Will Pass

For patients with relapsed/refractory chronic lymphocytic leukemia (CLL), long-term treatment with the phosphoinositol 3-kinase inhibitor idelalisib appears safe and effective, according to investigators.

Final results from a phase 3 trial confirmed survival advantages when idelalisib is used in combination with rituximab, reported lead author Jeff P. Sharman, MD, of Willamette Valley Cancer Institute and Research Center in Springfield, Ore., and colleagues.

During follow-up, which exceeded 5 years in some patients, no new idelalisib-related adverse events were encountered, supporting the safety of long-term use, the investigators noted. The report is in the Journal of Clinical Oncology.

This study was “pivotal” for treating elderly patients with relapsed CLL, the investigators wrote, as these patients previously had few treatment options beyond supportive or palliative care.

Earlier results from the study showed that adding idelalisib to rituximab raised overall response rates from about 15.5% to 83.6% and median progression-free survival from 6.5 months to 19.4 months, resulting in “significantly better clinical outcomes compared with those seen with rituximab alone,” leading to approval by the Food and Drug Administration.

During the primary study, 110 patients received a combination of idelalisib and rituximab, while 108 patients received rituximab and placebo. The median patient age was 71 years, with a median of three lines of prior therapy. The present analysis focused on the 110 patients in the combination group who received at least one dose of idelalisib, whether or not they elected to participate in the extension phase.

After a median follow-up of 18 months, ranging from 0.3 months to 67.6 months, the overall response rate was 85.5% and the median progression-free survival was 20.3 months, both of which are similar to earlier findings. Median overall survival was 40.6 months.

With a median duration of exposure of 16.2 months, the safety analysis revealed no new idelalisib-related adverse events.

However, the investigators pointed out that prolonged therapy often led to diarrhea, which ultimately occurred in about half of patients (46.4%). Roughly equal amounts of patients experienced grade 2 (17.3%) or grade 3 or greater diarrhea (16.4%). In cases of grade 3 or greater diarrhea, steroid therapy was recommended, typically resulting in symptom resolution within 2 weeks; however, “there were insufficient numbers of patients to determine if steroid therapy affected the duration of symptoms,” the investigators wrote.

“The longer-term data presented here confirm the previously reported efficacy of targeting PI3K with idelalisib in patients with relapsed/refractory CLL and support the use of [idelalisib and rituximab] in this patient population with careful management of potential [adverse events],” they wrote.

Gilead Sciences funded the study. Dr. Sharman reported financial relationships with Gilead and other companies.

SOURCE: Sharman JP et al. J Clin Oncol. 2019 Apr 17. doi: 10.1200/JCO.18.01460.

For patients with relapsed/refractory chronic lymphocytic leukemia (CLL), long-term treatment with the phosphoinositol 3-kinase inhibitor idelalisib appears safe and effective, according to investigators.

Final results from a phase 3 trial confirmed survival advantages when idelalisib is used in combination with rituximab, reported lead author Jeff P. Sharman, MD, of Willamette Valley Cancer Institute and Research Center in Springfield, Ore., and colleagues.

During follow-up, which exceeded 5 years in some patients, no new idelalisib-related adverse events were encountered, supporting the safety of long-term use, the investigators noted. The report is in the Journal of Clinical Oncology.

This study was “pivotal” for treating elderly patients with relapsed CLL, the investigators wrote, as these patients previously had few treatment options beyond supportive or palliative care.

Earlier results from the study showed that adding idelalisib to rituximab raised overall response rates from about 15.5% to 83.6% and median progression-free survival from 6.5 months to 19.4 months, resulting in “significantly better clinical outcomes compared with those seen with rituximab alone,” leading to approval by the Food and Drug Administration.

During the primary study, 110 patients received a combination of idelalisib and rituximab, while 108 patients received rituximab and placebo. The median patient age was 71 years, with a median of three lines of prior therapy. The present analysis focused on the 110 patients in the combination group who received at least one dose of idelalisib, whether or not they elected to participate in the extension phase.

After a median follow-up of 18 months, ranging from 0.3 months to 67.6 months, the overall response rate was 85.5% and the median progression-free survival was 20.3 months, both of which are similar to earlier findings. Median overall survival was 40.6 months.

With a median duration of exposure of 16.2 months, the safety analysis revealed no new idelalisib-related adverse events.

However, the investigators pointed out that prolonged therapy often led to diarrhea, which ultimately occurred in about half of patients (46.4%). Roughly equal amounts of patients experienced grade 2 (17.3%) or grade 3 or greater diarrhea (16.4%). In cases of grade 3 or greater diarrhea, steroid therapy was recommended, typically resulting in symptom resolution within 2 weeks; however, “there were insufficient numbers of patients to determine if steroid therapy affected the duration of symptoms,” the investigators wrote.

“The longer-term data presented here confirm the previously reported efficacy of targeting PI3K with idelalisib in patients with relapsed/refractory CLL and support the use of [idelalisib and rituximab] in this patient population with careful management of potential [adverse events],” they wrote.

Gilead Sciences funded the study. Dr. Sharman reported financial relationships with Gilead and other companies.

SOURCE: Sharman JP et al. J Clin Oncol. 2019 Apr 17. doi: 10.1200/JCO.18.01460.

For patients with relapsed/refractory chronic lymphocytic leukemia (CLL), long-term treatment with the phosphoinositol 3-kinase inhibitor idelalisib appears safe and effective, according to investigators.

Final results from a phase 3 trial confirmed survival advantages when idelalisib is used in combination with rituximab, reported lead author Jeff P. Sharman, MD, of Willamette Valley Cancer Institute and Research Center in Springfield, Ore., and colleagues.

During follow-up, which exceeded 5 years in some patients, no new idelalisib-related adverse events were encountered, supporting the safety of long-term use, the investigators noted. The report is in the Journal of Clinical Oncology.

This study was “pivotal” for treating elderly patients with relapsed CLL, the investigators wrote, as these patients previously had few treatment options beyond supportive or palliative care.

Earlier results from the study showed that adding idelalisib to rituximab raised overall response rates from about 15.5% to 83.6% and median progression-free survival from 6.5 months to 19.4 months, resulting in “significantly better clinical outcomes compared with those seen with rituximab alone,” leading to approval by the Food and Drug Administration.

During the primary study, 110 patients received a combination of idelalisib and rituximab, while 108 patients received rituximab and placebo. The median patient age was 71 years, with a median of three lines of prior therapy. The present analysis focused on the 110 patients in the combination group who received at least one dose of idelalisib, whether or not they elected to participate in the extension phase.

After a median follow-up of 18 months, ranging from 0.3 months to 67.6 months, the overall response rate was 85.5% and the median progression-free survival was 20.3 months, both of which are similar to earlier findings. Median overall survival was 40.6 months.

With a median duration of exposure of 16.2 months, the safety analysis revealed no new idelalisib-related adverse events.

However, the investigators pointed out that prolonged therapy often led to diarrhea, which ultimately occurred in about half of patients (46.4%). Roughly equal amounts of patients experienced grade 2 (17.3%) or grade 3 or greater diarrhea (16.4%). In cases of grade 3 or greater diarrhea, steroid therapy was recommended, typically resulting in symptom resolution within 2 weeks; however, “there were insufficient numbers of patients to determine if steroid therapy affected the duration of symptoms,” the investigators wrote.

“The longer-term data presented here confirm the previously reported efficacy of targeting PI3K with idelalisib in patients with relapsed/refractory CLL and support the use of [idelalisib and rituximab] in this patient population with careful management of potential [adverse events],” they wrote.

Gilead Sciences funded the study. Dr. Sharman reported financial relationships with Gilead and other companies.

SOURCE: Sharman JP et al. J Clin Oncol. 2019 Apr 17. doi: 10.1200/JCO.18.01460.

GENEVA – Circulating tumor cell (CTC) count is an independent predictor of both progression-free and overall survival in patients with advanced non–small cell lung cancer (NSCLC), according to data from 550 patients.

Will Pass/MDedge News

This is the largest CTC study to date and the first to compare test results from multiple centers, reported lead author Colin Lindsay, MD, PhD, of the University of Manchester (England) and colleagues. Among the centers, investigators found minimal variability in results guiding progression-free survival and no significant differences in results predicting overall survival. These findings suggest that CTC testing could be reproducible and reliable on a large scale, Dr. Lindsay said during a presentation at the European Lung Cancer Conference; he added that this conclusion addresses a previous concern about the process.

“A slight problem with the process is still that it is semi-automated,” Dr. Lindsay said at the meeting presented by the European Society for Medical Oncology. “The machine will harvest potential cells and stain potential cells, but the end step of the process is that a trained user in each laboratory will decide which cell is a CTC and which cell isn’t a CTC, and it’s that potential for user variability that was the basis of this study.”

The retrospective study involved 550 patients with NSCLC whose samples were processed at seven centers in multiple European countries, including 209 patients whose data was previously unpublished. The investigators looked for associations between CTC count and survival using Cox regression analysis and evaluated if CTCs could add value to prognostic clinicopathologic models based on c-indices and likelihood ratio statistics. CTC count was assessed as a continuous variable and, based on previous studies, using two categorical thresholds: at least 2 cells per 7.5 mL and at least 5 cells per 7.5 mL. In addition, the investigators looked for associations between NSCLC molecular subtypes and CTC levels.

The results showed that both cutoff levels were predictive of survival, with the higher threshold carrying a poorer prognosis. For progression-free survival, CTC counts of at least 2 cells per 7.5 mL carried a hazard ratio of 1.72, whereas the 5-cell threshold had a hazard ratio of 2.21 (P less than .001 for both). Similarly, overall survival hazard ratios for the lower and higher thresholds were 2.18 and 2.75, respectively (P less than .001 for both). When baseline CTC count was added to the analysis, predictive accuracy increased further, dropping P values tenfold, down to .0001. C-index models had a more modest impact. Although minor heterogeneity was detected among centers for prediction of progression-free survival, overall survival data was broadly reliable. Dr. Lindsay noted that intercenter differences seemed to diminish with greater testing experience. No relationships were detected between molecular subtypes and CTC profiles.

“It’s always good to finish a talk with the white elephant in the room,” Dr. Lindsay said in his concluding remarks. “Is there room for CTCs in non–small cell lung cancer? I believe they have the potential to complement ctDNA work by offering a cellular context, but [CTCs] aren’t there yet for clinical roll-out.”

Will Pass/MDedge News

Invited discussant Juergen Wolf, MD, of the University Hospital Cologne (Germany) provided a similar conclusion, suggesting that CTCs have a clear place in research, but their clinical value is debatable. He noted that ctDNA, the most similar diagnostic and prognostic tool under development, has a pragmatic edge because ctDNA samples are more amenable to shipping and handling. Dr. Wolf noted that ctDNA also has been shown to have value for treatment planning, specifically for the EGFR T790M resistance mutation. This latter point tied into a larger issue described by Dr. Wolf, who suggested that in the current treatment landscape for NSCLC, predictive testing needs to be actionable.

“We cannot draw a consequence of a prognostic biomarker,” Dr. Wolf said. “In the era of personalized medicine, what we need is predictive markers, predictive of the outcome of specific therapies.”The investigators disclosed financial relationships with AstraZeneca, Novartis, Pfizer, and others.

SOURCE: Lindsay C et al. ELCC 2019, Abstract 21O.

GENEVA – Circulating tumor cell (CTC) count is an independent predictor of both progression-free and overall survival in patients with advanced non–small cell lung cancer (NSCLC), according to data from 550 patients.

Will Pass/MDedge News

This is the largest CTC study to date and the first to compare test results from multiple centers, reported lead author Colin Lindsay, MD, PhD, of the University of Manchester (England) and colleagues. Among the centers, investigators found minimal variability in results guiding progression-free survival and no significant differences in results predicting overall survival. These findings suggest that CTC testing could be reproducible and reliable on a large scale, Dr. Lindsay said during a presentation at the European Lung Cancer Conference; he added that this conclusion addresses a previous concern about the process.

“A slight problem with the process is still that it is semi-automated,” Dr. Lindsay said at the meeting presented by the European Society for Medical Oncology. “The machine will harvest potential cells and stain potential cells, but the end step of the process is that a trained user in each laboratory will decide which cell is a CTC and which cell isn’t a CTC, and it’s that potential for user variability that was the basis of this study.”

The retrospective study involved 550 patients with NSCLC whose samples were processed at seven centers in multiple European countries, including 209 patients whose data was previously unpublished. The investigators looked for associations between CTC count and survival using Cox regression analysis and evaluated if CTCs could add value to prognostic clinicopathologic models based on c-indices and likelihood ratio statistics. CTC count was assessed as a continuous variable and, based on previous studies, using two categorical thresholds: at least 2 cells per 7.5 mL and at least 5 cells per 7.5 mL. In addition, the investigators looked for associations between NSCLC molecular subtypes and CTC levels.

The results showed that both cutoff levels were predictive of survival, with the higher threshold carrying a poorer prognosis. For progression-free survival, CTC counts of at least 2 cells per 7.5 mL carried a hazard ratio of 1.72, whereas the 5-cell threshold had a hazard ratio of 2.21 (P less than .001 for both). Similarly, overall survival hazard ratios for the lower and higher thresholds were 2.18 and 2.75, respectively (P less than .001 for both). When baseline CTC count was added to the analysis, predictive accuracy increased further, dropping P values tenfold, down to .0001. C-index models had a more modest impact. Although minor heterogeneity was detected among centers for prediction of progression-free survival, overall survival data was broadly reliable. Dr. Lindsay noted that intercenter differences seemed to diminish with greater testing experience. No relationships were detected between molecular subtypes and CTC profiles.

“It’s always good to finish a talk with the white elephant in the room,” Dr. Lindsay said in his concluding remarks. “Is there room for CTCs in non–small cell lung cancer? I believe they have the potential to complement ctDNA work by offering a cellular context, but [CTCs] aren’t there yet for clinical roll-out.”

Will Pass/MDedge News

Invited discussant Juergen Wolf, MD, of the University Hospital Cologne (Germany) provided a similar conclusion, suggesting that CTCs have a clear place in research, but their clinical value is debatable. He noted that ctDNA, the most similar diagnostic and prognostic tool under development, has a pragmatic edge because ctDNA samples are more amenable to shipping and handling. Dr. Wolf noted that ctDNA also has been shown to have value for treatment planning, specifically for the EGFR T790M resistance mutation. This latter point tied into a larger issue described by Dr. Wolf, who suggested that in the current treatment landscape for NSCLC, predictive testing needs to be actionable.

“We cannot draw a consequence of a prognostic biomarker,” Dr. Wolf said. “In the era of personalized medicine, what we need is predictive markers, predictive of the outcome of specific therapies.”The investigators disclosed financial relationships with AstraZeneca, Novartis, Pfizer, and others.

SOURCE: Lindsay C et al. ELCC 2019, Abstract 21O.

GENEVA – Circulating tumor cell (CTC) count is an independent predictor of both progression-free and overall survival in patients with advanced non–small cell lung cancer (NSCLC), according to data from 550 patients.

Will Pass/MDedge News

This is the largest CTC study to date and the first to compare test results from multiple centers, reported lead author Colin Lindsay, MD, PhD, of the University of Manchester (England) and colleagues. Among the centers, investigators found minimal variability in results guiding progression-free survival and no significant differences in results predicting overall survival. These findings suggest that CTC testing could be reproducible and reliable on a large scale, Dr. Lindsay said during a presentation at the European Lung Cancer Conference; he added that this conclusion addresses a previous concern about the process.

“A slight problem with the process is still that it is semi-automated,” Dr. Lindsay said at the meeting presented by the European Society for Medical Oncology. “The machine will harvest potential cells and stain potential cells, but the end step of the process is that a trained user in each laboratory will decide which cell is a CTC and which cell isn’t a CTC, and it’s that potential for user variability that was the basis of this study.”

The retrospective study involved 550 patients with NSCLC whose samples were processed at seven centers in multiple European countries, including 209 patients whose data was previously unpublished. The investigators looked for associations between CTC count and survival using Cox regression analysis and evaluated if CTCs could add value to prognostic clinicopathologic models based on c-indices and likelihood ratio statistics. CTC count was assessed as a continuous variable and, based on previous studies, using two categorical thresholds: at least 2 cells per 7.5 mL and at least 5 cells per 7.5 mL. In addition, the investigators looked for associations between NSCLC molecular subtypes and CTC levels.

The results showed that both cutoff levels were predictive of survival, with the higher threshold carrying a poorer prognosis. For progression-free survival, CTC counts of at least 2 cells per 7.5 mL carried a hazard ratio of 1.72, whereas the 5-cell threshold had a hazard ratio of 2.21 (P less than .001 for both). Similarly, overall survival hazard ratios for the lower and higher thresholds were 2.18 and 2.75, respectively (P less than .001 for both). When baseline CTC count was added to the analysis, predictive accuracy increased further, dropping P values tenfold, down to .0001. C-index models had a more modest impact. Although minor heterogeneity was detected among centers for prediction of progression-free survival, overall survival data was broadly reliable. Dr. Lindsay noted that intercenter differences seemed to diminish with greater testing experience. No relationships were detected between molecular subtypes and CTC profiles.

“It’s always good to finish a talk with the white elephant in the room,” Dr. Lindsay said in his concluding remarks. “Is there room for CTCs in non–small cell lung cancer? I believe they have the potential to complement ctDNA work by offering a cellular context, but [CTCs] aren’t there yet for clinical roll-out.”

Will Pass/MDedge News

Invited discussant Juergen Wolf, MD, of the University Hospital Cologne (Germany) provided a similar conclusion, suggesting that CTCs have a clear place in research, but their clinical value is debatable. He noted that ctDNA, the most similar diagnostic and prognostic tool under development, has a pragmatic edge because ctDNA samples are more amenable to shipping and handling. Dr. Wolf noted that ctDNA also has been shown to have value for treatment planning, specifically for the EGFR T790M resistance mutation. This latter point tied into a larger issue described by Dr. Wolf, who suggested that in the current treatment landscape for NSCLC, predictive testing needs to be actionable.

“We cannot draw a consequence of a prognostic biomarker,” Dr. Wolf said. “In the era of personalized medicine, what we need is predictive markers, predictive of the outcome of specific therapies.”The investigators disclosed financial relationships with AstraZeneca, Novartis, Pfizer, and others.

SOURCE: Lindsay C et al. ELCC 2019, Abstract 21O.

For patients with head and neck cutaneous squamous cell carcinoma (HNCSCC), the Brigham and Women’s Hospital (BWH) tumor classification system is better at predicting metastases and death than the American Joint Committee on Cancer Staging Manual, 8th edition (AJCC 8), based on a study involving 459 patients.

Using the AJCC 8 system, twice as many tumors were considered to be in a high tumor class, compared with the BWH system, reported lead author Emily Stamell Ruiz, MD, of Brigham and Women’s Hospital in Boston, and her colleagues. Using the BWH system could minimize the number of patients undergoing intensive monitoring and possibly therapy without missing those at high risk for poor outcomes.

“Identification of … tumors with significant risk of recurrence, progression to unresectability, or death is challenging owing to lack of accurate [cutaneous squamous cell carcinoma] risk stratification,” the investigators wrote in JAMA Dermatology.

Although AJCC 7 offered a method of classifying such tumors, validation and refinement have been challenging because of a lack of relevant data in the Surveillance, Epidemiology, and End Results Program. A previous study showed that the BWH system outperformed AJCC 7; however, until now, no study has compared the BWH system with AJCC 8, which was released in January 2018 with updated HNCSCC classifications. The BWH has four possible classifications defined by number of high-risk factors and presence or absence of bone invasion: T1, T2a, T2b, and T3. In comparison, the AJCC 8 has five possible classifications defined by tumor size and level of invasion: T1, T2, T3, T4a, and T4b.

The present study involved 459 patients with 680 HNCSCCs. The patients were staged by both BWH and AJCC 8 systems, then compared for accuracy of predicting poor outcomes, including nodal metastases, local recurrence, disease specific death, and overall survival.

The analysis showed that the BWH system had a specificity of 93% for predicting metastases or death, compared with 85% for the AJCC 8 (P less than .001). Sensitivity was not statistically significant between the two groups; however, the BWH system had a better positive predictive value, at 30%, compared with 17% from the AJCC 8. Of note, the AJCC 8 system grouped almost one-quarter of patients (23%) into the T2 and T3 groups, which led to poorer risk prediction, according to the investigators. These patients had a 13% risk of nodal metastasis and an 8% risk of disease-specific death. In contrast, the BWH system confined most poor outcomes into the T2b and T3 groups, which included just 9% of patients, raising risk of disease-specific death to 17% and risk of nodal metastasis to 24%, the latter of which aligns with previously published data.

“One reason for the equivalent outcomes in AJCC 8 T2 and T3 is that poor differentiation is not a risk factor,” the investigators explained. “Approximately 50% of nodal metastasis and overall death in AJCC 8 T2 occurred in patients with poorly differentiated tumors, increasing the risk of poor outcomes in this group. The risk of poor outcomes was lower in AJCC 8 T3, compared with BWH T2b because AJCC 8 T3 tumors are only required to have one of four risk factors whereas two risk factors are required for BWH T2b tumor class.”

The investigators concluded by highlighting the real-world benefits of the BWH system. “Use of BWH tumor classification may minimize the number of patients recommended for radiologic evaluation, close surveillance, and possible adjuvant therapy while still identifying most patients at risk for recurrence, metastasis, and death.”

The investigators reported no conflicts of interest.

SOURCE: Ruiz ES et al. JAMA Dermatol. 2019 Apr 10. doi: 10.1001/jamadermatol.2019.0032.

For patients with head and neck cutaneous squamous cell carcinoma (HNCSCC), the Brigham and Women’s Hospital (BWH) tumor classification system is better at predicting metastases and death than the American Joint Committee on Cancer Staging Manual, 8th edition (AJCC 8), based on a study involving 459 patients.

Using the AJCC 8 system, twice as many tumors were considered to be in a high tumor class, compared with the BWH system, reported lead author Emily Stamell Ruiz, MD, of Brigham and Women’s Hospital in Boston, and her colleagues. Using the BWH system could minimize the number of patients undergoing intensive monitoring and possibly therapy without missing those at high risk for poor outcomes.

“Identification of … tumors with significant risk of recurrence, progression to unresectability, or death is challenging owing to lack of accurate [cutaneous squamous cell carcinoma] risk stratification,” the investigators wrote in JAMA Dermatology.

Although AJCC 7 offered a method of classifying such tumors, validation and refinement have been challenging because of a lack of relevant data in the Surveillance, Epidemiology, and End Results Program. A previous study showed that the BWH system outperformed AJCC 7; however, until now, no study has compared the BWH system with AJCC 8, which was released in January 2018 with updated HNCSCC classifications. The BWH has four possible classifications defined by number of high-risk factors and presence or absence of bone invasion: T1, T2a, T2b, and T3. In comparison, the AJCC 8 has five possible classifications defined by tumor size and level of invasion: T1, T2, T3, T4a, and T4b.

The present study involved 459 patients with 680 HNCSCCs. The patients were staged by both BWH and AJCC 8 systems, then compared for accuracy of predicting poor outcomes, including nodal metastases, local recurrence, disease specific death, and overall survival.

The analysis showed that the BWH system had a specificity of 93% for predicting metastases or death, compared with 85% for the AJCC 8 (P less than .001). Sensitivity was not statistically significant between the two groups; however, the BWH system had a better positive predictive value, at 30%, compared with 17% from the AJCC 8. Of note, the AJCC 8 system grouped almost one-quarter of patients (23%) into the T2 and T3 groups, which led to poorer risk prediction, according to the investigators. These patients had a 13% risk of nodal metastasis and an 8% risk of disease-specific death. In contrast, the BWH system confined most poor outcomes into the T2b and T3 groups, which included just 9% of patients, raising risk of disease-specific death to 17% and risk of nodal metastasis to 24%, the latter of which aligns with previously published data.

“One reason for the equivalent outcomes in AJCC 8 T2 and T3 is that poor differentiation is not a risk factor,” the investigators explained. “Approximately 50% of nodal metastasis and overall death in AJCC 8 T2 occurred in patients with poorly differentiated tumors, increasing the risk of poor outcomes in this group. The risk of poor outcomes was lower in AJCC 8 T3, compared with BWH T2b because AJCC 8 T3 tumors are only required to have one of four risk factors whereas two risk factors are required for BWH T2b tumor class.”

The investigators concluded by highlighting the real-world benefits of the BWH system. “Use of BWH tumor classification may minimize the number of patients recommended for radiologic evaluation, close surveillance, and possible adjuvant therapy while still identifying most patients at risk for recurrence, metastasis, and death.”

The investigators reported no conflicts of interest.

SOURCE: Ruiz ES et al. JAMA Dermatol. 2019 Apr 10. doi: 10.1001/jamadermatol.2019.0032.

For patients with head and neck cutaneous squamous cell carcinoma (HNCSCC), the Brigham and Women’s Hospital (BWH) tumor classification system is better at predicting metastases and death than the American Joint Committee on Cancer Staging Manual, 8th edition (AJCC 8), based on a study involving 459 patients.

Using the AJCC 8 system, twice as many tumors were considered to be in a high tumor class, compared with the BWH system, reported lead author Emily Stamell Ruiz, MD, of Brigham and Women’s Hospital in Boston, and her colleagues. Using the BWH system could minimize the number of patients undergoing intensive monitoring and possibly therapy without missing those at high risk for poor outcomes.

“Identification of … tumors with significant risk of recurrence, progression to unresectability, or death is challenging owing to lack of accurate [cutaneous squamous cell carcinoma] risk stratification,” the investigators wrote in JAMA Dermatology.

Although AJCC 7 offered a method of classifying such tumors, validation and refinement have been challenging because of a lack of relevant data in the Surveillance, Epidemiology, and End Results Program. A previous study showed that the BWH system outperformed AJCC 7; however, until now, no study has compared the BWH system with AJCC 8, which was released in January 2018 with updated HNCSCC classifications. The BWH has four possible classifications defined by number of high-risk factors and presence or absence of bone invasion: T1, T2a, T2b, and T3. In comparison, the AJCC 8 has five possible classifications defined by tumor size and level of invasion: T1, T2, T3, T4a, and T4b.

The present study involved 459 patients with 680 HNCSCCs. The patients were staged by both BWH and AJCC 8 systems, then compared for accuracy of predicting poor outcomes, including nodal metastases, local recurrence, disease specific death, and overall survival.

The analysis showed that the BWH system had a specificity of 93% for predicting metastases or death, compared with 85% for the AJCC 8 (P less than .001). Sensitivity was not statistically significant between the two groups; however, the BWH system had a better positive predictive value, at 30%, compared with 17% from the AJCC 8. Of note, the AJCC 8 system grouped almost one-quarter of patients (23%) into the T2 and T3 groups, which led to poorer risk prediction, according to the investigators. These patients had a 13% risk of nodal metastasis and an 8% risk of disease-specific death. In contrast, the BWH system confined most poor outcomes into the T2b and T3 groups, which included just 9% of patients, raising risk of disease-specific death to 17% and risk of nodal metastasis to 24%, the latter of which aligns with previously published data.

“One reason for the equivalent outcomes in AJCC 8 T2 and T3 is that poor differentiation is not a risk factor,” the investigators explained. “Approximately 50% of nodal metastasis and overall death in AJCC 8 T2 occurred in patients with poorly differentiated tumors, increasing the risk of poor outcomes in this group. The risk of poor outcomes was lower in AJCC 8 T3, compared with BWH T2b because AJCC 8 T3 tumors are only required to have one of four risk factors whereas two risk factors are required for BWH T2b tumor class.”

The investigators concluded by highlighting the real-world benefits of the BWH system. “Use of BWH tumor classification may minimize the number of patients recommended for radiologic evaluation, close surveillance, and possible adjuvant therapy while still identifying most patients at risk for recurrence, metastasis, and death.”

The investigators reported no conflicts of interest.

SOURCE: Ruiz ES et al. JAMA Dermatol. 2019 Apr 10. doi: 10.1001/jamadermatol.2019.0032.

GLASGOW – Neurological abnormalities and elevated troponin predict mortality in patients with thrombotic thrombocytopenic purpura (TTP), according to retrospective analysis of 475 patients from the United Kingdom TTP registry.

Will Pass/MDedge News

In addition, low ADAMTS13 activity (less than 10%) was present in 92% of immune-mediated of TTP upon acute presentation, reported lead author Jin-Sup Shin, MD, of University College London Hospital, and colleagues.

Presenting at the annual meeting of the British Society for Haematology, Dr. Shin provided some background on TTP, a condition that most clinicians encounter infrequently.

“As recently as the 1980s and 90s, when etiology was not that well understood, TTP was associated with an untreated mortality of up to 90%,” Dr. Shin said. “However, based on improved understanding of pathophysiology, and through the creation of TTP registries worldwide, there have been major advances in diagnosis, treatment, and outcomes.”

To gain insight into diagnostic and prognostic characteristics of TTP, the investigators turned to data from 602 patients with clinically suspected TTP, based on an ADAMTS13 activity level less than 10% of normal and associated clinical signs. Out of these 602 patients, 475 consented to registry participation and data analysis.

The analysis revealed a mortality rate of 4%, although Dr. Shin said that “this is probably an underestimate of the true figure,” as it excludes those who died before treatment could be initiated.

Nearly three-quarters of patients were female. The median age at presentation was 43 years, with a range of 1-93 years. The most commonly represented racial/ethnic groups were white (60%) and Afro-Caribbean (22%). Some cases were congenital (16%), but the majority were immune mediated (84%).

The immune-mediated group was the primary focus of Dr. Shin’s report. In this cohort, 76% of cases were idiopathic, while the remainder had a defined precipitant; most common were infection, autoimmune disease, pregnancy, and HIV. The relapse rate among those with immune-mediated TTP was 19%, after a median time to relapse of 26 months.

In total, 71% of patients presented with neurological abnormalities, while slightly less than half (48%) had symptomatic thrombocytopenia (bleeding/petechiae).

Diagnostic tools showed that 64% of patients had an elevated troponin level, 92% had ADAMTS13 activity less than 10%, and 25% had a platelet count lower than 10 x 10⁹/L.

Median platelet count upon presentation was 15 x 10⁹/L, and median lactate dehydrogenase (LDH) exceeded 1,000 units/L. After 7 days of therapy, 58% of patients were still severely deficient in ADAMTS13 activity and 36% of patients still had a platelet count lower than 150 x 10⁹/L.

Where information was available, 30% of patients had positive auto-antibody screens, although not necessarily with signs or symptoms of autoimmune disease. A total of 93% of patients had elevated ADAMTS13 IgG antibody upon presentation. The median ADAMTS13 IgG antibody level at presentation was 37%, with a normal value being less than 6%.

Nearly half of patients with immune-mediated TTP (45%) required intensive care, and 10% of these patients were intubated and ventilated. Most patients were treated with steroids upon admission (81%). On average, 11 plasma exchanges (PEXs) were required before remission.

The investigators noted that “[t]he number of PEXs to remission appears to have decreased over the years.” As an example, a median of 14 PEXs were needed from 2009 to 2010, compared with 8 from 2017 to 2018.

Although rituximab usage in the acute setting held steady over the 10-year period, elective use increased. Out of 89 instances of subacute relapse, elective rituximab was given twice from 2009 to 2010, compared with 26 times from 2017 to 2018.

Comparing features of survival, the investigators found that the median ADAMTS13 IgG antibody level was higher among those who died. Other factors related to increased mortality risk included raised troponin (sevenfold increased risk) and neurological abnormalities, defined by reduced Glasgow Coma Scale score (sixfold increased risk).

“Our data confirm other registries worldwide; in particular, increased susceptibility in women, the Afro-Caribbean population, and those who are middle-aged,” Dr. Shin said. “Our data also show that elevated cardiac troponin and neurological involvement are indicators of poor prognosis. Also, raised antibody levels appear to be associated with a worse clinical outcome and increased mortality rate. These are clearly valuable markers in clinical practice, allowing for intensive care of high-risk patients.”

The investigators reported having no conflicts of interest.
 

GLASGOW – Neurological abnormalities and elevated troponin predict mortality in patients with thrombotic thrombocytopenic purpura (TTP), according to retrospective analysis of 475 patients from the United Kingdom TTP registry.

Will Pass/MDedge News

In addition, low ADAMTS13 activity (less than 10%) was present in 92% of immune-mediated of TTP upon acute presentation, reported lead author Jin-Sup Shin, MD, of University College London Hospital, and colleagues.

Presenting at the annual meeting of the British Society for Haematology, Dr. Shin provided some background on TTP, a condition that most clinicians encounter infrequently.

“As recently as the 1980s and 90s, when etiology was not that well understood, TTP was associated with an untreated mortality of up to 90%,” Dr. Shin said. “However, based on improved understanding of pathophysiology, and through the creation of TTP registries worldwide, there have been major advances in diagnosis, treatment, and outcomes.”

To gain insight into diagnostic and prognostic characteristics of TTP, the investigators turned to data from 602 patients with clinically suspected TTP, based on an ADAMTS13 activity level less than 10% of normal and associated clinical signs. Out of these 602 patients, 475 consented to registry participation and data analysis.

The analysis revealed a mortality rate of 4%, although Dr. Shin said that “this is probably an underestimate of the true figure,” as it excludes those who died before treatment could be initiated.

Nearly three-quarters of patients were female. The median age at presentation was 43 years, with a range of 1-93 years. The most commonly represented racial/ethnic groups were white (60%) and Afro-Caribbean (22%). Some cases were congenital (16%), but the majority were immune mediated (84%).

The immune-mediated group was the primary focus of Dr. Shin’s report. In this cohort, 76% of cases were idiopathic, while the remainder had a defined precipitant; most common were infection, autoimmune disease, pregnancy, and HIV. The relapse rate among those with immune-mediated TTP was 19%, after a median time to relapse of 26 months.

In total, 71% of patients presented with neurological abnormalities, while slightly less than half (48%) had symptomatic thrombocytopenia (bleeding/petechiae).

Diagnostic tools showed that 64% of patients had an elevated troponin level, 92% had ADAMTS13 activity less than 10%, and 25% had a platelet count lower than 10 x 10⁹/L.

Median platelet count upon presentation was 15 x 10⁹/L, and median lactate dehydrogenase (LDH) exceeded 1,000 units/L. After 7 days of therapy, 58% of patients were still severely deficient in ADAMTS13 activity and 36% of patients still had a platelet count lower than 150 x 10⁹/L.

Where information was available, 30% of patients had positive auto-antibody screens, although not necessarily with signs or symptoms of autoimmune disease. A total of 93% of patients had elevated ADAMTS13 IgG antibody upon presentation. The median ADAMTS13 IgG antibody level at presentation was 37%, with a normal value being less than 6%.

Nearly half of patients with immune-mediated TTP (45%) required intensive care, and 10% of these patients were intubated and ventilated. Most patients were treated with steroids upon admission (81%). On average, 11 plasma exchanges (PEXs) were required before remission.

The investigators noted that “[t]he number of PEXs to remission appears to have decreased over the years.” As an example, a median of 14 PEXs were needed from 2009 to 2010, compared with 8 from 2017 to 2018.

Although rituximab usage in the acute setting held steady over the 10-year period, elective use increased. Out of 89 instances of subacute relapse, elective rituximab was given twice from 2009 to 2010, compared with 26 times from 2017 to 2018.

Comparing features of survival, the investigators found that the median ADAMTS13 IgG antibody level was higher among those who died. Other factors related to increased mortality risk included raised troponin (sevenfold increased risk) and neurological abnormalities, defined by reduced Glasgow Coma Scale score (sixfold increased risk).

“Our data confirm other registries worldwide; in particular, increased susceptibility in women, the Afro-Caribbean population, and those who are middle-aged,” Dr. Shin said. “Our data also show that elevated cardiac troponin and neurological involvement are indicators of poor prognosis. Also, raised antibody levels appear to be associated with a worse clinical outcome and increased mortality rate. These are clearly valuable markers in clinical practice, allowing for intensive care of high-risk patients.”

The investigators reported having no conflicts of interest.
 

GLASGOW – Neurological abnormalities and elevated troponin predict mortality in patients with thrombotic thrombocytopenic purpura (TTP), according to retrospective analysis of 475 patients from the United Kingdom TTP registry.

Will Pass/MDedge News

In addition, low ADAMTS13 activity (less than 10%) was present in 92% of immune-mediated of TTP upon acute presentation, reported lead author Jin-Sup Shin, MD, of University College London Hospital, and colleagues.

Presenting at the annual meeting of the British Society for Haematology, Dr. Shin provided some background on TTP, a condition that most clinicians encounter infrequently.

“As recently as the 1980s and 90s, when etiology was not that well understood, TTP was associated with an untreated mortality of up to 90%,” Dr. Shin said. “However, based on improved understanding of pathophysiology, and through the creation of TTP registries worldwide, there have been major advances in diagnosis, treatment, and outcomes.”

To gain insight into diagnostic and prognostic characteristics of TTP, the investigators turned to data from 602 patients with clinically suspected TTP, based on an ADAMTS13 activity level less than 10% of normal and associated clinical signs. Out of these 602 patients, 475 consented to registry participation and data analysis.

The analysis revealed a mortality rate of 4%, although Dr. Shin said that “this is probably an underestimate of the true figure,” as it excludes those who died before treatment could be initiated.

Nearly three-quarters of patients were female. The median age at presentation was 43 years, with a range of 1-93 years. The most commonly represented racial/ethnic groups were white (60%) and Afro-Caribbean (22%). Some cases were congenital (16%), but the majority were immune mediated (84%).

The immune-mediated group was the primary focus of Dr. Shin’s report. In this cohort, 76% of cases were idiopathic, while the remainder had a defined precipitant; most common were infection, autoimmune disease, pregnancy, and HIV. The relapse rate among those with immune-mediated TTP was 19%, after a median time to relapse of 26 months.

In total, 71% of patients presented with neurological abnormalities, while slightly less than half (48%) had symptomatic thrombocytopenia (bleeding/petechiae).

Diagnostic tools showed that 64% of patients had an elevated troponin level, 92% had ADAMTS13 activity less than 10%, and 25% had a platelet count lower than 10 x 10⁹/L.

Median platelet count upon presentation was 15 x 10⁹/L, and median lactate dehydrogenase (LDH) exceeded 1,000 units/L. After 7 days of therapy, 58% of patients were still severely deficient in ADAMTS13 activity and 36% of patients still had a platelet count lower than 150 x 10⁹/L.

Where information was available, 30% of patients had positive auto-antibody screens, although not necessarily with signs or symptoms of autoimmune disease. A total of 93% of patients had elevated ADAMTS13 IgG antibody upon presentation. The median ADAMTS13 IgG antibody level at presentation was 37%, with a normal value being less than 6%.

Nearly half of patients with immune-mediated TTP (45%) required intensive care, and 10% of these patients were intubated and ventilated. Most patients were treated with steroids upon admission (81%). On average, 11 plasma exchanges (PEXs) were required before remission.

The investigators noted that “[t]he number of PEXs to remission appears to have decreased over the years.” As an example, a median of 14 PEXs were needed from 2009 to 2010, compared with 8 from 2017 to 2018.

Although rituximab usage in the acute setting held steady over the 10-year period, elective use increased. Out of 89 instances of subacute relapse, elective rituximab was given twice from 2009 to 2010, compared with 26 times from 2017 to 2018.

Comparing features of survival, the investigators found that the median ADAMTS13 IgG antibody level was higher among those who died. Other factors related to increased mortality risk included raised troponin (sevenfold increased risk) and neurological abnormalities, defined by reduced Glasgow Coma Scale score (sixfold increased risk).

“Our data confirm other registries worldwide; in particular, increased susceptibility in women, the Afro-Caribbean population, and those who are middle-aged,” Dr. Shin said. “Our data also show that elevated cardiac troponin and neurological involvement are indicators of poor prognosis. Also, raised antibody levels appear to be associated with a worse clinical outcome and increased mortality rate. These are clearly valuable markers in clinical practice, allowing for intensive care of high-risk patients.”

The investigators reported having no conflicts of interest.
 

GLASGOW – Most older patients with primary central nervous system lymphoma (PCNSL) can tolerate high-dose methotrexate-based chemotherapy and achieve similar outcomes as younger and fitter patients, according to a retrospective analysis of 244 patients in the United Kingdom.

Will Pass/MDedge News

For older patients – at least 65 years old – who received methotrexate-based regimens, treatment-related mortality was 6.8%, which is comparable with rates seen in trials involving younger patients, reported lead author Edward Poynton, MD, of University College Hospital in London.

Specifically, Dr. Poynton cited the phase 2 IELSG32 trial, which had a treatment-related mortality rate of 6% among patients up to age 70 years. These patients were treated with the established protocol for younger patients: chemotherapy with methotrexate, cytarabine, thiotepa, and rituximab (MATRix) followed by autologous stem cell transplant or whole-brain radiotherapy.

Introducing Dr. Poynton’s presentation at the annual meeting of the British Society for Haematology, Simon Rule, MD, of the University of Plymouth (England), added historical context to the new findings.

Will Pass/MDedge News

“When I started in hematology ... [PCNSL] was a universally fatal disease, pretty much,” Dr. Rule said. “And then we had methotrexate, and it worked occasionally. And then we had a randomized trial, which was randomization of methotrexate plus or minus high-dose cytarabine, showing benefit.”

This combination became the benchmark against which subsequent randomized trials were measured; however, such high-intensity regimens have raised concerns about safety and efficacy in older patients, Dr. Rule said, noting that the present study serves to inform clinicians about real-world outcomes in this population.

The retrospective analysis reviewed 244 patients who were aged at least 65 years when histologically diagnosed with PCNSL at 14 U.K. tertiary centers between 2012 and 2017. All patients received first-line care of any kind, ranging from best supportive care to clinical trial therapy. Patients were grouped into three treatment cohorts divided by level of frailty. Analysis showed that these divisions correlated with age, renal function, Eastern Cooperative Oncology Group performance status, and treatment intensity.

The frail group received palliative treatment consisting of whole-brain radiotherapy, an oral alkylator, or best supportive care. The less-fit group received methotrexate in combination with rituximab, an oral alkylator, or both. The fit group was most intensively treated, receiving high-dose methotrexate and cytarabine – with or without rituximab – or MATRix.

The primary objective was overall response rate, while the secondary objectives were median overall survival and progression-free survival.

The analysis showed that 79% of patients (n = 193) received methotrexate-based therapy of some kind, with 61% receiving three or more cycles of therapy and 30% requiring dose reductions. The overall response rate was 63%.

Dr. Poynton noted that about two-thirds of patients who achieved a partial response in early assessment went on to achieve a complete response. Patients in the fit group more often responded than those who were less fit (87% vs. 65%; P = .01) and more often received consolidation therapy (42% vs. 23%; P = .01).

Fitness level was also associated with median overall survival, which was longest in the fit group at 42 months. The other two groups had dramatically shorter survival times: 8 months in the less-fit group and just 2 months in the frail group.

A closer look at the data revealed some patterns, Dr. Poynton said.

“What we see is that age at diagnosis is significantly correlated with progression-free survival but not with overall survival,” he said, noting that, in contrast, performance status was associated with both survival measures.

Methotrexate dose also impacted both survival measures. Patients who received 75% or more of their induction dose over the course of treatment had better median overall survival and progression-free survival than those who received less than 75%. Similarly, consolidation therapy improved both survival measures.

Patients aged older than 70 years who received intensive chemotherapy had a treatment-related mortality rate of 4.8%, which is lower than the overall treatment-related mortality, Dr. Poynton reported.

Considering the correlation between methotrexate dose and survival, Dr. Poynton suggested that “dose reductions should be carefully considered.”

He also noted that patients in the fit cohort who received intensive chemotherapy had comparable outcomes with younger patients in prospective trials, and yet 44% of patients older than 65 years in the real world who received high-dose methotrexate with cytarabine would have been ineligible for the IELSG32 trial.

“We’ve been able to identify this cohort of patients retrospectively,” Dr. Poynton said. “They definitely exist, and I think we need to work harder at how are going to identify these patients prospectively in the future, so we know which of our patients who are older can benefit from intensive chemotherapy and which patients won’t.”

Dr. Poynton reported having no relevant financial disclosures. His coinvestigators reported relationships with AbbVie, Merck, Takeda, Jazz Pharmaceuticals, and others.

GLASGOW – Most older patients with primary central nervous system lymphoma (PCNSL) can tolerate high-dose methotrexate-based chemotherapy and achieve similar outcomes as younger and fitter patients, according to a retrospective analysis of 244 patients in the United Kingdom.

Will Pass/MDedge News

For older patients – at least 65 years old – who received methotrexate-based regimens, treatment-related mortality was 6.8%, which is comparable with rates seen in trials involving younger patients, reported lead author Edward Poynton, MD, of University College Hospital in London.

Specifically, Dr. Poynton cited the phase 2 IELSG32 trial, which had a treatment-related mortality rate of 6% among patients up to age 70 years. These patients were treated with the established protocol for younger patients: chemotherapy with methotrexate, cytarabine, thiotepa, and rituximab (MATRix) followed by autologous stem cell transplant or whole-brain radiotherapy.

Introducing Dr. Poynton’s presentation at the annual meeting of the British Society for Haematology, Simon Rule, MD, of the University of Plymouth (England), added historical context to the new findings.

Will Pass/MDedge News

“When I started in hematology ... [PCNSL] was a universally fatal disease, pretty much,” Dr. Rule said. “And then we had methotrexate, and it worked occasionally. And then we had a randomized trial, which was randomization of methotrexate plus or minus high-dose cytarabine, showing benefit.”

This combination became the benchmark against which subsequent randomized trials were measured; however, such high-intensity regimens have raised concerns about safety and efficacy in older patients, Dr. Rule said, noting that the present study serves to inform clinicians about real-world outcomes in this population.

The retrospective analysis reviewed 244 patients who were aged at least 65 years when histologically diagnosed with PCNSL at 14 U.K. tertiary centers between 2012 and 2017. All patients received first-line care of any kind, ranging from best supportive care to clinical trial therapy. Patients were grouped into three treatment cohorts divided by level of frailty. Analysis showed that these divisions correlated with age, renal function, Eastern Cooperative Oncology Group performance status, and treatment intensity.

The frail group received palliative treatment consisting of whole-brain radiotherapy, an oral alkylator, or best supportive care. The less-fit group received methotrexate in combination with rituximab, an oral alkylator, or both. The fit group was most intensively treated, receiving high-dose methotrexate and cytarabine – with or without rituximab – or MATRix.

The primary objective was overall response rate, while the secondary objectives were median overall survival and progression-free survival.

The analysis showed that 79% of patients (n = 193) received methotrexate-based therapy of some kind, with 61% receiving three or more cycles of therapy and 30% requiring dose reductions. The overall response rate was 63%.

Dr. Poynton noted that about two-thirds of patients who achieved a partial response in early assessment went on to achieve a complete response. Patients in the fit group more often responded than those who were less fit (87% vs. 65%; P = .01) and more often received consolidation therapy (42% vs. 23%; P = .01).

Fitness level was also associated with median overall survival, which was longest in the fit group at 42 months. The other two groups had dramatically shorter survival times: 8 months in the less-fit group and just 2 months in the frail group.

A closer look at the data revealed some patterns, Dr. Poynton said.

“What we see is that age at diagnosis is significantly correlated with progression-free survival but not with overall survival,” he said, noting that, in contrast, performance status was associated with both survival measures.

Methotrexate dose also impacted both survival measures. Patients who received 75% or more of their induction dose over the course of treatment had better median overall survival and progression-free survival than those who received less than 75%. Similarly, consolidation therapy improved both survival measures.

Patients aged older than 70 years who received intensive chemotherapy had a treatment-related mortality rate of 4.8%, which is lower than the overall treatment-related mortality, Dr. Poynton reported.

Considering the correlation between methotrexate dose and survival, Dr. Poynton suggested that “dose reductions should be carefully considered.”

He also noted that patients in the fit cohort who received intensive chemotherapy had comparable outcomes with younger patients in prospective trials, and yet 44% of patients older than 65 years in the real world who received high-dose methotrexate with cytarabine would have been ineligible for the IELSG32 trial.

“We’ve been able to identify this cohort of patients retrospectively,” Dr. Poynton said. “They definitely exist, and I think we need to work harder at how are going to identify these patients prospectively in the future, so we know which of our patients who are older can benefit from intensive chemotherapy and which patients won’t.”

Dr. Poynton reported having no relevant financial disclosures. His coinvestigators reported relationships with AbbVie, Merck, Takeda, Jazz Pharmaceuticals, and others.

GLASGOW – Most older patients with primary central nervous system lymphoma (PCNSL) can tolerate high-dose methotrexate-based chemotherapy and achieve similar outcomes as younger and fitter patients, according to a retrospective analysis of 244 patients in the United Kingdom.

Will Pass/MDedge News

For older patients – at least 65 years old – who received methotrexate-based regimens, treatment-related mortality was 6.8%, which is comparable with rates seen in trials involving younger patients, reported lead author Edward Poynton, MD, of University College Hospital in London.

Specifically, Dr. Poynton cited the phase 2 IELSG32 trial, which had a treatment-related mortality rate of 6% among patients up to age 70 years. These patients were treated with the established protocol for younger patients: chemotherapy with methotrexate, cytarabine, thiotepa, and rituximab (MATRix) followed by autologous stem cell transplant or whole-brain radiotherapy.

Introducing Dr. Poynton’s presentation at the annual meeting of the British Society for Haematology, Simon Rule, MD, of the University of Plymouth (England), added historical context to the new findings.

Will Pass/MDedge News

“When I started in hematology ... [PCNSL] was a universally fatal disease, pretty much,” Dr. Rule said. “And then we had methotrexate, and it worked occasionally. And then we had a randomized trial, which was randomization of methotrexate plus or minus high-dose cytarabine, showing benefit.”

This combination became the benchmark against which subsequent randomized trials were measured; however, such high-intensity regimens have raised concerns about safety and efficacy in older patients, Dr. Rule said, noting that the present study serves to inform clinicians about real-world outcomes in this population.

The retrospective analysis reviewed 244 patients who were aged at least 65 years when histologically diagnosed with PCNSL at 14 U.K. tertiary centers between 2012 and 2017. All patients received first-line care of any kind, ranging from best supportive care to clinical trial therapy. Patients were grouped into three treatment cohorts divided by level of frailty. Analysis showed that these divisions correlated with age, renal function, Eastern Cooperative Oncology Group performance status, and treatment intensity.

The frail group received palliative treatment consisting of whole-brain radiotherapy, an oral alkylator, or best supportive care. The less-fit group received methotrexate in combination with rituximab, an oral alkylator, or both. The fit group was most intensively treated, receiving high-dose methotrexate and cytarabine – with or without rituximab – or MATRix.

The primary objective was overall response rate, while the secondary objectives were median overall survival and progression-free survival.

The analysis showed that 79% of patients (n = 193) received methotrexate-based therapy of some kind, with 61% receiving three or more cycles of therapy and 30% requiring dose reductions. The overall response rate was 63%.

Dr. Poynton noted that about two-thirds of patients who achieved a partial response in early assessment went on to achieve a complete response. Patients in the fit group more often responded than those who were less fit (87% vs. 65%; P = .01) and more often received consolidation therapy (42% vs. 23%; P = .01).

Fitness level was also associated with median overall survival, which was longest in the fit group at 42 months. The other two groups had dramatically shorter survival times: 8 months in the less-fit group and just 2 months in the frail group.

A closer look at the data revealed some patterns, Dr. Poynton said.

“What we see is that age at diagnosis is significantly correlated with progression-free survival but not with overall survival,” he said, noting that, in contrast, performance status was associated with both survival measures.

Methotrexate dose also impacted both survival measures. Patients who received 75% or more of their induction dose over the course of treatment had better median overall survival and progression-free survival than those who received less than 75%. Similarly, consolidation therapy improved both survival measures.

Patients aged older than 70 years who received intensive chemotherapy had a treatment-related mortality rate of 4.8%, which is lower than the overall treatment-related mortality, Dr. Poynton reported.

Considering the correlation between methotrexate dose and survival, Dr. Poynton suggested that “dose reductions should be carefully considered.”

He also noted that patients in the fit cohort who received intensive chemotherapy had comparable outcomes with younger patients in prospective trials, and yet 44% of patients older than 65 years in the real world who received high-dose methotrexate with cytarabine would have been ineligible for the IELSG32 trial.

“We’ve been able to identify this cohort of patients retrospectively,” Dr. Poynton said. “They definitely exist, and I think we need to work harder at how are going to identify these patients prospectively in the future, so we know which of our patients who are older can benefit from intensive chemotherapy and which patients won’t.”

Dr. Poynton reported having no relevant financial disclosures. His coinvestigators reported relationships with AbbVie, Merck, Takeda, Jazz Pharmaceuticals, and others.

GLASGOW – Constant patient monitoring and early intervention with tocilizumab and steroids are essential to the safe delivery of chimeric antigen receptor (CAR) T-cell therapy in patients with non-Hodgkin lymphoma (NHL), according to a leading expert.

As a clinical researcher at MD Anderson Cancer Center in Houston, Loretta Nastoupil, MD has played an active role in the evolution of CAR T-cell therapy, from early trials to ongoing development of treatment protocols. During a presentation at the annual meeting of the British Society for Haematology, Dr. Nastoupil discussed leading topics in CAR T-cell therapy, with an emphasis on safe delivery.

“[Toxicity] is something we don’t talk about as much as we should, partly because this therapy works and it’s really exciting,” Dr. Nastoupil said. “But the toxicity is not something that I minimize, and it’s very challenging. It’s led us to restructure our inpatient services. It’s led to a lot of sleepless nights. These patients can do very, very well, or they can do very, very poorly in terms of toxicity and I think the most important strategy is recognition and early intervention.”

Monitoring

Early recognition depends on close monitoring, Dr. Nastoupil said, which is carried out by highly trained nursing staff who follow therapy-specific decision algorithms.

“We have nurses that are on the front line,” Dr. Nastoupil said. “They’re the most important group. We have staff that round on [patients] daily, but the nurses are there 24 hours a day. We have a flow sheet where they grade cytokine release syndrome and neurotoxicity every 8 hours, or if there is an acute change in symptoms or toxicity, they’ll do it in real time.”

Dr. Nastoupil said that if these toxicities are detected, intervention is occurring sooner than it did with some of the first patients to receive CAR-T cell therapy.

“Initially there was a lot of fear surrounding anything that would abort the CAR-T cell therapy,” Dr. Nastoupil said. “There was concern that if you were trying to mitigate some of the toxicity you might have a negative impact on efficacy ... [W]ith the first iteration of studies, generally we were waiting until grade 3 or higher cytokine release syndrome before initiating either tocilizumab and/or steroids. As the studies evolved, it started to move into grade 2 toxicity that we started using therapy, mostly because we started to see that those patients were still responding.”

At MD Anderson, these earlier interventions have decreased severity of adverse events.

“It’s rare nowadays to have grade 3 or 4 cytokine release syndrome because we are generally introducing abortive therapy at grade 2,” Dr. Nastoupil said, citing increased use of steroids and tocilizumab.

Currently, no consensus exists for managing these events, partly because clinicians are still learning about best management practices.

“There will be a consensus on management,” Dr. Nastoupil said. “I think that’s needed. The problem is, it will probably evolve as we get more experience with managing these patients. I think there’s been a little hesitation to put something out on paper knowing that a year from now that might change.”

Grading toxicity

In contrast, Dr. Nastoupil said that a consensus has been reached for grading acute toxicity. Of note, fever is now considered an essential element of cytokine release syndrome.

“The first thing we see [with cytokine release syndrome] is fever, generally speaking,” Dr. Nastoupil said. “That will prompt a workup for infection because these patients are going to be neutropenic. And we initiate broad spectrum antimicrobials.”

She said that some patients treated with CAR T-cell therapy have had disseminated fungal infections, so clinicians need to be on the lookout for septic shock.

To assess neurotoxicity, the team at MD Anderson uses an objective scoring system, called “CARTOX.” This helps maintain consistency when facing broadly different neurological presentations.

“There’s such a wide ranging spectrum of patients that are undergoing neurotoxicity you can’t expect someone, even myself, to be consistent when you are trying to tease out how serious it is,” Dr. Nastoupil said.

With CARTOX, nurses can easily score patients and call clinicians with results. Still, this doesn’t eliminate difficulties inherent to managing neurotoxicity, particularly when it is severe.

“I’d say one of the areas that is still very challenging is when [patients with neurotoxicity] are no longer responding,” Dr. Nastoupil said. “You have to be very mindful of seizure activity. We’ve had a couple of patients with status [epilepticus]. You don’t see seizure activity physically, but when you do an EEG, you pick it up.”

Dr. Nastoupil added that most centers are now giving patients prophylactic levetiracetam (Keppra) to lower seizure risk.

Choosing therapy

When selecting between the two therapies currently approved by the Food and Drug Administration – tisagenlecleucel (Kymriah) and axicabtagene ciloleucel (Yescarta) – based on safety, Dr. Nastoupil said that rates of cytokine release syndrome appear similar, but neurotoxicity rates may differ.

“Cytokine release syndrome in my opinion is probably more similar than different in terms of grade 3 or higher because tocilizumab and steroids work quite well in aborting those toxicities,” Dr. Nastoupil said. “But neurotoxicity still sticks out in my mind as the most striking difference, where with axicabtagene you see more grade 3 or higher neurotoxicity, though very, very few deaths as a result of this. But it’s very challenging in terms of management.”

According to Dr. Nastoupil, comparisons between CAR T-cell therapies have been complicated by differences in clinical trial methodologies. However, she offered a general conclusion regarding efficacy.

“[W]hat I’ll tell you, at the end of the day, is [that existing CAR T-cell therapies] all seem to sort of settle out around 30%-40% in terms of durable responses,” Dr. Nastoupil said.

Dr. Nastoupil concluded her presentation with an overview and look to the future.

“I do think [CAR T-cell therapy] is transformative, particularly for our chemo refractory patients,” she said. “There is nothing else like it. The problem right now is that it is only durable in 40% of patients. So can we be better at selecting out patients that are more likely to respond? Does introducing this in earlier lines of therapy increase that fraction of patients that are potentially cured?”

Considering these questions, she said: “We need more patients. We need more data. We need longer follow-up to understand the nuances of this therapy.”

Dr. Nastoupil previously reported financial relationships with Celgene, Genentech, Gilead, Merck, Novartis, Spectrum, and TG Therapeutics.

GLASGOW – Constant patient monitoring and early intervention with tocilizumab and steroids are essential to the safe delivery of chimeric antigen receptor (CAR) T-cell therapy in patients with non-Hodgkin lymphoma (NHL), according to a leading expert.

As a clinical researcher at MD Anderson Cancer Center in Houston, Loretta Nastoupil, MD has played an active role in the evolution of CAR T-cell therapy, from early trials to ongoing development of treatment protocols. During a presentation at the annual meeting of the British Society for Haematology, Dr. Nastoupil discussed leading topics in CAR T-cell therapy, with an emphasis on safe delivery.

“[Toxicity] is something we don’t talk about as much as we should, partly because this therapy works and it’s really exciting,” Dr. Nastoupil said. “But the toxicity is not something that I minimize, and it’s very challenging. It’s led us to restructure our inpatient services. It’s led to a lot of sleepless nights. These patients can do very, very well, or they can do very, very poorly in terms of toxicity and I think the most important strategy is recognition and early intervention.”

Monitoring

Early recognition depends on close monitoring, Dr. Nastoupil said, which is carried out by highly trained nursing staff who follow therapy-specific decision algorithms.

“We have nurses that are on the front line,” Dr. Nastoupil said. “They’re the most important group. We have staff that round on [patients] daily, but the nurses are there 24 hours a day. We have a flow sheet where they grade cytokine release syndrome and neurotoxicity every 8 hours, or if there is an acute change in symptoms or toxicity, they’ll do it in real time.”

Dr. Nastoupil said that if these toxicities are detected, intervention is occurring sooner than it did with some of the first patients to receive CAR-T cell therapy.

“Initially there was a lot of fear surrounding anything that would abort the CAR-T cell therapy,” Dr. Nastoupil said. “There was concern that if you were trying to mitigate some of the toxicity you might have a negative impact on efficacy ... [W]ith the first iteration of studies, generally we were waiting until grade 3 or higher cytokine release syndrome before initiating either tocilizumab and/or steroids. As the studies evolved, it started to move into grade 2 toxicity that we started using therapy, mostly because we started to see that those patients were still responding.”

At MD Anderson, these earlier interventions have decreased severity of adverse events.

“It’s rare nowadays to have grade 3 or 4 cytokine release syndrome because we are generally introducing abortive therapy at grade 2,” Dr. Nastoupil said, citing increased use of steroids and tocilizumab.

Currently, no consensus exists for managing these events, partly because clinicians are still learning about best management practices.

“There will be a consensus on management,” Dr. Nastoupil said. “I think that’s needed. The problem is, it will probably evolve as we get more experience with managing these patients. I think there’s been a little hesitation to put something out on paper knowing that a year from now that might change.”

Grading toxicity

In contrast, Dr. Nastoupil said that a consensus has been reached for grading acute toxicity. Of note, fever is now considered an essential element of cytokine release syndrome.

“The first thing we see [with cytokine release syndrome] is fever, generally speaking,” Dr. Nastoupil said. “That will prompt a workup for infection because these patients are going to be neutropenic. And we initiate broad spectrum antimicrobials.”

She said that some patients treated with CAR T-cell therapy have had disseminated fungal infections, so clinicians need to be on the lookout for septic shock.

To assess neurotoxicity, the team at MD Anderson uses an objective scoring system, called “CARTOX.” This helps maintain consistency when facing broadly different neurological presentations.

“There’s such a wide ranging spectrum of patients that are undergoing neurotoxicity you can’t expect someone, even myself, to be consistent when you are trying to tease out how serious it is,” Dr. Nastoupil said.

With CARTOX, nurses can easily score patients and call clinicians with results. Still, this doesn’t eliminate difficulties inherent to managing neurotoxicity, particularly when it is severe.

“I’d say one of the areas that is still very challenging is when [patients with neurotoxicity] are no longer responding,” Dr. Nastoupil said. “You have to be very mindful of seizure activity. We’ve had a couple of patients with status [epilepticus]. You don’t see seizure activity physically, but when you do an EEG, you pick it up.”

Dr. Nastoupil added that most centers are now giving patients prophylactic levetiracetam (Keppra) to lower seizure risk.

Choosing therapy

When selecting between the two therapies currently approved by the Food and Drug Administration – tisagenlecleucel (Kymriah) and axicabtagene ciloleucel (Yescarta) – based on safety, Dr. Nastoupil said that rates of cytokine release syndrome appear similar, but neurotoxicity rates may differ.

“Cytokine release syndrome in my opinion is probably more similar than different in terms of grade 3 or higher because tocilizumab and steroids work quite well in aborting those toxicities,” Dr. Nastoupil said. “But neurotoxicity still sticks out in my mind as the most striking difference, where with axicabtagene you see more grade 3 or higher neurotoxicity, though very, very few deaths as a result of this. But it’s very challenging in terms of management.”

According to Dr. Nastoupil, comparisons between CAR T-cell therapies have been complicated by differences in clinical trial methodologies. However, she offered a general conclusion regarding efficacy.

“[W]hat I’ll tell you, at the end of the day, is [that existing CAR T-cell therapies] all seem to sort of settle out around 30%-40% in terms of durable responses,” Dr. Nastoupil said.

Dr. Nastoupil concluded her presentation with an overview and look to the future.

“I do think [CAR T-cell therapy] is transformative, particularly for our chemo refractory patients,” she said. “There is nothing else like it. The problem right now is that it is only durable in 40% of patients. So can we be better at selecting out patients that are more likely to respond? Does introducing this in earlier lines of therapy increase that fraction of patients that are potentially cured?”

Considering these questions, she said: “We need more patients. We need more data. We need longer follow-up to understand the nuances of this therapy.”

Dr. Nastoupil previously reported financial relationships with Celgene, Genentech, Gilead, Merck, Novartis, Spectrum, and TG Therapeutics.

GLASGOW – Constant patient monitoring and early intervention with tocilizumab and steroids are essential to the safe delivery of chimeric antigen receptor (CAR) T-cell therapy in patients with non-Hodgkin lymphoma (NHL), according to a leading expert.

As a clinical researcher at MD Anderson Cancer Center in Houston, Loretta Nastoupil, MD has played an active role in the evolution of CAR T-cell therapy, from early trials to ongoing development of treatment protocols. During a presentation at the annual meeting of the British Society for Haematology, Dr. Nastoupil discussed leading topics in CAR T-cell therapy, with an emphasis on safe delivery.

“[Toxicity] is something we don’t talk about as much as we should, partly because this therapy works and it’s really exciting,” Dr. Nastoupil said. “But the toxicity is not something that I minimize, and it’s very challenging. It’s led us to restructure our inpatient services. It’s led to a lot of sleepless nights. These patients can do very, very well, or they can do very, very poorly in terms of toxicity and I think the most important strategy is recognition and early intervention.”

Monitoring

Early recognition depends on close monitoring, Dr. Nastoupil said, which is carried out by highly trained nursing staff who follow therapy-specific decision algorithms.

“We have nurses that are on the front line,” Dr. Nastoupil said. “They’re the most important group. We have staff that round on [patients] daily, but the nurses are there 24 hours a day. We have a flow sheet where they grade cytokine release syndrome and neurotoxicity every 8 hours, or if there is an acute change in symptoms or toxicity, they’ll do it in real time.”

Dr. Nastoupil said that if these toxicities are detected, intervention is occurring sooner than it did with some of the first patients to receive CAR-T cell therapy.

“Initially there was a lot of fear surrounding anything that would abort the CAR-T cell therapy,” Dr. Nastoupil said. “There was concern that if you were trying to mitigate some of the toxicity you might have a negative impact on efficacy ... [W]ith the first iteration of studies, generally we were waiting until grade 3 or higher cytokine release syndrome before initiating either tocilizumab and/or steroids. As the studies evolved, it started to move into grade 2 toxicity that we started using therapy, mostly because we started to see that those patients were still responding.”

At MD Anderson, these earlier interventions have decreased severity of adverse events.

“It’s rare nowadays to have grade 3 or 4 cytokine release syndrome because we are generally introducing abortive therapy at grade 2,” Dr. Nastoupil said, citing increased use of steroids and tocilizumab.

Currently, no consensus exists for managing these events, partly because clinicians are still learning about best management practices.

“There will be a consensus on management,” Dr. Nastoupil said. “I think that’s needed. The problem is, it will probably evolve as we get more experience with managing these patients. I think there’s been a little hesitation to put something out on paper knowing that a year from now that might change.”

Grading toxicity

In contrast, Dr. Nastoupil said that a consensus has been reached for grading acute toxicity. Of note, fever is now considered an essential element of cytokine release syndrome.

“The first thing we see [with cytokine release syndrome] is fever, generally speaking,” Dr. Nastoupil said. “That will prompt a workup for infection because these patients are going to be neutropenic. And we initiate broad spectrum antimicrobials.”

She said that some patients treated with CAR T-cell therapy have had disseminated fungal infections, so clinicians need to be on the lookout for septic shock.

To assess neurotoxicity, the team at MD Anderson uses an objective scoring system, called “CARTOX.” This helps maintain consistency when facing broadly different neurological presentations.

“There’s such a wide ranging spectrum of patients that are undergoing neurotoxicity you can’t expect someone, even myself, to be consistent when you are trying to tease out how serious it is,” Dr. Nastoupil said.

With CARTOX, nurses can easily score patients and call clinicians with results. Still, this doesn’t eliminate difficulties inherent to managing neurotoxicity, particularly when it is severe.

“I’d say one of the areas that is still very challenging is when [patients with neurotoxicity] are no longer responding,” Dr. Nastoupil said. “You have to be very mindful of seizure activity. We’ve had a couple of patients with status [epilepticus]. You don’t see seizure activity physically, but when you do an EEG, you pick it up.”

Dr. Nastoupil added that most centers are now giving patients prophylactic levetiracetam (Keppra) to lower seizure risk.

Choosing therapy

When selecting between the two therapies currently approved by the Food and Drug Administration – tisagenlecleucel (Kymriah) and axicabtagene ciloleucel (Yescarta) – based on safety, Dr. Nastoupil said that rates of cytokine release syndrome appear similar, but neurotoxicity rates may differ.

“Cytokine release syndrome in my opinion is probably more similar than different in terms of grade 3 or higher because tocilizumab and steroids work quite well in aborting those toxicities,” Dr. Nastoupil said. “But neurotoxicity still sticks out in my mind as the most striking difference, where with axicabtagene you see more grade 3 or higher neurotoxicity, though very, very few deaths as a result of this. But it’s very challenging in terms of management.”

According to Dr. Nastoupil, comparisons between CAR T-cell therapies have been complicated by differences in clinical trial methodologies. However, she offered a general conclusion regarding efficacy.

“[W]hat I’ll tell you, at the end of the day, is [that existing CAR T-cell therapies] all seem to sort of settle out around 30%-40% in terms of durable responses,” Dr. Nastoupil said.

Dr. Nastoupil concluded her presentation with an overview and look to the future.

“I do think [CAR T-cell therapy] is transformative, particularly for our chemo refractory patients,” she said. “There is nothing else like it. The problem right now is that it is only durable in 40% of patients. So can we be better at selecting out patients that are more likely to respond? Does introducing this in earlier lines of therapy increase that fraction of patients that are potentially cured?”

Considering these questions, she said: “We need more patients. We need more data. We need longer follow-up to understand the nuances of this therapy.”

Dr. Nastoupil previously reported financial relationships with Celgene, Genentech, Gilead, Merck, Novartis, Spectrum, and TG Therapeutics.

GLASGOW – Many patients receiving tyrosine kinase inhibitors (TKIs) are taking complementary therapies or eating foods that interfere with TKI metabolism, based on results of a British survey of patients with chronic myeloid leukemia.

©Ls9907/Thinkstockphotos.com

About one out of three patients with chronic myeloid leukemia (CML) reported taking complementary medicines, according to lead author David Sparksman, MD, of Norfolk and Norwich (England) University Hospital, and his colleagues.

Only a minority of patients were aware of the potential for dietary interactions with TKIs. However, even knowing the potential risk, about a quarter of patients still didn’t exclude these foods from their diets.

“These worrying results are unlikely to be confined to patients with CML,” the investigators wrote in an abstract presented at the annual meeting of the British Society for Haematology. “TKIs are used in the treatment of many other haematological malignancies.”

Because TKIs are metabolized by cytochrome P450 enzymes, inhibition of these enzymes by complementary therapies and foods may alter metabolism, and therefore, safety and efficacy of TKIs, according to the investigators.

“Use of complementary medicines and belief in their effectiveness is common,” the investigators wrote. “In a recent YouGov poll, 51% of those asked believed herbal medicine to be an effective treatment for illness.”

To investigate the prevalence of these beliefs and practices in a subset of cancer patients, the investigators identified 78 patients with CML undergoing follow-up at Norfolk and Norwich University Hospital. The median age of patients was 60 years. Eleven patients were excluded because they were not receiving a TKI and 6 patients declined to participate, leaving 61 patients in the final survey group.

Of these respondents, 41% had considered taking a complementary therapy and 34% were actively doing so. Further questioning revealed that about half of the patients taking a complementary medicine (52%) were taking a drug with known potential to interact with their TKI. Of these 11 patients, 5 were taking a complementary drug that would reduce serum concentrations of their TKI, potentially making it less effective. Conversely, six patients were taking a complementary drug that would increase serum concentrations, potentially increasing the risk of TKI side effects.

About 39% of respondents were aware of possible dietary interactions with TKIs, such as grapefruit. “Surprisingly,” the investigators said, 25% of patients with this knowledge still included such foods in their diet.

Dietary questioning revealed that among the patients who were unaware of food interactions, 67% were consuming foods that interact with TKIs.

Considering these results, the investigators offered some advice on patient communication and management.

“The use of complementary medicine should be discussed with all patients when starting TKIs and written information given to patients should highlight the potential dangers posed by substances which many patients currently regard as harmless,” thy wrote. “Since most patients will remain on treatment for many years, re-discussion about food and drug interactions should take place periodically to remind them of the potential risks.”

The investigators reported having no conflicts of interest.

GLASGOW – Many patients receiving tyrosine kinase inhibitors (TKIs) are taking complementary therapies or eating foods that interfere with TKI metabolism, based on results of a British survey of patients with chronic myeloid leukemia.

©Ls9907/Thinkstockphotos.com

About one out of three patients with chronic myeloid leukemia (CML) reported taking complementary medicines, according to lead author David Sparksman, MD, of Norfolk and Norwich (England) University Hospital, and his colleagues.

Only a minority of patients were aware of the potential for dietary interactions with TKIs. However, even knowing the potential risk, about a quarter of patients still didn’t exclude these foods from their diets.

“These worrying results are unlikely to be confined to patients with CML,” the investigators wrote in an abstract presented at the annual meeting of the British Society for Haematology. “TKIs are used in the treatment of many other haematological malignancies.”

Because TKIs are metabolized by cytochrome P450 enzymes, inhibition of these enzymes by complementary therapies and foods may alter metabolism, and therefore, safety and efficacy of TKIs, according to the investigators.

“Use of complementary medicines and belief in their effectiveness is common,” the investigators wrote. “In a recent YouGov poll, 51% of those asked believed herbal medicine to be an effective treatment for illness.”

To investigate the prevalence of these beliefs and practices in a subset of cancer patients, the investigators identified 78 patients with CML undergoing follow-up at Norfolk and Norwich University Hospital. The median age of patients was 60 years. Eleven patients were excluded because they were not receiving a TKI and 6 patients declined to participate, leaving 61 patients in the final survey group.

Of these respondents, 41% had considered taking a complementary therapy and 34% were actively doing so. Further questioning revealed that about half of the patients taking a complementary medicine (52%) were taking a drug with known potential to interact with their TKI. Of these 11 patients, 5 were taking a complementary drug that would reduce serum concentrations of their TKI, potentially making it less effective. Conversely, six patients were taking a complementary drug that would increase serum concentrations, potentially increasing the risk of TKI side effects.

About 39% of respondents were aware of possible dietary interactions with TKIs, such as grapefruit. “Surprisingly,” the investigators said, 25% of patients with this knowledge still included such foods in their diet.

Dietary questioning revealed that among the patients who were unaware of food interactions, 67% were consuming foods that interact with TKIs.

Considering these results, the investigators offered some advice on patient communication and management.

“The use of complementary medicine should be discussed with all patients when starting TKIs and written information given to patients should highlight the potential dangers posed by substances which many patients currently regard as harmless,” thy wrote. “Since most patients will remain on treatment for many years, re-discussion about food and drug interactions should take place periodically to remind them of the potential risks.”

The investigators reported having no conflicts of interest.

GLASGOW – Many patients receiving tyrosine kinase inhibitors (TKIs) are taking complementary therapies or eating foods that interfere with TKI metabolism, based on results of a British survey of patients with chronic myeloid leukemia.

©Ls9907/Thinkstockphotos.com

About one out of three patients with chronic myeloid leukemia (CML) reported taking complementary medicines, according to lead author David Sparksman, MD, of Norfolk and Norwich (England) University Hospital, and his colleagues.

Only a minority of patients were aware of the potential for dietary interactions with TKIs. However, even knowing the potential risk, about a quarter of patients still didn’t exclude these foods from their diets.

“These worrying results are unlikely to be confined to patients with CML,” the investigators wrote in an abstract presented at the annual meeting of the British Society for Haematology. “TKIs are used in the treatment of many other haematological malignancies.”

Because TKIs are metabolized by cytochrome P450 enzymes, inhibition of these enzymes by complementary therapies and foods may alter metabolism, and therefore, safety and efficacy of TKIs, according to the investigators.

“Use of complementary medicines and belief in their effectiveness is common,” the investigators wrote. “In a recent YouGov poll, 51% of those asked believed herbal medicine to be an effective treatment for illness.”

To investigate the prevalence of these beliefs and practices in a subset of cancer patients, the investigators identified 78 patients with CML undergoing follow-up at Norfolk and Norwich University Hospital. The median age of patients was 60 years. Eleven patients were excluded because they were not receiving a TKI and 6 patients declined to participate, leaving 61 patients in the final survey group.

Of these respondents, 41% had considered taking a complementary therapy and 34% were actively doing so. Further questioning revealed that about half of the patients taking a complementary medicine (52%) were taking a drug with known potential to interact with their TKI. Of these 11 patients, 5 were taking a complementary drug that would reduce serum concentrations of their TKI, potentially making it less effective. Conversely, six patients were taking a complementary drug that would increase serum concentrations, potentially increasing the risk of TKI side effects.

About 39% of respondents were aware of possible dietary interactions with TKIs, such as grapefruit. “Surprisingly,” the investigators said, 25% of patients with this knowledge still included such foods in their diet.

Dietary questioning revealed that among the patients who were unaware of food interactions, 67% were consuming foods that interact with TKIs.

Considering these results, the investigators offered some advice on patient communication and management.

“The use of complementary medicine should be discussed with all patients when starting TKIs and written information given to patients should highlight the potential dangers posed by substances which many patients currently regard as harmless,” thy wrote. “Since most patients will remain on treatment for many years, re-discussion about food and drug interactions should take place periodically to remind them of the potential risks.”

The investigators reported having no conflicts of interest.

GENEVA – Level of programmed death-ligand 1 (PD-L1) expression does not impact patient-reported outcomes (PROs) among those receiving durvalumab for stage III non–small cell lung cancer (NSCLC), according to a retrospective analysis of the phase III PACIFIC trial.

Will Pass/MDedge News

The findings support durvalumab for all comers regardless of PD-L1 expression, reported lead author Marina Garassino, MD, of Fondazione IRCCS – Instituto Nazionale dei Tumori in Milan, who presented findings at the European Lung Cancer Congress.

The PACIFIC trial involved 713 patients with stage III NSCLC who did not progress after platinum-based concurrent chemoradiotherapy, demonstrating both improved progression-free and overall survival. Patients were randomized 2:1 to receive either durvalumab (10 mg/kg) or placebo IV every 2 weeks for up to 1 year. Out of 713 patients involved in the trial, 63% had PD-L1 tumor expression level data available for the present analysis, allowing for subgrouping into five categories: expression level of at least 25%, less than 25%, at least 1%, less than 1%, or unknown. The investigators compared PROs from these cohorts using the European Organisation for Research and Treatment of Cancer core quality of life questionnaire and lung cancer module (EORTC QLQ-C30 and -LC13). With scores ranging from 1 to 100 points, clinically meaningful differences were defined by score changes exceeding 10 points. Changes during treatment, from baseline to week 48, were analyzed by a mixed model for repeated measures, overall responses for improvement rates by logistic regression, and hazard ratios for time to deterioration (TTD) by a stratified Cox proportional-hazards model.

The investigators found that most PROs remained consistent over time, without clinically meaningful variations between PD-L1 expression levels. However, as with the entire PACIFIC treatment population, patients in the present analysis showed changes in some PROs. At the meeting presented by the European Society for Medical Oncology, Dr. Garassino noted that it would be unrealistic to describe all PRO comparisons; instead, she presented several examples. For one, in patients receiving durvalumab, dysphagia and alopecia improved in four out of five PD-L1 subgroups and all subgroups, respectively, while patients in the placebo arm reported improvements in both measures regardless of PD-L1 expression. Other improvements tended to favor the durvalumab group; for instance, compared with other subgroups, patients with PD-L1 expression of at least 25% were more likely to report improved chest pain, physical functioning, pain, emotional functioning, and hemoptysis. In contrast, patients receiving placebo with PD-L1 expression less than 25% were more likely to report improved cough. Still, the investigators concluded that the overall picture did not suggest major differences in PROs by PD-L1 expression level, noting that global quality of life did not differ, and symptom improvement rates and time-to-deterioration measures generally aligned with the intent-to-treat population, judging by overlapping 95% confidence intervals and hazard ratios.

“These data support the PACIFIC regimen for the standard of care for stage III unresectable non–small cell lung cancer patients,” Dr. Garassino concluded.

Will Pass/MDedge News

Invited discussant Fabrice Barlesi, MD, PhD, of Aix-Marseille University, said that studies such as this one are important to ensure that investigator-implemented measures of response are calibrated to patient experiences. As an example, Dr. Barlesi noted that many clinicians would say that grade 2 diarrhea is a completely manageable adverse event, but not all patients would agree.

In this light, Dr. Barlesi said that the present findings are valuable, but they are not without flaws. He noted that 11 out of 13 symptoms from the quality of life lung cancer module were not reported, and that one-third of patients in the PACIFIC trial lacked PD-L1 expression level data.

Considering these shortcomings, and more broadly, difficulties comparing patient-reported outcome studies because of various measurement techniques, Dr. Barlesi called for standardization.

“We need to standardize the analysis of quality of life data,” Dr. Barlesi said. “We should correct for the multiplicity of tests. … we should identify some specific quality of life outcomes that we want to look at in the protocol.” He continued to suggest a variety of ideal characteristics for studies evaluating patient-reported outcomes, including defined statistical measures and protocols for missing data.

Without a standardized approach, “cross trial comparison will be a nightmare for all of us,” Dr. Barlesi said.

The study was funded by AstraZeneca. The investigators reported financial relationships with Roche, BMS, Lilly, and others.

SOURCE: Garassino et al. ELCC 2019. Abstract LBA2.

GENEVA – Level of programmed death-ligand 1 (PD-L1) expression does not impact patient-reported outcomes (PROs) among those receiving durvalumab for stage III non–small cell lung cancer (NSCLC), according to a retrospective analysis of the phase III PACIFIC trial.

Will Pass/MDedge News

The findings support durvalumab for all comers regardless of PD-L1 expression, reported lead author Marina Garassino, MD, of Fondazione IRCCS – Instituto Nazionale dei Tumori in Milan, who presented findings at the European Lung Cancer Congress.

The PACIFIC trial involved 713 patients with stage III NSCLC who did not progress after platinum-based concurrent chemoradiotherapy, demonstrating both improved progression-free and overall survival. Patients were randomized 2:1 to receive either durvalumab (10 mg/kg) or placebo IV every 2 weeks for up to 1 year. Out of 713 patients involved in the trial, 63% had PD-L1 tumor expression level data available for the present analysis, allowing for subgrouping into five categories: expression level of at least 25%, less than 25%, at least 1%, less than 1%, or unknown. The investigators compared PROs from these cohorts using the European Organisation for Research and Treatment of Cancer core quality of life questionnaire and lung cancer module (EORTC QLQ-C30 and -LC13). With scores ranging from 1 to 100 points, clinically meaningful differences were defined by score changes exceeding 10 points. Changes during treatment, from baseline to week 48, were analyzed by a mixed model for repeated measures, overall responses for improvement rates by logistic regression, and hazard ratios for time to deterioration (TTD) by a stratified Cox proportional-hazards model.

The investigators found that most PROs remained consistent over time, without clinically meaningful variations between PD-L1 expression levels. However, as with the entire PACIFIC treatment population, patients in the present analysis showed changes in some PROs. At the meeting presented by the European Society for Medical Oncology, Dr. Garassino noted that it would be unrealistic to describe all PRO comparisons; instead, she presented several examples. For one, in patients receiving durvalumab, dysphagia and alopecia improved in four out of five PD-L1 subgroups and all subgroups, respectively, while patients in the placebo arm reported improvements in both measures regardless of PD-L1 expression. Other improvements tended to favor the durvalumab group; for instance, compared with other subgroups, patients with PD-L1 expression of at least 25% were more likely to report improved chest pain, physical functioning, pain, emotional functioning, and hemoptysis. In contrast, patients receiving placebo with PD-L1 expression less than 25% were more likely to report improved cough. Still, the investigators concluded that the overall picture did not suggest major differences in PROs by PD-L1 expression level, noting that global quality of life did not differ, and symptom improvement rates and time-to-deterioration measures generally aligned with the intent-to-treat population, judging by overlapping 95% confidence intervals and hazard ratios.

“These data support the PACIFIC regimen for the standard of care for stage III unresectable non–small cell lung cancer patients,” Dr. Garassino concluded.

Will Pass/MDedge News

Invited discussant Fabrice Barlesi, MD, PhD, of Aix-Marseille University, said that studies such as this one are important to ensure that investigator-implemented measures of response are calibrated to patient experiences. As an example, Dr. Barlesi noted that many clinicians would say that grade 2 diarrhea is a completely manageable adverse event, but not all patients would agree.

In this light, Dr. Barlesi said that the present findings are valuable, but they are not without flaws. He noted that 11 out of 13 symptoms from the quality of life lung cancer module were not reported, and that one-third of patients in the PACIFIC trial lacked PD-L1 expression level data.

Considering these shortcomings, and more broadly, difficulties comparing patient-reported outcome studies because of various measurement techniques, Dr. Barlesi called for standardization.

“We need to standardize the analysis of quality of life data,” Dr. Barlesi said. “We should correct for the multiplicity of tests. … we should identify some specific quality of life outcomes that we want to look at in the protocol.” He continued to suggest a variety of ideal characteristics for studies evaluating patient-reported outcomes, including defined statistical measures and protocols for missing data.

Without a standardized approach, “cross trial comparison will be a nightmare for all of us,” Dr. Barlesi said.

The study was funded by AstraZeneca. The investigators reported financial relationships with Roche, BMS, Lilly, and others.

SOURCE: Garassino et al. ELCC 2019. Abstract LBA2.

GENEVA – Level of programmed death-ligand 1 (PD-L1) expression does not impact patient-reported outcomes (PROs) among those receiving durvalumab for stage III non–small cell lung cancer (NSCLC), according to a retrospective analysis of the phase III PACIFIC trial.

Will Pass/MDedge News

The findings support durvalumab for all comers regardless of PD-L1 expression, reported lead author Marina Garassino, MD, of Fondazione IRCCS – Instituto Nazionale dei Tumori in Milan, who presented findings at the European Lung Cancer Congress.

The PACIFIC trial involved 713 patients with stage III NSCLC who did not progress after platinum-based concurrent chemoradiotherapy, demonstrating both improved progression-free and overall survival. Patients were randomized 2:1 to receive either durvalumab (10 mg/kg) or placebo IV every 2 weeks for up to 1 year. Out of 713 patients involved in the trial, 63% had PD-L1 tumor expression level data available for the present analysis, allowing for subgrouping into five categories: expression level of at least 25%, less than 25%, at least 1%, less than 1%, or unknown. The investigators compared PROs from these cohorts using the European Organisation for Research and Treatment of Cancer core quality of life questionnaire and lung cancer module (EORTC QLQ-C30 and -LC13). With scores ranging from 1 to 100 points, clinically meaningful differences were defined by score changes exceeding 10 points. Changes during treatment, from baseline to week 48, were analyzed by a mixed model for repeated measures, overall responses for improvement rates by logistic regression, and hazard ratios for time to deterioration (TTD) by a stratified Cox proportional-hazards model.

The investigators found that most PROs remained consistent over time, without clinically meaningful variations between PD-L1 expression levels. However, as with the entire PACIFIC treatment population, patients in the present analysis showed changes in some PROs. At the meeting presented by the European Society for Medical Oncology, Dr. Garassino noted that it would be unrealistic to describe all PRO comparisons; instead, she presented several examples. For one, in patients receiving durvalumab, dysphagia and alopecia improved in four out of five PD-L1 subgroups and all subgroups, respectively, while patients in the placebo arm reported improvements in both measures regardless of PD-L1 expression. Other improvements tended to favor the durvalumab group; for instance, compared with other subgroups, patients with PD-L1 expression of at least 25% were more likely to report improved chest pain, physical functioning, pain, emotional functioning, and hemoptysis. In contrast, patients receiving placebo with PD-L1 expression less than 25% were more likely to report improved cough. Still, the investigators concluded that the overall picture did not suggest major differences in PROs by PD-L1 expression level, noting that global quality of life did not differ, and symptom improvement rates and time-to-deterioration measures generally aligned with the intent-to-treat population, judging by overlapping 95% confidence intervals and hazard ratios.

“These data support the PACIFIC regimen for the standard of care for stage III unresectable non–small cell lung cancer patients,” Dr. Garassino concluded.

Will Pass/MDedge News

Invited discussant Fabrice Barlesi, MD, PhD, of Aix-Marseille University, said that studies such as this one are important to ensure that investigator-implemented measures of response are calibrated to patient experiences. As an example, Dr. Barlesi noted that many clinicians would say that grade 2 diarrhea is a completely manageable adverse event, but not all patients would agree.

In this light, Dr. Barlesi said that the present findings are valuable, but they are not without flaws. He noted that 11 out of 13 symptoms from the quality of life lung cancer module were not reported, and that one-third of patients in the PACIFIC trial lacked PD-L1 expression level data.

Considering these shortcomings, and more broadly, difficulties comparing patient-reported outcome studies because of various measurement techniques, Dr. Barlesi called for standardization.

“We need to standardize the analysis of quality of life data,” Dr. Barlesi said. “We should correct for the multiplicity of tests. … we should identify some specific quality of life outcomes that we want to look at in the protocol.” He continued to suggest a variety of ideal characteristics for studies evaluating patient-reported outcomes, including defined statistical measures and protocols for missing data.

Without a standardized approach, “cross trial comparison will be a nightmare for all of us,” Dr. Barlesi said.

The study was funded by AstraZeneca. The investigators reported financial relationships with Roche, BMS, Lilly, and others.

SOURCE: Garassino et al. ELCC 2019. Abstract LBA2.

Patients who have recurrence of cutaneous squamous cell cancer of the head and neck (cSCC-HN) tend to have poor outcomes regardless of immune status, according to investigators.

Patients with surgically unsalvageable recurrent disease had the worst outcomes, reported lead author Lillian Sun, of the Cleveland Clinic, and her colleagues.

These findings support more intensive upfront therapy for patients with cSCC-HN, the investigators wrote in JAMA Dermatology. They noted that most patients with cSCC have good outcomes, with less than 5% experiencing recurrence or distant metastasis; however, “there is a subset of patients with adverse pathologic features and a more aggressive clinical course,” the investigators pointed out, “with substantially higher rates of locoregional recurrence (13%-41%) and distant metastasis (7%-16%) after surgical resection.”

According to the investigators, previous research has identified several patient factors that predict poor outcomes, such as invasiveness and differentiation, as well as chronic immunosuppression. To build on these data, and, in particular, to determine if immune suppression was linked with poor outcomes, the investigators conducted a retrospective analysis of 205 patients with cSCC-HN.

From this cohort, 72 patients had disease recurrence after surgery and radiotherapy. The average age of the patients was 71 years. About half were immunosuppressed (55.6%). On average, disease recurrence occurred slightly earlier in immunosuppressed patients (9.1 months) than in immunocompetent patients (10.1 months). Most patients had locoregional recurrence first, at rates of 65.6% and 77.5% among immunocompetent and immunosuppressed patients, respectively. Irrespective of immune status, median overall survival was 8.4 months and the 1-year overall survival rate was 43.2%. In contrast with previous findings, immune status was not statistically associated with median overall survival; immunocompetent patients did tend to live longer (12.9 months) than immunosuppressed patients (8.0 months), but this difference carried a P value of .90.

The investigators found that surgical candidacy after recurrence had the strongest impact on survival. Patients with surgically salvageable disease had a median overall survival of 26.1 months, compared with just 4.7 months for those who were not amenable to surgical salvage (P = .01). Among patients with unsalvageable disease, again, immune status did not have a significant impact on outcome.

“This study demonstrates that survival in this population is poor,” the investigators concluded. “Although we hypothesized that immunosuppressed status would be a significant contributor to outcomes in these patients, similar to findings in the upfront treatment setting, the current study suggests that this is not the case.”

The investigators reported clinical trial support from Genentech, Merck, and Bristol-Myers Squibb.

SOURCE: Sun et al. JAMA Derm. 27 Feb 2019. doi: 10.1001/jamadermatol.2018.5453.

Patients who have recurrence of cutaneous squamous cell cancer of the head and neck (cSCC-HN) tend to have poor outcomes regardless of immune status, according to investigators.

Patients with surgically unsalvageable recurrent disease had the worst outcomes, reported lead author Lillian Sun, of the Cleveland Clinic, and her colleagues.

These findings support more intensive upfront therapy for patients with cSCC-HN, the investigators wrote in JAMA Dermatology. They noted that most patients with cSCC have good outcomes, with less than 5% experiencing recurrence or distant metastasis; however, “there is a subset of patients with adverse pathologic features and a more aggressive clinical course,” the investigators pointed out, “with substantially higher rates of locoregional recurrence (13%-41%) and distant metastasis (7%-16%) after surgical resection.”

According to the investigators, previous research has identified several patient factors that predict poor outcomes, such as invasiveness and differentiation, as well as chronic immunosuppression. To build on these data, and, in particular, to determine if immune suppression was linked with poor outcomes, the investigators conducted a retrospective analysis of 205 patients with cSCC-HN.

From this cohort, 72 patients had disease recurrence after surgery and radiotherapy. The average age of the patients was 71 years. About half were immunosuppressed (55.6%). On average, disease recurrence occurred slightly earlier in immunosuppressed patients (9.1 months) than in immunocompetent patients (10.1 months). Most patients had locoregional recurrence first, at rates of 65.6% and 77.5% among immunocompetent and immunosuppressed patients, respectively. Irrespective of immune status, median overall survival was 8.4 months and the 1-year overall survival rate was 43.2%. In contrast with previous findings, immune status was not statistically associated with median overall survival; immunocompetent patients did tend to live longer (12.9 months) than immunosuppressed patients (8.0 months), but this difference carried a P value of .90.

The investigators found that surgical candidacy after recurrence had the strongest impact on survival. Patients with surgically salvageable disease had a median overall survival of 26.1 months, compared with just 4.7 months for those who were not amenable to surgical salvage (P = .01). Among patients with unsalvageable disease, again, immune status did not have a significant impact on outcome.

“This study demonstrates that survival in this population is poor,” the investigators concluded. “Although we hypothesized that immunosuppressed status would be a significant contributor to outcomes in these patients, similar to findings in the upfront treatment setting, the current study suggests that this is not the case.”

The investigators reported clinical trial support from Genentech, Merck, and Bristol-Myers Squibb.

SOURCE: Sun et al. JAMA Derm. 27 Feb 2019. doi: 10.1001/jamadermatol.2018.5453.

Patients who have recurrence of cutaneous squamous cell cancer of the head and neck (cSCC-HN) tend to have poor outcomes regardless of immune status, according to investigators.

Patients with surgically unsalvageable recurrent disease had the worst outcomes, reported lead author Lillian Sun, of the Cleveland Clinic, and her colleagues.

These findings support more intensive upfront therapy for patients with cSCC-HN, the investigators wrote in JAMA Dermatology. They noted that most patients with cSCC have good outcomes, with less than 5% experiencing recurrence or distant metastasis; however, “there is a subset of patients with adverse pathologic features and a more aggressive clinical course,” the investigators pointed out, “with substantially higher rates of locoregional recurrence (13%-41%) and distant metastasis (7%-16%) after surgical resection.”

According to the investigators, previous research has identified several patient factors that predict poor outcomes, such as invasiveness and differentiation, as well as chronic immunosuppression. To build on these data, and, in particular, to determine if immune suppression was linked with poor outcomes, the investigators conducted a retrospective analysis of 205 patients with cSCC-HN.

From this cohort, 72 patients had disease recurrence after surgery and radiotherapy. The average age of the patients was 71 years. About half were immunosuppressed (55.6%). On average, disease recurrence occurred slightly earlier in immunosuppressed patients (9.1 months) than in immunocompetent patients (10.1 months). Most patients had locoregional recurrence first, at rates of 65.6% and 77.5% among immunocompetent and immunosuppressed patients, respectively. Irrespective of immune status, median overall survival was 8.4 months and the 1-year overall survival rate was 43.2%. In contrast with previous findings, immune status was not statistically associated with median overall survival; immunocompetent patients did tend to live longer (12.9 months) than immunosuppressed patients (8.0 months), but this difference carried a P value of .90.

The investigators found that surgical candidacy after recurrence had the strongest impact on survival. Patients with surgically salvageable disease had a median overall survival of 26.1 months, compared with just 4.7 months for those who were not amenable to surgical salvage (P = .01). Among patients with unsalvageable disease, again, immune status did not have a significant impact on outcome.

“This study demonstrates that survival in this population is poor,” the investigators concluded. “Although we hypothesized that immunosuppressed status would be a significant contributor to outcomes in these patients, similar to findings in the upfront treatment setting, the current study suggests that this is not the case.”

The investigators reported clinical trial support from Genentech, Merck, and Bristol-Myers Squibb.

SOURCE: Sun et al. JAMA Derm. 27 Feb 2019. doi: 10.1001/jamadermatol.2018.5453.

For many patients with hemophilia A, with or without inhibitors, a monthly emicizumab injection is enough to ensure a high level of bleed control, based on results from the ongoing HAVEN 4 trial.

Most patients reported three or fewer treated bleeds, while slightly more than half had no treated bleeds at all, according to lead author Steven W. Pipe, MD, of the University of Michigan, Ann Arbor, and his colleagues. The investigators noted that results from this trial have already led to approval of a monthly dosing schedule in the United States and several other countries.

“This convenient regimen has the potential to improve the care of patients by decreasing their treatment burden, and increasing uptake and adherence to effective prophylaxis, which is known to decrease the development of debilitating secondary complications,” the investigators wrote. The report is in The Lancet Haematology.

The data were collected at 20 centers in 8 countries. Eligibility required that patients have severe congenital hemophilia A (less than 1% normal FVIII activity), or hemophilia A with FVIII inhibitors and concurrent treatment with bypassing agents or FVIII concentrates.

An initial run-in cohort that included seven patients assessed pharmacokinetics and safety. These patients received 6 mg/kg of emicizumab subcutaneously every 4 weeks for at least 24 weeks. After this group showed good responses, 41 additional patients were enrolled in an expansion cohort, which involved an initial loading phase of weekly doses at 3 mg/kg for the first month, followed by monthly dosing at 6 mg/kg for at least 6 months (24 weeks).

The efficacy endpoint of the study was bleed prevention, as measured by treated target joint bleeds, treated joint bleeds, treated spontaneous bleeds, all bleeds (untreated and treated), and annualized bleed rates for treated bleeds.

In the expansion cohort, the median number of bleeds in the 24-week period preceding enrollment was five. In the same group, five patients (12%) had FVIII inhibitors and 61% of patients exhibited at least one target joint.

After a median treatment of 25.6 weeks, the model-based annualized bleed rate for treated bleeds was 2.4, while the median annualized bleed rate was zero.

Slightly more than half of the patients (56.1%) reported no treated bleeds, 90% of patients reported 0-3 treated bleeds, and 85% of patients did not require treatment for targeted joint bleeds.

When untreated bleeds were included, the model-based annualized bleed rate was 4.5, while the median annualized bleed rate was 2.1. Almost one-third of patients (29%) had no bleeding events of any kind and most (80%) had 0-3 treated or untreated bleeds.

Overall, treatment was well tolerated, with no patients withdrawing from the study, discontinuing treatment, or requiring dose modifications. Laboratory parameters remained stable throughout. The most common treatment-related adverse event was injection-site reaction (22%), followed distantly by pre-syncope, chills, rash, and erythema, each of which occurred in 2% of patients.

“Overall, the results of HAVEN 4 are consistent with the findings of other HAVEN studies,” the investigators wrote. “The option of treatment with emicizumab every 4 weeks broadens the range of administration frequencies and allows clinicians to tailor treatment to each patient’s needs and preferences.”

F. Hoffman-La Roche and Chugai funded the study. The investigators reported financial relationships with the study sponsors and other companies.

SOURCE: Pipe SW et al. Lancet Haem. 2019 Apr 16. doi: 10.1016/S2352-3026(19)30054-7.

For many patients with hemophilia A, with or without inhibitors, a monthly emicizumab injection is enough to ensure a high level of bleed control, based on results from the ongoing HAVEN 4 trial.

Most patients reported three or fewer treated bleeds, while slightly more than half had no treated bleeds at all, according to lead author Steven W. Pipe, MD, of the University of Michigan, Ann Arbor, and his colleagues. The investigators noted that results from this trial have already led to approval of a monthly dosing schedule in the United States and several other countries.

“This convenient regimen has the potential to improve the care of patients by decreasing their treatment burden, and increasing uptake and adherence to effective prophylaxis, which is known to decrease the development of debilitating secondary complications,” the investigators wrote. The report is in The Lancet Haematology.

The data were collected at 20 centers in 8 countries. Eligibility required that patients have severe congenital hemophilia A (less than 1% normal FVIII activity), or hemophilia A with FVIII inhibitors and concurrent treatment with bypassing agents or FVIII concentrates.

An initial run-in cohort that included seven patients assessed pharmacokinetics and safety. These patients received 6 mg/kg of emicizumab subcutaneously every 4 weeks for at least 24 weeks. After this group showed good responses, 41 additional patients were enrolled in an expansion cohort, which involved an initial loading phase of weekly doses at 3 mg/kg for the first month, followed by monthly dosing at 6 mg/kg for at least 6 months (24 weeks).

The efficacy endpoint of the study was bleed prevention, as measured by treated target joint bleeds, treated joint bleeds, treated spontaneous bleeds, all bleeds (untreated and treated), and annualized bleed rates for treated bleeds.

In the expansion cohort, the median number of bleeds in the 24-week period preceding enrollment was five. In the same group, five patients (12%) had FVIII inhibitors and 61% of patients exhibited at least one target joint.

After a median treatment of 25.6 weeks, the model-based annualized bleed rate for treated bleeds was 2.4, while the median annualized bleed rate was zero.

Slightly more than half of the patients (56.1%) reported no treated bleeds, 90% of patients reported 0-3 treated bleeds, and 85% of patients did not require treatment for targeted joint bleeds.

When untreated bleeds were included, the model-based annualized bleed rate was 4.5, while the median annualized bleed rate was 2.1. Almost one-third of patients (29%) had no bleeding events of any kind and most (80%) had 0-3 treated or untreated bleeds.

Overall, treatment was well tolerated, with no patients withdrawing from the study, discontinuing treatment, or requiring dose modifications. Laboratory parameters remained stable throughout. The most common treatment-related adverse event was injection-site reaction (22%), followed distantly by pre-syncope, chills, rash, and erythema, each of which occurred in 2% of patients.

“Overall, the results of HAVEN 4 are consistent with the findings of other HAVEN studies,” the investigators wrote. “The option of treatment with emicizumab every 4 weeks broadens the range of administration frequencies and allows clinicians to tailor treatment to each patient’s needs and preferences.”

F. Hoffman-La Roche and Chugai funded the study. The investigators reported financial relationships with the study sponsors and other companies.

SOURCE: Pipe SW et al. Lancet Haem. 2019 Apr 16. doi: 10.1016/S2352-3026(19)30054-7.

For many patients with hemophilia A, with or without inhibitors, a monthly emicizumab injection is enough to ensure a high level of bleed control, based on results from the ongoing HAVEN 4 trial.

Most patients reported three or fewer treated bleeds, while slightly more than half had no treated bleeds at all, according to lead author Steven W. Pipe, MD, of the University of Michigan, Ann Arbor, and his colleagues. The investigators noted that results from this trial have already led to approval of a monthly dosing schedule in the United States and several other countries.

“This convenient regimen has the potential to improve the care of patients by decreasing their treatment burden, and increasing uptake and adherence to effective prophylaxis, which is known to decrease the development of debilitating secondary complications,” the investigators wrote. The report is in The Lancet Haematology.

The data were collected at 20 centers in 8 countries. Eligibility required that patients have severe congenital hemophilia A (less than 1% normal FVIII activity), or hemophilia A with FVIII inhibitors and concurrent treatment with bypassing agents or FVIII concentrates.

An initial run-in cohort that included seven patients assessed pharmacokinetics and safety. These patients received 6 mg/kg of emicizumab subcutaneously every 4 weeks for at least 24 weeks. After this group showed good responses, 41 additional patients were enrolled in an expansion cohort, which involved an initial loading phase of weekly doses at 3 mg/kg for the first month, followed by monthly dosing at 6 mg/kg for at least 6 months (24 weeks).

The efficacy endpoint of the study was bleed prevention, as measured by treated target joint bleeds, treated joint bleeds, treated spontaneous bleeds, all bleeds (untreated and treated), and annualized bleed rates for treated bleeds.

In the expansion cohort, the median number of bleeds in the 24-week period preceding enrollment was five. In the same group, five patients (12%) had FVIII inhibitors and 61% of patients exhibited at least one target joint.

After a median treatment of 25.6 weeks, the model-based annualized bleed rate for treated bleeds was 2.4, while the median annualized bleed rate was zero.

Slightly more than half of the patients (56.1%) reported no treated bleeds, 90% of patients reported 0-3 treated bleeds, and 85% of patients did not require treatment for targeted joint bleeds.

When untreated bleeds were included, the model-based annualized bleed rate was 4.5, while the median annualized bleed rate was 2.1. Almost one-third of patients (29%) had no bleeding events of any kind and most (80%) had 0-3 treated or untreated bleeds.

Overall, treatment was well tolerated, with no patients withdrawing from the study, discontinuing treatment, or requiring dose modifications. Laboratory parameters remained stable throughout. The most common treatment-related adverse event was injection-site reaction (22%), followed distantly by pre-syncope, chills, rash, and erythema, each of which occurred in 2% of patients.

“Overall, the results of HAVEN 4 are consistent with the findings of other HAVEN studies,” the investigators wrote. “The option of treatment with emicizumab every 4 weeks broadens the range of administration frequencies and allows clinicians to tailor treatment to each patient’s needs and preferences.”

F. Hoffman-La Roche and Chugai funded the study. The investigators reported financial relationships with the study sponsors and other companies.

SOURCE: Pipe SW et al. Lancet Haem. 2019 Apr 16. doi: 10.1016/S2352-3026(19)30054-7.