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TAILORx marks major advance for precision medicine in breast cancer
CHICAGO – , sparing them adverse effects and preventing overtreatment, TAILORx trial results show.
The findings, which were reported in the plenary session at the annual meeting of the American Society of Clinical Oncology and simultaneously published in the New England Journal of Medicine, mark a major advance in precision medicine.
The recurrence score is known to be prognostic and to be predictive of benefit from adding chemotherapy to endocrine therapy, Dr. Sparano said. “But there was a major gap: There was uncertain benefit for patients who had a midrange score, about two-thirds of all patients who are treated.”
The phase 3 TAILORx trial registered 10,273 women with hormone receptor–positive, HER2-negative, node-negative early-stage breast cancer, making it the largest adjuvant breast cancer trial to date. Analyses focused on the 6,711 evaluable women with a midrange recurrence score (defined as 11 through 25 in the trial), who were randomized to receive endocrine therapy alone or adjuvant chemotherapy plus endocrine therapy, with a noninferiority design. Of note, contemporary drugs and regimens were used.
Results at a median follow-up of 7.5 years showed that the trial met its primary endpoint: The risk of invasive disease-free survival events (invasive disease recurrence, second primary cancer, or death) was not inferior for women given endocrine therapy alone compared with counterparts given chemotherapy plus endocrine therapy (hazard ratio, 1.08; P = .26), Dr. Sparano reported.
The groups were also on par, with absolute differences of no more than 1% between rates, with respect to a variety of other efficacy outcomes: freedom from distant recurrence and any recurrence, and overall survival.
Findings were similar across most subgroups. But analyses suggested that women aged 50 years and younger having a recurrence score of 16-25 did fare better when they received chemotherapy. “Though exploratory from a statistical perspective, this is a highly clinically relevant observation,” he maintained. “It suggests ... that chemotherapy should be spared with caution in this subgroup, after a careful discussion of potential benefits and risks in a shared decision process.”
In other findings, analyses of the trial’s nonrandomized groups confirmed excellent outcomes among women with a low recurrence score (defined as 0-10) given endocrine therapy alone, and at the other end of the spectrum, need for a more aggressive approach, including chemotherapy, among women with a high recurrence score (defined as 26-100).
Ultimately, application of the recurrence score allowed 69% of the entire trial population to skip chemotherapy: all of those women with a score of 0-10 (16% of the trial population), those older than 50 years with a score of 11-25 (45%), and those aged 50 years or younger with a score of 11-15 (8%).
“Although this trial was designed in 2003, it was designed with the goal of addressing one of the themes at this 2018 meeting, expanding the reach of precision medicine,” Dr. Sparano pointed out. “It also embodies the core values of ASCO: By providing the highest level of evidence, it can have a direct and immediate impact on the care of our patients.”
An ongoing companion phase 3 trial, RxPONDER, is assessing the benefit of applying the recurrence score in women who are similar but instead have node-positive disease.
Tailoring treatment: ‘not too much and not too little’
“These are very important data because this is the most common form of breast cancer in the United States and other developed countries, and the most challenging decision we make with these patients is whether or not to recommend adjuvant chemotherapy with all of its side effects and with its potential benefits,” said ASCO Expert Harold Burstein, MD, PhD, FASCO. “The data provided here today from this massive NCI-sponsored trial show that the vast majority of women who have this test performed on their tumor can be told that they don’t need chemotherapy, and that can be said with tremendous confidence and reassurance.”
“This is not so much about de-escalation ... The goal of this study was not to just use less treatment, the goal was to tailor treatment – they chose the title very aptly, with the idea of saying some women are going to need more of one kind of therapy and less of another, and others will get a different treatment based on the biology of their tumor,” said Dr. Burstein, a medical oncologist at the Dana-Farber Cancer Institute and associate professor of medicine, Harvard Medical School, Boston.
“This is extraordinary data for breast cancer doctors and women who have breast cancer. It allows you to individualize treatment based on extraordinary science, which now has tremendous prospective validation,” he said. Overall, “women with breast cancer who are getting modern therapy are doing extraordinarily well, and this test shows us how to tailor that management so they get exactly the right amount of treatment – not too much and not too little.”
Study details
All of the women with hormone receptor–positive, HER2-negative, node-negative early-stage breast cancer enrolled in TAILORx met National Comprehensive Cancer Network guidelines for receiving adjuvant chemotherapy.
Roughly 69% had an intermediate recurrence score (11-25) and were randomized. All of the 17% having a low recurrence score (0-10) were given only endocrine therapy, and all of the 14% with a high recurrence score (26-100) were given both adjuvant chemotherapy and endocrine therapy.
Of note, the recurrence scores used to define midrange were adjusted downward from those conventionally used to account for exclusion of patients with higher-risk HER2-positive disease and to minimize potential for undertreatment, Dr. Sparano explained. “I think you will see changes in the near future as to how Genomic Health reports their results.”
Among the women with midrange scores who were randomized, the hazard ratio for invasive disease-free survival with endocrine therapy alone compared with chemotherapy plus endocrine therapy (1.08) fell well within the predefined hazard ratio for noninferiority (1.322). The 9-year rate of invasive disease–free survival was 83.3% with endocrine therapy and 84.3% with chemotherapy plus endocrine therapy.
The groups had similar rates of freedom from distant recurrence (94.5% vs. 95.0%; hazard ratio, 1.10; P = .48) and distant or locoregional recurrence (92.2% vs. 92.9%; hazard ratio, 1.11; P = .33), and similar overall survival (93.9% vs. 93.8%; hazard ratio for death, 0.99; P = .89).
In exploratory analyses, there was an interaction of age and recurrence score (P = .004) whereby women aged 50 or younger derived some benefit from chemotherapy if they had a recurrence score of 16-20 (9% fewer invasive disease–free survival events, including 2% fewer distant recurrences) or a recurrence score 21-25 (6% fewer invasive disease–free survival events, mainly distant recurrences). “This is information that could drive some younger women who have a recurrence score in this range to accept chemotherapy,” Dr. Sparano said.
The 9-year rate of distant recurrence averaged 5% among the women with midrange scores overall. It was just 3% among the women with a low recurrence score given endocrine therapy alone, but it was still 13% among the women with a high recurrence score despite receiving both endocrine therapy and chemotherapy. The last finding may “indicate the need to explore potentially more effective therapies in this setting,” he proposed.
Dr. Sparano disclosed that he has a consulting or advisory role with Genentech/Roche, Novartis, AstraZeneca, Celgene, Lilly, Celldex, Pfizer, Prescient Therapeutics, Juno Therapeutics, and Merrimack; has stock or other ownership interests with Metastat; and receives research funding (institutional) from Prescient Therapeutics, Deciphera, Genentech/Roche, Merck, Novartis, and Merrimack. This study received funding primarily from the National Cancer Institute, National Institutes of Health. Additional support was provided by the Breast Cancer Research Foundation, Komen Foundation, and U.S. Postal Service Breast Cancer Stamp.
SOURCE: Sparano et al. ASCO 2018 Abstract LBA1
CHICAGO – , sparing them adverse effects and preventing overtreatment, TAILORx trial results show.
The findings, which were reported in the plenary session at the annual meeting of the American Society of Clinical Oncology and simultaneously published in the New England Journal of Medicine, mark a major advance in precision medicine.
The recurrence score is known to be prognostic and to be predictive of benefit from adding chemotherapy to endocrine therapy, Dr. Sparano said. “But there was a major gap: There was uncertain benefit for patients who had a midrange score, about two-thirds of all patients who are treated.”
The phase 3 TAILORx trial registered 10,273 women with hormone receptor–positive, HER2-negative, node-negative early-stage breast cancer, making it the largest adjuvant breast cancer trial to date. Analyses focused on the 6,711 evaluable women with a midrange recurrence score (defined as 11 through 25 in the trial), who were randomized to receive endocrine therapy alone or adjuvant chemotherapy plus endocrine therapy, with a noninferiority design. Of note, contemporary drugs and regimens were used.
Results at a median follow-up of 7.5 years showed that the trial met its primary endpoint: The risk of invasive disease-free survival events (invasive disease recurrence, second primary cancer, or death) was not inferior for women given endocrine therapy alone compared with counterparts given chemotherapy plus endocrine therapy (hazard ratio, 1.08; P = .26), Dr. Sparano reported.
The groups were also on par, with absolute differences of no more than 1% between rates, with respect to a variety of other efficacy outcomes: freedom from distant recurrence and any recurrence, and overall survival.
Findings were similar across most subgroups. But analyses suggested that women aged 50 years and younger having a recurrence score of 16-25 did fare better when they received chemotherapy. “Though exploratory from a statistical perspective, this is a highly clinically relevant observation,” he maintained. “It suggests ... that chemotherapy should be spared with caution in this subgroup, after a careful discussion of potential benefits and risks in a shared decision process.”
In other findings, analyses of the trial’s nonrandomized groups confirmed excellent outcomes among women with a low recurrence score (defined as 0-10) given endocrine therapy alone, and at the other end of the spectrum, need for a more aggressive approach, including chemotherapy, among women with a high recurrence score (defined as 26-100).
Ultimately, application of the recurrence score allowed 69% of the entire trial population to skip chemotherapy: all of those women with a score of 0-10 (16% of the trial population), those older than 50 years with a score of 11-25 (45%), and those aged 50 years or younger with a score of 11-15 (8%).
“Although this trial was designed in 2003, it was designed with the goal of addressing one of the themes at this 2018 meeting, expanding the reach of precision medicine,” Dr. Sparano pointed out. “It also embodies the core values of ASCO: By providing the highest level of evidence, it can have a direct and immediate impact on the care of our patients.”
An ongoing companion phase 3 trial, RxPONDER, is assessing the benefit of applying the recurrence score in women who are similar but instead have node-positive disease.
Tailoring treatment: ‘not too much and not too little’
“These are very important data because this is the most common form of breast cancer in the United States and other developed countries, and the most challenging decision we make with these patients is whether or not to recommend adjuvant chemotherapy with all of its side effects and with its potential benefits,” said ASCO Expert Harold Burstein, MD, PhD, FASCO. “The data provided here today from this massive NCI-sponsored trial show that the vast majority of women who have this test performed on their tumor can be told that they don’t need chemotherapy, and that can be said with tremendous confidence and reassurance.”
“This is not so much about de-escalation ... The goal of this study was not to just use less treatment, the goal was to tailor treatment – they chose the title very aptly, with the idea of saying some women are going to need more of one kind of therapy and less of another, and others will get a different treatment based on the biology of their tumor,” said Dr. Burstein, a medical oncologist at the Dana-Farber Cancer Institute and associate professor of medicine, Harvard Medical School, Boston.
“This is extraordinary data for breast cancer doctors and women who have breast cancer. It allows you to individualize treatment based on extraordinary science, which now has tremendous prospective validation,” he said. Overall, “women with breast cancer who are getting modern therapy are doing extraordinarily well, and this test shows us how to tailor that management so they get exactly the right amount of treatment – not too much and not too little.”
Study details
All of the women with hormone receptor–positive, HER2-negative, node-negative early-stage breast cancer enrolled in TAILORx met National Comprehensive Cancer Network guidelines for receiving adjuvant chemotherapy.
Roughly 69% had an intermediate recurrence score (11-25) and were randomized. All of the 17% having a low recurrence score (0-10) were given only endocrine therapy, and all of the 14% with a high recurrence score (26-100) were given both adjuvant chemotherapy and endocrine therapy.
Of note, the recurrence scores used to define midrange were adjusted downward from those conventionally used to account for exclusion of patients with higher-risk HER2-positive disease and to minimize potential for undertreatment, Dr. Sparano explained. “I think you will see changes in the near future as to how Genomic Health reports their results.”
Among the women with midrange scores who were randomized, the hazard ratio for invasive disease-free survival with endocrine therapy alone compared with chemotherapy plus endocrine therapy (1.08) fell well within the predefined hazard ratio for noninferiority (1.322). The 9-year rate of invasive disease–free survival was 83.3% with endocrine therapy and 84.3% with chemotherapy plus endocrine therapy.
The groups had similar rates of freedom from distant recurrence (94.5% vs. 95.0%; hazard ratio, 1.10; P = .48) and distant or locoregional recurrence (92.2% vs. 92.9%; hazard ratio, 1.11; P = .33), and similar overall survival (93.9% vs. 93.8%; hazard ratio for death, 0.99; P = .89).
In exploratory analyses, there was an interaction of age and recurrence score (P = .004) whereby women aged 50 or younger derived some benefit from chemotherapy if they had a recurrence score of 16-20 (9% fewer invasive disease–free survival events, including 2% fewer distant recurrences) or a recurrence score 21-25 (6% fewer invasive disease–free survival events, mainly distant recurrences). “This is information that could drive some younger women who have a recurrence score in this range to accept chemotherapy,” Dr. Sparano said.
The 9-year rate of distant recurrence averaged 5% among the women with midrange scores overall. It was just 3% among the women with a low recurrence score given endocrine therapy alone, but it was still 13% among the women with a high recurrence score despite receiving both endocrine therapy and chemotherapy. The last finding may “indicate the need to explore potentially more effective therapies in this setting,” he proposed.
Dr. Sparano disclosed that he has a consulting or advisory role with Genentech/Roche, Novartis, AstraZeneca, Celgene, Lilly, Celldex, Pfizer, Prescient Therapeutics, Juno Therapeutics, and Merrimack; has stock or other ownership interests with Metastat; and receives research funding (institutional) from Prescient Therapeutics, Deciphera, Genentech/Roche, Merck, Novartis, and Merrimack. This study received funding primarily from the National Cancer Institute, National Institutes of Health. Additional support was provided by the Breast Cancer Research Foundation, Komen Foundation, and U.S. Postal Service Breast Cancer Stamp.
SOURCE: Sparano et al. ASCO 2018 Abstract LBA1
CHICAGO – , sparing them adverse effects and preventing overtreatment, TAILORx trial results show.
The findings, which were reported in the plenary session at the annual meeting of the American Society of Clinical Oncology and simultaneously published in the New England Journal of Medicine, mark a major advance in precision medicine.
The recurrence score is known to be prognostic and to be predictive of benefit from adding chemotherapy to endocrine therapy, Dr. Sparano said. “But there was a major gap: There was uncertain benefit for patients who had a midrange score, about two-thirds of all patients who are treated.”
The phase 3 TAILORx trial registered 10,273 women with hormone receptor–positive, HER2-negative, node-negative early-stage breast cancer, making it the largest adjuvant breast cancer trial to date. Analyses focused on the 6,711 evaluable women with a midrange recurrence score (defined as 11 through 25 in the trial), who were randomized to receive endocrine therapy alone or adjuvant chemotherapy plus endocrine therapy, with a noninferiority design. Of note, contemporary drugs and regimens were used.
Results at a median follow-up of 7.5 years showed that the trial met its primary endpoint: The risk of invasive disease-free survival events (invasive disease recurrence, second primary cancer, or death) was not inferior for women given endocrine therapy alone compared with counterparts given chemotherapy plus endocrine therapy (hazard ratio, 1.08; P = .26), Dr. Sparano reported.
The groups were also on par, with absolute differences of no more than 1% between rates, with respect to a variety of other efficacy outcomes: freedom from distant recurrence and any recurrence, and overall survival.
Findings were similar across most subgroups. But analyses suggested that women aged 50 years and younger having a recurrence score of 16-25 did fare better when they received chemotherapy. “Though exploratory from a statistical perspective, this is a highly clinically relevant observation,” he maintained. “It suggests ... that chemotherapy should be spared with caution in this subgroup, after a careful discussion of potential benefits and risks in a shared decision process.”
In other findings, analyses of the trial’s nonrandomized groups confirmed excellent outcomes among women with a low recurrence score (defined as 0-10) given endocrine therapy alone, and at the other end of the spectrum, need for a more aggressive approach, including chemotherapy, among women with a high recurrence score (defined as 26-100).
Ultimately, application of the recurrence score allowed 69% of the entire trial population to skip chemotherapy: all of those women with a score of 0-10 (16% of the trial population), those older than 50 years with a score of 11-25 (45%), and those aged 50 years or younger with a score of 11-15 (8%).
“Although this trial was designed in 2003, it was designed with the goal of addressing one of the themes at this 2018 meeting, expanding the reach of precision medicine,” Dr. Sparano pointed out. “It also embodies the core values of ASCO: By providing the highest level of evidence, it can have a direct and immediate impact on the care of our patients.”
An ongoing companion phase 3 trial, RxPONDER, is assessing the benefit of applying the recurrence score in women who are similar but instead have node-positive disease.
Tailoring treatment: ‘not too much and not too little’
“These are very important data because this is the most common form of breast cancer in the United States and other developed countries, and the most challenging decision we make with these patients is whether or not to recommend adjuvant chemotherapy with all of its side effects and with its potential benefits,” said ASCO Expert Harold Burstein, MD, PhD, FASCO. “The data provided here today from this massive NCI-sponsored trial show that the vast majority of women who have this test performed on their tumor can be told that they don’t need chemotherapy, and that can be said with tremendous confidence and reassurance.”
“This is not so much about de-escalation ... The goal of this study was not to just use less treatment, the goal was to tailor treatment – they chose the title very aptly, with the idea of saying some women are going to need more of one kind of therapy and less of another, and others will get a different treatment based on the biology of their tumor,” said Dr. Burstein, a medical oncologist at the Dana-Farber Cancer Institute and associate professor of medicine, Harvard Medical School, Boston.
“This is extraordinary data for breast cancer doctors and women who have breast cancer. It allows you to individualize treatment based on extraordinary science, which now has tremendous prospective validation,” he said. Overall, “women with breast cancer who are getting modern therapy are doing extraordinarily well, and this test shows us how to tailor that management so they get exactly the right amount of treatment – not too much and not too little.”
Study details
All of the women with hormone receptor–positive, HER2-negative, node-negative early-stage breast cancer enrolled in TAILORx met National Comprehensive Cancer Network guidelines for receiving adjuvant chemotherapy.
Roughly 69% had an intermediate recurrence score (11-25) and were randomized. All of the 17% having a low recurrence score (0-10) were given only endocrine therapy, and all of the 14% with a high recurrence score (26-100) were given both adjuvant chemotherapy and endocrine therapy.
Of note, the recurrence scores used to define midrange were adjusted downward from those conventionally used to account for exclusion of patients with higher-risk HER2-positive disease and to minimize potential for undertreatment, Dr. Sparano explained. “I think you will see changes in the near future as to how Genomic Health reports their results.”
Among the women with midrange scores who were randomized, the hazard ratio for invasive disease-free survival with endocrine therapy alone compared with chemotherapy plus endocrine therapy (1.08) fell well within the predefined hazard ratio for noninferiority (1.322). The 9-year rate of invasive disease–free survival was 83.3% with endocrine therapy and 84.3% with chemotherapy plus endocrine therapy.
The groups had similar rates of freedom from distant recurrence (94.5% vs. 95.0%; hazard ratio, 1.10; P = .48) and distant or locoregional recurrence (92.2% vs. 92.9%; hazard ratio, 1.11; P = .33), and similar overall survival (93.9% vs. 93.8%; hazard ratio for death, 0.99; P = .89).
In exploratory analyses, there was an interaction of age and recurrence score (P = .004) whereby women aged 50 or younger derived some benefit from chemotherapy if they had a recurrence score of 16-20 (9% fewer invasive disease–free survival events, including 2% fewer distant recurrences) or a recurrence score 21-25 (6% fewer invasive disease–free survival events, mainly distant recurrences). “This is information that could drive some younger women who have a recurrence score in this range to accept chemotherapy,” Dr. Sparano said.
The 9-year rate of distant recurrence averaged 5% among the women with midrange scores overall. It was just 3% among the women with a low recurrence score given endocrine therapy alone, but it was still 13% among the women with a high recurrence score despite receiving both endocrine therapy and chemotherapy. The last finding may “indicate the need to explore potentially more effective therapies in this setting,” he proposed.
Dr. Sparano disclosed that he has a consulting or advisory role with Genentech/Roche, Novartis, AstraZeneca, Celgene, Lilly, Celldex, Pfizer, Prescient Therapeutics, Juno Therapeutics, and Merrimack; has stock or other ownership interests with Metastat; and receives research funding (institutional) from Prescient Therapeutics, Deciphera, Genentech/Roche, Merck, Novartis, and Merrimack. This study received funding primarily from the National Cancer Institute, National Institutes of Health. Additional support was provided by the Breast Cancer Research Foundation, Komen Foundation, and U.S. Postal Service Breast Cancer Stamp.
SOURCE: Sparano et al. ASCO 2018 Abstract LBA1
REPORTING FROM ASCO 2018
Key clinical point: The majority of women with HR-positive, HER2-negative, node-negative early-stage breast cancer who have an intermediate recurrence score can safely skip adjuvant chemotherapy.
Major finding: Among women with an Oncotype DX Recurrence Score in the midrange (11-25), invasive disease–free survival with endocrine therapy alone was not inferior to that with chemotherapy plus endocrine therapy (hazard ratio, 1.08; P = .26).
Study details: A phase 3 trial among 10,273 women with HR-positive, HER2-negative, node-negative early-stage breast cancer, with a noninferiority randomized component among the 6,711 women with a midrange recurrence score (TAILORx trial).
Disclosures: Dr. Sparano disclosed that he has a consulting or advisory role with Genentech/Roche, Novartis, AstraZeneca, Celgene, Lilly, Celldex, Pfizer, Prescient Therapeutics, Juno Therapeutics, and Merrimack; has stock or other ownership interests with MetaStat; and receives research funding (institutional) from Prescient Therapeutics, Deciphera, Genentech/Roche, Merck, Novartis, and Merrimack. This study received funding primarily from the National Cancer Institute, National Institutes of Health. Additional support was provided by the Breast Cancer Research Foundation, Komen Foundation, and U.S. Postal Service Breast Cancer Stamp.
Source: Sparano et al. ASCO 2018 Abstract LBA1.
Red-Brown Plaque on the Leg
The Diagnosis: Wells Syndrome
A punch biopsy taken from the perimeter of the lesion demonstrated mild spongiosis overlying a dense nodular to diffuse infiltrate of lymphocytes, neutrophils, and numerous eosinophils, some involving underlying fat lobules (Figure, A and B). In some areas, eosinophilic degeneration of collagen bundles surrounded by a rim of histiocytes, "flame features," were observed (Figure C). The clinical and histological features were consistent with Wells syndrome (WS), also known as eosinophilic cellulitis. Given the localized mild nature of the disease, the patient was started on a midpotency topical corticosteroid.
Wells syndrome is a rare inflammatory condition characterized by clinical polymorphism, suggestive histologic findings, and a recurrent course.1,2 This condition is especially rare in children.3,4 Caputo et al1 described 7 variants in their case series of 19 patients: classic plaque-type variant (the most common clinical presentation in children); annular granuloma-like (the most common clinical presentation in adults); urticarialike; bullous; papulonodular; papulovesicular; and fixed drug eruption-like. Wells syndrome is thought to result from excess production of IL-5 in response to a hypersensitivity reaction to an exogenous or endogenous circulating antigen.3,4 Increased levels of IL-5 enhance eosinophil accumulation in the skin, degranulation, and subsequent tissue destruction.3,4 Reported triggers include insect bites, viral and bacterial infections, drug eruptions, recent vaccination, and paraphenylenediamine in henna tattoos.3-7 Additionally, WS has been reported in the setting of gastrointestinal pathologies, such as celiac disease and ulcerative colitis, and with asthma exacerbations.8,9 However, in half of pediatric cases, no trigger can be identified.7
Clinically, WS presents with pruritic, mildly tender plaques.7 Lesions may be localized or diffuse and range from mild annular or circinate plaques with infiltrated borders to cellulitic-appearing lesions that are occasionally associated with bullae.5,6 Patients often report prodromal symptoms of burning and pruritus.5,6 Lesions rapidly progress over 2 to 3 days, pass through a blue grayish discoloration phase, and gradually resolve over 2 to 8 weeks.5,6,10 Although patients generally heal without scarring, WS lesions have been described to resolve with atrophy and hyperpigmentation resembling morphea.5-7 Additionally, patients typically experience a relapsing remitting course over months to years with eventual spontaneous resolution.1,5 Patients also may experience systemic symptoms including fever, lymphadenopathy, and arthralgia, though they do not develop more widespread systemic manifestations.2,3,7
Diagnosis of WS is based on clinicopathologic correlation. Histopathology of WS lesions demonstrates 3 phases. The acute phase demonstrates edema of the superficial and mid dermis with a dense dermal eosinophilic infiltrate.1,6,10 The subacute granulomatous phase demonstrates flame figures in the dermis.1,2,6,7,10 Flame figures consist of palisading groups of eosinophils and histiocytes around a core of degenerating basophilic collagen bundles associated with major basic protein.1,2,6,7,10 Finally, in the resolution phase, eosinophils gradually disappear while histiocytes and giant cells persist, forming microgranulomas.1,2,10 Notably, no vasculitis is observed and direct immunofluorescence is negative.3,7 Although flame figures are suggestive of WS, they are not pathognomonic and are observed in other conditions including Churg-Strauss syndrome, parasitic and fungal infections, herpes gestationis, bullous pemphigoid, and follicular mucinosis.2,5
Wells syndrome is a self-resolving and benign condition.1,10 Physicians are recommended to gather a complete history including review of medications and vaccinations; a history of insect bites, infections, and asthma; laboratory workup consisting of a complete blood cell count with differential and stool samples for ova and parasites; and a skin biopsy if the diagnosis is unclear.7 Identification and treatment of underlying causes often results in resolution.6 Systemic corticosteroids frequently are used in both adult and pediatric patients, though practitioners should consider alternative treatments when recurrences occur to avoid steroid side effects.3,6 Midpotency topical corticosteroids present a safe alternative to systemic corticosteroids in the pediatric population, especially in cases of localized WS without systemic symptoms.3 Other medications reported in the literature include cyclosporine, dapsone, antimalarial medications, and azathioprine.6 Despite appropriate therapy, patients and physicians should anticipate recurrence over months to years.1,6
- Caputo R, Marzano AV, Vezzoli P, et al. Wells syndrome in adults and children: a report of 19 cases. Arch Dermatol. 2006;142:1157-1161.
- Smith SM, Kiracofe EA, Clark LN, et al. Idiopathic hypereosinophilic syndrome with cutaneous manifestations and flame figures: a spectrum of eosinophilic dermatoses whose features overlap with Wells' syndrome. Am J Dermatopathol. 2015;37:910-914.
- Gilliam AE, Bruckner AL, Howard RM, et al. Bullous "cellulitis" with eosinophilia: case report and review of Wells' syndrome in childhood. Pediatrics. 2005;116:E149-E155.
- Nacaroglu HT, Celegen M, Karkıner CS, et al. Eosinophilic cellulitis (Wells' syndrome) caused by a temporary henna tattoo. Postepy Dermatol Alergol. 2014;31:322-324.
- Heelan K, Ryan JF, Shear NH, et al. Wells syndrome (eosinophilic cellulitis): proposed diagnostic criteria and a literature review of the drug-induced variant. J Dermatol Case Rep. 2013;7:113-120.
- Sinno H, Lacroix JP, Lee J, et al. Diagnosis and management of eosinophilic cellulitis (Wells' syndrome): a case series and literature review. Can J Plast Surg. 2012;20:91-97.
- Cherng E, McClung AA, Rosenthal HM, et al. Wells' syndrome associated with parvovirus in a 5-year-old boy. Pediatr Dermatol. 2012;29:762-764.
- Eren M, Açikalin M. A case report of Wells' syndrome in a celiac patient. Turk J Gastroenterol. 2010;21:172-174.
- Cruz MJ, Mota A, Baudrier T, et al. Recurrent Wells' syndrome associated with allergic asthma exacerbation. Cutan Ocul Toxicol. 2012;31:154-156.
- Van der Straaten S, Wojciechowski M, Salgado R, et al. Eosinophilic cellulitis or Wells' syndrome in a 6-year-old child. Eur J Pediatr. 2006;165:197-198.
The Diagnosis: Wells Syndrome
A punch biopsy taken from the perimeter of the lesion demonstrated mild spongiosis overlying a dense nodular to diffuse infiltrate of lymphocytes, neutrophils, and numerous eosinophils, some involving underlying fat lobules (Figure, A and B). In some areas, eosinophilic degeneration of collagen bundles surrounded by a rim of histiocytes, "flame features," were observed (Figure C). The clinical and histological features were consistent with Wells syndrome (WS), also known as eosinophilic cellulitis. Given the localized mild nature of the disease, the patient was started on a midpotency topical corticosteroid.
Wells syndrome is a rare inflammatory condition characterized by clinical polymorphism, suggestive histologic findings, and a recurrent course.1,2 This condition is especially rare in children.3,4 Caputo et al1 described 7 variants in their case series of 19 patients: classic plaque-type variant (the most common clinical presentation in children); annular granuloma-like (the most common clinical presentation in adults); urticarialike; bullous; papulonodular; papulovesicular; and fixed drug eruption-like. Wells syndrome is thought to result from excess production of IL-5 in response to a hypersensitivity reaction to an exogenous or endogenous circulating antigen.3,4 Increased levels of IL-5 enhance eosinophil accumulation in the skin, degranulation, and subsequent tissue destruction.3,4 Reported triggers include insect bites, viral and bacterial infections, drug eruptions, recent vaccination, and paraphenylenediamine in henna tattoos.3-7 Additionally, WS has been reported in the setting of gastrointestinal pathologies, such as celiac disease and ulcerative colitis, and with asthma exacerbations.8,9 However, in half of pediatric cases, no trigger can be identified.7
Clinically, WS presents with pruritic, mildly tender plaques.7 Lesions may be localized or diffuse and range from mild annular or circinate plaques with infiltrated borders to cellulitic-appearing lesions that are occasionally associated with bullae.5,6 Patients often report prodromal symptoms of burning and pruritus.5,6 Lesions rapidly progress over 2 to 3 days, pass through a blue grayish discoloration phase, and gradually resolve over 2 to 8 weeks.5,6,10 Although patients generally heal without scarring, WS lesions have been described to resolve with atrophy and hyperpigmentation resembling morphea.5-7 Additionally, patients typically experience a relapsing remitting course over months to years with eventual spontaneous resolution.1,5 Patients also may experience systemic symptoms including fever, lymphadenopathy, and arthralgia, though they do not develop more widespread systemic manifestations.2,3,7
Diagnosis of WS is based on clinicopathologic correlation. Histopathology of WS lesions demonstrates 3 phases. The acute phase demonstrates edema of the superficial and mid dermis with a dense dermal eosinophilic infiltrate.1,6,10 The subacute granulomatous phase demonstrates flame figures in the dermis.1,2,6,7,10 Flame figures consist of palisading groups of eosinophils and histiocytes around a core of degenerating basophilic collagen bundles associated with major basic protein.1,2,6,7,10 Finally, in the resolution phase, eosinophils gradually disappear while histiocytes and giant cells persist, forming microgranulomas.1,2,10 Notably, no vasculitis is observed and direct immunofluorescence is negative.3,7 Although flame figures are suggestive of WS, they are not pathognomonic and are observed in other conditions including Churg-Strauss syndrome, parasitic and fungal infections, herpes gestationis, bullous pemphigoid, and follicular mucinosis.2,5
Wells syndrome is a self-resolving and benign condition.1,10 Physicians are recommended to gather a complete history including review of medications and vaccinations; a history of insect bites, infections, and asthma; laboratory workup consisting of a complete blood cell count with differential and stool samples for ova and parasites; and a skin biopsy if the diagnosis is unclear.7 Identification and treatment of underlying causes often results in resolution.6 Systemic corticosteroids frequently are used in both adult and pediatric patients, though practitioners should consider alternative treatments when recurrences occur to avoid steroid side effects.3,6 Midpotency topical corticosteroids present a safe alternative to systemic corticosteroids in the pediatric population, especially in cases of localized WS without systemic symptoms.3 Other medications reported in the literature include cyclosporine, dapsone, antimalarial medications, and azathioprine.6 Despite appropriate therapy, patients and physicians should anticipate recurrence over months to years.1,6
The Diagnosis: Wells Syndrome
A punch biopsy taken from the perimeter of the lesion demonstrated mild spongiosis overlying a dense nodular to diffuse infiltrate of lymphocytes, neutrophils, and numerous eosinophils, some involving underlying fat lobules (Figure, A and B). In some areas, eosinophilic degeneration of collagen bundles surrounded by a rim of histiocytes, "flame features," were observed (Figure C). The clinical and histological features were consistent with Wells syndrome (WS), also known as eosinophilic cellulitis. Given the localized mild nature of the disease, the patient was started on a midpotency topical corticosteroid.
Wells syndrome is a rare inflammatory condition characterized by clinical polymorphism, suggestive histologic findings, and a recurrent course.1,2 This condition is especially rare in children.3,4 Caputo et al1 described 7 variants in their case series of 19 patients: classic plaque-type variant (the most common clinical presentation in children); annular granuloma-like (the most common clinical presentation in adults); urticarialike; bullous; papulonodular; papulovesicular; and fixed drug eruption-like. Wells syndrome is thought to result from excess production of IL-5 in response to a hypersensitivity reaction to an exogenous or endogenous circulating antigen.3,4 Increased levels of IL-5 enhance eosinophil accumulation in the skin, degranulation, and subsequent tissue destruction.3,4 Reported triggers include insect bites, viral and bacterial infections, drug eruptions, recent vaccination, and paraphenylenediamine in henna tattoos.3-7 Additionally, WS has been reported in the setting of gastrointestinal pathologies, such as celiac disease and ulcerative colitis, and with asthma exacerbations.8,9 However, in half of pediatric cases, no trigger can be identified.7
Clinically, WS presents with pruritic, mildly tender plaques.7 Lesions may be localized or diffuse and range from mild annular or circinate plaques with infiltrated borders to cellulitic-appearing lesions that are occasionally associated with bullae.5,6 Patients often report prodromal symptoms of burning and pruritus.5,6 Lesions rapidly progress over 2 to 3 days, pass through a blue grayish discoloration phase, and gradually resolve over 2 to 8 weeks.5,6,10 Although patients generally heal without scarring, WS lesions have been described to resolve with atrophy and hyperpigmentation resembling morphea.5-7 Additionally, patients typically experience a relapsing remitting course over months to years with eventual spontaneous resolution.1,5 Patients also may experience systemic symptoms including fever, lymphadenopathy, and arthralgia, though they do not develop more widespread systemic manifestations.2,3,7
Diagnosis of WS is based on clinicopathologic correlation. Histopathology of WS lesions demonstrates 3 phases. The acute phase demonstrates edema of the superficial and mid dermis with a dense dermal eosinophilic infiltrate.1,6,10 The subacute granulomatous phase demonstrates flame figures in the dermis.1,2,6,7,10 Flame figures consist of palisading groups of eosinophils and histiocytes around a core of degenerating basophilic collagen bundles associated with major basic protein.1,2,6,7,10 Finally, in the resolution phase, eosinophils gradually disappear while histiocytes and giant cells persist, forming microgranulomas.1,2,10 Notably, no vasculitis is observed and direct immunofluorescence is negative.3,7 Although flame figures are suggestive of WS, they are not pathognomonic and are observed in other conditions including Churg-Strauss syndrome, parasitic and fungal infections, herpes gestationis, bullous pemphigoid, and follicular mucinosis.2,5
Wells syndrome is a self-resolving and benign condition.1,10 Physicians are recommended to gather a complete history including review of medications and vaccinations; a history of insect bites, infections, and asthma; laboratory workup consisting of a complete blood cell count with differential and stool samples for ova and parasites; and a skin biopsy if the diagnosis is unclear.7 Identification and treatment of underlying causes often results in resolution.6 Systemic corticosteroids frequently are used in both adult and pediatric patients, though practitioners should consider alternative treatments when recurrences occur to avoid steroid side effects.3,6 Midpotency topical corticosteroids present a safe alternative to systemic corticosteroids in the pediatric population, especially in cases of localized WS without systemic symptoms.3 Other medications reported in the literature include cyclosporine, dapsone, antimalarial medications, and azathioprine.6 Despite appropriate therapy, patients and physicians should anticipate recurrence over months to years.1,6
- Caputo R, Marzano AV, Vezzoli P, et al. Wells syndrome in adults and children: a report of 19 cases. Arch Dermatol. 2006;142:1157-1161.
- Smith SM, Kiracofe EA, Clark LN, et al. Idiopathic hypereosinophilic syndrome with cutaneous manifestations and flame figures: a spectrum of eosinophilic dermatoses whose features overlap with Wells' syndrome. Am J Dermatopathol. 2015;37:910-914.
- Gilliam AE, Bruckner AL, Howard RM, et al. Bullous "cellulitis" with eosinophilia: case report and review of Wells' syndrome in childhood. Pediatrics. 2005;116:E149-E155.
- Nacaroglu HT, Celegen M, Karkıner CS, et al. Eosinophilic cellulitis (Wells' syndrome) caused by a temporary henna tattoo. Postepy Dermatol Alergol. 2014;31:322-324.
- Heelan K, Ryan JF, Shear NH, et al. Wells syndrome (eosinophilic cellulitis): proposed diagnostic criteria and a literature review of the drug-induced variant. J Dermatol Case Rep. 2013;7:113-120.
- Sinno H, Lacroix JP, Lee J, et al. Diagnosis and management of eosinophilic cellulitis (Wells' syndrome): a case series and literature review. Can J Plast Surg. 2012;20:91-97.
- Cherng E, McClung AA, Rosenthal HM, et al. Wells' syndrome associated with parvovirus in a 5-year-old boy. Pediatr Dermatol. 2012;29:762-764.
- Eren M, Açikalin M. A case report of Wells' syndrome in a celiac patient. Turk J Gastroenterol. 2010;21:172-174.
- Cruz MJ, Mota A, Baudrier T, et al. Recurrent Wells' syndrome associated with allergic asthma exacerbation. Cutan Ocul Toxicol. 2012;31:154-156.
- Van der Straaten S, Wojciechowski M, Salgado R, et al. Eosinophilic cellulitis or Wells' syndrome in a 6-year-old child. Eur J Pediatr. 2006;165:197-198.
- Caputo R, Marzano AV, Vezzoli P, et al. Wells syndrome in adults and children: a report of 19 cases. Arch Dermatol. 2006;142:1157-1161.
- Smith SM, Kiracofe EA, Clark LN, et al. Idiopathic hypereosinophilic syndrome with cutaneous manifestations and flame figures: a spectrum of eosinophilic dermatoses whose features overlap with Wells' syndrome. Am J Dermatopathol. 2015;37:910-914.
- Gilliam AE, Bruckner AL, Howard RM, et al. Bullous "cellulitis" with eosinophilia: case report and review of Wells' syndrome in childhood. Pediatrics. 2005;116:E149-E155.
- Nacaroglu HT, Celegen M, Karkıner CS, et al. Eosinophilic cellulitis (Wells' syndrome) caused by a temporary henna tattoo. Postepy Dermatol Alergol. 2014;31:322-324.
- Heelan K, Ryan JF, Shear NH, et al. Wells syndrome (eosinophilic cellulitis): proposed diagnostic criteria and a literature review of the drug-induced variant. J Dermatol Case Rep. 2013;7:113-120.
- Sinno H, Lacroix JP, Lee J, et al. Diagnosis and management of eosinophilic cellulitis (Wells' syndrome): a case series and literature review. Can J Plast Surg. 2012;20:91-97.
- Cherng E, McClung AA, Rosenthal HM, et al. Wells' syndrome associated with parvovirus in a 5-year-old boy. Pediatr Dermatol. 2012;29:762-764.
- Eren M, Açikalin M. A case report of Wells' syndrome in a celiac patient. Turk J Gastroenterol. 2010;21:172-174.
- Cruz MJ, Mota A, Baudrier T, et al. Recurrent Wells' syndrome associated with allergic asthma exacerbation. Cutan Ocul Toxicol. 2012;31:154-156.
- Van der Straaten S, Wojciechowski M, Salgado R, et al. Eosinophilic cellulitis or Wells' syndrome in a 6-year-old child. Eur J Pediatr. 2006;165:197-198.
A healthy 7-year-old boy presented with an enlarging hyperpigmented plaque on the anterior aspect of the lower left leg of 2 months' duration. His mother reported onset following a mosquito bite. Clotrimazole was used without improvement. His mother denied recent travel, similar lesions in close contacts, fever, asthma, and arthralgia. Physical examination revealed a 5.2 ×3-cm nonscaly, red-brown, ovoid, thin plaque with a slightly raised border.
A Peek at Our June 2018 Issue
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Antidepressants and children
Does Sleep Help Protect Against Amyloid Plaques?
A cardinal feature of Alzheimer disease is the way beta-amyloid—generally a metabolic waste product—clumps to form amyloid plaques. Now a National Institute on Alcohol Abuse and Alcoholism (NIAAA) study indicates that sleep may be an important link in that process. The researchers found that losing just 1 night of sleep led to an immediate increase in beta-amyloid.
Researchers used positron emission tomography to scan the brains of 20 healthy volunteers, aged 22 to 72 years, after a night of rested sleep and after being awake for 31 hours. They found beta-amyloid increases of about 5% after the sleep deprivation in the thalamus and hippocampus, regions especially vulnerable to damage in the early stages of Alzheimer disease, the researchers say. The study participants with larger increases also reported worse mood after sleep deprivation.
It is important to note, the researchers add, that the link between sleep disorders and Alzheimer risk is considered by many scientists to be bidirectional, since elevated beta-amyloid also may cause sleep disturbance.
It is unknown, the researchers say, whether the increase in beta-amyloid in the study participants would subside after a night of rest.
A cardinal feature of Alzheimer disease is the way beta-amyloid—generally a metabolic waste product—clumps to form amyloid plaques. Now a National Institute on Alcohol Abuse and Alcoholism (NIAAA) study indicates that sleep may be an important link in that process. The researchers found that losing just 1 night of sleep led to an immediate increase in beta-amyloid.
Researchers used positron emission tomography to scan the brains of 20 healthy volunteers, aged 22 to 72 years, after a night of rested sleep and after being awake for 31 hours. They found beta-amyloid increases of about 5% after the sleep deprivation in the thalamus and hippocampus, regions especially vulnerable to damage in the early stages of Alzheimer disease, the researchers say. The study participants with larger increases also reported worse mood after sleep deprivation.
It is important to note, the researchers add, that the link between sleep disorders and Alzheimer risk is considered by many scientists to be bidirectional, since elevated beta-amyloid also may cause sleep disturbance.
It is unknown, the researchers say, whether the increase in beta-amyloid in the study participants would subside after a night of rest.
A cardinal feature of Alzheimer disease is the way beta-amyloid—generally a metabolic waste product—clumps to form amyloid plaques. Now a National Institute on Alcohol Abuse and Alcoholism (NIAAA) study indicates that sleep may be an important link in that process. The researchers found that losing just 1 night of sleep led to an immediate increase in beta-amyloid.
Researchers used positron emission tomography to scan the brains of 20 healthy volunteers, aged 22 to 72 years, after a night of rested sleep and after being awake for 31 hours. They found beta-amyloid increases of about 5% after the sleep deprivation in the thalamus and hippocampus, regions especially vulnerable to damage in the early stages of Alzheimer disease, the researchers say. The study participants with larger increases also reported worse mood after sleep deprivation.
It is important to note, the researchers add, that the link between sleep disorders and Alzheimer risk is considered by many scientists to be bidirectional, since elevated beta-amyloid also may cause sleep disturbance.
It is unknown, the researchers say, whether the increase in beta-amyloid in the study participants would subside after a night of rest.
Single-agent acalabrutinib ‘impressive’ in patients with WM
CHICAGO—Acalabrutinib monotherapy was highly effective in Waldenström’s macroglobulinemia (WM) in a phase 2 study, investigator Roger Owen, MD, reported at the 2018 ASCO Annual Meeting.
The BTK inhibitor was effective in both treatment-naïve and relapsed/refractory patients, with overall response rates for both groups in excess of 90%, and “amazing” major response rates—partial response or better—of approximately 80%, Dr Owen said.
Dr Owen, of the St James's Institute of Oncology, Leeds Teaching Hospitals NHS Trust in Leeds, UK, reported the findings as abstract 7501.*
Durations of response were excellent, according to Dr Owen, who also reported 2-year progression-free survival of 90% in treatment-naïve patients and 82% in relapsed/refractory patients.
The safety profile was favorable, with most adverse events of low grade, and a very limited number of dropouts due to adverse events, according to the investigator.
“I think this study clearly demonstrates the highly effective nature of acalabrutinib in Waldenström’s macroglobulinemia,” Dr Owen stated.
Acalabrutinib is a selective BTK inhibitor with minimal off-target activity, he said. The BTK inhibitor ibrutinib also has demonstrated activity in Waldenström’s, but has been associated with toxicities such as atrial fibrillation and bleeding, he noted.
In this phase 2 acalabrutinib study (NCT02180724), which included 14 treatment-naïve and 92 relapsed/refractory patients, atrial fibrillation occurred in 5 patients. However, 4 of those cases were grade 1-2, and only one was grade 3, according to Dr Owen.
Investigators observed grade 3 hypertension in 3 relapsed/refractory patients.
Bleeding events occurred in more than half of patients, though only 3 of those events were grade 3, and no patient discontinued treatment due to a bleeding episode.
These efficacy results are “impressive,” and the fact that very few cardiac events were seen is important, said Bruce D. Cheson, MD, of Georgetown University Medical Center in Washington, DC.
Dr Cheson commented on the acalabrutinib results in his presentation during ASCO on non-chemotherapy treatments for lymphoid malignancies.
“One can construct a non-chemo algorithm now for Waldenström’s, for patients who are MYD88 mutated, which is more than 90% of patients,” he said. “Right now ibrutinib, and perhaps in the future acalabrutinib, can be the initial therapy with or without rituximab based on the results of ongoing trials.”
However, single non-chemotherapy agents will not be sufficient to achieve cure of lymphoid malignancies, Dr Cheson added.
“We need to carefully develop rational combinations, identifying biomarkers for response, for resistance, for toxicity,” he said.
The study was sponsored by Acerta Pharma BV.
*Data presented at the meeting differ from the abstract.
CHICAGO—Acalabrutinib monotherapy was highly effective in Waldenström’s macroglobulinemia (WM) in a phase 2 study, investigator Roger Owen, MD, reported at the 2018 ASCO Annual Meeting.
The BTK inhibitor was effective in both treatment-naïve and relapsed/refractory patients, with overall response rates for both groups in excess of 90%, and “amazing” major response rates—partial response or better—of approximately 80%, Dr Owen said.
Dr Owen, of the St James's Institute of Oncology, Leeds Teaching Hospitals NHS Trust in Leeds, UK, reported the findings as abstract 7501.*
Durations of response were excellent, according to Dr Owen, who also reported 2-year progression-free survival of 90% in treatment-naïve patients and 82% in relapsed/refractory patients.
The safety profile was favorable, with most adverse events of low grade, and a very limited number of dropouts due to adverse events, according to the investigator.
“I think this study clearly demonstrates the highly effective nature of acalabrutinib in Waldenström’s macroglobulinemia,” Dr Owen stated.
Acalabrutinib is a selective BTK inhibitor with minimal off-target activity, he said. The BTK inhibitor ibrutinib also has demonstrated activity in Waldenström’s, but has been associated with toxicities such as atrial fibrillation and bleeding, he noted.
In this phase 2 acalabrutinib study (NCT02180724), which included 14 treatment-naïve and 92 relapsed/refractory patients, atrial fibrillation occurred in 5 patients. However, 4 of those cases were grade 1-2, and only one was grade 3, according to Dr Owen.
Investigators observed grade 3 hypertension in 3 relapsed/refractory patients.
Bleeding events occurred in more than half of patients, though only 3 of those events were grade 3, and no patient discontinued treatment due to a bleeding episode.
These efficacy results are “impressive,” and the fact that very few cardiac events were seen is important, said Bruce D. Cheson, MD, of Georgetown University Medical Center in Washington, DC.
Dr Cheson commented on the acalabrutinib results in his presentation during ASCO on non-chemotherapy treatments for lymphoid malignancies.
“One can construct a non-chemo algorithm now for Waldenström’s, for patients who are MYD88 mutated, which is more than 90% of patients,” he said. “Right now ibrutinib, and perhaps in the future acalabrutinib, can be the initial therapy with or without rituximab based on the results of ongoing trials.”
However, single non-chemotherapy agents will not be sufficient to achieve cure of lymphoid malignancies, Dr Cheson added.
“We need to carefully develop rational combinations, identifying biomarkers for response, for resistance, for toxicity,” he said.
The study was sponsored by Acerta Pharma BV.
*Data presented at the meeting differ from the abstract.
CHICAGO—Acalabrutinib monotherapy was highly effective in Waldenström’s macroglobulinemia (WM) in a phase 2 study, investigator Roger Owen, MD, reported at the 2018 ASCO Annual Meeting.
The BTK inhibitor was effective in both treatment-naïve and relapsed/refractory patients, with overall response rates for both groups in excess of 90%, and “amazing” major response rates—partial response or better—of approximately 80%, Dr Owen said.
Dr Owen, of the St James's Institute of Oncology, Leeds Teaching Hospitals NHS Trust in Leeds, UK, reported the findings as abstract 7501.*
Durations of response were excellent, according to Dr Owen, who also reported 2-year progression-free survival of 90% in treatment-naïve patients and 82% in relapsed/refractory patients.
The safety profile was favorable, with most adverse events of low grade, and a very limited number of dropouts due to adverse events, according to the investigator.
“I think this study clearly demonstrates the highly effective nature of acalabrutinib in Waldenström’s macroglobulinemia,” Dr Owen stated.
Acalabrutinib is a selective BTK inhibitor with minimal off-target activity, he said. The BTK inhibitor ibrutinib also has demonstrated activity in Waldenström’s, but has been associated with toxicities such as atrial fibrillation and bleeding, he noted.
In this phase 2 acalabrutinib study (NCT02180724), which included 14 treatment-naïve and 92 relapsed/refractory patients, atrial fibrillation occurred in 5 patients. However, 4 of those cases were grade 1-2, and only one was grade 3, according to Dr Owen.
Investigators observed grade 3 hypertension in 3 relapsed/refractory patients.
Bleeding events occurred in more than half of patients, though only 3 of those events were grade 3, and no patient discontinued treatment due to a bleeding episode.
These efficacy results are “impressive,” and the fact that very few cardiac events were seen is important, said Bruce D. Cheson, MD, of Georgetown University Medical Center in Washington, DC.
Dr Cheson commented on the acalabrutinib results in his presentation during ASCO on non-chemotherapy treatments for lymphoid malignancies.
“One can construct a non-chemo algorithm now for Waldenström’s, for patients who are MYD88 mutated, which is more than 90% of patients,” he said. “Right now ibrutinib, and perhaps in the future acalabrutinib, can be the initial therapy with or without rituximab based on the results of ongoing trials.”
However, single non-chemotherapy agents will not be sufficient to achieve cure of lymphoid malignancies, Dr Cheson added.
“We need to carefully develop rational combinations, identifying biomarkers for response, for resistance, for toxicity,” he said.
The study was sponsored by Acerta Pharma BV.
*Data presented at the meeting differ from the abstract.
Once-weekly carfilzomib combo improves PFS in R/R MM
CHICAGO—A once-weekly regimen of carfilzomib plus dexamethasone shows a favorable benefit-risk profile for patients with relapsed or refractory (R/R) multiple myeloma (MM), according to a new study.
“The more convenient dosing schedule can improve access to an efficacious therapy for patients unable to make twice-weekly visits to the clinic,” said investigator Maria-Victoria Mateos, MD, of the Hospital Clinico Universitario de Salamanca-IBSAL in Salamanca, Spain.
Dr Mateos presented results of the randomized, phase 3 study (abstract 8000) at the 2018 ASCO Annual Meeting. The results were also published in The Lancet.
Twice-weekly carfilzomib at 27 mg/m2 is approved as a single agent and in combination with lenalidomide or dexamethasone for the treatment of relapsed/refractory MM.
To develop a more convenient carfilzomib regimen, once-weekly carfilzomib plus dexamethasone was assessed in the phase 1/2 CHAMPION-1 study, showing good response rates (77%) and a median PFS of 12.6 months.
At ASCO, Dr Mateos presented the results from the pre-planned interim analysis of the phase 3 ARROW study (NCT02412878), comparing the two-drug regimen once-weekly vs twice-weekly.
Study design
The 478 patients, median age 66 years, had 2 to 3 prior therapies and prior exposure to a proteasome inhibitor and an immunomodulatory agent. Baseline characteristics were generally balanced, she said.
Investigators randomized patients to receive either once- or twice-weekly carfilzomib plus dexamethasone.
The once-weekly group received carfilzomib 20 mg/m2 intravenously on day 1 of cycle 1 and 70 mg/m2 on days 1, 8, and 15 of all subsequent cycles.
The twice-weekly group received the same carfilzomib dose on day 1, cycle 1 and 27 mg/m2 on days 8, 9, 15, and 16 thereafter. All patients received dexamethasone at 40 mg on days 1, 8, 15 (all cycles), and day 22 (cycles 1–9 only).
The primary endpoint was progression-free survival (PFS). Secondary endpoints were overall response rate, overall survival, safety, and pharmacokinetics.
Results
The study met the primary endpoint of PFS, with a median PFS for the once-weekly dose of 11.2 months and 7.6 months for the twice-weekly dose.
In addition, “patients who received once-weekly carfilzomib plus dexamethasone achieved a statistically significant higher overall response rate (62.9%) than patients who received the twice-weekly dose (40.8%),” Dr Mateos said.
Similarly, more patients achieved a complete response or better (7.1%) with the once-weekly dose than the twice-weekly dose (1.7%).
Safety
The overall safety profile was comparable between the 2 treatment groups and no new safety risks were identified.
Grade 3 or higher adverse events occurred in 67.6% (once-weekly) and 61.7% (twice-weekly) of patients.
Treatment-related grade 5 adverse events occurred in 5 patients (2.1%) in the once-weekly group and in 2 patients (0.9%) in the twice-weekly group.
The incidence of grade 3 or higher hypertension and cardiac failure was similar in both groups.
“Exposure-adjusted incidence of grade 3 or higher adverse events was slightly higher in the once-weekly vs the twice-weekly group,” Dr Mateos explained, “but the exposure-adjusted incidence for severe adverse events and adverse events leading to discontinuation of carfilzomib or death were similar between the treatment groups,” she said.
The ARROW study was supported by Amgen Inc.
CHICAGO—A once-weekly regimen of carfilzomib plus dexamethasone shows a favorable benefit-risk profile for patients with relapsed or refractory (R/R) multiple myeloma (MM), according to a new study.
“The more convenient dosing schedule can improve access to an efficacious therapy for patients unable to make twice-weekly visits to the clinic,” said investigator Maria-Victoria Mateos, MD, of the Hospital Clinico Universitario de Salamanca-IBSAL in Salamanca, Spain.
Dr Mateos presented results of the randomized, phase 3 study (abstract 8000) at the 2018 ASCO Annual Meeting. The results were also published in The Lancet.
Twice-weekly carfilzomib at 27 mg/m2 is approved as a single agent and in combination with lenalidomide or dexamethasone for the treatment of relapsed/refractory MM.
To develop a more convenient carfilzomib regimen, once-weekly carfilzomib plus dexamethasone was assessed in the phase 1/2 CHAMPION-1 study, showing good response rates (77%) and a median PFS of 12.6 months.
At ASCO, Dr Mateos presented the results from the pre-planned interim analysis of the phase 3 ARROW study (NCT02412878), comparing the two-drug regimen once-weekly vs twice-weekly.
Study design
The 478 patients, median age 66 years, had 2 to 3 prior therapies and prior exposure to a proteasome inhibitor and an immunomodulatory agent. Baseline characteristics were generally balanced, she said.
Investigators randomized patients to receive either once- or twice-weekly carfilzomib plus dexamethasone.
The once-weekly group received carfilzomib 20 mg/m2 intravenously on day 1 of cycle 1 and 70 mg/m2 on days 1, 8, and 15 of all subsequent cycles.
The twice-weekly group received the same carfilzomib dose on day 1, cycle 1 and 27 mg/m2 on days 8, 9, 15, and 16 thereafter. All patients received dexamethasone at 40 mg on days 1, 8, 15 (all cycles), and day 22 (cycles 1–9 only).
The primary endpoint was progression-free survival (PFS). Secondary endpoints were overall response rate, overall survival, safety, and pharmacokinetics.
Results
The study met the primary endpoint of PFS, with a median PFS for the once-weekly dose of 11.2 months and 7.6 months for the twice-weekly dose.
In addition, “patients who received once-weekly carfilzomib plus dexamethasone achieved a statistically significant higher overall response rate (62.9%) than patients who received the twice-weekly dose (40.8%),” Dr Mateos said.
Similarly, more patients achieved a complete response or better (7.1%) with the once-weekly dose than the twice-weekly dose (1.7%).
Safety
The overall safety profile was comparable between the 2 treatment groups and no new safety risks were identified.
Grade 3 or higher adverse events occurred in 67.6% (once-weekly) and 61.7% (twice-weekly) of patients.
Treatment-related grade 5 adverse events occurred in 5 patients (2.1%) in the once-weekly group and in 2 patients (0.9%) in the twice-weekly group.
The incidence of grade 3 or higher hypertension and cardiac failure was similar in both groups.
“Exposure-adjusted incidence of grade 3 or higher adverse events was slightly higher in the once-weekly vs the twice-weekly group,” Dr Mateos explained, “but the exposure-adjusted incidence for severe adverse events and adverse events leading to discontinuation of carfilzomib or death were similar between the treatment groups,” she said.
The ARROW study was supported by Amgen Inc.
CHICAGO—A once-weekly regimen of carfilzomib plus dexamethasone shows a favorable benefit-risk profile for patients with relapsed or refractory (R/R) multiple myeloma (MM), according to a new study.
“The more convenient dosing schedule can improve access to an efficacious therapy for patients unable to make twice-weekly visits to the clinic,” said investigator Maria-Victoria Mateos, MD, of the Hospital Clinico Universitario de Salamanca-IBSAL in Salamanca, Spain.
Dr Mateos presented results of the randomized, phase 3 study (abstract 8000) at the 2018 ASCO Annual Meeting. The results were also published in The Lancet.
Twice-weekly carfilzomib at 27 mg/m2 is approved as a single agent and in combination with lenalidomide or dexamethasone for the treatment of relapsed/refractory MM.
To develop a more convenient carfilzomib regimen, once-weekly carfilzomib plus dexamethasone was assessed in the phase 1/2 CHAMPION-1 study, showing good response rates (77%) and a median PFS of 12.6 months.
At ASCO, Dr Mateos presented the results from the pre-planned interim analysis of the phase 3 ARROW study (NCT02412878), comparing the two-drug regimen once-weekly vs twice-weekly.
Study design
The 478 patients, median age 66 years, had 2 to 3 prior therapies and prior exposure to a proteasome inhibitor and an immunomodulatory agent. Baseline characteristics were generally balanced, she said.
Investigators randomized patients to receive either once- or twice-weekly carfilzomib plus dexamethasone.
The once-weekly group received carfilzomib 20 mg/m2 intravenously on day 1 of cycle 1 and 70 mg/m2 on days 1, 8, and 15 of all subsequent cycles.
The twice-weekly group received the same carfilzomib dose on day 1, cycle 1 and 27 mg/m2 on days 8, 9, 15, and 16 thereafter. All patients received dexamethasone at 40 mg on days 1, 8, 15 (all cycles), and day 22 (cycles 1–9 only).
The primary endpoint was progression-free survival (PFS). Secondary endpoints were overall response rate, overall survival, safety, and pharmacokinetics.
Results
The study met the primary endpoint of PFS, with a median PFS for the once-weekly dose of 11.2 months and 7.6 months for the twice-weekly dose.
In addition, “patients who received once-weekly carfilzomib plus dexamethasone achieved a statistically significant higher overall response rate (62.9%) than patients who received the twice-weekly dose (40.8%),” Dr Mateos said.
Similarly, more patients achieved a complete response or better (7.1%) with the once-weekly dose than the twice-weekly dose (1.7%).
Safety
The overall safety profile was comparable between the 2 treatment groups and no new safety risks were identified.
Grade 3 or higher adverse events occurred in 67.6% (once-weekly) and 61.7% (twice-weekly) of patients.
Treatment-related grade 5 adverse events occurred in 5 patients (2.1%) in the once-weekly group and in 2 patients (0.9%) in the twice-weekly group.
The incidence of grade 3 or higher hypertension and cardiac failure was similar in both groups.
“Exposure-adjusted incidence of grade 3 or higher adverse events was slightly higher in the once-weekly vs the twice-weekly group,” Dr Mateos explained, “but the exposure-adjusted incidence for severe adverse events and adverse events leading to discontinuation of carfilzomib or death were similar between the treatment groups,” she said.
The ARROW study was supported by Amgen Inc.
One Heck of a Check-up
ANSWER
The correct interpretation includes sinus bradycardia with marked sinus arrhythmia and junctional escape beats, and an intraventricular conduction delay.
This type of ECG is not ideal for calculating the ventricular rate via the 30/150/100 method. An easier method is to multiply the number of QRS complexes in the rhythm strip by six (an ECG at standard paper speed takes 10 s; 6 × 10 s = 60 s). In the absence of a permanent pacemaker, variation of a few beats/min from the computer reading is acceptable. In this case, multiplying 9 x 6 yields a rate of 54 beats/min (close to the computer reading of 55) and reveals sinus bradycardia.
Looking at the lead I rhythm strip, notice that while the QRS complexes in the fourth and eighth beats look similar to the others, they are not preceded by P waves; the T waves of these two beats are also not similar to the others. These represent junctional escape beats, with a possible retrograde P wave in the T-wave complex. The long pauses and the absence of a P wave prior to the fourth and eighth beats make this a sinus arrhythmia.
The diagnosis of an intraventricular conduction delay can be made by the duration of the QRS complex (122 ms), which is above normal limits. This ECG does not meet the clear criteria for a right bundle branch block (QRS ≥ 120 ms, terminal broad S wave in lead I, RSR’ in V1) or left bundle branch block (QRS ≥ 120 ms, ST depressions and inverted T waves, particularly in I, aVL, V5, and V6).
ANSWER
The correct interpretation includes sinus bradycardia with marked sinus arrhythmia and junctional escape beats, and an intraventricular conduction delay.
This type of ECG is not ideal for calculating the ventricular rate via the 30/150/100 method. An easier method is to multiply the number of QRS complexes in the rhythm strip by six (an ECG at standard paper speed takes 10 s; 6 × 10 s = 60 s). In the absence of a permanent pacemaker, variation of a few beats/min from the computer reading is acceptable. In this case, multiplying 9 x 6 yields a rate of 54 beats/min (close to the computer reading of 55) and reveals sinus bradycardia.
Looking at the lead I rhythm strip, notice that while the QRS complexes in the fourth and eighth beats look similar to the others, they are not preceded by P waves; the T waves of these two beats are also not similar to the others. These represent junctional escape beats, with a possible retrograde P wave in the T-wave complex. The long pauses and the absence of a P wave prior to the fourth and eighth beats make this a sinus arrhythmia.
The diagnosis of an intraventricular conduction delay can be made by the duration of the QRS complex (122 ms), which is above normal limits. This ECG does not meet the clear criteria for a right bundle branch block (QRS ≥ 120 ms, terminal broad S wave in lead I, RSR’ in V1) or left bundle branch block (QRS ≥ 120 ms, ST depressions and inverted T waves, particularly in I, aVL, V5, and V6).
ANSWER
The correct interpretation includes sinus bradycardia with marked sinus arrhythmia and junctional escape beats, and an intraventricular conduction delay.
This type of ECG is not ideal for calculating the ventricular rate via the 30/150/100 method. An easier method is to multiply the number of QRS complexes in the rhythm strip by six (an ECG at standard paper speed takes 10 s; 6 × 10 s = 60 s). In the absence of a permanent pacemaker, variation of a few beats/min from the computer reading is acceptable. In this case, multiplying 9 x 6 yields a rate of 54 beats/min (close to the computer reading of 55) and reveals sinus bradycardia.
Looking at the lead I rhythm strip, notice that while the QRS complexes in the fourth and eighth beats look similar to the others, they are not preceded by P waves; the T waves of these two beats are also not similar to the others. These represent junctional escape beats, with a possible retrograde P wave in the T-wave complex. The long pauses and the absence of a P wave prior to the fourth and eighth beats make this a sinus arrhythmia.
The diagnosis of an intraventricular conduction delay can be made by the duration of the QRS complex (122 ms), which is above normal limits. This ECG does not meet the clear criteria for a right bundle branch block (QRS ≥ 120 ms, terminal broad S wave in lead I, RSR’ in V1) or left bundle branch block (QRS ≥ 120 ms, ST depressions and inverted T waves, particularly in I, aVL, V5, and V6).
He remained stable for six years, but then his exertional angina returned. Repeat catheterization showed progressive disease in the right coronary artery (RCA) with new disease in an obtuse marginal (OM) branch of the circumflex artery. His LVEF had also diminished to 38%. Stents were placed in the RCA and OM arteries, and his ß-blocker dose was increased.
Today, he reports that over the past six months, his heart rate has been slow and often skips beats. He stopped taking his ß-blocker, hoping it would help speed up his heart; it didn’t. He says he feels fine right now (although his heart continues to skip beats). He says he can climb a flight of stairs without difficulty and denies chest pain, dyspnea, dizziness, or syncope. At night, he sleeps on one or two pillows. He denies orthopnea, paroxysmal nocturnal dyspnea, or peripheral edema.
Medical history includes type 2 diabetes (controlled with diet and exercise), degenerative joint disease, and hyperlipidemia. Surgical history includes a tonsillectomy and trigger finger repair of the left third digit. His current medications include clopidogrel, losartan, pravastatin, spironolactone, and aspirin. He has no known drug allergies.
The patient used to be a heavy smoker (> 2 packs/d) but quit after his first stent was placed. He drinks one to two glasses of wine per week and denies recreational drug use.
Family history is positive for coronary artery disease and stroke. His father died of CAD at age 60, and his mother of heart failure at 58.
A review of systems is noncontributory. Vital signs include a blood pressure of 118/80 mm Hg; pulse, 53 beats/min; temperature, 37°C; respiratory rate, 14 breaths/min-1; and O2 saturation, 96% on room air. His weight is 214 lb and his height, 70 in.
Physical exam reveals an alert, well-kept male in no distress. Pertinent findings include a regularly irregular pulse and normal S1 and S2, with no murmurs, gallops, or rubs. The lungs are clear bilaterally. The abdomen is soft and benign with no organomegaly. Peripheral pulses are 2+ bilaterally, and there is no peripheral edema or calf tenderness. Neurologic exam shows a grossly intact sensory and motor system with no focal signs.
An ECG reveals a ventricular rate of 55 beats/min; PR interval, 146 ms; QRS duration, 122 ms; QT/QTc interval, 424/405 ms; P axis, 60°; R axis, 38°; and T axis, 29°. What is your interpretation?
A clinical pathway to standardize use of maintenance IV fluids
Clinical question
Can an evidence-based clinical pathway improve adherence to recent recommendations to use isotonic solutions for maintenance intravenous fluids in hospitalized children?
Background
The traditional teaching regarding composition of maintenance intravenous fluids (IVF) in children has been based on the Holliday-Segar method.1 Since its publication in Pediatrics in 1957, concerns have been raised regarding the risk of iatrogenic hyponatremia caused by giving hypotonic fluids determined by this method,2 especially in patients with an elevated risk of increased antidiuretic hormone (ADH) secretion.3 Multiple recent systematic reviews and meta-analyses have confirmed that isotonic IVF reduces the risk of hyponatremia in hospitalized children.4
Study design
Interrupted time series analysis before and after pathway implementation.
Setting
370-bed tertiary care free-standing children’s hospital.
Synopsis
A multidisciplinary team was assembled, comprising physicians and nurses in hospital medicine, general pediatrics, emergency medicine, and nephrology. After a systematic review of the recent literature, a clinical algorithm and web-based training module were developed. Faculty in general pediatrics, hospital medicine, and emergency medicine were required to complete the module, while medical and surgical residents were encouraged but not required to complete the module. A maintenance IVF order set was created and embedded into all order sets previously containing IVF orders and was also available in stand-alone form.
Inclusion criteria (“pathway eligible”) included being euvolemic and requiring IVF. Exclusion criteria included fluid status derangements, critical illness, severe serum sodium abnormalities (serum sodium ≥150 mEq/L or ≤130 mEq/L) use of TPN or ketogenic diet. In the order set, IVF composition was determined based on risk factors for increased ADH secretion. Inclusion of potassium in IVF was also determined by the pathway.
Over the 1-year study period, 11,602 pathway-eligible encounters in 10,287 patients were reviewed. Use of isotonic maintenance IVF increased significantly from 9.3% to 50.6%, while use of hypotonic fluids decreased from 94.2% to 56.6%. Use of potassium-containing IVF increased from 52.9% to 75.3%. Dysnatremia continued to occur due to hypotonic IVF use.
Bottom line
A combined clinical pathway and training module to standardize the composition of IVF is feasible, and results in increased use of isotonic and potassium-containing fluids.
Citation
Rooholamini S, Clifton H, Haaland W, et al. Outcomes of a clinical pathway to standardize use of maintenance intravenous fluids. Hosp Pediatr. 2017 Dec;7(12):703-9.
Dr. Chang is a pediatric hospitalist at Baystate Children’s Hospital in Springfield, Mass., and is the pediatric editor of The Hospitalist.
References
1. Holliday MA et al. The maintenance need for water in parenteral fluid therapy. Pediatrics 1957;19:823-32.
2. Friedman JN et al. Comparison of isotonic and hypotonic intravenous maintenance fluids: a randomized clinical trial. JAMA Pediatr. 2015;169:445-51.
3. Fuchs J et al. Current Issues in Intravenous Fluid Use in Hospitalized Children. Rev Recent Clin Trials. 2017;12:284-9.
4. McNab S et al. Isotonic versus hypotonic solutions for maintenance intravenous fluid administration in children. Cochrane Database. Syst Rev 2014:CD009457.
Clinical question
Can an evidence-based clinical pathway improve adherence to recent recommendations to use isotonic solutions for maintenance intravenous fluids in hospitalized children?
Background
The traditional teaching regarding composition of maintenance intravenous fluids (IVF) in children has been based on the Holliday-Segar method.1 Since its publication in Pediatrics in 1957, concerns have been raised regarding the risk of iatrogenic hyponatremia caused by giving hypotonic fluids determined by this method,2 especially in patients with an elevated risk of increased antidiuretic hormone (ADH) secretion.3 Multiple recent systematic reviews and meta-analyses have confirmed that isotonic IVF reduces the risk of hyponatremia in hospitalized children.4
Study design
Interrupted time series analysis before and after pathway implementation.
Setting
370-bed tertiary care free-standing children’s hospital.
Synopsis
A multidisciplinary team was assembled, comprising physicians and nurses in hospital medicine, general pediatrics, emergency medicine, and nephrology. After a systematic review of the recent literature, a clinical algorithm and web-based training module were developed. Faculty in general pediatrics, hospital medicine, and emergency medicine were required to complete the module, while medical and surgical residents were encouraged but not required to complete the module. A maintenance IVF order set was created and embedded into all order sets previously containing IVF orders and was also available in stand-alone form.
Inclusion criteria (“pathway eligible”) included being euvolemic and requiring IVF. Exclusion criteria included fluid status derangements, critical illness, severe serum sodium abnormalities (serum sodium ≥150 mEq/L or ≤130 mEq/L) use of TPN or ketogenic diet. In the order set, IVF composition was determined based on risk factors for increased ADH secretion. Inclusion of potassium in IVF was also determined by the pathway.
Over the 1-year study period, 11,602 pathway-eligible encounters in 10,287 patients were reviewed. Use of isotonic maintenance IVF increased significantly from 9.3% to 50.6%, while use of hypotonic fluids decreased from 94.2% to 56.6%. Use of potassium-containing IVF increased from 52.9% to 75.3%. Dysnatremia continued to occur due to hypotonic IVF use.
Bottom line
A combined clinical pathway and training module to standardize the composition of IVF is feasible, and results in increased use of isotonic and potassium-containing fluids.
Citation
Rooholamini S, Clifton H, Haaland W, et al. Outcomes of a clinical pathway to standardize use of maintenance intravenous fluids. Hosp Pediatr. 2017 Dec;7(12):703-9.
Dr. Chang is a pediatric hospitalist at Baystate Children’s Hospital in Springfield, Mass., and is the pediatric editor of The Hospitalist.
References
1. Holliday MA et al. The maintenance need for water in parenteral fluid therapy. Pediatrics 1957;19:823-32.
2. Friedman JN et al. Comparison of isotonic and hypotonic intravenous maintenance fluids: a randomized clinical trial. JAMA Pediatr. 2015;169:445-51.
3. Fuchs J et al. Current Issues in Intravenous Fluid Use in Hospitalized Children. Rev Recent Clin Trials. 2017;12:284-9.
4. McNab S et al. Isotonic versus hypotonic solutions for maintenance intravenous fluid administration in children. Cochrane Database. Syst Rev 2014:CD009457.
Clinical question
Can an evidence-based clinical pathway improve adherence to recent recommendations to use isotonic solutions for maintenance intravenous fluids in hospitalized children?
Background
The traditional teaching regarding composition of maintenance intravenous fluids (IVF) in children has been based on the Holliday-Segar method.1 Since its publication in Pediatrics in 1957, concerns have been raised regarding the risk of iatrogenic hyponatremia caused by giving hypotonic fluids determined by this method,2 especially in patients with an elevated risk of increased antidiuretic hormone (ADH) secretion.3 Multiple recent systematic reviews and meta-analyses have confirmed that isotonic IVF reduces the risk of hyponatremia in hospitalized children.4
Study design
Interrupted time series analysis before and after pathway implementation.
Setting
370-bed tertiary care free-standing children’s hospital.
Synopsis
A multidisciplinary team was assembled, comprising physicians and nurses in hospital medicine, general pediatrics, emergency medicine, and nephrology. After a systematic review of the recent literature, a clinical algorithm and web-based training module were developed. Faculty in general pediatrics, hospital medicine, and emergency medicine were required to complete the module, while medical and surgical residents were encouraged but not required to complete the module. A maintenance IVF order set was created and embedded into all order sets previously containing IVF orders and was also available in stand-alone form.
Inclusion criteria (“pathway eligible”) included being euvolemic and requiring IVF. Exclusion criteria included fluid status derangements, critical illness, severe serum sodium abnormalities (serum sodium ≥150 mEq/L or ≤130 mEq/L) use of TPN or ketogenic diet. In the order set, IVF composition was determined based on risk factors for increased ADH secretion. Inclusion of potassium in IVF was also determined by the pathway.
Over the 1-year study period, 11,602 pathway-eligible encounters in 10,287 patients were reviewed. Use of isotonic maintenance IVF increased significantly from 9.3% to 50.6%, while use of hypotonic fluids decreased from 94.2% to 56.6%. Use of potassium-containing IVF increased from 52.9% to 75.3%. Dysnatremia continued to occur due to hypotonic IVF use.
Bottom line
A combined clinical pathway and training module to standardize the composition of IVF is feasible, and results in increased use of isotonic and potassium-containing fluids.
Citation
Rooholamini S, Clifton H, Haaland W, et al. Outcomes of a clinical pathway to standardize use of maintenance intravenous fluids. Hosp Pediatr. 2017 Dec;7(12):703-9.
Dr. Chang is a pediatric hospitalist at Baystate Children’s Hospital in Springfield, Mass., and is the pediatric editor of The Hospitalist.
References
1. Holliday MA et al. The maintenance need for water in parenteral fluid therapy. Pediatrics 1957;19:823-32.
2. Friedman JN et al. Comparison of isotonic and hypotonic intravenous maintenance fluids: a randomized clinical trial. JAMA Pediatr. 2015;169:445-51.
3. Fuchs J et al. Current Issues in Intravenous Fluid Use in Hospitalized Children. Rev Recent Clin Trials. 2017;12:284-9.
4. McNab S et al. Isotonic versus hypotonic solutions for maintenance intravenous fluid administration in children. Cochrane Database. Syst Rev 2014:CD009457.
Emicizumab gets priority review for hemophilia A without inhibitors
The Food and Drug Administration has granted priority review to Roche’s emicizumab-kxwh (Hemlibra) for the treatment of adults and children with hemophilia A without factor VIII inhibitors.
The agency is scheduled to make a decision on approval in October 2018.
Among patients aged 12 years and older without factor VIII inhibitors, emicizumab-kxwh prophylaxis every week reduced treated bleeds by 96% (P less than .0001) and treated bleeds were reduced by 97% (P less than .0001) in patients who were treated every 2 weeks, according to Roche. The drug-treated group was compared with patients who received no prophylaxis. Another arm of the study examined patients who had previously received factor VIII prophylaxis and then switched to emicizumab-kxwh prophylaxis. In an intrapatient comparison, emicizumab-kxwh showed a 68% reduction in treated bleeds, which was statistically significant and demonstrated superior efficacy to factor VIII prophylaxis.
Emicizumab-kxwh was approved by FDA in November 2017 for routine prophylaxis for adults and children with hemophilia A with factor VIII inhibitors. That approval was based on results from the HAVEN 1 and HAVEN 2 studies.
The Food and Drug Administration has granted priority review to Roche’s emicizumab-kxwh (Hemlibra) for the treatment of adults and children with hemophilia A without factor VIII inhibitors.
The agency is scheduled to make a decision on approval in October 2018.
Among patients aged 12 years and older without factor VIII inhibitors, emicizumab-kxwh prophylaxis every week reduced treated bleeds by 96% (P less than .0001) and treated bleeds were reduced by 97% (P less than .0001) in patients who were treated every 2 weeks, according to Roche. The drug-treated group was compared with patients who received no prophylaxis. Another arm of the study examined patients who had previously received factor VIII prophylaxis and then switched to emicizumab-kxwh prophylaxis. In an intrapatient comparison, emicizumab-kxwh showed a 68% reduction in treated bleeds, which was statistically significant and demonstrated superior efficacy to factor VIII prophylaxis.
Emicizumab-kxwh was approved by FDA in November 2017 for routine prophylaxis for adults and children with hemophilia A with factor VIII inhibitors. That approval was based on results from the HAVEN 1 and HAVEN 2 studies.
The Food and Drug Administration has granted priority review to Roche’s emicizumab-kxwh (Hemlibra) for the treatment of adults and children with hemophilia A without factor VIII inhibitors.
The agency is scheduled to make a decision on approval in October 2018.
Among patients aged 12 years and older without factor VIII inhibitors, emicizumab-kxwh prophylaxis every week reduced treated bleeds by 96% (P less than .0001) and treated bleeds were reduced by 97% (P less than .0001) in patients who were treated every 2 weeks, according to Roche. The drug-treated group was compared with patients who received no prophylaxis. Another arm of the study examined patients who had previously received factor VIII prophylaxis and then switched to emicizumab-kxwh prophylaxis. In an intrapatient comparison, emicizumab-kxwh showed a 68% reduction in treated bleeds, which was statistically significant and demonstrated superior efficacy to factor VIII prophylaxis.
Emicizumab-kxwh was approved by FDA in November 2017 for routine prophylaxis for adults and children with hemophilia A with factor VIII inhibitors. That approval was based on results from the HAVEN 1 and HAVEN 2 studies.