Jennifer Smith

The presence of complex karyotype (CK) does not affect survival in patients with relapsed/refractory chronic lymphocytic leukemia (CLL) who are treated with idelalisib, according to a new analysis.

Researchers analyzed data from two clinical trials of idelalisib, given alone or in combination with rituximab, and found no significant difference in overall survival (OS) between patients with and without CK.

Karl-Anton Kreuzer, MD, of the University of Cologne (Germany), and colleagues described these findings in a letter to Leukemia.

The researchers evaluated patients with previously treated CLL who were enrolled in a phase 3 trial and received either idelalisib plus rituximab or rituximab plus placebo. Patients from either treatment arm could enroll in an extension study of idelalisib monotherapy.

There were 220 patients randomized to idelalisib plus rituximab (n = 110) or placebo plus rituximab (n = 110) in the primary study, and 161 of these patients were enrolled in the extension study.

The final analysis included 120 patients who were successfully karyotyped – 63 from the idelalisib-rituximab arm and 57 from the placebo-rituximab arm. Less than half of patients in each arm were CK-positive – 41% (26/63) of the idelalisib arm and 42% (24/57) of the placebo arm.

The researchers wrote that baseline characteristics were “mostly balanced” between the CK-positive and CK-negative groups in each treatment arm. The only significant difference was that fewer CK-positive patients in the placebo arm had a creatinine clearance of 30-59 mL/min (P = .0324).

Results

There were no significant differences in outcomes between CK-positive and CK-negative patients who received idelalisib and rituximab. The overall response rate was 81% in CK-positive patients and 89% in CK-negative patients (P = .3509). The median progression-free survival was 20.9 months and 19.4 months, respectively (P = .5848).

The median OS was 28.3 months in the CK-positive group and 49.7 months in the CK-negative group (P = .2099). The copresence of CK and del(17p), TP53 mutation, or del(11q) didn’t significantly affect OS, the researchers noted.

Among all CK-positive patients, the median OS was 28.3 months in the idelalisib-rituximab arm and 9.2 months in the placebo-rituximab arm (P = .0412).

“Our analysis suggests that CK-positive patients treated with idelalisib/rituximab did not exhibit a significantly shortened survival compared with those who were CK negative,” the researchers wrote. “In addition, the primary beneficial effect of adding idelalisib to rituximab treatment in [relapsed/refractory] CLL patients with CK was reflected in OS prolongation compared to those who received only rituximab.”

The researchers noted that this study has limitations, so prospective clinical trials are needed to guide treatment of patients with relapsed/refractory CLL and CK.

Both trials of idelalisib were sponsored by Gilead. The researchers reported relationships, including employment, with Gilead and other companies. They also disclosed funding from the German government and from nonprofit organizations in Germany.

[email protected]

SOURCE: Kreuzer K-A et al. Leukemia. 2019 Aug 19. doi: 10.1038/s41375-019-0533-6.

The presence of complex karyotype (CK) does not affect survival in patients with relapsed/refractory chronic lymphocytic leukemia (CLL) who are treated with idelalisib, according to a new analysis.

Researchers analyzed data from two clinical trials of idelalisib, given alone or in combination with rituximab, and found no significant difference in overall survival (OS) between patients with and without CK.

Karl-Anton Kreuzer, MD, of the University of Cologne (Germany), and colleagues described these findings in a letter to Leukemia.

The researchers evaluated patients with previously treated CLL who were enrolled in a phase 3 trial and received either idelalisib plus rituximab or rituximab plus placebo. Patients from either treatment arm could enroll in an extension study of idelalisib monotherapy.

There were 220 patients randomized to idelalisib plus rituximab (n = 110) or placebo plus rituximab (n = 110) in the primary study, and 161 of these patients were enrolled in the extension study.

The final analysis included 120 patients who were successfully karyotyped – 63 from the idelalisib-rituximab arm and 57 from the placebo-rituximab arm. Less than half of patients in each arm were CK-positive – 41% (26/63) of the idelalisib arm and 42% (24/57) of the placebo arm.

The researchers wrote that baseline characteristics were “mostly balanced” between the CK-positive and CK-negative groups in each treatment arm. The only significant difference was that fewer CK-positive patients in the placebo arm had a creatinine clearance of 30-59 mL/min (P = .0324).

Results

There were no significant differences in outcomes between CK-positive and CK-negative patients who received idelalisib and rituximab. The overall response rate was 81% in CK-positive patients and 89% in CK-negative patients (P = .3509). The median progression-free survival was 20.9 months and 19.4 months, respectively (P = .5848).

The median OS was 28.3 months in the CK-positive group and 49.7 months in the CK-negative group (P = .2099). The copresence of CK and del(17p), TP53 mutation, or del(11q) didn’t significantly affect OS, the researchers noted.

Among all CK-positive patients, the median OS was 28.3 months in the idelalisib-rituximab arm and 9.2 months in the placebo-rituximab arm (P = .0412).

“Our analysis suggests that CK-positive patients treated with idelalisib/rituximab did not exhibit a significantly shortened survival compared with those who were CK negative,” the researchers wrote. “In addition, the primary beneficial effect of adding idelalisib to rituximab treatment in [relapsed/refractory] CLL patients with CK was reflected in OS prolongation compared to those who received only rituximab.”

The researchers noted that this study has limitations, so prospective clinical trials are needed to guide treatment of patients with relapsed/refractory CLL and CK.

Both trials of idelalisib were sponsored by Gilead. The researchers reported relationships, including employment, with Gilead and other companies. They also disclosed funding from the German government and from nonprofit organizations in Germany.

[email protected]

SOURCE: Kreuzer K-A et al. Leukemia. 2019 Aug 19. doi: 10.1038/s41375-019-0533-6.

The presence of complex karyotype (CK) does not affect survival in patients with relapsed/refractory chronic lymphocytic leukemia (CLL) who are treated with idelalisib, according to a new analysis.

Researchers analyzed data from two clinical trials of idelalisib, given alone or in combination with rituximab, and found no significant difference in overall survival (OS) between patients with and without CK.

Karl-Anton Kreuzer, MD, of the University of Cologne (Germany), and colleagues described these findings in a letter to Leukemia.

The researchers evaluated patients with previously treated CLL who were enrolled in a phase 3 trial and received either idelalisib plus rituximab or rituximab plus placebo. Patients from either treatment arm could enroll in an extension study of idelalisib monotherapy.

There were 220 patients randomized to idelalisib plus rituximab (n = 110) or placebo plus rituximab (n = 110) in the primary study, and 161 of these patients were enrolled in the extension study.

The final analysis included 120 patients who were successfully karyotyped – 63 from the idelalisib-rituximab arm and 57 from the placebo-rituximab arm. Less than half of patients in each arm were CK-positive – 41% (26/63) of the idelalisib arm and 42% (24/57) of the placebo arm.

The researchers wrote that baseline characteristics were “mostly balanced” between the CK-positive and CK-negative groups in each treatment arm. The only significant difference was that fewer CK-positive patients in the placebo arm had a creatinine clearance of 30-59 mL/min (P = .0324).

Results

There were no significant differences in outcomes between CK-positive and CK-negative patients who received idelalisib and rituximab. The overall response rate was 81% in CK-positive patients and 89% in CK-negative patients (P = .3509). The median progression-free survival was 20.9 months and 19.4 months, respectively (P = .5848).

The median OS was 28.3 months in the CK-positive group and 49.7 months in the CK-negative group (P = .2099). The copresence of CK and del(17p), TP53 mutation, or del(11q) didn’t significantly affect OS, the researchers noted.

Among all CK-positive patients, the median OS was 28.3 months in the idelalisib-rituximab arm and 9.2 months in the placebo-rituximab arm (P = .0412).

“Our analysis suggests that CK-positive patients treated with idelalisib/rituximab did not exhibit a significantly shortened survival compared with those who were CK negative,” the researchers wrote. “In addition, the primary beneficial effect of adding idelalisib to rituximab treatment in [relapsed/refractory] CLL patients with CK was reflected in OS prolongation compared to those who received only rituximab.”

The researchers noted that this study has limitations, so prospective clinical trials are needed to guide treatment of patients with relapsed/refractory CLL and CK.

Both trials of idelalisib were sponsored by Gilead. The researchers reported relationships, including employment, with Gilead and other companies. They also disclosed funding from the German government and from nonprofit organizations in Germany.

[email protected]

SOURCE: Kreuzer K-A et al. Leukemia. 2019 Aug 19. doi: 10.1038/s41375-019-0533-6.

Nivolumab has “limited intracranial activity” in patients with clear cell renal cell carcinoma (ccRCC) and previously untreated brain metastases, according to researchers.

In a phase 2 trial, nivolumab produced an intracranial response rate of 12% in ccRCC patients with previously untreated brain metastases.

The median intracranial progression-free survival (PFS) was longer among patients who had received prior focal therapy than among those with previously untreated brain metastases.

These results suggest “brain imaging and focal therapy should be considered before immune checkpoint inhibitors in patients with metastatic ccRCC,” Ronan Flippot, MD, of Université Paris-Saclay in Villejuif, France, and colleagues wrote in the Journal of Clinical Oncology.

Dr. Flippot and colleagues conducted this analysis of patients from the phase 2 GETUG-AFU 26 NIVOREN trial (NCT03013335). The researchers looked at 73 ccRCC patients with asymptomatic brain metastases who had received at least one prior line of antiangiogenic treatment.

Patients were divided into two cohorts. Cohort A included patients with previously untreated brain metastases (n = 39), and cohort B included patients who had received focal therapy for brain metastases (n = 34).

Baseline characteristics were similar between the cohorts. The median ages were 61 years in cohort A (range, 39-77) and 58 years in cohort B (range, 33-78). Most patients had grade 3-4 tumors (64% in cohort A and 78% in cohort B), and most had one brain lesion (67% and 59%, respectively). The median sum of the diameters of target lesions was 11 mm in cohort A and 17 mm in cohort B.

All patients received intravenous nivolumab at 3 mg/kg every 2 weeks until they progressed, developed unacceptable toxicity, died, withdrew consent, or the investigator stopped treatment.

The median follow-up was 23.6 months in cohort A and 20.2 months in cohort B. The median duration of treatment was 4.9 months and 4.5 months, respectively. Five patients in cohort A and four in cohort B were still receiving nivolumab at the data cutoff.

Response

The primary endpoint was the intracranial response rate in cohort A, which was 12%. All four responders achieved a complete response. At baseline, all of them had grade 1-2 disease and a single brain lesion smaller than 1 cm.

Thirteen patients (38%) in cohort A had stable intracranial disease as their best response, and 17 (50%) had progressive intracranial disease. The remaining five patients could not be evaluated because they progressed and died before the first evaluation.

The extracranial response rate in cohort A was 21%, and all seven responders had partial responses. Ten patients had stable extracranial disease (30%), and 16 had extracranial progression (49%). The remaining six patients were not evaluable for extracranial response.

All four patients who achieved a complete intracranial response had a partial extracranial response. Six patients (18%) had discordant intracranial and extracranial responses.
 

Survival

The median intracranial PFS in cohort A was 2.7 months in cohort A versus 4.8 months in cohort B. When the researchers adjusted for baseline characteristics, they found that prior focal therapy decreased the risk of intracranial progression (hazard ratio, 0.49).

The median extracranial PFS was 2.8 months in cohort A versus 2.6 months in cohort B. The median global PFS was 2.4 months in cohort A versus 2.5 months in cohort B.

The overall survival rates at 12 months were 66.7% in cohort A and 58.8% in cohort B.

Safety

The most common treatment-related adverse events (in cohort A and B, respectively) were asthenia (21% and 24%) and rash (10% and 9%).

Grade 3/4 treatment-related adverse events occurred in four patients in cohort A and five in cohort B. In cohort A, these events were asthenia, elevated liver function tests, dyspnea, and atrioventricular block. In cohort B, the events were diarrhea, musculoskeletal pain, psoriasis, hypophosphatemia, and elevated creatinine (in two patients).

The patient who developed atrioventricular block permanently discontinued nivolumab. There were no other treatment-related adverse events that led to discontinuation.

This study was supported by Bristol-Myers Squibb. The researchers disclosed relationships with Bristol-Myers Squibb and many other companies.

SOURCE: Flippot R et al. J Clin Oncol. 2019 Aug 10;37(23):2008-16.

Nivolumab has “limited intracranial activity” in patients with clear cell renal cell carcinoma (ccRCC) and previously untreated brain metastases, according to researchers.

In a phase 2 trial, nivolumab produced an intracranial response rate of 12% in ccRCC patients with previously untreated brain metastases.

The median intracranial progression-free survival (PFS) was longer among patients who had received prior focal therapy than among those with previously untreated brain metastases.

These results suggest “brain imaging and focal therapy should be considered before immune checkpoint inhibitors in patients with metastatic ccRCC,” Ronan Flippot, MD, of Université Paris-Saclay in Villejuif, France, and colleagues wrote in the Journal of Clinical Oncology.

Dr. Flippot and colleagues conducted this analysis of patients from the phase 2 GETUG-AFU 26 NIVOREN trial (NCT03013335). The researchers looked at 73 ccRCC patients with asymptomatic brain metastases who had received at least one prior line of antiangiogenic treatment.

Patients were divided into two cohorts. Cohort A included patients with previously untreated brain metastases (n = 39), and cohort B included patients who had received focal therapy for brain metastases (n = 34).

Baseline characteristics were similar between the cohorts. The median ages were 61 years in cohort A (range, 39-77) and 58 years in cohort B (range, 33-78). Most patients had grade 3-4 tumors (64% in cohort A and 78% in cohort B), and most had one brain lesion (67% and 59%, respectively). The median sum of the diameters of target lesions was 11 mm in cohort A and 17 mm in cohort B.

All patients received intravenous nivolumab at 3 mg/kg every 2 weeks until they progressed, developed unacceptable toxicity, died, withdrew consent, or the investigator stopped treatment.

The median follow-up was 23.6 months in cohort A and 20.2 months in cohort B. The median duration of treatment was 4.9 months and 4.5 months, respectively. Five patients in cohort A and four in cohort B were still receiving nivolumab at the data cutoff.

Response

The primary endpoint was the intracranial response rate in cohort A, which was 12%. All four responders achieved a complete response. At baseline, all of them had grade 1-2 disease and a single brain lesion smaller than 1 cm.

Thirteen patients (38%) in cohort A had stable intracranial disease as their best response, and 17 (50%) had progressive intracranial disease. The remaining five patients could not be evaluated because they progressed and died before the first evaluation.

The extracranial response rate in cohort A was 21%, and all seven responders had partial responses. Ten patients had stable extracranial disease (30%), and 16 had extracranial progression (49%). The remaining six patients were not evaluable for extracranial response.

All four patients who achieved a complete intracranial response had a partial extracranial response. Six patients (18%) had discordant intracranial and extracranial responses.
 

Survival

The median intracranial PFS in cohort A was 2.7 months in cohort A versus 4.8 months in cohort B. When the researchers adjusted for baseline characteristics, they found that prior focal therapy decreased the risk of intracranial progression (hazard ratio, 0.49).

The median extracranial PFS was 2.8 months in cohort A versus 2.6 months in cohort B. The median global PFS was 2.4 months in cohort A versus 2.5 months in cohort B.

The overall survival rates at 12 months were 66.7% in cohort A and 58.8% in cohort B.

Safety

The most common treatment-related adverse events (in cohort A and B, respectively) were asthenia (21% and 24%) and rash (10% and 9%).

Grade 3/4 treatment-related adverse events occurred in four patients in cohort A and five in cohort B. In cohort A, these events were asthenia, elevated liver function tests, dyspnea, and atrioventricular block. In cohort B, the events were diarrhea, musculoskeletal pain, psoriasis, hypophosphatemia, and elevated creatinine (in two patients).

The patient who developed atrioventricular block permanently discontinued nivolumab. There were no other treatment-related adverse events that led to discontinuation.

This study was supported by Bristol-Myers Squibb. The researchers disclosed relationships with Bristol-Myers Squibb and many other companies.

SOURCE: Flippot R et al. J Clin Oncol. 2019 Aug 10;37(23):2008-16.

Nivolumab has “limited intracranial activity” in patients with clear cell renal cell carcinoma (ccRCC) and previously untreated brain metastases, according to researchers.

In a phase 2 trial, nivolumab produced an intracranial response rate of 12% in ccRCC patients with previously untreated brain metastases.

The median intracranial progression-free survival (PFS) was longer among patients who had received prior focal therapy than among those with previously untreated brain metastases.

These results suggest “brain imaging and focal therapy should be considered before immune checkpoint inhibitors in patients with metastatic ccRCC,” Ronan Flippot, MD, of Université Paris-Saclay in Villejuif, France, and colleagues wrote in the Journal of Clinical Oncology.

Dr. Flippot and colleagues conducted this analysis of patients from the phase 2 GETUG-AFU 26 NIVOREN trial (NCT03013335). The researchers looked at 73 ccRCC patients with asymptomatic brain metastases who had received at least one prior line of antiangiogenic treatment.

Patients were divided into two cohorts. Cohort A included patients with previously untreated brain metastases (n = 39), and cohort B included patients who had received focal therapy for brain metastases (n = 34).

Baseline characteristics were similar between the cohorts. The median ages were 61 years in cohort A (range, 39-77) and 58 years in cohort B (range, 33-78). Most patients had grade 3-4 tumors (64% in cohort A and 78% in cohort B), and most had one brain lesion (67% and 59%, respectively). The median sum of the diameters of target lesions was 11 mm in cohort A and 17 mm in cohort B.

All patients received intravenous nivolumab at 3 mg/kg every 2 weeks until they progressed, developed unacceptable toxicity, died, withdrew consent, or the investigator stopped treatment.

The median follow-up was 23.6 months in cohort A and 20.2 months in cohort B. The median duration of treatment was 4.9 months and 4.5 months, respectively. Five patients in cohort A and four in cohort B were still receiving nivolumab at the data cutoff.

Response

The primary endpoint was the intracranial response rate in cohort A, which was 12%. All four responders achieved a complete response. At baseline, all of them had grade 1-2 disease and a single brain lesion smaller than 1 cm.

Thirteen patients (38%) in cohort A had stable intracranial disease as their best response, and 17 (50%) had progressive intracranial disease. The remaining five patients could not be evaluated because they progressed and died before the first evaluation.

The extracranial response rate in cohort A was 21%, and all seven responders had partial responses. Ten patients had stable extracranial disease (30%), and 16 had extracranial progression (49%). The remaining six patients were not evaluable for extracranial response.

All four patients who achieved a complete intracranial response had a partial extracranial response. Six patients (18%) had discordant intracranial and extracranial responses.
 

Survival

The median intracranial PFS in cohort A was 2.7 months in cohort A versus 4.8 months in cohort B. When the researchers adjusted for baseline characteristics, they found that prior focal therapy decreased the risk of intracranial progression (hazard ratio, 0.49).

The median extracranial PFS was 2.8 months in cohort A versus 2.6 months in cohort B. The median global PFS was 2.4 months in cohort A versus 2.5 months in cohort B.

The overall survival rates at 12 months were 66.7% in cohort A and 58.8% in cohort B.

Safety

The most common treatment-related adverse events (in cohort A and B, respectively) were asthenia (21% and 24%) and rash (10% and 9%).

Grade 3/4 treatment-related adverse events occurred in four patients in cohort A and five in cohort B. In cohort A, these events were asthenia, elevated liver function tests, dyspnea, and atrioventricular block. In cohort B, the events were diarrhea, musculoskeletal pain, psoriasis, hypophosphatemia, and elevated creatinine (in two patients).

The patient who developed atrioventricular block permanently discontinued nivolumab. There were no other treatment-related adverse events that led to discontinuation.

This study was supported by Bristol-Myers Squibb. The researchers disclosed relationships with Bristol-Myers Squibb and many other companies.

SOURCE: Flippot R et al. J Clin Oncol. 2019 Aug 10;37(23):2008-16.

Deferasirox plus deferoxamine is more effective than deferasirox alone for treating iron overload in patients with thalassemia major, according to a single-center study.

Over the course of 1 year of treatment, deferasirox plus deferoxamine significantly increased myocardial T2* and significantly reduced serum ferritin, whereas deferasirox alone had no significant effect on either endpoint. Neither treatment had a significant effect on hepatic iron.

Deferasirox plus deferoxamine caused a significantly greater increase in alanine aminotransferase, aspartate aminotransferase, and bilirubin. Other adverse events were similar between the treatment groups.

Aziz Eghbali, MD, of Arak (Iran) University of Medical Sciences and colleagues described this study in Transfusion and Apheresis Science.

The team conducted a randomized, double-blind trial of patients with thalassemia major. Of the 62 patients enrolled, 55 were randomized and evaluable. At baseline, the mean patient age was 24.5 years, and 67.3% were female.

The patients were randomized to receive oral deferasirox at 30 mg/kg daily either alone (n = 27) or with subcutaneous deferoxamine at 50 mg/kg for 5 days a week (n = 28). In both groups, patients received treatment for 12 months.

There were no significant differences between the groups in baseline characteristics such as myocardial or hepatic iron, transfusion volume, or white blood cell and platelet counts.

Results

The study’s primary endpoints were changes in myocardial T2* and hepatic T2* from baseline to 12 months. Changes in serum ferritin and adverse events were secondary endpoints.

Myocardial T2* decreased slightly in the monotherapy group, from 23.3 plus or minus 7.4 ms at baseline to 22.1 plus or minus 6.9 ms at 12 months (P = .3) but increased significantly in the combination group, from 23.1 plus or minus 7.5 ms to 27.1 plus or minus 7.0 ms (P less than .05). The difference between the groups was significant (P = .01).

There was no significant change in hepatic iron in either group. Hepatic T2* was 7.0 plus or minus 5.6 ms at baseline and 7.0 plus or minus 5.3 ms at 12 months in the monotherapy group (P = .7). In the combination group, hepatic T2* increased from 9.8 plus or minus 8.8 ms to 10.2 plus or minus 8.2 ms (P = .5). The between-group difference was not significant (P = .094).

Serum ferritin decreased from 1,390 plus or minus 816 mcg/ml to 1,085 plus or minus 919 mcg/mL in the monotherapy group (P = .06) and from 1,446 plus or minus 987 mcg/mL to 737 plus or minus 459 mcg/mL in the combination group (P less than .01). The between-group difference was significant (P = .001).

Increases in alanine aminotransferase, aspartate aminotransferase, and bilirubin were significantly greater in the combination group than in the monotherapy group (P less than .05 for all). Combination therapy also prompted an increase in alkaline phosphatase, but this was not significantly greater than in the monotherapy group (P = .3).

Blood urea nitrogen levels increased in both groups, but levels remained within the normal range. There were no increases in serum creatinine in either group.

Rates of mild gastrointestinal adverse events were similar in the monotherapy and combination groups (40% and 39%, respectively), as were rates of transient skin rashes (18% and 14%, respectively).

There were no deaths, and none of the patients stopped treatment because of severe adverse events.

This study was supported by Arak University of Medical Sciences. The researchers reported having no conflicts of interest.

[email protected]

SOURCE: Eghbali A et al. Transfus Apher Sci. 2019 Aug;58(4):429-33.
 

Deferasirox plus deferoxamine is more effective than deferasirox alone for treating iron overload in patients with thalassemia major, according to a single-center study.

Over the course of 1 year of treatment, deferasirox plus deferoxamine significantly increased myocardial T2* and significantly reduced serum ferritin, whereas deferasirox alone had no significant effect on either endpoint. Neither treatment had a significant effect on hepatic iron.

Deferasirox plus deferoxamine caused a significantly greater increase in alanine aminotransferase, aspartate aminotransferase, and bilirubin. Other adverse events were similar between the treatment groups.

Aziz Eghbali, MD, of Arak (Iran) University of Medical Sciences and colleagues described this study in Transfusion and Apheresis Science.

The team conducted a randomized, double-blind trial of patients with thalassemia major. Of the 62 patients enrolled, 55 were randomized and evaluable. At baseline, the mean patient age was 24.5 years, and 67.3% were female.

The patients were randomized to receive oral deferasirox at 30 mg/kg daily either alone (n = 27) or with subcutaneous deferoxamine at 50 mg/kg for 5 days a week (n = 28). In both groups, patients received treatment for 12 months.

There were no significant differences between the groups in baseline characteristics such as myocardial or hepatic iron, transfusion volume, or white blood cell and platelet counts.

Results

The study’s primary endpoints were changes in myocardial T2* and hepatic T2* from baseline to 12 months. Changes in serum ferritin and adverse events were secondary endpoints.

Myocardial T2* decreased slightly in the monotherapy group, from 23.3 plus or minus 7.4 ms at baseline to 22.1 plus or minus 6.9 ms at 12 months (P = .3) but increased significantly in the combination group, from 23.1 plus or minus 7.5 ms to 27.1 plus or minus 7.0 ms (P less than .05). The difference between the groups was significant (P = .01).

There was no significant change in hepatic iron in either group. Hepatic T2* was 7.0 plus or minus 5.6 ms at baseline and 7.0 plus or minus 5.3 ms at 12 months in the monotherapy group (P = .7). In the combination group, hepatic T2* increased from 9.8 plus or minus 8.8 ms to 10.2 plus or minus 8.2 ms (P = .5). The between-group difference was not significant (P = .094).

Serum ferritin decreased from 1,390 plus or minus 816 mcg/ml to 1,085 plus or minus 919 mcg/mL in the monotherapy group (P = .06) and from 1,446 plus or minus 987 mcg/mL to 737 plus or minus 459 mcg/mL in the combination group (P less than .01). The between-group difference was significant (P = .001).

Increases in alanine aminotransferase, aspartate aminotransferase, and bilirubin were significantly greater in the combination group than in the monotherapy group (P less than .05 for all). Combination therapy also prompted an increase in alkaline phosphatase, but this was not significantly greater than in the monotherapy group (P = .3).

Blood urea nitrogen levels increased in both groups, but levels remained within the normal range. There were no increases in serum creatinine in either group.

Rates of mild gastrointestinal adverse events were similar in the monotherapy and combination groups (40% and 39%, respectively), as were rates of transient skin rashes (18% and 14%, respectively).

There were no deaths, and none of the patients stopped treatment because of severe adverse events.

This study was supported by Arak University of Medical Sciences. The researchers reported having no conflicts of interest.

[email protected]

SOURCE: Eghbali A et al. Transfus Apher Sci. 2019 Aug;58(4):429-33.
 

Deferasirox plus deferoxamine is more effective than deferasirox alone for treating iron overload in patients with thalassemia major, according to a single-center study.

Over the course of 1 year of treatment, deferasirox plus deferoxamine significantly increased myocardial T2* and significantly reduced serum ferritin, whereas deferasirox alone had no significant effect on either endpoint. Neither treatment had a significant effect on hepatic iron.

Deferasirox plus deferoxamine caused a significantly greater increase in alanine aminotransferase, aspartate aminotransferase, and bilirubin. Other adverse events were similar between the treatment groups.

Aziz Eghbali, MD, of Arak (Iran) University of Medical Sciences and colleagues described this study in Transfusion and Apheresis Science.

The team conducted a randomized, double-blind trial of patients with thalassemia major. Of the 62 patients enrolled, 55 were randomized and evaluable. At baseline, the mean patient age was 24.5 years, and 67.3% were female.

The patients were randomized to receive oral deferasirox at 30 mg/kg daily either alone (n = 27) or with subcutaneous deferoxamine at 50 mg/kg for 5 days a week (n = 28). In both groups, patients received treatment for 12 months.

There were no significant differences between the groups in baseline characteristics such as myocardial or hepatic iron, transfusion volume, or white blood cell and platelet counts.

Results

The study’s primary endpoints were changes in myocardial T2* and hepatic T2* from baseline to 12 months. Changes in serum ferritin and adverse events were secondary endpoints.

Myocardial T2* decreased slightly in the monotherapy group, from 23.3 plus or minus 7.4 ms at baseline to 22.1 plus or minus 6.9 ms at 12 months (P = .3) but increased significantly in the combination group, from 23.1 plus or minus 7.5 ms to 27.1 plus or minus 7.0 ms (P less than .05). The difference between the groups was significant (P = .01).

There was no significant change in hepatic iron in either group. Hepatic T2* was 7.0 plus or minus 5.6 ms at baseline and 7.0 plus or minus 5.3 ms at 12 months in the monotherapy group (P = .7). In the combination group, hepatic T2* increased from 9.8 plus or minus 8.8 ms to 10.2 plus or minus 8.2 ms (P = .5). The between-group difference was not significant (P = .094).

Serum ferritin decreased from 1,390 plus or minus 816 mcg/ml to 1,085 plus or minus 919 mcg/mL in the monotherapy group (P = .06) and from 1,446 plus or minus 987 mcg/mL to 737 plus or minus 459 mcg/mL in the combination group (P less than .01). The between-group difference was significant (P = .001).

Increases in alanine aminotransferase, aspartate aminotransferase, and bilirubin were significantly greater in the combination group than in the monotherapy group (P less than .05 for all). Combination therapy also prompted an increase in alkaline phosphatase, but this was not significantly greater than in the monotherapy group (P = .3).

Blood urea nitrogen levels increased in both groups, but levels remained within the normal range. There were no increases in serum creatinine in either group.

Rates of mild gastrointestinal adverse events were similar in the monotherapy and combination groups (40% and 39%, respectively), as were rates of transient skin rashes (18% and 14%, respectively).

There were no deaths, and none of the patients stopped treatment because of severe adverse events.

This study was supported by Arak University of Medical Sciences. The researchers reported having no conflicts of interest.

[email protected]

SOURCE: Eghbali A et al. Transfus Apher Sci. 2019 Aug;58(4):429-33.
 

Three researchers have won CancerLinQ Discovery Research Support Grants from the American Society of Clinical Oncology, and two researchers have received a National Institutes of Health R21 grant.

Igor Astsaturov, MD, PhD, and Edna Cukierman, PhD, both of Fox Chase Cancer Center in Philadelphia, won the R21 grant. The pair will receive $432,410 over 2 years for their research on pancreatic cancer.

With their work, Dr. Astsaturov and Dr. Cukierman are “hoping to describe the structural and functional nature of cell-cell contact, or oncogenic synapses, associated with cancer-associated fibroblasts and pancreatic cells,” according to Fox Chase.

Each 1-year grant covers the cost of a CancerLinQ Discovery data set and a meeting at ASCO headquarters. The grants also contribute to personnel and/or research expenses. The grants are funded by the ASCO Foundation’s Mission Endowment of Conquer Cancer.

Movers in Medicine highlights career moves and personal achievements by hematologists and oncologists. Did you switch jobs, take on a new role, climb a mountain? Tell us all about it at [email protected], and you could be featured in Movers in Medicine.

[email protected]

Three researchers have won CancerLinQ Discovery Research Support Grants from the American Society of Clinical Oncology, and two researchers have received a National Institutes of Health R21 grant.

Igor Astsaturov, MD, PhD, and Edna Cukierman, PhD, both of Fox Chase Cancer Center in Philadelphia, won the R21 grant. The pair will receive $432,410 over 2 years for their research on pancreatic cancer.

With their work, Dr. Astsaturov and Dr. Cukierman are “hoping to describe the structural and functional nature of cell-cell contact, or oncogenic synapses, associated with cancer-associated fibroblasts and pancreatic cells,” according to Fox Chase.

Each 1-year grant covers the cost of a CancerLinQ Discovery data set and a meeting at ASCO headquarters. The grants also contribute to personnel and/or research expenses. The grants are funded by the ASCO Foundation’s Mission Endowment of Conquer Cancer.

Movers in Medicine highlights career moves and personal achievements by hematologists and oncologists. Did you switch jobs, take on a new role, climb a mountain? Tell us all about it at [email protected], and you could be featured in Movers in Medicine.

[email protected]

Three researchers have won CancerLinQ Discovery Research Support Grants from the American Society of Clinical Oncology, and two researchers have received a National Institutes of Health R21 grant.

Igor Astsaturov, MD, PhD, and Edna Cukierman, PhD, both of Fox Chase Cancer Center in Philadelphia, won the R21 grant. The pair will receive $432,410 over 2 years for their research on pancreatic cancer.

With their work, Dr. Astsaturov and Dr. Cukierman are “hoping to describe the structural and functional nature of cell-cell contact, or oncogenic synapses, associated with cancer-associated fibroblasts and pancreatic cells,” according to Fox Chase.

Each 1-year grant covers the cost of a CancerLinQ Discovery data set and a meeting at ASCO headquarters. The grants also contribute to personnel and/or research expenses. The grants are funded by the ASCO Foundation’s Mission Endowment of Conquer Cancer.

Movers in Medicine highlights career moves and personal achievements by hematologists and oncologists. Did you switch jobs, take on a new role, climb a mountain? Tell us all about it at [email protected], and you could be featured in Movers in Medicine.

[email protected]

Treatment with the immune checkpoint inhibitor (ICI) pembrolizumab can induce lipodystrophy with severe metabolic complications, according to a case study.

A 47-year-old woman received pembrolizumab to treat metastatic melanoma and developed immune-related generalized acquired lipodystrophy. The condition has persisted 12 months after she stopped taking pembrolizumab.

Julie Delyon, MD, PhD, of Saint-Louis Hospital in Paris, and colleagues described this case in the British Journal of Dermatology.

The patient was diagnosed with BRAF-mutated, stage IV melanoma with bone and lymph node metastases. She received pembrolizumab at 2 mg/kg every 3 weeks as first-line treatment. She achieved a complete response and was still in remission at last follow-up.

The patient was obese at baseline, with a body mass index of 40 kg/m², but she did not have diabetes, hepatic steatosis, or dyslipidemia.

Within 2 months of starting pembrolizumab, the patient observed “some major changes to her physical appearance,” according to Dr. Delyon and colleagues. At 10 months, the patient had severe lipodystrophy.

The patient experienced a change in fat distribution – namely, severe peripheral lipoatrophy and an accumulation of trunk fat. Imaging revealed a decrease in subcutaneous adipose tissue, which contrasted with an increase in visceral fat observed from baseline.

The patient also developed “moderate hirsutism, facial and limb atrophy, and prominent forearm and leg muscles and veins,” according to the authors. She had impaired glucose tolerance with insulin resistance, reduced concentrations of leptin and adiponectin, hypertriglyceridemia, a low level of HDL cholesterol, and hepatic steatosis.

Analyses of subcutaneous fat revealed adipose tissue atrophy with edema, lipophages, and CD3+/CD4+ T-cell infiltration of the fat and vessel walls. This suggested that the lipodystrophy had an autoimmune origin, according to the authors.

The patient had no family history of autoimmune disease or lipodystrophy. She tested negative for mutations in 23 genes associated with generalized lipodystrophy.

The patient also tested negative for HIV, antinuclear antibodies, native anti-DNA, and anti-insulin receptor antibodies. There were no signs of panniculitis, and the authors noted that “there were no arguments in favor of hyperthyroidism, Cushing syndrome, or acromegaly.”

In an attempt to reverse the lipodystrophy, the researchers stopped pembrolizumab treatment. The patient was treated for diabetes and hypertriglyceridemia as well. She could not receive corticosteroids because of the risk of severe metabolic complications, and she didn’t receive metreleptin because it wasn’t available. The patient still had lipodystrophy 12 months after stopping pembrolizumab.

Dr. Delyon and colleagues wrote that this case suggests pembrolizumab, and perhaps other anti–programmed death 1 therapies, may cause lipodystrophy with severe metabolic complications. “The long-term side effects of such metabolic adverse events, although rare, are unknown and will probably become a topic of utmost importance, considering the increasing rate of remission following ICIs and their use in the adjuvant setting.”

Two coauthors reported relationships with Merck, which markets pembrolizumab as Keytruda. The authors also reported relationships with Bristol-Myers Squibb, Pierre Fabre, Takeda, Innate Pharma, LEO Pharma, Roche, GlaxoSmithKline, Novartis, and Amgen.

[email protected]

SOURCE: Delyon J et al. Br J Dermatol. 2019 May 11. doi: 10.1111/bjd.18124.

Treatment with the immune checkpoint inhibitor (ICI) pembrolizumab can induce lipodystrophy with severe metabolic complications, according to a case study.

A 47-year-old woman received pembrolizumab to treat metastatic melanoma and developed immune-related generalized acquired lipodystrophy. The condition has persisted 12 months after she stopped taking pembrolizumab.

Julie Delyon, MD, PhD, of Saint-Louis Hospital in Paris, and colleagues described this case in the British Journal of Dermatology.

The patient was diagnosed with BRAF-mutated, stage IV melanoma with bone and lymph node metastases. She received pembrolizumab at 2 mg/kg every 3 weeks as first-line treatment. She achieved a complete response and was still in remission at last follow-up.

The patient was obese at baseline, with a body mass index of 40 kg/m², but she did not have diabetes, hepatic steatosis, or dyslipidemia.

Within 2 months of starting pembrolizumab, the patient observed “some major changes to her physical appearance,” according to Dr. Delyon and colleagues. At 10 months, the patient had severe lipodystrophy.

The patient experienced a change in fat distribution – namely, severe peripheral lipoatrophy and an accumulation of trunk fat. Imaging revealed a decrease in subcutaneous adipose tissue, which contrasted with an increase in visceral fat observed from baseline.

The patient also developed “moderate hirsutism, facial and limb atrophy, and prominent forearm and leg muscles and veins,” according to the authors. She had impaired glucose tolerance with insulin resistance, reduced concentrations of leptin and adiponectin, hypertriglyceridemia, a low level of HDL cholesterol, and hepatic steatosis.

Analyses of subcutaneous fat revealed adipose tissue atrophy with edema, lipophages, and CD3+/CD4+ T-cell infiltration of the fat and vessel walls. This suggested that the lipodystrophy had an autoimmune origin, according to the authors.

The patient had no family history of autoimmune disease or lipodystrophy. She tested negative for mutations in 23 genes associated with generalized lipodystrophy.

The patient also tested negative for HIV, antinuclear antibodies, native anti-DNA, and anti-insulin receptor antibodies. There were no signs of panniculitis, and the authors noted that “there were no arguments in favor of hyperthyroidism, Cushing syndrome, or acromegaly.”

In an attempt to reverse the lipodystrophy, the researchers stopped pembrolizumab treatment. The patient was treated for diabetes and hypertriglyceridemia as well. She could not receive corticosteroids because of the risk of severe metabolic complications, and she didn’t receive metreleptin because it wasn’t available. The patient still had lipodystrophy 12 months after stopping pembrolizumab.

Dr. Delyon and colleagues wrote that this case suggests pembrolizumab, and perhaps other anti–programmed death 1 therapies, may cause lipodystrophy with severe metabolic complications. “The long-term side effects of such metabolic adverse events, although rare, are unknown and will probably become a topic of utmost importance, considering the increasing rate of remission following ICIs and their use in the adjuvant setting.”

Two coauthors reported relationships with Merck, which markets pembrolizumab as Keytruda. The authors also reported relationships with Bristol-Myers Squibb, Pierre Fabre, Takeda, Innate Pharma, LEO Pharma, Roche, GlaxoSmithKline, Novartis, and Amgen.

[email protected]

SOURCE: Delyon J et al. Br J Dermatol. 2019 May 11. doi: 10.1111/bjd.18124.

Treatment with the immune checkpoint inhibitor (ICI) pembrolizumab can induce lipodystrophy with severe metabolic complications, according to a case study.

A 47-year-old woman received pembrolizumab to treat metastatic melanoma and developed immune-related generalized acquired lipodystrophy. The condition has persisted 12 months after she stopped taking pembrolizumab.

Julie Delyon, MD, PhD, of Saint-Louis Hospital in Paris, and colleagues described this case in the British Journal of Dermatology.

The patient was diagnosed with BRAF-mutated, stage IV melanoma with bone and lymph node metastases. She received pembrolizumab at 2 mg/kg every 3 weeks as first-line treatment. She achieved a complete response and was still in remission at last follow-up.

The patient was obese at baseline, with a body mass index of 40 kg/m², but she did not have diabetes, hepatic steatosis, or dyslipidemia.

Within 2 months of starting pembrolizumab, the patient observed “some major changes to her physical appearance,” according to Dr. Delyon and colleagues. At 10 months, the patient had severe lipodystrophy.

The patient experienced a change in fat distribution – namely, severe peripheral lipoatrophy and an accumulation of trunk fat. Imaging revealed a decrease in subcutaneous adipose tissue, which contrasted with an increase in visceral fat observed from baseline.

The patient also developed “moderate hirsutism, facial and limb atrophy, and prominent forearm and leg muscles and veins,” according to the authors. She had impaired glucose tolerance with insulin resistance, reduced concentrations of leptin and adiponectin, hypertriglyceridemia, a low level of HDL cholesterol, and hepatic steatosis.

Analyses of subcutaneous fat revealed adipose tissue atrophy with edema, lipophages, and CD3+/CD4+ T-cell infiltration of the fat and vessel walls. This suggested that the lipodystrophy had an autoimmune origin, according to the authors.

The patient had no family history of autoimmune disease or lipodystrophy. She tested negative for mutations in 23 genes associated with generalized lipodystrophy.

The patient also tested negative for HIV, antinuclear antibodies, native anti-DNA, and anti-insulin receptor antibodies. There were no signs of panniculitis, and the authors noted that “there were no arguments in favor of hyperthyroidism, Cushing syndrome, or acromegaly.”

In an attempt to reverse the lipodystrophy, the researchers stopped pembrolizumab treatment. The patient was treated for diabetes and hypertriglyceridemia as well. She could not receive corticosteroids because of the risk of severe metabolic complications, and she didn’t receive metreleptin because it wasn’t available. The patient still had lipodystrophy 12 months after stopping pembrolizumab.

Dr. Delyon and colleagues wrote that this case suggests pembrolizumab, and perhaps other anti–programmed death 1 therapies, may cause lipodystrophy with severe metabolic complications. “The long-term side effects of such metabolic adverse events, although rare, are unknown and will probably become a topic of utmost importance, considering the increasing rate of remission following ICIs and their use in the adjuvant setting.”

Two coauthors reported relationships with Merck, which markets pembrolizumab as Keytruda. The authors also reported relationships with Bristol-Myers Squibb, Pierre Fabre, Takeda, Innate Pharma, LEO Pharma, Roche, GlaxoSmithKline, Novartis, and Amgen.

[email protected]

SOURCE: Delyon J et al. Br J Dermatol. 2019 May 11. doi: 10.1111/bjd.18124.

Selinexor plus low-dose dexamethasone can produce responses in patients with triple-class refractory multiple myeloma, according to the phase 2 STORM trial.

Wikimedia Commons/KGH/Creative Commons License

The combination produced a response rate of 26% in patients who were refractory to at least one proteasome inhibitor, one immunomodulatory agent, and daratumumab.

The most common grade 3/4 adverse events in this trial were thrombocytopenia (59%), anemia (44%), hyponatremia (22%), and neutropenia (21%).

Ajai Chari, MD, of the Mount Sinai School of Medicine, New York, and colleagues reported these results in the New England Journal of Medicine.

The STORM trial included 123 patients with multiple myeloma who had previously received bortezomib, carfilzomib, lenalidomide, pomalidomide, daratumumab, and an alkylating agent. Their disease was refractory to at least one proteasome inhibitor, one immunomodulatory drug, and daratumumab.

The patients had received a median of 7 (range, 3-18) prior treatment regimens, and their median time since diagnosis was 6.6 years (range, 1.1-23.4 years). The median age at baseline was 65.2 years (range, 40-86 years), 58% of patients were men, and 53% had high-risk cytogenetics. In addition, 36% of patients had thrombocytopenia and 16% had neutropenia at baseline.

The patients received oral selinexor at 80 mg twice weekly plus dexamethasone at 20 mg twice weekly until disease progression, death, or discontinuation. Doses were modified in response to adverse events.

Results

In total, 96% of patients (118/123) discontinued treatment. The most common reasons for discontinuation were disease progression (n = 65) and adverse events (n = 38).

Of the 122 patients evaluable for efficacy, 26% achieved a partial response or better, and 39% had a minimal response or better. There were 24 partial responses, 16 minimal responses, 6 very good partial responses, and 2 stringent complete responses. Forty-eight patients had stable disease.

The median duration of response was 4.4 months, the median progression-free survival was 3.7 months, and the median overall survival was 8.6 months.

The median overall survival was 15.6 months in responders, 5.9 months in patients with stable disease, and 1.7 months in those who progressed.

All 123 patients were evaluable for safety, and 63% of them experienced serious adverse events. Pneumonia (11%) and sepsis (9%) were the most common serious events.

The most common treatment-emergent nonhematologic adverse events were fatigue (73%), nausea (72%), decreased appetite (56%), decreased weight (50%), diarrhea (46%), vomiting (38%), hyponatremia (37%), upper respiratory tract infection (23%), constipation (22%), and dyspnea (22%).

Treatment-emergent hematologic adverse events included thrombocytopenia (73%), anemia (67%), neutropenia (40%), leukopenia (33%), and lymphopenia (16%).

Eighty percent of patients had adverse events leading to dose modification or interruption. The most common of these were thrombocytopenia (43%), fatigue (16%), and neutropenia (11%).

“Because most patients involved in the study were older and frail, with limited end-organ reserve and at increased risk for adverse events, dose modifications were anticipated and were specified along with supportive care in the protocol,” the researchers wrote.


“The adverse events that were observed in the study were a function of dose, schedule, and baseline clinical characteristics (e.g., cytopenias). Thrombocytopenia … was reversible and was managed with dose interruptions and thrombopoietin-receptor agonists.”

There were 28 deaths on study, with 16 patients dying of disease progression and 12 dying from an adverse event. Two of the fatal adverse events were considered treatment related – sepsis in one patient and pneumonia with concurrent disease progression in another patient.

The researchers reported ties with Karyopharm Therapeutics, which sponsored the study, and many other companies.

[email protected]

SOURCE: Chari A et al. N Engl J Med 2019;381:727-38.

Selinexor plus low-dose dexamethasone can produce responses in patients with triple-class refractory multiple myeloma, according to the phase 2 STORM trial.

Wikimedia Commons/KGH/Creative Commons License

The combination produced a response rate of 26% in patients who were refractory to at least one proteasome inhibitor, one immunomodulatory agent, and daratumumab.

The most common grade 3/4 adverse events in this trial were thrombocytopenia (59%), anemia (44%), hyponatremia (22%), and neutropenia (21%).

Ajai Chari, MD, of the Mount Sinai School of Medicine, New York, and colleagues reported these results in the New England Journal of Medicine.

The STORM trial included 123 patients with multiple myeloma who had previously received bortezomib, carfilzomib, lenalidomide, pomalidomide, daratumumab, and an alkylating agent. Their disease was refractory to at least one proteasome inhibitor, one immunomodulatory drug, and daratumumab.

The patients had received a median of 7 (range, 3-18) prior treatment regimens, and their median time since diagnosis was 6.6 years (range, 1.1-23.4 years). The median age at baseline was 65.2 years (range, 40-86 years), 58% of patients were men, and 53% had high-risk cytogenetics. In addition, 36% of patients had thrombocytopenia and 16% had neutropenia at baseline.

The patients received oral selinexor at 80 mg twice weekly plus dexamethasone at 20 mg twice weekly until disease progression, death, or discontinuation. Doses were modified in response to adverse events.

Results

In total, 96% of patients (118/123) discontinued treatment. The most common reasons for discontinuation were disease progression (n = 65) and adverse events (n = 38).

Of the 122 patients evaluable for efficacy, 26% achieved a partial response or better, and 39% had a minimal response or better. There were 24 partial responses, 16 minimal responses, 6 very good partial responses, and 2 stringent complete responses. Forty-eight patients had stable disease.

The median duration of response was 4.4 months, the median progression-free survival was 3.7 months, and the median overall survival was 8.6 months.

The median overall survival was 15.6 months in responders, 5.9 months in patients with stable disease, and 1.7 months in those who progressed.

All 123 patients were evaluable for safety, and 63% of them experienced serious adverse events. Pneumonia (11%) and sepsis (9%) were the most common serious events.

The most common treatment-emergent nonhematologic adverse events were fatigue (73%), nausea (72%), decreased appetite (56%), decreased weight (50%), diarrhea (46%), vomiting (38%), hyponatremia (37%), upper respiratory tract infection (23%), constipation (22%), and dyspnea (22%).

Treatment-emergent hematologic adverse events included thrombocytopenia (73%), anemia (67%), neutropenia (40%), leukopenia (33%), and lymphopenia (16%).

Eighty percent of patients had adverse events leading to dose modification or interruption. The most common of these were thrombocytopenia (43%), fatigue (16%), and neutropenia (11%).

“Because most patients involved in the study were older and frail, with limited end-organ reserve and at increased risk for adverse events, dose modifications were anticipated and were specified along with supportive care in the protocol,” the researchers wrote.


“The adverse events that were observed in the study were a function of dose, schedule, and baseline clinical characteristics (e.g., cytopenias). Thrombocytopenia … was reversible and was managed with dose interruptions and thrombopoietin-receptor agonists.”

There were 28 deaths on study, with 16 patients dying of disease progression and 12 dying from an adverse event. Two of the fatal adverse events were considered treatment related – sepsis in one patient and pneumonia with concurrent disease progression in another patient.

The researchers reported ties with Karyopharm Therapeutics, which sponsored the study, and many other companies.

[email protected]

SOURCE: Chari A et al. N Engl J Med 2019;381:727-38.

Selinexor plus low-dose dexamethasone can produce responses in patients with triple-class refractory multiple myeloma, according to the phase 2 STORM trial.

Wikimedia Commons/KGH/Creative Commons License

The combination produced a response rate of 26% in patients who were refractory to at least one proteasome inhibitor, one immunomodulatory agent, and daratumumab.

The most common grade 3/4 adverse events in this trial were thrombocytopenia (59%), anemia (44%), hyponatremia (22%), and neutropenia (21%).

Ajai Chari, MD, of the Mount Sinai School of Medicine, New York, and colleagues reported these results in the New England Journal of Medicine.

The STORM trial included 123 patients with multiple myeloma who had previously received bortezomib, carfilzomib, lenalidomide, pomalidomide, daratumumab, and an alkylating agent. Their disease was refractory to at least one proteasome inhibitor, one immunomodulatory drug, and daratumumab.

The patients had received a median of 7 (range, 3-18) prior treatment regimens, and their median time since diagnosis was 6.6 years (range, 1.1-23.4 years). The median age at baseline was 65.2 years (range, 40-86 years), 58% of patients were men, and 53% had high-risk cytogenetics. In addition, 36% of patients had thrombocytopenia and 16% had neutropenia at baseline.

The patients received oral selinexor at 80 mg twice weekly plus dexamethasone at 20 mg twice weekly until disease progression, death, or discontinuation. Doses were modified in response to adverse events.

Results

In total, 96% of patients (118/123) discontinued treatment. The most common reasons for discontinuation were disease progression (n = 65) and adverse events (n = 38).

Of the 122 patients evaluable for efficacy, 26% achieved a partial response or better, and 39% had a minimal response or better. There were 24 partial responses, 16 minimal responses, 6 very good partial responses, and 2 stringent complete responses. Forty-eight patients had stable disease.

The median duration of response was 4.4 months, the median progression-free survival was 3.7 months, and the median overall survival was 8.6 months.

The median overall survival was 15.6 months in responders, 5.9 months in patients with stable disease, and 1.7 months in those who progressed.

All 123 patients were evaluable for safety, and 63% of them experienced serious adverse events. Pneumonia (11%) and sepsis (9%) were the most common serious events.

The most common treatment-emergent nonhematologic adverse events were fatigue (73%), nausea (72%), decreased appetite (56%), decreased weight (50%), diarrhea (46%), vomiting (38%), hyponatremia (37%), upper respiratory tract infection (23%), constipation (22%), and dyspnea (22%).

Treatment-emergent hematologic adverse events included thrombocytopenia (73%), anemia (67%), neutropenia (40%), leukopenia (33%), and lymphopenia (16%).

Eighty percent of patients had adverse events leading to dose modification or interruption. The most common of these were thrombocytopenia (43%), fatigue (16%), and neutropenia (11%).

“Because most patients involved in the study were older and frail, with limited end-organ reserve and at increased risk for adverse events, dose modifications were anticipated and were specified along with supportive care in the protocol,” the researchers wrote.


“The adverse events that were observed in the study were a function of dose, schedule, and baseline clinical characteristics (e.g., cytopenias). Thrombocytopenia … was reversible and was managed with dose interruptions and thrombopoietin-receptor agonists.”

There were 28 deaths on study, with 16 patients dying of disease progression and 12 dying from an adverse event. Two of the fatal adverse events were considered treatment related – sepsis in one patient and pneumonia with concurrent disease progression in another patient.

The researchers reported ties with Karyopharm Therapeutics, which sponsored the study, and many other companies.

[email protected]

SOURCE: Chari A et al. N Engl J Med 2019;381:727-38.

Fresher blood products are not necessarily better for patients with beta thalassemia, according to a pair of experts.

Red blood cell units stored less than 2 weeks are ideal, but older units are acceptable, and phenotype matching should take priority over unit age, advised Ashutosh Lal, MD, and Elliott Vichinsky, MD, both of UCSF Benioff Children’s Hospital Oakland (Calif.). They discussed these and other recommendations for transfusing patients with thalassemia during a webinar hosted by the Centers for Disease Control and Prevention.

Indications for transfusion

Dr. Lal said patients with beta thalassemia major should be transfused if their hemoglobin is less than 7 g/dL on two occasions 2 weeks apart at baseline, or if their hemoglobin is greater than 7 g/dL and they have symptoms of anemia.

Patients with hemoglobin E beta thalassemia major should be transfused only if they have symptoms of anemia.

“The rationale is that, in beta thalassemia major, it is well established that, once the hemoglobin levels fall below 7 g/dL in young children, there is going to be massive bone marrow expansion, and there will be severe symptoms from anemia,” Dr. Lal said. “But the relationship of hemoglobin with symptoms in E beta thalassemia is less precise.”

The symptoms that should prompt transfusion include slowed growth, skeletal facial changes, splenomegaly, symptomatic or moderate to severe extramedullary hematopoiesis, cerebrovascular events, venous thromboembolism, pulmonary hypertension, osteoporotic fracture, and impaired quality of life in adults.

Dr. Lal said physicians should consider a 6-month trial of transfusions if the indication is unclear. He also noted that red cell antigen genotyping should be performed in all patients who may need transfusions.

Blood products

Dr. Lal said beta thalassemia patients should receive packed red blood cells that are leukoreduced prior to storage. The storage solution can be citrate-phosphate-dextrose solution with adenine (hematocrit 75%) or additive solution (hematocrit 60%).

“It’s important to note that the hematocrit of the two is quite different, and that needs to be inculcated into the decisions on how much volume to transfuse to younger children,” Dr. Lal said.

He noted that units should not be irradiated, as this damages the red cell membrane. And patients with severe allergic reactions should receive washed red blood cells because washing units removes residual donor plasma proteins.

Finally, units should be less than 2 weeks old if possible. Dr. Lal said using fresh units increases the survival of red blood cells post transfusion. However, he and Dr. Vichinsky both stressed that older units are acceptable, and phenotype matching is more important than the age of the unit.

Phenotype matching

Beta thalassemia patients who do not have preexisting alloantibodies or have transient autoantibodies should be matched to Rh and Kell, according to Dr. Lal.

Patients with preexisting alloantibodies should be matched to Rh, Kell, Duffy, Kidd, S, and the specific alloantibody. Patients with persistent autoantibodies should be matched to Rh, Kell, Duffy, Kidd, S, and any alloantibody.

Patients who start transfusions after 5 years of age should be matched to Rh, Kell, Duffy, Kidd, and S. Pregnant patients should be matched to Rh, Kell, Duffy, Kidd, and S, and units should be cytomegalovirus negative.

How to transfuse

Dr. Lal said the pretransfusion hemoglobin target is 10 g/dL, with a range of 9.5-10.5 g/dL in beta thalassemia major and a range of 9.0-10.5 g/dL for E beta thalassemia. A target of 10 g/dL is adequate for most individuals, Dr. Lal said, but he recommends individualization of hemoglobin target for patients with E beta thalassemia.

In general, patients should be transfused every 3 weeks, although 4 weeks is acceptable in younger children and those with hemoglobin E beta thalassemia.

As for the volume of a transfusion, children should receive 4 mL per kg of body weight, per gram increase in hemoglobin desired. Partial units can be used to avoid undertransfusion.

For adults, in general, those with pretransfusion hemoglobin less than 10 g/dL should receive three units, and those with pretransfusion hemoglobin of 10 g/dL or greater should receive two units.

The hemoglobin threshold should be adjusted based on fatigue or bone pain, Dr. Lal said. He also noted that patients with intact spleens have higher transfusion needs.

The rate of transfusion should be 5 mL/kg/hour in children and 200-300 mL/hour in adults, based on tolerance. Patients with impaired cardiac function should receive a reduced blood volume at a reduced rate.

Non–transfusion dependent thalassemia

Dr. Vichinsky discussed recommendations for non–transfusion dependent thalassemia (NTDT), noting that these patients may need transient transfusions to prevent morbidity.

Hemoglobin should not be the sole determinant of transfusion need in NTDT patients, he said. Their well-being – activity level, growth, and skeletal changes – is more important than hemoglobin levels. However, patients with hemoglobin levels less than 7 g/dL often have severe morbidity, and those with levels of 10 g/dL or greater are usually protected from severe morbidity.

Indications for transfusion in NTDT patients include:
 

• Growth failure.
• Hematopoietic tumors.
• Pulmonary hypertension.
• Silent brain infarcts.
• Skin ulcers.
• Severe bone pain.
• Poor quality of life.
• Frequent hemolytic crises.
• Marked and enlarging spleen.
• Failure of secondary sex development.
• Cosmetic and facial changes.
• Pregnancy.

“There is a risk to transfusing this population,” Dr. Vichinsky said. “They’re older, and when you transfuse them, they can get iron overloaded.”

He added that splenectomized NTDT patients have a high risk of alloimmunization, and the transfusion duration should be serially reevaluated in NTDT patients.

Alpha thalassemia major

For alpha thalassemia major, Dr. Vichinsky discussed the importance of prevention, screening, and fetal therapy. He said couples with a fetus at risk of alpha thalassemia major should be identified early and offered, in addition to termination, the option of early fetal transfusion.

Dr. Vichinsky recommended prenatal testing and monitoring of at-risk pregnancies with ultrasound. If the fetus requires a transfusion, monitoring hemoglobin Barts and hemoglobin A is necessary.

A fetus that requires a transfusion should receive packed red blood cells that are cytomegalovirus negative, are less than 7 days old, have been irradiated, have a hemoglobin mass greater than 75%, and have been optimally cross matched with the mother first.

“These babies appear, with serial transfusions, to survive and have a relatively normal neonatal period,” Dr. Vichinsky said.

He added, however, that postnatal management of alpha thalassemia major involves an aggressive transfusion protocol. These patients should be transfused to a higher hemoglobin level than patients with beta thalassemia – roughly 12 g/dL versus 10 g/dL.

These and Dr. Lal’s recommendations are based on information in the Standards of Care Guidelines for Thalassemia – Oakland 2011, the Thalassemia International Federation Guidelines – 2014, the Thalassemia Management Checklists: United States – 2018, the Thalassemia Western Consortium Consensus: US – 2019, and the International Collaboration for Transfusion Medicine Guidelines – 2019.

Dr. Lal and Dr. Vichinsky did not disclose any conflicts of interest.

[email protected]

Fresher blood products are not necessarily better for patients with beta thalassemia, according to a pair of experts.

Red blood cell units stored less than 2 weeks are ideal, but older units are acceptable, and phenotype matching should take priority over unit age, advised Ashutosh Lal, MD, and Elliott Vichinsky, MD, both of UCSF Benioff Children’s Hospital Oakland (Calif.). They discussed these and other recommendations for transfusing patients with thalassemia during a webinar hosted by the Centers for Disease Control and Prevention.

Indications for transfusion

Dr. Lal said patients with beta thalassemia major should be transfused if their hemoglobin is less than 7 g/dL on two occasions 2 weeks apart at baseline, or if their hemoglobin is greater than 7 g/dL and they have symptoms of anemia.

Patients with hemoglobin E beta thalassemia major should be transfused only if they have symptoms of anemia.

“The rationale is that, in beta thalassemia major, it is well established that, once the hemoglobin levels fall below 7 g/dL in young children, there is going to be massive bone marrow expansion, and there will be severe symptoms from anemia,” Dr. Lal said. “But the relationship of hemoglobin with symptoms in E beta thalassemia is less precise.”

The symptoms that should prompt transfusion include slowed growth, skeletal facial changes, splenomegaly, symptomatic or moderate to severe extramedullary hematopoiesis, cerebrovascular events, venous thromboembolism, pulmonary hypertension, osteoporotic fracture, and impaired quality of life in adults.

Dr. Lal said physicians should consider a 6-month trial of transfusions if the indication is unclear. He also noted that red cell antigen genotyping should be performed in all patients who may need transfusions.

Blood products

Dr. Lal said beta thalassemia patients should receive packed red blood cells that are leukoreduced prior to storage. The storage solution can be citrate-phosphate-dextrose solution with adenine (hematocrit 75%) or additive solution (hematocrit 60%).

“It’s important to note that the hematocrit of the two is quite different, and that needs to be inculcated into the decisions on how much volume to transfuse to younger children,” Dr. Lal said.

He noted that units should not be irradiated, as this damages the red cell membrane. And patients with severe allergic reactions should receive washed red blood cells because washing units removes residual donor plasma proteins.

Finally, units should be less than 2 weeks old if possible. Dr. Lal said using fresh units increases the survival of red blood cells post transfusion. However, he and Dr. Vichinsky both stressed that older units are acceptable, and phenotype matching is more important than the age of the unit.

Phenotype matching

Beta thalassemia patients who do not have preexisting alloantibodies or have transient autoantibodies should be matched to Rh and Kell, according to Dr. Lal.

Patients with preexisting alloantibodies should be matched to Rh, Kell, Duffy, Kidd, S, and the specific alloantibody. Patients with persistent autoantibodies should be matched to Rh, Kell, Duffy, Kidd, S, and any alloantibody.

Patients who start transfusions after 5 years of age should be matched to Rh, Kell, Duffy, Kidd, and S. Pregnant patients should be matched to Rh, Kell, Duffy, Kidd, and S, and units should be cytomegalovirus negative.

How to transfuse

Dr. Lal said the pretransfusion hemoglobin target is 10 g/dL, with a range of 9.5-10.5 g/dL in beta thalassemia major and a range of 9.0-10.5 g/dL for E beta thalassemia. A target of 10 g/dL is adequate for most individuals, Dr. Lal said, but he recommends individualization of hemoglobin target for patients with E beta thalassemia.

In general, patients should be transfused every 3 weeks, although 4 weeks is acceptable in younger children and those with hemoglobin E beta thalassemia.

As for the volume of a transfusion, children should receive 4 mL per kg of body weight, per gram increase in hemoglobin desired. Partial units can be used to avoid undertransfusion.

For adults, in general, those with pretransfusion hemoglobin less than 10 g/dL should receive three units, and those with pretransfusion hemoglobin of 10 g/dL or greater should receive two units.

The hemoglobin threshold should be adjusted based on fatigue or bone pain, Dr. Lal said. He also noted that patients with intact spleens have higher transfusion needs.

The rate of transfusion should be 5 mL/kg/hour in children and 200-300 mL/hour in adults, based on tolerance. Patients with impaired cardiac function should receive a reduced blood volume at a reduced rate.

Non–transfusion dependent thalassemia

Dr. Vichinsky discussed recommendations for non–transfusion dependent thalassemia (NTDT), noting that these patients may need transient transfusions to prevent morbidity.

Hemoglobin should not be the sole determinant of transfusion need in NTDT patients, he said. Their well-being – activity level, growth, and skeletal changes – is more important than hemoglobin levels. However, patients with hemoglobin levels less than 7 g/dL often have severe morbidity, and those with levels of 10 g/dL or greater are usually protected from severe morbidity.

Indications for transfusion in NTDT patients include:
 

• Growth failure.
• Hematopoietic tumors.
• Pulmonary hypertension.
• Silent brain infarcts.
• Skin ulcers.
• Severe bone pain.
• Poor quality of life.
• Frequent hemolytic crises.
• Marked and enlarging spleen.
• Failure of secondary sex development.
• Cosmetic and facial changes.
• Pregnancy.

“There is a risk to transfusing this population,” Dr. Vichinsky said. “They’re older, and when you transfuse them, they can get iron overloaded.”

He added that splenectomized NTDT patients have a high risk of alloimmunization, and the transfusion duration should be serially reevaluated in NTDT patients.

Alpha thalassemia major

For alpha thalassemia major, Dr. Vichinsky discussed the importance of prevention, screening, and fetal therapy. He said couples with a fetus at risk of alpha thalassemia major should be identified early and offered, in addition to termination, the option of early fetal transfusion.

Dr. Vichinsky recommended prenatal testing and monitoring of at-risk pregnancies with ultrasound. If the fetus requires a transfusion, monitoring hemoglobin Barts and hemoglobin A is necessary.

A fetus that requires a transfusion should receive packed red blood cells that are cytomegalovirus negative, are less than 7 days old, have been irradiated, have a hemoglobin mass greater than 75%, and have been optimally cross matched with the mother first.

“These babies appear, with serial transfusions, to survive and have a relatively normal neonatal period,” Dr. Vichinsky said.

He added, however, that postnatal management of alpha thalassemia major involves an aggressive transfusion protocol. These patients should be transfused to a higher hemoglobin level than patients with beta thalassemia – roughly 12 g/dL versus 10 g/dL.

These and Dr. Lal’s recommendations are based on information in the Standards of Care Guidelines for Thalassemia – Oakland 2011, the Thalassemia International Federation Guidelines – 2014, the Thalassemia Management Checklists: United States – 2018, the Thalassemia Western Consortium Consensus: US – 2019, and the International Collaboration for Transfusion Medicine Guidelines – 2019.

Dr. Lal and Dr. Vichinsky did not disclose any conflicts of interest.

[email protected]

Fresher blood products are not necessarily better for patients with beta thalassemia, according to a pair of experts.

Red blood cell units stored less than 2 weeks are ideal, but older units are acceptable, and phenotype matching should take priority over unit age, advised Ashutosh Lal, MD, and Elliott Vichinsky, MD, both of UCSF Benioff Children’s Hospital Oakland (Calif.). They discussed these and other recommendations for transfusing patients with thalassemia during a webinar hosted by the Centers for Disease Control and Prevention.

Indications for transfusion

Dr. Lal said patients with beta thalassemia major should be transfused if their hemoglobin is less than 7 g/dL on two occasions 2 weeks apart at baseline, or if their hemoglobin is greater than 7 g/dL and they have symptoms of anemia.

Patients with hemoglobin E beta thalassemia major should be transfused only if they have symptoms of anemia.

“The rationale is that, in beta thalassemia major, it is well established that, once the hemoglobin levels fall below 7 g/dL in young children, there is going to be massive bone marrow expansion, and there will be severe symptoms from anemia,” Dr. Lal said. “But the relationship of hemoglobin with symptoms in E beta thalassemia is less precise.”

The symptoms that should prompt transfusion include slowed growth, skeletal facial changes, splenomegaly, symptomatic or moderate to severe extramedullary hematopoiesis, cerebrovascular events, venous thromboembolism, pulmonary hypertension, osteoporotic fracture, and impaired quality of life in adults.

Dr. Lal said physicians should consider a 6-month trial of transfusions if the indication is unclear. He also noted that red cell antigen genotyping should be performed in all patients who may need transfusions.

Blood products

Dr. Lal said beta thalassemia patients should receive packed red blood cells that are leukoreduced prior to storage. The storage solution can be citrate-phosphate-dextrose solution with adenine (hematocrit 75%) or additive solution (hematocrit 60%).

“It’s important to note that the hematocrit of the two is quite different, and that needs to be inculcated into the decisions on how much volume to transfuse to younger children,” Dr. Lal said.

He noted that units should not be irradiated, as this damages the red cell membrane. And patients with severe allergic reactions should receive washed red blood cells because washing units removes residual donor plasma proteins.

Finally, units should be less than 2 weeks old if possible. Dr. Lal said using fresh units increases the survival of red blood cells post transfusion. However, he and Dr. Vichinsky both stressed that older units are acceptable, and phenotype matching is more important than the age of the unit.

Phenotype matching

Beta thalassemia patients who do not have preexisting alloantibodies or have transient autoantibodies should be matched to Rh and Kell, according to Dr. Lal.

Patients with preexisting alloantibodies should be matched to Rh, Kell, Duffy, Kidd, S, and the specific alloantibody. Patients with persistent autoantibodies should be matched to Rh, Kell, Duffy, Kidd, S, and any alloantibody.

Patients who start transfusions after 5 years of age should be matched to Rh, Kell, Duffy, Kidd, and S. Pregnant patients should be matched to Rh, Kell, Duffy, Kidd, and S, and units should be cytomegalovirus negative.

How to transfuse

Dr. Lal said the pretransfusion hemoglobin target is 10 g/dL, with a range of 9.5-10.5 g/dL in beta thalassemia major and a range of 9.0-10.5 g/dL for E beta thalassemia. A target of 10 g/dL is adequate for most individuals, Dr. Lal said, but he recommends individualization of hemoglobin target for patients with E beta thalassemia.

In general, patients should be transfused every 3 weeks, although 4 weeks is acceptable in younger children and those with hemoglobin E beta thalassemia.

As for the volume of a transfusion, children should receive 4 mL per kg of body weight, per gram increase in hemoglobin desired. Partial units can be used to avoid undertransfusion.

For adults, in general, those with pretransfusion hemoglobin less than 10 g/dL should receive three units, and those with pretransfusion hemoglobin of 10 g/dL or greater should receive two units.

The hemoglobin threshold should be adjusted based on fatigue or bone pain, Dr. Lal said. He also noted that patients with intact spleens have higher transfusion needs.

The rate of transfusion should be 5 mL/kg/hour in children and 200-300 mL/hour in adults, based on tolerance. Patients with impaired cardiac function should receive a reduced blood volume at a reduced rate.

Non–transfusion dependent thalassemia

Dr. Vichinsky discussed recommendations for non–transfusion dependent thalassemia (NTDT), noting that these patients may need transient transfusions to prevent morbidity.

Hemoglobin should not be the sole determinant of transfusion need in NTDT patients, he said. Their well-being – activity level, growth, and skeletal changes – is more important than hemoglobin levels. However, patients with hemoglobin levels less than 7 g/dL often have severe morbidity, and those with levels of 10 g/dL or greater are usually protected from severe morbidity.

Indications for transfusion in NTDT patients include:
 

• Growth failure.
• Hematopoietic tumors.
• Pulmonary hypertension.
• Silent brain infarcts.
• Skin ulcers.
• Severe bone pain.
• Poor quality of life.
• Frequent hemolytic crises.
• Marked and enlarging spleen.
• Failure of secondary sex development.
• Cosmetic and facial changes.
• Pregnancy.

“There is a risk to transfusing this population,” Dr. Vichinsky said. “They’re older, and when you transfuse them, they can get iron overloaded.”

He added that splenectomized NTDT patients have a high risk of alloimmunization, and the transfusion duration should be serially reevaluated in NTDT patients.

Alpha thalassemia major

For alpha thalassemia major, Dr. Vichinsky discussed the importance of prevention, screening, and fetal therapy. He said couples with a fetus at risk of alpha thalassemia major should be identified early and offered, in addition to termination, the option of early fetal transfusion.

Dr. Vichinsky recommended prenatal testing and monitoring of at-risk pregnancies with ultrasound. If the fetus requires a transfusion, monitoring hemoglobin Barts and hemoglobin A is necessary.

A fetus that requires a transfusion should receive packed red blood cells that are cytomegalovirus negative, are less than 7 days old, have been irradiated, have a hemoglobin mass greater than 75%, and have been optimally cross matched with the mother first.

“These babies appear, with serial transfusions, to survive and have a relatively normal neonatal period,” Dr. Vichinsky said.

He added, however, that postnatal management of alpha thalassemia major involves an aggressive transfusion protocol. These patients should be transfused to a higher hemoglobin level than patients with beta thalassemia – roughly 12 g/dL versus 10 g/dL.

These and Dr. Lal’s recommendations are based on information in the Standards of Care Guidelines for Thalassemia – Oakland 2011, the Thalassemia International Federation Guidelines – 2014, the Thalassemia Management Checklists: United States – 2018, the Thalassemia Western Consortium Consensus: US – 2019, and the International Collaboration for Transfusion Medicine Guidelines – 2019.

Dr. Lal and Dr. Vichinsky did not disclose any conflicts of interest.

[email protected]

The Food and Drug Administration has approved fedratinib (Inrebic), an oral JAK2/FLT3 inhibitor, to treat myelofibrosis.
 

Fedratinib is approved to treat adults with intermediate-2 or high-risk primary or secondary (post–polycythemia vera or post–essential thrombocythemia) myelofibrosis.

The prescribing information for fedratinib includes a boxed warning detailing the risk of serious and fatal encephalopathy, including Wernicke’s.

The encephalopathy risk prompted Sanofi to stop developing fedratinib in 2013. The FDA placed a clinical hold on all trials of fedratinib after potential cases of Wernicke’s encephalopathy were observed in eight patients.

The FDA lifted the clinical hold in 2017, and Celgene Corporation decided to develop fedratinib when the company acquired Impact Biomedicines in 2018.

In the phase 3 JAKARTA trial, fedratinib significantly reduced splenomegaly and symptom burden in patients with primary or secondary myelofibrosis (JAMA Oncol. 2015 Aug;1[5]:643-51). In the phase 2 JAKARTA2 trial, fedratinib produced responses in myelofibrosis patients previously treated with ruxolitinib (Lancet Haematol. 2017 Jul;4[7]:e317-e324).

Fedratinib received orphan drug designation from the FDA, and the application for fedratinib received priority review.

The FDA granted approval of fedratinib to Impact Biomedicines, a wholly owned subsidiary of Celgene.

[email protected]

The Food and Drug Administration has approved fedratinib (Inrebic), an oral JAK2/FLT3 inhibitor, to treat myelofibrosis.
 

Fedratinib is approved to treat adults with intermediate-2 or high-risk primary or secondary (post–polycythemia vera or post–essential thrombocythemia) myelofibrosis.

The prescribing information for fedratinib includes a boxed warning detailing the risk of serious and fatal encephalopathy, including Wernicke’s.

The encephalopathy risk prompted Sanofi to stop developing fedratinib in 2013. The FDA placed a clinical hold on all trials of fedratinib after potential cases of Wernicke’s encephalopathy were observed in eight patients.

The FDA lifted the clinical hold in 2017, and Celgene Corporation decided to develop fedratinib when the company acquired Impact Biomedicines in 2018.

In the phase 3 JAKARTA trial, fedratinib significantly reduced splenomegaly and symptom burden in patients with primary or secondary myelofibrosis (JAMA Oncol. 2015 Aug;1[5]:643-51). In the phase 2 JAKARTA2 trial, fedratinib produced responses in myelofibrosis patients previously treated with ruxolitinib (Lancet Haematol. 2017 Jul;4[7]:e317-e324).

Fedratinib received orphan drug designation from the FDA, and the application for fedratinib received priority review.

The FDA granted approval of fedratinib to Impact Biomedicines, a wholly owned subsidiary of Celgene.

[email protected]

The Food and Drug Administration has approved fedratinib (Inrebic), an oral JAK2/FLT3 inhibitor, to treat myelofibrosis.
 

Fedratinib is approved to treat adults with intermediate-2 or high-risk primary or secondary (post–polycythemia vera or post–essential thrombocythemia) myelofibrosis.

The prescribing information for fedratinib includes a boxed warning detailing the risk of serious and fatal encephalopathy, including Wernicke’s.

The encephalopathy risk prompted Sanofi to stop developing fedratinib in 2013. The FDA placed a clinical hold on all trials of fedratinib after potential cases of Wernicke’s encephalopathy were observed in eight patients.

The FDA lifted the clinical hold in 2017, and Celgene Corporation decided to develop fedratinib when the company acquired Impact Biomedicines in 2018.

In the phase 3 JAKARTA trial, fedratinib significantly reduced splenomegaly and symptom burden in patients with primary or secondary myelofibrosis (JAMA Oncol. 2015 Aug;1[5]:643-51). In the phase 2 JAKARTA2 trial, fedratinib produced responses in myelofibrosis patients previously treated with ruxolitinib (Lancet Haematol. 2017 Jul;4[7]:e317-e324).

Fedratinib received orphan drug designation from the FDA, and the application for fedratinib received priority review.

The FDA granted approval of fedratinib to Impact Biomedicines, a wholly owned subsidiary of Celgene.

[email protected]

A literature review has failed to provide new insights regarding the burden of mild hemophilia A.

Crystal/Wikimedia Commons/Creative Commons Attribution 2.0

In the 17 studies reviewed, mean annual bleeding rates (ABRs) were largely unreported. Data on joint pain and damage, quality of life (QOL), societal impacts, and costs of care were limited and inconsistent across the studies.

The review “revealed a lack of evidence” in adults with mild hemophilia A, Flora Peyvandi, MD, PhD, of Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico in Milan and colleagues wrote in Haemophilia.

The researchers reviewed data from 10 studies conducted in Europe, 6 in North America, and 1 in Japan. Six studies were prospective cohort or registry studies, six were retrospective, and five studies were surveys or outcomes research.

The studies included 3,213 patients with mild hemophilia A aged 13 years or older. There were few details on treatment protocols, but patients received factor VIII concentrates, recombinant factor VIII, and desmopressin.

Most studies did not report mean ABRs. For the three that did, the mean ABRs were 0.44, 0.56, and 4.5. Six studies reported the percentage of patients with bleeding events, and those numbers ranged from 5.5% (1/18) to 90.7% (68/75).

Data on joint pain and damage were not standardized across studies, so the researchers were unable to draw any conclusions. One study showed no significant difference in Health Assessment Questionnaire pain score between patients with mild hemophilia A and control subjects. In another study, 5% of patients with mild hemophilia A reported having severe joint pain in the previous year, and 15% of patients reported moderate joint pain.

The researchers also found it difficult to draw conclusions about QOL. Three studies reported QOL data, and all used a different instrument.

In a study using the SF-36, general health and emotional role functioning were both significantly lower for patients with mild hemophilia A than for age-matched healthy control subjects (P less than .05). In a study using the SF-12, the physical component summary was significantly higher for patients with mild hemophilia A than for those with severe disease (P = .014).

In a study using the Haemo-QOL-A, there were no significant differences between patients with mild and severe hemophilia A. However, Dr. Peyvandi and colleagues noted that this study required long-term use of factor VIII concentrate, so the mild hemophilia A patients in this group were “probably not representative” of the overall mild hemophilia A population.

Societal impacts were difficult to assess because of a lack of standardization across studies. One study showed no significant difference in employment between patients with mild hemophilia A and healthy controls. In a U.S.-based study, patients with mild hemophilia A missed an average of 6.2 workdays per year, and 4.7 days were caused by their hemophilia. A study in Italy showed that patients with mild hemophilia A missed an average of 3.4 workdays per year.

Just two studies included data on health care costs for patients with mild hemophilia A. The mean cost of care was €793 per year in a study from Portugal published in 2015. In a U.S. study published in 1995, the annual cost of care was $22,182.

“Considering the limitations of the current body of evidence, higher-quality studies in this area are needed,” Dr. Peyvandi and colleagues wrote. “Such studies would report both bleeding and other clinical outcomes based on common definitions and for a representative population of mild [hemophilia A] adults. Areas for further research include more robust comparison to healthy controls or population norms, especially for QOL and other patient-reported outcomes.”

Seven of the eight researchers reported relationships, including employment, with BioMarin. Dr. Peyvandi reported relationships with Sanofi, Grifols, Novo Nordisk, Roche, Takeda, Sobi, Bioverativ, Spark Therapeutics, Sysmex, and CSL Behring.

[email protected]

SOURCE: Peyvandi F et al. Haemophilia. 2019 Jul 11. doi: 10.1111/hae.13777.

A literature review has failed to provide new insights regarding the burden of mild hemophilia A.

Crystal/Wikimedia Commons/Creative Commons Attribution 2.0

In the 17 studies reviewed, mean annual bleeding rates (ABRs) were largely unreported. Data on joint pain and damage, quality of life (QOL), societal impacts, and costs of care were limited and inconsistent across the studies.

The review “revealed a lack of evidence” in adults with mild hemophilia A, Flora Peyvandi, MD, PhD, of Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico in Milan and colleagues wrote in Haemophilia.

The researchers reviewed data from 10 studies conducted in Europe, 6 in North America, and 1 in Japan. Six studies were prospective cohort or registry studies, six were retrospective, and five studies were surveys or outcomes research.

The studies included 3,213 patients with mild hemophilia A aged 13 years or older. There were few details on treatment protocols, but patients received factor VIII concentrates, recombinant factor VIII, and desmopressin.

Most studies did not report mean ABRs. For the three that did, the mean ABRs were 0.44, 0.56, and 4.5. Six studies reported the percentage of patients with bleeding events, and those numbers ranged from 5.5% (1/18) to 90.7% (68/75).

Data on joint pain and damage were not standardized across studies, so the researchers were unable to draw any conclusions. One study showed no significant difference in Health Assessment Questionnaire pain score between patients with mild hemophilia A and control subjects. In another study, 5% of patients with mild hemophilia A reported having severe joint pain in the previous year, and 15% of patients reported moderate joint pain.

The researchers also found it difficult to draw conclusions about QOL. Three studies reported QOL data, and all used a different instrument.

In a study using the SF-36, general health and emotional role functioning were both significantly lower for patients with mild hemophilia A than for age-matched healthy control subjects (P less than .05). In a study using the SF-12, the physical component summary was significantly higher for patients with mild hemophilia A than for those with severe disease (P = .014).

In a study using the Haemo-QOL-A, there were no significant differences between patients with mild and severe hemophilia A. However, Dr. Peyvandi and colleagues noted that this study required long-term use of factor VIII concentrate, so the mild hemophilia A patients in this group were “probably not representative” of the overall mild hemophilia A population.

Societal impacts were difficult to assess because of a lack of standardization across studies. One study showed no significant difference in employment between patients with mild hemophilia A and healthy controls. In a U.S.-based study, patients with mild hemophilia A missed an average of 6.2 workdays per year, and 4.7 days were caused by their hemophilia. A study in Italy showed that patients with mild hemophilia A missed an average of 3.4 workdays per year.

Just two studies included data on health care costs for patients with mild hemophilia A. The mean cost of care was €793 per year in a study from Portugal published in 2015. In a U.S. study published in 1995, the annual cost of care was $22,182.

“Considering the limitations of the current body of evidence, higher-quality studies in this area are needed,” Dr. Peyvandi and colleagues wrote. “Such studies would report both bleeding and other clinical outcomes based on common definitions and for a representative population of mild [hemophilia A] adults. Areas for further research include more robust comparison to healthy controls or population norms, especially for QOL and other patient-reported outcomes.”

Seven of the eight researchers reported relationships, including employment, with BioMarin. Dr. Peyvandi reported relationships with Sanofi, Grifols, Novo Nordisk, Roche, Takeda, Sobi, Bioverativ, Spark Therapeutics, Sysmex, and CSL Behring.

[email protected]

SOURCE: Peyvandi F et al. Haemophilia. 2019 Jul 11. doi: 10.1111/hae.13777.

A literature review has failed to provide new insights regarding the burden of mild hemophilia A.

Crystal/Wikimedia Commons/Creative Commons Attribution 2.0

In the 17 studies reviewed, mean annual bleeding rates (ABRs) were largely unreported. Data on joint pain and damage, quality of life (QOL), societal impacts, and costs of care were limited and inconsistent across the studies.

The review “revealed a lack of evidence” in adults with mild hemophilia A, Flora Peyvandi, MD, PhD, of Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico in Milan and colleagues wrote in Haemophilia.

The researchers reviewed data from 10 studies conducted in Europe, 6 in North America, and 1 in Japan. Six studies were prospective cohort or registry studies, six were retrospective, and five studies were surveys or outcomes research.

The studies included 3,213 patients with mild hemophilia A aged 13 years or older. There were few details on treatment protocols, but patients received factor VIII concentrates, recombinant factor VIII, and desmopressin.

Most studies did not report mean ABRs. For the three that did, the mean ABRs were 0.44, 0.56, and 4.5. Six studies reported the percentage of patients with bleeding events, and those numbers ranged from 5.5% (1/18) to 90.7% (68/75).

Data on joint pain and damage were not standardized across studies, so the researchers were unable to draw any conclusions. One study showed no significant difference in Health Assessment Questionnaire pain score between patients with mild hemophilia A and control subjects. In another study, 5% of patients with mild hemophilia A reported having severe joint pain in the previous year, and 15% of patients reported moderate joint pain.

The researchers also found it difficult to draw conclusions about QOL. Three studies reported QOL data, and all used a different instrument.

In a study using the SF-36, general health and emotional role functioning were both significantly lower for patients with mild hemophilia A than for age-matched healthy control subjects (P less than .05). In a study using the SF-12, the physical component summary was significantly higher for patients with mild hemophilia A than for those with severe disease (P = .014).

In a study using the Haemo-QOL-A, there were no significant differences between patients with mild and severe hemophilia A. However, Dr. Peyvandi and colleagues noted that this study required long-term use of factor VIII concentrate, so the mild hemophilia A patients in this group were “probably not representative” of the overall mild hemophilia A population.

Societal impacts were difficult to assess because of a lack of standardization across studies. One study showed no significant difference in employment between patients with mild hemophilia A and healthy controls. In a U.S.-based study, patients with mild hemophilia A missed an average of 6.2 workdays per year, and 4.7 days were caused by their hemophilia. A study in Italy showed that patients with mild hemophilia A missed an average of 3.4 workdays per year.

Just two studies included data on health care costs for patients with mild hemophilia A. The mean cost of care was €793 per year in a study from Portugal published in 2015. In a U.S. study published in 1995, the annual cost of care was $22,182.

“Considering the limitations of the current body of evidence, higher-quality studies in this area are needed,” Dr. Peyvandi and colleagues wrote. “Such studies would report both bleeding and other clinical outcomes based on common definitions and for a representative population of mild [hemophilia A] adults. Areas for further research include more robust comparison to healthy controls or population norms, especially for QOL and other patient-reported outcomes.”

Seven of the eight researchers reported relationships, including employment, with BioMarin. Dr. Peyvandi reported relationships with Sanofi, Grifols, Novo Nordisk, Roche, Takeda, Sobi, Bioverativ, Spark Therapeutics, Sysmex, and CSL Behring.

[email protected]

SOURCE: Peyvandi F et al. Haemophilia. 2019 Jul 11. doi: 10.1111/hae.13777.

Jorge E. Cortes, MD, is set to become director of the Georgia Cancer Center in Augusta on Sept. 1. In this new position, Dr. Cortes will further the center’s missions of obtaining National Cancer Institute designation and reducing the burden of cancer in Georgia.

Dr. Cortes was previously deputy chair and professor of medicine in the department of leukemia at MD Anderson Cancer Center in Houston. He received his medical degree in 1986 and began working at MD Anderson in 1991. His clinical interests include acute and chronic leukemias, myelodysplastic syndromes, and myeloproliferative neoplasms.

Fern M. Anari, MD, joined Fox Chase Cancer Center in Philadelphia in August. Dr. Anari is now an assistant professor in the division of genitourinary medical oncology within the department of hematology/oncology.

Movers in Medicine highlights career moves and personal achievements by hematologists and oncologists. Did you switch jobs, take on a new role, climb a mountain? Tell us all about it at [email protected], and you could be featured in Movers in Medicine.

[email protected]

Jorge E. Cortes, MD, is set to become director of the Georgia Cancer Center in Augusta on Sept. 1. In this new position, Dr. Cortes will further the center’s missions of obtaining National Cancer Institute designation and reducing the burden of cancer in Georgia.

Dr. Cortes was previously deputy chair and professor of medicine in the department of leukemia at MD Anderson Cancer Center in Houston. He received his medical degree in 1986 and began working at MD Anderson in 1991. His clinical interests include acute and chronic leukemias, myelodysplastic syndromes, and myeloproliferative neoplasms.

Fern M. Anari, MD, joined Fox Chase Cancer Center in Philadelphia in August. Dr. Anari is now an assistant professor in the division of genitourinary medical oncology within the department of hematology/oncology.

Movers in Medicine highlights career moves and personal achievements by hematologists and oncologists. Did you switch jobs, take on a new role, climb a mountain? Tell us all about it at [email protected], and you could be featured in Movers in Medicine.

[email protected]

Jorge E. Cortes, MD, is set to become director of the Georgia Cancer Center in Augusta on Sept. 1. In this new position, Dr. Cortes will further the center’s missions of obtaining National Cancer Institute designation and reducing the burden of cancer in Georgia.

Dr. Cortes was previously deputy chair and professor of medicine in the department of leukemia at MD Anderson Cancer Center in Houston. He received his medical degree in 1986 and began working at MD Anderson in 1991. His clinical interests include acute and chronic leukemias, myelodysplastic syndromes, and myeloproliferative neoplasms.

Fern M. Anari, MD, joined Fox Chase Cancer Center in Philadelphia in August. Dr. Anari is now an assistant professor in the division of genitourinary medical oncology within the department of hematology/oncology.

Movers in Medicine highlights career moves and personal achievements by hematologists and oncologists. Did you switch jobs, take on a new role, climb a mountain? Tell us all about it at [email protected], and you could be featured in Movers in Medicine.

[email protected]