Clinical Insights: February 2017

Friday, February 17, 2017

Release Date: February 17, 2017
Expiration Date: February 17, 2018


This activity is provided free of charge.

STATEMENT OF NEED

This CE article is designed to serve as an update on cancer detection and prevention and to facilitate clinical awareness of current and new research regarding state-of-the-art care for those with or at risk for cancer.
TARGET AUDIENCE

Advanced practice nurses, registered nurses, and other healthcare professionals who care for cancer patients may articipate in this CE activity.
 
EDUCATIONAL OBJECTIVES

Upon completion, participants should be able to:
  • Describe new preventive options and treatments for patients with cancer
  • Identify options for individualizing the treatment for patients with  cancer
  • Assess new evidence to facilitate survivorship and supportive care for patientswith cancer
ACCREDITATION/CREDIT DESIGNATION STATEMENT

Physicians’ Education Resource®, LLC is approved by the California Board of Registered Nursing,Provider #16669 for 1.0 Contact Hours.
 
DISCLOSURES/RESOLUTION OF COI

It is the policy of Physicians’ Education Resource®, LLC (PER®) to ensure the fair balance, independence, objectivity, and scientific objectivity in all of our CE activities. Everyone who is in a position to control the content of an educational activity is required to disclose all relevant financial relationships with any commercial interest as part of the activity planning process. PER® has implemented mechanisms to identify and resolve all conflicts of interest prior to release of this activity.The planners and authors of this CE activity have disclosed no relevant financial relationships with any commercial interests pertaining to this activity.
METHOD OF PARTICIPATION
  1. Read the articles in this section in its entirety.
  2. Go to www.gotoper.com/go/ONN17Feb
  3. Complete and submit the CE posttest and activity evaluation.
  4. Print your CE Certificate.
OFF-LABEL DISCLOSURE/DISCLAIMER

This CE activity may or may not discuss investigational, unapproved, or off-label use of drugs. Participants are advised to consult prescribing information for any products discussed. The information provided in this CE activity is for continuing medical nursing purposes only and is not meant to substitute for the independent medical judgment of a nurse or other healthcare provider relative to diagnostic, treatment, or management options for a specific patient’s medical condition. The opinions expressed in the content are solely those of the individual authors and do not reflect those of PER®.
2016 San Antonio Breast Cancer Symposium

Everolimus/Fulvestrant Combo Improves Survival in HR+ disease

Lisa Miller

The addition of the mTOR inhibitor everolimus (Afinitor) to fulvestrant (Faslodex) significantly improved progression-free survival (PFS) in postmenopausal patients with metastatic hormone receptor (HR)-positive, HER2-negative breast cancer who are resistant to aromatase inhibitor (AI) therapy, according to findings from the phase II PrECOG 0102 trial presented at the 2016 San Antonio Breast Cancer Symposium. Abstract S1-02

In the study, the everolimus/fulvestrant combination doubled median PFS rates compared with fulvestrant alone, from 5.1 months with fulvestrant only to 10.4 months with the combination (HR, 0.60; 95% CI, 0.40-0.92; P = .02).

“We feel that the study provides additional evidence that adding everolimus to anti-estrogen therapy in AI-resistant disease improves clinical outcomes,” said Noah S. Kornblum, MD, assistant professor of medicine, Albert Einstein College of Medicine, and attending physician of medicine, Montefiore-Einstein Center for Cancer Care.

The authors had hypothesized that the combination of everolimus and fulvestrant could be used to treat AI-resistant disease, which usually develops in most patients with HR-positive breast cancer treated with AI therapy.

Prior research has shown that AI resistance can be overcome by targeting the PI3K-AKTmTOR pathway. In the phase III BOLERO-2 trial,1 the addition of the mTOR inhibitor to exemestane improved PFS rates from 3.2 months on exemestane alone to 7.8 months with the combination. The combination was approved in 2012 for the treatment of postmenopausal women with advanced HR-positive, HER2-negative breast cancer, largely based on results from BOLERO-2.

The patient population in the PrECOG trial was similar to those in the BOLERO-2 study, yet Kornblum believes that patients in the PrECOG placebo arm may have had longer PFS rates than those in the BOLERO-2 placebo arm due to the superiority of high-dose fulvestrant over exemestane.

“There are some potential advantages of fulvestrant in some people’s minds over steroidal AIs, such as exemestane,” Kornblum said. We don’t really have a direct comparison of these 2 combinations, but I think [fulvestrant and everolimus] does offer some [additional] options and it’s nice to have great options.”

Patients in the PrECOG trial were eligible if they had relapsed while on adjuvant AI therapy or had progressed after an AI therapy for metastatic disease; had an ECOG performance status score of 0 or 1, and had previously received no more than 1 chemotherapy regimen.

The 130 patients were randomized 1:1 in the induction phase to receive either highdose fulvestrant in addition to 10 mg of everolimus or fulvestrant with matching placebo. Patients continued treatment until progression or unacceptable toxicity for a maximum of 48 weeks. After 48 weeks, patients moved on to the continuation phase and could continue fulvestrant treatment with or without everolimus.

The combination was associated with additional toxicity compared with the fulvestrant-alone arm with grade 3 adverse events (AEs) occurring in 48% of patients in the combination arm versus 14% in the fulvestrant-only group. The most common grade 3 AEs in the combination arm included stomatitis in 9% of patients, pneumonitis in 6%, fatigue in 5%, and hyperglycemia in 6%.

The safety profile of the everolimus/fulvestrant combination was consistent with that of the everolimus/exemestane combination in the BOLERO-2 trial, and Kornblum added that there is a learning curve for clinicians in managing the safety and toxicity profiles for these combinations.

For instance, Kornblum noted that in the trial, supportive care with prophylactic corticosteroid mouthwash was not used, which could have alleviated the frequency of cases of stomatitis. Recent data have shown that the use of corticosteroid mouthwash reduces the risk of low-grade stomatitis. “That information was not known at the inception and conduction of this study,” he said.
REFERENCE
1.Yardley DA, Noguchi S, Pritchard KI, et al. Everolimus plus exemestane in postmenopausal patients with HR(+) breast cancer: BOLERO-2 final progression-free survival analysis. Adv Ther. 2013;30(10):870-874.

Post-Mastectomy Radiation Linked to Implant Complications for Some Women

Allie Casey

For patients with breast cancer who have undergone breast reconstruction surgery, radiation therapy increased complications and lowered patient-reported satisfaction, according to data from a large, multicenter study presented at the 2016 San Antonio Breast Cancer Symposium. However, this was not the case for patients who received autologous reconstruction, whereby the woman’s own body tissues are used to create a new breast. Abstract S3-07

Many challenging decisions are involved for women diagnosed with early-stage breast cancer, ones that will affect their long-term disease control and quality of life, according to study author Reshma Jagsi, MD, DPhil.

Despite evidence supporting the benefits of post-mastectomy radiotherapy in some patients, “Many patients must still decide whether they feel that the benefits outweigh the risks,” explained Jagsi, professor and deputy chair in the Department of Radiation Oncology at the University of Michigan. “One of the risks of radiation therapy is that it may affect the options and outcomes for breast reconstruction, which many women who receive mastectomy desire.”

This study collected medical and patient-reported outcomes data from women who were a median age of 49 and diagnosed with breast cancer and elected different types of reconstruction between 2012 and 2015: 553 of these patients received radiotherapy, and 1461 patients did not. About 38% and 25% of the patients who did and did not receive radiotherapy, respectively, received autologous reconstruction, and the rest received implant reconstruction.

From there, researchers determined whether radiotherapy was associated with complications developed post-reconstruction, such as hematoma or wound infection. They also measured patient satisfaction using a BREAST-Q patient-reported outcome instrument, 1 and 2 years after reconstruction.

At 1 year of follow-up, 28.8% of patients who had radiotherapy and 22.3% who did not, had at least 1 of the measured complications. At 2 years of follow-up, 34.1% and 22.5% of those who did and did not receive radiotherapy, respectively, experienced a complication with their breast reconstruction.

After accounting for several variables, the researchers determined that radiotherapy was linked to more than double the odds of developing complications in patients who received implants. However, for those patients who received autologous reconstruction, radiotherapy was not associated with complications. Additionally, the BREAST-Q scores of patients who had received radiation showed significantly lower patient-reported satisfaction than those of the patients who did not receive radiation. Once more, these differences were not shown among the patients with autologous reconstruction.

Currently, well-established approaches to integrate post-mastectomy radiotherapy and breast reconstruction are lacking, noted Jagsi.

“Although women must still weigh multiple factors, including the differences in operative time and rehabilitation required for different approaches when selecting their preferred type of reconstruction, those who plan to receive post-mastectomy radiation therapy should be informed of the substantial and significant impact of radiotherapy observed in the current study among patients who received implant reconstruction.”

However, those patients who intended to pursue autologous reconstruction could be reassured by these findings: “Outcomes among patients receiving autologous reconstruction did not appear substantially worse than those of unirradiated patients by 2 years.”
 Nurse Perspective  
Deirdre Kiely, MS, MPA, RN, ANP
Deirdre Kiely, MS, MPA, RN, ANP
Nurse Practitioner
Perlmutter Cancer Center
Christiana Care Health System
Wilmington, DE
 

Breast cancer is a common disease among American women resulting in an increased awareness of breast cancer-related issues. Despite growing attention to the informational priorities of patients in a shared decision making model of care, patients report that provision of adequate information is an unmet need throughout their cancer experience. This is especially concerning for patients with cancer who must make complex decisions about their treatment based on an understanding of medical information in an unfamiliar learning environment.
The summary of the post-mastectomy radiation therapy (PMRT) data presented at the 2016 San Antonio Breast Cancer Symposium highlights the complexity of decision making around reconstructive options after mastectomy. Although patients with early-stage breast cancer may opt for 
a mastectomy, they will probably not meet the criteria to have PMRT and can consider a wider range of reconstructive options. The indication for PMRT is a patient who presents with a high risk of local recurrence where the long-term benefits of radiation outweigh potential short- or long-term adverse effects.
Researcher Reshma Jagsi, MD, DPhil, noted that patients who undergo PMRT after implant-based reconstruction report increased complications and lower satisfaction than those who undergo autologous reconstruction. An additional outcome measure of locoregional control, however, should also be considered, because this is the goal of radiation treatment.
A multidisciplinary approach to surgical planning should include the breast surgeon, plastic reconstructive surgeon, and radiation oncologist addressing preoperative consideration of risks/benefits of the planned surgery. The option of a staged reconstruction where a tissue expander (rather than the permanent implant) is placed at the time of the mastectomy and is in place during radiation would address risk of complications such as capsular contracture. The risks of delaying systemic adjuvant treatment during a longer recovery period after autologous reconstruction should also be considered.
The alignment of information needs and consideration of patient preference for involvement during comprehensive healthcare discussions makes for a more effective and meaningful provider–patient interaction. When patients are encouraged to communicate their concerns, they take an active role in tailoring their care and are generally more satisfied with the overall experience.

Loperamide Plus Budesonide Eases Diarrhea With Neratinib in HER2-Positive Breast Cancer

Silas Inman

Prophylactic treatment with the combination of loperamide and budesonide reduced the rate of grade ≥3 diarrhea associated with neratinib to 15% compared with 39.9% observed in the ExteNET trial. The rate of all-grade diarrhea was 65% with the prophylactic regimen versus 95.4% in ExteNET, according to findings from the phase II CONTROL trial presented at the 2016 San Antonio Breast Cancer Symposium. Abstract P2-11-03

“Previously, the ExteNET clinical trial had shown a benefit of the drug neratinib in patients with stage I to III breast cancer. There was a benefit of neratinib given in the adjuvant setting after 1 year of trastuzumab,” said Carlos H. Barcenas, MD, MSc, assistant professor, The University of Texas MD Anderson Cancer Center. “The problem with this drug is that it gives a lot of diarrhea. This study sought to characterize the diarrhea and control it.”

The international open-label CONTROL trial enrolled patients with stage I to IIIc HER2-positive breast cancer across 4 cohorts focused on diarrhea prophylaxis. All patients had completed trastuzumab-based therapy ≤1 year prior to enrollment. The study included more patients with HR-positive disease and more with stage I tumors compared with those enrolled in ExteNET.

Neratinib was administered at 240 mg once daily for 1 year. Loperamide was given at a variety of doses, with 3 doses of single-agent loperamide examined along with a combination of loperamide and budesonide. In this group, loperamide was given for 2 cycles at 4 mg 3 times per day for days 1 to 14. This was followed by 4 mg twice daily for days 15 to 56. Budesonide was given at 9 mg once daily for 1 cycle. After 2 cycles, loperamide was given as needed at ≤16 mg per day.

In the single-agent loperamide arms (n = 135), 100% of patients had received prior neoadjuvant trastuzumab compared with 87.5% of those in the budesonide arm (n = 40). More patients were treated with pertuzumab before entering the trial in the combination arm (55%) versus the single-agent groups (40%). The median time since last dose of trastuzumab was 4.1 months in the single-agent group and 4.3 months in the budesonide arm.

The median neratinib exposure in the budesonide arm was less compared with the loperamide monotherapy group (1.8 vs 7.5 months), suggesting that additional diarrhea events could still occur. In general, most of the events in the loperamide single-agent arm occurred during the first 2 months of therapy.

“The budesonide data is very early, we only have a couple of months, so of course some of this data may change over time as it matures a little bit more,” Barcenas said. “The preliminary results look very promising.”

Diarrhea of any grade occurred in 75.5% of patients treated with loperamide alone. These events were grade 1 (24.4%), grade 2 (23.0%), and grade 3 (28.1%) in severity. In the budesonide arm, patients had grade 1 (32.5%), grade 2 (17.5%), and grade 3 (15%) diarrhea. There were no grade 4 or 5 events.

“Fifteen percent with the budesonide is a good number but the idea is to increase it a bit more,” said Barcenas. “Although we think it is inflammatory, it might be multifactorial, so we want to use multiple agents. The next agent that we’ll be testing is called colestipol, which is a bile acid sequestrant.”

Patients had grade ≥3 diarrhea for a median cumulative duration of 3.0 days in the loperamide monotherapy arm compared with 2.5 days for budesonide. In the ExteNET trial, grade ≥3 diarrhea persisted for 5 days. Patients had a median of 2 episodes of all-grade diarrhea in the single-agent and combination arm compared with 8 episodes without prophylaxis in ExteNET.

There were significantly fewer dose holds, reductions, and discontinuations related to treatment-emergent diarrhea in the prophylaxis arms. For the combination, dose holds were required for 7.5% of patients and dose reductions were needed for 5%. Five percent of patients discontinued therapy and none required hospitalization. In the ExteNET trial, treatment holds were needed for 33.9% of patients and dose reductions were required for 26.4%. Treatment was discontinued for 16.8% of patients and 1.4% required hospitalization.

Prior treatment with pertuzumab led to higher rates of diarrhea. In those in the loperamide single-agent arm, 35.2% of pertuzumab pretreated patients had grade 3 diarrhea compared with 23.5% in those who did not receive the antibody. In the budesonide cohort, the rates were 13.6% and 16.7%, for pertuzumab-treated and not-treated patients, respectively. “The diarrhea is controllable and there are different strategies that we’re exploring,” Barcenas said. “The study is still open and enrolling.”

The rate of constipation was significantly increased with the use of diarrhea prophylaxis. All-grade constipation went from 8.2% in the ExteNET trial to 54.1% with loperamide and 47.5% with loperamide plus budesonide. There were additional increases in fatigue and nausea, which are likely secondary to loperamide, said Barcenas.

“Of course, everything comes with a cost. For loperamide with this combination there was an increase in constipation and nausea and also fatigue,” said Barcenas. “It is a balancing act between decreasing diarrhea but also trying not to increase too much the constipation.”
2016 American Society of Hematology Annual Meeting

Subcutaneous Daratumumab Safe, Effective in Relapsed Myeloma

Jason M. Broderick

Subcutaneous delivery of daratumumab (Darzalex) was well tolerated with comparable efficacy to the FDA-approved intravenous dose in patients with relapsed/refractory multiple myeloma, according to results from the phase Ib PAVO trial. Abstract 1149

“The tolerability, safety, and pharmacokinetic data support continued development of subcutaneous daratumumab in different settings,” lead author Saad Z. Usmani, MD, of the Levine Cancer Institute/Carolinas HealthCare System, said when presenting the results at the 2016 annual meeting of the American Society of Hematology held December 3-6 in San Diego.

The open-label, multicenter, dose-escalation phase Ib PAVO study examined whether subcutaneous (SC) daratumumab that takes only minutes to administer could be as safe and effective as the current IV dosing regimen that lasts several hours per dose.

To enable SC delivery, recombinant human hyaluronidase (rHuPH20) was administered along with daratumumab.

Enrolled patients had relapsed/refractory multiple myeloma and received at least 2 prior lines of therapy but had not been treated with anti-CD38 agents. Patients were examined in 2 groups. The first group of 8 patients received a 1200-mg fixed SC dose of daratumumab combined with rHuPH20 at 30,000 U. The second group of 45 patients received SC daratumumab at 1800 mg and rHuPH20 at 45,000 U. The infusion times for the 2 doses were 20 and 30 minutes, respectively, for each 28-day cycle.

The primary endpoints of the study were pharmacokinetics and safety. Secondary endpoints included overall response rate (ORR), complete response (CR) rate, duration of response, and time to response. Baseline patient demographics and treatment history were well balanced between the 2 groups.

At data cutoff on November 15, 2016, deeper responses were observed in the 1800-mg group versus the 1200-mg arm. In the 1800-mg group, the ORR was 38% (n = 17), which included a stringent complete response rate of 2%, a very good partial response rate of 7%, and a partial response (PR) rate of 29%. The minimal response (MR), stable disease (SD), and progressive disease (PD) rates were 11%, 38%, and 13%, respectively.

Among patients receiving the 1200-mg dose the ORR was 25% (n = 2), comprised of all PRs. The MR, SD, and PD rates were 13%, 50%, and 13%, respectively. The responses in both groups were consistent to what has been observed with the IV formulation.

Eighty-eight percent (n = 7) of the 1200-mg arm discontinued treatment due to progressive disease (n = 5), patient withdrawal (n = 1), or death (n = 1). Thirty-three percent (n = 15) of the 1800-mg arm discontinued treatment due to progressive disease (n = 12), physician decision (n = 2), or death (n = 1).

The most common all-grade hematologic treatment-emergent adverse events (TEAEs) were anemia and thrombocytopenia, which occurred in 25% versus 31% and 38% versus 18% of the 1200-mg and 1800-mg arms, respectively. The most common all-grade nonhematologic TEAEs were upper respiratory infection, insomnia, and decreased appetite, which occurred in 38% versus 9%, 38% versus 9%, and 38% versus 7% of the 1200-mg and 1800-mg arms, respectively.

Grade 3/4 TEAEs in the 1200 mg-arm included hypertension (n = 2), fatigue (n = 2), anemia (n = 1), thrombocytopenia (n = 1), neutropenia (n = 1). In the 1800-mg arm, grade 3/4 TEAEs included anemia (n = 6), thrombocytopenia (n = 3), neutropenia (n = 3), lymphopenia (n = 3), hypertension (n = 2), device-related infection (n = 2), hyponatremia (n = 2), and fatigue (n =1). Infusion-related reactions (IRRs) in the 1800-mg group were mostly grade 1 or 2, and they occurred in about 24% of the patients. Usmani noted that both the AE and IRR profiles aligned with previous experience with the IV daratumumab formulation. Only 1 grade 3 IRR was observed and it occurred in a patient in the 1200-mg group.

The overall incidence of IRRs in this arm was 13%. No grade 4 IRRs were reported. All IRRs occurred during or within 4 hours of the first infusion. Abdominal wall SC injections were well tolerated.

With regard to pharmacokinetics, Usmani said, “The 1800-mg dose appears to be replicating what we have observed with the 16-mg/kg IV dose in previous studies.” However, a simulation of the mean concentration of SC and IV dosing showed lower levels with the 1200-mg subcutaneous dose than with what has been observed with the IV dose.

In November 2015, the FDA approved daratumumab as a monotherapy for patients with multiple myeloma following at least 3 prior therapies. In November 2016, the FDA approved it in combination with lenalidomide and dexamethasone or bortezomib and dexamethasone for patients with relapsed, multiple myeloma following at least 1 prior therapy.
 Nurse Perspective  
Melissa Baker, RN, MSN, OCN, APN-C
Melissa Baker, RN, MSN, OCN, APN-C
Adult Blood & Marrow Stem Cell Transplantation Programs
John Theurer Cancer Center

Hackensack, NJ 

Daratumumab (DARA) is currently administered as an intravenous (IV) infusion. While IV DARA is well tolerated and highly efficacious, more than half of patients experience infusion-related reactions (IRR). The phase Ib PAVO study is the first to assess subcutaneous (SC) administration of DARA + PH20 in patients with relapsed or refractory multiple myeloma. Overall, data from this trial indicate:
  • DARA can be combined safelywith rHuPH20.
  • SC DARA is well tolerated with low IRR rates.
  • Pharmacokinetic profile of the 1800-mg dose is consistent with DARA 16 mg/kg IV.
  • Efficacy of SC DARA is consistent with IV DARA (38% overall response rate).
In general, safety, efficacy, preference, and pharmacoeconomics govern the choice of administration route. When safety and efficacy of IV and SC formulations are equivalent, choosing the option that favors patient preference will increase treatment adherence and improve patient satisfaction, whereas attention to pharmacoeconomics can help address the issue of nursing staff shortages and may reduce healthcare costs.
The transition from IV to SC DARA has the potential to provide multiple benefits. With SC administration, chair time and pharmaceutical preparation time are reduced. SC administration constitutes an alternative for patients with poor venous access, limits infectious complications, may be performed in the ambulatory setting, and may allow self-administration in educated patients. One of the biggest advantages of SC over IV administration is patient convenience and the potential to improve compliance.
From a nursing perspective, it is important to consider patient characteristic– related factors (eg, body-mass index, age, comorbidities) with SC chemotherapeutics. Would IV DARA be better suited for overweight or underweight individuals? Would thrombocytopenia influence mode of administration to decrease bleeding risk? Inflammation or irritation at the injection site, leakage of drug, and allergic reactions also can be disadvantages associated with SC administration.
Sites of administration typically need to be rotated, and the injected volume is limited to approximately 2 mL to reduce pain. Separate injection sites per dose may be required, which can cause discomfort. In general, SC injections in the abdomen cause fewer injection site reactions compared to the thigh, likely the reason the PAVO trial tested SC DARA in the abdomen.
Adopting a nursing protocol for SC chemotherapeutic administration that aims to reduce the incidence and severity of injection site reactions—while ensuring drug delivery into the adipose tissue—will facilitate the benefits associated with the SC route. Injection site nursing protocols should include guidelines for site selection, needle size, volume of medication per site, patient education for post-injection care, and guidelines for documentation.

Ibrutinib Shows Promise in Treating GVHD After Stem Cell Transplant

Chase Doyle

An FDA-approved blood cancer drug has demonstrated encouraging findings, including an overall response rate (ORR) of 67%, in treatment of patients with chronic graft-versus-host-disease (cGVHD) that was not resolved by corticoste-roids. Abstract LBA3

In a multicenter study presented at the 2016 American Society of Hematology Annual Meeting, ibrutinib (Imbruvica) showed clinically meaningful and durable responses in patients who failed at least 1 prior treatment for cGVHD. In addition, the majority of responders were able to reduce steroid doses to an acceptable minimal level.

Of the 42 participants who experienced GVHD, 67% responded to ibrutinib, and 71% had sustained improvements over a 5-month period. According to the researchers, the results are encouraging for a subset of patients with limited treatment options beyond corticosteroids.

Lead author of the study, David Miklos, MD, PhD, called the findings “remarkable” and said that ibrutinib appears to exceed the therapeutic benefits of other agents. “This is a very high response rate,” said Miklos, associate professor of Blood and Marrow Transplantation at the Stanford University Medical Center. “Clinicians will find these data support the use of ibrutinib in patients with steroid-refractory chronic GVHD, who currently suffer a range of symptoms that can be chronic and debilitating.”

Chronic GVHD is a serious complication of allogeneic stem cell transplantation (ASCT), in which the transplanted stem cells attack the patient’s body, causing symptoms such as rashes, mouth ulcers, dry eyes, gastrointestinal problems, shortness of breath, and decreased mobility in the joints and limbs. Although immune-suppressing corticosteroid medications are the standard treatment for cGVHD, they do not benefit all patients, Miklos explained.

For the multicenter, open-label, phase II study, researchers enrolled 42 patients with steroid dependent/refractory cGVHD following ASCT. Patients had failed 3 or fewer prior therapies for cGVHD and had either more than 25% body surface area involving an erythematous rash or a National Institutes of Health (NIH) mouth score greater than 4.

Ibrutinib was administered daily at 420 mg until cGVHD progression or unacceptable toxicities. The primary endpoint was cGVHD response based on the 2005 NIH consensus response criteria.

Results showed that 21% of responders had a complete response and 19% had a partial response. Seventy-one percent of the 28 responders had a sustained cGVHD response of at least 5 months.

Furthermore, cGVHD response was observed across multiple organs: 56% (20/25) of patients with 2 or more involved organs at base-line responded in at least 2 organs, and 42% of patients with 3 or more involved organs at baseline responded in at least 3 organs.

Patients also had meaningful improvement in their cGVHD symptoms as assessed by Lee Symptom Score improvements of greater than 7 points. Consistent with this improvement, clinician-assessed and patient-reported reductions in overall cGVHD severities were reported throughout the study, as well.

In addition, patients on ibrutinib experienced reductions in corticosteroid doses. Overall, 26 patients achieved corticosteroid doses less than .15 mg/kg daily while on ibrutinib and 5 responders were able to discontinue all corticosteroid treatment.

Regarding safety, 45% of participants experienced serious adverse events (AEs) such as pneumonia, septic shock, or severe fever. Additional AEs include fatigue, diarrhea, muscle spasms, nausea, and bruising.

As Miklos reported, however, these side effects are consistent with those previously reported for ibrutinib and those observed in patients with cGVHD on concomitant corticosteroids.

Overall, he added, ibrutinib represents a promising potential new therapy for GVHD.

“By targeting allogeneic B cells and TH2 lymphocytes, ibrutinib is targeting a pathogenic mechanism that we believe causes GVHD, while leaving protective and antitumor cytotoxic T cells intact,” said Miklos.

“This is a targeted therapy that does not just bluntly suppress the immune system; it leaves patients better able to fight their cancer as well as viral infections.”

Miklos and colleagues are recruiting participants for additional trials that will further investigate the use of ibrutinib in preventing or treating GVHD and compare it with other agents.

High Rates of Symptoms, Impairment in Patients With Myeloproliferative Neoplasms

Lauren M. Green

Patients with myeloproliferative disorders have a high symptom burden that significantly affects emotional status, quality of life, and functional ability, an international patient survey showed. Abstract 4267

The survey showed that 90% of patients reported 1 or more symptoms within the past 12 months, the most common symptom being fatigue/tiredness. A substantial proportion of patients with myelofibrosis (MF), polycythemia vera (PV), and essential thrombocythemia (ET) reported multiple troubling symptoms, which often were rated as 6 or higher on a severity scale of 0-10.
A dozen types of symptoms affected one-fourth or more of the 699 survey participants, Claire N. Harrison, DM, deputy clinical director of cancer and hematology at Guy’s and St. Thomas’ Hospital in London, reported at the American Society of Hematology meeting.
“The findings from this international survey indicate that many patients with myeloproliferative neoplasms (MPNs) experience a high disease burden, including a high prevalence of symptoms and reduction in emotional well-being, quality of life, activities of daily living, and ability to work,” Harrison and colleagues concluded in a poster presentation.
“When patients with myeloproliferative neoplasms are treated, care should be taken in trying to manage patient disease burden to minimize the impact on patients’ daily lives.”
The findings came from the global MPN LANDMARK survey, conducted in Australia, Canada, Germany, Italy, Japan, and the United Kingdom. Patients in those countries completed comprehensive surveys designed to assess the impact of MPNs on symptoms, quality of life, and normal activities.
This global survey involved 174 patients with MF, 223 with PV, and 302 with ET. Geographic distribution consisted of 10 patients from Australia, 64 from Canada, 149 from Germany, 106 from Italy, 84 from Japan, and 286 from the UK. Patients were recruited by clinical practices and patient support groups.

Fatigue is Most Common Complaint

The survey consisted of 63 questions, some of which had multiple items. Patients completed the questionnaire online, and the survey required 25 to 30 minutes to complete. Physicians completed a companion survey, results of which will be reported at a later date, according to Harrison.
Fatigue or tiredness was the single most common symptom, reported by 64%, 54%, and 45% of patients with ET, MF, and PV, respectively. The types of symptoms and symptom burden varied by MPN type:
  • MF—Abdominal discomfort (30%), shortness of breath (29%), night sweats (29%), and difficulty sleeping (27%)
  • PV—Pruritus (28%), loss of concentration (27%), night sweats (25%), and dizziness (25%)
  • ET—Dizziness (33%), night sweats (31%), bruising (30%), and difficulty sleeping (28%)
Similarly, fatigue ranked at the top of the list of “most severe symptoms” for patients with all 3 types of MPNs. The mean severity scores for fatigue (scale of 0-10) were 6.68 for MF, 6.53 for PV, and 6.44 for ET. “Inactivity” followed, with mean scores of 6.7 for MF, 5.97 for ET, and 5.54 for PV. Patients with ET had a mean severity score of 7.89 for “other symptoms not listed” and 6.92 for blood clots.
Overall, more than 25 different symptoms had mean severity scores exceeding 5. Asked whether MPN symptoms affected quality of life, three-fourths of the patients agreed strongly (29%) or somewhat (47%). The proportion of agreement was similar across the 3 types of MPN.
One fourth of all the patients said their disease frequently caused emotional hardship, and 29% said they frequently felt anxious or worried.
An 8-item assessment of MPNs’ effect on quality of life showed generally similar responses across patients with the 3 types of conditions. A test for statistical significance showed that patients with MF had higher mean scores for feeling anxious or worried (P = .02), physical hardship (P <.001), and emotional hardship (P = .005).
About half (48%) of the patients said they frequently felt satisfied with their ability to cope with their disease. Harrison and colleagues found that 33%, 24%, and 23% of patients with MF, PV, and ET, respectively, said their condition caused emotional hardship. Additionally, 34%, 29%, and 26% of patients with MF, PV, and ET reported feeling anxious or worried about their disease.

Acitivites of Daily Living Impacted

Twenty-seven percent of patients felt their condition had a high impact on them or their caregivers. Other evidence of interference with activities of daily living included pain-limiting activities (24%), interference with family or social life (26%), and interference with daily activities (26%). Two-thirds of patients with PV or ET reported never needing a caregiver, as compared with 42% of patients with MF (P < .001).
The survey also revealed that 20% of patients had to reduce hours at work because of their disease. Overall, almost 7% reported increased absenteeism from work because of MPNs, 31% worked while sick, and 35% felt their condition impaired their ability to work.
Employed patients with MF reported missing an average of 4.8 hours from work the previous 7 days, followed by 3.3 hours among patients with PV, and 2.6 hours among those with ET.
Finally, 37.8%, 35.5%, and 33.4% of patients with MF, PV, and ET, respectively, reported work impairment as a result of their condition. Additionally, 44.9%, 39.9%, and 38.1% of patients with MF, PV, and ET reported impairment in their overall activity.
The researchers noted that additional analyses of clinician–patient interaction, differences by country, and treatment patterns are planned.
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