AJMCtv Interviews: ASH19 Edition

Lena Winestone, MD, Assistant Professor of Pediatrics, University of California, San Francisco

What have you found regarding how neighborhoods, specifically if they are those with low income and low education, impact survival in children with cancer?

We found that children with acute myeloid leukemia, a type of leukemia that aff ects children, have an increased risk of mortality if they come from a low-income or

high-poverty neighborhood. In particular, we looked at that and broke it down in several diff erent ways. We looked at the risk of relapse and found that there was an increased risk of relapse among those patients. And in addition, we found that they had a higher risk of toxicity that led to mortality among that patient population. Finally, we looked at early mortality as a marker, potentially, of access to care, and found that low-income patients also have a substantial increased risk of

early mortality or death during the fi rst course of chemotherapy, suggesting that a component of what’s going on may be related to access.

Reference

Winestone LE, Getz KD, Bona KO, et al. Area-based socioeconomic disparities in survival of children with newly diagnosed acute myeloid leukemia: a report from the Children’s Oncology Group. Presented at: 61st—American Society of Hematology Annual Meeting & Exposition; December 7-10, 2019; Orlando, FL. Abstract 703.–ash.confex.com/ash/2019/webprogram/Paper130978.html. Accessed December 21, 2019.

Michael Wang, MD, Professor, Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center

What were your findings of using ibrutinib as a frontline treatment in patients in mantle cell lymphoma (MCL), and how might these findings change treatment decision making for these patients?

A perfect example of the toxicities of chemotherapy is the Hyper-CVAD [cyclophosphamide, vincristine, doxorubicin and dexamethasone] chemotherapy. Hyper-CVAD has been used for young patients newly diagnosed with mantle cell lymphoma. [To receive] Hyper-CVAD, you have to be in the hospital for 7 days, and then every month for 8 cycles, therefore, 8 months; and [approximately] 20% of patients after 15 years will develop another cancer. So, in order to cut down this therapy, you cannot say, “Hey, Dr Wang, today I have ibrutinib and I don’t need Hyper-CVAD,” that’s not science. In science and clinical medicine, you cannot go from one extreme to the other extreme, you have to have a stepwise, gradual fashion.

So, WINDOW-1 clinical trial was designed—and it [was] presented in a poster¹—we used an ibrutinib chemo-free window—why’s it called a window, because before strictly heading to chemotherapy, we use rituximab-ibrutinib in the window period and we fi nd out, after we get a complete remission, then we can use the chemotherapy with only 50% of the original dosage? The WINDOW-1 [clinical trial] utilized the chemo-free therapy upfront with ibrutinib and rituximab; in this case, the response rate is nearly 100%. The CR [complete remission] rate is between 92% to 94%, and you can see it in my poster and in my abstract. And my God, this is very powerful. And then, after patients are already in CR, we given them 4 cycles of chemo consolidation.

This, so far, is very successful. I have presented these data many times. We think we made progress to cut down the chemotherapy by incorporating, in a rational way, the chemo-free therapy. And of course, you never want to stop—the WINDOW-2 trial, in addition to ibrutinib and rituximab, we added another chemo-free agent, called venetoclax, which is targeting BCL-2—very powerful. And with this we try to drive the overall response rate to 100%. And then, if the patient is low-risk, there will be no chemotherapy needed. High-risk … blastoid, big tumors, and complex karyotype, 4 cycles. Low-risk none, intermediate[-risk] only 2 cycles. You can see from WINDOW-1 to WINDOW-2, gradually we are reducing chemo and try to further improve efficacy and decrease mortality from the toxicities. So, it’s a very exciting time for chemo-free therapy.

Reference

Wang ML, Jain P, Lee HJ, et al. Frontline treatment with ibrutinib plus rituximab (IR) followed by short course R-HyperCVAD/MTX is extremely potent and safe in patients (age ≤ 65 years) with mantle cell lymphoma (MCL)—results of phase-II WINDOW-1 clinical trial. Presented at: 61st American Society of Hematology Annual Meeting & Exposition; December 7-10, 2019; Orlando, FL. Abstract 3987. ash.confex.com/ash/2019/webprogram/Paper126044.html. Accessed December 21, 2019.

C. Ola Landgren, MD, PhD, Professor of Medicine, Chief of Myeloma Service, Memorial Sloan Kettering Cancer Center

Carfilzomib is currently approved to treat patients with relapsed or refractory multiple myeloma—what did you find regarding the safety and efficacy ofcarfilzomib in newly diagnosed patients?

At [the 61st American Society of Hematology (ASH) Annual Meeting & Exposition] 2019, I’m the lead presenter, I’m the lead principal investigator for a phase 2 trial developed at [Memorial] Sloan Kettering, where we used the combination of carfi lzomib with lenalidomide, dexamethasone, and also daratumumab. This is a phase 2 trial targeting newly diagnosed multiple myeloma patients.

The cohort I present uses once a week dosing with carfi lzomib—it’s a so-called 20/56 mg per meter squared dosing. So, 20 mg per meter squared, the first dose, and every other dose after that 56 mg per meter squared. So, once a week on a 4-week schedule means day 1, day 8, and day 15. Daratumumab is given standard dosing per the FDA label, which is 16 mg/kg body weight and is given weekly for the fi rst 2 cycles and then is every other week for another 4 cycles. And the last cycles are once every 4 weeks. This phase 2 trial includes a total of 8 cycles of therapy. And the patient can go on [the trial], if they have a new diagnosis of myeloma, they fi t the standard eligibility criteria, and it doesn’t matter if they are younger or older, it doesn’t matter if they are transplant candidates or not. Because the study is designed to look at minimal residual disease (MRD) as the primary end point after 8 cycles.

In the current literature, the best published MRD rates are in the range of around 30% or 40% or so—in this study that’s not yet published, but presented

at the ASH 2019, we report MRD rate of around 80%, and this is without bone marrow transplantation.

Reference

Landgren O, Hultcrantz M, Lesokhin AM, et al. Weekly carfilzomib, lenalidomide, dexamethasone and daratumumab (wKRd-D) combination therapy provides unprecedented MRD negativity rates in newly diagnosed multiple myeloma: a clinical and correlative phase 2 study. Presented at: 61st¡American Society of Hematology Annual Meeting & Exposition; December 7-10, 2019; Orlando, FL. Abstract 862. ash.confex.com/ash/2019/webprogram/Paper126378.html. Accessed December 21, 2019.

Lindsey Roeker, MD, Clinical Fellow, Memorial Sloan Kettering Cancer Center

What are some of the real-world unknowns regarding treatment patterns in CLL [chronic lymphocytic leukemia]?

Right now, we have basically prospective data showing the effi cacy of a lot of novel agents—which is fantastic. But how they work in sequences is still an unknown question. We have small numbers of patients that have been treated with a novel agent after a novel agent. So, venetoclax after ibrutinib, we know that works. But the converse, whether ibrutinib works after venetoclax, is still somewhat of a question. We have real-world data to support the use in people who have not previously been exposed to a BTK [Bruton tyrosine kinase] inhibitor, or for patients who have previously seen a BTK inhibitor but stopped because of intolerance. For patients who have actually previously failed a BTK inhibitor, it seems to be a less-eff ective strategy.

But that’s all real-world data, retrospective. We don’t have a prospective, large data set to support that practice. So, I think that’s still a piece that we’re trying to figure out.

Adam Olszewski, MD, Associate Professor of Medicine, Warren Alpert Medical School, Brown University

Why is palliative care not used earlier for patients with hematologic malignancies?

This is a very interesting and complex and heavily researched issue, actually. There are many studies that show patients with hematologic malignancies receive less end-of-life, less appropriate end-of-life care. So, they are receiving much more aggressive end-of-life care. And it is very easy to theorize about this, how this is happening, that, you know, patients with blood cancers have, that are often hanging in this state, where further treatment is always possible and remission is always possible. And that makes it very diffi cult for patients and for clinicians to actually recognize the moment where palliative care should come in to help manage patients’ symptoms and maybe start thinking about really what are further goals of care and what the patient is expecting in terms of their realistic life expectancy.

A lot of research is showing that both clinicians have diffi culty with this and patients may have diffi culty with this as well. There’s some prognostic discordance between patients and clinicians when discussing the prognosis of patients with leukemias and lymphomas, and myelomas as well. And then clinicians often have that perception that private care was developed for management of solid tumors, and that the needs of blood cancer patients may not be met fully with what has been developed. I feel that palliative care physicians are actually quite prepared to manage blood cancer patients, although they also need additional training because approaching a patient, you know a young person with multiple relapsed lymphoma or leukemia is quite diff erent from often older patients with solid tumor that progressed as many lines of chemotherapy.

So, I think there are barriers on the clinician side, on the patient side, and there are also some systemic barriers. The study, it was shown, during this ASH, demonstrated that only a very, very small number of patients actually billed palliative care services early during the course of their disease—at least 30 days prior to their death. This was barely 2% even though it is increasing in the recent years.

But the difficulty that arises is also realization that the way we are billing and documenting these services is actually very diffi cult to capture later on through health services research. And that actually refl ects challenges with billing and arranging and putting on this layer of palliative care over the layer of standard clinical care, which is still not fully recognized by insurers and organizations. So, I think there’s also some systemic barriers that have to be overcome in integrating this truly.