumab. Both of these have excellent, high response rates in very heavily pretreated patients after autologous transplants and usually after brentuximab vedotin.

The 2016 ASH Annual Meeting was the first time both of these were presented in full form. Nivolumab was actually published by my colleague Eunice L. Kwak, MD, PhD. The excellent results led to an accelerated FDA approval for nivolumab in patients with Hodgkin lymphoma who relapse after autologous transplant and who fail brentuximab vedotin.

Both the pembrolizumab and nivolumab trials had 3 cohorts. Basically, they were relapse/refractory patients after autologous transplants, most of whom had brentuximab vedotin, which is the label for nivolumab, but some of them did not have brentuximab vedotin. There were some patients who were not candidates for transplants; most of them were older patients who, for 1 reason or another, were not fit to undergo transplant.

The bottom line is that they all showed an ORR of around 65% in all cohorts in both drugs, within the complete response rate of about 22%. They had longer follow-up data than had been shown before, which demonstrated durable responses. Most of the responses occurred after 2 to 3 months.

The last one was a combination of nivolumab with brentuximab vedotin prior to transplant in relapsed patients after first-line treatment. They gave 4 cycles of the 2 drugs together. In the first cycle, they staggered the drugs. In the second, third, and fourth cycle, they gave them together. Approximately 20% of patients on this follow-up had gone on to autologous transplant. They had good stem cell collection. The ORR was quite impressive at around 90%, and there was around a 60% to 65% complete response rate—which is very impressive.

Are there any ongoing studies that have the potential to change practice?

What is interesting about this is that we have 2 newer regimens. Nivolumab is not chemotherapy; it is immunotherapy. Brentuximab vedotin is chemotherapy, but it's a new delivery system—an antibody-drug conjugate&mdash;that delivers the drug to the tumors. That is very intriguing and provocative; perhaps we do not have to give people high-dose regimens such as ICE (ifosfamide, carboplatin and etoposide), ESHAP (etoposide, methylprednisolone, cytarabine, and cisplatin), and DHAP (dexamethasone, high-dose cytarabine, and cisplatin). Perhaps you could get away with this type of treatment before transplant.

We want to achieve a PET complete response with the use of ESHAP or ICE prior to transplant because we have shown that the outcomes are much better if the PET is negative prior to the transplant. If you can achieve that with what is in these heavy-duty chemotherapy regimens, that would be very interesting. However, these are early data and it has to be confirmed in other trials, as well as further follow-up data.

Nivolumab and pembrolizumab are very exciting because, for the first time ever, there is a treatment that works that is not chemotherapy. Even brentuximab vedotin is a kind of chemotherapy; it is a better delivery system, but it's still chemotherapy.

If pembrolizumab gets approved, will there be any sequencing challenges? How would you decide what therapy to use first?

Now, you have drugs with a high response rate that are not chemotherapy. There are real opportunities for this. The question is going to be how to introduce these drugs as early as possible into people who you can possibly identify as being the 10% to 15% of patients who are truly chemotherapy resistant.

I believe nivolumab’s label is for use in patients who relapse after transplant following failure to brentuximab vedotin. I suspect the filing for pembrolizumab may be similar. They say, at the present time, they have very similar response rates and very similar toxicity profiles. More data may be important to see which one might be preferable.

Reflect on the data that we heard at the 2016 ASH Annual Meeting. If you jumped ahead 5 or 10 years, what does the landscape for Hodgkin lymphoma look like?

It should be pointed out that we are talking about a very small number of patients. This is not going to be a big moneymaker for the companies because the number of patients who relapse after transplant and brentuximab vedotin who are available for this are a small number of patients. At the present time, I don't see a big difference between these drugs.

We've been curing this disease for 40 years. Seventy percent of patients are cured with ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine). The biggest thing that we can do is to eliminate radiation therapy when it's not needed. That's the thing that has the biggest effect on long-term outcome. This is because these patients, after 10 years, begin to get toxicities particularly related to radiation therapy, led by second primary cancers and followed by cardiovascular disease.

We actually have looked at our long-term results and we found, after 5 years or so, the deaths due to Hodgkin lymphoma plateau. Deaths due to other causes begin to be picked up after 10 years and, after 20 years, they exceed those due to Hodgkin lymphoma.

The things that are not causes of mortality are also causes of serious morbidity in the survivors, namely second prior cancers and cardiovascular events. The biggest thing we can do to improve this is to get rid of radiation therapy and, if it’s necessary, to use it safely.

 entitled, “Radiation Therapy for Hodgkin Lymphoma: Can It Be Administered More Safely if Necessary?" We argue for drastically reduced treatment ports that will reduce the off-target effects of other organs, in the case of mediastinal radiation to the heart, lungs, and breasts. I don't know if this can be done, but this is a direction the radiation oncologist should go in.

Limiting and eliminating radiation therapy is the most important thing we can do to improve long-term outcomes. There is a real opportunity now for immune-based therapies and better chemotherapy to improve the results in initial treatment. The ECHELON-1 study is a randomized phase III trial of 1240 patients comparing ABVD—which we've been using for 40 years&mdash;with brentuximab vedotin plus AVD. The trial has completed accrual. We are all interested to see if, for the first time in 40 years, actually adding a new drug to the backbone of the regimen we have been using will improve response and progression-free survival upfront.

Timmerman J, Engert A, Younes A, et al. Checkmate 205 update with minimum 12-month follow up: a phase 2 study of nivolumab in patients with relapsed/refractory classical Hodgkin lymphoma. Presented at: 58th ASH Annual Meeting and Exposition; December 3-6, 2016; San Diego, CA. Abstract 1110.

Chen RW, Zinzani PL, Fanale MA, et al. Pembrolizumab for relapsed/refractory classical Hodgkin lymphoma (R/R cHL): phase 2 KEYNOTE-087 study. 

Since the FDA approval of nivolumab in May 2016, researchers continue to explore agent as well as its fellow PD-1 inhibitor, pembrolizumab, in various treatment settings for patients with Hodgkin lymphoma.

Hodgkin Lymphoma Field Evolving With Immunotherapy, Adjustments to Standard Approaches

Emerging therapies in myeloproliferative disorders such as chronic myeloid leukemia (CML), polycythemia vera (PV), and myelofibrosis could have the potential to shake up the landscape. But, during the 2016 

 State of the Science Summit on Hematologic Malignancies, Michael J. Mauro, MD, noted that there is a great deal of work ahead for researchers.

“It's still a battle for patients,” said Mauro. “They still have long journeys, side effect management, a lot of decision making with multiple medications, and new drugs on the horizon. However, this is a very good ending to what was really the breaking story of targeted therapy in cancer.”

: What did you lecture on at this State of the Science Summit?

In an interview during the meeting, Mauro, a hematologist and leader of the Myeloproliferative Neoplasms Program at Memorial Sloan Kettering Cancer Center, discusses the major questions regarding the current state of CML, as well as explorative options for patients with PV and myelofibrosis.

: Regarding state of the art for CML, some of the major questions we have are, “What is new from a therapeutic standpoint for patients with highly resistant CML?” and “Can patients who have been on therapy and are in deep remission stop therapy?” There were a number of presentations at the 2016 ASH Annual Meeting about these topics.

There was a presentation of updated data from the phase I trial of ABL001—which is a fourth-generation tyrosine kinase inhibitor (TKI) that is given orally once or twice daily&mdash;showing very good safety and preliminary efficacy for patients with any stage of CML. We have a phase II dose established and a real signal that this drug could not only be a drug used in the salvaged setting, but perhaps combined earlier in lines of therapy.

Also, at the 2016 ASH Annual Meeting and in the last year, we have seen a lot of development around treatment-free remission. There's been a change in the NCCN guidelines that were just updated for CML. We now have a little rulebook to go by through the NCCN. That wasn't really the case before, it was really just regulated through clinical trials. We have more mature data coming out of ASH for patients from a larger European trial. It's a little bit better guidance on how long a patient should be in treatment, how long they should be in deep remission, and more.

What are some of these pivotal studies for CML?

Some other studies from ASH showed us that maybe patients can reduce their dose of a TKI before a discontinuation without showing significant relapse. There was also a little more information on the type of factors that play into what patients are successful with treatment-free remission. This includes changes in the immune system, the immune cell repertoire, and patients who are successful with TKI therapy. Those are the highlights for CML.

The EURO-SKI trial looked at the success of treatment-free remission in a very large number of patients—over 700&mdash;from Europe. Part of the most innovative findings was learning patients need to be on TKI or in deep remission for about 5.8 years for it to be the most successful. That was the dividing line where success was higher versus lower.

What do you imagine the landscape of CML looking like in 5 to 10 years?

What are the optimal ways of managing some of these side effects?

We are starting to shape the picture of what a patient with CML might need to look like before they can think about treatment-free remission, from the EURO-SKI trial.

For myeloproliferative disorders—CML specifically&mdash;we're getting better and better targeted therapies. We're really coming “full circle” in that we're not only putting a high fraction of patients in remission without what people consider conventional chemotherapy, but we are really talking about a functional cure, which plenty of people didn't think was possible. That is great news.

Decision making for patients with CML takes some thought and finesse. First, TKI therapy is based on patients' profiles and perhaps their comorbidities. Comorbidities play an important role in CML. They may have more of an impact than CML responses shown in a recent paper by Germans in the 

. The side effect management encompasses knowing what a patient's comorbidities are and thinking TKI may be best for them. When you're looking at resistant disease, you're obviously going to think a little bit differently about comorbidities. However, they need to be managed.

What is important to highlight regarding myeloproliferative neoplasms (MPNs)?

The most important breaking story is likely cardiovascular or vascular risk. Patients need to have a good base on cardiovascular assessment, like they should have in primary care—or maybe at the direction of the oncologist to see a specialist to know what their comorbidity really is. They need to manage that as they navigate through TKI therapy, as well as drugs with vascular risk.

Here, we are a little further behind CML. However, we are really making nice progress. One important thing in 2016 was the update of the World Health Organization's (WHO) definitions of MPNs. What used to be called masked polycythemia vera (mPV) is now identified, which means we've lowered the bar and recognized patients with PV. Patients who have lower but still elevated hemoglobin levels may have PV and should be evaluated and diagnosed as such.

We've recognized a prefibrotic form of myelofibrosis, which was always tough to separate from thrombocytosis or overt myelofibrosis. It's now a category in WHO. We've received some nice clarification of what were the trickier forms of MPNs to diagnose.

We've also seen the first appearance of guidelines for MPNs from the NCCN. We don't have the full set of treatment guidelines. What we have now for myelofibrosis is some direction on how to treat our patients based on their risk. There was an important notification that patients should have their symptoms assessed by a symptom-assessment scale—a tool that's been validated and published. We shouldn't forget about autologous transplant with such patients.

When we think about therapeutics, there have been some big questions in the field and thinking about PV and thrombocytosis for ET. There is a large trial that has accrued and is asking this question for high-risk patients without previous therapy: is interferon versus hydroxyurea—which tends to be the standard&mdash;more effective? What's the real benefit? It’s too early to say.

At the 2016 ASH Annual Meeting, through the MPN consortium, we saw a presentation of this important study that is showing pretty equal results with regards to hematologic response, bone marrow, and molecular response. The thinking is that you will probably need to wait a little longer to see that data mature to fully assess it.

Also at the meeting, with regard to myelofibrosis, we've had ruxolitinib (Jakafi) approved for many years and have been looking for competition. Can there be a different JAK inhibitor that could offset some of the anemia we see with ruxolitinib? What about patients with low platelets? They're hard to treat. There are updated data from studies of pacritinib, which is a JAK inhibitor, with the possibility to be useful in patients with low platelets.

Who are the most appropriate patients to receive ruxolitinib?

Can you speak to ruxolitinib’s role in PV?

Not presented at ASH, but in the background, is updated data on momelotinib, another JAK inhibitor with a probable ability to offset anemia. Some of its trials showed that it could hold its ground and offer some of the similar benefits of ruxolitinib, but not as complete as we thought. We are soon going to have alternative JAK inhibitors that allow us to treat patients with more difficult blood count imbalances.

It's important to identify the patient that can benefit from JAK inhibitor therapy. It's going to be the patient with symptoms and high-risk disease. The main benefits of ruxolitinib are going to be spleen size reduction and symptom management. These patients, by default, are often some of the higher-risk patients, particularly with enlarged spleens. It's remarkable to see the symptom control and the improvement in quality of life. Even the improvement in survival is probably due to global reduction of complications such as thrombosis and comorbid complications from the burden of advanced myelofibrosis.

Ruxolitinib has been approved for PV for a while now. It probably stands on the middle ground as the drug we would think of after some initial therapy—whether or not it's hydroxyurea. I mentioned that interferon and hydroxyurea are battling for first place in the higher-risk PV patient. Ruxolitinib offers the ability to render someone's phlebotomy independent and show spleen size reduction and good symptom improvement, similar to how we see it in myelofibrosis. It's an improved drug for the patient who doesn't respond to hydroxyurea.

Emerging therapies in myeloproliferative disorders such as chronic myeloid leukemia, polycythemia vera, and myelofibrosis could have the potential to shake up the landscape.

Landscape for Myeloproliferative Disorders Becoming More Defined With Improved Treatments, Biomarkers

Though T-cell lymphoma is a more rare hematologic malignancy, researchers are exploring therapies such as brentuximab vedotin (Adcetris) to improve outcomes for these patients.

For example, the double-blind, randomized, multicenter, phase III ECHELON-2 trial is comparing brentuximab vedotin plus doxorubicin, prednisone, and cyclophosphamide (CHP) with standard CHOP as a potential frontline treatment for patients with CD30-positive mature T-cell lymphomas (NCT01777152). The primary endpoint is progression-free survival (PFS) with an estimated completion date of December 2017.

“Now, there's this constant stream of clinical trials adding to standard therapy or instead of standard therapy,” says Steven Horwitz, MD, who lectured on T-cell lymphoma during the 2016 

® State of the Science Summit on Hematologic Malignancies. “For a patient who is interested, there probably is access to something new or different if they want to try something different from the standard.”

: Can you provide an overview of your research with T-cell lymphoma?

What are some current clinical trials that are happening in relation to T-cell lymphoma?

Horwitz, an associate attending physician at Memorial Sloan Kettering Cancer Center, sat down for an interview during the meeting to discuss standard initial therapy for patients with T-cell lymphoma with a look ahead to what the community can expect next in the field.

: In my presentation, I discussed T-cell lymphoma, and highlighted what some of our standard initial approaches are, as well as some of the newer data that do not yet modify our standard approach—but maybe they will on the horizon. I also went into some newer data in relapse diseases, including a couple of subtypes, some things that were published this past fall, and a couple of more relevant abstracts from the 2016 ASH Annual Meeting that may be practice relevant, if not totally practice changing.

In terms of the upfront setting, a trial that is accrued now but we are waiting on data, is adding brentuximab vedotin to standard combination chemotherapy. This is the ECHELON-2 study, which adds brentuximab to CHP, which is a combination of doxorubicin, prednisone and cyclophosphamide. That was randomized in a double-blinded fashion against CHOP plus placebo.

It's a study with more than 400 patients, which is by far the biggest for a prospective randomized study we have in T-cell lymphoma. It's going to give us a lot of very good quality data. It just finished accrual within the past month, so data will likely be out within the next year or 2. That's probably the next thing that has the best chance of really improving, or stepping up standard of care, in patients with anaplastic large cell lymphoma, and perhaps across the board in any of the CD30-expressing T-cell lymphomas. That's pretty exciting.

What abstracts from the 2016 ASH Annual Meeting could be practice changing?

Another new, ongoing study is looking at the addition of lenalidomide (Revlimid) to standard combination chemotherapy. There is another study adding romidepsin (Istodax) upfront. As we get results from those studies within the next couple of years, we are going to have a wave of studies saying, "Is something really better than CHOP?" or, "Is adding 1 of these newer drugs really making a difference for some subset of the patients?"

There were not a ton of studies in T-cell lymphoma. There was a randomized study called the ALCANZA study, which randomized patients with cutaneous T-cell lymphoma that expressed CD30. They defined it in that study as 10% or greater. There were a couple phase II studies about brentuximab vedotin that looked promising, but this was a randomized study where, in rare diseases like T-cell lymphoma, we have very few randomized studies against standard treatments. In this case it was bexarotene or methotrexate.

There was a 100-patient study done in the United States, Europe, and Australia—really powerfully in favor of brentuximab vedotin. Therefore, the overall response rate was much higher&mdash;about 68% for the single agent&mdash;which recapitulates the small phase II studies, so there wasn't really regression in a multicenter setting.

There’s another study of the drug in which the responses were at least 4 months durable, which was the primary endpoint. That was significantly better for brentuximab vedotin. The PFS is more than 4 times better, so that drug in a big, international study looked a lot better than a lot of the other standard therapies we commonly use.

That is the kind of thing where we are going to say that this drug has a high response rate and some chance of complete responses, which is very different than the moderate response we get from a lot of other drugs. That is going to factor into decision-making, partly because the patients with cutaneous T-cell lymphoma are so symptomatic. Depth of response and degree of response has a big impact on quality of life. That is the one that's ready to use. It's using the same guidelines. This is the third study now looking at that drug in that setting.

The other interesting data in cutaneous T-cell lymphoma was with pembrolizumab (Keytruda), so now we’re looking at checkpoint inhibitors. We don't have a lot of data in T-cell lymphoma. This was a phase II study in mycosis fungoides and Sézary syndrome. The response rate was about 38%. A lot of the responses were durable, and people were still in remission at 6 to 12 months.

What are some of the biggest challenges that remain in this field?

This may be a new drug to be able to get access to which, in a decent-sized study, looks like it has pretty good activity. These patients who have cutaneous T-cell lymphoma move from one treatment to another. As they get further along in their course, you're often looking for new treatments. Typically, that's investigational therapy. There may be some access at checkpoint inhibition based on these data for those patients.

The main problem in these systemic T-cell lymphomas is that we just don't carry enough people. We do combination chemotherapy and we add autotransplant in first remission. But even with all that, the cure rates probably don't get much above 40% or 45%. It's a disease where we need new and better therapies. It's nice to see that some of the new therapies have now moved to the frontline setting, and we'll see what those studies show. If those randomized studies are better, those will be new standards of care. If they're negative, then we are back to the drawing board.

Is T-cell lymphoma considered to be a heterogeneous disease?

We are also doing research to move beyond this one-size-fits-all approach. A lot of the drugs approved in relapse T-cell lymphoma were treated in unselected patients. In addition to finding newer and better therapies, we also want to understand whom those treatments are most likely to work in. This way, we can better select which patients are likely to benefit from which therapies, and then look at potential combinations.

Because it's rare from a clinical trial-understanding standpoint, we tend to lump them together; however, there are more than 20 different subtypes. Even as we get more of an understanding of the genetics and of the disease, we see that—even with some of those top subsets&mdash;there is some heterogeneity. That's surprising. As you learn more, you start splitting these things up more and more. When you don't have very good tools and it's chemotherapy, it may not make a ton of sense to stratify. You treat everybody and see what happens.

What is it like to see these checkpoint inhibitors making their way through the hematology field?

As we have more targeted therapies—to target CD30, CCR4, and PI3K&mdash;then it's probably more important to understand where those targets are important in which patients. We need to be smarter about selecting patients to enroll on clinical trials, to understand if you're hitting those targets, and to see if it makes an impact on the disease. If not, how will we figure that out and improve those treatments?

It's exciting. We're kind of late to the game. These drugs have been around for a while. In solid tumors, you are seeing some fairly durable responses in a number of diseases.

In T-cell lymphoma, there has been some concern because you are targeting things that are on the tumor cells—you're not just targeting the immune system. There's a lot of overlap between malignant T cells and normal T cells. In some early studies, it is unclear whether a patient’s disease accelerated or the treatment is just not effective. It's nice to see studies where you are seeing the majority of patients have stable or better disease. You're seeing some real, durable responses.

What are the takeaways for community oncologists to apply to clinical practice?

There was some interesting data at the ASH meeting about some other novel approaches. There are several drugs that are looking at CD47 or that pathway, which is more of a macrophage target. It may be a way of stimulating the immune system to fight tumor cells without directly stimulating T cells and getting other immune effector cells involved. There were some very early data there, but that's another strategy that is being looked at and could be relevant in T-cell lymphoma.

In terms of T-cell lymphoma, there's a lot of heterogeneity. Get your stories straight. Make sure you understand the diagnosis. Clarify the goals of treatment with patients. Sometimes we hear that it's a horrible disease and it's fairly hopeless. I would say while the cure rates are not what we want, in a patient who can get an aggressive approach; they're still in the 40% to 45% range.

Though T-cell lymphoma is a more rare hematologic malignancy, researchers are exploring therapies such as brentuximab vedotin to improve outcomes for these patients.

T-Cell Lymphoma Options Burgeoning With Ongoing Clinical Trials

A combination regimen of the BCL-2 inhibitor venetoclax (Venclexta) plus low-dose cytarabine (Depocyt) demonstrated an acceptable safety and pharmacokinetic profile in elderly patients with treatment-naïve acute myeloid leukemia (AML), according to findings of a phase I dose-expansion study presented at the 2016 ASH Annual Meeting.

Results showed that the overall response rate was 75%, with an estimated 12-month overall survival (OS) rate of 74.7%. The majority of patients, all of whom (n = 20) were ineligible for intensive anthracycline-containing chemotherapy, experienced clinical remissions. The median OS had not been reached.

Further clinical trials exploring this early, yet encouraging regimen, add to a growing list of promising therapies for patients with AML, including midostaurin (PKC412) for patients with newly diagnosed 

-mutated disease. The FDA granted a priority review to midostaurin for this indication in November 2016.

Additionally, venetoclax received a breakthrough therapy designation by the FDA in January 2016 for use in combination with hypomethylating agents in treatment-naïve patients ineligible for standard high-dose induction treatment.

Pracinostat, an HDAC inhibitor, was also granted a breakthrough therapy designation for use in combination with azacitidine (Vidaza) for newly diagnosed patients who are aged more than 75 years or are ineligible for intensive chemotherapy.

“I want people to know it is an exciting time,” says Martin S. Tallman, MD, hematologic oncologist, chief of Leukemia Service, Memorial Sloan Kettering Cancer Center. “We have many new exciting agents—novel agents&mdash;that are going to be rapidly incorporated into the treatment of patients with AML. Finally, we are going to make significant progress in the field.”

: Can you provide an overview of your presentation?

Tallman, who lectured on the changing AML landscape during the 2016 

® State of the Science Summit on Hematologic Malignancies, sat down for an interview to discuss these novel therapies and the future role of transplantation in more detail.

: The presentation has to do with the state of the art in the treatment of AML in 2017. The state of the art rests on a number of principles. First, the disease is really defined today by cytogenetic and molecular or genomic abnormalities. Second, induction chemotherapy can be intensified for the benefit of patients. Third, consolidation might be able to be deintensified. Fourth, the benefit of allogeneic transplantation has only increased, and there has been an expanded pool of patients who may benefit from transplantation.

What role will transplant continue to have as more agents are developed and improved going forward?

Fifth, there is an increasing awareness of the importance of minimal residual disease studies, both following intensive chemotherapy and before allogeneic transplantation. Finally, and perhaps the most exciting, is the development of new agents that are very promising in the treatment of AML today.

More patients are able to undergo transplantation. First of all, we’re able to transplant older adults more safely. We have been able to expand the pool of patients who are potential candidates because of increasing graph sources such as umbilical cord, haploidentical transplant, and combinations of umbilical cord and haploidentical transplant.

Are there any characteristics that patients might have in which you don’t recommend they undergo transplant?

What are some of the novel agents that are moving down the pipeline?

A very important principle that has emerged is that patients who have minimal residual disease before transplantation have less favorable outcomes after transplantation. Now, there are major efforts to try to eradicate all evidence of disease before undergoing transplantation.

Patients who have favorable-risk disease, have core binding factor AML, or have acute promyelocytic leukemia, are patients who have a sufficiently favorable outcome without transplantation. Then, they are not going to benefit from transplantation.

One of them is the drug called venetoclax. Venetoclax is a BCL-2 inhibitor. It’s actually been approved for patients with chronic lymphocytic leukemia, but it’s been used very successfully now by patients with myeloid leukemia, particularly in combination with hypomethylating agents such as decitabine (Dacogen) or azacitidine. There have been several studies that have combined it with azacitidine or decitabine, suggesting that the drug in combination is very effective in AML.

At the 2016 ASH Annual Meeting, there was an abstract combining venetoclax with low-dose cytarabine. This is a drug regimen that we don’t give so often anymore but, when combined with venetoclax, looks very promising in the setting of AML. That’s one of the most exciting drugs.

What does the landscape of AML look like to you in the next 5 to 10 years? 

There’s another drug that is not as much of a therapeutic drug as it is a supportive care drug, and that is eltrombopag (Promacta). Eltrombopag is a thrombopoietin-receptor agonist designed to stimulate platelet production following intense chemotherapy for AML. There were several abstracts at the meeting suggesting that, when given an induction or consolidation, there is marked increase in platelet count and we may be able to obviate the need for platelet transfusions and perhaps decrease bleeding.

I honestly think there has never been a more exciting time. People say that, but it is really true. We have more drugs with unique mechanisms of action that have effectiveness on their own but are now being combined with each other in chemotherapy. The future is going to be combining novel agents with induction chemotherapy and with each other. We are looking at an exciting next several decades.

Wei A, Strickland SA, Roboz GJ, et al. Safety and efficacy of venetoclax plus low-dose cytarabine in treatment-naive patients aged ≥65 years with acute myeloid leukemia. Presented at: 58th ASH Annual Meeting and Exposition; December 3-6, 2016; San Diego, CA. Abstract 102.

A combination regimen of the BCL-2 inhibitor venetoclax plus low-dose cytarabine demonstrated an acceptable safety and pharmacokinetic profile in elderly patients with treatment-naïve acute myeloid leukemia.

Novel Therapies Likely to Transform AML Landscape

Novel therapies are being investigated in 2 areas of hematologic malignancies, but the first-line setting is where the brunt of research needs to be conducted, explains Andrew D. Zelenetz, MD, PhD.

For patients with indolent lymphoma or chronic lymphocytic leukemia (CLL), the optimal frontline choice does not exactly exist, he says. While treatment options have evolved and improved over time, researchers are still debating between bendamustine- or CHOP-based regimens for follicular lymphoma, for example. And while chemoimmunotherapy remains a standard frontline approach for younger, fit patients with CLL, it’s not as clear as to what is best for the older patient population.

Zelenetz, the medical director of Quality Informatics at Memorial Sloan Kettering Cancer Center, spoke on indolent lymphoma and CLL treatment during the 2016 

® State of the Science Summit on Hematologic Malignancies. In an interview during the meeting, he discussed how the field has evolved over the last several years to include more effective treatments, and the work being done to determine optimal first-line therapies in both spaces.

: When you are diagnosed with follicular lymphoma, your expected survival is inferior to the age match general population, but not by very much. The median survivals in this disease have changed from 8 to 10 years 25 years ago, to 16 to 20 years as a median survival today.

We know that first-line therapy is important. First-line therapy can result in long progression-free survival (PFS). We’re still struggling to find the optimal first-line therapy, whether it’s bendamustine-based, or CHOP or CVP; the answer is not crystal clear.

One of the interesting things we saw from the 2016 ASH Annual Meeting is what’s called the GALLIUM trial, which is bendamustine plus CHOP or CVP combined with rituximab (Rituxan) or obinutuzumab (Gazyva). This was a head-to-head comparison of rituximab versus obinutuzumab in indolent lymphoma. The follicular lymphoma cohort was spoken about at the presentation, while the non-follicular indolent cohort wasn’t. It actually met its endpoint. The statistical plan was looking for an improvement (with obinutuzumab)—a hazard ratio of 0.74. The hazard ratio is 0.66. That corresponds to a 50% increase in the PFS.

People think that not much has been accomplished because the curves don’t look that different, but the curves can’t look that different. A 50% increase in PFS is going to correlate to about a 10-year survival after first-line therapy. That’s pretty impressive, and it’s going to be hard to beat. We have a large, randomized study comparing rituximab and lenalidomide (Revlimid) with rituximab chemotherapy, but it’s going to be hard to beat a median PFS of 10 years with chemoimmunotherapy.

In the CLL world, we are still struggling with first-line therapy. There’s a group of patients, particularly young, fit patients with mutated immunoglobulin genes, who have a 10-year PFS in the range of 70%. They’re probably cured. There are very few events in that group of patients. From that group, which is a very small group, we can define a standard of care, which is FCR (fludarabine, cyclophosphamide, and rituximab).

However, for the older patient or the fit patient who does not have a mutated immunoglobulin gene, chemoimmunotherapy works, but will fail. Findings from the RESONATE-2 trial suggest that you can give ibrutinib (Imbruvica). However, the problem with ibrutinib is it’s going to be far too expensive in the United States, let alone the rest of the world. This is the economic challenge of introducing new drugs early in the treatment paradigm. We know ibrutinib works really well after chemoimmunotherapy. In the selected patient, ibrutinib should be used. We now have idelalisib (Zydelig) and venetoclax (Venclexta), so we have other options in the relapsed refractory setting.

There are a couple of the emerging things from the 2016 ASH Annual Meeting in the relapse setting for indolent lymphoma. Ibrutinib looks okay in marginal zone lymphoma, but positively awful in follicular lymphoma. Again, this is pointing out that all indolent lymphomas are not created equal; these are different diseases.

Going back to indolent lymphoma, you mentioned there’s no optimal first-line choice. What are the factors you consider when looking at a patient to determine which therapy you are going to give them first?

In upfront CLL, following chemoimmunotherapy, there seems to be a role for lenalidomide maintenance. Here’s yet another treatment we have that can [improve] PFS—not in itself a very cheap one either&mdash;but at least this was demonstrated in a particularly high-risk population that did not achieve an minimal residual disease (MRD)-negative status. These are patients who had greater than 10

 but another adverse feature, such as an unmutated immunoglobulin gene, 

 mutation, or deletion 17p. This group of patients, when selected, had a clear benefit in PFS. It is too early to see any survival difference, and there may not be an overall survival (OS) difference given the ability to treat patients in the relapsed setting.

It’s interesting because the GALLIUM study is actually the first large-scale, well-done study of a bendamustine-containing treatment. People may argue we already have the StiL trial and the BRIGHT trial, but the StiL trial was a community-based study. The toxicity was dramatically underreported, as well as the long-term consequences because the follow-up wasn’t very good.

Given the data we saw at this year’s ASH Annual Meeting, where do you see the future for indolent lymphomas going?

In CLL, what is your go-to approach for when patients fail on either ibrutinib or idelalisib?

The BRIGHT study was an overall response rate study, so follow-up essentially ended at response. One of the things we’ve seen in the GALLIUM study is there is an excess early-death rate in bendamustine-treated patients. When I first saw that data number months ago, I was concerned. That will have a bearing on what I do in the upfront setting. I will probably give a little more old-fashioned CVP and stick to CHOP-based treatments. Based on the data, integration of obinutuzumab in chemoimmunotherapy and follicular lymphoma really is the right way to go.

The challenge is going to be in identifying high-risk patients. If the median time to progression is going to be around 10 years, what we really need to do is identify those 20% or so patients who fail within the first 12 months or the first 24 months. Those patients have a very poor survival, but the challenge has been to identify them when we first treat them. Those are the patients who need to be targeted for novel treatment strategies because chemoimmunotherapy is a very effective treatment for the standard-risk patient.

There are 2 ways to fail a kinase inhibitor. One is to progress. If you progress on ibrutinib, then going to the other kinase inhibitor apparently doesn’t work very well. We know that from a retrospective study presented at the 2015 ASH Annual Meeting by Anthony Mato, MD.

Secondly, you can fail if you’re intolerant of the drug. You come off of ibrutinib because you have severe muscle cramping and you just can’t tolerate any more. You have copious diarrhea on idelalisib but you’re responding, then switching to the alternative kinase inhibitor is a viable treatment strategy.

However, for patients who are progressing on ibrutinib and idelalisib, we saw preliminary data from Jeffrey Jones, MD demonstrating that single-agent venetoclax is very effective in this group of patients with very high response rates. A number of patients were actually able to achieve an MRD state. We do have treatment options for patients who are progressing on the kinase inhibitors.

Acalabrutinib and BGB-3111 are pseudo next-generation [drugs]. The reason they are pseudo-next generation is they’re really not “next-generation” drugs. They have exactly the same mechanisms of action. They bind to the active site cysteine and they covalently modify the drug.

We know that acalabrutinib and BGB-3111 don’t interfere with antibody-dependent cell-mediated cytotoxicity in culture, so they should play better in vivo with monoclonal antibodies. That has to be proven. There should be fewer T-cell effects with acalabrutinib and BGB-3111. We know they can achieve very high levels of occupancy of BTK and are highly active in CLL.

What are your thoughts on the ongoing research exploring nivolumab (Opdivo) in CLL?

What are the important takeaways oncologists should have?

If you had the 2 drugs at the same time in the laboratory and had to pick 1, you might have picked 1 of the others, but once ibrutinib is there it becomes pretty hard to displace—unless there’s a clear differentiating factor. That might be in combination with drugs. Limited duration of therapy in combination might be more effective with 1 or the other of the BTK inhibitors.

There was a trial of nivolumab combined with ibrutinib with Richter’s transformation. All of the activity observed with nivolumab was in patients who had Richter’s transformation, which is the activity you would expect ibrutinib to have in patients with CLL. Nivolumab really added something to patients with Richter’s transformation, but not very much to patients with CLL.

We are in an evolving era of management of indolent lymphoma. Initial therapy is providing very long and durable benefits. The benefits we are seeing now are better than the OS from 2 decades ago. Chemoimmunotherapy remains the standard of care. Personally, I’m going to use less bendamustine.

With CLL, the major challenge is figuring out how to use the novel agents in a much more effective way rather than giving them continuously. What I hope community oncologists will do is try to get involved in novel clinical trials, get their patients enrolled or refer them to these trials because we need to learn how to optimally use these new agents.

Novel therapies are being investigated in 2 areas of hematologic malignancies, but the first-line setting is where the brunt of research needs to be conducted.

Elizabeth Leick