CLL

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.

The Food and Drug Administration has granted breakthrough therapy designation to acalabrutinib (Calquence) as a monotherapy for adults with chronic lymphocytic leukemia (CLL).

The Bruton tyrosine kinase inhibitor is already approved for the treatment of adults with mantle cell lymphoma who have received at least one prior therapy, and multiple trials are underway to evaluate the drug’s use in a variety of B-cell malignancies, according to the drug’s sponsor, AstraZeneca.

The current designation was based on preliminary results from two phase 3 trials – ELEVATE-TN and ASCEND. In the three-arm ELEVATE-TN trial, researchers evaluated acalabrutinib alone or in combination with obinutuzumab versus chlorambucil plus obinutuzumab in previously untreated patients with CLL. In the two-arm ASCEND trial, previously treated patients with CLL were randomized to receive acalabrutinib monotherapy or the physician’s choice of either rituximab plus idelalisib or rituximab plus bendamustine.

Interim analyses of the two trials showed that acalabrutinib alone, or in combination, significantly improved progression-free survival without raising safety concerns.

Breakthrough therapy designation allows for an expedited review by the FDA for treatments aimed at treating serious conditions where there is preliminary clinical evidence showing a substantial improvement over an available therapy or a clinically significant endpoint.

[email protected]

The Food and Drug Administration has granted breakthrough therapy designation to acalabrutinib (Calquence) as a monotherapy for adults with chronic lymphocytic leukemia (CLL).

The Bruton tyrosine kinase inhibitor is already approved for the treatment of adults with mantle cell lymphoma who have received at least one prior therapy, and multiple trials are underway to evaluate the drug’s use in a variety of B-cell malignancies, according to the drug’s sponsor, AstraZeneca.

The current designation was based on preliminary results from two phase 3 trials – ELEVATE-TN and ASCEND. In the three-arm ELEVATE-TN trial, researchers evaluated acalabrutinib alone or in combination with obinutuzumab versus chlorambucil plus obinutuzumab in previously untreated patients with CLL. In the two-arm ASCEND trial, previously treated patients with CLL were randomized to receive acalabrutinib monotherapy or the physician’s choice of either rituximab plus idelalisib or rituximab plus bendamustine.

Interim analyses of the two trials showed that acalabrutinib alone, or in combination, significantly improved progression-free survival without raising safety concerns.

Breakthrough therapy designation allows for an expedited review by the FDA for treatments aimed at treating serious conditions where there is preliminary clinical evidence showing a substantial improvement over an available therapy or a clinically significant endpoint.

[email protected]

The Food and Drug Administration has granted breakthrough therapy designation to acalabrutinib (Calquence) as a monotherapy for adults with chronic lymphocytic leukemia (CLL).

The Bruton tyrosine kinase inhibitor is already approved for the treatment of adults with mantle cell lymphoma who have received at least one prior therapy, and multiple trials are underway to evaluate the drug’s use in a variety of B-cell malignancies, according to the drug’s sponsor, AstraZeneca.

The current designation was based on preliminary results from two phase 3 trials – ELEVATE-TN and ASCEND. In the three-arm ELEVATE-TN trial, researchers evaluated acalabrutinib alone or in combination with obinutuzumab versus chlorambucil plus obinutuzumab in previously untreated patients with CLL. In the two-arm ASCEND trial, previously treated patients with CLL were randomized to receive acalabrutinib monotherapy or the physician’s choice of either rituximab plus idelalisib or rituximab plus bendamustine.

Interim analyses of the two trials showed that acalabrutinib alone, or in combination, significantly improved progression-free survival without raising safety concerns.

Breakthrough therapy designation allows for an expedited review by the FDA for treatments aimed at treating serious conditions where there is preliminary clinical evidence showing a substantial improvement over an available therapy or a clinically significant endpoint.

[email protected]

The Bruton tyrosine kinase (BTK) inhibitor zanubrutinib appears safe and effective for patients with B-cell malignancies, according to results from a phase 1 trial.

©Ed Uthman/Flickr

Among patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL), the overall response rate was 96.2%, reported Constantine Si Lun Tam, MD, of Peter MacCallum Cancer Centre in Melbourne and colleagues.

“Zanubrutinib (BGB-3111) is a highly specific next-generation BTK inhibitor with favorable oral bioavailability, as shown in preclinical studies,” the investigators wrote in Blood. “Compared with ibrutinib, zanubrutinib has shown greater selectivity for BTK and fewer off-target effects in multiple in vitro enzymatic and cell-based assays.”

The current, open-label trial involved 144 patients with B-cell malignancies. To determine optimal dosing, the investigators recruited 17 patients with relapsed/refractory B-cell malignancies who had received at least one prior therapy. The dose expansion part of the study assessed responses in multiple cohorts, including patients with CLL/SLL, mantle cell lymphoma, and Waldenström macroglobulinemia. The primary endpoints were safety and tolerability, including maximum tolerated dose. Efficacy findings were also reported.

During dose escalation, no dose-limiting toxicities were observed, so the highest dose – 320 mg once daily or 160 mg twice daily – was selected for further testing.

The investigators highlighted efficacy and safety findings from 94 patients with CLL/SLL who were involved in dose expansion. Although nearly one-quarter (23.4%) were treatment-naive, the median number of prior therapies was two, and some patients had high-risk features, such as adverse cytogenetics, including 19.1% with a TP53 mutation and 23.3% with a 17p deletion. After a median follow-up of 13.7 months, 94.7% of these patients were still undergoing treatment.

Out of the initial 94 patients with CLL/SLL, 78 were evaluable for efficacy. The overall response rate was 96.2%, including two (2.6%) complete responses, 63 (80.8%) partial responses, and 10 (12.8%) partial responses with lymphocytosis. The median progression-free survival had not been reached, and the 12-month estimated progression-free survival was 100%.

In regard to safety, the most common adverse events were contusion (35.1%), upper respiratory tract infection (33.0%), cough (25.5%), diarrhea (21.3%), fatigue (19.1%), back pain (14.9%), hematuria (14.9%), headache (13.8%), nausea (13.8%), rash (12.8%), arthralgia (11.7%), muscle spasms (11.7%), and urinary tract infection (10.6%).

A number of other adverse events were reported, although these occurred in less than 10% of patients.

More than one-third of patients (36.2%) experienced grade 3 or higher adverse events, with neutropenia being most common (6.4%), followed by pneumonia , hypertension, and anemia, which each occurred in 2.1% of patients, and less commonly, back pain, nausea, urinary tract infection, purpura, cellulitis, and squamous cell carcinoma of the skin, which each occurred in 1.1% of patients.

“In this first-in-human study, zanubrutinib demonstrated encouraging activity in patients with relapsed/refractory and treatment-naive CLL/SLL, with good tolerability,” the investigators concluded. “Two ongoing randomized studies of zanubrutinib versus ibrutinib (NCT03053440 and NCT03734016) aim to determine whether consistent, continuous BTK blockade with a selective inhibitor results in fewer off-target effects and translates into improvements in disease control.”

The study was funded by BeiGene USA, which is developing the drug. The investigators reported relationships with the study sponsor, as well as Janssen, Pharmacyclics, AbbVie, and others.

SOURCE: Tam CSL et al. Blood. 2019 Jul 24. doi: 10.1182/blood.2019001160.

The Bruton tyrosine kinase (BTK) inhibitor zanubrutinib appears safe and effective for patients with B-cell malignancies, according to results from a phase 1 trial.

©Ed Uthman/Flickr

Among patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL), the overall response rate was 96.2%, reported Constantine Si Lun Tam, MD, of Peter MacCallum Cancer Centre in Melbourne and colleagues.

“Zanubrutinib (BGB-3111) is a highly specific next-generation BTK inhibitor with favorable oral bioavailability, as shown in preclinical studies,” the investigators wrote in Blood. “Compared with ibrutinib, zanubrutinib has shown greater selectivity for BTK and fewer off-target effects in multiple in vitro enzymatic and cell-based assays.”

The current, open-label trial involved 144 patients with B-cell malignancies. To determine optimal dosing, the investigators recruited 17 patients with relapsed/refractory B-cell malignancies who had received at least one prior therapy. The dose expansion part of the study assessed responses in multiple cohorts, including patients with CLL/SLL, mantle cell lymphoma, and Waldenström macroglobulinemia. The primary endpoints were safety and tolerability, including maximum tolerated dose. Efficacy findings were also reported.

During dose escalation, no dose-limiting toxicities were observed, so the highest dose – 320 mg once daily or 160 mg twice daily – was selected for further testing.

The investigators highlighted efficacy and safety findings from 94 patients with CLL/SLL who were involved in dose expansion. Although nearly one-quarter (23.4%) were treatment-naive, the median number of prior therapies was two, and some patients had high-risk features, such as adverse cytogenetics, including 19.1% with a TP53 mutation and 23.3% with a 17p deletion. After a median follow-up of 13.7 months, 94.7% of these patients were still undergoing treatment.

Out of the initial 94 patients with CLL/SLL, 78 were evaluable for efficacy. The overall response rate was 96.2%, including two (2.6%) complete responses, 63 (80.8%) partial responses, and 10 (12.8%) partial responses with lymphocytosis. The median progression-free survival had not been reached, and the 12-month estimated progression-free survival was 100%.

In regard to safety, the most common adverse events were contusion (35.1%), upper respiratory tract infection (33.0%), cough (25.5%), diarrhea (21.3%), fatigue (19.1%), back pain (14.9%), hematuria (14.9%), headache (13.8%), nausea (13.8%), rash (12.8%), arthralgia (11.7%), muscle spasms (11.7%), and urinary tract infection (10.6%).

A number of other adverse events were reported, although these occurred in less than 10% of patients.

More than one-third of patients (36.2%) experienced grade 3 or higher adverse events, with neutropenia being most common (6.4%), followed by pneumonia , hypertension, and anemia, which each occurred in 2.1% of patients, and less commonly, back pain, nausea, urinary tract infection, purpura, cellulitis, and squamous cell carcinoma of the skin, which each occurred in 1.1% of patients.

“In this first-in-human study, zanubrutinib demonstrated encouraging activity in patients with relapsed/refractory and treatment-naive CLL/SLL, with good tolerability,” the investigators concluded. “Two ongoing randomized studies of zanubrutinib versus ibrutinib (NCT03053440 and NCT03734016) aim to determine whether consistent, continuous BTK blockade with a selective inhibitor results in fewer off-target effects and translates into improvements in disease control.”

The study was funded by BeiGene USA, which is developing the drug. The investigators reported relationships with the study sponsor, as well as Janssen, Pharmacyclics, AbbVie, and others.

SOURCE: Tam CSL et al. Blood. 2019 Jul 24. doi: 10.1182/blood.2019001160.

The Bruton tyrosine kinase (BTK) inhibitor zanubrutinib appears safe and effective for patients with B-cell malignancies, according to results from a phase 1 trial.

©Ed Uthman/Flickr

Among patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL), the overall response rate was 96.2%, reported Constantine Si Lun Tam, MD, of Peter MacCallum Cancer Centre in Melbourne and colleagues.

“Zanubrutinib (BGB-3111) is a highly specific next-generation BTK inhibitor with favorable oral bioavailability, as shown in preclinical studies,” the investigators wrote in Blood. “Compared with ibrutinib, zanubrutinib has shown greater selectivity for BTK and fewer off-target effects in multiple in vitro enzymatic and cell-based assays.”

The current, open-label trial involved 144 patients with B-cell malignancies. To determine optimal dosing, the investigators recruited 17 patients with relapsed/refractory B-cell malignancies who had received at least one prior therapy. The dose expansion part of the study assessed responses in multiple cohorts, including patients with CLL/SLL, mantle cell lymphoma, and Waldenström macroglobulinemia. The primary endpoints were safety and tolerability, including maximum tolerated dose. Efficacy findings were also reported.

During dose escalation, no dose-limiting toxicities were observed, so the highest dose – 320 mg once daily or 160 mg twice daily – was selected for further testing.

The investigators highlighted efficacy and safety findings from 94 patients with CLL/SLL who were involved in dose expansion. Although nearly one-quarter (23.4%) were treatment-naive, the median number of prior therapies was two, and some patients had high-risk features, such as adverse cytogenetics, including 19.1% with a TP53 mutation and 23.3% with a 17p deletion. After a median follow-up of 13.7 months, 94.7% of these patients were still undergoing treatment.

Out of the initial 94 patients with CLL/SLL, 78 were evaluable for efficacy. The overall response rate was 96.2%, including two (2.6%) complete responses, 63 (80.8%) partial responses, and 10 (12.8%) partial responses with lymphocytosis. The median progression-free survival had not been reached, and the 12-month estimated progression-free survival was 100%.

In regard to safety, the most common adverse events were contusion (35.1%), upper respiratory tract infection (33.0%), cough (25.5%), diarrhea (21.3%), fatigue (19.1%), back pain (14.9%), hematuria (14.9%), headache (13.8%), nausea (13.8%), rash (12.8%), arthralgia (11.7%), muscle spasms (11.7%), and urinary tract infection (10.6%).

A number of other adverse events were reported, although these occurred in less than 10% of patients.

More than one-third of patients (36.2%) experienced grade 3 or higher adverse events, with neutropenia being most common (6.4%), followed by pneumonia , hypertension, and anemia, which each occurred in 2.1% of patients, and less commonly, back pain, nausea, urinary tract infection, purpura, cellulitis, and squamous cell carcinoma of the skin, which each occurred in 1.1% of patients.

“In this first-in-human study, zanubrutinib demonstrated encouraging activity in patients with relapsed/refractory and treatment-naive CLL/SLL, with good tolerability,” the investigators concluded. “Two ongoing randomized studies of zanubrutinib versus ibrutinib (NCT03053440 and NCT03734016) aim to determine whether consistent, continuous BTK blockade with a selective inhibitor results in fewer off-target effects and translates into improvements in disease control.”

The study was funded by BeiGene USA, which is developing the drug. The investigators reported relationships with the study sponsor, as well as Janssen, Pharmacyclics, AbbVie, and others.

SOURCE: Tam CSL et al. Blood. 2019 Jul 24. doi: 10.1182/blood.2019001160.

Patients with previously untreated chronic lymphocytic leukemia (CLL) aged 70 years or younger who received ibrutinib/rituximab therapy experienced significantly greater progression-free survival, compared with those who received standard chemotherapy with fludarabine, cyclophosphamide, and rituximab (89.4% vs. 72.9% at 3 years; hazard ratio, 0.35; 95% confidence interval, 0.22-0.56; P less than .001), according to results from a randomized, phase 3 trial published in the New England Journal of Medicine (2019;381:432-43).

Ed Uthman/Flickr

We first reported on the results of this trial when they were presented at the annual meeting of the American Society of Hematology. Find our coverage at the link below.

[email protected]

Patients with previously untreated chronic lymphocytic leukemia (CLL) aged 70 years or younger who received ibrutinib/rituximab therapy experienced significantly greater progression-free survival, compared with those who received standard chemotherapy with fludarabine, cyclophosphamide, and rituximab (89.4% vs. 72.9% at 3 years; hazard ratio, 0.35; 95% confidence interval, 0.22-0.56; P less than .001), according to results from a randomized, phase 3 trial published in the New England Journal of Medicine (2019;381:432-43).

Ed Uthman/Flickr

We first reported on the results of this trial when they were presented at the annual meeting of the American Society of Hematology. Find our coverage at the link below.

[email protected]

Patients with previously untreated chronic lymphocytic leukemia (CLL) aged 70 years or younger who received ibrutinib/rituximab therapy experienced significantly greater progression-free survival, compared with those who received standard chemotherapy with fludarabine, cyclophosphamide, and rituximab (89.4% vs. 72.9% at 3 years; hazard ratio, 0.35; 95% confidence interval, 0.22-0.56; P less than .001), according to results from a randomized, phase 3 trial published in the New England Journal of Medicine (2019;381:432-43).

Ed Uthman/Flickr

We first reported on the results of this trial when they were presented at the annual meeting of the American Society of Hematology. Find our coverage at the link below.

[email protected]

Mutations in Bruton’s tyrosine kinase (BTK) are associated with progression of chronic lymphocytic leukemia (CLL) in patients taking ibrutinib, according to a new study.

Courtesy Wikimedia Commons/Nephron/Creative Commons BY-SA-3.0

Researchers analyzed a “real-life” cohort of CLL patients taking ibrutinib for about 3 years and found that patients with BTK mutations were significantly more likely to progress (P = .0005).

“Our findings support that mutational analysis should be considered in patients receiving ibrutinib who have residual clonal lymphocytosis, and that clinical trials are needed to evaluate whether patients with a BTK mutation may benefit from an early switch to another treatment,” wrote Anne Quinquenel, MD, PhD, of Hôpital Robert Debré, Université Reims (France) Champagne-Ardenne, and colleagues. Their report is in Blood.

The researchers studied 57 CLL patients who were still on ibrutinib after at least 3 years and provided fresh blood samples. The median time between the start of ibrutinib and sample collection was 3.5 years.

All 57 patients had minimal residual disease at baseline. Of the 55 patients with response data available, 48 had a partial response, and 7 had a partial response with lymphocytosis.

Mutational profiling was possible in 30 patients who had a CLL clone greater than or equal to 0.5 x 10⁹/L.

BTK mutations were present in 17 of the 30 patients (57%). There were 20 BTK mutations in total, all were at C481, and 14 were at C481S.

The researchers also identified 15 patients with TP53 mutations and 4 patients with phospholipase Cg2 (PLCG2) mutations. All 4 patients with PLCG2 mutations also had a BTK mutation and a TP53 mutation.

However, there were no significant associations between BTK mutations and other mutations. BTK mutations were not associated with the number of previous therapies a patient received or the need for ibrutinib dose interruptions or reductions.

The researchers assessed CLL progression at median of 8.5 months from sample collection and found the presence of a BTK mutation was significantly associated with progression (P = .0005).

Of the 17 patients with a BTK mutation, 14 progressed with one case of Richter’s syndrome. Three patients who progressed were still on ibrutinib, nine patients received venetoclax, and two patients died without further treatment.

Of the 13 patients without BTK mutations, just two patients progressed. One patient died without further treatment, and the other received venetoclax.

The event-free survival was significantly shorter in patients with a BTK mutation than in those without (P = .0380), but there was no significant difference in overall survival.

This research was supported by Sunesis Pharmaceuticals and the Force Hemato (fonds de recherche clinique en hématologie) foundation. The researchers reported relationships with Janssen, Gilead, Roche, and AbbVie.

[email protected]

SOURCE: Quinquenel A et al. Blood. 2019 Jun 26. doi: 10.1182/blood.2019000854.

Mutations in Bruton’s tyrosine kinase (BTK) are associated with progression of chronic lymphocytic leukemia (CLL) in patients taking ibrutinib, according to a new study.

Courtesy Wikimedia Commons/Nephron/Creative Commons BY-SA-3.0

Researchers analyzed a “real-life” cohort of CLL patients taking ibrutinib for about 3 years and found that patients with BTK mutations were significantly more likely to progress (P = .0005).

“Our findings support that mutational analysis should be considered in patients receiving ibrutinib who have residual clonal lymphocytosis, and that clinical trials are needed to evaluate whether patients with a BTK mutation may benefit from an early switch to another treatment,” wrote Anne Quinquenel, MD, PhD, of Hôpital Robert Debré, Université Reims (France) Champagne-Ardenne, and colleagues. Their report is in Blood.

The researchers studied 57 CLL patients who were still on ibrutinib after at least 3 years and provided fresh blood samples. The median time between the start of ibrutinib and sample collection was 3.5 years.

All 57 patients had minimal residual disease at baseline. Of the 55 patients with response data available, 48 had a partial response, and 7 had a partial response with lymphocytosis.

Mutational profiling was possible in 30 patients who had a CLL clone greater than or equal to 0.5 x 10⁹/L.

BTK mutations were present in 17 of the 30 patients (57%). There were 20 BTK mutations in total, all were at C481, and 14 were at C481S.

The researchers also identified 15 patients with TP53 mutations and 4 patients with phospholipase Cg2 (PLCG2) mutations. All 4 patients with PLCG2 mutations also had a BTK mutation and a TP53 mutation.

However, there were no significant associations between BTK mutations and other mutations. BTK mutations were not associated with the number of previous therapies a patient received or the need for ibrutinib dose interruptions or reductions.

The researchers assessed CLL progression at median of 8.5 months from sample collection and found the presence of a BTK mutation was significantly associated with progression (P = .0005).

Of the 17 patients with a BTK mutation, 14 progressed with one case of Richter’s syndrome. Three patients who progressed were still on ibrutinib, nine patients received venetoclax, and two patients died without further treatment.

Of the 13 patients without BTK mutations, just two patients progressed. One patient died without further treatment, and the other received venetoclax.

The event-free survival was significantly shorter in patients with a BTK mutation than in those without (P = .0380), but there was no significant difference in overall survival.

This research was supported by Sunesis Pharmaceuticals and the Force Hemato (fonds de recherche clinique en hématologie) foundation. The researchers reported relationships with Janssen, Gilead, Roche, and AbbVie.

[email protected]

SOURCE: Quinquenel A et al. Blood. 2019 Jun 26. doi: 10.1182/blood.2019000854.

Mutations in Bruton’s tyrosine kinase (BTK) are associated with progression of chronic lymphocytic leukemia (CLL) in patients taking ibrutinib, according to a new study.

Courtesy Wikimedia Commons/Nephron/Creative Commons BY-SA-3.0

Researchers analyzed a “real-life” cohort of CLL patients taking ibrutinib for about 3 years and found that patients with BTK mutations were significantly more likely to progress (P = .0005).

“Our findings support that mutational analysis should be considered in patients receiving ibrutinib who have residual clonal lymphocytosis, and that clinical trials are needed to evaluate whether patients with a BTK mutation may benefit from an early switch to another treatment,” wrote Anne Quinquenel, MD, PhD, of Hôpital Robert Debré, Université Reims (France) Champagne-Ardenne, and colleagues. Their report is in Blood.

The researchers studied 57 CLL patients who were still on ibrutinib after at least 3 years and provided fresh blood samples. The median time between the start of ibrutinib and sample collection was 3.5 years.

All 57 patients had minimal residual disease at baseline. Of the 55 patients with response data available, 48 had a partial response, and 7 had a partial response with lymphocytosis.

Mutational profiling was possible in 30 patients who had a CLL clone greater than or equal to 0.5 x 10⁹/L.

BTK mutations were present in 17 of the 30 patients (57%). There were 20 BTK mutations in total, all were at C481, and 14 were at C481S.

The researchers also identified 15 patients with TP53 mutations and 4 patients with phospholipase Cg2 (PLCG2) mutations. All 4 patients with PLCG2 mutations also had a BTK mutation and a TP53 mutation.

However, there were no significant associations between BTK mutations and other mutations. BTK mutations were not associated with the number of previous therapies a patient received or the need for ibrutinib dose interruptions or reductions.

The researchers assessed CLL progression at median of 8.5 months from sample collection and found the presence of a BTK mutation was significantly associated with progression (P = .0005).

Of the 17 patients with a BTK mutation, 14 progressed with one case of Richter’s syndrome. Three patients who progressed were still on ibrutinib, nine patients received venetoclax, and two patients died without further treatment.

Of the 13 patients without BTK mutations, just two patients progressed. One patient died without further treatment, and the other received venetoclax.

The event-free survival was significantly shorter in patients with a BTK mutation than in those without (P = .0380), but there was no significant difference in overall survival.

This research was supported by Sunesis Pharmaceuticals and the Force Hemato (fonds de recherche clinique en hématologie) foundation. The researchers reported relationships with Janssen, Gilead, Roche, and AbbVie.

[email protected]

SOURCE: Quinquenel A et al. Blood. 2019 Jun 26. doi: 10.1182/blood.2019000854.

The Food and Drug Administration has approved rituximab-pvvr (Ruxience) for adults with non-Hodgkin lymphoma, chronic lymphocytic leukemia (CLL), and granulomatosis with polyangiitis and microscopic polyangiitis. It is the first biosimilar approved to treat these two rare autoimmune conditions.

Specifically, the biosimilar product is approved as single-agent therapy for relapsed or refractory, low grade or follicular, CD20-positive B-cell non-Hodgkin lymphoma; in combination with chemotherapy for other types of previously untreated CD20-positive B-cell non-Hodgkin lymphoma; and as a single agent for nonprogressing, low-grade, CD20-positive B-cell non-Hodgkin lymphoma after first-line chemotherapy treatment. It is also approved for both previously untreated and previously treated CD20-positive CLL in combination with chemotherapy. And it is approved for granulomatosis with polyangiitis and microscopic polyangiitis in combination with glucocorticoids.

The approval is based on demonstration that rituximab-pvvr had no clinically meaningful differences in safety or efficacy when compared with the reference drug, rituximab (Rituxan), according to a release from the biosimilar’s developer. As with rituximab, rituximab-pvvr’s label comes with an FDA boxed warning. In the biosimilar’s case, it warns against fatal infusion-related reactions, severe mucocutaneous reactions, hepatitis B virus reactivation, and progressive multifocal leukoencephalopathy. Other adverse reactions include fever, headache, neutropenia, and lymphopenia.

[email protected]

The Food and Drug Administration has approved rituximab-pvvr (Ruxience) for adults with non-Hodgkin lymphoma, chronic lymphocytic leukemia (CLL), and granulomatosis with polyangiitis and microscopic polyangiitis. It is the first biosimilar approved to treat these two rare autoimmune conditions.

Specifically, the biosimilar product is approved as single-agent therapy for relapsed or refractory, low grade or follicular, CD20-positive B-cell non-Hodgkin lymphoma; in combination with chemotherapy for other types of previously untreated CD20-positive B-cell non-Hodgkin lymphoma; and as a single agent for nonprogressing, low-grade, CD20-positive B-cell non-Hodgkin lymphoma after first-line chemotherapy treatment. It is also approved for both previously untreated and previously treated CD20-positive CLL in combination with chemotherapy. And it is approved for granulomatosis with polyangiitis and microscopic polyangiitis in combination with glucocorticoids.

The approval is based on demonstration that rituximab-pvvr had no clinically meaningful differences in safety or efficacy when compared with the reference drug, rituximab (Rituxan), according to a release from the biosimilar’s developer. As with rituximab, rituximab-pvvr’s label comes with an FDA boxed warning. In the biosimilar’s case, it warns against fatal infusion-related reactions, severe mucocutaneous reactions, hepatitis B virus reactivation, and progressive multifocal leukoencephalopathy. Other adverse reactions include fever, headache, neutropenia, and lymphopenia.

[email protected]

The Food and Drug Administration has approved rituximab-pvvr (Ruxience) for adults with non-Hodgkin lymphoma, chronic lymphocytic leukemia (CLL), and granulomatosis with polyangiitis and microscopic polyangiitis. It is the first biosimilar approved to treat these two rare autoimmune conditions.

Specifically, the biosimilar product is approved as single-agent therapy for relapsed or refractory, low grade or follicular, CD20-positive B-cell non-Hodgkin lymphoma; in combination with chemotherapy for other types of previously untreated CD20-positive B-cell non-Hodgkin lymphoma; and as a single agent for nonprogressing, low-grade, CD20-positive B-cell non-Hodgkin lymphoma after first-line chemotherapy treatment. It is also approved for both previously untreated and previously treated CD20-positive CLL in combination with chemotherapy. And it is approved for granulomatosis with polyangiitis and microscopic polyangiitis in combination with glucocorticoids.

The approval is based on demonstration that rituximab-pvvr had no clinically meaningful differences in safety or efficacy when compared with the reference drug, rituximab (Rituxan), according to a release from the biosimilar’s developer. As with rituximab, rituximab-pvvr’s label comes with an FDA boxed warning. In the biosimilar’s case, it warns against fatal infusion-related reactions, severe mucocutaneous reactions, hepatitis B virus reactivation, and progressive multifocal leukoencephalopathy. Other adverse reactions include fever, headache, neutropenia, and lymphopenia.

[email protected]

The strategy of simultaneously inhibiting proliferation and reactivating apoptosis can eradicate chronic lymphocytic leukemia (CLL) in a large share of patients, suggest results from the phase 2 CLARITY trial.

©Ed Uthman/Flickr

“Both ibrutinib and venetoclax are active in CLL with improved survival; however, as monotherapies, both currently are given until disease progression,” wrote Peter Hillmen, MBChB, PhD, St. James’s University Hospital, Leeds, England, and his colleagues.

In the single-arm, open-label trial, the investigators treated 53 patients with relapsed or refractory CLL with combination ibrutinib (Imbruvica), a small-molecule inhibitor of Bruton’s tyrosine kinase, and venetoclax (Venclexta), a small molecule inhibitor of the anti-apoptotic protein Bcl-2. The primary endpoint was MRD negativity, defined as presence of fewer than one CLL cell in 10,000 leukocytes, after 12 months of combination therapy.

Results reported in the Journal of Clinical Oncology showed that the combination was highly active, with 53% of patients achieving MRD negativity in the blood and 36% achieving MRD negativity in the marrow.

Most patients, 89%, had a treatment response, and slightly more than half, 51%, achieved a complete remission. With a median 21.1-month follow-up, only a single patient experienced progression and all were still alive.

Adverse effects were generally manageable. Grade 3-4 adverse events of special interest included 34 cases of neutropenia and 1 case of biochemical tumor lysis syndrome that was managed by delaying venetoclax.

“We have demonstrated promising efficacy that indicates potent synergy between ibrutinib and venetoclax for inducing MRD-negative responses with manageable adverse effects,” the investigators wrote. “The observation that a significant proportion of patients experience MRD-negative remission indicates that this combination can be given for a limited period and then stopped after patients achieve a deep remission.”


Whether the combination leads to permanent disease eradication in certain patients is still unclear, the investigators added.

The trial was supported by Bloodwise under the Trials Acceleration Programme, by the National Institute for Health Research Leeds Clinical Research Facility, and by an unrestricted educational grant from Janssen-Cilag and AbbVie. Ibrutinib was provided free of charge by Janssen-Cilag, and venetoclax was provided free of charge by AbbVie. Dr. Hillman reported financial relationships with Janssen, AbbVie, Roche, Pharmacyclics, and Gilead Sciences.

SOURCE: Hillmen P et al. J Clin Oncol. 2019 Jul 11. doi: 10.1200/JCO.19.00894.

The strategy of simultaneously inhibiting proliferation and reactivating apoptosis can eradicate chronic lymphocytic leukemia (CLL) in a large share of patients, suggest results from the phase 2 CLARITY trial.

©Ed Uthman/Flickr

“Both ibrutinib and venetoclax are active in CLL with improved survival; however, as monotherapies, both currently are given until disease progression,” wrote Peter Hillmen, MBChB, PhD, St. James’s University Hospital, Leeds, England, and his colleagues.

In the single-arm, open-label trial, the investigators treated 53 patients with relapsed or refractory CLL with combination ibrutinib (Imbruvica), a small-molecule inhibitor of Bruton’s tyrosine kinase, and venetoclax (Venclexta), a small molecule inhibitor of the anti-apoptotic protein Bcl-2. The primary endpoint was MRD negativity, defined as presence of fewer than one CLL cell in 10,000 leukocytes, after 12 months of combination therapy.

Results reported in the Journal of Clinical Oncology showed that the combination was highly active, with 53% of patients achieving MRD negativity in the blood and 36% achieving MRD negativity in the marrow.

Most patients, 89%, had a treatment response, and slightly more than half, 51%, achieved a complete remission. With a median 21.1-month follow-up, only a single patient experienced progression and all were still alive.

Adverse effects were generally manageable. Grade 3-4 adverse events of special interest included 34 cases of neutropenia and 1 case of biochemical tumor lysis syndrome that was managed by delaying venetoclax.

“We have demonstrated promising efficacy that indicates potent synergy between ibrutinib and venetoclax for inducing MRD-negative responses with manageable adverse effects,” the investigators wrote. “The observation that a significant proportion of patients experience MRD-negative remission indicates that this combination can be given for a limited period and then stopped after patients achieve a deep remission.”


Whether the combination leads to permanent disease eradication in certain patients is still unclear, the investigators added.

The trial was supported by Bloodwise under the Trials Acceleration Programme, by the National Institute for Health Research Leeds Clinical Research Facility, and by an unrestricted educational grant from Janssen-Cilag and AbbVie. Ibrutinib was provided free of charge by Janssen-Cilag, and venetoclax was provided free of charge by AbbVie. Dr. Hillman reported financial relationships with Janssen, AbbVie, Roche, Pharmacyclics, and Gilead Sciences.

SOURCE: Hillmen P et al. J Clin Oncol. 2019 Jul 11. doi: 10.1200/JCO.19.00894.

The strategy of simultaneously inhibiting proliferation and reactivating apoptosis can eradicate chronic lymphocytic leukemia (CLL) in a large share of patients, suggest results from the phase 2 CLARITY trial.

©Ed Uthman/Flickr

“Both ibrutinib and venetoclax are active in CLL with improved survival; however, as monotherapies, both currently are given until disease progression,” wrote Peter Hillmen, MBChB, PhD, St. James’s University Hospital, Leeds, England, and his colleagues.

In the single-arm, open-label trial, the investigators treated 53 patients with relapsed or refractory CLL with combination ibrutinib (Imbruvica), a small-molecule inhibitor of Bruton’s tyrosine kinase, and venetoclax (Venclexta), a small molecule inhibitor of the anti-apoptotic protein Bcl-2. The primary endpoint was MRD negativity, defined as presence of fewer than one CLL cell in 10,000 leukocytes, after 12 months of combination therapy.

Results reported in the Journal of Clinical Oncology showed that the combination was highly active, with 53% of patients achieving MRD negativity in the blood and 36% achieving MRD negativity in the marrow.

Most patients, 89%, had a treatment response, and slightly more than half, 51%, achieved a complete remission. With a median 21.1-month follow-up, only a single patient experienced progression and all were still alive.

Adverse effects were generally manageable. Grade 3-4 adverse events of special interest included 34 cases of neutropenia and 1 case of biochemical tumor lysis syndrome that was managed by delaying venetoclax.

“We have demonstrated promising efficacy that indicates potent synergy between ibrutinib and venetoclax for inducing MRD-negative responses with manageable adverse effects,” the investigators wrote. “The observation that a significant proportion of patients experience MRD-negative remission indicates that this combination can be given for a limited period and then stopped after patients achieve a deep remission.”


Whether the combination leads to permanent disease eradication in certain patients is still unclear, the investigators added.

The trial was supported by Bloodwise under the Trials Acceleration Programme, by the National Institute for Health Research Leeds Clinical Research Facility, and by an unrestricted educational grant from Janssen-Cilag and AbbVie. Ibrutinib was provided free of charge by Janssen-Cilag, and venetoclax was provided free of charge by AbbVie. Dr. Hillman reported financial relationships with Janssen, AbbVie, Roche, Pharmacyclics, and Gilead Sciences.

SOURCE: Hillmen P et al. J Clin Oncol. 2019 Jul 11. doi: 10.1200/JCO.19.00894.

In this edition of “How I will treat my next patient,” I highlight two recent presentations regarding potential improvements in the convenience and tolerability of treatment for two hematologic malignancies: multiple myeloma and chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL).

SC-Dara in myeloma

At the 2019 annual meeting of the American Society of Clinical Oncology, Maria-Victoria Mateos, MD, PhD, and colleagues, reported the results of COLUMBA, a phase 3 evaluation in 522 patients with multiple myeloma who were randomized to subcutaneous daratumumab (SC-Dara) or standard intravenous infusions of daratumumab (IV-Dara). A previous phase 1b study (Blood. 2017;130:838) had suggested comparable efficacy from the more convenient SC regime. Whereas conventional infusions of IV-Dara (16 mg/kg) take several hours, the SC formulation (1,800 mg–flat dose) is delivered in minutes. In COLUMBA, patients were randomized between SC- and IV-Dara weekly (cycles 1-2), then every 2 weeks (cycles 3-6), then every 4 weeks until disease progression.

Among the IV-Dara patients, the median duration of the first infusion was 421 minutes in cycle 1, 255 minutes in cycle 2, and 205 minutes in subsequent cycles – compatible with standard practice in the United States. As reported, at a median follow-up of 7.46 months, the efficacy (overall response rate, complete response rate, stringent-complete response rate, very good-partial response rate, progression-free survival, and 6-month overall survival) and safety profile were non-inferior for SC-Dara. SC-Dara patients also reported higher satisfaction with therapy.
 

What this means in practice

It is always a good idea to await publication of the manuscript because there may be study details and statistical nuances that make SC-Dara appear better than it will prove to be. For example, patient characteristics were slightly different between the two arms. Peer review of the final manuscript could be important in placing these results in context.

However, for treatments that demand frequent office visits over many months, reducing treatment burden for patients has value. Based on COLUMBA, it appears likely that SC-Dara will be a major convenience for patients, without obvious drawbacks in efficacy or toxicity. Meanwhile, flat dosing will be a time-saver for physicians, nursing, and pharmacy staff. If the price of the SC formulation is not exorbitant, I would expect a “win-win” that will support converting from IV- to SC-Dara as standard practice.

Acalabrutinib in CLL/SLL

Preclinical studies have shown acalabrutinib (Acala) to be more selective for Bruton’s tyrosine kinase (BTK) than the first-in-class agent ibrutinib, with less off-target kinase inhibition. As reported at the 2019 annual congress of the European Hematology Association by Paolo Ghia, MD, PhD, and colleagues in the phase 3 ASCEND trial, 310 patients with previously treated CLL were randomized between oral Acala twice daily and treatment of physician’s choice (TPC) – either idelalisib plus rituximab (maximum of seven infusions) or bendamustine plus rituximab (maximum of six cycles).

Progression-free survival was the primary endpoint. At a median of 16.1 months, progression-free survival had not been reached for Acala, in comparison with 16.5 months for TPC. Significant benefit of Acala was observed in all prognostic subsets.

Although there was no difference in overall survival at a median follow-up of about 16 months, 85% of Acala patients had a response lasting at least 12 months, compared with 60% of TPC patients. Adverse events of any grade occurred in 94% of patients treated with Acala, with 45% being grade 3-4 toxicities and six treatment-related deaths.

What this means in practice

The vast majority of CLL/SLL patients will relapse after primary therapy and will require further treatment, so the progression-free survival improvement associated with Acala in ASCEND is eye-catching. However, there are important considerations that demand closer scrutiny.

With oral agents administered until progression or unacceptable toxicity, low-grade toxicities can influence patient adherence, quality of life, and potentially the need for dose reduction or treatment interruptions. Regimens of finite duration and easy adherence monitoring may be, on balance, preferred by patients and providers – especially if the oral agent can be given in later-line with comparable overall survival.

With ibrutinib (Blood. 2017;129:2612-5), Paul M. Barr, MD, and colleagues demonstrated that higher dose intensity was associated with improved progression-free survival and that holds were associated with worsened progression-free survival. Acala’s promise of high efficacy and lower off-target toxicity will be solidified if the large (more than 500 patients) phase 3 ACE-CL-006 study (Acala vs. ibrutinib) demonstrates its relative benefit from efficacy, toxicity, and adherence perspectives, in comparison with a standard therapy that similarly demands adherence until disease progression or unacceptable toxicity.

Dr. Lyss has been a community-based medical oncologist and clinical researcher for more than 35 years, practicing in St. Louis. His clinical and research interests are in the prevention, diagnosis, and treatment of breast and lung cancers and in expanding access to clinical trials to medically underserved populations.

In this edition of “How I will treat my next patient,” I highlight two recent presentations regarding potential improvements in the convenience and tolerability of treatment for two hematologic malignancies: multiple myeloma and chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL).

SC-Dara in myeloma

At the 2019 annual meeting of the American Society of Clinical Oncology, Maria-Victoria Mateos, MD, PhD, and colleagues, reported the results of COLUMBA, a phase 3 evaluation in 522 patients with multiple myeloma who were randomized to subcutaneous daratumumab (SC-Dara) or standard intravenous infusions of daratumumab (IV-Dara). A previous phase 1b study (Blood. 2017;130:838) had suggested comparable efficacy from the more convenient SC regime. Whereas conventional infusions of IV-Dara (16 mg/kg) take several hours, the SC formulation (1,800 mg–flat dose) is delivered in minutes. In COLUMBA, patients were randomized between SC- and IV-Dara weekly (cycles 1-2), then every 2 weeks (cycles 3-6), then every 4 weeks until disease progression.

Among the IV-Dara patients, the median duration of the first infusion was 421 minutes in cycle 1, 255 minutes in cycle 2, and 205 minutes in subsequent cycles – compatible with standard practice in the United States. As reported, at a median follow-up of 7.46 months, the efficacy (overall response rate, complete response rate, stringent-complete response rate, very good-partial response rate, progression-free survival, and 6-month overall survival) and safety profile were non-inferior for SC-Dara. SC-Dara patients also reported higher satisfaction with therapy.
 

What this means in practice

It is always a good idea to await publication of the manuscript because there may be study details and statistical nuances that make SC-Dara appear better than it will prove to be. For example, patient characteristics were slightly different between the two arms. Peer review of the final manuscript could be important in placing these results in context.

However, for treatments that demand frequent office visits over many months, reducing treatment burden for patients has value. Based on COLUMBA, it appears likely that SC-Dara will be a major convenience for patients, without obvious drawbacks in efficacy or toxicity. Meanwhile, flat dosing will be a time-saver for physicians, nursing, and pharmacy staff. If the price of the SC formulation is not exorbitant, I would expect a “win-win” that will support converting from IV- to SC-Dara as standard practice.

Acalabrutinib in CLL/SLL

Preclinical studies have shown acalabrutinib (Acala) to be more selective for Bruton’s tyrosine kinase (BTK) than the first-in-class agent ibrutinib, with less off-target kinase inhibition. As reported at the 2019 annual congress of the European Hematology Association by Paolo Ghia, MD, PhD, and colleagues in the phase 3 ASCEND trial, 310 patients with previously treated CLL were randomized between oral Acala twice daily and treatment of physician’s choice (TPC) – either idelalisib plus rituximab (maximum of seven infusions) or bendamustine plus rituximab (maximum of six cycles).

Progression-free survival was the primary endpoint. At a median of 16.1 months, progression-free survival had not been reached for Acala, in comparison with 16.5 months for TPC. Significant benefit of Acala was observed in all prognostic subsets.

Although there was no difference in overall survival at a median follow-up of about 16 months, 85% of Acala patients had a response lasting at least 12 months, compared with 60% of TPC patients. Adverse events of any grade occurred in 94% of patients treated with Acala, with 45% being grade 3-4 toxicities and six treatment-related deaths.

What this means in practice

The vast majority of CLL/SLL patients will relapse after primary therapy and will require further treatment, so the progression-free survival improvement associated with Acala in ASCEND is eye-catching. However, there are important considerations that demand closer scrutiny.

With oral agents administered until progression or unacceptable toxicity, low-grade toxicities can influence patient adherence, quality of life, and potentially the need for dose reduction or treatment interruptions. Regimens of finite duration and easy adherence monitoring may be, on balance, preferred by patients and providers – especially if the oral agent can be given in later-line with comparable overall survival.

With ibrutinib (Blood. 2017;129:2612-5), Paul M. Barr, MD, and colleagues demonstrated that higher dose intensity was associated with improved progression-free survival and that holds were associated with worsened progression-free survival. Acala’s promise of high efficacy and lower off-target toxicity will be solidified if the large (more than 500 patients) phase 3 ACE-CL-006 study (Acala vs. ibrutinib) demonstrates its relative benefit from efficacy, toxicity, and adherence perspectives, in comparison with a standard therapy that similarly demands adherence until disease progression or unacceptable toxicity.

Dr. Lyss has been a community-based medical oncologist and clinical researcher for more than 35 years, practicing in St. Louis. His clinical and research interests are in the prevention, diagnosis, and treatment of breast and lung cancers and in expanding access to clinical trials to medically underserved populations.

In this edition of “How I will treat my next patient,” I highlight two recent presentations regarding potential improvements in the convenience and tolerability of treatment for two hematologic malignancies: multiple myeloma and chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL).

SC-Dara in myeloma

At the 2019 annual meeting of the American Society of Clinical Oncology, Maria-Victoria Mateos, MD, PhD, and colleagues, reported the results of COLUMBA, a phase 3 evaluation in 522 patients with multiple myeloma who were randomized to subcutaneous daratumumab (SC-Dara) or standard intravenous infusions of daratumumab (IV-Dara). A previous phase 1b study (Blood. 2017;130:838) had suggested comparable efficacy from the more convenient SC regime. Whereas conventional infusions of IV-Dara (16 mg/kg) take several hours, the SC formulation (1,800 mg–flat dose) is delivered in minutes. In COLUMBA, patients were randomized between SC- and IV-Dara weekly (cycles 1-2), then every 2 weeks (cycles 3-6), then every 4 weeks until disease progression.

Among the IV-Dara patients, the median duration of the first infusion was 421 minutes in cycle 1, 255 minutes in cycle 2, and 205 minutes in subsequent cycles – compatible with standard practice in the United States. As reported, at a median follow-up of 7.46 months, the efficacy (overall response rate, complete response rate, stringent-complete response rate, very good-partial response rate, progression-free survival, and 6-month overall survival) and safety profile were non-inferior for SC-Dara. SC-Dara patients also reported higher satisfaction with therapy.
 

What this means in practice

It is always a good idea to await publication of the manuscript because there may be study details and statistical nuances that make SC-Dara appear better than it will prove to be. For example, patient characteristics were slightly different between the two arms. Peer review of the final manuscript could be important in placing these results in context.

However, for treatments that demand frequent office visits over many months, reducing treatment burden for patients has value. Based on COLUMBA, it appears likely that SC-Dara will be a major convenience for patients, without obvious drawbacks in efficacy or toxicity. Meanwhile, flat dosing will be a time-saver for physicians, nursing, and pharmacy staff. If the price of the SC formulation is not exorbitant, I would expect a “win-win” that will support converting from IV- to SC-Dara as standard practice.

Acalabrutinib in CLL/SLL

Preclinical studies have shown acalabrutinib (Acala) to be more selective for Bruton’s tyrosine kinase (BTK) than the first-in-class agent ibrutinib, with less off-target kinase inhibition. As reported at the 2019 annual congress of the European Hematology Association by Paolo Ghia, MD, PhD, and colleagues in the phase 3 ASCEND trial, 310 patients with previously treated CLL were randomized between oral Acala twice daily and treatment of physician’s choice (TPC) – either idelalisib plus rituximab (maximum of seven infusions) or bendamustine plus rituximab (maximum of six cycles).

Progression-free survival was the primary endpoint. At a median of 16.1 months, progression-free survival had not been reached for Acala, in comparison with 16.5 months for TPC. Significant benefit of Acala was observed in all prognostic subsets.

Although there was no difference in overall survival at a median follow-up of about 16 months, 85% of Acala patients had a response lasting at least 12 months, compared with 60% of TPC patients. Adverse events of any grade occurred in 94% of patients treated with Acala, with 45% being grade 3-4 toxicities and six treatment-related deaths.

What this means in practice

The vast majority of CLL/SLL patients will relapse after primary therapy and will require further treatment, so the progression-free survival improvement associated with Acala in ASCEND is eye-catching. However, there are important considerations that demand closer scrutiny.

With oral agents administered until progression or unacceptable toxicity, low-grade toxicities can influence patient adherence, quality of life, and potentially the need for dose reduction or treatment interruptions. Regimens of finite duration and easy adherence monitoring may be, on balance, preferred by patients and providers – especially if the oral agent can be given in later-line with comparable overall survival.

With ibrutinib (Blood. 2017;129:2612-5), Paul M. Barr, MD, and colleagues demonstrated that higher dose intensity was associated with improved progression-free survival and that holds were associated with worsened progression-free survival. Acala’s promise of high efficacy and lower off-target toxicity will be solidified if the large (more than 500 patients) phase 3 ACE-CL-006 study (Acala vs. ibrutinib) demonstrates its relative benefit from efficacy, toxicity, and adherence perspectives, in comparison with a standard therapy that similarly demands adherence until disease progression or unacceptable toxicity.

Dr. Lyss has been a community-based medical oncologist and clinical researcher for more than 35 years, practicing in St. Louis. His clinical and research interests are in the prevention, diagnosis, and treatment of breast and lung cancers and in expanding access to clinical trials to medically underserved populations.

AMSTERDAM – For patients with relapsed or refractory chronic lymphocytic leukemia (CLL), monotherapy with the Bruton tyrosine kinase (BTK) inhibitor acalabrutinib (Calquence) was associated with better progression-free survival and a more tolerable safety profile than rituximab combined with either idelalisib (Zydelig) or bendamustine, an interim analysis from the phase 3 ASCEND trial showed.

Among 310 patients with previously treated CLL followed for a median of 16.1 months, the primary endpoint of median progression-free survival (PFS), as assessed by independent reviewers, had not been reached for patients treated with acalabrutinib, compared with 16.5 months for patients treated with idelalisib and rituximab (IdR) or bendamustine and rituximab (BR), reported Paolo Ghia, MD, PhD, from Università Vita-Salute San Raffaele in Milan.

“We show that acalabrutinib improved progression-free survival across all groups, including those with high-risk features,” he said at the annual congress of the European Hematology Association.

Acalabrutinib is approved in the United States for treatment of mantle cell lymphoma that has progressed on at least one prior therapy. It has been shown in preclinical studies to be more selective for BTK than the first-in-class agent ibrutinib (Imbruvica), with less off-target kinase inhibition, Dr. Ghia said.

ASCEND was designed to see whether acalabrutinib monotherapy could offer superior PFS to IdR or BR in patients with CLL who had progressed or were refractory to at least one prior line of therapy.

Patients were randomly assigned, with 155 patients in each arm, to either acalabrutinib 100 mg orally twice daily or the investigator’s choice of either idelalisib 150 mg orally twice daily plus IV rituximab at an initial dose of 375 mg/m², followed by up to seven doses at 500 mg/m² delivered every 2 weeks for four infusions, then every 4 weeks for the remaining three infusions or IV bendamustine 70 mg/m² on days 1 and 2 of each cycle, plus rituximab at the 375 mg/m² dose on day 1 for the first cycle, followed by 500 mg/m² for up to six total cycles.

Dr. Ghia presented results of an interim analysis planned for when two-thirds of the predicted PFS events (approximately 79) had occurred.

The baseline patient characteristics were generally similar, with a median age of 68 years in the acalabrutinib arm and 67 years in the comparison arm. Almost half of all patients in each arm had bulky disease, defined as 5 cm or greater. The majority of patients had two or more prior lines of therapy.

The primary endpoint of PFS as assessed by independent review favored acalabrutinib, with a hazard ratio of 0.31 (P less than .0001). Results were similar when acalabrutinib was compared with each of the regimens in the comparison arm (HR, 0.29 vs. IdR, 0.36 vs. BR; P less than .001 for each comparison).

Acalabrutinib was also superior in patients with high-risk cytogenetic features, compared with the other two regimens combined (HR, 0.27; P less than .001).

The benefit of the BTK inhibitor was consistent across all subgroups, including age, sex, performance status, Rai stage at screening, bulky/nonbulky disease, number of prior therapies, presence or absence of deletion 17p or TP53 mutation, mutated or unmutated immunoglobulin heavy chain, and complex/noncomplex karyotype.

Reviewer-assessed objective response rates were similar, occurring in 81% of patients on acalabrutinib and 76% of patients on other regimens.

There were no complete responses in the acalabrutinib arm, compared with two complete responses in the comparison arm. The majority of responses in each arm were partial responses (81% and 74%, respectively).

The median duration of response was not reached with acalabrutinib, compared with 13.6 months with the other therapies (HR, 0.33; P less than .0001).

In all, 85% of patients on acalabrutinib had a response lasting at least 12 months, compared with 60% of patients on the other regimens. There was no difference in overall survival at the 16.1-month median follow-up.

Adverse events of any grade occurred in 94% of patients on acalabrutinib, 99% on IdR, and 80% on BR; the respective incidences of serious adverse events were 29%, 56%, and 26%. Grade 3-4 adverse events occurred in 45%, 86%, and 43% of patients, respectively.

There were 13 treatment-related deaths. Six deaths in the acalabrutinib arm were caused by brain neoplasm, cachexia, cerebral ischemia, malignant lung tumor, neuroendocrine carcinoma, and sepsis. Five deaths among IdR-treated patients included chronic heart failure, cardiopulmonary disease, interstitial lung disease, MI, and pseudomonal pneumonia. Two deaths in BR-treated patients were attributed to acute cardiac failure and a gastric neoplasm.

The results show that “acalabrutinib has demonstrated efficacy in previously untreated and relapsed/refractory CLL and may be considered as an option in the future treatment paradigm,” Dr. Ghia said.

Acalabrutinib monotherapy is currently being compared with ibrutinib monotherapy in patients with relapsed/refractory CLL; in addition, the phase 3 ELEVATE-TN study investigating acalabrutinib in combination with obinutuzumab (Gazyva) versus obinutuzumab plus chlorambucil has reached its primary PFS endpoint and will be reported soon, Dr. Ghia said.

The ASCEND trial is sponsored by Acerta Pharma; AstraZeneca holds majority shares in the company. Dr. Ghia reported consulting fees and honoraria from AstraZeneca and other companies, and research funding from several different companies.

SOURCE: Ghia P et al. EHA Congress, Abstract LB2606.

AMSTERDAM – For patients with relapsed or refractory chronic lymphocytic leukemia (CLL), monotherapy with the Bruton tyrosine kinase (BTK) inhibitor acalabrutinib (Calquence) was associated with better progression-free survival and a more tolerable safety profile than rituximab combined with either idelalisib (Zydelig) or bendamustine, an interim analysis from the phase 3 ASCEND trial showed.

Among 310 patients with previously treated CLL followed for a median of 16.1 months, the primary endpoint of median progression-free survival (PFS), as assessed by independent reviewers, had not been reached for patients treated with acalabrutinib, compared with 16.5 months for patients treated with idelalisib and rituximab (IdR) or bendamustine and rituximab (BR), reported Paolo Ghia, MD, PhD, from Università Vita-Salute San Raffaele in Milan.

“We show that acalabrutinib improved progression-free survival across all groups, including those with high-risk features,” he said at the annual congress of the European Hematology Association.

Acalabrutinib is approved in the United States for treatment of mantle cell lymphoma that has progressed on at least one prior therapy. It has been shown in preclinical studies to be more selective for BTK than the first-in-class agent ibrutinib (Imbruvica), with less off-target kinase inhibition, Dr. Ghia said.

ASCEND was designed to see whether acalabrutinib monotherapy could offer superior PFS to IdR or BR in patients with CLL who had progressed or were refractory to at least one prior line of therapy.

Patients were randomly assigned, with 155 patients in each arm, to either acalabrutinib 100 mg orally twice daily or the investigator’s choice of either idelalisib 150 mg orally twice daily plus IV rituximab at an initial dose of 375 mg/m², followed by up to seven doses at 500 mg/m² delivered every 2 weeks for four infusions, then every 4 weeks for the remaining three infusions or IV bendamustine 70 mg/m² on days 1 and 2 of each cycle, plus rituximab at the 375 mg/m² dose on day 1 for the first cycle, followed by 500 mg/m² for up to six total cycles.

Dr. Ghia presented results of an interim analysis planned for when two-thirds of the predicted PFS events (approximately 79) had occurred.

The baseline patient characteristics were generally similar, with a median age of 68 years in the acalabrutinib arm and 67 years in the comparison arm. Almost half of all patients in each arm had bulky disease, defined as 5 cm or greater. The majority of patients had two or more prior lines of therapy.

The primary endpoint of PFS as assessed by independent review favored acalabrutinib, with a hazard ratio of 0.31 (P less than .0001). Results were similar when acalabrutinib was compared with each of the regimens in the comparison arm (HR, 0.29 vs. IdR, 0.36 vs. BR; P less than .001 for each comparison).

Acalabrutinib was also superior in patients with high-risk cytogenetic features, compared with the other two regimens combined (HR, 0.27; P less than .001).

The benefit of the BTK inhibitor was consistent across all subgroups, including age, sex, performance status, Rai stage at screening, bulky/nonbulky disease, number of prior therapies, presence or absence of deletion 17p or TP53 mutation, mutated or unmutated immunoglobulin heavy chain, and complex/noncomplex karyotype.

Reviewer-assessed objective response rates were similar, occurring in 81% of patients on acalabrutinib and 76% of patients on other regimens.

There were no complete responses in the acalabrutinib arm, compared with two complete responses in the comparison arm. The majority of responses in each arm were partial responses (81% and 74%, respectively).

The median duration of response was not reached with acalabrutinib, compared with 13.6 months with the other therapies (HR, 0.33; P less than .0001).

In all, 85% of patients on acalabrutinib had a response lasting at least 12 months, compared with 60% of patients on the other regimens. There was no difference in overall survival at the 16.1-month median follow-up.

Adverse events of any grade occurred in 94% of patients on acalabrutinib, 99% on IdR, and 80% on BR; the respective incidences of serious adverse events were 29%, 56%, and 26%. Grade 3-4 adverse events occurred in 45%, 86%, and 43% of patients, respectively.

There were 13 treatment-related deaths. Six deaths in the acalabrutinib arm were caused by brain neoplasm, cachexia, cerebral ischemia, malignant lung tumor, neuroendocrine carcinoma, and sepsis. Five deaths among IdR-treated patients included chronic heart failure, cardiopulmonary disease, interstitial lung disease, MI, and pseudomonal pneumonia. Two deaths in BR-treated patients were attributed to acute cardiac failure and a gastric neoplasm.

The results show that “acalabrutinib has demonstrated efficacy in previously untreated and relapsed/refractory CLL and may be considered as an option in the future treatment paradigm,” Dr. Ghia said.

Acalabrutinib monotherapy is currently being compared with ibrutinib monotherapy in patients with relapsed/refractory CLL; in addition, the phase 3 ELEVATE-TN study investigating acalabrutinib in combination with obinutuzumab (Gazyva) versus obinutuzumab plus chlorambucil has reached its primary PFS endpoint and will be reported soon, Dr. Ghia said.

The ASCEND trial is sponsored by Acerta Pharma; AstraZeneca holds majority shares in the company. Dr. Ghia reported consulting fees and honoraria from AstraZeneca and other companies, and research funding from several different companies.

SOURCE: Ghia P et al. EHA Congress, Abstract LB2606.

AMSTERDAM – For patients with relapsed or refractory chronic lymphocytic leukemia (CLL), monotherapy with the Bruton tyrosine kinase (BTK) inhibitor acalabrutinib (Calquence) was associated with better progression-free survival and a more tolerable safety profile than rituximab combined with either idelalisib (Zydelig) or bendamustine, an interim analysis from the phase 3 ASCEND trial showed.

Among 310 patients with previously treated CLL followed for a median of 16.1 months, the primary endpoint of median progression-free survival (PFS), as assessed by independent reviewers, had not been reached for patients treated with acalabrutinib, compared with 16.5 months for patients treated with idelalisib and rituximab (IdR) or bendamustine and rituximab (BR), reported Paolo Ghia, MD, PhD, from Università Vita-Salute San Raffaele in Milan.

“We show that acalabrutinib improved progression-free survival across all groups, including those with high-risk features,” he said at the annual congress of the European Hematology Association.

Acalabrutinib is approved in the United States for treatment of mantle cell lymphoma that has progressed on at least one prior therapy. It has been shown in preclinical studies to be more selective for BTK than the first-in-class agent ibrutinib (Imbruvica), with less off-target kinase inhibition, Dr. Ghia said.

ASCEND was designed to see whether acalabrutinib monotherapy could offer superior PFS to IdR or BR in patients with CLL who had progressed or were refractory to at least one prior line of therapy.

Patients were randomly assigned, with 155 patients in each arm, to either acalabrutinib 100 mg orally twice daily or the investigator’s choice of either idelalisib 150 mg orally twice daily plus IV rituximab at an initial dose of 375 mg/m², followed by up to seven doses at 500 mg/m² delivered every 2 weeks for four infusions, then every 4 weeks for the remaining three infusions or IV bendamustine 70 mg/m² on days 1 and 2 of each cycle, plus rituximab at the 375 mg/m² dose on day 1 for the first cycle, followed by 500 mg/m² for up to six total cycles.

Dr. Ghia presented results of an interim analysis planned for when two-thirds of the predicted PFS events (approximately 79) had occurred.

The baseline patient characteristics were generally similar, with a median age of 68 years in the acalabrutinib arm and 67 years in the comparison arm. Almost half of all patients in each arm had bulky disease, defined as 5 cm or greater. The majority of patients had two or more prior lines of therapy.

The primary endpoint of PFS as assessed by independent review favored acalabrutinib, with a hazard ratio of 0.31 (P less than .0001). Results were similar when acalabrutinib was compared with each of the regimens in the comparison arm (HR, 0.29 vs. IdR, 0.36 vs. BR; P less than .001 for each comparison).

Acalabrutinib was also superior in patients with high-risk cytogenetic features, compared with the other two regimens combined (HR, 0.27; P less than .001).

The benefit of the BTK inhibitor was consistent across all subgroups, including age, sex, performance status, Rai stage at screening, bulky/nonbulky disease, number of prior therapies, presence or absence of deletion 17p or TP53 mutation, mutated or unmutated immunoglobulin heavy chain, and complex/noncomplex karyotype.

Reviewer-assessed objective response rates were similar, occurring in 81% of patients on acalabrutinib and 76% of patients on other regimens.

There were no complete responses in the acalabrutinib arm, compared with two complete responses in the comparison arm. The majority of responses in each arm were partial responses (81% and 74%, respectively).

The median duration of response was not reached with acalabrutinib, compared with 13.6 months with the other therapies (HR, 0.33; P less than .0001).

In all, 85% of patients on acalabrutinib had a response lasting at least 12 months, compared with 60% of patients on the other regimens. There was no difference in overall survival at the 16.1-month median follow-up.

Adverse events of any grade occurred in 94% of patients on acalabrutinib, 99% on IdR, and 80% on BR; the respective incidences of serious adverse events were 29%, 56%, and 26%. Grade 3-4 adverse events occurred in 45%, 86%, and 43% of patients, respectively.

There were 13 treatment-related deaths. Six deaths in the acalabrutinib arm were caused by brain neoplasm, cachexia, cerebral ischemia, malignant lung tumor, neuroendocrine carcinoma, and sepsis. Five deaths among IdR-treated patients included chronic heart failure, cardiopulmonary disease, interstitial lung disease, MI, and pseudomonal pneumonia. Two deaths in BR-treated patients were attributed to acute cardiac failure and a gastric neoplasm.

The results show that “acalabrutinib has demonstrated efficacy in previously untreated and relapsed/refractory CLL and may be considered as an option in the future treatment paradigm,” Dr. Ghia said.

Acalabrutinib monotherapy is currently being compared with ibrutinib monotherapy in patients with relapsed/refractory CLL; in addition, the phase 3 ELEVATE-TN study investigating acalabrutinib in combination with obinutuzumab (Gazyva) versus obinutuzumab plus chlorambucil has reached its primary PFS endpoint and will be reported soon, Dr. Ghia said.

The ASCEND trial is sponsored by Acerta Pharma; AstraZeneca holds majority shares in the company. Dr. Ghia reported consulting fees and honoraria from AstraZeneca and other companies, and research funding from several different companies.

SOURCE: Ghia P et al. EHA Congress, Abstract LB2606.

AMSTERDAM – After 5 years, a large majority of patients with chronic lymphocytic leukemia treated with front-line ibrutinib (Imbruvica) have not experienced disease progression, and the median progression-free survival has still not been reached, long-term follow-up from the RESONATE-2 shows.

Neil Osterweil/MDedge News

The 5-year estimated progression-free survival (PFS) rates were 70% for patients who had been randomized to receive ibrutinib monotherapy, compared with 12% for patients randomized to chlorambucil, reported Alessandra Tedeschi, MD, from Azienda Ospedaliera Niguarda Ca’ Granda in Milan.

Ibrutinib was also associated with a halving of risk for death, compared with chlorambucil, she said at the annual congress of the European Hematology Association.

“Importantly, the rate of progression during ibrutinib treatment was very low; only 8 – that is, 6% of patients” – experienced disease progression while receiving ibrutinib, she noted.

In the RESONATE-2 (PCYC-1115) trial, investigators enrolled 269 adults aged 65 years and older with previously untreated CLL/small lymphocytic lymphoma (SLL). Patients at the younger end of the age range (65-69 years) had to have comorbidities that would have made them ineligible for the FCR chemotherapy regimen (fludarabine, cyclophosphamide, and rituximab). Additionally, patients with the deleterious 17p deletion were excluded.

Patients were stratified by performance status and Rai stage and then randomized to receive either ibrutinib 420 mg once daily until disease progression or unacceptable toxicity (136 patients) or chlorambucil 0.5 mg/kg to a maximum of 0.8 mg/kg for up to 12 cycles (133 patients). The trial also had an extension study for patients who had disease progression as confirmed by an independent review committee or who had completed the RESONATE-2 trial. Of the 133 patients in the chlorambucil arm, 76 (57% of the intention-to-treat population) were crossed over to ibrutinib following disease progression.

The median duration of ibrutinib treatment was 57.1 months, with 73% of patients being on it for more than 3 years, 65% for more than 4 years, and 27% for more than 5 years. As of the data cutoff, 79 patients (58%) were continuing with ibrutinib on study.

At 5 years, 70% of ibrutinib-treated patients and 12% of chlorambucil-treated patients were estimated to be progression-free and alive (hazard ratio for PFS with ibrutinib 0.146 (95% confidence interval, 0.10-0.22). The benefit of ibrutinib was consistent for patients with high-risk genomic features, including the 11q deletion and unmutated immunoglobulin heavy-chain variable genes.

Estimated 5-year overall survival was also better with ibrutinib, at 83% vs. 68% (hazard ratio, 0.45; 95% CI, 0.266-0.761).

The most common grade 3 or greater adverse events occurring with ibrutinib were neutropenia (13%), pneumonia (12%), hypertension (8%), anemia (7%), hyponatremia (6%), atrial fibrillation (5%), and cataract (5%). The rates of most adverse events decreased over time, and dose reductions because of adverse events also diminished over time, from 5% of patients in the first year down to zero in years 4 through 5.

Patients responded to subsequent CLL therapies following ibrutinib discontinuation, including chemoimmunotherapy and other kinase inhibitors, Dr. Tedeschi said.

The trial was sponsored by Pharmacyclics with collaboration from Janssen Research & Development. Dr. Tedeschi reported advisory board activities with Janssen, AbbVie, and BeiGene.

SOURCE: Tedeschi A et al. EHA Congress, Abstract S107.

AMSTERDAM – After 5 years, a large majority of patients with chronic lymphocytic leukemia treated with front-line ibrutinib (Imbruvica) have not experienced disease progression, and the median progression-free survival has still not been reached, long-term follow-up from the RESONATE-2 shows.

Neil Osterweil/MDedge News

The 5-year estimated progression-free survival (PFS) rates were 70% for patients who had been randomized to receive ibrutinib monotherapy, compared with 12% for patients randomized to chlorambucil, reported Alessandra Tedeschi, MD, from Azienda Ospedaliera Niguarda Ca’ Granda in Milan.

Ibrutinib was also associated with a halving of risk for death, compared with chlorambucil, she said at the annual congress of the European Hematology Association.

“Importantly, the rate of progression during ibrutinib treatment was very low; only 8 – that is, 6% of patients” – experienced disease progression while receiving ibrutinib, she noted.

In the RESONATE-2 (PCYC-1115) trial, investigators enrolled 269 adults aged 65 years and older with previously untreated CLL/small lymphocytic lymphoma (SLL). Patients at the younger end of the age range (65-69 years) had to have comorbidities that would have made them ineligible for the FCR chemotherapy regimen (fludarabine, cyclophosphamide, and rituximab). Additionally, patients with the deleterious 17p deletion were excluded.

Patients were stratified by performance status and Rai stage and then randomized to receive either ibrutinib 420 mg once daily until disease progression or unacceptable toxicity (136 patients) or chlorambucil 0.5 mg/kg to a maximum of 0.8 mg/kg for up to 12 cycles (133 patients). The trial also had an extension study for patients who had disease progression as confirmed by an independent review committee or who had completed the RESONATE-2 trial. Of the 133 patients in the chlorambucil arm, 76 (57% of the intention-to-treat population) were crossed over to ibrutinib following disease progression.

The median duration of ibrutinib treatment was 57.1 months, with 73% of patients being on it for more than 3 years, 65% for more than 4 years, and 27% for more than 5 years. As of the data cutoff, 79 patients (58%) were continuing with ibrutinib on study.

At 5 years, 70% of ibrutinib-treated patients and 12% of chlorambucil-treated patients were estimated to be progression-free and alive (hazard ratio for PFS with ibrutinib 0.146 (95% confidence interval, 0.10-0.22). The benefit of ibrutinib was consistent for patients with high-risk genomic features, including the 11q deletion and unmutated immunoglobulin heavy-chain variable genes.

Estimated 5-year overall survival was also better with ibrutinib, at 83% vs. 68% (hazard ratio, 0.45; 95% CI, 0.266-0.761).

The most common grade 3 or greater adverse events occurring with ibrutinib were neutropenia (13%), pneumonia (12%), hypertension (8%), anemia (7%), hyponatremia (6%), atrial fibrillation (5%), and cataract (5%). The rates of most adverse events decreased over time, and dose reductions because of adverse events also diminished over time, from 5% of patients in the first year down to zero in years 4 through 5.

Patients responded to subsequent CLL therapies following ibrutinib discontinuation, including chemoimmunotherapy and other kinase inhibitors, Dr. Tedeschi said.

The trial was sponsored by Pharmacyclics with collaboration from Janssen Research & Development. Dr. Tedeschi reported advisory board activities with Janssen, AbbVie, and BeiGene.

SOURCE: Tedeschi A et al. EHA Congress, Abstract S107.

AMSTERDAM – After 5 years, a large majority of patients with chronic lymphocytic leukemia treated with front-line ibrutinib (Imbruvica) have not experienced disease progression, and the median progression-free survival has still not been reached, long-term follow-up from the RESONATE-2 shows.

Neil Osterweil/MDedge News

The 5-year estimated progression-free survival (PFS) rates were 70% for patients who had been randomized to receive ibrutinib monotherapy, compared with 12% for patients randomized to chlorambucil, reported Alessandra Tedeschi, MD, from Azienda Ospedaliera Niguarda Ca’ Granda in Milan.

Ibrutinib was also associated with a halving of risk for death, compared with chlorambucil, she said at the annual congress of the European Hematology Association.

“Importantly, the rate of progression during ibrutinib treatment was very low; only 8 – that is, 6% of patients” – experienced disease progression while receiving ibrutinib, she noted.

In the RESONATE-2 (PCYC-1115) trial, investigators enrolled 269 adults aged 65 years and older with previously untreated CLL/small lymphocytic lymphoma (SLL). Patients at the younger end of the age range (65-69 years) had to have comorbidities that would have made them ineligible for the FCR chemotherapy regimen (fludarabine, cyclophosphamide, and rituximab). Additionally, patients with the deleterious 17p deletion were excluded.

Patients were stratified by performance status and Rai stage and then randomized to receive either ibrutinib 420 mg once daily until disease progression or unacceptable toxicity (136 patients) or chlorambucil 0.5 mg/kg to a maximum of 0.8 mg/kg for up to 12 cycles (133 patients). The trial also had an extension study for patients who had disease progression as confirmed by an independent review committee or who had completed the RESONATE-2 trial. Of the 133 patients in the chlorambucil arm, 76 (57% of the intention-to-treat population) were crossed over to ibrutinib following disease progression.

The median duration of ibrutinib treatment was 57.1 months, with 73% of patients being on it for more than 3 years, 65% for more than 4 years, and 27% for more than 5 years. As of the data cutoff, 79 patients (58%) were continuing with ibrutinib on study.

At 5 years, 70% of ibrutinib-treated patients and 12% of chlorambucil-treated patients were estimated to be progression-free and alive (hazard ratio for PFS with ibrutinib 0.146 (95% confidence interval, 0.10-0.22). The benefit of ibrutinib was consistent for patients with high-risk genomic features, including the 11q deletion and unmutated immunoglobulin heavy-chain variable genes.

Estimated 5-year overall survival was also better with ibrutinib, at 83% vs. 68% (hazard ratio, 0.45; 95% CI, 0.266-0.761).

The most common grade 3 or greater adverse events occurring with ibrutinib were neutropenia (13%), pneumonia (12%), hypertension (8%), anemia (7%), hyponatremia (6%), atrial fibrillation (5%), and cataract (5%). The rates of most adverse events decreased over time, and dose reductions because of adverse events also diminished over time, from 5% of patients in the first year down to zero in years 4 through 5.

Patients responded to subsequent CLL therapies following ibrutinib discontinuation, including chemoimmunotherapy and other kinase inhibitors, Dr. Tedeschi said.

The trial was sponsored by Pharmacyclics with collaboration from Janssen Research & Development. Dr. Tedeschi reported advisory board activities with Janssen, AbbVie, and BeiGene.

SOURCE: Tedeschi A et al. EHA Congress, Abstract S107.