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Clinical

In a phase 3 study, imetelstat has shown prolonged transfusion independence and hemoglobin increase in the relapsed or refractory myelodysplastic syndrome population.

Imetelstat Displays Significant Efficacy in R/R Myelodysplastic Syndrome

Results from the phase 3 COMMANDS study were presented in a press briefing ahead of the 2023 ASCO Annual Meeting.

Luspatercept Increases Probability of Transfusion Independence in Lower-Risk MDS

The FDA has approved avapritinib for adult patients with indolent systemic mastocytosis based on findings from the phase 2 PIONEER trial.



FDA Approves Avapritinib for Indolent Systemic Mastocytosis

A phase 3 trial evaluating roxadustat for the treatment of anemia in patients receiving concurrent chemotherapy for non-myeloid malignancies met its primary end point.

Roxadustat Proves Noninferior to Erythropoietin Alfa in Non-Myeloid Malignancies

The proportion of patients with myelodysplastic syndromes who achieved red blood cell transfusion independence in the first 28 weeks was 47.5% for patients given roxadustat vs 33.3% for patients given placebo for the treatment of anemia.

Roxadustat Misses Efficacy End Point in Phase 3 MDS Study

Yazan Samhouri, MD, a hematologist/oncologist in the Division of Hematology and Cellular Therapy at Allegheny Health Network (AHN), discusses some of the current research that his team at AHN is working on.

According to Samhouri, experts at AHN have been advancing treatments for patients, including taking a giant leap forward with chimeric antigen receptor (CAR) T-cell therapy. While CAR T-cell therapy is only offered at a few cancer centers in the country, AHN is one of them.

Through using CAR T-cell therapy that is manufactured by them, clinicians at AHN are able to combat some of the most challenging cancers, including leukemia and lymphoma. With this type of therapy, there is even the potential to provide patients with a chance at remission.

In addition to research regarding CAR T-cell and cellular therapy, experts are always looking to improve upon the combination or discover better options. New clinical trials are also focusing efforts in the diffuse large B-cell lymphoma space, as well as for patients with primary central nervous system (CNS) lymphoma. These trials, according to Samhouri, are already beginning and accruing patients.

At Allegheny Health Network, we have a mission of being a center for cellular therapy. We produce our own CAR T-cell product. We have an in-house product that we have an investigation initiated in clinical trials in diffuse large B-cell lymphoma currently, and we are expanding that into other sites. We are working on starting a new clinical trial for primary CNS lymphoma using our in-house product, and we are excited about it.

Also, 2 parts of the cellular therapy is our tumor infiltrating lymphocyte program [TILs program] and we have a few clinical trials that are already accruing. That is for different disease sites, and we are expanding on that soon as well.

Videos

Yazan Samhouri, MD, discusses some of the current research that his team at AHN is working on.


Ongoing Research in the Hematology Space at AHN 

Gayathri Ravi, MD, assistant professor at University of Alabama, Birmingham, discusses the role minimal residual disease (MRD) plays in decision making and treating patients with hematologic malignancies.

According to Ravi, the use of MRD is becoming more relevant in today's practice, especially in the myeloma space. This is attributed to MRD being a strong prognostic factor.

Experts are working to find MRD-adapted treatment and management can be applied in real-world practice. Ravi notes that it will be important to determine the feasibility of using MRD in academic centers, as well as when involving community partners.

Additionally, there are still questions that need to be answered by research regarding the use of MRD, when to measure patients, how frequently to measure patients, and more.

We do know that MRD is a strong prognostic factor. We do know that people who are not able to achieve MRD negativity have early-risk of progression and relapse. At this time, most of the trials have been conducted during treatment time points to measure MRD to look at post-induction therapy, post-transplant, post-consolidation, and periodically during maintenance therapy, mostly in the trial setting and not outside in the real practice.

What we do not know is if MRD alone is sufficient to decide on discontinuation of therapy, or should we monitor additional parameters in addition to the regular myeloma labs that we measure? If so, how frequently should we measure that, especially when we decide to take patients off treatment? We do not have data on that, so that is something that is critical, especially if we are looking at MRD-based therapies where we talk about monitoring patients off treatment. Then, we need to know when we need to measure them, how frequently we need to measure them, and what else we need to measure.

Gayathri Ravi, MD, discusses the role minimal residual disease plays in decision making and treating patients with hematologic malignancies.

News

Utilizing MRD Testing in the Myeloma Space

Ben Derman, MD, assistant professor of medicine at the University of Chicago Medical Center, discussed results from a trial investigating minimal residual disease (MRD)-guided discontinuation of maintenance therapy in patients with multiple myeloma.

The prospective MRD2STOP trial (NCT04108624) enrolled 38 patients who had complete responses to therapy and MRD negativity at the 10

 threshold after 1 year of maintenance and permitted them to stop maintenance therapy. At 15 months follow-up, only 2 patients had progression, both of whom only had biochemical disease progression, and there were no deaths. Five patients had a resurgence of MRD positivity, including the 2 who progressed.

 MRD threshold based on filtered CD138-positive cells, and 4 out of the 5 patients who lost MRD negativity at 10

 after discontinuation had detectable disease at 10

 before discontinuing therapy. Derman says this suggests that patients who have detectable disease at this higher threshold may be poor candidates for discontinuing therapy, whereas others appear to be able to safely discontinue their maintenance regimen with a lower risk of recurrence.

We only have 15 months of follow-up so far on the study, but of the 38 patients who enrolled in discontinuation, we had 2 who had disease progression, 1 at 12 months, 1 at 18 months, and both were what we call biochemical progression. They didn't have bone disease, they didn't have new fractures, and these were patients that just had lab parameters showing progression. Fortunately, we've had 0 deaths. Of those 38 patients, just to come back to that, we had 5 patients who had MRD resurgence at 10

, meaning they went from MRD negative to MRD positive at some point in this study. Only 2 of those 5 patients had disease progression, like I just mentioned.

What's interesting about this is the fact that 4 out of those 5 patients who had MRD resurgence were found to have detectable disease using our 10

 assay is not only feasible but may be able to tell us who should not actually discontinue, because if you have a detectable disease on that assay, it might be telling us that something is not right here. There's still some small amount of disease that we wouldn't have been able to detect using the 10-6 assay.

Ben Derman, MD, discussed results from a trial investigating minimal residual disease–guided discontinuation of maintenance therapy in patients with multiple myeloma.

Higher MRD Threshold Could Guide Discontinuation of Myeloma Maintenance

Skye Montoya, a PhD candidate at the University of Miami Sylvester Cancer Center, discusses new research into the novel bioavailable degrader of Bruton tyrosine kinase (BTK), NX-2127.

This is a new mechanism of treatment for patients with chronic lymphocytic leukemia or B-cell malignancies that looks to 

 instead of just inhibiting it. The novel degrader NX-2127 has already shown promising early signs of degrading BTK, and impacting mutations of the BTK protein, such as BTK-wild type. 

By catalyzing the degradation of the BTK protein this becomes an important target for treatment of patients with B-cell malignancies as the B-cell development, differentiation, and signaling helps lymphoma and leukemia cells survive.

Now, research that Montoya is a part of, is looking at finding the signaling mechanism in the disease and how the degrader can be carried downstream to degrade all of the protein. She discusses how this is the first BTK degrader to actively be used with patients in the clinic showing promising activity for these patients. Moreover, she discusses how this impacts patients who have had to undergo multiple lines of therapy.

 We have a lot of different inhibitors for BTK, especially with treatment for CLL or other [patients with] B-cell malignancies. But when resistance occurs from acquired mutations to BTK, it becomes a problem of finding a way to treat the patients. These degraders, especially our new BTK degrader NX-2127, offers a very exciting avenue, as far as, how we can treat patients that did develop resistance, and especially for the patients that have been on multiple lines of therapy in the past.

New research of the BTK degrader NX-2127 shows promising results for breaking down resistance to the therapy in the lymphoma and leukemia settings. 

Breaking Down Resistance to BTK Inhibitors

Gayathri Ravi, MD, assistant professor at University of Alabama, Birmingham, discusses the main objectives of the study she presented during a poster session at the 64th Annual American Society of Hematology Meeting (ASH). The presentation discussed the role of minimal residual disease (MRD) testing in patients with newly diagnosed multiple myeloma.

According to Ravi, MRD is a strong prognostic factor and patients unable to achieve MRD negativity tend to have an early-risk of progression and relapse. However, most studies evaluate MRD in the clinical trial setting and there is not a lot of research measuring MRD in real practice.

As a result, investigators created this clinical academic-community pathway where they aimed to assess the optimal treatment and MRD-based monitoring of patients with newly diagnosed multiple myeloma. Patients enrolled in the study were also required to be eligible for autologous stem cell transplant (ASCT).

Investigators sought to evaluate the reproducibility of quadruplet induction/consolidation therapy, ASCT, and MRD-informed treatment in the real-world setting.

We presented my study as a poster [at ASH] to look at the real-world applicability of quadruplet induction, as well as MRD-based feasibility adaptive treatments to see it in the real-world setting.

Our main objective of the study looked at the reproducibility of the quadruplet induction in the real-world setting. We know the data from clinical trials like GRIFFIN [NCT02874742], but we do not know if that's reproducible in the real-world. That was 1 of the objectives, and the other 1 was MRD. It's becoming more and more relevant in today's practice of myeloma, so we tried to see how we could apply MRD-adapted treatment and management in real-world practice, as well as to see what the feasibility of that is, not just in an academic center, but also with involving our community partners.

Gayathri Ravi, MD, discusses the role of minimal residual disease testing in patients with newly diagnosed multiple myeloma.

Evaluating MRD Testing in the Real-World Setting for Patients Multiple Myeloma

Robert J. Soiffer, MD, the chair of the executive committee for clinical programs, vice chair of the department of medical oncology, chief of the division of hematologic malignancies, and institute physician at Dana-Farber Cancer Institute, discusses the approaches to integrating chimeric antigen receptor (CAR) T-cell therapy into the treatment of hematologic malignancies.

Soiffer says that currently CAR T-cell therapies have not had an impact in myeloid malignancies, including acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS), due to the difficulty targeting the cancer. CAR T cells may also target healthy hematopoietic stem cells in these patients, causing significant adverse events. One potential solution would be combining CAR T-cell therapy with allogeneic hematopoietic stem cell transplant (SCT) to introduce healthy stem cells that would not be targeted.

In addition, hematologists need to determine how to introduce CAR T-cell therapies in patients with non-Hodgkin lymphoma, according to Soiffer, now that they have been approved for large B-cell lymphomas. Based on the trials, patients who are refractory to primary therapy or have an early relapse within 12 months after therapy should be considered as candidates for CAR T-cell therapy as an alternative to cytoreductive chemotherapy followed by autologous SCT.

 At the present time, in terms of AML and MDS for which we often do allogeneic transplants, CAR T cells have not yet had an impact. I think there are some challenges with CAR T-cell therapy for AML as to determining what the correct target is for AML. There are also challenges in terms of concern for the consequences of a successful CAR T-cell eradication in leukemia because those CAR T cells may actually target normal hematopoietic stem cells and result in prolonged aplasia and low blood counts. It may be that we're going to have to combine—if we will get to the point where we have a successful CAR T cells for AML—we may have to combine that with allogeneic transplant. Integrate it so that we have a sequential approach where we either first eliminate the tumor with CAR T cells and then go on to perform an allogeneic transplant or conceivably vice versa in the opposite direction.

So, that's the future. For the present, I think that we will need to decide as a community, how we're going to integrate CAR T-cell therapy in for patients with non-Hodgkin lymphoma, high-risk large cell lymphoma specifically, who are either primary refractory, or who have had an early relapse after their initial therapy.

Robert J. Soiffer, MD, discusses the approaches to integrating chimeric antigen receptor T-cell therapy into the treatment of hematologic malignancies.

Impact of CAR T-Cell Therapy on Use of SCT for Hematologic Malignancies

Martin Dreyling, MD, Department of Internal Medicine III, LMU University Hospital Munich, in Germany, discusses findings from the phase 3 TRIANGLE study (NCT02858258) of ibrutinib (Imbruvica) in patients with mantle cell lymphoma (MCL).

presented at the 2022 ASH Annual Meeting.

According to Dreyling, the addition of ibrutinib to standard chemoimmunotherapy induction followed by autologous stem cell transplantation (ASCT) and 2 years of maintenance ibrutinib can improve outcomes vs standard chemoimmunotherapy induction and ASCT alone for younger patients with MCL.

In this study, a huge study with almost 900 patients, we could show that first of all, the add on ARM A plus I, autologous transplant plus ibrutinib, did result not only in a statistically significant but also a clinically meaningful improvement of progression-free survival [PFS]. So after 3 years, it's in the range of 15%.

The second comparison is autologous vs ibrutinib, interestingly. The predefined statistical question was superiority of autologous transplant. It's only worthwhile, the additional toxicity if it's significantly worse. Now to our surprise, the curves are flipping and therefore the ibrutinib arm is again about 50% improve PFS better after 3 years than the autologous transplant.

The third question we don't know yet. If you take ibrutinib for granted, what about additional autologous transplant? But what we have seen in fact is that the combination maybe not totally unexpected, has an increased toxicity. Therefore the data as they are now, in my opinion, are clear that definitely the autofocus standalone arm is no more standard of care and the ibrutinib containing only arm is the best tolerated 1.

Martin Dreyling, MD, discusses findings from the phase 3 TRIANGLE study of ibrutinib in patients with mantle cell lymphoma.

TRIANGLE Study of Ibrutinib Shows High Efficacy in MCL 

Ronald S. Go, MD, hematologist/oncologist at the Mayo Clinic in Rochester, Michigan, discusses what community oncologists should know regarding the guidelines on managing patients with histiocytic neoplasms.

At the end of 2021, The National Comprehensive Cancer Network (NCCN) released 

Clinical Practice Guidelines in Oncology for histiocytic neoplasms 

which provide recommendations on assisting, diagnosing, and treating adult patients with histiocytic neoplasms. The NCCN compiled data from small retrospective studies, case series, and case reports to help create the guidelines.

According to Go, diagnosing this rare group of heterogeneous cancers can be challenging. He recommends experts keep in mind that molecular studies, including next-generation sequencing for mutations that are common in these diseases, can be very helpful when performed in addition to microscopic diagnosis, and immunohistochemistry staining.

One thing that we have learned about these conditions is that the diagnosis can be challenging. For example, it is not uncommon for patients to require multiple biopsies in order to arrive at a histopathologic diagnosis. This is because the tumor cells or the cancer cells are quite scanty in these lesions, whether it's in the bone or the lymph node, or the kidneys, and therefore, multiple biopsies are required.

The other thing that we have learned about these conditions is that in addition to microscopic diagnosis, and immunohistochemistry staining, molecular studies, such as next-generation sequencing for mutations that are common in these diseases, like BRAF, or MAP kinase pathway mutations are very helpful. Oncologists should perform next-generation sequencing, and if common mutations are found, it helps solidify the diagnosis even though under the microscope or the histopathologic diagnosis case, the pathologic features may not be completely diagnostic. Finally, it helps to have the pathology slides be reviewed. Expert centers can help with this.

Ronald S. Go, MD, discusses what community oncologists should know regarding the guidelines on managing patients with histiocytic neoplasms.


Recommendations for Diagnosing and Treating Rare Histiocytic Neoplasms

Nicolas Gazeau, MS, postdoctoral research scholar at Fred Hutchinson Cancer Center, discusses next steps and unmet needs following a positive retrospective study of anakinra (Kineret) for the management of neurotoxicity and cytokine release syndrome (CRS) in patients who received chimeric antigen receptor (CAR) T-cell therapy.

Investigators are looking at drugs for managing immune effector cell–associated neurotoxicity syndrome (ICANS) and CRS, which are potentially dangerous adverse events (AEs) associated with CAR T-cell therapy. This retrospective study of 43 patients who received CAR T-cell therapy showed faster recovery from CRS and ICANS and lower non-relapse mortality for those who received a higher dose—8 mg/kg per day—of anakinra. Antitumor response to the CAR T-cell therapy was also improved in this group.

Nicolas Gazeau, MS, discusses next steps and unmet needs following a positive retrospective study of anakinra for the management of neurotoxicity and cytokine release syndrome in patients who received chimeric antigen receptor T-cell therapy.

HEMATOLOGY

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