ASH-EHA Joint Symposium Dives Deep Into the Leukemia—Down Syndrome Connection

Although several associations between constitutional syndromes, such as Down syndrome (DS), and predisposition to cancers have been recognized, recommendations for surveillance or clear association between the two are lacking. Speakers at a joint symposium between the American Society of Hematology (ASH) and the European Hematology Association (EHA), held December 2, 2018, during the 60th ASH Annual Meeting & Exposition in San Diego, California, highlighted the current understanding of cancer surveillance screening, as well as translational studies that target pathways in these and related hematologic malignancies.

Between 5% and 30% of children with DS are born with transient leukemia of DS (TL-DS), also called transient myelop- roliferative disorder.

 Mutations in the transcription factor gene GATA1, in conjunction with trisomy 21 (T21), are key drivers of this myeloproliferative disorder. Research has shown that TL-DS may lead to early death in 15% to 23% of cases; survivors may develop acute myeloid leukemia (AML) of DS in the first 4 years of their life. Although guidelines for management of TL-DS were recently developed in the United Kingdom,

The first presentation during the joint session, “Leukemia in Down Syndrome: Why Does It Happen and Why Is It Important?” was by Irene Roberts, MD, MRC Molecular Haematology Unit and Paediatrics, MRC Weatherall Institute of Molecular Medicine, Oxford, United Kingdom.

There is increased susceptibility to leukemia in DS—both myeloid and lymphoid leukemias are common&mdash;and young children are especially susceptible, Roberts said. “The incidence ratio for AML is 12 in adults and 114 in children. On the other hand, the incidence of acute lymphoblastic leukemia is 13 in adults and 27 in children less than 4 years of age,” Roberts told the audience. The incidence is negligible in solid tumors.

For her talk, Roberts focused on AML. Myeloid leukemia of DS (ML-DS) originates in fetal life and presents before the child is 4 years. “It is preceded by a stage called transient abnormal myelopoiesis, or TAM,” Roberts explained. Development of TAM and ML-DS both require trisomy 21 and acquired GATA1 mutations.

Neonatal preleukemia, she said, results from the N-terminal truncation of GATA1 protein, called GATA1s, in T21 cells. Additional mutations cause ML-DS in persisting mutant GATA1 cells and result in ML-DS before age 4.

What is the importance and relevance of leukemia in DS? Roberts listed several characteristics of this phenomenon, based on what is known in the literature combined with her laboratory’s findings:

It provides a model of the natural history of leukemia within a defined time window

T21 leads to adapting to aneuploidy, gene dosage, and T21 in non-DS leukemias

Constitutional syndromes with malignant potential are managed to implement research findings in the clinic

There are policy and societal issues associated with this phenomenon beyond the leukemia itself

Neonates with higher blasts and clinical TAM had more severe disease, as determined by using hepatomegaly, effusions, and splenomegaly. Disease severity was determined based on infiltration of tissue into mutant blast cells and fibrosis.

Roberts said that GATA1 mutations in DS neonates predict for translation of GATA1s, which is the N-terminal truncated protein. It can lead to abnormal platelet production in DS neonates. Other characteristics of TAM are giant platelets and megakaryocyte fragments.

A significant finding is that GATA1 mutations likely develop late in the second trimester or early in the third trimester of fetal development. The progression of TAM to ML-DS has several driver mutations, but the 2 most frequent mutations are in Cohesin and CTCF.

Roberts summed her findings by delineating clinical implications of the leukemia—DS relationship. “Children at high risk of developing myeloid leukemia within 4 years can be identified

at birth based on the percentage of blasts and also by GATA1 mutation analysis,” she said. This would also provide insight into those children who are at a low or no risk of developing myeloid leukemia, based on their blast count.

“A close liaison among hematologists, pediatricians, and neonatologists for guideline development would be important,” which she highlighted has recently been done in the United Kingdom.

Presenting the developments in the United States was John D. Crispino, PhD, MBA, Division of Hematology and Oncology, Northwestern University, Chicago, Illinois.

GATA1, a zinc finger-binding transcription factor, is important for megakaryopoiesis, Crispino said, with N-terminal mutants leading to congenital dyserythropoietic anemia, congenital thrombocytopenia, and congenital erythropoietic porphyria. The GATA1s mutation can result in transient abnormal myelo- poiesis, ML-DS, congenital hypoplastic anemia, and Diamond Blackfan anemia. The importance of GATA1 in erythropoiesis is underscored by the fact that GATA1-deficient mice die of anemia, Crispino said.

Crispino’s laboratory conducted high-throughput studies in vitro to identify small molecule drugs that could target the GATA1 deficiency in cells and to query if these drugs had disease-altering activity. Subsequent studies evaluated small molecule drugs that could force polyploidization in megakaryocytes and their maturation. This eventually led to the identification of Aurora kinase, which regulates cell cycle and proliferation, as a potential target, the inhibition of which can induce polyploidy and differentiation in megakaryocytic leukemia cells. Additionally, “the Aurora kinase inhibitor, alisertib, also caused a delayed differentiation-associated apoptosis,” Crispino said.

In mouse studies, primary human megakaryocyte leukemia cells are placed in mice, which were then treated with 2 cycles of alisertib and bone marrow was assayed at 27 days. The drug reduced immature human megakaryocytes in the mice and upregulated the mature megakaryocytes. The study also found alisertib to have a survival effect.

Crispino’s group then treated a myeloproliferative neoplasms—AML cell line with alisertib and found that it increased both polyploidization and GATA1 protein expression. When mice injected with these cells were subsequently injected with 3 cycles of alisertib, the infiltrated mice had a high platelet count and transient increase in hemoglobin and hematocrit.

Because these studies identified Aurora kinase A as a therapeutic target in myelofibrosis, further studies are now evaluating the drug in the clinic.

“Can this strategy be used in the treatment of other GATA1 deficiency syndromes?” Crispino asked. This question remains unanswered.

Roberts I, Alford K, Hall G, Juban G, et al; Oxford-Imperial Down Syndrome Cohort Study Group. GATA1&#8208;mutant clones are frequent and often unsuspected in babies with Down syndrome: identification of a population at risk of leukemia. 

 2013;122(24):3908-3917. doi: 10.1182/blood-2013-07-515148.

Tunstall O, Bhatnagar N, James B; British Society for Haematology. Guide- lines for the investigation and management of Transient Leukaemia of Down Syndrome. 

 2018;182(2):200-211. doi: 10.1111/bjh.15390.

NCI Director Highlights a Year of Progress in Hematology, Outlines Areas of Focus Going Forward

"Now more than a year into the job, I’ve heard from a lot of stakeholders. I’ve heard from doctors and scientists, patients and advocates, and one clear fact from all those conversations is this: it is a great time to be a cancer scientist and a cancer doctor in the United States,” said Norman Sharpless, MD, director of the National Cancer Institute (NCI), as he addressed a crowd at the 60th American Society of Hematology Annual Meeting & Exposition held December 1-4, 2018, in San Diego, California.

Sharpless highlighted numerous recent advancements in the care of hematologic malignancies, including moxetumomab pasudotox-tdfk, a new treatment for hairy cell leukemia, which hasn’t had a new treatment option in 20 years, as well as the 2 chimeric antigen receptor T-cell therapies approved in the last year: tisagenlecleucel and axicabtagene ciloleucel.

He also brought attention to 2 NCI-supported trials of both younger and older patients with chronic lymphocytic leukemia that identified a chemotherapy-free approach using rituximab and ibrutinib rather than drugs like bendamustine and fludarabine for these patients. “This is really important because we now have a relatively gentle regimen that works really well for these patients,” he said.

Sharpless called the past year an “extraordinary period” for acute myeloid leukemia, which came after decades of limited progress. In the last year and a half, the FDA has approved 8 new drugs for the disease, including 2 isocitrate dehydrogenase inhibitors, 2 Flt-3 inhibitors, and venetoclax.

Advancements like these are a result of detailed, elegant basic science, according to Sharpless. “There’s this great basic science that’s developing in hematologic cancers, and these scientific developments are translating into meaningful therapies for patients,” he said.

However, despite this progress, many will rightly say it’s not enough, said Sharpless, with many of these new therapies being only moderately effective and sometimes not curative. He called these therapies singles and doubles, noting that we still need home runs.

Following a listening tour to hear from stake- holders across the hematologic landscape, Sharpless identified areas that, while they are not new concepts, we need to sharpen our focus on in the next few years. He outlined 4 focus areas:

 Supporting the cancer research enterprise by focusing on the workforce cancer investigators

Reaffirming the NCI’s commitment to basic science to drive novel approaches and technologies

Increasing data aggregation and interpretation to speed work across the cancer enterprise

 Fully realizing the power of clinical trials through innovative design, administration, and analyses

Articles

Evidence-Based Oncology

Updates from the annual ASH meeting, December 2018.

Policy

Ted Okon, Executive Director, Community Oncology Alliance

What are some policy priorities for the Community Oncology Alliance (COA) in 2019? 

I think the top priorities when you look at COA, and as we move into 2019, are going to be surrounding these middlemen. These pharmacy benefit managers have gotten so brazen, and we have more examples of where cancer patients cannot get their medications on time or at all, or get the wrong dose or too much of the medication.

I saw one case recently where a patient received $172,000 of drugs that were totally wasted. So, we’re going to be looking at this and we’re going to be looking at these middlemen getting in the way of the patient and the physician making a decision about their therapy.

We’re seeing too many preauthorizations being held up, so this is a top priority. We’re very concerned about the federal government now giving these middlemen more power, especially in Part B, which is chemotherapy delivered in the physician’s office.

Lalan Wilfong, MD, Executive Vice President of Quality Programs, Texas Oncology 

We will be all over that, and any proposals at all that get in the way of the physician and the patient making informed decisions and going ahead with timely cancer treatment.

What are some key learnings in the Oncology Care Model (OCM) and how can they be applied to other reform models?

There have been a lot of key learnings from the OCM and how it would relate to other payment models. One is that attribution is key and making that an easy process for the practices. They have to know that the patients they enroll in the model are in the model and have that collaboration with the payer to make sure that the attribution is done well and done quickly for the practice.

Looking at total cost of care is difficult, and figuring out what the practice is and is not responsible for can be very difficult to do. Case mix is a huge issue as well; with breast cancer, for example, there can be quite a lot of variation in the appropriate price of care for different patient populations. Especially for small practices with small populations, just a little bit of a case-mix difference can cause huge variations in the total cost of care.

I think the big key learning is that whatever payment model you’re in requires significant collaboration between the practice and the payer. A lot of trust has to go into that relationship—trust that the payer will give you timely information, and trust that the practice will do what they say they will do and really look at improving the value that they provide to the patients.

What is the struggle for reimbursement for new innovative cancer therapies?

The cost of cancer care is rising dramatically, and the cost of new innovative cancer therapies is quite high for many reasons. It’s difficult to address that in a practice because we don’t control the cost of care. You just want to provide the appropriate care for the appropriate patient at the appropriate time— that’s the mantra for taking good care of patients.

It’s a difficult question to figure out how we can address that in the care that we provide. I think pathways is one way to do that, where we can look at what an appropriate, new, innovative therapy is and which patient population it should be given to. Doing innovative payment adjustments is also important so the practices aren’t discouraged from using novel therapies where appropriate. I think the challenge is figuring out which novel therapies are appropriate for which patients and making sure you’re utilizing them appropriately for the patients that you have.

What has been Texas Oncology’s experience with the OCM thus far? 

The OCM has been challenging for Texas Oncology—as it has been for all practices&mdash;but it did make us stop and think about how to take care of patients and be more patient-centric than we ever have been before.

A lot of good has come out of the program for us: having shared decision making with patients, really thinking about the cost of care, and having access for our patients [to go to] our clinics to avoid hospitalizations and emergency departments; all of which has been very good for our patients and the patient care that we provide.

The things we’ve succeeded in are simply those—making sure that we have access to our patients, making sure that we keep them out of the hospital and the emergency department&mdash;and we have done really well in those areas and have shown improvement over time in those areas for patient care.

We’ve done some very simple things for drug utilization—drugs are a big cost of cancer care&mdash;and we’ve done some very simple things for managing drugs and utilization. For example, using pathways and looking at other drugs, like antiemetics and growth factors, and making sure we’re using those appropriately.

Bo Gamble, Director, Strategic Practice Initiatives, Community Oncology Alliance

What we’re challenged with right now is that next step, that next hurdle where things get a little bit more complicated. I feel like we’ve done the easy things, and the things that are easy to rally around and do well with for the practice, but now we’ve got to start making some very tough decisions to make that next hurdle and really succeed in the program.

How does the Community Oncology Alliance (COA) view “value” in oncology, and how is that distinction determined?

That’s a great question, and it’s a question that we often get asked. COA’s perspective on value is: let’s ask all of the different stakeholders, and let’s try to come up with a model that can meet that statement or meet the value guide for everyone whether they’re a patient or an employer. A patient has their own set of values, providers have their own set of values, and the people that pay for it have their own set of values.

So, let’s come together and make sure we understand that, especially when we present the model and all the options for whatever your definition [of value] may be. To us, there’s no simple definition. But the model, the payment system, and the delivery system need to consider all of the different aspects of value.

Where do you think the future of the Oncology Care Model (OCM) is headed? How will the design model change?

I think the OCM will live its life for the next 2.5 years. They have been fairly vocal about living out the life of the model. So, it’ll end 2.5 years after this December, and then they’ll have to read reports, and maybe 3 years or 2.5 years after that they’ll come to a conclusion, “OK, well what did we learn?” Now, that’s a lifetime to me as far as reform goes.

We’re trying to learn from what we’ve seen so far, what they’ve done well, and what they struggled with, and then create sort of a baseline or a template for changing the way cancer care is to be reviewed and rewarded for everyone, not just Medicare. So, that means making it simpler—hopefully&mdash;and communicating and communicating and communicating again, because you’re going to have to. Introducing different participants, maybe national payers, is something we haven’t done in the past; maybe some big employers as well, to give them the tools to get started.

Lyn Fitzgerald, Senior Vice President, US & Global Development, National Comprehensive Cancer Network

We’ve learned a lot from the complexity of this one and the communication (or sometimes the lack thereof). Sometimes they’re a little too rigid when making changes—and at times they need to be&mdash;but sometimes they need to talk through some solutions and try to make it better for everyone. It needs to change; they’re doing a great job trying to get that process started, but we need to finish that process.

Do you think there should be greater adoption of risk-based models, and if so, why?

In a study I had read, there was, I believe, a 23% in- crease over the past 2 years, so there is a growth rate relative to adoption of alternative payment models. But relative to risk, the question is preparedness. I’m not quite certain that the system is equipped to provide a comfort level for clinicians so that they’re ready to take on 2-sided risk.

For example, something that was published in your journal, I think it was in April, David Nash from Jefferson talked about why providers were not willing to take on 2-sided risk. It was that they felt they did not have control over variation and quality within the system, and also that their lack of control was overestimated. I believe that has to do with a lack of infrastructure, so the technology is not there; the data and the feedback around medical information and claims information to allow a practice or a health system to prepare may not be there in the broader scheme for there to be wider adoption at more than the pace we’re moving at now.

How is the National Comprehensive Cancer Network (NCCN) working to define and assess “value” in cancer care?

So, in 2015, NCCN introduced the NCCN Evidence Blocks, which is a tool that allowed for clinicians and patients to have a conversation about what is important to a patient’s individual value system. We’d consider the efficacy of a therapy, safety, quality of the evidence, consistency of the evidence, and affordability.

The categories of preference are another step; it’s another tool to help clinicians understand what optimal care is. We believe that value truly is defined by an individual patient’s need, and so the categories of preference allow for our panel members to signal to clinicians, of all the recommendations in the NCCN guidelines, which are the preferred ones.

What is the struggle with reimbursement for new innovative cancer therapies?

You know, it’s interesting, because my feeling is that doctors want to do what’s right by patients, and doctors are evidence-driven. And so, truly the greatest thing that can help a provider feel comfortable providing an innovative therapy to a patient is the evidence behind that therapy.

Elizabeth Griffiths, MD, Associate Professor of Oncology, Department of Medicine, Roswell Park Comprehensive Cancer Center

So whether they’re in the [Oncology Care Model] or any type of alternative payment model, the strength of the evidence is the strength of the efficacy. The outcomes will drive the use of that innovation.

How are mutational data helping inform clinical prognosis and treatment protocol?

I think we’re beginning to understand that mutational profiles can tell us something about the character of the leukemia. Historically, we [defined] patients as either fit for induction or unfit, and we made therapy decision largely based on those clinical factors. Using mutational profiles, we can actually identify patients whose disease is likely to be intransigent to conventional chemotherapies, and with that approach, we can actually slate patients to receive therapies that are more likely to benefit them.

So, instead of giving them traditional cytotoxic therapies, which tend to have a very low rate of remission induction, in say, patients with p53-mutant disease or complex karyotype. We might offer them an alternative induction strategy, potentially with a novel therapeutic combination, like one of the venetoclax combinations. I think that recognition is likely to change the way we approach patients in the future.

Right now, a fit patient would still likely be offered a conventional induction strategy or Vyxeos, the CPX-351 liposomal cytarabine— daunorubicin combination. But perhaps in the future, we might be able to change our approach.

Kavita Patel, MD, MS, Nonresident Senior Fellow, Brookings Institution

I think the molecular profiling has also unveiled a variety of targets that we can use in combination with traditional chemotherapeutics. So, as highlighted by Keith W. Pratz, MD, associate professor of oncology, John Hopkins University, and Eytan Stein, MD, hematologic oncologist, Memorial Sloan Kettering Cancer Center, up-front combinations of both novel Flt-3 inhibitors and IDH [isocitrate dehydrogenase] inhibitors with conventional chemotherapy like 7+3 can provide really substantial rates of remission induction success and potentially deep molecular emissions, which may translate into better long- term survival for patients.

How has the Oncology Care Model (OCM) evolved? What do you think it does well, and what are some of the pain points that participating practices continue to face?

The OCM has evolved in a couple of interesting ways. Data are now a very regular kind of term with the OCM practices. Almost all of them have done something with the access to claims data that they have, so that’s actually progress.

The second thing that they’ve all noticed is that these transformation activities—care transformation and quality improvement&mdash;are all actually working. Not necessarily in the way they might have thought, but they’re making patients feel like they’re getting better care and, in some cases, they’re delivering on improvements in quality measures.

The thing that’s still not working as well is this kind of clunkiness with things like attribution. It takes a long time—there’s a lag in how CMS processes the data about attribution and what we call reconciliation. It might take doctors up to about 18 months to ultimately know if the patient they thought they were taking care of is actually acknowledged by Medicare as their patient, and then vice versa. People that they thought were their patients are not neces- sarily theirs, and they don’t find out until about a year later. So, there are still some clunky things that have to do with how Medicare just processes claims under the model.

Can you discuss some of the key trends from the OCM’s second performance period results?

Practices overall are doing better, but it’s not like it’s a massive shift. There were improvements from the first to second performance period, but we ultimately haven’t seen a large majority of practices with improvements. Now, what I don’t know about is the financial; CMS doesn’t publish the financial improvements, so you’re hearing kind of fits and spurts about practices saving money that did not save it before.

Theresa H.M. Keegan, PhD, MS, Associate Professor, Hematology and Oncology, University of California, Davis, Comprehensive Cancer Center

So overall, I would say if I were sitting in CMS’s shoes, I’d be like, “Yes, this program is still working and it’s working well.” I don’t know if it’s necessarily “meeting the expectations” of what people thought they would be when they started the OCM, but I spend a lot of time looking at all of CMS’ models and this is a model that’s doing pretty well compared to [accountable care organizations and some others. So even I would step back from performance period 2 and say that this is a model that’s working.

How represented are adolescents and young adults in clinical trials?

Overall, AYAs, which are adolescents and young adults—and we typically define that as 15 to 39 years of age&mdash;are less represented in clinical trials than children. So, back in 2006, we reported that 14% of AYAs participated in clinical trials. This was using population-based data in the Surveillance, Epidemiology, and End Results Program. This is in contrast

to children, where approximately 90% are treated at institutions with NCI [National Cancer Institute]—sponsored clinical trials and as many as two-thirds [are] participating in clinical trials. So, there’s pretty dramatic differences by age, in terms of clinical trial participation.

Has representation changed over recent years? 

So, not really, actually. Part of our goal was to look at changes over time. There’s been substantial efforts to increase both access to and participation for AYAs in clinical trials, and this is really because we’ve noticed less improvement in AYAs in survival over the past 30 years, and this has been attributed to lower participation in clinical trials as well as a number of other factors.

So, our goal was to look to see if we have seen an increase in participation over time. We were able to do some work ourselves in population-based data and found that in 2012 and 2013, we saw a modest increase from 15% to 18%, and these were in patients with acute lymphoblastic leukemia [ALL], Hodgkin, non-Hodgkin lymphoma patients, and sarcoma. But really, no significant increases over time.

Jeff Sharman, MD, Medical Oncologist, Willamette Valley Cancer Institute and Research Center; Medical Director, The US Oncology Network

There was a suggestion that there is an increased participation in ALL trials, and this has been noted by others. So, that may be the one exception; that for those patients that there is some increase in trial accrual. And there has been a lot of attention given to adolescent and young adult patients with ALL. But again, overall and in general, we don’t see increased clinical trial participation.

How does the standard of care for CLL differ based on treatment setting?

Chronic lymphocytic leukemia [CLL] is a slow-growing disease. It takes a long time for many patients to have their disease grow to a point where it needs treatment, and when patients need their first-line therapy, there are a lot of choices out there, and they’re broadly divided into a chemoimmunotherapy approach or a targeted-agent approach.

We’re going to see information in the plenary session that that exact question is being addressed in a study where patients get either ibrutinib, ibrutinib and rituximab, or bendamustine and rituximab. The findings of the study, and this is kind of somewhat an older population, is that the progression-free survival would appear to favor those patients treated with ibrutinib compared with chemoimmunotherapy.

But if you dive a little bit deeper and look at the different types of subgroups—and as we begin to talk about personalized medicine, there are some markers where the benefit of ibrutinib over chemoimmunotherapy is very clear&mdash;there are other groups where you can make an argument for a fixed-duration chemoimmunotherapy-based approach.

When you get to the relapsed setting, it really does tend to favor more of the novel targeted therapies, such as ibrutinib or venetoclax, compared with chemotherapy-based treatment.

How has the era of personalized medicine changed the way you think about treatment for patients with CLL?

Personalized medicine is a complex topic because what it generally refers to is a notion that you might find some feature or marker that’s unique to a patient and then select therapy on the basis of that marker. In the case of chronic lymphocytic leukemia, the disease is divided primarily into 2 groups of patients: those who have what’s called a mutated B-cell receptor and those who have an unmutated B-cell receptor.

In this case, mutation is good. It means you tend to have a slower-growing disease, fewer high-risk genetic markers for chemotherapy resistance, and so forth. So, by looking at the IGHV [immunoglobulin heavy chain variable] mutation or the B-cell receptor mutation status, those patients who have mutated disease are generally those patients who are going to benefit from a chemoimmunotherapy approach, whereas the patients who are unmutated are going to clearly benefit more from the novel targeted agent approach.

Robert M. Rifkin, MD, FACP, Medical Director, Biosimilars; Associate Chair, Hematology Research, McKesson Specialty Health 

AJMC®TV interviews let you catch up on what’s new and important about changes in healthcare, with insights from key decision makers&mdash;from the clinician, to the health plan leader, to the regulator. When every minute in your day matters, AJMC®TV interviews keep you informed. Access the video clips at ajmc.com/interviews.
 

AJMCtv® Interviews, January 2019

Integrating Contemporary Palliative Care in the Treatment of Blood Cancers

"Placing patients in the context of his or her family” and “caring for the living” were how palliative care was defined by one of the speakers participating in the Special Symposium on Quality at the 60th American Society of Hematology Annual Meeting & Exposition, held December 1-4, 2018, in San Diego, California. The speakers were tasked with reviewing the difference in the quality of symptom management, palliative care, and end-of-life (EOL) care delivered to patients with blood cancer and patients with other life-threatening illnesses.

Integrated palliative care, which combines care coordination for comorbidities, behavioral health issues, and EOL care, was proved to lend both symptom control and psychosocial support.

 However, these services are not always readily accessible to patients, especially in rural areas and among populations with sparse access to medical care. Organizations like Project ECHO (Extension for Community Health Outcomes) are working to fill this gap.

Additionally, controversy persists on whether patients with liquid cancers receive appropriate symptom management or whether they receive higher-intensity care, such as chemotherapy in the few weeks prior to death or a low hospice referral. Questions have also been raised over measuring the quality of symptom management and palliative care.

Palliative care is traditionally defined as “interdisciplinary care focused on improving the quality of life for persons of any age who are living with any serious illness, and for their families,” said Anthony O’Brien, MB, FRCPI, medical director of Marymount Hospice and consultant physician in palliative medicine at Cork University Hospital, Ireland, who was the first presenter.

Quality-of-life (QOL) is multifaceted and dynamic and changes over time. The traditional definition embraces patients of all ages and places the patient in the context of his or her family, O’Brien said.

O’Brien shared the clinical practice guidelines for quality palliative care, which he said are focused on life rather than death. The guidelines are:

Focus on physical, functional, psychological, practical, and spiritual consequences of a serious illness

Build on the belief that early integration of palliative care improves QOL for patients and their families

“This is not a sequential approach, rather an integrated/concurrent model of care, alongside potentially curative treatment” that the patient is receiving, he added, defining palliative care as caring for the living rather than caring for a bodily organ, age, or lack of response to treatment.

“Beyond evidence-based medicine, palliative care is a model of interpersonal medicine that is effective and has narrative competence, where we try to understand the patient’s narrative,” O’Brien said. Pointing out that several organizations, including the American Society of Clinical Oncology, are committed to integrating palliative care in the main frame of healthcare systems, he added that such integration is extremely beneficial to patients within the context of their QOL, mood, satisfaction with care, symptom burden, and “sometimes survival.”

O’Brien concluded his talk by highlighting the discomfort of treating physicians in broaching this discussion, as was documented by a study that interviewed hematologists on the topic.

The authors found that despite the positive attitude toward palliative care, barriers included difficulty with defining the role of specialist palliative care services, which resulted in referral timing being determined by their personal confidence in providing EOL care. Additionally, the participating physicians indicated the lack of an inpatient palliative care unit as a barrier to offering palliative care to their patients. O’Brien firmly believes that families must plan for dying the same way they plan for the birth of a child, and he is a strong proponent of a frank dialogue between physicians and patients.

When it comes to measuring the quality of palliative services, however, Kelly Marie Trevino, PhD, assistant attending psychol- ogist at Memorial Sloan Kettering Cancer Center, wondered whether existing measures are meaningful and sufficient to fulfill patient needs. Trevino believes that quality measures can be used to evaluate the processes being implemented throughout the administration of care, not just toward EOL.

Although the National Quality Forum’s focus for quality of palliative care includes safety, benefit, equity, timeliness, patient-cen- teredness, and efficiency of care, Trevino listed the measures that care providers currently use:

Pain management: pain screening, pain assessment, patients treated with an opioid given a bowel regimen, and patients with advanced cancer assessed for pain during outpatient visit, with documentation of a discussion of spiritual/religious concerns that patients/caregivers did not want to mention

Dyspnea management: dyspnea screening and treatment

Care preference measures: patients in the intensive care unit who have documented care and treatment preferences

Quality of care with EOL measures: comfortable dying, hospitalized patients who die an expected death with an implantable cardioverter defibrillator that has been deactivated, family evaluation of hospice care, and bereaved family survey

Providing an update on where the field currently stands, Trevino said that some of the existing quality measures are acceptable, but gaps persist. She particularly pointed out gaps in EOL care measures and the importance of patient-reported outcomes in this process, which she said are often underutilized in healthcare.

“There is inadequate attention to the disease trajectory as well. So, integration of palliative care from the beginning of treatment to EOL is important.”

Meyers FJ, Linder J, Beckett L, Christensen S, Blais J, Gandara DR. Simultaneous care: a model approach to the perceived conflict between investigational therapy and palliative care. 

Arora S, Smith T, Snead J, et al. Project ECHO: an effective means of increasing palliative care capacity. 

Wright B, Forbes K. Haematologists’ perceptions of palliative care and specialist palliative care referral: a qualitative study. 

 2017;7(1):39-45. doi: 10.1136/ bmjspcare-2014-000689.

Treating R/R CLL With Ibrutinib Alongside CAR T-Cell Therapy Reduces Toxicity, Findings Show

Patients with relapsed or refractory (R/R) chronic lymphocytic leukemia (CLL) may have a new treatment option with chimeric antigen receptor (CAR) T-cell therapy, and for patients who have already been treated with ibrutinib, continuing the targeted therapy may decrease cytokine release syndrome (CRS), based on results presented at the 60th American Society of Hematology Annual Meeting & Exposition, December 1-4, 2018, in San Diego, California.

Researchers led by Jordan Gauthier, MD, treated a total of 43 patients, starting with 24 patients with CLL were treated with ibrutinib until their condition worsened and the targeted therapy was stopped. These patients were then treated with JCAR014, a CAR T-cell therapy being developed by Juno Therapeutics.

Then, the research team treated a second cohort of 19 patients with ibrutinib; this group was similar in age and level of disease as the first group. The second cohort started ibrutinib and stayed on it during CAR T-cell therapy and for 3 months afterward.

Gauthier and his colleagues reported the following results:

83% of the patients who took ibrutinib alongside CAR T-cell therapy had either a complete or partial response.

59% of the patients who took ibrutinib prior to CAR T-cell treatment, but stopped beforehand, had a complete or partial response to therapy.

Administration of ibrutinib and JCAR014 was well-tolerated in most patients; ibrutinib was reduced or discontinued in 6 patients (35%) at a median of 21 days after the start of CAR T-cell infusion.

One patient in the cohort taking ibrutinib with CAR T-cell therapy died due to fatal cardiac arrhythmia. One patient in the cohort that stopped ibrutinib before CAR T-cell therapy died from severe CRS and neurotoxicity.

Although the percentage of patients with grade 1 CRS was the same between the 2 groups, the number was 26% higher in the group that stopped ibrutinib before CAR

The authors said results must be confirmed in a larger study, but they expressed optimism with the findings. “To our knowledge, these are the most encouraging results that have been seen to date in humans with a combination of CAR T cells and a targeted agent,” Gauthier said in a press briefing.

 “While the CAR T cells expanded robustly in both groups and led to high rates of response, we did not observe a single case of severe CRS in patients receiving ibrutinib during CAR T therapy.”

Gauthier J, Hirayama AV, Hay KA, et al. Efficacy and toxicity of CD19 CAR-T cells alone or in combination with ibrutinib for relapsed and/or refractory CLL. Presented at 60th American Society of Hematology Annu- al Meeting; December 1-4, 2018; San Diego, California. Abstract 299.

ASH 2018: Concurrent ibrutinib may improve outcomes, reduce toxicity of CAR T-cell therapy in relapsed or refractory CLL. The ASCO Post. http://www.ascopost.com/News/59527?rel=0" . Published December 2, 2018. Accessed December 18, 2018.

Teens, Young Adults With Public Insurance Linked to Worse Outcomes in Leukemia, Lymphoma

Adolescents and young adults (AYAs), defined as those 15 to 39 years of age, have not seen the same improvement in cancer survival as other age groups in recent decades. In addition, being uninsured or on public insurance, such as Medicaid, has been associated with worse overall survival than having commercial insurance.

Authors from the University of California, Davis, presented a study at the 60th American Society of Hematology Meeting & Exposition, held in San Diego, California, linking Medicaid to the California Cancer Registry to take a fresh look at these interrelated issues The research team identified AYAs diagnosed with non-Hodgkin lymphoma (NHL), Hodgkin lymphoma, (HL) acute lymphocytic lymphoma (ALL), and acute myeloid lymphoma (AML) between 2005 and 2014. These patients were classified by what type of insurance they had, including whether they had Medicaid at diagnosis or whether they were not in Medicaid and had to enroll after their received their diagnosis.

Of the 11,667 patients in the study, 4435 had NHL, 4161 had HL, 1549 had ALL, and 1522 had AML. Private insurance was most common among those with HL (66%) and NHL (60%), followed by AML (50%) and ALL (37%). Of the participants, 4059 had Medicaid, including 41% of this group who had been enrolled continuously, 43% who were enrolled upon diagnosis, and 15% who were not enrolled continuously throughout treatment. According to the authors, only 2% to 4% of patients, depending on diagnosis, remained uninsured.

Even after adjusting for socioeconomic factors, baseline comorbidities, and the type of facility where the patient was treated, patients with NHL or HL who received Medicaid discontinuously or upon diagnosis were more likely to have gotten their diagnosis at a later stage (either stage III or IV) than patients with other types of insurance. For patients with NHL, even having continuous Medicaid coverage—meaning those who were insured prior to diagnosis&mdash;had higher odds of late-stage disease. Similarly, having Medicaid at any point was associated with lower survival than private insurance. For AML, there was no similar link; for ALL, the associa- tion was seen with continuous Medicaid and other types of public coverage, although discontinuous Medicaid trended toward significance.

“Our study demonstrates that a significant proportion of patients previously thought to have public insurance were discontinuously insured with Medicaid or uninsured at time of diagnosis, only receiving Medicaid after diagnosis,” the authors wrote. “While important, insurance enrollment at diagnosis does not provide the same prediagnosis access to services as those with continuous enrollment.”

“Medicaid, regardless of type of enrollment, was associated with worse survival in AYAs with NHL, HL, and ALL relative to private insurance. Therefore, future studies should focus on factors influencing worse outcomes for AYA patients with public insurance,” they wrote.

Alvarez E, Parsons H, Maguire F, et al. Worse outcomes associated with public insurance in AYAs with leukemia and lymphoma. In: Proceedings from the American Society of Hematology Annual Meeting: December 1-3, 2018; San Diego, CA. Abstract 977. ash.confex.com/ash/2018/webprogram/Paper115519. html. Accessed January 9, 2019.

Quality of Life

Biosimilar Beats Subcutaneous Rituximab on Cost Savings in NHL

The launch of biosimilar rituximab is an eagerly awaited event among US healthcare stakeholders who are cognizant of the high cost of intravenous (IV) administered rituximab in treating non-Hodgkin lymphoma (NHL).

 At the same time, another innovation in rituximab delivery—a subcutaneously administered rituximab formulation&mdash;has the potential to save both cost and time.

During the 60th American Society of Hematology Annual Meeting & Exposition in San Diego, California, researchers presented findings from a time-and-cost simulation of subcutaneous rituximab (Rituxan Hycela), brand-name IV rituximab (Rituxan), and biosimilar IV rituximab from the US payer perspective.

 The simulation analysis was performed for 1 patient with NHL over the course of 6 cycles of treatment with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) using either standard or rapid infusion times.

The investigators derived costs of the subcu- taneous and the IV reference rituximab products from first-quarter 2018 average sales prices and 2018 reimbursement rates as listed in the Current Procedural Terminology code set. Costs for the proposed biosimilar were estimated at 15% to 35% discounts to the reference IV rituximab.

The investigators found that, following the first cycle of IV reference rituximab, switching to the subcutaneous formulation saves 650, 720, and 791 minutes (for patients with small, average, and large body sizes, respectively) over the next 5 cycles compared with continuing to use an IV option.

Costs for 6 cycles of R-CHOP, assuming a switch from the IV reference rituximab to the subcutaneous presentation at cycle 2, were $54 higher than rapid infusion but $104 lower than the standard infusion of the IV reference for patients with small body size. For patients with medium body size, the cost of subcutaneous administration was $3854 and $4012 lower than the cost of rapid and standard IV administration, respectively. For patients with large body size, the subcutaneous product saved $7762 and $7920 versus the 2 IV infusion speeds.

However, compared with an IV biosimilar rituximab, the subcutaneous option was costlier. For patients with small body size, the subcutaneous formulation cost between $3647 and $8649 more versus standard infusion and between $3805 and $8807 more versus rapid infusion of the biosimilar. For patients with medium body size, these ranges were $325 to $6109 and $484 to $6267 for the 2 infusion speeds. For patients with large body size, at a biosimilar discount of 25% or greater, subcutaneous administration cost at least $286 more than a standard infusion rate, and at a discount of at least 24%, at least $116 more than the biosimilar delivered by rapid infusion.

The researchers concluded that, although subcutaneous rituximab in R-CHOP saves on both time and cost versus using the reference IV rituximab, using a biosimilar IV rituximab saves on costs versus subcutaneous administration in small- and average-sized patients at all levels of biosimilar discount, and in large patients if discounted by 25% and 24%.

In an email to The Center for Biosimilars

, the research team said that, although further investigation is warranted to better evaluate whether these time and cost savings can be achieved in clinical practice, “we believe in the value of simulation models to advance our understanding of the potential time- and cost-savings for different formulations of oncology biosimilars. Further real- world evidence is essential in helping assess how biosimilars may help enable access to medicines for patients who may not otherwise afford them.

“What we can say,” added the authors, “is that biosimilar medicines are the future of healthcare, providing vital treatments for prevalent, chronic cancer conditions. And, biosimilars deliver the same efficacy and safety that patients and physicians trust and rely upon from reference biologics.”

Davio K. FDA approves Celltrion’s rituximab’s biosimilar, Truxima. The Center for Biosimilars website. centerforbiosimilars.com/news/fda-approves-celltrions-rituximab-biosimilar-truxima. Published November 28, 2018. Accessed December 13, 2018.

McBride A, Balu S, Campbell K, MacDonald K, Abraham I. Subcu- taneous versus intravenous rituximab in non-Hodgkin lymphoma treated with R-CHOP: economic modeling for the US. Presented at: 60th American Society of Hematology Annual Meeting & Exposition; December 1-4, 2018; San Diego, CA. Abstract 4776. ash.confex.com/ ash/2018/webprogram/Paper113283.html.

Cost-Effective Use of White Blood Cell Growth Factors in the Veterans Administration

Although the prophylaxis of neutropenia is crucial for patients undergoing cytotoxic chemotherapy to maintain dose intensity of their anticancer regimens, using granulocyte colony-stimulating factor (G-CSF) agents does increase the cost of treatment. Long-acting G-CSF agents (such as pegfilgrastim) instead of short-acting agents (like filgrastim) has the potential to push costs even higher. For health systems like the Veterans Health Administration (VHA), where controlling costs while providing high-quality care is of heightened concern, achieving the best value for money in the prophylaxis of neutropenia can help to control the cost of cancer care.

During the 60th American Society of Hematology Annual Meeting and Exposition in San Diego, California, Kevin Knopf, MD, chairman of hematology/oncology at Highland Hospital in Oakland, California, and colleagues presented research on the most cost-effective approach to using G-CSF therapies in the VHA.

Knopf and his team surveyed 23 VHA sites on their use of brand- name filgrastim (Neupogen); tbo-filgrastim (Granix), a follow-on filgrastim that was approved prior to the establishment of the US’ biosimilar approval pathway; biosimilar filgrastim (Zarxio); and brand-name pegfilgrastim (Neulasta). The researchers also estimated costs for the use of G-CSFs based on 340B pricing. Biosimilar pegfilgrastim was not included in this analysis.

The most cost-effective strategy, they found, was to use only tbo-filgrastim, as such an approach would result in a cost of $62,336 per 100 patient episodes. Eighteen of the 23 surveyed sites used tbo-filgrastim as their preferred treatment, making the VHA 73% efficient and highly cost-effective. Costs for G-CSF use in each of the sites ranged from a minimum of $62,336 per 100 patient episodes in 4 sites to a maximum of $201,356 per 100 patient episodes at 2 sites, delivering a mean cost of $99,080. Most sites, the researchers reported, were able to avoid the use of the long- acting and higher-cost pegfilgrastim; only 27% of patients across the surveyed hospitals had received Neulasta.

Furthermore, the adoption of biosimilar and follow-on filgrastim in the VHA has been rapid, the researchers said. None of the sites surveyed were using the brand-name filgrastim for new patients, and 6 of the 23 sites indicated that they were comfortable with switching patients who had previously received the branded filgrastim to a cost-saving option. Despite the willingness of the VHA to adopt follow-on and biosimilar filgrastim, however, simply switching patients to tbo-filgrastim from the brand-name option provided only a small cost savings—just 2.2%&mdash;under 340B pricing.

According to the authors, other approaches to reducing the cost of G-CSF therapy are likely to have a greater impact on the overall cost of care than a switch to biosimilars. Such approaches include avoiding the use of G-CSF therapies in cases in which there is no convincing evidence of their efficacy (for example, in patients who are classified as low-risk), and continuing to use short-acting agents instead of long-acting ones whenever possible.

Furthermore, Knopf said in an interview with The Center for Biosimilars

, there is some limited evidence that it may be feasible to prevent neutropenia by using 2-day or 4-day courses of filgrastim rather than 8-day courses. He cited a nonrandomized trial conducted in the 1990s that found that, in patients with early breast cancer, the frequency of G-CSF administration could be shortened to just 2 administrations, on days 8 and 12, without altering the patients’ outcomes.

Knopf emphasized that further investigation will be necessary to demonstrate whether shorter treatment courses are indeed effective, such an approach could deliver an additional 50% to 75% cost savings.

Knopf K, Hrureshky W, Love B, Norris L, Bennett CL. Cost-effective use of white blood cell growth factors in the Veterans Administration. Presented at the 60th Annual Meeting and Ex- position of the American Society of Hematology; December 1-4, 2018; San Diego, California. Abstract 4761. ash.confex.com/ash/2018/webprogram/Paper119724.html.

Papaldo P, Lopez M, Marolla P, et al. Impact of five prophylactic filgrastim schedules on hematologic toxicity in early breast cancer patients treated with epirubicin and cyclophos- phamide. 

 2005;23:6908-6918. doi: 10.1200/JCO.2005.03.099.

Biosimilar Filgrastim Performs in Stem Cell Mobilization

In 2016, the Saskatchewan Cancer Agency switched from the brand-name filgrastim, Neupogen, to a biosimilar, Apotex’s Grastofil, for stem cell mobilization prior to autologous stem cell transplants (ASCTs).

In a study presented at the 60th American Society of Hematology Annual Meeting, held December 1-4, 2018, in San Diego, California, researchers sought to determine the safety and efficacy of using a biosimilar for this setting.

In order to analyze the efficacy of the 2 products, the study’s authors reviewed patient charts and compared the efficacy of CD34+ collection in 170 patients who received the brand-name filgrastim with 47 patients who received the biosimilar between 2012 and 2018.

They found that the brand name and the biosimilar demonstrated similar efficacy for stem cell mobilization, as 92.4% of the patients treated with the brand name product had a successful harvest (defined as a collection of 2x106 or more CD34+ cells for patients planned for 1 stem cell transplant and 4x106 or more CD34+ cells for patients planned for

2 transplants), compared with 100% of the patients taking the biosimilar.

January 2019

Policy

AJMCtv® Interviews, January 2019

Quality of Life

Cost of Care: Biosimilars

Cost of Care

Clinical: Lymphoma

Clinical: Myelofibrosis

Clinical: Chronic Lymphocytic Leukemia

Clinical: Multiple Myeloma

Clinical: CAR T-Cell Therapy