Professor Anas Younes, Chief of the lymphoma service at Memorial Sloan Kettering Cancer Center in New York, USA, spoke to medwireNews about the current issues in lymphoma practice, from staying informed on the ever-increasing clinical advances in the field to patient awareness of treatment options in the digital era.
Professor Anas Younes (Memorial Sloan Kettering Cancer Center, New York, USA)
Keeping informed – a clear unmet need for physicians
Younes highlights the challenge practitioners face in keeping updated on the wealth of information regarding the treatment of the various lymphoma subtypes, especially for community oncologists who may be less familiar with lymphoma than the more common tumor types, such as breast or lung.
“Clinical oncologists and their clinical practices […] want to have access to useful, credible information about how to prioritize clinical trials...”
Community practitioners “need to update their knowledge because some of these subsets are potentially curable cancers,” he says, recognizing that the “average busy oncologist” may not be aware of the latest information because of the overwhelming number of advances in the science of lymphoma, drug development, drug approvals, and combination strategies.
Younes says that for physicians to meet this clinical need they should:
· Stay informed of the latest regimens for the curable types of lymphoma, such as diffuse large cell lymphoma or Hodgkin lymphoma;
· Know about the status of newly approved agents for different types of lymphoma;
· Be aware of information about potentially active agents currently in clinical trials.
However, maintaining this knowledge base can be difficult. For example, Younes explains that an oncologist looking for a third- or fourth-line therapy for a patient with mantle cell lymphoma, or other non-curable subtypes, would be unable to make a decision on which treatment to prescribe using information currently available in databases such as clinicaltrials.gov.
“Clinical oncologists and their clinical practices […] want to have access to useful, credible information about how to prioritize clinical trials and navigate through it for their patients,” he emphasizes.
Eagerly awaited lymphoma trial results
There are several clinical trials that lymphoma specialists are keen to learn the results of and which, if positive, will change the standard of care, Younes says.
In particular, results are awaited from the PHOENIX trial involving newly diagnosed patients with the non-germinal center B-cell subtype of diffuse B-cell lymphoma.
This phase III study compares the effects of an R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) regimen given with placebo or the Bruton’s tyrosine kinase inhibitor ibrutinib on event-free survival, with the final data collection for this primary outcome expected to be completed in June 2018. The trial will also report on secondary outcomes including overall survival, progression-free survival, complete response rate, and side effects.
Younes is also looking forward to two sets of phase III results for the antibody–drug conjugate against CD30 brentuximab vedotin from the ECHELON-1 and 2 trials.
The open-label, ECHELON-1 trial of patients with advanced classical Hodgkin lymphoma compares first-line brentuximab vedotin given alongside doxorubicin, vinblastine, and dacarbazine with a conventional ABVD regimen (doxorubicin, bleomycin, vinblastine, and dacarbazine).
And running in parallel, the ECHELON-2 trial has recruited patients with CD30-positive mature T-cell lymphoma to compare brentuximab vedotin alongside doxorubicin, vincristine plus prednisone against standard CHOP chemotherapy.
Immunotherapy platforms and genetic markers take the stage
The next stage in treatment development for lymphoma will be the incorporation of the new immunotherapy platforms in the front-line relapsed setting, such as chimeric antigen receptor (CAR) T-cell therapy, checkpoint inhibitors, and bispecific antibodies, Younes says.
“The field is maturing now to see combinations of these different platforms with standard chemotherapy or other targeted agents,” he comments.
The US Food and Drug Administration gave accelerated approval in 2016 for the checkpoint inhibitor nivolumab for classical Hodgkin lymphoma that has relapsed or progressed after stem cell transplantation and after post-transplantation brentuximab vedotin, with approval for pembrolizumab expected to follow.
Nivolumab, pembrolizumab, or atezolizumab may also have activity against non-Hodgkin lymphoma in combination with other agents in the front-line relapsed setting, Younes says.
In addition, he suggests that research should focus on “dividing and conquering the different lymphomas, the different pathways and biomarkers, and the genetic landscape,” allowing treatment to be tailored to individual patients.
Although such treatment options are not currently available, there are ongoing studies to identify targets that may guide future therapies, such as the detection of mutations in isocitrate dehydrogenase (IDH)2 in around a fifth of angioimmunoblastic T-cell lymphomas [1], among other malignancies and diseases.
This has led to several phase I/II clinical trials assessing the novel IDH2 inhibitor, AG-221, in patients with hematologic malignancy harboring the IDH2 mutation and those with angioimmunoblastic T-cell lymphoma or advanced solid tumors with an IDH2 mutation.
Alterations in EP300, which encodes the histone acetyltransferase p300, have also been detected in a B-cell lymphoma cell line [2] and this has, in turn, led to the possibility of targeted therapies, such as the histone deacetylase (HDAC) 1, 2, 3, and 11 inhibitor mocetinostat.
Ongoing studies into this agent include an open-label phase II trial in patients with diffuse large B-cell lymphoma or follicular lymphoma that carries a mutation in EP300 or a second acetyltransferase gene, CREBBP, and a phase IB/II trial in relapsed or refractory Hodgkin lymphoma in combination with brentuximab vedotin.
Increasing treatment options in the digital era – A good problem to have
The increasing number of treatments available for lymphoma means that oncologists have to choose from a variety of different therapy options.
“And with the increased access of patients and caregivers to information online, this can be confusing for them too,” Younes says.
He notes that this confusion frequently leads to patients visiting different doctors and clinical centers for opinions on the best treatment for their lymphoma and being given multiple correct answers to choose between.
“It’s a good problem to have, to have options, but again it can be confusing for patients,” Younes says.
Patient-reported outcomes and side effects in the clinic
Not only is the number of treatments increasing but also, for certain drugs, the length of time patients take them. Patients may now take some lymphoma agents until disease progression or toxicity, such as ibrutinib or the PI3K inhibitor idelalisib, approved in the USA as a third-line treatment for malignancies including follicular B-cell non-Hodgkin lymphoma and small lymphyocytic lymphoma.
This “forever” use requires clinicians to look at the long-term efficacy, safety, toxicity, and financial issues, Younes observes, leading to the need for patient-reported outcome studies.
In some cases, such as with idelalisib, uncommon but serious toxicities have arisen after the agent was approved, he explains.
“Fatigue is a complicated issue,”
Furthermore, weight gain and fatigue are frequently reported by lymphoma patients during or after treatment, including in patients who have been cured.
“Fatigue is a complicated issue,” Younes comments, noting that it is not always related to anemia, a side effect that can be managed with growth factors and other treatments.
“It’s multifactorial and requires a more thoughtful investigation in some instances”, he continues.
Lymphoma survivorship clinics perhaps need to consider factors such as thyroid issues, weight gain, and early menopause that can contribute to fatigue and be addressed individually, Younes advises.
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