Editor’s Note: The Society of Hospital Medicine’s (SHM’s) Physician in Training Committee launched a scholarship program in 2015 for medical students to help transform health care and revolutionize patient care. The program has been expanded for the 2017-2018 year, offering two options for students to receive funding and engage in scholarly work during their first, second, and third years of medical school. As a part of the program, recipients are required to write about their experiences on a biweekly basis.

I’m a rising second year medical student working this summer on a project to determine predictors for pediatric clinical deterioration and unplanned transfers to the pediatric ICU.

We’re hoping to identify characteristics of the pediatric population that is more prone to these unplanned transfers, as well as determine what clinical signs serve as reliable warnings so that an intervention can be designed to prevent these emergency transfers.

Farah Hussain is a second year medical student at the University of Cincinnati and student researcher at Cincinnati Children’s Hospital Medical Center. Her research interests involve bettering patient care in vulnerable populations.

Editor’s Note: The Society of Hospital Medicine’s (SHM’s) Physician in Training Committee launched a scholarship program in 2015 for medical students to help transform health care and revolutionize patient care. The program has been expanded for the 2017-2018 year, offering two options for students to receive funding and engage in scholarly work during their first, second, and third years of medical school. As a part of the program, recipients are required to write about their experiences on a biweekly basis.

I’m a rising second year medical student working this summer on a project to determine predictors for pediatric clinical deterioration and unplanned transfers to the pediatric ICU.

We’re hoping to identify characteristics of the pediatric population that is more prone to these unplanned transfers, as well as determine what clinical signs serve as reliable warnings so that an intervention can be designed to prevent these emergency transfers.

Farah Hussain is a second year medical student at the University of Cincinnati and student researcher at Cincinnati Children’s Hospital Medical Center. Her research interests involve bettering patient care in vulnerable populations.

Editor’s Note: The Society of Hospital Medicine’s (SHM’s) Physician in Training Committee launched a scholarship program in 2015 for medical students to help transform health care and revolutionize patient care. The program has been expanded for the 2017-2018 year, offering two options for students to receive funding and engage in scholarly work during their first, second, and third years of medical school. As a part of the program, recipients are required to write about their experiences on a biweekly basis.

I’m a rising second year medical student working this summer on a project to determine predictors for pediatric clinical deterioration and unplanned transfers to the pediatric ICU.

We’re hoping to identify characteristics of the pediatric population that is more prone to these unplanned transfers, as well as determine what clinical signs serve as reliable warnings so that an intervention can be designed to prevent these emergency transfers.

Farah Hussain is a second year medical student at the University of Cincinnati and student researcher at Cincinnati Children’s Hospital Medical Center. Her research interests involve bettering patient care in vulnerable populations.

Some studies have suggested that circulating plasma cells (CPCs) might have prognostic value in multiple myeloma (MM), but the findings remain controversial, say researchers from Zhengzhou University in the People’s Republic of China. However, the development of highly sensitive and specific diagnostic methods, such as polymerase chain reaction (PCR) and flow cytometry (FCM), the researchers say, make it possible to explore whether CPCs can serve as a biomarker in MM. To that end, they conducted the first meta-analysis to provide better insight into the prognostic value of CPCs in MM.

The researchers examined findings from 11 studies involving 2,943 patients in 5 countries. Peripheral blood samples were analyzed using FCM, PCR, slide-based immunofluorescence assay (IF), and conventional morphology (CM).

Circulating plasma cell status reflected aggressive disease more than tumor burden, the researchers say. Patients in the CPC-positive groups had more aggressive disease and a worse overall survival (OS) rate compared with patients in the CPC-negative groups. The presence of CPCs was “strikingly” associated with elevated the International Staging System score but not the Durie-Salm staging system (DS) score. This difference may be associated, the researchers suggest, with the fact that the DS stage predominantly reflects tumor burden, which is significantly reduced now by newer therapies.

In subgroup analyses, the patients in the FCM and CM  groups had worse prognosis for both disease progression and OS. The PCR subgroup showed prognostic significance for disease progression but not OS, and the IF subgroup for OS but not disease progression.

One question the researchers were also interested in answering was whether it mattered when the sample was taken. However, pooled hazard ratios for OS and disease progression were “fairly stable,” they say, and not influenced by sampling time. Regardless of whether CPCs are detected in an early stage or in relapse patients, the researchers add, CPC status may serve as a useful tool to guide treatment and prognosis.

Source:
Li J, Wang N, Tesfaluul N, Gao X, Liu S, Yue B. PLoS One. 2017;12(7):e0181447.
doi: 10.1371/journal.pone.0181447.

Some studies have suggested that circulating plasma cells (CPCs) might have prognostic value in multiple myeloma (MM), but the findings remain controversial, say researchers from Zhengzhou University in the People’s Republic of China. However, the development of highly sensitive and specific diagnostic methods, such as polymerase chain reaction (PCR) and flow cytometry (FCM), the researchers say, make it possible to explore whether CPCs can serve as a biomarker in MM. To that end, they conducted the first meta-analysis to provide better insight into the prognostic value of CPCs in MM.

The researchers examined findings from 11 studies involving 2,943 patients in 5 countries. Peripheral blood samples were analyzed using FCM, PCR, slide-based immunofluorescence assay (IF), and conventional morphology (CM).

Circulating plasma cell status reflected aggressive disease more than tumor burden, the researchers say. Patients in the CPC-positive groups had more aggressive disease and a worse overall survival (OS) rate compared with patients in the CPC-negative groups. The presence of CPCs was “strikingly” associated with elevated the International Staging System score but not the Durie-Salm staging system (DS) score. This difference may be associated, the researchers suggest, with the fact that the DS stage predominantly reflects tumor burden, which is significantly reduced now by newer therapies.

In subgroup analyses, the patients in the FCM and CM  groups had worse prognosis for both disease progression and OS. The PCR subgroup showed prognostic significance for disease progression but not OS, and the IF subgroup for OS but not disease progression.

One question the researchers were also interested in answering was whether it mattered when the sample was taken. However, pooled hazard ratios for OS and disease progression were “fairly stable,” they say, and not influenced by sampling time. Regardless of whether CPCs are detected in an early stage or in relapse patients, the researchers add, CPC status may serve as a useful tool to guide treatment and prognosis.

Source:
Li J, Wang N, Tesfaluul N, Gao X, Liu S, Yue B. PLoS One. 2017;12(7):e0181447.
doi: 10.1371/journal.pone.0181447.

Some studies have suggested that circulating plasma cells (CPCs) might have prognostic value in multiple myeloma (MM), but the findings remain controversial, say researchers from Zhengzhou University in the People’s Republic of China. However, the development of highly sensitive and specific diagnostic methods, such as polymerase chain reaction (PCR) and flow cytometry (FCM), the researchers say, make it possible to explore whether CPCs can serve as a biomarker in MM. To that end, they conducted the first meta-analysis to provide better insight into the prognostic value of CPCs in MM.

The researchers examined findings from 11 studies involving 2,943 patients in 5 countries. Peripheral blood samples were analyzed using FCM, PCR, slide-based immunofluorescence assay (IF), and conventional morphology (CM).

Circulating plasma cell status reflected aggressive disease more than tumor burden, the researchers say. Patients in the CPC-positive groups had more aggressive disease and a worse overall survival (OS) rate compared with patients in the CPC-negative groups. The presence of CPCs was “strikingly” associated with elevated the International Staging System score but not the Durie-Salm staging system (DS) score. This difference may be associated, the researchers suggest, with the fact that the DS stage predominantly reflects tumor burden, which is significantly reduced now by newer therapies.

In subgroup analyses, the patients in the FCM and CM  groups had worse prognosis for both disease progression and OS. The PCR subgroup showed prognostic significance for disease progression but not OS, and the IF subgroup for OS but not disease progression.

One question the researchers were also interested in answering was whether it mattered when the sample was taken. However, pooled hazard ratios for OS and disease progression were “fairly stable,” they say, and not influenced by sampling time. Regardless of whether CPCs are detected in an early stage or in relapse patients, the researchers add, CPC status may serve as a useful tool to guide treatment and prognosis.

Source:
Li J, Wang N, Tesfaluul N, Gao X, Liu S, Yue B. PLoS One. 2017;12(7):e0181447.
doi: 10.1371/journal.pone.0181447.

Patients with advanced malignancies may develop pancreatitis during therapy for their cancer. Acute pancreatitis is inflammation of the pancreas. Common symptoms include abdominal pain, nausea, vomiting, shortness of breath, dehydration. Laboratory evidence of acute pancreatitis includes elevations of the amylase and lipase. Mild pancreatitis occurs when there is no organ dysfunction, moderate pancreatitis is associated with one organ dysfunction, and severe pancreatitis is complicated by multiple organ dysfunction. Hypotension, hypocalcemia, or anemia suggest a more severe course of the pancreatitis. In some instances, the pancreatitis may be an adverse reaction to the therapy being given. However, other causes such as hypercalcemia, hypertriglyceridemia, cholelithiasis, and underlying malignancy must be ruled out before ascribing pancreatitis to a specific drug. To date, two classifications systems have been proposed by Trivedi¹ and Badalov² to evaluate the degree to which a drug is responsible for pancreatitis (Table 1). Furthermore, Naranjo and colleagues have proposed a more general method of assessing the causal relationship between drugs and adverse events.³ The Naranjo algorithm is not specific for pancreatitis. Jones and colleagues⁴ reported that 0.1%-2% of acute pancreatitis cases were owing to drugs. In 2015, they listed the older chemotherapy agents associated with pancreatitis. However, more recently, many new agents have been approved for the management of cancers. The newer classes of antineoplastic agents including proteasome inhibitors, immune-modulating agents, tyrosine kinase inhibitors, monoclonal antibodies against programmed cell death-1 (PD-1) and its ligand PD-L1 and antibody-toxin conjugates are now associated with acute pancreatitis.

Methods

We conducted a search in PubMed, Google Scholar, and Micromedex for pancreatitis related to antineoplastic agents, including proteasome inhibitors, immune checkpoint inhibitors, monoclonal antibodies, immune-modulating agents, drug-induced pancreatitis. Terms used for the searches included each specific agent and pancreatitis, immunotherapy and pancreatitis, tyrosine kinase inhibitors and pancreatitis, auto immune pancreatitis, and toxicities of molecular target therapies. Reference lists from the identified manuscripts were reviewed for further studies of pancreatitis as a result of antineoplastic therapy. The most recent search date was February 15, 2017.

The degree to which each agent was associated with inducing pancreatitis was evaluated using the Badalov classification system² in addition to the Naranjo Adverse Drug Reaction (ADR) Probability Scale.³ The Naranjo scale consists of 10 questions with values assigned to each answer. Total scores range from -4 to 13, where 13-9 indicates the reaction is considered definitely attributable to the drug; 8-5, probably attributable; 4-1, possibly attributable; and ≤0, doubtful if attributable.

A total of 67 manuscripts and abstracts were identified. Four manuscripts and 3 abstracts were excluded because they had insufficient information about possible pancreatitis or there was a presence of multiple other agents or conditions that might have caused pancreatitis. In total, 60 publications met inclusion criteria and were evaluated.

Results

Immune checkpoint inhibitors

In a review of toxicities of anti-programmed cell death-1 (PD-1) therapy, pancreatitis was reported to occur in about 1.8% of patients who received nivolumab or pembrolizumab.⁵ The 9 patients with pancreatitis attributed to an immune etiology were treated with corticosteroids. Pancreatitis was grade 2 in 3 patients (1.5-2 times upper limit of normal [ULN]), grade 3 in 4 patients (>2-5 ULN), and grade 4 ( >5 ULN) in 2 patients.

In asymptomatic individuals, pancreatitis has been detected on a positron-emission tomography–computed tomography (CT) scan after anti-PD-1 therapy.⁵ By contrast, there was a case report of a patient treated with nivolumab for lung cancer who developed anorexia, vomiting, and back pain on day 18 of therapy with an elevation of the amylase and lipase levels, but a negative CT.⁶ Later the patient developed a swollen pancreas on CT. Autoimmune pancreatitis comes in two forms. The most common relates to elevated levels of immunoglobulin G4 (IgG4; normal, 135 mg/dL ULN)⁷ The mechanism of immune pancreatitis associated with anti-PD-1 therapy is unknown.

Ipilimumab (an anti-CTLA4 antibody) has been approved by the US Food and Drug Administration (FDA) for the treatment of melanoma. Pancreatitis occurred in 1 patient in a phase 1 trial in pediatric patients.⁹ In a summary of 14 phase 1-3 trials of ipilimumab in advanced melanoma, pancreatitis was reported in fewer than 1% of the patients.¹⁰ In management guidelines for therapy with ipilimumab, pancreatitis may present as an asymptomatic increase in the levels of amylase and lipase, or with fevers, malaise, or abdominal pain. Oral prednisone or dexamethasone were given for the immune pancreatitis, but the decline in enzymes was slow, often taking months.¹¹ In a preclinical model of autoimmune pancreatitis due to the blocking of CTLA4, there was suppression of regulatory T-cell function. The autoimmune pancreatitis responded to cyclosporin or rapamycin but there are no clinical data for these agents.¹² The anti-PD-L1 agent atezolizumab has been associated with acute pancreatitis in 2 of 1,978 patients (0.1%).¹³ A review by Champiat and colleagues on dysimmune toxcities related to immune checkpoint inhibitors includes pancreatitis as an autoimmune complication of such therapies.¹⁴

Blinatumomab is an anti-CD19–directed CD3 T-cell engager that has been approved by the FDA for refractory B-cell acute lymphoblastic leukemia. In August 2016, the maker of the drug, Amgen, advised hematologists and oncologists that since February 2016, 10 patients out of more than 2,000 treated with blinatumomab had developed pancreatitis.¹⁵ Other medications the patients were receiving such as high-dose steroids might have caused or contributed to the pancreatitis. In one case, the pancreatitis improved with stopping blinatumomab but worsened with re-challenge. It is possible that the mechanism of the associated pancreatitis relates to a change in immune checkpoint inhibition. CD19-positive, CD24-high, CD27-positive regulatory B cells are decreased in autoimmune pancreatitis.¹⁶ Treatment with blinatumomab may decrease the CD19-positive cells.

Molecularly targeted agents, including TKIs

Molecularly targeted agents such as tyrosine kinase inhibitors (TKIs) or other kinase inhibitors have been associated with pancreatitis.^{17, 18} In a retrospective study by Tiruman and colleagues,¹⁹ the investigators found 91 patients with pancreatitis on imaging, of whom 15 were receiving molecularly target drugs. The pancreatitis was asymptomatic in 2 patients, but 13 had abdominal pain, many with nausea. Four of the patients also had gallstones, but the drug was deemed to be the cause of the pancreatitis. In 4 of the 9 patients in whom a rechallenge was done with the TKI, the pancreatitis relapsed. The pancreatitis resolved in 14 of the 15 patients; 1 patient died because of progressive cancer before the pancreatitis resolved. The pancreatitis was mild, 7 of the 15 patients had normal pancreatic enzymes and the pancreatitis was diagnosed by radiology.

Ghatlia and colleagues¹⁷ performed a meta-analysis of trials of TKI. They found 9 cases of pancreatitis in patients on sunitinib therapy. Of those, 4 patients were on sunitinib alone, and 5 were on other chemotherapy agents in combination with sunitinib. Eight cases of pancreatitis due to sorafenib were found. Three of the patients were on sorafenib alone, and 5 were on other chemotherapy including 1 on transcatheter embolization (TACE). Three cases of pancreatitis were associated with vandetanib; 2 of those patients had other concurrent chemotherapy. One case of axitinib induced pancreatitis was described.

Pancreatitis was reported in the phase 1 trials of sorafenib and sunitinib. In all, 3 of 69 patients treated with sorafenib had grade 3 pancreatitis and asymptomatic elevations of amylase and lipase levels were present in about 5% of patients receiving sunitinib.^18,19

Other TKIs associated with pancreatitis include pazopanib,^20,21 axitinib,²² and nilotinib.²³ Pezzilli and coleagues²⁴ described 5 patients with pancreatitis on sorafenib, 3 on sunitinib, 6 on nilotinib. It is possible that some of these cases appeared in other reviews. Ibrutinib, an inhibitor of Bruton’s tyrosine kinase, caused a single case of pancreatitis in 9 patients.²⁵

Vemurafenib, a BRAF kinase inhibitor, was associated with pancreatitis in one case. In this case, the pancreatitis resolved on stopping the medication but recurred when vemurafenib rechallenge was attempted.²⁶ There is a report of dabrafenib being associated with pancreatitis in 1 patient.²⁷

Agents that inhibit the TKIs associated with BCR-ABL in chronic myelogenous leukemia are associated with acute pancreatitis. Imatinib-induced pancreatitis was reported in a small number of cases.²⁸ Nilotinib has caused amylase/lipase elevations with and without symptomatic pancreatitis.^29,30 Ponatinib, an inhibitor of BCR-ABL tyrosine kinase, is associated with pancreatitis.³¹ Pancreatitis occurred in 11 of 81 patients treated with ponatinib, and in 8 patients it was described as serious. Further elevation of amylase or lipase levels without clinical pancreatitis was noted in 7 other patients.

Proteosome inhibitors

In 2010, Elouni and colleagues³² reported a case of IV bortezomib-induced pancreatitis, which recurred on rechallenge with bortezomib. This same patient was also reported in an abstract in 2009.³³ In 2009, there was an editorial comment which was added to the end of the abstract that the World Health Organization Adverse Drug Reaction database had 11 reports of bortezomib associated pancreatitis. Talamo and colleagues³⁴ reported a case of bortezomib-induced pancreatitis due to bortezomib that had been administered subcutaneously. At that time, they also summarized 7 previous reports of bortezomib-associated pancreatitis. The mechanism of bortezomib-induced pancreatitis is not known.^35-37

Fotoh and colleagues reported a patient with myeloma who had elevated triglyceride levels after bortezomib therapy.³⁸ In one case of bortezomib-associated pancreatitis, the patient had an elevated triglyceride level, but it was not extremely high.³⁹ Multiple myeloma itself may be associated with hyperlipidemia but only rarely.⁴⁰ Gozetti and colleagues reported a patient who developed hyperlipidemia after two courses of bortezomib;⁴¹ stopping bisphosphonates may be associated with a rise in triglycerides. There was one case of carfilzomib causing pancreatitis during a phase 1 trial.⁴²

Older chemotherapy agents

Reviews of drug-induced pancreatitis have listed many chemotherapy agents which may cause pancreatitis.^1,43 The agent most frequently associated with acute pancreatitis has been asparaginase,⁴⁴ with 2%-16% of patients undergoing asparaginase therapy developing pancreatitis. Asparaginase-related pancreatitis is grade 3 or 4 in 5%-10% of patients, and recurs in 63% of patients on rechallenge. Other chemotherapy agents associated with pancreatitis include: mercaptopurine, cytosine arabinoside, cisplatin, interferon alfa-2b, doxorubicin, tamoxifen, gefitinib, vinorelbine, oxaliplatin, levamisole, methotrexate, azathioprine, 5-fluorouracil, capecitabine, ifosfamide, paclitaxel, and all-trans retinoic acid.

Oxaliplatin carries a 0.1%-2% incidence of drug-induced pancreatitis. In one series of 6 patients, cessation of the agent allowed for resolution of symptoms and decrease in serum lipase and amylase levels.⁴⁵ With capecitabine there are 2 case reports of pancreatitis.⁴⁶ Cases of pancreatitis associated with trifluridine or tipiracil were not present in the literature.

Thalidomide caused severe pancreatitis in a patient when it was used to treat chronic graft-versus-host disease.⁴⁷ This patient suffered recurrent pancreatitis on retreatment with the thalidomide. The authors further referenced two other suspected cases of thalidomide-induced, acute pancreatitis. However, in view of the extensive use of thalidomide for multiple myeloma before the development of lenalidomide, thalidomide-associated pancreatitis would be <1% of patients.

Agents that cause hypertriglyceridemia may cause pancreatitis. This mechanism has been reported as the cause of pancreatitis for everolimus⁴⁸ and tamoxifen.^49,50-52 Everolimus causes elevated triglycerides in 30%-50% of patients. There are case reports and a review of tamoxifen-associated pancreatitis caused by elevated triglycerides.⁵² There has also been a case of temsirolimus-associated pancreatitis,⁵³ another agent that elevates triglycerides.

Pancreatitis associated with hepatic embolization or HIPEC

TACE leads to symptomatic acute pancreatitis in 0.4%-2% of patients, but nonselective TACE (into the hepatic artery and not just feeder vessels), may lead to elevated amylase levels in 15%-40% of patients.^54-56 The risk of pancreatitis would depend on which chemotherapy drug is being infused into the liver. It would also be greater if the chemotherapy has to be infused into a larger part of the liver than into a small portion of the liver. In one patient, severe pancreatitis secondary to TACE occurred after two previous embolizations; prior embolization may have led to occlusion of the previously infused vessels.⁵⁷ Radioembolization with 90Y microspheres was associated with one case of pancreatitis in 112 consecutive patients.⁵⁸ The postembolization syndrome in the first 24 hours after the procedure may involve fever, abdominal pain, nausea, and vomiting due to acute pancreatitis in some instances.

Acute pancreatitis has also been described as a complication of hyperthermic intraperitoneal chemotherapy (HIPEC).^59,60 Two of 13 patients receiving HIPEC for gastric cancer developed pancreatitis.⁵⁹ In 25 patients with colon cancer who were treated with HIPEC, 1 patient had pancreatitis.⁶⁰

Antibody-drug conjugates

Muzaffar and colleagues reported a patient with acute pancreatitis 3 days after starting therapy with ado-trastuzumab emtansine.⁶¹ Urru and colleagues⁶² reported a patient who developed acute pancreatitis after brentuximab vedotin therapy. Ghandi and colleagues⁶³ identified 2 cases of fatal acute pancreatitis with brentuximab vedotin and 6 cases of nonfatal pancreatitis. Two of the nonfatal patients were rechallenged, and 1 developed recurrent pancreatitis. Because abdominal pain may occur in up to 18% of patients receiving brentuximab vedotin, the incidence of pancreatitis may be underestimated with this agent.⁶⁴

In Table 2, ado-trastuzumab emtansine and brentuximab vedotin are listed with incidence and level of association given by the Baldavo² and Naranjo.³ With greater awareness, the incidence of pancreatitis associated with these agents may rise or fall as more data is accumulated. In many instances, there are insufficient numbers of reported cases or insufficient information in single-case reports to complete the entire table.

Discussion

Acute pancreatitis is an uncommon complication of tyrosine kinase inhibitors, other kinase inhibitors, proteasome inhibitors, monoclonal antibody-drug conjugates and anti-PD-1 immunotherapies. As nausea, abdominal pain, emesis are common in patients with cancer on antineoplastic therapy, some patients may have acute pancreatitis which is undiagnosed. It is not clear whether a patient with pancreatitis secondary to a TKI can be safely switched to a different TKI. As more molecularly targeted agents and more monoclonal antibodies targeting PD-L1 and PD-1 are under development, screening for amylase and lipase levels during phase 1/2 testing may prove helpful.

The natural history of cancer-drug–associated pancreatitis may depend on which agent is the cause. Although there are descriptions of the course of autoimmune pancreatitis, these studies have not included pancreatitis associated with anti-PD-L1 or -PD-1 therapies.⁶⁵ It is possible that once an autoimmune pancreatitis has developed, simply stopping the inciting anti-PD-L1 or -PD-1 antibody may not lead to immediate resolution. Therapy with combined immune checkpoint blockade agents (eg, nivolumab and ipilimumab) may cause a higher incidence of pancreatitis than therapy with a single agent.⁶⁶

In a report of 119 patients with melanoma who were treated with nivolumab and ipilimumab, there were 2 cases of acute pancreatitis, though 20% of patients had a grade 3 or higher amylase level, and just over 6% had a grade 3 or higher lipase.⁶⁷ Stopping this type of immunotherapy early for grade 1,2, or 3 rises in pancreatic enzymes might prevent symptomatic pancreatitis from developing, but would stop potentially curative therapy for many patients who would have never developed clinically serious pancreatitis. Patients who suffer immune toxicities with anti-PD-1 therapies may be more apt to obtain some clinical benefit. The development of immune-related toxicities in patients treated with ipilimumab ( an anti CTLA4 antibody) seemed to correlate the tumor regression.⁶⁸ This has also been suggested by the fact that the development of vitiligo correlates with clinical response in melanoma patients treated with nivolumab.⁶⁹ Although clinically significant pancreatitis might be averted by stopping immune therapies earlier, stopping before it is deemed necessary might prevent cancer patients from receiving life-prolonging therapy.

Acute pancreatitis in general is severe in about 25% of cases and is associated with a significant risk of death. Scoring systems such as Ranson criteria and Apache 2 are used to assess the severity of pancreatitis although their utility is debated.⁷⁰ Asparaginase is the chemotherapy agent most frequently associated with pancreatitis. It has been used to treat acute lymphoblastic leukemia for more than 30 years. This allowed for a study of 5,185 children and young adults who received asparaginase to determine what clinical factors and genomic factors were associated with the development of acute pancreatitis in 117 individuals.⁷¹ Further information gathered from programs such as the FDA and the adverse drug reaction program at Northwestern University in Chicago, coupled with the publication of other cases of pancreatitis associated with newer cancer agents may provide more insight into the mechanism causing pancreatitis due to a specific agent. With more cases being published, it may also become possible to determine if there are specific predisposing factors based on the clearance or metabolism of the offending agent or any genetic predisposition for drug-related pancreatitis.

Patients with advanced malignancies may develop pancreatitis during therapy for their cancer. Acute pancreatitis is inflammation of the pancreas. Common symptoms include abdominal pain, nausea, vomiting, shortness of breath, dehydration. Laboratory evidence of acute pancreatitis includes elevations of the amylase and lipase. Mild pancreatitis occurs when there is no organ dysfunction, moderate pancreatitis is associated with one organ dysfunction, and severe pancreatitis is complicated by multiple organ dysfunction. Hypotension, hypocalcemia, or anemia suggest a more severe course of the pancreatitis. In some instances, the pancreatitis may be an adverse reaction to the therapy being given. However, other causes such as hypercalcemia, hypertriglyceridemia, cholelithiasis, and underlying malignancy must be ruled out before ascribing pancreatitis to a specific drug. To date, two classifications systems have been proposed by Trivedi¹ and Badalov² to evaluate the degree to which a drug is responsible for pancreatitis (Table 1). Furthermore, Naranjo and colleagues have proposed a more general method of assessing the causal relationship between drugs and adverse events.³ The Naranjo algorithm is not specific for pancreatitis. Jones and colleagues⁴ reported that 0.1%-2% of acute pancreatitis cases were owing to drugs. In 2015, they listed the older chemotherapy agents associated with pancreatitis. However, more recently, many new agents have been approved for the management of cancers. The newer classes of antineoplastic agents including proteasome inhibitors, immune-modulating agents, tyrosine kinase inhibitors, monoclonal antibodies against programmed cell death-1 (PD-1) and its ligand PD-L1 and antibody-toxin conjugates are now associated with acute pancreatitis.

Methods

We conducted a search in PubMed, Google Scholar, and Micromedex for pancreatitis related to antineoplastic agents, including proteasome inhibitors, immune checkpoint inhibitors, monoclonal antibodies, immune-modulating agents, drug-induced pancreatitis. Terms used for the searches included each specific agent and pancreatitis, immunotherapy and pancreatitis, tyrosine kinase inhibitors and pancreatitis, auto immune pancreatitis, and toxicities of molecular target therapies. Reference lists from the identified manuscripts were reviewed for further studies of pancreatitis as a result of antineoplastic therapy. The most recent search date was February 15, 2017.

The degree to which each agent was associated with inducing pancreatitis was evaluated using the Badalov classification system² in addition to the Naranjo Adverse Drug Reaction (ADR) Probability Scale.³ The Naranjo scale consists of 10 questions with values assigned to each answer. Total scores range from -4 to 13, where 13-9 indicates the reaction is considered definitely attributable to the drug; 8-5, probably attributable; 4-1, possibly attributable; and ≤0, doubtful if attributable.

A total of 67 manuscripts and abstracts were identified. Four manuscripts and 3 abstracts were excluded because they had insufficient information about possible pancreatitis or there was a presence of multiple other agents or conditions that might have caused pancreatitis. In total, 60 publications met inclusion criteria and were evaluated.

Results

Immune checkpoint inhibitors

In a review of toxicities of anti-programmed cell death-1 (PD-1) therapy, pancreatitis was reported to occur in about 1.8% of patients who received nivolumab or pembrolizumab.⁵ The 9 patients with pancreatitis attributed to an immune etiology were treated with corticosteroids. Pancreatitis was grade 2 in 3 patients (1.5-2 times upper limit of normal [ULN]), grade 3 in 4 patients (>2-5 ULN), and grade 4 ( >5 ULN) in 2 patients.

In asymptomatic individuals, pancreatitis has been detected on a positron-emission tomography–computed tomography (CT) scan after anti-PD-1 therapy.⁵ By contrast, there was a case report of a patient treated with nivolumab for lung cancer who developed anorexia, vomiting, and back pain on day 18 of therapy with an elevation of the amylase and lipase levels, but a negative CT.⁶ Later the patient developed a swollen pancreas on CT. Autoimmune pancreatitis comes in two forms. The most common relates to elevated levels of immunoglobulin G4 (IgG4; normal, 135 mg/dL ULN)⁷ The mechanism of immune pancreatitis associated with anti-PD-1 therapy is unknown.

Ipilimumab (an anti-CTLA4 antibody) has been approved by the US Food and Drug Administration (FDA) for the treatment of melanoma. Pancreatitis occurred in 1 patient in a phase 1 trial in pediatric patients.⁹ In a summary of 14 phase 1-3 trials of ipilimumab in advanced melanoma, pancreatitis was reported in fewer than 1% of the patients.¹⁰ In management guidelines for therapy with ipilimumab, pancreatitis may present as an asymptomatic increase in the levels of amylase and lipase, or with fevers, malaise, or abdominal pain. Oral prednisone or dexamethasone were given for the immune pancreatitis, but the decline in enzymes was slow, often taking months.¹¹ In a preclinical model of autoimmune pancreatitis due to the blocking of CTLA4, there was suppression of regulatory T-cell function. The autoimmune pancreatitis responded to cyclosporin or rapamycin but there are no clinical data for these agents.¹² The anti-PD-L1 agent atezolizumab has been associated with acute pancreatitis in 2 of 1,978 patients (0.1%).¹³ A review by Champiat and colleagues on dysimmune toxcities related to immune checkpoint inhibitors includes pancreatitis as an autoimmune complication of such therapies.¹⁴

Blinatumomab is an anti-CD19–directed CD3 T-cell engager that has been approved by the FDA for refractory B-cell acute lymphoblastic leukemia. In August 2016, the maker of the drug, Amgen, advised hematologists and oncologists that since February 2016, 10 patients out of more than 2,000 treated with blinatumomab had developed pancreatitis.¹⁵ Other medications the patients were receiving such as high-dose steroids might have caused or contributed to the pancreatitis. In one case, the pancreatitis improved with stopping blinatumomab but worsened with re-challenge. It is possible that the mechanism of the associated pancreatitis relates to a change in immune checkpoint inhibition. CD19-positive, CD24-high, CD27-positive regulatory B cells are decreased in autoimmune pancreatitis.¹⁶ Treatment with blinatumomab may decrease the CD19-positive cells.

Molecularly targeted agents, including TKIs

Molecularly targeted agents such as tyrosine kinase inhibitors (TKIs) or other kinase inhibitors have been associated with pancreatitis.^{17, 18} In a retrospective study by Tiruman and colleagues,¹⁹ the investigators found 91 patients with pancreatitis on imaging, of whom 15 were receiving molecularly target drugs. The pancreatitis was asymptomatic in 2 patients, but 13 had abdominal pain, many with nausea. Four of the patients also had gallstones, but the drug was deemed to be the cause of the pancreatitis. In 4 of the 9 patients in whom a rechallenge was done with the TKI, the pancreatitis relapsed. The pancreatitis resolved in 14 of the 15 patients; 1 patient died because of progressive cancer before the pancreatitis resolved. The pancreatitis was mild, 7 of the 15 patients had normal pancreatic enzymes and the pancreatitis was diagnosed by radiology.

Ghatlia and colleagues¹⁷ performed a meta-analysis of trials of TKI. They found 9 cases of pancreatitis in patients on sunitinib therapy. Of those, 4 patients were on sunitinib alone, and 5 were on other chemotherapy agents in combination with sunitinib. Eight cases of pancreatitis due to sorafenib were found. Three of the patients were on sorafenib alone, and 5 were on other chemotherapy including 1 on transcatheter embolization (TACE). Three cases of pancreatitis were associated with vandetanib; 2 of those patients had other concurrent chemotherapy. One case of axitinib induced pancreatitis was described.

Pancreatitis was reported in the phase 1 trials of sorafenib and sunitinib. In all, 3 of 69 patients treated with sorafenib had grade 3 pancreatitis and asymptomatic elevations of amylase and lipase levels were present in about 5% of patients receiving sunitinib.^18,19

Other TKIs associated with pancreatitis include pazopanib,^20,21 axitinib,²² and nilotinib.²³ Pezzilli and coleagues²⁴ described 5 patients with pancreatitis on sorafenib, 3 on sunitinib, 6 on nilotinib. It is possible that some of these cases appeared in other reviews. Ibrutinib, an inhibitor of Bruton’s tyrosine kinase, caused a single case of pancreatitis in 9 patients.²⁵

Vemurafenib, a BRAF kinase inhibitor, was associated with pancreatitis in one case. In this case, the pancreatitis resolved on stopping the medication but recurred when vemurafenib rechallenge was attempted.²⁶ There is a report of dabrafenib being associated with pancreatitis in 1 patient.²⁷

Agents that inhibit the TKIs associated with BCR-ABL in chronic myelogenous leukemia are associated with acute pancreatitis. Imatinib-induced pancreatitis was reported in a small number of cases.²⁸ Nilotinib has caused amylase/lipase elevations with and without symptomatic pancreatitis.^29,30 Ponatinib, an inhibitor of BCR-ABL tyrosine kinase, is associated with pancreatitis.³¹ Pancreatitis occurred in 11 of 81 patients treated with ponatinib, and in 8 patients it was described as serious. Further elevation of amylase or lipase levels without clinical pancreatitis was noted in 7 other patients.

Proteosome inhibitors

In 2010, Elouni and colleagues³² reported a case of IV bortezomib-induced pancreatitis, which recurred on rechallenge with bortezomib. This same patient was also reported in an abstract in 2009.³³ In 2009, there was an editorial comment which was added to the end of the abstract that the World Health Organization Adverse Drug Reaction database had 11 reports of bortezomib associated pancreatitis. Talamo and colleagues³⁴ reported a case of bortezomib-induced pancreatitis due to bortezomib that had been administered subcutaneously. At that time, they also summarized 7 previous reports of bortezomib-associated pancreatitis. The mechanism of bortezomib-induced pancreatitis is not known.^35-37

Fotoh and colleagues reported a patient with myeloma who had elevated triglyceride levels after bortezomib therapy.³⁸ In one case of bortezomib-associated pancreatitis, the patient had an elevated triglyceride level, but it was not extremely high.³⁹ Multiple myeloma itself may be associated with hyperlipidemia but only rarely.⁴⁰ Gozetti and colleagues reported a patient who developed hyperlipidemia after two courses of bortezomib;⁴¹ stopping bisphosphonates may be associated with a rise in triglycerides. There was one case of carfilzomib causing pancreatitis during a phase 1 trial.⁴²

Older chemotherapy agents

Reviews of drug-induced pancreatitis have listed many chemotherapy agents which may cause pancreatitis.^1,43 The agent most frequently associated with acute pancreatitis has been asparaginase,⁴⁴ with 2%-16% of patients undergoing asparaginase therapy developing pancreatitis. Asparaginase-related pancreatitis is grade 3 or 4 in 5%-10% of patients, and recurs in 63% of patients on rechallenge. Other chemotherapy agents associated with pancreatitis include: mercaptopurine, cytosine arabinoside, cisplatin, interferon alfa-2b, doxorubicin, tamoxifen, gefitinib, vinorelbine, oxaliplatin, levamisole, methotrexate, azathioprine, 5-fluorouracil, capecitabine, ifosfamide, paclitaxel, and all-trans retinoic acid.

Oxaliplatin carries a 0.1%-2% incidence of drug-induced pancreatitis. In one series of 6 patients, cessation of the agent allowed for resolution of symptoms and decrease in serum lipase and amylase levels.⁴⁵ With capecitabine there are 2 case reports of pancreatitis.⁴⁶ Cases of pancreatitis associated with trifluridine or tipiracil were not present in the literature.

Thalidomide caused severe pancreatitis in a patient when it was used to treat chronic graft-versus-host disease.⁴⁷ This patient suffered recurrent pancreatitis on retreatment with the thalidomide. The authors further referenced two other suspected cases of thalidomide-induced, acute pancreatitis. However, in view of the extensive use of thalidomide for multiple myeloma before the development of lenalidomide, thalidomide-associated pancreatitis would be <1% of patients.

Agents that cause hypertriglyceridemia may cause pancreatitis. This mechanism has been reported as the cause of pancreatitis for everolimus⁴⁸ and tamoxifen.^49,50-52 Everolimus causes elevated triglycerides in 30%-50% of patients. There are case reports and a review of tamoxifen-associated pancreatitis caused by elevated triglycerides.⁵² There has also been a case of temsirolimus-associated pancreatitis,⁵³ another agent that elevates triglycerides.

Pancreatitis associated with hepatic embolization or HIPEC

TACE leads to symptomatic acute pancreatitis in 0.4%-2% of patients, but nonselective TACE (into the hepatic artery and not just feeder vessels), may lead to elevated amylase levels in 15%-40% of patients.^54-56 The risk of pancreatitis would depend on which chemotherapy drug is being infused into the liver. It would also be greater if the chemotherapy has to be infused into a larger part of the liver than into a small portion of the liver. In one patient, severe pancreatitis secondary to TACE occurred after two previous embolizations; prior embolization may have led to occlusion of the previously infused vessels.⁵⁷ Radioembolization with 90Y microspheres was associated with one case of pancreatitis in 112 consecutive patients.⁵⁸ The postembolization syndrome in the first 24 hours after the procedure may involve fever, abdominal pain, nausea, and vomiting due to acute pancreatitis in some instances.

Acute pancreatitis has also been described as a complication of hyperthermic intraperitoneal chemotherapy (HIPEC).^59,60 Two of 13 patients receiving HIPEC for gastric cancer developed pancreatitis.⁵⁹ In 25 patients with colon cancer who were treated with HIPEC, 1 patient had pancreatitis.⁶⁰

Antibody-drug conjugates

Muzaffar and colleagues reported a patient with acute pancreatitis 3 days after starting therapy with ado-trastuzumab emtansine.⁶¹ Urru and colleagues⁶² reported a patient who developed acute pancreatitis after brentuximab vedotin therapy. Ghandi and colleagues⁶³ identified 2 cases of fatal acute pancreatitis with brentuximab vedotin and 6 cases of nonfatal pancreatitis. Two of the nonfatal patients were rechallenged, and 1 developed recurrent pancreatitis. Because abdominal pain may occur in up to 18% of patients receiving brentuximab vedotin, the incidence of pancreatitis may be underestimated with this agent.⁶⁴

In Table 2, ado-trastuzumab emtansine and brentuximab vedotin are listed with incidence and level of association given by the Baldavo² and Naranjo.³ With greater awareness, the incidence of pancreatitis associated with these agents may rise or fall as more data is accumulated. In many instances, there are insufficient numbers of reported cases or insufficient information in single-case reports to complete the entire table.

Discussion

Acute pancreatitis is an uncommon complication of tyrosine kinase inhibitors, other kinase inhibitors, proteasome inhibitors, monoclonal antibody-drug conjugates and anti-PD-1 immunotherapies. As nausea, abdominal pain, emesis are common in patients with cancer on antineoplastic therapy, some patients may have acute pancreatitis which is undiagnosed. It is not clear whether a patient with pancreatitis secondary to a TKI can be safely switched to a different TKI. As more molecularly targeted agents and more monoclonal antibodies targeting PD-L1 and PD-1 are under development, screening for amylase and lipase levels during phase 1/2 testing may prove helpful.

The natural history of cancer-drug–associated pancreatitis may depend on which agent is the cause. Although there are descriptions of the course of autoimmune pancreatitis, these studies have not included pancreatitis associated with anti-PD-L1 or -PD-1 therapies.⁶⁵ It is possible that once an autoimmune pancreatitis has developed, simply stopping the inciting anti-PD-L1 or -PD-1 antibody may not lead to immediate resolution. Therapy with combined immune checkpoint blockade agents (eg, nivolumab and ipilimumab) may cause a higher incidence of pancreatitis than therapy with a single agent.⁶⁶

In a report of 119 patients with melanoma who were treated with nivolumab and ipilimumab, there were 2 cases of acute pancreatitis, though 20% of patients had a grade 3 or higher amylase level, and just over 6% had a grade 3 or higher lipase.⁶⁷ Stopping this type of immunotherapy early for grade 1,2, or 3 rises in pancreatic enzymes might prevent symptomatic pancreatitis from developing, but would stop potentially curative therapy for many patients who would have never developed clinically serious pancreatitis. Patients who suffer immune toxicities with anti-PD-1 therapies may be more apt to obtain some clinical benefit. The development of immune-related toxicities in patients treated with ipilimumab ( an anti CTLA4 antibody) seemed to correlate the tumor regression.⁶⁸ This has also been suggested by the fact that the development of vitiligo correlates with clinical response in melanoma patients treated with nivolumab.⁶⁹ Although clinically significant pancreatitis might be averted by stopping immune therapies earlier, stopping before it is deemed necessary might prevent cancer patients from receiving life-prolonging therapy.

Acute pancreatitis in general is severe in about 25% of cases and is associated with a significant risk of death. Scoring systems such as Ranson criteria and Apache 2 are used to assess the severity of pancreatitis although their utility is debated.⁷⁰ Asparaginase is the chemotherapy agent most frequently associated with pancreatitis. It has been used to treat acute lymphoblastic leukemia for more than 30 years. This allowed for a study of 5,185 children and young adults who received asparaginase to determine what clinical factors and genomic factors were associated with the development of acute pancreatitis in 117 individuals.⁷¹ Further information gathered from programs such as the FDA and the adverse drug reaction program at Northwestern University in Chicago, coupled with the publication of other cases of pancreatitis associated with newer cancer agents may provide more insight into the mechanism causing pancreatitis due to a specific agent. With more cases being published, it may also become possible to determine if there are specific predisposing factors based on the clearance or metabolism of the offending agent or any genetic predisposition for drug-related pancreatitis.

Patients with advanced malignancies may develop pancreatitis during therapy for their cancer. Acute pancreatitis is inflammation of the pancreas. Common symptoms include abdominal pain, nausea, vomiting, shortness of breath, dehydration. Laboratory evidence of acute pancreatitis includes elevations of the amylase and lipase. Mild pancreatitis occurs when there is no organ dysfunction, moderate pancreatitis is associated with one organ dysfunction, and severe pancreatitis is complicated by multiple organ dysfunction. Hypotension, hypocalcemia, or anemia suggest a more severe course of the pancreatitis. In some instances, the pancreatitis may be an adverse reaction to the therapy being given. However, other causes such as hypercalcemia, hypertriglyceridemia, cholelithiasis, and underlying malignancy must be ruled out before ascribing pancreatitis to a specific drug. To date, two classifications systems have been proposed by Trivedi¹ and Badalov² to evaluate the degree to which a drug is responsible for pancreatitis (Table 1). Furthermore, Naranjo and colleagues have proposed a more general method of assessing the causal relationship between drugs and adverse events.³ The Naranjo algorithm is not specific for pancreatitis. Jones and colleagues⁴ reported that 0.1%-2% of acute pancreatitis cases were owing to drugs. In 2015, they listed the older chemotherapy agents associated with pancreatitis. However, more recently, many new agents have been approved for the management of cancers. The newer classes of antineoplastic agents including proteasome inhibitors, immune-modulating agents, tyrosine kinase inhibitors, monoclonal antibodies against programmed cell death-1 (PD-1) and its ligand PD-L1 and antibody-toxin conjugates are now associated with acute pancreatitis.

Methods

We conducted a search in PubMed, Google Scholar, and Micromedex for pancreatitis related to antineoplastic agents, including proteasome inhibitors, immune checkpoint inhibitors, monoclonal antibodies, immune-modulating agents, drug-induced pancreatitis. Terms used for the searches included each specific agent and pancreatitis, immunotherapy and pancreatitis, tyrosine kinase inhibitors and pancreatitis, auto immune pancreatitis, and toxicities of molecular target therapies. Reference lists from the identified manuscripts were reviewed for further studies of pancreatitis as a result of antineoplastic therapy. The most recent search date was February 15, 2017.

The degree to which each agent was associated with inducing pancreatitis was evaluated using the Badalov classification system² in addition to the Naranjo Adverse Drug Reaction (ADR) Probability Scale.³ The Naranjo scale consists of 10 questions with values assigned to each answer. Total scores range from -4 to 13, where 13-9 indicates the reaction is considered definitely attributable to the drug; 8-5, probably attributable; 4-1, possibly attributable; and ≤0, doubtful if attributable.

A total of 67 manuscripts and abstracts were identified. Four manuscripts and 3 abstracts were excluded because they had insufficient information about possible pancreatitis or there was a presence of multiple other agents or conditions that might have caused pancreatitis. In total, 60 publications met inclusion criteria and were evaluated.

Results

Immune checkpoint inhibitors

In a review of toxicities of anti-programmed cell death-1 (PD-1) therapy, pancreatitis was reported to occur in about 1.8% of patients who received nivolumab or pembrolizumab.⁵ The 9 patients with pancreatitis attributed to an immune etiology were treated with corticosteroids. Pancreatitis was grade 2 in 3 patients (1.5-2 times upper limit of normal [ULN]), grade 3 in 4 patients (>2-5 ULN), and grade 4 ( >5 ULN) in 2 patients.

In asymptomatic individuals, pancreatitis has been detected on a positron-emission tomography–computed tomography (CT) scan after anti-PD-1 therapy.⁵ By contrast, there was a case report of a patient treated with nivolumab for lung cancer who developed anorexia, vomiting, and back pain on day 18 of therapy with an elevation of the amylase and lipase levels, but a negative CT.⁶ Later the patient developed a swollen pancreas on CT. Autoimmune pancreatitis comes in two forms. The most common relates to elevated levels of immunoglobulin G4 (IgG4; normal, 135 mg/dL ULN)⁷ The mechanism of immune pancreatitis associated with anti-PD-1 therapy is unknown.

Ipilimumab (an anti-CTLA4 antibody) has been approved by the US Food and Drug Administration (FDA) for the treatment of melanoma. Pancreatitis occurred in 1 patient in a phase 1 trial in pediatric patients.⁹ In a summary of 14 phase 1-3 trials of ipilimumab in advanced melanoma, pancreatitis was reported in fewer than 1% of the patients.¹⁰ In management guidelines for therapy with ipilimumab, pancreatitis may present as an asymptomatic increase in the levels of amylase and lipase, or with fevers, malaise, or abdominal pain. Oral prednisone or dexamethasone were given for the immune pancreatitis, but the decline in enzymes was slow, often taking months.¹¹ In a preclinical model of autoimmune pancreatitis due to the blocking of CTLA4, there was suppression of regulatory T-cell function. The autoimmune pancreatitis responded to cyclosporin or rapamycin but there are no clinical data for these agents.¹² The anti-PD-L1 agent atezolizumab has been associated with acute pancreatitis in 2 of 1,978 patients (0.1%).¹³ A review by Champiat and colleagues on dysimmune toxcities related to immune checkpoint inhibitors includes pancreatitis as an autoimmune complication of such therapies.¹⁴

Blinatumomab is an anti-CD19–directed CD3 T-cell engager that has been approved by the FDA for refractory B-cell acute lymphoblastic leukemia. In August 2016, the maker of the drug, Amgen, advised hematologists and oncologists that since February 2016, 10 patients out of more than 2,000 treated with blinatumomab had developed pancreatitis.¹⁵ Other medications the patients were receiving such as high-dose steroids might have caused or contributed to the pancreatitis. In one case, the pancreatitis improved with stopping blinatumomab but worsened with re-challenge. It is possible that the mechanism of the associated pancreatitis relates to a change in immune checkpoint inhibition. CD19-positive, CD24-high, CD27-positive regulatory B cells are decreased in autoimmune pancreatitis.¹⁶ Treatment with blinatumomab may decrease the CD19-positive cells.

Molecularly targeted agents, including TKIs

Molecularly targeted agents such as tyrosine kinase inhibitors (TKIs) or other kinase inhibitors have been associated with pancreatitis.^{17, 18} In a retrospective study by Tiruman and colleagues,¹⁹ the investigators found 91 patients with pancreatitis on imaging, of whom 15 were receiving molecularly target drugs. The pancreatitis was asymptomatic in 2 patients, but 13 had abdominal pain, many with nausea. Four of the patients also had gallstones, but the drug was deemed to be the cause of the pancreatitis. In 4 of the 9 patients in whom a rechallenge was done with the TKI, the pancreatitis relapsed. The pancreatitis resolved in 14 of the 15 patients; 1 patient died because of progressive cancer before the pancreatitis resolved. The pancreatitis was mild, 7 of the 15 patients had normal pancreatic enzymes and the pancreatitis was diagnosed by radiology.

Ghatlia and colleagues¹⁷ performed a meta-analysis of trials of TKI. They found 9 cases of pancreatitis in patients on sunitinib therapy. Of those, 4 patients were on sunitinib alone, and 5 were on other chemotherapy agents in combination with sunitinib. Eight cases of pancreatitis due to sorafenib were found. Three of the patients were on sorafenib alone, and 5 were on other chemotherapy including 1 on transcatheter embolization (TACE). Three cases of pancreatitis were associated with vandetanib; 2 of those patients had other concurrent chemotherapy. One case of axitinib induced pancreatitis was described.

Pancreatitis was reported in the phase 1 trials of sorafenib and sunitinib. In all, 3 of 69 patients treated with sorafenib had grade 3 pancreatitis and asymptomatic elevations of amylase and lipase levels were present in about 5% of patients receiving sunitinib.^18,19

Other TKIs associated with pancreatitis include pazopanib,^20,21 axitinib,²² and nilotinib.²³ Pezzilli and coleagues²⁴ described 5 patients with pancreatitis on sorafenib, 3 on sunitinib, 6 on nilotinib. It is possible that some of these cases appeared in other reviews. Ibrutinib, an inhibitor of Bruton’s tyrosine kinase, caused a single case of pancreatitis in 9 patients.²⁵

Vemurafenib, a BRAF kinase inhibitor, was associated with pancreatitis in one case. In this case, the pancreatitis resolved on stopping the medication but recurred when vemurafenib rechallenge was attempted.²⁶ There is a report of dabrafenib being associated with pancreatitis in 1 patient.²⁷

Agents that inhibit the TKIs associated with BCR-ABL in chronic myelogenous leukemia are associated with acute pancreatitis. Imatinib-induced pancreatitis was reported in a small number of cases.²⁸ Nilotinib has caused amylase/lipase elevations with and without symptomatic pancreatitis.^29,30 Ponatinib, an inhibitor of BCR-ABL tyrosine kinase, is associated with pancreatitis.³¹ Pancreatitis occurred in 11 of 81 patients treated with ponatinib, and in 8 patients it was described as serious. Further elevation of amylase or lipase levels without clinical pancreatitis was noted in 7 other patients.

Proteosome inhibitors

In 2010, Elouni and colleagues³² reported a case of IV bortezomib-induced pancreatitis, which recurred on rechallenge with bortezomib. This same patient was also reported in an abstract in 2009.³³ In 2009, there was an editorial comment which was added to the end of the abstract that the World Health Organization Adverse Drug Reaction database had 11 reports of bortezomib associated pancreatitis. Talamo and colleagues³⁴ reported a case of bortezomib-induced pancreatitis due to bortezomib that had been administered subcutaneously. At that time, they also summarized 7 previous reports of bortezomib-associated pancreatitis. The mechanism of bortezomib-induced pancreatitis is not known.^35-37

Fotoh and colleagues reported a patient with myeloma who had elevated triglyceride levels after bortezomib therapy.³⁸ In one case of bortezomib-associated pancreatitis, the patient had an elevated triglyceride level, but it was not extremely high.³⁹ Multiple myeloma itself may be associated with hyperlipidemia but only rarely.⁴⁰ Gozetti and colleagues reported a patient who developed hyperlipidemia after two courses of bortezomib;⁴¹ stopping bisphosphonates may be associated with a rise in triglycerides. There was one case of carfilzomib causing pancreatitis during a phase 1 trial.⁴²

Older chemotherapy agents

Reviews of drug-induced pancreatitis have listed many chemotherapy agents which may cause pancreatitis.^1,43 The agent most frequently associated with acute pancreatitis has been asparaginase,⁴⁴ with 2%-16% of patients undergoing asparaginase therapy developing pancreatitis. Asparaginase-related pancreatitis is grade 3 or 4 in 5%-10% of patients, and recurs in 63% of patients on rechallenge. Other chemotherapy agents associated with pancreatitis include: mercaptopurine, cytosine arabinoside, cisplatin, interferon alfa-2b, doxorubicin, tamoxifen, gefitinib, vinorelbine, oxaliplatin, levamisole, methotrexate, azathioprine, 5-fluorouracil, capecitabine, ifosfamide, paclitaxel, and all-trans retinoic acid.

Oxaliplatin carries a 0.1%-2% incidence of drug-induced pancreatitis. In one series of 6 patients, cessation of the agent allowed for resolution of symptoms and decrease in serum lipase and amylase levels.⁴⁵ With capecitabine there are 2 case reports of pancreatitis.⁴⁶ Cases of pancreatitis associated with trifluridine or tipiracil were not present in the literature.

Thalidomide caused severe pancreatitis in a patient when it was used to treat chronic graft-versus-host disease.⁴⁷ This patient suffered recurrent pancreatitis on retreatment with the thalidomide. The authors further referenced two other suspected cases of thalidomide-induced, acute pancreatitis. However, in view of the extensive use of thalidomide for multiple myeloma before the development of lenalidomide, thalidomide-associated pancreatitis would be <1% of patients.

Agents that cause hypertriglyceridemia may cause pancreatitis. This mechanism has been reported as the cause of pancreatitis for everolimus⁴⁸ and tamoxifen.^49,50-52 Everolimus causes elevated triglycerides in 30%-50% of patients. There are case reports and a review of tamoxifen-associated pancreatitis caused by elevated triglycerides.⁵² There has also been a case of temsirolimus-associated pancreatitis,⁵³ another agent that elevates triglycerides.

Pancreatitis associated with hepatic embolization or HIPEC

TACE leads to symptomatic acute pancreatitis in 0.4%-2% of patients, but nonselective TACE (into the hepatic artery and not just feeder vessels), may lead to elevated amylase levels in 15%-40% of patients.^54-56 The risk of pancreatitis would depend on which chemotherapy drug is being infused into the liver. It would also be greater if the chemotherapy has to be infused into a larger part of the liver than into a small portion of the liver. In one patient, severe pancreatitis secondary to TACE occurred after two previous embolizations; prior embolization may have led to occlusion of the previously infused vessels.⁵⁷ Radioembolization with 90Y microspheres was associated with one case of pancreatitis in 112 consecutive patients.⁵⁸ The postembolization syndrome in the first 24 hours after the procedure may involve fever, abdominal pain, nausea, and vomiting due to acute pancreatitis in some instances.

Acute pancreatitis has also been described as a complication of hyperthermic intraperitoneal chemotherapy (HIPEC).^59,60 Two of 13 patients receiving HIPEC for gastric cancer developed pancreatitis.⁵⁹ In 25 patients with colon cancer who were treated with HIPEC, 1 patient had pancreatitis.⁶⁰

Antibody-drug conjugates

Muzaffar and colleagues reported a patient with acute pancreatitis 3 days after starting therapy with ado-trastuzumab emtansine.⁶¹ Urru and colleagues⁶² reported a patient who developed acute pancreatitis after brentuximab vedotin therapy. Ghandi and colleagues⁶³ identified 2 cases of fatal acute pancreatitis with brentuximab vedotin and 6 cases of nonfatal pancreatitis. Two of the nonfatal patients were rechallenged, and 1 developed recurrent pancreatitis. Because abdominal pain may occur in up to 18% of patients receiving brentuximab vedotin, the incidence of pancreatitis may be underestimated with this agent.⁶⁴

In Table 2, ado-trastuzumab emtansine and brentuximab vedotin are listed with incidence and level of association given by the Baldavo² and Naranjo.³ With greater awareness, the incidence of pancreatitis associated with these agents may rise or fall as more data is accumulated. In many instances, there are insufficient numbers of reported cases or insufficient information in single-case reports to complete the entire table.

Discussion

Acute pancreatitis is an uncommon complication of tyrosine kinase inhibitors, other kinase inhibitors, proteasome inhibitors, monoclonal antibody-drug conjugates and anti-PD-1 immunotherapies. As nausea, abdominal pain, emesis are common in patients with cancer on antineoplastic therapy, some patients may have acute pancreatitis which is undiagnosed. It is not clear whether a patient with pancreatitis secondary to a TKI can be safely switched to a different TKI. As more molecularly targeted agents and more monoclonal antibodies targeting PD-L1 and PD-1 are under development, screening for amylase and lipase levels during phase 1/2 testing may prove helpful.

The natural history of cancer-drug–associated pancreatitis may depend on which agent is the cause. Although there are descriptions of the course of autoimmune pancreatitis, these studies have not included pancreatitis associated with anti-PD-L1 or -PD-1 therapies.⁶⁵ It is possible that once an autoimmune pancreatitis has developed, simply stopping the inciting anti-PD-L1 or -PD-1 antibody may not lead to immediate resolution. Therapy with combined immune checkpoint blockade agents (eg, nivolumab and ipilimumab) may cause a higher incidence of pancreatitis than therapy with a single agent.⁶⁶

In a report of 119 patients with melanoma who were treated with nivolumab and ipilimumab, there were 2 cases of acute pancreatitis, though 20% of patients had a grade 3 or higher amylase level, and just over 6% had a grade 3 or higher lipase.⁶⁷ Stopping this type of immunotherapy early for grade 1,2, or 3 rises in pancreatic enzymes might prevent symptomatic pancreatitis from developing, but would stop potentially curative therapy for many patients who would have never developed clinically serious pancreatitis. Patients who suffer immune toxicities with anti-PD-1 therapies may be more apt to obtain some clinical benefit. The development of immune-related toxicities in patients treated with ipilimumab ( an anti CTLA4 antibody) seemed to correlate the tumor regression.⁶⁸ This has also been suggested by the fact that the development of vitiligo correlates with clinical response in melanoma patients treated with nivolumab.⁶⁹ Although clinically significant pancreatitis might be averted by stopping immune therapies earlier, stopping before it is deemed necessary might prevent cancer patients from receiving life-prolonging therapy.

Acute pancreatitis in general is severe in about 25% of cases and is associated with a significant risk of death. Scoring systems such as Ranson criteria and Apache 2 are used to assess the severity of pancreatitis although their utility is debated.⁷⁰ Asparaginase is the chemotherapy agent most frequently associated with pancreatitis. It has been used to treat acute lymphoblastic leukemia for more than 30 years. This allowed for a study of 5,185 children and young adults who received asparaginase to determine what clinical factors and genomic factors were associated with the development of acute pancreatitis in 117 individuals.⁷¹ Further information gathered from programs such as the FDA and the adverse drug reaction program at Northwestern University in Chicago, coupled with the publication of other cases of pancreatitis associated with newer cancer agents may provide more insight into the mechanism causing pancreatitis due to a specific agent. With more cases being published, it may also become possible to determine if there are specific predisposing factors based on the clearance or metabolism of the offending agent or any genetic predisposition for drug-related pancreatitis.

More women are living longer with distant metastatic breast cancer (MBC), according to a National Cancer Institute study. Between 1992-1994 and 2005-2012, 5-year relative survival among women who were diagnosed with MBC at ages 15 to 49 doubled, from 18% to 36%.

Researchers also found that relative survival time increased from 22.3 months to 38.7 months for women diagnosed aged 15 -49 years, and from 19.1 months to 29.7 months for those aged 50 – 64 years.

Moreover, a “small but meaningful” number of women are living years after an initial diagnosis of MBC, the study found. More than 11% of women diagnosed between 2000-2004 aged < 64 years survived ≥ 10 years. Although nearly half of women with MBC have had it for ≤ 2 , one third have lived with it for ≥ 5 years.

The study findings “make clear that the majority of MBC patients, those who are diagnosed with non-metastatic cancer but progress to distant disease, have never been properly documented,” said Angela Mariotto, PhD, chief of the NCI Data Analytics Branch of the Division of Cancer Control and Population Sciences. By including women with recurrence, the study provides a more accurate number of women in the U.S. living with MBC, which can help with health care planning.

More women are living longer with distant metastatic breast cancer (MBC), according to a National Cancer Institute study. Between 1992-1994 and 2005-2012, 5-year relative survival among women who were diagnosed with MBC at ages 15 to 49 doubled, from 18% to 36%.

Researchers also found that relative survival time increased from 22.3 months to 38.7 months for women diagnosed aged 15 -49 years, and from 19.1 months to 29.7 months for those aged 50 – 64 years.

Moreover, a “small but meaningful” number of women are living years after an initial diagnosis of MBC, the study found. More than 11% of women diagnosed between 2000-2004 aged < 64 years survived ≥ 10 years. Although nearly half of women with MBC have had it for ≤ 2 , one third have lived with it for ≥ 5 years.

The study findings “make clear that the majority of MBC patients, those who are diagnosed with non-metastatic cancer but progress to distant disease, have never been properly documented,” said Angela Mariotto, PhD, chief of the NCI Data Analytics Branch of the Division of Cancer Control and Population Sciences. By including women with recurrence, the study provides a more accurate number of women in the U.S. living with MBC, which can help with health care planning.

More women are living longer with distant metastatic breast cancer (MBC), according to a National Cancer Institute study. Between 1992-1994 and 2005-2012, 5-year relative survival among women who were diagnosed with MBC at ages 15 to 49 doubled, from 18% to 36%.

Researchers also found that relative survival time increased from 22.3 months to 38.7 months for women diagnosed aged 15 -49 years, and from 19.1 months to 29.7 months for those aged 50 – 64 years.

Moreover, a “small but meaningful” number of women are living years after an initial diagnosis of MBC, the study found. More than 11% of women diagnosed between 2000-2004 aged < 64 years survived ≥ 10 years. Although nearly half of women with MBC have had it for ≤ 2 , one third have lived with it for ≥ 5 years.

The study findings “make clear that the majority of MBC patients, those who are diagnosed with non-metastatic cancer but progress to distant disease, have never been properly documented,” said Angela Mariotto, PhD, chief of the NCI Data Analytics Branch of the Division of Cancer Control and Population Sciences. By including women with recurrence, the study provides a more accurate number of women in the U.S. living with MBC, which can help with health care planning.

Photo by Marja Helander

England and Scotland are changing some of their policies regarding blood donation, shortening the deferral periods for donors who engage in “high-risk” sexual behavior.

Wales is considering making the same changes to its blood donation policies but has not yet made a commitment to do so.

The policy changes will mean that men who have sex with men (MSM), commercial sex workers, and people with sexual partners who have a high risk of sexually transmitted infections (including those who have been sexually active in areas where HIV is common) will be able to donate blood after 3 months have passed since their last sexual activity.

At present, MSMs and individuals with high-risk sexual partners can only donate blood after 12 months have passed since their last sexual activity, and commercial sex workers are permanently banned from giving blood.

The change in deferral periods will begin to take effect in England in early 2018 and in Scotland in November 2017. Until then, the existing rules still apply.

The Advisory Committee on the Safety of Blood, Tissues and Organs (SaBTO), which advises UK ministers and health departments, recommended the aforementioned policy changes following a review of blood donor criteria and risk assessment of certain behaviors.

SaBTO also recommended shortening the deferral period for potential donors who have undergone acupuncture, piercing, tattooing, and endoscopy, as well as those with a history of non-prescribed injectable drug use.

However, this change requires changing UK legislation, in addition to a derogation from or amendments to current European Union legislation.

“We welcome the review by SaBTO and the recommendations,” said Moira Carter, Associate Director of Donor Services and Transport for the Scottish National Blood Transfusion Service.

“The updates for donor eligibility will allow more people the opportunity to give blood. The changes take into account the latest available medical and scientific evidence about the risk of acquiring infections that can be passed on in blood, along with evidence supporting the reliability of the blood screening tests we use.”

“We’re pleased that the lifetime ban on former and current sex workers has been lifted, and the deferral period is now in line with other deferrals based on sexual behavior,” said Alex Phillips, Blood Donations Policy Lead at Terrence Higgins Trust in London.

“We know from our research that the majority of sex workers take great care of their sexual health, with 98% of sex workers we asked rating their sexual health as very important, 76% having a sexual health check up every 3 months, and 98% knowing their HIV status.”

“Medical evidence is, of course, constantly and quickly being updated, so it’s important that the deferral periods are regularly reviewed in line with the latest evidence. We therefore hope that today’s changes will pave the way for more progress as further evidence becomes available.”

Photo by Marja Helander

England and Scotland are changing some of their policies regarding blood donation, shortening the deferral periods for donors who engage in “high-risk” sexual behavior.

Wales is considering making the same changes to its blood donation policies but has not yet made a commitment to do so.

The policy changes will mean that men who have sex with men (MSM), commercial sex workers, and people with sexual partners who have a high risk of sexually transmitted infections (including those who have been sexually active in areas where HIV is common) will be able to donate blood after 3 months have passed since their last sexual activity.

At present, MSMs and individuals with high-risk sexual partners can only donate blood after 12 months have passed since their last sexual activity, and commercial sex workers are permanently banned from giving blood.

The change in deferral periods will begin to take effect in England in early 2018 and in Scotland in November 2017. Until then, the existing rules still apply.

The Advisory Committee on the Safety of Blood, Tissues and Organs (SaBTO), which advises UK ministers and health departments, recommended the aforementioned policy changes following a review of blood donor criteria and risk assessment of certain behaviors.

SaBTO also recommended shortening the deferral period for potential donors who have undergone acupuncture, piercing, tattooing, and endoscopy, as well as those with a history of non-prescribed injectable drug use.

However, this change requires changing UK legislation, in addition to a derogation from or amendments to current European Union legislation.

“We welcome the review by SaBTO and the recommendations,” said Moira Carter, Associate Director of Donor Services and Transport for the Scottish National Blood Transfusion Service.

“The updates for donor eligibility will allow more people the opportunity to give blood. The changes take into account the latest available medical and scientific evidence about the risk of acquiring infections that can be passed on in blood, along with evidence supporting the reliability of the blood screening tests we use.”

“We’re pleased that the lifetime ban on former and current sex workers has been lifted, and the deferral period is now in line with other deferrals based on sexual behavior,” said Alex Phillips, Blood Donations Policy Lead at Terrence Higgins Trust in London.

“We know from our research that the majority of sex workers take great care of their sexual health, with 98% of sex workers we asked rating their sexual health as very important, 76% having a sexual health check up every 3 months, and 98% knowing their HIV status.”

“Medical evidence is, of course, constantly and quickly being updated, so it’s important that the deferral periods are regularly reviewed in line with the latest evidence. We therefore hope that today’s changes will pave the way for more progress as further evidence becomes available.”

Photo by Marja Helander

England and Scotland are changing some of their policies regarding blood donation, shortening the deferral periods for donors who engage in “high-risk” sexual behavior.

Wales is considering making the same changes to its blood donation policies but has not yet made a commitment to do so.

The policy changes will mean that men who have sex with men (MSM), commercial sex workers, and people with sexual partners who have a high risk of sexually transmitted infections (including those who have been sexually active in areas where HIV is common) will be able to donate blood after 3 months have passed since their last sexual activity.

At present, MSMs and individuals with high-risk sexual partners can only donate blood after 12 months have passed since their last sexual activity, and commercial sex workers are permanently banned from giving blood.

The change in deferral periods will begin to take effect in England in early 2018 and in Scotland in November 2017. Until then, the existing rules still apply.

The Advisory Committee on the Safety of Blood, Tissues and Organs (SaBTO), which advises UK ministers and health departments, recommended the aforementioned policy changes following a review of blood donor criteria and risk assessment of certain behaviors.

SaBTO also recommended shortening the deferral period for potential donors who have undergone acupuncture, piercing, tattooing, and endoscopy, as well as those with a history of non-prescribed injectable drug use.

However, this change requires changing UK legislation, in addition to a derogation from or amendments to current European Union legislation.

“We welcome the review by SaBTO and the recommendations,” said Moira Carter, Associate Director of Donor Services and Transport for the Scottish National Blood Transfusion Service.

“The updates for donor eligibility will allow more people the opportunity to give blood. The changes take into account the latest available medical and scientific evidence about the risk of acquiring infections that can be passed on in blood, along with evidence supporting the reliability of the blood screening tests we use.”

“We’re pleased that the lifetime ban on former and current sex workers has been lifted, and the deferral period is now in line with other deferrals based on sexual behavior,” said Alex Phillips, Blood Donations Policy Lead at Terrence Higgins Trust in London.

“We know from our research that the majority of sex workers take great care of their sexual health, with 98% of sex workers we asked rating their sexual health as very important, 76% having a sexual health check up every 3 months, and 98% knowing their HIV status.”

“Medical evidence is, of course, constantly and quickly being updated, so it’s important that the deferral periods are regularly reviewed in line with the latest evidence. We therefore hope that today’s changes will pave the way for more progress as further evidence becomes available.”

Micrograph showing MM

MADRID—New research suggests one triplet regimen may be more active but also more toxic than another in patients with newly diagnosed multiple myeloma (MM).

In the FORTE trial, the combination of carfilzomib, lenalidomide, and dexamethasone (KRD) produced higher response rates than carfilzomib, cyclophosphamide, and dexamethasone (KCD).

However, treatment with KRD also produced significantly more grade 3/4 non-hematologic adverse events (AEs) and serious AEs than the KCD regimen.

Francesca Gay, MD, PhD, of University of Torino in Italy, presented these results, from a planned interim analysis of FORTE, at the 22nd Congress of the European Hematology Association (EHA) as abstract S410.

The trial enrolled 477 MM patients younger than 65 years of age.

The patients were randomized to receive:

• Four 28-day KCD cycles (n=154)

  Carfilzomib at 20 mg/m² (for cycles 1 and 2) or 36 mg/m² (for subsequent cycles) on days 1, 2, 8, 9, 15, and 16

  Cyclophosphamide at 300 mg/m² on days 1, 8, and 15

  Dexamethasone at 20 mg on days 1, 2, 8, 9, 15, 16, 22, and 23

• Four 28-day KRD cycles (n=309)

  Carfilzomib and dexamethasone as above

  Lenalidomide at 25 mg on days 1-21

After the fourth induction cycle, all patients received cyclophosphamide at 2 g/m², followed by peripheral blood stem cell (PBSC) collection for autologous stem cell transplant.

Patient characteristics

The median age was 57 (range, 52-62) in the KCD arm and the KRD arm (range, 51-62). In both arms, 55% of patients were male.

Roughly half of patients in both arms had an ISS stage of I (52% in the KCD arm and 51% in the KRD arm), 31% of patients in both arms were stage II, and 17% were stage III.

Fifty-eight percent of patients in the KCD arm and 59% in the KRD arm did not have t(4;14), t(14;16), or del17. Thirty-one percent and 26%, respectively, did have one of these cytogenetic abnormalities. (For the remaining patients, cytogenetic risk data were missing.)

PBSC mobilization and response

The median number of PBSCs collected was 8.6 x 10⁶/kg in the KCD arm and 6.3 x 10⁶/kg in the KRD arm. Plerixafor was required in 6% of patients in the KCD arm and 28% of patients in the KRD arm (P<0.001).

Ninety-two percent of patients in the KCD arm and 96% in the KRD arm had a partial response or better. Sixty-one percent and 74%, respectively, had a very good partial response (P=0.01). Six percent and 15%, respectively, had a complete response.

Safety

Grade 3/4 hematologic AEs and serious AEs (in the KRD and KCD arms, respectively) were thrombocytopenia (2% and 1%), neutropenia (6% and 5%), and anemia (2% and 3%). Seven percent of KRD patients and 6% of KCD patients had at least 1 grade 3/4 or serious hematologic AE.

Grade 3/4 non-hematologic AEs and serious AEs (in the KRD and KCD arms, respectively) included dermatologic events (8% and 1%, P<0.001), renal events (1% and 2%), fever (4% and 1%), infections (5% and 3%), gastrointestinal AEs (2% and 1%), hepatic events (8% and 1%, P<0.001), venous thromboembolism (1% and 0%), hypertension (3% and 2%), and cardiac events (1% and 2%).

Thirty-two percent of KRD patients and 16% of KCD patients had at least 1 grade 3/4 or serious non-hematologic AE (P<0.001).

Four percent of patients in the KRD arm and 2% in the KCD arm discontinued treatment due to AEs. Fifteen percent and 6%, respectively, reduced the dose of at least 1 drug (P=0.005).

One percent of patients in the KRD arm and 2% in the KCD arm died from AEs. In the KCD arm, 1 patient had a sudden death, and 1 died of pneumonia. In the KRD arm, there was 1 sudden death in a patient with sepsis, 1 patient died of infection, and 1 died of cardiac arrest (this patient previously discontinued treatment due to renal failure).

Micrograph showing MM

MADRID—New research suggests one triplet regimen may be more active but also more toxic than another in patients with newly diagnosed multiple myeloma (MM).

In the FORTE trial, the combination of carfilzomib, lenalidomide, and dexamethasone (KRD) produced higher response rates than carfilzomib, cyclophosphamide, and dexamethasone (KCD).

However, treatment with KRD also produced significantly more grade 3/4 non-hematologic adverse events (AEs) and serious AEs than the KCD regimen.

Francesca Gay, MD, PhD, of University of Torino in Italy, presented these results, from a planned interim analysis of FORTE, at the 22nd Congress of the European Hematology Association (EHA) as abstract S410.

The trial enrolled 477 MM patients younger than 65 years of age.

The patients were randomized to receive:

• Four 28-day KCD cycles (n=154)

  Carfilzomib at 20 mg/m² (for cycles 1 and 2) or 36 mg/m² (for subsequent cycles) on days 1, 2, 8, 9, 15, and 16

  Cyclophosphamide at 300 mg/m² on days 1, 8, and 15

  Dexamethasone at 20 mg on days 1, 2, 8, 9, 15, 16, 22, and 23

• Four 28-day KRD cycles (n=309)

  Carfilzomib and dexamethasone as above

  Lenalidomide at 25 mg on days 1-21

After the fourth induction cycle, all patients received cyclophosphamide at 2 g/m², followed by peripheral blood stem cell (PBSC) collection for autologous stem cell transplant.

Patient characteristics

The median age was 57 (range, 52-62) in the KCD arm and the KRD arm (range, 51-62). In both arms, 55% of patients were male.

Roughly half of patients in both arms had an ISS stage of I (52% in the KCD arm and 51% in the KRD arm), 31% of patients in both arms were stage II, and 17% were stage III.

Fifty-eight percent of patients in the KCD arm and 59% in the KRD arm did not have t(4;14), t(14;16), or del17. Thirty-one percent and 26%, respectively, did have one of these cytogenetic abnormalities. (For the remaining patients, cytogenetic risk data were missing.)

PBSC mobilization and response

The median number of PBSCs collected was 8.6 x 10⁶/kg in the KCD arm and 6.3 x 10⁶/kg in the KRD arm. Plerixafor was required in 6% of patients in the KCD arm and 28% of patients in the KRD arm (P<0.001).

Ninety-two percent of patients in the KCD arm and 96% in the KRD arm had a partial response or better. Sixty-one percent and 74%, respectively, had a very good partial response (P=0.01). Six percent and 15%, respectively, had a complete response.

Safety

Grade 3/4 hematologic AEs and serious AEs (in the KRD and KCD arms, respectively) were thrombocytopenia (2% and 1%), neutropenia (6% and 5%), and anemia (2% and 3%). Seven percent of KRD patients and 6% of KCD patients had at least 1 grade 3/4 or serious hematologic AE.

Grade 3/4 non-hematologic AEs and serious AEs (in the KRD and KCD arms, respectively) included dermatologic events (8% and 1%, P<0.001), renal events (1% and 2%), fever (4% and 1%), infections (5% and 3%), gastrointestinal AEs (2% and 1%), hepatic events (8% and 1%, P<0.001), venous thromboembolism (1% and 0%), hypertension (3% and 2%), and cardiac events (1% and 2%).

Thirty-two percent of KRD patients and 16% of KCD patients had at least 1 grade 3/4 or serious non-hematologic AE (P<0.001).

Four percent of patients in the KRD arm and 2% in the KCD arm discontinued treatment due to AEs. Fifteen percent and 6%, respectively, reduced the dose of at least 1 drug (P=0.005).

One percent of patients in the KRD arm and 2% in the KCD arm died from AEs. In the KCD arm, 1 patient had a sudden death, and 1 died of pneumonia. In the KRD arm, there was 1 sudden death in a patient with sepsis, 1 patient died of infection, and 1 died of cardiac arrest (this patient previously discontinued treatment due to renal failure).

Micrograph showing MM

MADRID—New research suggests one triplet regimen may be more active but also more toxic than another in patients with newly diagnosed multiple myeloma (MM).

In the FORTE trial, the combination of carfilzomib, lenalidomide, and dexamethasone (KRD) produced higher response rates than carfilzomib, cyclophosphamide, and dexamethasone (KCD).

However, treatment with KRD also produced significantly more grade 3/4 non-hematologic adverse events (AEs) and serious AEs than the KCD regimen.

Francesca Gay, MD, PhD, of University of Torino in Italy, presented these results, from a planned interim analysis of FORTE, at the 22nd Congress of the European Hematology Association (EHA) as abstract S410.

The trial enrolled 477 MM patients younger than 65 years of age.

The patients were randomized to receive:

• Four 28-day KCD cycles (n=154)

  Carfilzomib at 20 mg/m² (for cycles 1 and 2) or 36 mg/m² (for subsequent cycles) on days 1, 2, 8, 9, 15, and 16

  Cyclophosphamide at 300 mg/m² on days 1, 8, and 15

  Dexamethasone at 20 mg on days 1, 2, 8, 9, 15, 16, 22, and 23

• Four 28-day KRD cycles (n=309)

  Carfilzomib and dexamethasone as above

  Lenalidomide at 25 mg on days 1-21

After the fourth induction cycle, all patients received cyclophosphamide at 2 g/m², followed by peripheral blood stem cell (PBSC) collection for autologous stem cell transplant.

Patient characteristics

The median age was 57 (range, 52-62) in the KCD arm and the KRD arm (range, 51-62). In both arms, 55% of patients were male.

Roughly half of patients in both arms had an ISS stage of I (52% in the KCD arm and 51% in the KRD arm), 31% of patients in both arms were stage II, and 17% were stage III.

Fifty-eight percent of patients in the KCD arm and 59% in the KRD arm did not have t(4;14), t(14;16), or del17. Thirty-one percent and 26%, respectively, did have one of these cytogenetic abnormalities. (For the remaining patients, cytogenetic risk data were missing.)

PBSC mobilization and response

The median number of PBSCs collected was 8.6 x 10⁶/kg in the KCD arm and 6.3 x 10⁶/kg in the KRD arm. Plerixafor was required in 6% of patients in the KCD arm and 28% of patients in the KRD arm (P<0.001).

Ninety-two percent of patients in the KCD arm and 96% in the KRD arm had a partial response or better. Sixty-one percent and 74%, respectively, had a very good partial response (P=0.01). Six percent and 15%, respectively, had a complete response.

Safety

Grade 3/4 hematologic AEs and serious AEs (in the KRD and KCD arms, respectively) were thrombocytopenia (2% and 1%), neutropenia (6% and 5%), and anemia (2% and 3%). Seven percent of KRD patients and 6% of KCD patients had at least 1 grade 3/4 or serious hematologic AE.

Grade 3/4 non-hematologic AEs and serious AEs (in the KRD and KCD arms, respectively) included dermatologic events (8% and 1%, P<0.001), renal events (1% and 2%), fever (4% and 1%), infections (5% and 3%), gastrointestinal AEs (2% and 1%), hepatic events (8% and 1%, P<0.001), venous thromboembolism (1% and 0%), hypertension (3% and 2%), and cardiac events (1% and 2%).

Thirty-two percent of KRD patients and 16% of KCD patients had at least 1 grade 3/4 or serious non-hematologic AE (P<0.001).

Four percent of patients in the KRD arm and 2% in the KCD arm discontinued treatment due to AEs. Fifteen percent and 6%, respectively, reduced the dose of at least 1 drug (P=0.005).

One percent of patients in the KRD arm and 2% in the KCD arm died from AEs. In the KCD arm, 1 patient had a sudden death, and 1 died of pneumonia. In the KRD arm, there was 1 sudden death in a patient with sepsis, 1 patient died of infection, and 1 died of cardiac arrest (this patient previously discontinued treatment due to renal failure).

Micrograph showing CLL

LUGANO, SWITZERLAND—A sequential treatment regimen can produce a high overall response rate (ORR) in patients with treatment-naïve (TN) or relapsed/refractory (RR) chronic lymphocytic leukemia (CLL), results of the CLL2-BAG study suggest.

Patients who received bendamustine followed by obinutuzumab and venetoclax achieved an ORR of 95%, and 87% of them were negative for minimal residual disease (MRD) in the peripheral blood.

In addition, this regimen did not lead to cumulative or unexpected toxicity, according to study investigator Paula Cramer, MD, of University Hospital of Cologne in Germany.

Dr Cramer presented results from CLL2-BAG at the 14th International Conference on Malignant Lymphoma (ICML). The trial was sponsored by the German CLL Study Group.

CLL2-BAG included 63 patients—34 with TN and 29 with RR CLL. The median age was 58 (range, 43-76) and 61 (range, 28-77), respectively.

Thirty-five percent of TN patients had bulky disease (>5 cm), as did 45% of RR patients. Twelve percent and 10%, respectively, had massive splenomegaly (>20 cm)

Twenty-one percent of TN patients and 35% of RR patients were Binet stage A. Thirty-two percent and 21%, respectively, were stage B, and 47% and 45%, respectively, were stage C.

Treatment

Patients first underwent debulking with bendamustine, given at 70 mg/m² on days 1 and 2 for two 28-day cycles. They then received induction with obinutuzumab and venetoclax for six 28-day cycles.

In cycle 1, patients received obinutuzumab at 100 mg or 900 mg on day 1 or 2 and 1000 mg on days 8 and 15. For cycles 2-6, patients received 1000 mg of obinutuzumab on day 1.

In cycle 2, patients received venetoclax at 20 mg on days 1-7, 50 mg on days 8-14, 100 mg on days 15-21, and 200 mg on days 22-28. For cycles 3-6, they received venetoclax at 400 mg on days 1-28.

Patients also received maintenance with obinutuzumab and venetoclax for 2 to 8 cycles with a duration of 84 days. Obinutuzumab was given at 1000 mg on day 1 of each cycle, and venetoclax was given at 400 mg on days 1-84.

Maintenance was continued until patients completed 24 months of maintenance therapy, until 3 months after patients achieved a complete response (CR) or CR with incomplete count recovery (CRi) and MRD negativity, until progression of CLL or start of new CLL treatment, or until unacceptable toxicity.

ORR, MRD, and survival

At the end of induction, the ORR was 95% in the entire population—100% among TN patients and 90% among RR patients.

The rate of CR was 8%, 9%, and 7%, respectively. The rate of unconfirmed/clinical CR/CRi was 32%, 41%, and 21%, respectively.

Five percent of patients progressed, all of them in the RR group.

Eighty-seven percent of evaluable patients were MRD negative (<10^-4) in the peripheral blood, including 91% of TN patients and 83% of RR patients. Two patients (3%) were missing data on MRD status in peripheral blood.

Thirteen percent of all evaluable patients were MRD negative in the bone marrow, including 12% of TN patients and 14% of RR patients. The remaining patients (87%, 88%, and 86%, respectively) were missing data on MRD status in the bone marrow.

The progression-free survival at 15 months was 100% in the TN patients and 83% in the RR patients.

Adverse events

After debulking, 28.1% of TN patients and 46.7% of RR patients had experienced adverse events (AEs).

These included (in TN and RR patients, respectively) neutropenia (9.4% and 13.3%), anemia (6.3% and 20.0%), thrombocytopenia (6.3% and 6.7%), infections (6.3% and 6.7%), coronary artery disorders (1 TN patient, 3.1%), rash (1 TN patient, 3.1%), tumor lysis syndrome (1 TN patient, 3.1%), vomiting (1 TN patient, 3.1%), and pyrexia (1 RR patient, 6.7%).

After induction, 54.3% of TN patients and 80.6% of RR patients had experienced AEs.

These included (in TN and RR patients, respectively) neutropenia (34.3% and 54.8%), infections (8.6% and 29.0%), thrombocytopenia (2.9% and 22.6%), infusion-related reactions (5 RR patients, 16.1%), neoplasms (2.9% and 9.7%), hypertension (2.9% and 6.5%), coronary artery disorders (2.9% and 6.5%), anemia (3 RR patients, 9.7%), and tumor lysis syndrome (2 RR patients, 6.5%).

Micrograph showing CLL

LUGANO, SWITZERLAND—A sequential treatment regimen can produce a high overall response rate (ORR) in patients with treatment-naïve (TN) or relapsed/refractory (RR) chronic lymphocytic leukemia (CLL), results of the CLL2-BAG study suggest.

Patients who received bendamustine followed by obinutuzumab and venetoclax achieved an ORR of 95%, and 87% of them were negative for minimal residual disease (MRD) in the peripheral blood.

In addition, this regimen did not lead to cumulative or unexpected toxicity, according to study investigator Paula Cramer, MD, of University Hospital of Cologne in Germany.

Dr Cramer presented results from CLL2-BAG at the 14th International Conference on Malignant Lymphoma (ICML). The trial was sponsored by the German CLL Study Group.

CLL2-BAG included 63 patients—34 with TN and 29 with RR CLL. The median age was 58 (range, 43-76) and 61 (range, 28-77), respectively.

Thirty-five percent of TN patients had bulky disease (>5 cm), as did 45% of RR patients. Twelve percent and 10%, respectively, had massive splenomegaly (>20 cm)

Twenty-one percent of TN patients and 35% of RR patients were Binet stage A. Thirty-two percent and 21%, respectively, were stage B, and 47% and 45%, respectively, were stage C.

Treatment

Patients first underwent debulking with bendamustine, given at 70 mg/m² on days 1 and 2 for two 28-day cycles. They then received induction with obinutuzumab and venetoclax for six 28-day cycles.

In cycle 1, patients received obinutuzumab at 100 mg or 900 mg on day 1 or 2 and 1000 mg on days 8 and 15. For cycles 2-6, patients received 1000 mg of obinutuzumab on day 1.

In cycle 2, patients received venetoclax at 20 mg on days 1-7, 50 mg on days 8-14, 100 mg on days 15-21, and 200 mg on days 22-28. For cycles 3-6, they received venetoclax at 400 mg on days 1-28.

Patients also received maintenance with obinutuzumab and venetoclax for 2 to 8 cycles with a duration of 84 days. Obinutuzumab was given at 1000 mg on day 1 of each cycle, and venetoclax was given at 400 mg on days 1-84.

Maintenance was continued until patients completed 24 months of maintenance therapy, until 3 months after patients achieved a complete response (CR) or CR with incomplete count recovery (CRi) and MRD negativity, until progression of CLL or start of new CLL treatment, or until unacceptable toxicity.

ORR, MRD, and survival

At the end of induction, the ORR was 95% in the entire population—100% among TN patients and 90% among RR patients.

The rate of CR was 8%, 9%, and 7%, respectively. The rate of unconfirmed/clinical CR/CRi was 32%, 41%, and 21%, respectively.

Five percent of patients progressed, all of them in the RR group.

Eighty-seven percent of evaluable patients were MRD negative (<10^-4) in the peripheral blood, including 91% of TN patients and 83% of RR patients. Two patients (3%) were missing data on MRD status in peripheral blood.

Thirteen percent of all evaluable patients were MRD negative in the bone marrow, including 12% of TN patients and 14% of RR patients. The remaining patients (87%, 88%, and 86%, respectively) were missing data on MRD status in the bone marrow.

The progression-free survival at 15 months was 100% in the TN patients and 83% in the RR patients.

Adverse events

After debulking, 28.1% of TN patients and 46.7% of RR patients had experienced adverse events (AEs).

These included (in TN and RR patients, respectively) neutropenia (9.4% and 13.3%), anemia (6.3% and 20.0%), thrombocytopenia (6.3% and 6.7%), infections (6.3% and 6.7%), coronary artery disorders (1 TN patient, 3.1%), rash (1 TN patient, 3.1%), tumor lysis syndrome (1 TN patient, 3.1%), vomiting (1 TN patient, 3.1%), and pyrexia (1 RR patient, 6.7%).

After induction, 54.3% of TN patients and 80.6% of RR patients had experienced AEs.

These included (in TN and RR patients, respectively) neutropenia (34.3% and 54.8%), infections (8.6% and 29.0%), thrombocytopenia (2.9% and 22.6%), infusion-related reactions (5 RR patients, 16.1%), neoplasms (2.9% and 9.7%), hypertension (2.9% and 6.5%), coronary artery disorders (2.9% and 6.5%), anemia (3 RR patients, 9.7%), and tumor lysis syndrome (2 RR patients, 6.5%).

Micrograph showing CLL

LUGANO, SWITZERLAND—A sequential treatment regimen can produce a high overall response rate (ORR) in patients with treatment-naïve (TN) or relapsed/refractory (RR) chronic lymphocytic leukemia (CLL), results of the CLL2-BAG study suggest.

Patients who received bendamustine followed by obinutuzumab and venetoclax achieved an ORR of 95%, and 87% of them were negative for minimal residual disease (MRD) in the peripheral blood.

In addition, this regimen did not lead to cumulative or unexpected toxicity, according to study investigator Paula Cramer, MD, of University Hospital of Cologne in Germany.

Dr Cramer presented results from CLL2-BAG at the 14th International Conference on Malignant Lymphoma (ICML). The trial was sponsored by the German CLL Study Group.

CLL2-BAG included 63 patients—34 with TN and 29 with RR CLL. The median age was 58 (range, 43-76) and 61 (range, 28-77), respectively.

Thirty-five percent of TN patients had bulky disease (>5 cm), as did 45% of RR patients. Twelve percent and 10%, respectively, had massive splenomegaly (>20 cm)

Twenty-one percent of TN patients and 35% of RR patients were Binet stage A. Thirty-two percent and 21%, respectively, were stage B, and 47% and 45%, respectively, were stage C.

Treatment

Patients first underwent debulking with bendamustine, given at 70 mg/m² on days 1 and 2 for two 28-day cycles. They then received induction with obinutuzumab and venetoclax for six 28-day cycles.

In cycle 1, patients received obinutuzumab at 100 mg or 900 mg on day 1 or 2 and 1000 mg on days 8 and 15. For cycles 2-6, patients received 1000 mg of obinutuzumab on day 1.

In cycle 2, patients received venetoclax at 20 mg on days 1-7, 50 mg on days 8-14, 100 mg on days 15-21, and 200 mg on days 22-28. For cycles 3-6, they received venetoclax at 400 mg on days 1-28.

Patients also received maintenance with obinutuzumab and venetoclax for 2 to 8 cycles with a duration of 84 days. Obinutuzumab was given at 1000 mg on day 1 of each cycle, and venetoclax was given at 400 mg on days 1-84.

Maintenance was continued until patients completed 24 months of maintenance therapy, until 3 months after patients achieved a complete response (CR) or CR with incomplete count recovery (CRi) and MRD negativity, until progression of CLL or start of new CLL treatment, or until unacceptable toxicity.

ORR, MRD, and survival

At the end of induction, the ORR was 95% in the entire population—100% among TN patients and 90% among RR patients.

The rate of CR was 8%, 9%, and 7%, respectively. The rate of unconfirmed/clinical CR/CRi was 32%, 41%, and 21%, respectively.

Five percent of patients progressed, all of them in the RR group.

Eighty-seven percent of evaluable patients were MRD negative (<10^-4) in the peripheral blood, including 91% of TN patients and 83% of RR patients. Two patients (3%) were missing data on MRD status in peripheral blood.

Thirteen percent of all evaluable patients were MRD negative in the bone marrow, including 12% of TN patients and 14% of RR patients. The remaining patients (87%, 88%, and 86%, respectively) were missing data on MRD status in the bone marrow.

The progression-free survival at 15 months was 100% in the TN patients and 83% in the RR patients.

Adverse events

After debulking, 28.1% of TN patients and 46.7% of RR patients had experienced adverse events (AEs).

These included (in TN and RR patients, respectively) neutropenia (9.4% and 13.3%), anemia (6.3% and 20.0%), thrombocytopenia (6.3% and 6.7%), infections (6.3% and 6.7%), coronary artery disorders (1 TN patient, 3.1%), rash (1 TN patient, 3.1%), tumor lysis syndrome (1 TN patient, 3.1%), vomiting (1 TN patient, 3.1%), and pyrexia (1 RR patient, 6.7%).

After induction, 54.3% of TN patients and 80.6% of RR patients had experienced AEs.

These included (in TN and RR patients, respectively) neutropenia (34.3% and 54.8%), infections (8.6% and 29.0%), thrombocytopenia (2.9% and 22.6%), infusion-related reactions (5 RR patients, 16.1%), neoplasms (2.9% and 9.7%), hypertension (2.9% and 6.5%), coronary artery disorders (2.9% and 6.5%), anemia (3 RR patients, 9.7%), and tumor lysis syndrome (2 RR patients, 6.5%).

Title: Large-scale implementation of the I-PASS handover system at an academic medical center

Clinical Question: Is a system-wide I-PASS handover system able to be effectively implemented?

Background: Handovers (also referred to as “handoffs”) in patient care are ubiquitous and are increasing, especially in academic medicine. Errors in handovers are associated with poor patient outcomes. I-PASS (Illness Severity, Patient Summary, Action List, Situational Awareness, Synthesis by Receiver) is a handover system that is thought to improve efficiency and accuracy of handovers, however generalized roll-out within a large academic hospital remains daunting.

Dr. Rankin is a hospitalist and director of the family medicine residency inpatient service at the University of New Mexico.

Title: Large-scale implementation of the I-PASS handover system at an academic medical center

Clinical Question: Is a system-wide I-PASS handover system able to be effectively implemented?

Background: Handovers (also referred to as “handoffs”) in patient care are ubiquitous and are increasing, especially in academic medicine. Errors in handovers are associated with poor patient outcomes. I-PASS (Illness Severity, Patient Summary, Action List, Situational Awareness, Synthesis by Receiver) is a handover system that is thought to improve efficiency and accuracy of handovers, however generalized roll-out within a large academic hospital remains daunting.

Dr. Rankin is a hospitalist and director of the family medicine residency inpatient service at the University of New Mexico.

Title: Large-scale implementation of the I-PASS handover system at an academic medical center

Clinical Question: Is a system-wide I-PASS handover system able to be effectively implemented?

Background: Handovers (also referred to as “handoffs”) in patient care are ubiquitous and are increasing, especially in academic medicine. Errors in handovers are associated with poor patient outcomes. I-PASS (Illness Severity, Patient Summary, Action List, Situational Awareness, Synthesis by Receiver) is a handover system that is thought to improve efficiency and accuracy of handovers, however generalized roll-out within a large academic hospital remains daunting.

Dr. Rankin is a hospitalist and director of the family medicine residency inpatient service at the University of New Mexico.

The long slog toward release of revised U.S. guidelines for treating hypertension may end in September. Or not.

Authoritative U.S. guidelines for managing high blood pressure have traveled a rocky and serpentine path ever since the expert group originally constituted as the Eighth Joint National Committee (JNC 8) released its controversial report in early 2014, when it relaxed the target blood pressure for most adults aged 60-79 years from less than 140 mm Hg to under 150/90 mm Hg (JAMA. 2014 Feb 5;3311[5]:507-20). A few months before those recommendations came out, the National Heart, Lung, and Blood Institute, which since 1977 had organized seven preceding iterations of U.S. blood pressure guidelines, handed off oversight of the project and any future updates to the American Heart Association, the American College of Cardiology, and the American Society of Hypertension. A year later, an expert panel organized by those three groups reset the blood pressure target for most U.S. adults with coronary artery disease back to a pressure of less than 140/90 mm Hg (Hypertension. 2015 Jun;65[6]:1372-1407), and that has been the prevailing U.S. standard in the 2-plus years since.

A few months later, in September 2015, data from the SPRINT trial in more than 9,000 patients with high cardiovascular risk first came out and showed that treating to a target systolic blood pressure of less than 120 mm Hg led to a significant 25% reduction in cardiovascular disease events, compared with controls treated to a systolic pressure of less than 140 mm Hg (N Engl J Med. 2015 Nov 26;373[22]:2103-16). Ever since, the big question surrounding blood pressure targets in U.S. practice has been, when would new official guidelines emerge that took the SPRINT findings into consideration? It now looks like it will finally happen in September 2017.

That’s when the ASH and the AHA’s Hypertension Council will for the first time hold a joint annual meeting, after many years when each organization had its own, individual annual meeting. The ASH’s traditional spring meeting didn’t happen this year; early fall has traditionally been when the AHA’s Hypertension Council meets.

The Council’s posted preliminary program for the September meeting showed, as of late July, an opening session the morning of September 14 called a “Review of AHA Scientific Statement 2017.” On the ASH’s website is a virtual flier for a session the afternoon of September 15 on the “2017 Guidelines for Adult and Pediatric Hypertension.”

[email protected]

On Twitter @mitchelzoler

The long slog toward release of revised U.S. guidelines for treating hypertension may end in September. Or not.

Authoritative U.S. guidelines for managing high blood pressure have traveled a rocky and serpentine path ever since the expert group originally constituted as the Eighth Joint National Committee (JNC 8) released its controversial report in early 2014, when it relaxed the target blood pressure for most adults aged 60-79 years from less than 140 mm Hg to under 150/90 mm Hg (JAMA. 2014 Feb 5;3311[5]:507-20). A few months before those recommendations came out, the National Heart, Lung, and Blood Institute, which since 1977 had organized seven preceding iterations of U.S. blood pressure guidelines, handed off oversight of the project and any future updates to the American Heart Association, the American College of Cardiology, and the American Society of Hypertension. A year later, an expert panel organized by those three groups reset the blood pressure target for most U.S. adults with coronary artery disease back to a pressure of less than 140/90 mm Hg (Hypertension. 2015 Jun;65[6]:1372-1407), and that has been the prevailing U.S. standard in the 2-plus years since.

A few months later, in September 2015, data from the SPRINT trial in more than 9,000 patients with high cardiovascular risk first came out and showed that treating to a target systolic blood pressure of less than 120 mm Hg led to a significant 25% reduction in cardiovascular disease events, compared with controls treated to a systolic pressure of less than 140 mm Hg (N Engl J Med. 2015 Nov 26;373[22]:2103-16). Ever since, the big question surrounding blood pressure targets in U.S. practice has been, when would new official guidelines emerge that took the SPRINT findings into consideration? It now looks like it will finally happen in September 2017.

That’s when the ASH and the AHA’s Hypertension Council will for the first time hold a joint annual meeting, after many years when each organization had its own, individual annual meeting. The ASH’s traditional spring meeting didn’t happen this year; early fall has traditionally been when the AHA’s Hypertension Council meets.

The Council’s posted preliminary program for the September meeting showed, as of late July, an opening session the morning of September 14 called a “Review of AHA Scientific Statement 2017.” On the ASH’s website is a virtual flier for a session the afternoon of September 15 on the “2017 Guidelines for Adult and Pediatric Hypertension.”

[email protected]

On Twitter @mitchelzoler

The long slog toward release of revised U.S. guidelines for treating hypertension may end in September. Or not.

Authoritative U.S. guidelines for managing high blood pressure have traveled a rocky and serpentine path ever since the expert group originally constituted as the Eighth Joint National Committee (JNC 8) released its controversial report in early 2014, when it relaxed the target blood pressure for most adults aged 60-79 years from less than 140 mm Hg to under 150/90 mm Hg (JAMA. 2014 Feb 5;3311[5]:507-20). A few months before those recommendations came out, the National Heart, Lung, and Blood Institute, which since 1977 had organized seven preceding iterations of U.S. blood pressure guidelines, handed off oversight of the project and any future updates to the American Heart Association, the American College of Cardiology, and the American Society of Hypertension. A year later, an expert panel organized by those three groups reset the blood pressure target for most U.S. adults with coronary artery disease back to a pressure of less than 140/90 mm Hg (Hypertension. 2015 Jun;65[6]:1372-1407), and that has been the prevailing U.S. standard in the 2-plus years since.

A few months later, in September 2015, data from the SPRINT trial in more than 9,000 patients with high cardiovascular risk first came out and showed that treating to a target systolic blood pressure of less than 120 mm Hg led to a significant 25% reduction in cardiovascular disease events, compared with controls treated to a systolic pressure of less than 140 mm Hg (N Engl J Med. 2015 Nov 26;373[22]:2103-16). Ever since, the big question surrounding blood pressure targets in U.S. practice has been, when would new official guidelines emerge that took the SPRINT findings into consideration? It now looks like it will finally happen in September 2017.

That’s when the ASH and the AHA’s Hypertension Council will for the first time hold a joint annual meeting, after many years when each organization had its own, individual annual meeting. The ASH’s traditional spring meeting didn’t happen this year; early fall has traditionally been when the AHA’s Hypertension Council meets.

The Council’s posted preliminary program for the September meeting showed, as of late July, an opening session the morning of September 14 called a “Review of AHA Scientific Statement 2017.” On the ASH’s website is a virtual flier for a session the afternoon of September 15 on the “2017 Guidelines for Adult and Pediatric Hypertension.”

[email protected]

On Twitter @mitchelzoler

A 5% drop in use of the MMR vaccine could triple the cases of measles among children aged 2-11 years in the United States, based on data from a mathematical model published in JAMA Pediatrics.

Increased reluctance among parents to vaccinate children has led to calls for a government commission on vaccine safety, wrote Nathan C. Lo of Stanford (Calif.) University, and Peter J. Hotez, MD, PhD, of Baylor College of Medicine, Houston (JAMA Pediatr. 2017 Jul 24. doi: 10.1001/jamapediatrics.2017.1695).

The researchers sought to estimate the potential impact of reduced vaccination on public health and the economy, using the MMR vaccine as an example. They collected vaccination data from the Centers for Disease Control and Prevention, created a mathematical model, and estimated $20,000 per case of measles from a public health perspective. They simulated a measles outbreak following the importation of measles into a county in the United States, and estimated the size of an outbreak based on local vaccine coverage.
In the model population, the average baseline coverage for MMR vaccination was 93% prevalence (varying by state from 87% to 97%). The average prevalence of nonmedical exemptions was 2%; state prevalence ranged from 0.4% to 6.2%. The annual number of measles cases was 48.

Using the model, a drop in MMR vaccination as little as 5% “would result in a threefold increase in national measles cases in this age group, for a total of 150 cases and an additional $2.1 million in economic costs to the public sector,” the researchers said. By contrast, increasing national MMR coverage to 95% would reduce the number of cases by 20%, they predicted.

“These estimates would be substantially higher if unvaccinated infants, adolescents, and adult populations are also considered,” Mr. Lo and Dr. Hotez said.

The study findings were limited by the use of a model and simulation of vaccine coverage, and by restricting the study to children aged 2-11 years.

However, the results “directly confront the notion that measles is no longer a threat in the United States,” and suggest “substantial public health and economic consequences with even minor reductions in MMR coverage due to vaccine hesitancy,” they emphasized. “Removal of the nonmedical personal belief exemptions for childhood vaccination may mitigate these consequences.”

Mr. Lo disclosed funding from Stanford’s Medical Scientist Training Program; no financial conflicts were disclosed.

A 5% drop in use of the MMR vaccine could triple the cases of measles among children aged 2-11 years in the United States, based on data from a mathematical model published in JAMA Pediatrics.

Increased reluctance among parents to vaccinate children has led to calls for a government commission on vaccine safety, wrote Nathan C. Lo of Stanford (Calif.) University, and Peter J. Hotez, MD, PhD, of Baylor College of Medicine, Houston (JAMA Pediatr. 2017 Jul 24. doi: 10.1001/jamapediatrics.2017.1695).

The researchers sought to estimate the potential impact of reduced vaccination on public health and the economy, using the MMR vaccine as an example. They collected vaccination data from the Centers for Disease Control and Prevention, created a mathematical model, and estimated $20,000 per case of measles from a public health perspective. They simulated a measles outbreak following the importation of measles into a county in the United States, and estimated the size of an outbreak based on local vaccine coverage.
In the model population, the average baseline coverage for MMR vaccination was 93% prevalence (varying by state from 87% to 97%). The average prevalence of nonmedical exemptions was 2%; state prevalence ranged from 0.4% to 6.2%. The annual number of measles cases was 48.

Using the model, a drop in MMR vaccination as little as 5% “would result in a threefold increase in national measles cases in this age group, for a total of 150 cases and an additional $2.1 million in economic costs to the public sector,” the researchers said. By contrast, increasing national MMR coverage to 95% would reduce the number of cases by 20%, they predicted.

“These estimates would be substantially higher if unvaccinated infants, adolescents, and adult populations are also considered,” Mr. Lo and Dr. Hotez said.

The study findings were limited by the use of a model and simulation of vaccine coverage, and by restricting the study to children aged 2-11 years.

However, the results “directly confront the notion that measles is no longer a threat in the United States,” and suggest “substantial public health and economic consequences with even minor reductions in MMR coverage due to vaccine hesitancy,” they emphasized. “Removal of the nonmedical personal belief exemptions for childhood vaccination may mitigate these consequences.”

Mr. Lo disclosed funding from Stanford’s Medical Scientist Training Program; no financial conflicts were disclosed.

A 5% drop in use of the MMR vaccine could triple the cases of measles among children aged 2-11 years in the United States, based on data from a mathematical model published in JAMA Pediatrics.

Increased reluctance among parents to vaccinate children has led to calls for a government commission on vaccine safety, wrote Nathan C. Lo of Stanford (Calif.) University, and Peter J. Hotez, MD, PhD, of Baylor College of Medicine, Houston (JAMA Pediatr. 2017 Jul 24. doi: 10.1001/jamapediatrics.2017.1695).

The researchers sought to estimate the potential impact of reduced vaccination on public health and the economy, using the MMR vaccine as an example. They collected vaccination data from the Centers for Disease Control and Prevention, created a mathematical model, and estimated $20,000 per case of measles from a public health perspective. They simulated a measles outbreak following the importation of measles into a county in the United States, and estimated the size of an outbreak based on local vaccine coverage.
In the model population, the average baseline coverage for MMR vaccination was 93% prevalence (varying by state from 87% to 97%). The average prevalence of nonmedical exemptions was 2%; state prevalence ranged from 0.4% to 6.2%. The annual number of measles cases was 48.

Using the model, a drop in MMR vaccination as little as 5% “would result in a threefold increase in national measles cases in this age group, for a total of 150 cases and an additional $2.1 million in economic costs to the public sector,” the researchers said. By contrast, increasing national MMR coverage to 95% would reduce the number of cases by 20%, they predicted.

“These estimates would be substantially higher if unvaccinated infants, adolescents, and adult populations are also considered,” Mr. Lo and Dr. Hotez said.

The study findings were limited by the use of a model and simulation of vaccine coverage, and by restricting the study to children aged 2-11 years.

However, the results “directly confront the notion that measles is no longer a threat in the United States,” and suggest “substantial public health and economic consequences with even minor reductions in MMR coverage due to vaccine hesitancy,” they emphasized. “Removal of the nonmedical personal belief exemptions for childhood vaccination may mitigate these consequences.”

Mr. Lo disclosed funding from Stanford’s Medical Scientist Training Program; no financial conflicts were disclosed.