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Friday, August 10, 2018

Previous research has revealed that patients with acute myeloid leukemia (AML) who also have a particular mutation the gene NPM1 have a higher rate of remission with chemotherapy. About one-third of leukemia patients possess this favorable mutation, but until now, how it helps improve outcomes has remained unknown.

Scientists from the University of Illinois at Chicago (UIC) report on how this mutation helps improve sensitivity to chemotherapy in patients (JCI Insight 2018; doi:10.1172/jci.insight.121583).

The protein coded for by the NPM1 gene affects the location and activity of another protein called FOXM1. FOXM1 activates other cancer-promoting genes and has been found to be elevated in cancer cells. The presence of FOXM1, especially at high levels, is a strong predictor of worse treatment outcomes and decreased survival in patients with cancer. When the NPM1 gene is mutated, FOXM1 can't activate additional oncogenes, so patients with this mutation tend to respond better to chemotherapy. A drug that targets and incapacitates FOXM1 in patients without the beneficial NPM1 mutation may help improve the efficacy of chemotherapy.

Patients with AML have a high risk of death from uncontrolled infection, fatigue easily, and get organ damage because they lack adequate numbers of oxygen-carrying red blood cells. They are also at high risk for dangerous bleeding because of low numbers of cells that help with blood clotting. It has been known that patients with a mutation in the NPM1 gene have a better response to standard chemotherapy, with up to 80 percent of patients being cured compared to just 40 percent for patients without the mutation.

In previous studies, researchers at UIC led by Andrei Gartel, PhD, Associate Professor of Molecular Genetics, discovered that one of the roles of the NPM protein is to stabilize FOXM1 and keep it in the nucleus where it can activate other cancer-promoting genes. Gartel and his colleagues determined that when the NPM1 gene is mutated, FOXM1 migrates out of the nucleus and into the cell's cytoplasm, where it can't interact with DNA. This may explain why patients with this NPM1 mutation have a much better response to chemotherapy and are less likely to relapse.

In their current study, Gartel and his colleagues further explored the relationship between NPM1 and FOXM1 in patients with AML. The researchers analyzed bone marrow cells taken via biopsies from 77 patients with AML and found that the presence of FOXM1 in the cells' nuclei was a strong predictor of poor treatment outcome for individual patients.

"When we then looked in the patients' medical records, we saw that those with FOXM1 present in the nucleus of their cancer cells had worse treatment outcomes, higher rates of chemotherapy resistance and lower survival rates compared to patients without FOXM1 present in the nucleus," said Irum Khan, MD, Assistant Professor of Clinical Medicine in the UIC College of Medicine and first author on the paper.

In mice engineered to overproduce FOXM1 that were caused to develop leukemia, following treatment with cytarabine, a drug commonly used to treat AML, the mice had more residual disease compared to control mice with AML and normal levels of FOXM1.

"Our finding suggests that overexpression of FOXM1 directly induces chemoresistance, which matches what we saw in our analysis of patients' FOXM1 levels and their treatment outcomes," said Khan.

Next, the researchers demonstrated that they could produce a therapeutic response in patient AML cells grown in the lab using a novel oral drug called ixazomib, which is approved to treat multiple myeloma. In the current paper, Gartel and his colleagues show that ixazomib works in part by suppressing FOXM1.

When the patient cancer cells were treated with ixazomib plus standard chemotherapy drugs used to treat AML (cytarabine and anthracyclines) the cells showed a higher death rate compared with standard chemotherapy alone. "Ixazomib produced a synergized chemotherapeutic response when added to standard chemotherapy," Gartel said. "We believe this is caused by ixazomib inhibiting the activity of FOXM1."

"There is a real unmet need for new ways to get around the resistance to chemotherapy that patients who don't have this beneficial mutation often face," concluded Khan. "Drugs that suppress FOXM1 in combination with the standard treatment, such as ixazomib, should result in better outcomes, but clinical trials will ultimately be needed to prove this theory."

Monday, June 25, 2018

​These are undeniably exciting and complex times in oncology care and cancer research. Breakthroughs are happening thanks to technology, increased data sharing, and scientific insight. Unfortunately, those diagnosed with rarer cancers see fewer innovations and upgrades to their standard of care. Arguably, common cancers receive greater awareness and funding to make both small improvements and greater advancements regularly in care, compared to those affected by and researching rarer cancers. This is mainly due to lower rates of incidence, fewer patients to involve and, in some cases, limited opportunities for care due to aggressive onset and late stage diagnoses. Malignant mesothelioma is just one example of a cancer where innovation has fallen far behind need, resulting in a standard of care that, by comparison to more common cancers, has not seen significant improvements over the last decade.

With an average of 3,000 diagnoses annually in the U.S., mesothelioma typically presents with an aggressive onset as it is often detected in an advanced stage. This cancer also has an extremely long latency period because it is caused by exposure to asbestos that could have occurred between 10 years and 50 years prior, leaving individuals unaware they are at risk of developing it. Research has evolved and accelerated in almost every facet of oncology care, but seeing the full scope of how translational medicine is impacting researchers, clinicians and patients can be difficult. Looking into the recently available treatment options and innovations into this rare cancer is a specific illustrator of the relationship between emerging options and the ways in which patients and standards of care are seeing improvements at an unprecedented rate.

Previous research breakthroughs have helped advance treatment, but potential options for those with mesothelioma have largely come from insights into other cancers, namely melanoma and lung cancer. Rather than waiting for results to come in from more well-funded areas, personalized cancer vaccines have the promise of research working directly into the treatment of this rare cancer. This offers patients and oncologists new options that are being developed at a speed not experienced before. Given the cancer's extremely low survival rate, coupled with its short life expectancy, the availability of research and clinical trials into drug therapies specifically targeting mesothelioma could be revolutionary.

Looking into the connection between melanoma and mesothelioma through the BAP1 gene has unlocked many discoveries into the progression and makeup of the group of malignancies that share it. This has led to a greater understanding of this group and the way cancers behave, yet has not produced any comprehensive advances related to standard of care or clinical options for those with mesothelioma. One step further, research into lung cancer and the PD-L1 protein have advanced beyond merely making a connection with mesothelioma and into the clinical setting for mesothelioma patients. Although for those who are healthy enough or in the proper stage, these trials have seen mixed results in availability and efficacy for those who qualify for the drug therapy.

Personalized cancer vaccines work to mitigate the inconsistency those looking to participate in trials often encounter, both in qualifying for and in response to treatment. By sequencing the DNA and studying mutations unique to each patient, antigens are targeted to the tumor, meaning patients can immediately begin treatment customized to their needs. This bypasses the current life cycle of research that leaves patients and specialists waiting for therapies to become available. It can also address the issue that many encounter even after trials do recruit that there's no guarantee they'll be able to qualify for. While personalized cancer vaccines are still in the early stages of use, the promise they hold is uniquely significant for those with rare cancers.

Diagnostic tools are also becoming more advanced and can now hone in on and detect biomarkers specific to mesothelioma with greater accuracy. From breath tests to liquid biopsies, proteomics are joining genomics in having a greater role in cancer therapy. Currently, to arrive at a conclusive diagnosis, a full needle biopsy, along with imaging and results from testing fluid samples from ascites and pulmonary edemas that often accompany symptom onset, are all needed. The tests, scans, analysis, and lab work take up precious time and resources for mesothelioma patients, who face an average prognosis of 15 months. Efficient testing and early detection can be the difference between having available treatment options to explore or left with palliative measures only for some patients.

A recent study focused on surface level proteomics, in particular through human serums derived from patients, looked for a set of biomarkers specific to mesothelioma. From highly targeted ones like mesothelin to more general cancer markers, the tests have shown promise for less-invasive and more-efficient detection without the standard course of tests. European researchers are working on yet another promising area of proteomic research focusing on breath tests to detect protein markers specific to pleural mesothelioma. Ongoing study results have provided consistent and effective data showing promise in not only detecting markers for mesothelioma and benign chronic asbestos-related diseases and controls, but also those distinct to malignancy.

Immunotherapy and biologics are undoubtedly the next frontier of cancer treatment, but surgical innovations are paving the way for less-invasive, more-accurate and effective options today. For complex cancers like mesothelioma that are often not discovered until later stages, a multimodal approach is often necessary. Small surgical advancements are one more step toward fostering successful patient outcomes.

One such innovation related to treating peritoneal mesothelioma is revisiting the element of chemotherapy immediately after removing malignant tissue and organs through Pressurized Intraperitoneal Aerosol Chemotherapy (PIPAC) and Pressurized Intrathoracic Aerosol Chemotherapy (PITAC). The pressurized aerosol version of this treatment is helpful in a number of ways. A recent study found that the surgical administration of this chemotherapy was found to be successful and less-invasive compared to a traditional wash through Hyperthermic Intraperitoneal Chemotherapy (HIPEC) after tumor resection. Being a spray, rather than a liquid wash, allows the drug to reach farther into areas of the body through a controlled, consistent application. This also provides a less-invasive surgical method of chemotherapy delivery, with the aerosol able to be administered through a laparoscopic procedure rather than full incision into the peritoneal cavity, helping patients recover faster with less healing time needed.

With so much research happening in so many areas of focus, measuring progress and promise through a narrowed lens can be helpful to assess where we are in moving oncology care forward.

This article was authored by staff from the Mesothelioma Cancer Alliance. This organization serves as a source of information, support, and community for those affected by mesothelioma cancer and asbestos-related diseases.

Tuesday, June 19, 2018

The American Association for Cancer Research (AACR) joins 70 NCI-designated cancer centers and five national cancer organizations in urging increased HPV vaccination rates and screening measures to prevent the human devastation caused by HPV-related cancers. Insufficient vaccination is a public health threat, and the AACR calls upon the nation's physicians, parents, and young adults to take advantage of this opportunity to eliminate several different types of cancer in men and women.

According to the CDC, HPV is responsible for almost all cervical cancers, a substantial proportion of head and neck cancers, and the majority of anal, vulvar, vaginal, and penile cancers. CDC data shows that approximately 41,000 new HPV-related cancers are being diagnosed in the U.S. each year, 17,300 of which are diagnosed in men and about 23,700 of which are diagnosed in women. The overall annual direct medical cost of HPV-related diseases is at least $8 billion.

 "This call to action, which is shared by our nation's leading cancer organizations, is an important first step in the elimination of HPV-related cancers," said Margaret Foti, PhD, MD (hc), Chief Executive Officer of the AACR. "The long-term investment in biomedical research has led to a series of scientific discoveries that have enabled us to reach this juncture where we now have highly effective tools and well-defined steps for putting an end to HPV-related cancers."

Since its introduction in 2006, more than 100 million doses of the HPV vaccine have been distributed nationally. The CDC recommends all 11- to 12-year-old girls and boys receive the HPV vaccine. The Department of Health and Human Services, through the Healthy People 2020 initiative, has introduced a goal of reaching a vaccination rate of 80 percent for both girls and boys by the year 2020. However, as of 2016, only 49.5 percent of girls and 37.5 percent of boys in the U.S. had completed the HPV vaccine series, according to the CDC.

Research shows that certain barriers must be overcome to improve vaccination rates. One such barrier is a lack of strong recommendations from physicians; another is that parents may not be aware that this vaccine protects against several types of cancer in both men and women.

Foti added, "Today's call to action will bring the entire cancer research and cancer control community together to focus its efforts on the very achievable and life-saving goal of eliminating HPV-related cancers in the U.S. The AACR looks forward to marshaling its resources in support of this important effort."  

Tuesday, June 5, 2018

By Catlin Nalley

Since the current chronic lymphocytic leukemia literature (CLL) focuses primarily on the objective aspects of diagnosis, active observation, prognosis and management, a group of researchers sought to gain a better understanding of the subjective experiences of patients. Initial data was recently presented at the 2018 American Society of Clinical Oncology (ASCO) Annual Meeting (Abstract 7532).

Led by the CLL Society Inc., a patient-driven, physician-curated nonprofit organization that focuses on the unmet needs of the CLL community, the team aimed to "understand how CLL and its management, including the health care team, diagnosis, education, active observation, prognostic testing, and the options of clinical trial affect the lives of those with CLL and what was important to patients. The goal was to better understand CLL from the patient's perspective to inform health care providers in best meeting their patients' needs."

Study Methodology

With this goal in mind, investigators utilized the 2017 CLL Diagnosis and Treatment Assessment: The Patient View (2017 CLLDATA) survey, which consisted of 64 multi-part questions. The survey was available online or on paper and took place between October and December 2017.

Eligible patients were U.S. residents age 18 years or older who had a diagnosis of CLL/SLL. Participants had to have a working knowledge of English and provide informed consent.

The survey was conducted anonymously and utilized the CLL Society database, Facebook, and online CLL patient forums. Additionally, information cards were distributed in the offices of principal investigators as well as physicians in the community that refer to those investigators.

Researchers analyzed data using descriptive methods. Statistical significance was evaluated using chi-square. According to investigators, analyses and comparisons occurred between multiple subgroups based on age, gender, treatments status, high-risk versus low-risk, and patients treated by a general hematologist/oncologist, CLL expert, or both.

Among the 1,147 useable responses, the median age was 64 years and 46 participants were male. Ninety-six percent were Caucasian. The median time from diagnoses was 5 years and treatment status was as follows: watch and wait (43%); receiving or completed first treatment (25%); and receiving or completed second or later treatment (32%).

Key Observations

Data showed that at the time of diagnosis 48 percent of patients were told they had a "good" cancer by their health care practitioner.

Additionally, 44 percent of participants heard the phrase, "You will die with CLL, not from CLL" and 41 percent were told, "If I had to choose a cancer, this is the one I would want." Patients reported these statements, among others, equally regardless of the type of physician managing their treatment, according to investigators.

Researchers noted that only 13 percent of patients surveyed reported needing treatment within 3 months of diagnosis. Among patients undergoing active observation (87%), 91 percent said that their doctor explained why therapy was not warranted.

The study authors wanted to gain more insight into the emotional response to active observation, according to Betsy Dennison, RN, MS, of the CLL Society. "We wanted to find out more about how [patients] are feeling because they don't see the doctor as often," he noted. "How are they coping with that and what more can we do to support them?"

"When active observation was recommended, patients report anxiety (56%), relief (52%), and confusion (31%). Thirty-four percent and 16 percent of patients report that discussing prognostics increased their anxiety and confusion, respectively," according to study authors.

During active observation, 17 percent of survey respondents reported having no disease-related symptoms. Researchers found that patients reported fatigue (51%), enlarged nodes (47%), anxiety (39%), depression (21%), and night sweats (21%). Among patients undergoing active observation, 653 (66%) utilized herbals and other alternative treatments for CLL management.

The investigators also took a closer look at the patient experience related to clinical trial options. Among patients who were invited to join a clinical trial, but declined cited a number of reasons for their decision, including: preference for a proven treatment (38%), distance from the trial site (29%), fear (20%), and frequent imaging (20%).

Patients who chose to participate in a clinical trial did so because their health care team suggested it as a good option (71%). Other reasons included access to the latest treatments (69%), close monitoring of disease (67%), confidence in the trial team (65%), a desire to help others (56%), and medications provided for free (54%).

"A lot of patients felt very strongly about participating and wanting to feel like they are making a positive effect on society," noted Dennison.

Conclusions, Next Steps

"To our knowledge, this is the largest survey of CLL patients. Much can be learned by detailed surveying of CLL patients throughout their disease," according to researchers. "These include previously unrecognized suboptimal interactions between the CLL patient and the health care provider."

Given that 72 percent of patients reported being offered language similar to "CLL is a good cancer" at the time of diagnoses, investigators recommend that "this might be better replaced with the facts that CLL is a variable disease, with some patients never needing treatment and others experiencing more aggressive disease."

Other recommendations based on these findings include additional support for patients undergoing active observation and access to clinical trials for appropriate patients regardless of where they are being treated.

"Understanding how patients experience their disease is critical to improve communication between patients and their health care providers, which will ultimately advance CLL outcomes," study authors concluded. Additional data from this survey will be reported in the future.

Catlin Nalley is associate editor.

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Tuesday, June 5, 2018

By Catlin Nalley​

Given the therapeutic needs of patients with chronic lymphocytic leukemia (CLL) relapsed/refractory (R/R) to B-cell receptor pathway inhibitors, such as ibrutinib and idelalisib, researchers sought to evaluate the durability of response to venetoclax among this patient population.

Findings from the phase II study were recently presented at the 2018 American Society of Clinical Oncology (ASCO) Annual Meeting (Abstract 7512).

Methodology, Results

Patients with CLL refractory to treatment or who had progressed after discontinuation of prior treatment ibrutinib and/or idelalisib were enrolled in the phase II, open-label, multicenter trial.

Once daily venetoclax was administered with an initial dose of 20 mg daily for 1 week followed by weekly dose ramp up to reach the target dose of 400 mg by week 5, according to researchers. In an effort to mitigate tumor lysis syndrome, beginning at least 72 hours before initial venetoclax administration patients received prophylaxis with uric acid-lowering agents and hydration.

Key inclusion criteria, included an ECOG score of 2 or less, adequate bone marrow function, and creatinine clearance greater than or equal to 50 mL/min. Patients were excluded if they had biopsy-confirmed Richter's transformation, active and uncontrolled autoimmune cytopenias, and a history of allogeneic stem cell transplantation within 1 year of study entry.

The study enrolled 127 patients who had received a median of four prior therapies. Over the course of their treatment, 91 patients received prior ibrutinib while 36 received previous idelalisib and 24 patients underwent both therapies. Forty percent of patients had 17p deletion and 28 percent had mutated TP53.

"After a median of 17 months on venetoclax, the best overall response rate was 66 percent per investigators (INV) and 70 percent by independent review committee (IRC)," researchers reported. "Per INV (median follow-up, 16 months), estimated median progression-free survival (PFS) was 25 months (18-month rate, 66%); neither median duration of response (18-month rate: 75%) nor median overall survival (18-month rate: 88%) was reached."

Among 77 patients assessed, 32 had undetectable blood minimal residual disease (MRD); additionally, nine of these patients were also undetectable in bone marrow. Median PFS for patients with undetectable MRD in blood was not reached compared to 21.9 months for patients with positive blood MRD.

Venetoclax was discontinued by 64 patients, most commonly for CLL progression, adverse events, and Richter's transformation.

Patients experienced at least one adverse event. Data showed that common, any-grade adverse events, included GI AEs (diarrhea [50%], nausea [49%]) and cytopenias (anemia [43%], neutropenia [41%], thrombocytopenia [28%], decreased white blood cell count [28%]).

Discussion

"Based on longer follow-up, venetoclax monotherapy demonstrates robust activity, with good tolerability in patients with CLL R/R to ibrutinib and/or idelalisib," study authors wrote. "Though most patients achieved PR, outcomes appear durable with undetectable MRD."

Commenting on the study results during ASCO, Alexey V. Danilov, MD, PhD, Associate Professor of Medicine at Oregon Health & Science University, noted that the durable responses among this pretreated, high-risk patient group were very impressive.

"Essentially, almost all patients developed some sort of response to [this therapy]," he concluded. "Venetoclax produces durable responses in ibrutinib/idelalisib-resistant CLL."

Catlin Nalley is associate editor.