The Tisch Cancer Institute

Ronald Hoffman, MD, professor of medicine, hematology, and medical oncology and director of the Myeloproliferative Diseases Program at The Icahn School of Medicine at Mount Sinai, discusses the current polycythemia vera treatment paradigm.

Patients under the age of 60 or who have not experienced a prior thrombotic event are typically treated with phlebotomy with the goal of maintaining hematocrit at a level of less than 45%, Hoffman explains.

Conversely, patients over the age of 60 or who have had a prior thrombotic event usually receive myelosuppressive therapy, such as pegylated interferon or hydroxyurea, which is the current standard of care. If patients progress on those agents, they will be given the JAK1/2 inhibitor ruxolitinib (Jakafi). Additionally, it is not uncommon for patients to receive aspirin, Hoffman adds.

All these therapeutic strategies are geared toward reducing the incidence of thrombosis. However, the most important metric is sustaining hematocrit at a level of less than 45%, Hoffman says. Notably, none of the available treatment options prevent disease progression to myelofibrosis or acute myeloid leukemia (AML), Hoffman concludes.

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Ronald Hoffman, MD, discusses the current polycythemia vera treatment paradigm.

Dr. Hoffman on the Current Polycythemia Vera Treatment Paradigm

John P. Sfakianos, MD, an assistant professor of urology and urologic oncology at the Icahn School of Medicine at Mount Sinai Health System, discusses the utility of adjuvant therapy in bladder cancer management.

One of the concerns that are always faced with removing bladder tumors is that it is done through the urethra, says Sfakianos. The tumor is scraped away in this confined space causing concern that tumor cells may be spread to different areas. It is known that the disease itself is multifocal, because whatever caused the first tumor was likely a carcinogen in the urine, which is in contact throughout the remainder of the bladder; this can likely cause the same damage in another area of the bladder.

When surgeons go in to remove the tumors, adjuvant therapy will immediately be used, usually in the form of chemotherapy, such as mitomycin or gemcitabine. Adjuvant therapy is recommended to be used up to 24 hours after resection, and the sooner this therapy is used the better. It is believe that this approach minimizes the ability for the cancer cells to spread to other parts of the bladder. Morever, if there is damage and the tumor develops somewhere else, adjuvant therapy can reduce the recurrence of these non-muscle invasive tumors, concludes Sfakianos.

John P. Sfakianos, MD, discusses the utility of adjuvant therapy in bladder cancer management.

Dr. Sfakianos on the Utility of Adjuvant Therapy in Bladder Cancer Management

Joshua Brody, MD, director, Lymphoma program, Icahn School of Medicine, Mount Sinai Hospital, discusses addressing required resistance to immunotherapy in non-Hodgkin lymphoma.

Despite the promising data seen with in-situ vaccines in the field, it is common knowledge that patients’ tumors can become resistant to vaccines or any type of immunotherapy through antigen escape, explains Brody. With regard to CAR T-cell therapy, this can mean the loss of CD19 from the tumor. With bispecific antibodies against CD20, this can mean CD20 loss, adds Brody. With every other type of immunotherapy where T cells recognize tumors through their major histocompatibility (MHC) class 1 expression, it can be MHC class 1 loss. This has been well described for many types of cancer after a patient receives a PD-1 inhibitor. In fact, class 1 loss is one of the most common types of resistance to checkpoint inhibitors, notes Brody.

Investigators started to observe this in some of the patients with advanced-stage indolent non-Hodgkin lymphoma who had been treated with an 

. Brody and colleagues shared some data that have been developed in the lab in their attempt to address antigen escape. They found that there are many ways to solve the problem of antigen escape in CAR T-cells. After giving an anti-CD19 CAR T-cell, an anti-CD22 CAR T-cell can be given as treatment, in case the patient lost the CD19 antigen, concludes Brody.

Joshua Brody, MD, discusses addressing required resistance to immunotherapy in non-Hodgkin lymphoma.

Dr. Brody on Addressing Acquired Resistance to Immunotherapy in Non-Hodgkin Lymphoma

Adilia Hormigo, MD, PhD, director of the neuro-oncology program, professor of neurology, neurosurgery, and medicine, Tisch Cancer Institute, Mount Sinai Hospital, discusses the impact of the coronavirus disease 2019 (COVID-19) on high density areas.

There have been less admissions to the intensive care unit at Mount Sinai and other metropolitan hospitals, suggesting that New York City may be past the peak of COVID-19, says Hormigo.

However, it is hard to determine when the city can safely begin to open. When the city does reopen, it is unlikely to operate as it did prior to the pandemic, says Hormigo. For such dense areas such as New York City, it will be difficult to enforce social distancing.

Adilia Hormigo, MD, PhD, discusses the impact of the coronavirus disease 2019 (COVID-19) on high density areas.

Dr. Hormigo on the Impact of COVID-19 on High Density Areas

A United States population-based outcome analysis of real-world patients with myelofibrosis who had discontinued ruxolitinib (Jakafi) demonstrated an increase in morbidity burden and identified the risk factors of survival outcomes, according to John O. Mascarenhas, MD.

"Patients who discontinue ruxolitinib have been shown in several studies to have poor outcomes as it relates to survival, with a median survival that's approximately 1 year; that is concerning, because it suggests that we really don't have effective strategies for most of these patients once they have enjoyed success with ruxolitinib and then stopped treatment," said Mascarenhas. "It really highlights a need to understand the disease biology and to develop therapies either in combination with ruxolitinib to extend that duration or benefit, or to salvage patients' outcomes after they come off ruxolitinib."

For the analysis, Mascarenhas and colleagues identified a total of 290 patients with myelofibrosis between 2006 and 2015 who were treated with and then discontinued ruxolitinib. Only those with ≥90 days of medical history prior to index diagnosis and part A, B, and D enrollment at the time of index diagnosis were included. Investigators evaluated for morbidities in the 30 days following ruxolitinib initiation, prior to discontinuation, and after discontinuation. The incidence of cytopenias and efficacy outcomes were assessed from baseline.

The median age of those included in the analysis was 68 years, with an equal proportion regarding gender. Additionally, the median time to ruxolitinib discontinuation was 284 days, with a median follow-up after discontinuation of 70.9 days.

Most of the patients included in the analysis were diagnosed with anemia and more than 30% of patients received red blood cell transfusions during the 30-day time frame prior to and following discontinuation of ruxolitinib. After treatment discontinuation, half of the patients went on to develop cytopenias. Following discontinuation, the median treatment progression-free survival (PFS) and overall survival (OS) were 6.0 months versus 11.1 months, respectively.

Investigators found that the age at ruxolitinib discontinuation (HR, 2.071; 95% CI, 1.320-3.248), Charlston Comorbidity Index score (HR, 1.172; 95% CI, 1.093-1.257), and gender (HR, 1.620; 95% CI, 1.108-2.369) increased the risk of treatment progression or death.

"One of the reasons why this study is important is that it emphasizes the point that therapies evaluated in the second line, following ruxolitinib failure, really need to start considering OS as an important end point, because it's poor," said Mascarenhas. "This has been demonstrated, and patients want to live longer obviously with a good quality of life."

, Mascarenhas, an associate professor of medicine, hematology, and medical oncology at the Icahn School of Medicine at Mount Sinai; director of the Adult Leukemia Program and leader of Clinical Investigation within the Myeloproliferative Disorders Program at Mount Sinai; and a member of the Tisch Cancer Institute, discussed patient characteristics and outcomes following ruxolitinib discontinuation in myelofibrosis and research efforts being made to address a large unmet need in the space.

: Could you begin by providing some background on the impact of ruxolitinib in the myelofibrosis treatment paradigm?

: In 2011, ruxolitinib was approved by the FDA for myelofibrosis, and then in 2014, for polycythemia vera; this clearly was a large step forward for myelofibrosis treatment. Prior to ruxolitinib, we really didn't have effective tools to address symptom burden and splenomegaly, which are 2 important aspects of the disease process.

With the commercial availability of ruxolitinib, quality of life, and even outcomes, of patients with myelofibrosis clearly changed. Patients definitely feel better; they have less spleen-related complaints; they can eat more, there's reversal of cachexia, and thus, an improvement in performance; and they are living longer than they would in the absence of ruxolitinib.

That being said, we also realize that all those benefits come with a price tag. There's an element of myelosuppression—cytopenias, anemia, and thrombocytopenia can occur&mdash;but otherwise, it's a relatively well tolerated drug. We also now know that there's some degree of infectious risk, whether it be [herpes] zoster, urinary tract infections, or pneumonia. Still, the benefit outweighs the risk of the drug.

Unfortunately, for many patients, that benefit is not long lived. The median time to discontinuation is approximately 3 years, and 85% of patients discontinue by 5 years. Although [ruxolitinib] is a huge step forward in the treatment paradigm for myelofibrosis, there are still clear unmet needs. For example, patients with low platelets at onset, so less than 50,000 [per microliter] or those who have significant anemia and transfusion requirements are 2 [groups that are not] effectively addressed by ruxolitinib. Another very urgent unmet need would be [patients] after ruxolitinib discontinuation in whom survival outcomes are poor.

What was the inspiration behind conducting this retrospective analysis?

Several studies have been conducted to try and understand what happens to patients after ruxolitinib fails; again, this can look different for different people, so even the concise definition of that is not agreed upon. As such, we set out to evaluate that further by looking at 3 claims databases. The idea was to look at this from a little bit of a different angle; [rather than examining this] from the specific patient perspective, we looked at it from a claims-based angle.

The 3 databases included a commercial database, an electronic health record that was linked to a claims database, and then the Surveillance, Epidemiology, and End Results (SEER)-Medicare linked database. We assessed patients of various ages. Obviously, the SEER Medicare linked database included those who were 65 years and older, and then the other 2 databases included patients under 65 years, so we really took a broad range of patients. Notably, this was linked with prescriptions and ICD codes rather than the physician's direct experience with the patient at their institution.

The analysis involved a 9-year period, ranging from 2006 to 2015 and the criteria to be included in this study to have had at least 90 days of medical history, a diagnosis of myelofibrosis—primary or secondary as by the inclusion of ICD codes&mdash;and having a prescription for ruxolitinib in the database. A total of 290 patients who fit that description were identified across these 3 databases; these were nonoverlapping patients and the median age was about 68 years. Additionally, there was even distribution between men and women and the median time [to] ruxolitinib [discontinuation] was approximately 284 [days]. Patients had a median follow-up of about 70 days of data after [ruxolitinib discontinuation].

We were able to show that there's a certain degree of cytopenias in patients [who] start ruxolitinib, but that progressively gets worse during their treatment, and particularly after they come off treatment; I believe this is the first time this has been shown in this setting. For example, when looking at anemia, thrombocytopenia, and neutropenia, the incidence 30 days prior to starting ruxolitinib was 36%, 12%, and 2%, respectively. However, when you look at 30 days prior to stopping ruxolitinib, the [incidence of] anemia rose to 45%, to 12% for thrombocytopenia, and to 18% for neutropenia. If you look at these numbers 30 days after stopping ruxolitinib, those numbers rise to 53% for anemia, 23% for thrombocytopenia, and 10% for neutropenia. These data demonstrate a pattern of worsening cytopenias, which is obviously concerning. [This] includes the 33% of patients who became red blood cell transfusion dependent on ruxolitinib; one-third of the patients [were dependent] at the time of discontinuation.

There is a significant burden and morbidity associated with this disease and being on this drug; unfortunately, at the time of discontinuation, it is significant. If you look at end points that are very meaningful, like median OS, it was approximately 11 months [in this analysis]. We also did an analysis looking at time to median treatment PFS, and that was about 6 months. These data speak to the fact that outcomes are not good and that we don't really have effective treatment available to alter that course. We also know that cytopenias, with death as a competing event, occurred in about 75% of patients at 18 months following discontinuation; as such, there's a significant morbidity and mortality aspect. If you look at potential risk factors, when we did variable analyses, we saw that age over 65 and an increase in the Charlston Comorbidity Index or worsening of performance status is associated with an increased hazard for death.

The study highlights the fact that across a large claims database, in a patient population that's validated and has adequate data, whether [patients] are above 65 or [younger] than 65, the outcomes are poor. There's this high morbidity in terms of cytopenias and the mortality rate is poor, as well. These data just highlight the fact that there's an unmet need here for additional therapies.

That's why studies with, for example, imetelstat, the Geron compound that was run in a phase 2 study, [are needed]. What was always interesting about that study was, if you look at the survival outcome, the median survival for the active dose, which was 9.4 mg/kg given every 3 weeks, was 30 months; that's much more favorable than what we're seeing [with ruxolitinib], which is about 1 year. Of course, that was a study that didn't have a control arm per say. The control arm [evaluated] the low dose, and the low-dose arm had [a median survival of] 19 months. [Those results] suggested that there is a survival benefit [with that approach]. However, that was an open-label phase 2 study, so the next study that needs to be done is a randomized phase 3 study of imetelstat compared with best available therapy, with a primary end point of OS. I believe it such a study would mark the first time such an important end point would have been the focus in myelofibrosis.

Beyond imetelstat, what other novel agents are being examined in this patient population?

The field is very competitive now in terms of finding alternatives for patients who come off ruxolitinib, as well as commercial alternatives. It has to be noted that fedratinib (Inrebic) is an FDA-approved therapy with a broad, open label that is indicated for patients with a diagnosis of myelofibrosis and a platelet count of greater than or equal to 50 x 10

L. If you look at the JAKARTA-2 study, which was a phase 2 study that evaluated fedratinib as a second-line option for patients in whom ruxolitinib failed, that agent proved to be effective with response rates with splenomegaly, for example, of 30%. You could clearly achieve responses and salvage responses as it relates to spleen and symptom burden with fedratinib with the understanding that it is also a FLT3 inhibitor, so there are some GI toxicities. One needs to be aware of those toxicities and proactively manage that aspect [of treatment]. Fedratinib provides another JAK inhibitor option to patients within the community.

Beyond that, there's a lot of interesting work that's informed by laboratory studies. Some of these efforts include examining the addition of a drug like CPI-0610 to ruxolitinib in patients who are having a suboptimal response, and then drugs like navitoclax, which is a BCL-2 inhibitor. Many [agents are] in the pipeline that are being developed in an attempt to salvage responses either as a single agent or in combination with the goal of [managing] spleen symptoms, [improving] quality of life, and hopefully, [increasing] OS.

What is your take-home message to your colleagues?

Enroll. My recommendation always is to enroll patients, because myelofibrosis is a rare disease. We know that 2 approved therapies are commercially available and those should be used [in these patients]. However, the reality is that there is still a lot of unmet need in this chronic, aggressive hematologic malignancy. As such, if you have patients who have low platelets, I would strongly consider enrollment [on a clinical trial], if possible. I do realize that it's not always possible and that many logistics are involved.

However, for patients with low platelets, the PACIFICA study, for example, is evaluating pacritinib as a novel JAK inhibitor. For patients with transfusion dependence, the MOMENTUM study is evaluating momelotinib. CPI-0610 will eventually roll into a phase 3 study [for examination in the] up front setting for treatment-naïve patients. Investigators will compare the agent in combination to single-agent ruxolitinib in JAK inhibitor—naïve patients. As I said, I would also like to see imetelstat move into a phase 3 study for survival; it would be an important study. Several studies capture many unmet needs, and if access is provided to patients to [enroll on] those studies, that's really important; that's how the agents will eventually get to the commercial space.

Mascarenhas J, Mehra M, He J, et al. Patient characteristics and outcomes after ruxolitinib discontinuation in patients with myelofibrosis [published ahead of print March 31, 2020]. 

Articles

John O. Mascarenhas, MD, discusses patient characteristics and outcomes following ruxolitinib discontinuation in myelofibrosis and research efforts being made to address a large unmet need in the space.

Ruxolitinib Discontinuation in Myelofibrosis Leads to Increased Morbidity Burden, Underscoring Unmet Need

Che-Kai Tsao, MD, medical director of the Ruttenberg Treatment Center at the Tisch Cancer Institute of Mount Sinai Hospital and an associate professor of medicine, hematology, and medical oncology at the Icahn School of Medicine at Mount Sinai, shares strategies to improve outcomes in renal cell carcinoma (RCC).

Overall, 3 areas should be considered when attempting to improve outcomes for patients with regional disease, says Tsao. First, it is important to determine the disease can be better characterized. Developing an understanding of who to treat and who not to treat is also necessary. Some of the strategies to do this can include better imaging and, potentially, the use of biomarkers, which is not currently a standard; that is still an area of active investigation. Some of the prediction models that currently exist might also be used to understand which patients recur or not.

The second strategy would be to consider whether better surgery could be performed, adds Tsao. Now, routine lymph node dissection in patients with regional disease is not considered a standard. However, studies show that by performing a lymph node dissection, one can better understand whether patients truly have disease in their lymph nodes; that information could help determine who is at a higher risk for recurrence.

Third, it has to do with effective systemic therapy, says Tsao. The treatment landscape is changing and many exciting combination therapies have emerged, both in immunotherapy as well as targeted therapy, concludes Tsao.

Che-Kai Tsao, MD, shares strategies to improve outcomes in renal cell carcinoma.

Dr. Tsao on Improving Outcomes in RCC

Overall, 3 areas should be considered when attempting to improveoutcomes for patients with regional disease, says Tsao. First, it is important to determine the disease can be better characterized.Developing an understanding of who to treat and who not to treat is also necessary. Some of the strategies to do this can include better imaging and, potentially, the use of biomarkers, which is not currently a standard; that is still an area of active investigation. Some of the prediction models that currently exist might also be used to understand which patients recur or not.

The second strategy would be to consider whether better surgery could be performed, adds Tsao. Now, routine lymph node dissection in patients with regional disease is not considered a standard. However, studies show that by performing a lymph node dissection, one can better understand whether patients truly have disease in their lymph nodes; that information could help determine who is at a higher risk for recurrence.

Third, it has to do with effective systemic therapy, says Tsao. The treatment landscape is changing and many exciting combination therapies have emerged, both in immunotherapy as well as targeted therapy, concludes Tsao.

John P. Sfakianos, MD, an assistant professor of urology and urologic oncology at the Icahn School of Medicine at Mount Sinai Health System, discusses the importance of restaging transurethral resection of bladder tumors (TURBTs).

Patients with localized bladder cancer must be appropriately staged, says Sfakianos. It is very important to differentiate a non-muscle invasive tumor from a muscle-invasive tumor because the treatments drastically differ. With muscle-invasive tumors, multimodal therapies and more radical treatments must be considered, while intravesical treatments should be considered for those with non-muscle invasive tumors, says Sfakianos.

If a patient has a non-muscle invasive tumor and a minimal amount of disease in the bladder at the time of treatment, they are going to achieve the best response rate, adds Sfakianos; these patients have a better response rate than someone who has a single TURBT with adjuvant therapy. The reason for that is because the patient is probably getting a better effect and the disease is being minimized. Thirty percent to 50% of patients will still have tumors at the time of restaging, and up to 20% of patients will have a higher stage than initially thought; this changes the therapy that these patients receive, concludes Sfakianos.

John P. Sfakianos, MD, discusses the importance of restaging transurethral resection of bladder tumors.

Dr. Sfakianos on Importance of Restaging Transurethral Resection of Bladder Tumors

If a patient has a non-muscle invasive tumor and a minimal amount of disease in the bladder at the time of treatment, theyare going to achieve the best response rate, adds Sfakianos; these patients have a better response rate than someone who has a single TURBT with adjuvant therapy. The reason for that is because the patient is probably getting a better effect and the disease is being minimized. Thirty percent to 50% of patients will still have tumors at the time of restaging, and up to 20% of patients will have a higher stage than initially thought; thischanges the therapy that these patients receive, concludes Sfakianos.

William K. Oh, MD, chief of the Division of Hematology and Medical Oncology at the Mount Sinai Health System; deputy director of the Tisch Cancer Institute; professor of medicine and urology and Ezra M. Greenspan, MD Professor in Clinical Cancer Therapeutics at Mount Sinai Hospital, discusses challenges with developing novel targeted agents in prostate cancer.

In terms of finding novel targets for prostate cancer, the field remains a little uncertain, says Oh. For example, investigators know that 

 mutations, PTEN loss, and TMPRSS2-ERG fusions are all very common; however, they have not been able to identify ways to specifically target these potential markers. This has been the biggest challenge faced in the space, according to Oh. Investigators also are aware that DNA damage repair mutations lead to a targetable and actionable mutation, but so far, only a small percentage of the biomarkers are helping to inform the decision of which treatment should be given to which patient, concludes Oh.

William K. Oh, MD, discusses challenges with developing novel targeted agents in prostate cancer.

The Tisch Cancer Institute

Dr. Hoffman on the Current Polycythemia Vera Treatment Paradigm

Dr. Sfakianos on the Utility of Adjuvant Therapy in Bladder Cancer Management

Dr. Brody on Addressing Acquired Resistance to Immunotherapy in Non-Hodgkin Lymphoma

Dr. Hormigo on the Impact of COVID-19 on High Density Areas

Ruxolitinib Discontinuation in Myelofibrosis Leads to Increased Morbidity Burden, Underscoring Unmet Need

Dr. Tsao on Improving Outcomes in RCC

Dr. Tsao on Improving Outcomes in RCC

Dr. Sfakianos on Importance of Restaging Transurethral Resection of Bladder Tumors

Dr. Sfakianos on Importance of Restaging Transurethral Resection of Bladder Tumors

Dr. Oh on Challenges With Developing Novel Targeted Agents in Prostate Cancer