Lisa Miller

After publishing them in October 2016,the National Comprehensive Cancer Network (NCCN) is already seeking to update and expand their guidelines for diagnosing and treating patients with myeloproliferative neoplasms (MPNs).

The guidelines focused initially on diagnosing each of the MPNs and treatment options for patients with myelofibrosis, as that was the disease type with the greatest unmet need, Ruben A. Mesa, M.D., explained in an interview with 

 following his presentation at the 2017 NCCN Annual Conference.

“The myeloproliferative neoplasms were probably one of the most significant of the hematologic malignancies that did not yet have NCCN guidelines,” said Mesa, a professor of medicine and chair of hematology at Mayo Clinic in Phoenix, and chair of the panel for the NCCN guidelines on MPNs. “The guidelines are very helpful in terms of improving quality of care by providing more homogeneity of care in the US, trying to bring in current evidence regarding treatment that can be utilized, as well as clarifying the role of a variety of things, ranging from transplantation to therapies.”

The guidelines look to explain the criteria for diagnosing each of the MPNs, including the World Health Organization’s (WHO) recent update to the classification of MPNs, and risk assessment. Yet currently treatment options are only included for patients with myelofibrosis in this edition of the guidelines. Treatment guidelines for patients with polycythemia vera (PV) or essential thrombocythemia (ET) are expected in the update, which Mesa remarked are expected in the summer of this year.

The myelofibrosis guidelines incorporate scoring systems for risk stratification, including the International Prognostic Scoring System (IPSS), the Dynamic IPSS (DIPSS) and the DIPSS-Plus. Mesa also noted that the guidelines endorse the 2013 International Working Group for Myelofibrosis Research and Treatment and European LeukemiaNet consensus response criteria, as well as the scoring system for total symptom burden.

“In myelofibrosis there are clinical improvement criteria that can stand alone. You can have reduction in splenomegaly that counts as a response. What that leads to for the clinical decision making is more subtle, and like all of these guidelines, they are married to clinical experience and expertise in terms of the character of response, and how that balances against any negatives that come with the treatment in terms of side effects or toxicities, as well as expense,” he said.

The guidelines also describe the prognostic significance of a number of common mutations in patients with primary myelofibrosis. Patients with an MPL W515L/K mutation, for example, have a higher risk of thrombosis compared with patients who have a CALR mutation, and they usually have an intermediate prognosis. Those who do not have JAK2, MPL or CALR mutations have an interior prognosis compared to patients with these driver mutations, with lower leukemia-free and overall survival rates. Patients with TP53 mutations are associated with a greater risk for transformation to acute myeloid leukemia.

 For patients with low-risk asymptomatic myelofibrosis, the guidelines recommend either observation for signs and symptoms of disease progression or a clinical trial. For symptomatic patients who are low-risk, the guidelines suggest interferons, a clinical trial, or Jakafi (ruxolitinib)—the only FDA-approved targeted agent for patients with myelofibrosis. Jakafi, a JAK1/2 inhibitor, is also recommended for patients with intermediate-1 and -2 disease, especially for those with intermediate-2 disease who are not candidates for transplant and have a high platelet count.

“Ruxolitinib is the only FDA-approved therapy, so obviously, it leaves you somewhat challenged when you fail that therapy,” Mesa said. “That’s the greatest unmet need and certainly many of the current clinical trials are aimed at trying to assist patients that have ‘failed ruxolitinib.’”

Although the guidelines do consider some options for when a patient is Jakafi -intolerant or resistant, including agents such as fludarabine and busulfan, they strongly encourage clinical trials. However, Mesa noted that in the expected updates to the MPN guidelines, they will delve further into more options for patients following progression on Jakafi.

Mesa also addressed in his presentation several promising second-line agents currently in development, including pacritinib, momelotinib, imetelstat and PRM-151. “We’ve seen data recently that certainly was encouraging. Although neither agent is approved yet, both pacritinib and momelotinib had beneficial data in that second-line setting. Data from two clinical trials are eagerly anticipated for PRM-151, the anti-fibrosing agent, as well as imetelstat. Those are two second-lines studies that are of great interest,” Mesa said.

“We desperately need other agents approved because we really only have one approved drug: ruxolitinib…. If a second drug becomes approved we will undoubtedly work to revise the guidelines in a very rapid fashion to provide clarity and situational use,” Mesa continued.

He remarked that the guidelines are a starting point for oncologists who are less familiar with diagnosing and treating patients with these diseases, yet the experience of oncologists more familiar with MPNs could outweigh the recommendations in the guidelines.

“We’re hopeful that [the guidelines] will be a good resource for community oncologists in clarifying a range of issues with these diseases,” Mesa concluded. “How one walks that path, there’s a lot of individual factors and clinical experience that are highly relevant.”

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NCCN May Already Be Updating MPN Guidelines

Immunotherapy efficacy may be compromised if the patient takes antibiotics up to a month before treatment, according to the results of a retrospective analysis presented during a presscast of the 2017 Genitourinary Cancers Symposium, which raised concern about the relationship between gut microbacteria and antibiotics and their effect on immune checkpoint blockade agents.

In patients with metastatic renal cell carcinoma (mRCC), patients who had received broad-spectrum antibiotics had a shorter median progression-free survival (PFS) rate when treated with checkpoint inhibitor immunotherapy than those who had not received antibiotics of 2.3 versus 8.1 months, respectively.

Previous preclinical studies using mouse models have suggested an association between antibiotics and the efficacy of immune checkpoint blockade agents. 

“This is the first analysis evaluating the impact of antibiotics on outcome in mRCC patients treated in the era of immune checkpoint blockade,” said investigator Lisa Derosa, M.D., Ph.D. candidate, of the Gustave Roussy Cancer Institute, Paris-Sud University in Villejuif, France.

Researchers analyzed 80 patients with mRCC who were being treated with checkpoint inhibitors on trials at the Gustave Roussy institute. Immunotherapy treatments included single-agent anti—PD-1/PD-L1 therapy (67 patients), a combination of a PD-1 inhibitor and a CTLA-4 inhibitor (10 patients), and a combination of anti–PD-L1 therapy and Avastin (bevacizumab; three patients).

A majority of the enrolled patients were male (65 percent), 88 percent had a clear-cell histology, and 80 percent of the patients had prior nephrectomy. Twenty-one percent had favorable disease by International mRCC Database Consortium (IMDC) risk standards, 57 percent had intermediate IMDC risk, and 22 percent had poor-risk disease. Sixteen patients (20 percent) had received antibiotics up to one month prior to starting treatment with immunotherapy, including mostly beta-lactamases or fluoroquinolones.

At a median follow-up of six months, overall survival (OS) results were not yet able to be reached in the overall population, but a negative trend was already noted for patients who received prior antibiotics. The objective response rate also favored patients who had not received antibiotics.

In a subgroup of 62 patients who were treated with Opdivo (nivolumab) monotherapy, patients who had not taken antibiotics showed a greater PFS rate, which also achieved statistical significance. OS in the Opdivo monotherapy subgroup was also significantly higher in patients who had not taken recent antibiotics.

 “Derosa shows that antibiotic therapy may have a direct impact on how well the PD-1 inhibitor nivolumab works in patients with kidney cancer,” said Sumanta K. Pal, M.D., who moderated the presentation.

A multivariate analysis for prognostic risk factors showed a hazard ratio of 4.17 for patients who had not received antibiotics compared with those that had taken antibiotics. Patients with a lower Karnofsky performance statuses also showed an increased hazard ratio.

“Immune-based therapies for cancer may have a complex interplay with the host’s microbiome,” commented Pal, an assistant clinical professor in the Department of Medical Oncology and Therapeutics Research and co-director of the Kidney Cancer Program at City of Hope in Duarte, California. “Antibiotics may influence the bacterial composition of our gut, and this could in turn impact how effective immune therapy is.”

Derosa stated that the data was preliminary but that it encouraged longer follow-up and further studies to confirm the hypothesis of the study.

“The observations that Derosa makes have some consistency with preclinical observation,” Pal said. “We may be able to offer some insights as to whether or not bacterial composition of the gut could affect clinical outcomes and that might help us guide antibiotic usage.” Pal also suggested that these findings are not yet mature enough to impact clinical practice. The researchers plan to enroll additional patients in this study to investigate the mechanism of action. Other studies exploring the relationship between antibiotics and the efficacy of immunotherapy agents in lung cancer and kidney cancer are ongoing.

Patients with metastatic kidney cancer may see a decreased efficacy of their immunotherapy regimen if they recently took antibiotics.

Antibiotics May Compromise Immunotherapy Efficacy in Kidney Cancer

Philadelphia chromosome (Ph)-like acute lymphoblastic leukemia (ALL) accounts for more than 20 percent of all adult patients with ALL and is correlated with poor outcomes, according to a study in the 

The study evaluated the prevalence and genomic landscape of Ph-like ALL in this patient population with the intention of driving future clinical trials toward common targetable rearrangements in this subgroup.

“It’s basic genomic research but it has enormous translational implications,” said Charles Mullighan, M.D., M.B.B.S., a corresponding author of the report, in an interview with 

. “If one can identify these patients, they are excellent candidates for the addition of tyrosine kinase inhibitor (TKI) therapy.”

Researchers examined samples from 798 patients with B-cell ALL between the ages of 21 and 86. Gene-expression profiling was performed on the samples and patients were classified according to a coefficient (0-1) based on analysis of a 15-gene quantitative reverse transcriptase polymerase chain reaction low-density array. Patients with a coefficient of 0.5 to 1 were classified as having Ph-like ALL. In the study, 194 patients (24.3 percent) were found to have Ph-like ALL.

BCR-ABL1—rearranged ALL was identified in 23.2 percent of the patients and MLL-rearranged ALL was identifed in 15.4 percent.

The patient population was divided into three groups based on age: young adult patients (aged 21-39; 344 patients), adult patients (aged 40-59; 304 patients), and older adult patients (aged 60-861; 150 patients). The prevalence of Ph-like ALL was greatest among young adult patients at 27.9 percent. Adult patients had a frequency of Ph-like ALL of 20.4 percent and older adult patients, 24 percent.

Patients with non—Ph-like ALL had better survival rates than patients with Ph-like ALL with a five-year event-free survival (EFS) rate of 49.3 percent versus 22.5. The five-year overall survival (OS) rate for patients with non– Ph-like ALL was 52.4 percent versus 28.8 percent.

Survival disparities between patients with Ph-like ALL and non—Ph-like ALL were increased in younger patients. The five-year EFS rate for young adult patients with Ph-like ALL was 24.1 percent versus 60.5 percent. For adult patients with Ph-like ALL the five-year EFS was 21.4 percent versus 38.7 percent for non– Ph-like ALL. Five-year OS for young adults with Ph-like ALL was 25.4 percent versus 64.2 percent. OS for adult patients with Ph-like ALL was 27 percent versus 44.9 percent.

The survival differences for older adult patients with Ph-like ALL were lower than older adults with non—Ph-like ALL, but these differences were not statistically significant. Older adult patients with Ph-like ALL had a three-year EFS of 8 percent and a three-year OS of 13.5 percent versus 33.3 percent and 37.9 percent, respectively, for older adult patients with non–Ph-like ALL. The authors noted that the smaller group of older adult patients could have affected the significance of these findings.

Ph-positive ALL has been studied in depth in pediatric and adult patients, as this well-known subtype was associated with a poor outcome. However, the rate of Ph-like ALL—which Mullighan notes has a similar gene expression profile to Ph-positive ALL but lacks BCR-ABL1&mdash;in older patients was previously unknown.

“It had been known for many years that the frequency of Ph-positive leukemia, BCR-ABL—positive ALL, rises with increasing age. There are some data suggesting that the frequency of Ph-like ALL may not continually increase throughout age, so we were very interested in doing a comprehensive study with a large number of patients to define the prevalence of Ph-like ALL across the age spectrum of adulthood, and also to identify the underlying genetic lesions and see how they compare to those we had described in children and young adults,” said Mullighan, co-leader of the Hematological Malignancies Program at St. Jude Children’s Research Hospital.

The prevalence of Ph-like ALL across various age groups and the association with a worse outcome stimulates the need for more clinical trials to study ways to treat this subpopulation. To that end, the researchers explored the genetic landscape of adult patients with Ph-like ALL to find mutations and pathways that could be targeted with available therapies.

Of the 194 patients with Ph-like ALL in the study, genomic alterations activating kinase signaling were identified in 171 patients (88.1 percent). Of these, 99 patients (51 percent) had high expression of CRLF2, 25 of which also had a mutation of Janus kinases (JAK1/JAK2). The frequency of CRLF2 overexpression was highest among older adult patients at 58.4 percent compared with 51.1 percent in young adults and 46.8 percent in adult patients.

Alterations in kinase-activating genes identified included ABL class fusions in 9.8 percent of patients, that have not been recognized in B-cell ALL disease before: FIP1L1- PDGFRA, SNX29-PDGFRB, SMU1-JAK2, ZNF340-JAK2, THADA- EPOR, SMARCA4-TYK2, ZNF340-TYK2, ZYMM2-FLT3, DNTT-BLNK, TMEM2-PTK2B and KANK1-CBL1.

Alterations in cytokine receptor genes included sequence mutations of IL74, SH2B3, JAK1 or JAK3 and rearrangement of TYK2 in 7.2 percent of patients; Ras pathway mutations of KRAS, NF1, PTPN11 and CBL1 in 3.6 percent; and uncommon fusions, including FLT3, NTRK3, BLNK and PTK2B in 4.1 percent.

Rearrangements activating kinase signaling were found in 126 patients (65 percent) including 32 different rearrangements across 14 kinase or cytokine receptor genes. Further, 11 rearrangements were identified that have not been recognized in B-cell ALL disease before: FIP1L1- PDGFRA, SNX29-PDGFRB, SMU1-JAK2, ZNF340-JAK2, THADA- EPOR, SMARCA4-TYK2, ZNF340-TYK2, ZYMM2-FLT3, DNTT-BLNK, TMEM2-PTK2B and KANK1-CBL1.

The frequency of kinase fusions did not differ greatly between age groups, except for EPOR rearrangements, which were found more often in younger adults than in older adults.

Patients with a rearrangement of CRLF2, JAK2/EPOR, or ABL class genes were more likely to have a higher coefficient used in the classification of Ph-like ALL and were associated with a worse outcome. For patients harboring CRLF2 rearrangements, 68 percent were assigned a coefficient between 0.9 and 1, on the higher end of the spectrum, and 79 percent of patients with a JAK2/EPOR rearrangement had a coefficient between 0.9 and 1. Ninety percent of patients with an ABL-associated rearrangement had a coefficient between 0.9 and 1. However, patients with CRLF2 or JAK2/EPOR rearrangements were associated with worse 5-year EFS and OS rates than patients with ABL class rearrangements.

“This study confirmed that this is a prevalent form of leukemia, with similar kinase-activating genetic alterations to those previously described, but importantly, as we continue to sequence more cases, we find more lesions that we haven’t found before,” said Mullighan. “One of our key take-home messages from this study is that accurate management really needs accurate sequencing rather than just candidate testing approaches for the most common fusions.”

In the study, the authors suggested that the identification of patients with Ph-like ALL be incorporated in the design of future clinical trials.

In terms of potential treatment options, Ph-like ALL is characterized by a variety of genetic alterations in adults, most of which can be targeted by existing therapies, the study authors noted.

“In the context of these studies, the [most] promising approach is a TKI,” said Mullighan.

The study authors note that approximately 70 percent of the patients with Ph-like ALL could benefit from treatment with JAK inhibitors, such as Jakafi (ruxolitinib). Patients harboring CRLF2 rearrangements, JAK2/ EPOR rearrangements, and sequence mutations of JAK1, JAK3, IL7R or SH2B3, could all be treated with a JAK inhibitor.

Preclinical studies have shown the efficacy of Jakafi in Ph-like ALL or early T-cell precursor ALL. In a study of patient-derived murine xenograft models of ALL treated with the JAK1/2 inhibitor Jakafi, the treatment showed activity in all 6 of the xenograft models.

Patients harboring ABL1, ABL2, CSF1R, PDGFRA, or PDGFRB rearrangements could all benefit from being treated with ABL inhibitors, such as Gleevec (imatinib) or Sprycel (dasatinib), both of which have been approved for the treatment of patients with Ph-positive ALL.

In a previous study of Ph-like ALL, the researchers noted that cell lines and human leukemic cells in vitro expressing ABL1, ABL2, CSF1R, and PDGFRB fusions were sensitive to dasatinib.

 Previous reports of patients with other tumor types expressing an ETV6-NTRK3 fusion have shown responses to the ALK inhibitor Xalkori (crizotinib).

“There are likely other forms of therapy that could treat this form of leukemia as well that are not necessarily related to the genetics,” Mullighan said. “But in terms of how these findings directly inform therapy, the implication is for TKIs... and inhibitors of ABL and JAK2 inhibitors are the 2 main agents moving ahead in to clinical trials. There are a number of other kinases as well that require other TKIs that are less commonly mutated or rearranged but are also very likely to respond and they’ll need to be tested in future work.”

Trials assessing the addition of TKI therapy to chemotherapy have commenced, including a trial studying the combination of Jakafi or Sprycel with chemotherapy in adult patients with Ph-like ALL (

There is a need for more targeted clinical trials for patients with ALL, since many of them have Philadelphia chromosome (Ph)-like acute lymphoblastic leukemia. 

The Need for Targeted Clinical Trials in ALL

Previously treated patients with a rare subtype of melanoma had durable activity on Keytruda (pembrolizumab), according to data from three clinical trials presented at the 2017 European Cancer Congress in Amsterdam.

Patients with mucosal melanoma (84 patients) treated with Keytruda in the KEYNOTE-001, KEYNOTE-002 and KEYNOTE-006 studies demonstrated a median duration of response of 27.6 months.

These data are particularly important because they show that patients with this rare subtype of melanoma can benefit from anti—PD-1 therapy, said investigator Marcus Butler, M.D., in a statement.

“At this stage we don’t know why some mucosal melanoma patients responded to pembrolizumab, while others did not. This is an important question and research is ongoing,” Butler, of the Cancer Clinical Research Unit of the Princess Margaret Cancer Centre, explained.

In the three KEYNOTE trials, 84 of 1,567 patients (5 percent) had mucosal melanoma. Of these 84 patients, 57 percent were women, 49 percent were at least 65 years old, and 32 percent had an ECOG performance status of 1. Eight percent of the patients had 

 V600 mutations, 81 percent had M1c disease, and of the patients with known PD-L1 status, 70 percent had PD-L1—positive tumors.

All of the patients were previously treated; 90 percent of patients had received at least one prior therapy, and 8 percent had received more than three therapies. Thirty-nine percent of patients had previously been treated with Yervoy (ipilimumab).

Across the three KEYNOTE trials, patients received Keytruda at three different doses: 2 mg/kg every three weeks, 10 mg/kg every three weeks, or 10 mg/kg every two weeks.

The objective response rate (ORR) in the patients with mucosal melanoma was 19 percent with 16 patients responding, and the disease control rate (DCR) was 31 percent. The median progression-free survival (PFS) rate was 2.8 months and the median overall survival (OS) rate was 11.3 months.

“Sixteen of these patients (19 percent) responded to treatment with pembrolizumab, of whom 12 are still alive without their disease progressing and, so far, the longest time some of these patients have continued to be successfully treated is more than 27 months,” said Butler.

Of the patients previously treated with Yervoy, the ORR was 15 percent with five patients responding and the DCR was 27 percent. “Our results show that patients benefited from Keytruda regardless of whether or not they had been pre-treated with ipilimumab,” said Butler. In the three trials, patients with nonmucosal melanoma had an ORR of 33 percent and the DCR was 47 percent. The median PFS was 4.2 months and the median OS was 23.5 months.

In his presentation, Butler emphasized the impact that immunotherapy has had thus far on the treatment landscape of melanoma.

“Immunotherapy for melanoma has revolutionized treatment of the disease. There are some patients with mucosal melanoma who have had complete responses to Keytruda and essentially return to a normal life. Some, of course, have less spectacular responses, but they still benefit from therapy,” said Butler.

He added that earlier studies have previously excluded patients with mucosal melanoma, as it is a rare subtype of the disease.

“These findings suggest that mucosal melanoma patients should be offered immunotherapy as standard of care and not excluded. Response rates may be a bit lower than for other types of melanoma, so further studies to improve benefit need to be conducted,” he said.

“For rare cancer types, it is difficult to evaluate new treatments in normal sized trials. But here, Butler and colleagues pull three trials together and show that long-lasting responses also occur with pembrolizumab in patients with mucosal melanoma,” Peter Naredi, chair of the European Cancer Congress and president of the European Cancer Organization, said in a statement.

Three recent trials showed that Keytruda had a durable response for patients with a rare subtype of melanoma.

Author | Lisa Miller

NCCN May Already Be Updating MPN Guidelines

Antibiotics May Compromise Immunotherapy Efficacy in Kidney Cancer

The Need for Targeted Clinical Trials in ALL

Keytruda Benefits Rare Melanoma Subtype in Three Trials