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FDA expands indication for bosutinib in newly diagnosed CML
Bosutinib is now approved for the treatment of adults with newly diagnosed chronic phase Philadelphia chromosome–positive (Ph+) chronic myelogenous leukemia (CML).
The Food and Drug Administration granted accelerated approval for bosutinib (Bosulif), which is marketed by Pfizer. The approval is based on data from the randomized, multicenter phase 3 BFORE trial of 487 patients with Ph+ newly diagnosed chronic phase CML who received either bosutinib or imatinib 400 mg once daily. Major molecular response at 12 months was 47.2% (95% confidence interval, 40.9-53.4) in the bosutinib arm and 36.9% (95% CI, 30.8-43.0) in the imatinib arm (two-sided P = .0200).
Bosutinib, a kinase inhibitor, was first approved in September 2012 for the treatment of adult patients with chronic, accelerated, or blast phase Ph+ CML with resistance or intolerance to prior therapy.
The recommended dose of bosutinib for newly diagnosed chronic phase Ph+ CML is 400 mg orally once daily with food.
The most common adverse reactions to the drug in newly diagnosed CML patients are diarrhea, nausea, thrombocytopenia, rash, increased alanine aminotransferase, abdominal pain, and increased aspartate aminotransferase.
Bosutinib is now approved for the treatment of adults with newly diagnosed chronic phase Philadelphia chromosome–positive (Ph+) chronic myelogenous leukemia (CML).
The Food and Drug Administration granted accelerated approval for bosutinib (Bosulif), which is marketed by Pfizer. The approval is based on data from the randomized, multicenter phase 3 BFORE trial of 487 patients with Ph+ newly diagnosed chronic phase CML who received either bosutinib or imatinib 400 mg once daily. Major molecular response at 12 months was 47.2% (95% confidence interval, 40.9-53.4) in the bosutinib arm and 36.9% (95% CI, 30.8-43.0) in the imatinib arm (two-sided P = .0200).
Bosutinib, a kinase inhibitor, was first approved in September 2012 for the treatment of adult patients with chronic, accelerated, or blast phase Ph+ CML with resistance or intolerance to prior therapy.
The recommended dose of bosutinib for newly diagnosed chronic phase Ph+ CML is 400 mg orally once daily with food.
The most common adverse reactions to the drug in newly diagnosed CML patients are diarrhea, nausea, thrombocytopenia, rash, increased alanine aminotransferase, abdominal pain, and increased aspartate aminotransferase.
Bosutinib is now approved for the treatment of adults with newly diagnosed chronic phase Philadelphia chromosome–positive (Ph+) chronic myelogenous leukemia (CML).
The Food and Drug Administration granted accelerated approval for bosutinib (Bosulif), which is marketed by Pfizer. The approval is based on data from the randomized, multicenter phase 3 BFORE trial of 487 patients with Ph+ newly diagnosed chronic phase CML who received either bosutinib or imatinib 400 mg once daily. Major molecular response at 12 months was 47.2% (95% confidence interval, 40.9-53.4) in the bosutinib arm and 36.9% (95% CI, 30.8-43.0) in the imatinib arm (two-sided P = .0200).
Bosutinib, a kinase inhibitor, was first approved in September 2012 for the treatment of adult patients with chronic, accelerated, or blast phase Ph+ CML with resistance or intolerance to prior therapy.
The recommended dose of bosutinib for newly diagnosed chronic phase Ph+ CML is 400 mg orally once daily with food.
The most common adverse reactions to the drug in newly diagnosed CML patients are diarrhea, nausea, thrombocytopenia, rash, increased alanine aminotransferase, abdominal pain, and increased aspartate aminotransferase.
FDA updates nilotinib product label outlining criteria for discontinuation
for patients who meet certain criteria. Nilotinib, a kinase inhibitor that blocks the BCR-ABL protein that promotes abnormal cell growth, was originally approved in 2007 and was indicated for use in patients with Philadelphia chromosome positive (Ph+) chronic myeloid leukemia (CML). In accordance with the new label update, patients who have early phase CML, have been using nilotinib for 3 years or more, and whose leukemia has responded to treatment according to a test that has received FDA marketing authorization, may be eligible to discontinue use of nilotinib.
The information that led to the FDA approved label update was based on two single-arm trials of patients with chronic phase Ph+ CML. The trial measured the length of time patients were able to discontinue use of nilotinib without leukemia returning, and who had entered treatment-free remission (TFR). In the first trial, among 190 newly diagnosed CML patients who discontinued taking nilotinib after using the drug for 3 or more years, 51.6% were still in TFR after about 1 year (48 weeks) and 48.9% were still in TFR after nearly 2 years (96 weeks). Similar results were seen in the second trial, among 126 patients, with 57.9% in TFR after about a year (48 weeks) and 53.2% in TFR after approximately 2 years (96 weeks).
An important element of these trials was regular monitoring of specific RNA information that specifies the level of BCR-ABL protein in the blood using a diagnostic test that has received FDA marketing authorization. Monitoring with a test that accurately detects the reductions of RNA information in the blood with accuracy and precision is critical in discontinuing the use of nilotinib. This monitoring will allow physicians to detect the first signs of relapse.
“Patients diagnosed with CML generally face a lifetime of treatment to keep their leukemia from growing or recurring,” said Richard Pazdur, MD, acting director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research. “Today’s approval shows that some patients may be able to stop treatment with Tasigna altogether if they are showing a strong response to therapy. While we welcome this progress in patient care, it’s important to note that any discontinuation of treatment still means patients must be regularly monitored for disease recurrence,” Dr. Pazdur said in the FDA statement.
Common side effects after discontinuing use of nilotinib include body aches and pain in the bones and extremities. Severe side effects of taking nilotinib can include myelosuppression, blockages in the heart and arteries, and inflammation of the pancreas. Severe liver damage can also occur.
Severe side effects typically associated with nilotinib administration occurred less frequently in patients who discontinued the drug. However, the long-term outcomes of patients discontinuing versus continuing treatment are unknown at this time, the FDA noted.
for patients who meet certain criteria. Nilotinib, a kinase inhibitor that blocks the BCR-ABL protein that promotes abnormal cell growth, was originally approved in 2007 and was indicated for use in patients with Philadelphia chromosome positive (Ph+) chronic myeloid leukemia (CML). In accordance with the new label update, patients who have early phase CML, have been using nilotinib for 3 years or more, and whose leukemia has responded to treatment according to a test that has received FDA marketing authorization, may be eligible to discontinue use of nilotinib.
The information that led to the FDA approved label update was based on two single-arm trials of patients with chronic phase Ph+ CML. The trial measured the length of time patients were able to discontinue use of nilotinib without leukemia returning, and who had entered treatment-free remission (TFR). In the first trial, among 190 newly diagnosed CML patients who discontinued taking nilotinib after using the drug for 3 or more years, 51.6% were still in TFR after about 1 year (48 weeks) and 48.9% were still in TFR after nearly 2 years (96 weeks). Similar results were seen in the second trial, among 126 patients, with 57.9% in TFR after about a year (48 weeks) and 53.2% in TFR after approximately 2 years (96 weeks).
An important element of these trials was regular monitoring of specific RNA information that specifies the level of BCR-ABL protein in the blood using a diagnostic test that has received FDA marketing authorization. Monitoring with a test that accurately detects the reductions of RNA information in the blood with accuracy and precision is critical in discontinuing the use of nilotinib. This monitoring will allow physicians to detect the first signs of relapse.
“Patients diagnosed with CML generally face a lifetime of treatment to keep their leukemia from growing or recurring,” said Richard Pazdur, MD, acting director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research. “Today’s approval shows that some patients may be able to stop treatment with Tasigna altogether if they are showing a strong response to therapy. While we welcome this progress in patient care, it’s important to note that any discontinuation of treatment still means patients must be regularly monitored for disease recurrence,” Dr. Pazdur said in the FDA statement.
Common side effects after discontinuing use of nilotinib include body aches and pain in the bones and extremities. Severe side effects of taking nilotinib can include myelosuppression, blockages in the heart and arteries, and inflammation of the pancreas. Severe liver damage can also occur.
Severe side effects typically associated with nilotinib administration occurred less frequently in patients who discontinued the drug. However, the long-term outcomes of patients discontinuing versus continuing treatment are unknown at this time, the FDA noted.
for patients who meet certain criteria. Nilotinib, a kinase inhibitor that blocks the BCR-ABL protein that promotes abnormal cell growth, was originally approved in 2007 and was indicated for use in patients with Philadelphia chromosome positive (Ph+) chronic myeloid leukemia (CML). In accordance with the new label update, patients who have early phase CML, have been using nilotinib for 3 years or more, and whose leukemia has responded to treatment according to a test that has received FDA marketing authorization, may be eligible to discontinue use of nilotinib.
The information that led to the FDA approved label update was based on two single-arm trials of patients with chronic phase Ph+ CML. The trial measured the length of time patients were able to discontinue use of nilotinib without leukemia returning, and who had entered treatment-free remission (TFR). In the first trial, among 190 newly diagnosed CML patients who discontinued taking nilotinib after using the drug for 3 or more years, 51.6% were still in TFR after about 1 year (48 weeks) and 48.9% were still in TFR after nearly 2 years (96 weeks). Similar results were seen in the second trial, among 126 patients, with 57.9% in TFR after about a year (48 weeks) and 53.2% in TFR after approximately 2 years (96 weeks).
An important element of these trials was regular monitoring of specific RNA information that specifies the level of BCR-ABL protein in the blood using a diagnostic test that has received FDA marketing authorization. Monitoring with a test that accurately detects the reductions of RNA information in the blood with accuracy and precision is critical in discontinuing the use of nilotinib. This monitoring will allow physicians to detect the first signs of relapse.
“Patients diagnosed with CML generally face a lifetime of treatment to keep their leukemia from growing or recurring,” said Richard Pazdur, MD, acting director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research. “Today’s approval shows that some patients may be able to stop treatment with Tasigna altogether if they are showing a strong response to therapy. While we welcome this progress in patient care, it’s important to note that any discontinuation of treatment still means patients must be regularly monitored for disease recurrence,” Dr. Pazdur said in the FDA statement.
Common side effects after discontinuing use of nilotinib include body aches and pain in the bones and extremities. Severe side effects of taking nilotinib can include myelosuppression, blockages in the heart and arteries, and inflammation of the pancreas. Severe liver damage can also occur.
Severe side effects typically associated with nilotinib administration occurred less frequently in patients who discontinued the drug. However, the long-term outcomes of patients discontinuing versus continuing treatment are unknown at this time, the FDA noted.
Nilotinib label updated with info on discontinuation
The US Food and Drug Administration (FDA) has approved an update to the product label for nilotinib (Tasigna) that includes information about how to discontinue the drug in certain patients.
Nilotinib, which was first approved by the FDA in 2007, is indicated for the treatment of patients with Philadelphia chromosome positive (Ph+) chronic myeloid leukemia (CML).
The updated prescribing information for the drug now outlines which of these patients may be eligible to stop receiving nilotinib.
Patients with chronic phase, Ph+ CML who have been taking nilotinib for 3 years or more (as first-line treatment or after failure with imatinib) and have achieved a sustained deep molecular response may be eligible to stop treatment.
Patients must have maintained a molecular response of at least MR4.0 for 1 year prior to discontinuation and achieved an MR4.5 at their last assessment.
Patients must have typical BCR-ABL transcripts (e13a2/b2a2 or e14a2/b3a2), no history of accelerated phase or blast crisis, and no past attempts at treatment discontinuation that resulted in relapse.
After discontinuation, patients must be monitored for possible loss of major molecular response (MMR). BCR-ABL transcript levels must be assessed and a complete blood count with differential performed monthly for 1 year, then every 6 weeks for the second year, and every 12 weeks thereafter.
BCR-ABL transcript levels should be measured using the MolecularMD MRDxTM BCR-ABL test, an FDA-authorized companion diagnostic validated to measure down to MR4.5.
If patients lose MMR, they must restart nilotinib within 4 weeks and receive the dose level they were receiving prior to discontinuation.
BCR-ABL transcript levels should be monitored every 2 weeks until they are lower than MMR for 4 consecutive measurements. Patients can then return to the original monitoring schedule.
The update of nilotinib’s label to include this information was based on results from 2 single-arm trials—ENESTfreedom and ENESTop.
ENESTfreedom
This phase 2 trial included 215 patients with Ph+, chronic phase CML. Researchers evaluated stopping treatment in 190 patients who had achieved a response of MR4.5 with nilotinib as first-line treatment. The patients had sustained deep molecular response for 1 year prior to treatment discontinuation.
Ninety-six weeks after stopping treatment, 48.9% of patients were still in MMR, also known as treatment-free remission (TFR).
Of the 88 patients who restarted nilotinib due to loss of MMR by the cut-off date, 98.9% were able to regain MMR (n=87). One patient discontinued the study at 7.1 weeks without regaining MMR after reinitiating treatment with nilotinib. Eighty-one patients (92.0%) regained MR4.5 by the cut-off date.
Common adverse events (AEs) in patients who discontinued nilotinib included musculoskeletal symptoms such as body aches, bone pain, and pain in extremities. However, these AEs decreased over time.
The incidence of musculoskeletal pain-related AEs decreased from 34.0% to 9.0% during the first and second 48 weeks of the TFR phase, respectively. In comparison, the incidence of such AEs was 17.0% during the treatment consolidation phase.
ENESTop
This phase 2 trial included 163 patients with Ph+, chronic phase CML. Researchers evaluated stopping treatment in 126 patients who had previously received imatinib, then switched to nilotinib and sustained a molecular response for 1 year prior to stopping nilotinib.
At 96 weeks, 53.2% of patients were still in TFR.
Fifty-six patients with confirmed loss of MR4.0 or loss of MMR restarted nilotinib by the cut-off date. Of these patients, 92.9% (n=52) regained both MR4.0 and MR4.5.
As in ENESTfreedom, patients who discontinued nilotinib had musculoskeletal symptoms that decreased over time.
The incidence of musculoskeletal pain-related AEs decreased from 47.9% to 15.1% during the first and second 48 weeks of the TFR phase, respectively. In comparison, the incidence of such AEs was 13.7% during the treatment consolidation phase.
Additional data from ENESTop and ENESTfreedom, as well as the recommendations for stopping nilotinib, are included in the updated prescribing information, which is available at https://www.us.tasigna.com/. 
The US Food and Drug Administration (FDA) has approved an update to the product label for nilotinib (Tasigna) that includes information about how to discontinue the drug in certain patients.
Nilotinib, which was first approved by the FDA in 2007, is indicated for the treatment of patients with Philadelphia chromosome positive (Ph+) chronic myeloid leukemia (CML).
The updated prescribing information for the drug now outlines which of these patients may be eligible to stop receiving nilotinib.
Patients with chronic phase, Ph+ CML who have been taking nilotinib for 3 years or more (as first-line treatment or after failure with imatinib) and have achieved a sustained deep molecular response may be eligible to stop treatment.
Patients must have maintained a molecular response of at least MR4.0 for 1 year prior to discontinuation and achieved an MR4.5 at their last assessment.
Patients must have typical BCR-ABL transcripts (e13a2/b2a2 or e14a2/b3a2), no history of accelerated phase or blast crisis, and no past attempts at treatment discontinuation that resulted in relapse.
After discontinuation, patients must be monitored for possible loss of major molecular response (MMR). BCR-ABL transcript levels must be assessed and a complete blood count with differential performed monthly for 1 year, then every 6 weeks for the second year, and every 12 weeks thereafter.
BCR-ABL transcript levels should be measured using the MolecularMD MRDxTM BCR-ABL test, an FDA-authorized companion diagnostic validated to measure down to MR4.5.
If patients lose MMR, they must restart nilotinib within 4 weeks and receive the dose level they were receiving prior to discontinuation.
BCR-ABL transcript levels should be monitored every 2 weeks until they are lower than MMR for 4 consecutive measurements. Patients can then return to the original monitoring schedule.
The update of nilotinib’s label to include this information was based on results from 2 single-arm trials—ENESTfreedom and ENESTop.
ENESTfreedom
This phase 2 trial included 215 patients with Ph+, chronic phase CML. Researchers evaluated stopping treatment in 190 patients who had achieved a response of MR4.5 with nilotinib as first-line treatment. The patients had sustained deep molecular response for 1 year prior to treatment discontinuation.
Ninety-six weeks after stopping treatment, 48.9% of patients were still in MMR, also known as treatment-free remission (TFR).
Of the 88 patients who restarted nilotinib due to loss of MMR by the cut-off date, 98.9% were able to regain MMR (n=87). One patient discontinued the study at 7.1 weeks without regaining MMR after reinitiating treatment with nilotinib. Eighty-one patients (92.0%) regained MR4.5 by the cut-off date.
Common adverse events (AEs) in patients who discontinued nilotinib included musculoskeletal symptoms such as body aches, bone pain, and pain in extremities. However, these AEs decreased over time.
The incidence of musculoskeletal pain-related AEs decreased from 34.0% to 9.0% during the first and second 48 weeks of the TFR phase, respectively. In comparison, the incidence of such AEs was 17.0% during the treatment consolidation phase.
ENESTop
This phase 2 trial included 163 patients with Ph+, chronic phase CML. Researchers evaluated stopping treatment in 126 patients who had previously received imatinib, then switched to nilotinib and sustained a molecular response for 1 year prior to stopping nilotinib.
At 96 weeks, 53.2% of patients were still in TFR.
Fifty-six patients with confirmed loss of MR4.0 or loss of MMR restarted nilotinib by the cut-off date. Of these patients, 92.9% (n=52) regained both MR4.0 and MR4.5.
As in ENESTfreedom, patients who discontinued nilotinib had musculoskeletal symptoms that decreased over time.
The incidence of musculoskeletal pain-related AEs decreased from 47.9% to 15.1% during the first and second 48 weeks of the TFR phase, respectively. In comparison, the incidence of such AEs was 13.7% during the treatment consolidation phase.
Additional data from ENESTop and ENESTfreedom, as well as the recommendations for stopping nilotinib, are included in the updated prescribing information, which is available at https://www.us.tasigna.com/.
The US Food and Drug Administration (FDA) has approved an update to the product label for nilotinib (Tasigna) that includes information about how to discontinue the drug in certain patients.
Nilotinib, which was first approved by the FDA in 2007, is indicated for the treatment of patients with Philadelphia chromosome positive (Ph+) chronic myeloid leukemia (CML).
The updated prescribing information for the drug now outlines which of these patients may be eligible to stop receiving nilotinib.
Patients with chronic phase, Ph+ CML who have been taking nilotinib for 3 years or more (as first-line treatment or after failure with imatinib) and have achieved a sustained deep molecular response may be eligible to stop treatment.
Patients must have maintained a molecular response of at least MR4.0 for 1 year prior to discontinuation and achieved an MR4.5 at their last assessment.
Patients must have typical BCR-ABL transcripts (e13a2/b2a2 or e14a2/b3a2), no history of accelerated phase or blast crisis, and no past attempts at treatment discontinuation that resulted in relapse.
After discontinuation, patients must be monitored for possible loss of major molecular response (MMR). BCR-ABL transcript levels must be assessed and a complete blood count with differential performed monthly for 1 year, then every 6 weeks for the second year, and every 12 weeks thereafter.
BCR-ABL transcript levels should be measured using the MolecularMD MRDxTM BCR-ABL test, an FDA-authorized companion diagnostic validated to measure down to MR4.5.
If patients lose MMR, they must restart nilotinib within 4 weeks and receive the dose level they were receiving prior to discontinuation.
BCR-ABL transcript levels should be monitored every 2 weeks until they are lower than MMR for 4 consecutive measurements. Patients can then return to the original monitoring schedule.
The update of nilotinib’s label to include this information was based on results from 2 single-arm trials—ENESTfreedom and ENESTop.
ENESTfreedom
This phase 2 trial included 215 patients with Ph+, chronic phase CML. Researchers evaluated stopping treatment in 190 patients who had achieved a response of MR4.5 with nilotinib as first-line treatment. The patients had sustained deep molecular response for 1 year prior to treatment discontinuation.
Ninety-six weeks after stopping treatment, 48.9% of patients were still in MMR, also known as treatment-free remission (TFR).
Of the 88 patients who restarted nilotinib due to loss of MMR by the cut-off date, 98.9% were able to regain MMR (n=87). One patient discontinued the study at 7.1 weeks without regaining MMR after reinitiating treatment with nilotinib. Eighty-one patients (92.0%) regained MR4.5 by the cut-off date.
Common adverse events (AEs) in patients who discontinued nilotinib included musculoskeletal symptoms such as body aches, bone pain, and pain in extremities. However, these AEs decreased over time.
The incidence of musculoskeletal pain-related AEs decreased from 34.0% to 9.0% during the first and second 48 weeks of the TFR phase, respectively. In comparison, the incidence of such AEs was 17.0% during the treatment consolidation phase.
ENESTop
This phase 2 trial included 163 patients with Ph+, chronic phase CML. Researchers evaluated stopping treatment in 126 patients who had previously received imatinib, then switched to nilotinib and sustained a molecular response for 1 year prior to stopping nilotinib.
At 96 weeks, 53.2% of patients were still in TFR.
Fifty-six patients with confirmed loss of MR4.0 or loss of MMR restarted nilotinib by the cut-off date. Of these patients, 92.9% (n=52) regained both MR4.0 and MR4.5.
As in ENESTfreedom, patients who discontinued nilotinib had musculoskeletal symptoms that decreased over time.
The incidence of musculoskeletal pain-related AEs decreased from 47.9% to 15.1% during the first and second 48 weeks of the TFR phase, respectively. In comparison, the incidence of such AEs was 13.7% during the treatment consolidation phase.
Additional data from ENESTop and ENESTfreedom, as well as the recommendations for stopping nilotinib, are included in the updated prescribing information, which is available at https://www.us.tasigna.com/.
FDA expands approved use of bosutinib in CML
The US Food and Drug Administration (FDA) has expanded the approved indication for bosutinib (BOSULIF®).
The tyrosine kinase inhibitor (TKI) is now approved to treat adults with newly diagnosed, chronic phase, Philadelphia chromosome-positive (Ph+) chronic myelogenous leukemia (CML).
Bosutinib has accelerated approval for this indication. The approval was based on molecular and cytogenetic response rates.
Continued approval may be contingent upon verification and confirmation of clinical benefit in an ongoing, long-term follow-up trial.
Bosutinib was first approved by the FDA in September 2012. At that time, the TKI was approved to treat adults with chronic, accelerated, or blast phase Ph+ CML with resistance or intolerance to prior therapy.
A 400 mg tablet of bosutinib was recently approved by the FDA, adding to the previously approved 100 mg and 500 mg strengths.
The recommended dose of bosutinib for newly diagnosed patients is 400 mg orally once daily with food.
For patients who are resistant or intolerant to prior TKI therapy, the recommended dose is 500 mg orally once daily with food.
BFORE trial
The approval of bosutinib in adults with newly diagnosed, chronic phase, Ph+ CML was based on the phase 3 BFORE trial. Results from the trial were presented at the 2017 ASCO Annual Meeting.
In this ongoing study, researchers are comparing bosutinib and imatinib as first-line treatment of chronic phase CML.
As of the ASCO presentation, the trial had enrolled 536 patients who were randomized 1:1 to receive bosutinib (n=268) or imatinib (n=268).
The presentation included results in a modified intent-to-treat population of Ph+ patients with e13a2/e14a2 transcripts who had at least 12 months of follow-up. In this group, there were 246 patients in the bosutinib arm and 241 in the imatinib arm.
Most of the patients were still on therapy at the 12-month mark or beyond—78% in the bosutinib arm and 73.2% in the imatinib arm. The median treatment duration was 14.1 months and 13.8 months, respectively.
At 12 months, the rate of major molecular response was 47.2% in the bosutinib arm and 36.9% in the imatinib arm (P=0.02). The rate of complete cytogenetic response was 77.2% and 66.4%, respectively (P<0.008).
One patient in the bosutinib arm and 4 in the imatinib arm discontinued treatment due to disease progression, while 12.7% and 8.7%, respectively, discontinued treatment due to drug-related toxicity.
Adverse events that were more common in the bosutinib arm than the imatinib arm included grade 3 or higher diarrhea (7.8% vs 0.8%), increased alanine levels (19% vs 1.5%), increased aspartate levels (9.7% vs 1.9%), cardiovascular events (3% vs 0.4%), and peripheral vascular events (1.5% vs 1.1%).
Cerebrovascular events were more common with imatinib than bosutinib (0.4% and 0%, respectively).
Pfizer and Avillion entered into an exclusive collaborative development agreement in 2014 to conduct the BFORE trial.
Under the terms of the agreement, Avillion provided funding and conducted the trial to generate the clinical data used to support regulatory filings for marketing authorization for bosutinib as first-line treatment for patients with chronic phase, Ph+ CML.
With this approval, Avillion is eligible to receive milestone payments from Pfizer. Pfizer retains all rights to commercialize bosutinib globally.
The US Food and Drug Administration (FDA) has expanded the approved indication for bosutinib (BOSULIF®).
The tyrosine kinase inhibitor (TKI) is now approved to treat adults with newly diagnosed, chronic phase, Philadelphia chromosome-positive (Ph+) chronic myelogenous leukemia (CML).
Bosutinib has accelerated approval for this indication. The approval was based on molecular and cytogenetic response rates.
Continued approval may be contingent upon verification and confirmation of clinical benefit in an ongoing, long-term follow-up trial.
Bosutinib was first approved by the FDA in September 2012. At that time, the TKI was approved to treat adults with chronic, accelerated, or blast phase Ph+ CML with resistance or intolerance to prior therapy.
A 400 mg tablet of bosutinib was recently approved by the FDA, adding to the previously approved 100 mg and 500 mg strengths.
The recommended dose of bosutinib for newly diagnosed patients is 400 mg orally once daily with food.
For patients who are resistant or intolerant to prior TKI therapy, the recommended dose is 500 mg orally once daily with food.
BFORE trial
The approval of bosutinib in adults with newly diagnosed, chronic phase, Ph+ CML was based on the phase 3 BFORE trial. Results from the trial were presented at the 2017 ASCO Annual Meeting.
In this ongoing study, researchers are comparing bosutinib and imatinib as first-line treatment of chronic phase CML.
As of the ASCO presentation, the trial had enrolled 536 patients who were randomized 1:1 to receive bosutinib (n=268) or imatinib (n=268).
The presentation included results in a modified intent-to-treat population of Ph+ patients with e13a2/e14a2 transcripts who had at least 12 months of follow-up. In this group, there were 246 patients in the bosutinib arm and 241 in the imatinib arm.
Most of the patients were still on therapy at the 12-month mark or beyond—78% in the bosutinib arm and 73.2% in the imatinib arm. The median treatment duration was 14.1 months and 13.8 months, respectively.
At 12 months, the rate of major molecular response was 47.2% in the bosutinib arm and 36.9% in the imatinib arm (P=0.02). The rate of complete cytogenetic response was 77.2% and 66.4%, respectively (P<0.008).
One patient in the bosutinib arm and 4 in the imatinib arm discontinued treatment due to disease progression, while 12.7% and 8.7%, respectively, discontinued treatment due to drug-related toxicity.
Adverse events that were more common in the bosutinib arm than the imatinib arm included grade 3 or higher diarrhea (7.8% vs 0.8%), increased alanine levels (19% vs 1.5%), increased aspartate levels (9.7% vs 1.9%), cardiovascular events (3% vs 0.4%), and peripheral vascular events (1.5% vs 1.1%).
Cerebrovascular events were more common with imatinib than bosutinib (0.4% and 0%, respectively).
Pfizer and Avillion entered into an exclusive collaborative development agreement in 2014 to conduct the BFORE trial.
Under the terms of the agreement, Avillion provided funding and conducted the trial to generate the clinical data used to support regulatory filings for marketing authorization for bosutinib as first-line treatment for patients with chronic phase, Ph+ CML.
With this approval, Avillion is eligible to receive milestone payments from Pfizer. Pfizer retains all rights to commercialize bosutinib globally.
The US Food and Drug Administration (FDA) has expanded the approved indication for bosutinib (BOSULIF®).
The tyrosine kinase inhibitor (TKI) is now approved to treat adults with newly diagnosed, chronic phase, Philadelphia chromosome-positive (Ph+) chronic myelogenous leukemia (CML).
Bosutinib has accelerated approval for this indication. The approval was based on molecular and cytogenetic response rates.
Continued approval may be contingent upon verification and confirmation of clinical benefit in an ongoing, long-term follow-up trial.
Bosutinib was first approved by the FDA in September 2012. At that time, the TKI was approved to treat adults with chronic, accelerated, or blast phase Ph+ CML with resistance or intolerance to prior therapy.
A 400 mg tablet of bosutinib was recently approved by the FDA, adding to the previously approved 100 mg and 500 mg strengths.
The recommended dose of bosutinib for newly diagnosed patients is 400 mg orally once daily with food.
For patients who are resistant or intolerant to prior TKI therapy, the recommended dose is 500 mg orally once daily with food.
BFORE trial
The approval of bosutinib in adults with newly diagnosed, chronic phase, Ph+ CML was based on the phase 3 BFORE trial. Results from the trial were presented at the 2017 ASCO Annual Meeting.
In this ongoing study, researchers are comparing bosutinib and imatinib as first-line treatment of chronic phase CML.
As of the ASCO presentation, the trial had enrolled 536 patients who were randomized 1:1 to receive bosutinib (n=268) or imatinib (n=268).
The presentation included results in a modified intent-to-treat population of Ph+ patients with e13a2/e14a2 transcripts who had at least 12 months of follow-up. In this group, there were 246 patients in the bosutinib arm and 241 in the imatinib arm.
Most of the patients were still on therapy at the 12-month mark or beyond—78% in the bosutinib arm and 73.2% in the imatinib arm. The median treatment duration was 14.1 months and 13.8 months, respectively.
At 12 months, the rate of major molecular response was 47.2% in the bosutinib arm and 36.9% in the imatinib arm (P=0.02). The rate of complete cytogenetic response was 77.2% and 66.4%, respectively (P<0.008).
One patient in the bosutinib arm and 4 in the imatinib arm discontinued treatment due to disease progression, while 12.7% and 8.7%, respectively, discontinued treatment due to drug-related toxicity.
Adverse events that were more common in the bosutinib arm than the imatinib arm included grade 3 or higher diarrhea (7.8% vs 0.8%), increased alanine levels (19% vs 1.5%), increased aspartate levels (9.7% vs 1.9%), cardiovascular events (3% vs 0.4%), and peripheral vascular events (1.5% vs 1.1%).
Cerebrovascular events were more common with imatinib than bosutinib (0.4% and 0%, respectively).
Pfizer and Avillion entered into an exclusive collaborative development agreement in 2014 to conduct the BFORE trial.
Under the terms of the agreement, Avillion provided funding and conducted the trial to generate the clinical data used to support regulatory filings for marketing authorization for bosutinib as first-line treatment for patients with chronic phase, Ph+ CML.
With this approval, Avillion is eligible to receive milestone payments from Pfizer. Pfizer retains all rights to commercialize bosutinib globally.
Company launches digital PCR test for monitoring CML
Bio-Rad Laboratories, Inc., has launched the QXDx BCR-ABL %IS Kit, a digital polymerase chain reaction (PCR) test that can monitor molecular response to therapy in patients with chronic myeloid leukemia (CML).
The kit has a CE-IVD mark and is available for in vitro diagnostic use in Europe, Hong Kong, and New Zealand.
The QXDx BCR-ABL %IS Kit uses Bio-Rad’s Droplet Digital PCR (ddPCR) technology to provide an absolute measure of BCR-ABL transcripts.
The kit measures BCR-ABL1 and ABL1 chromosomal transcripts in total RNA from whole blood of t(9;22)-positive CML patients expressing BCR-ABL1 fusion transcripts type e13a2 and/or e14a2.
The QXDx BCR-ABL %IS Kit measures the e13a2 and/or e14a2 transcripts of BCR-ABL1, normalized to the ABL1 endogenous control. The kit does not differentiate between e13a2 and e14a2 transcripts and does not monitor other rare fusion transcripts resulting from t(9;22).
The kit’s results are reported as percent reduction from a baseline of 100% on the International Scale (%IS) and on a log molecular reduction (MR) scale.
The kit is able to detect deep molecular response values of MR 4.7 (%IS 0.002) or MR 5.0 (%IS 0.001) in 2- or 4-well formats. This exceeds the typical limitations of reverse transcription quantitative PCR-based tests that are reliable down to MR 4.5 (%IS 0.0032).
Bio-Rad says the QXDx BCR-ABL %IS Kit delivers absolute quantitation, which eliminates the need for standard curves and minimizes variation between samples. The kit also provides scalable throughput, allowing for testing of 8 to 48 samples per run.
The QXDx BCR-ABL %IS Kit can be used with Bio-Rad’s QX200 AutoDG ddPCR Dx System or with the QX200 ddPCR Dx System. The QXDx BCR-ABL %IS Kit uses QuantaSoft Software v1.7 for data acquisition and output.
Bio-Rad Laboratories, Inc., has launched the QXDx BCR-ABL %IS Kit, a digital polymerase chain reaction (PCR) test that can monitor molecular response to therapy in patients with chronic myeloid leukemia (CML).
The kit has a CE-IVD mark and is available for in vitro diagnostic use in Europe, Hong Kong, and New Zealand.
The QXDx BCR-ABL %IS Kit uses Bio-Rad’s Droplet Digital PCR (ddPCR) technology to provide an absolute measure of BCR-ABL transcripts.
The kit measures BCR-ABL1 and ABL1 chromosomal transcripts in total RNA from whole blood of t(9;22)-positive CML patients expressing BCR-ABL1 fusion transcripts type e13a2 and/or e14a2.
The QXDx BCR-ABL %IS Kit measures the e13a2 and/or e14a2 transcripts of BCR-ABL1, normalized to the ABL1 endogenous control. The kit does not differentiate between e13a2 and e14a2 transcripts and does not monitor other rare fusion transcripts resulting from t(9;22).
The kit’s results are reported as percent reduction from a baseline of 100% on the International Scale (%IS) and on a log molecular reduction (MR) scale.
The kit is able to detect deep molecular response values of MR 4.7 (%IS 0.002) or MR 5.0 (%IS 0.001) in 2- or 4-well formats. This exceeds the typical limitations of reverse transcription quantitative PCR-based tests that are reliable down to MR 4.5 (%IS 0.0032).
Bio-Rad says the QXDx BCR-ABL %IS Kit delivers absolute quantitation, which eliminates the need for standard curves and minimizes variation between samples. The kit also provides scalable throughput, allowing for testing of 8 to 48 samples per run.
The QXDx BCR-ABL %IS Kit can be used with Bio-Rad’s QX200 AutoDG ddPCR Dx System or with the QX200 ddPCR Dx System. The QXDx BCR-ABL %IS Kit uses QuantaSoft Software v1.7 for data acquisition and output.
Bio-Rad Laboratories, Inc., has launched the QXDx BCR-ABL %IS Kit, a digital polymerase chain reaction (PCR) test that can monitor molecular response to therapy in patients with chronic myeloid leukemia (CML).
The kit has a CE-IVD mark and is available for in vitro diagnostic use in Europe, Hong Kong, and New Zealand.
The QXDx BCR-ABL %IS Kit uses Bio-Rad’s Droplet Digital PCR (ddPCR) technology to provide an absolute measure of BCR-ABL transcripts.
The kit measures BCR-ABL1 and ABL1 chromosomal transcripts in total RNA from whole blood of t(9;22)-positive CML patients expressing BCR-ABL1 fusion transcripts type e13a2 and/or e14a2.
The QXDx BCR-ABL %IS Kit measures the e13a2 and/or e14a2 transcripts of BCR-ABL1, normalized to the ABL1 endogenous control. The kit does not differentiate between e13a2 and e14a2 transcripts and does not monitor other rare fusion transcripts resulting from t(9;22).
The kit’s results are reported as percent reduction from a baseline of 100% on the International Scale (%IS) and on a log molecular reduction (MR) scale.
The kit is able to detect deep molecular response values of MR 4.7 (%IS 0.002) or MR 5.0 (%IS 0.001) in 2- or 4-well formats. This exceeds the typical limitations of reverse transcription quantitative PCR-based tests that are reliable down to MR 4.5 (%IS 0.0032).
Bio-Rad says the QXDx BCR-ABL %IS Kit delivers absolute quantitation, which eliminates the need for standard curves and minimizes variation between samples. The kit also provides scalable throughput, allowing for testing of 8 to 48 samples per run.
The QXDx BCR-ABL %IS Kit can be used with Bio-Rad’s QX200 AutoDG ddPCR Dx System or with the QX200 ddPCR Dx System. The QXDx BCR-ABL %IS Kit uses QuantaSoft Software v1.7 for data acquisition and output.
Companies launch generic busulfan in US
Two companies have announced the US launch of a generic busulfan product, Myleran Injection.
Mylan NV and Aspen have partnered to develop Myleran (busulfan) Injection, 60 mg/10 mL (6 mg/mL) Single-dose Vial, a generic version of Otsuka Pharmaceutical’s Busulfex® Injection.
The US Food and Drug Administration approved Myleran Injection for use in combination with cyclophosphamide as a conditioning regimen prior to allogeneic hematopoietic stem cell transplant in patients with chronic myeloid leukemia.
Two companies have announced the US launch of a generic busulfan product, Myleran Injection.
Mylan NV and Aspen have partnered to develop Myleran (busulfan) Injection, 60 mg/10 mL (6 mg/mL) Single-dose Vial, a generic version of Otsuka Pharmaceutical’s Busulfex® Injection.
The US Food and Drug Administration approved Myleran Injection for use in combination with cyclophosphamide as a conditioning regimen prior to allogeneic hematopoietic stem cell transplant in patients with chronic myeloid leukemia.
Two companies have announced the US launch of a generic busulfan product, Myleran Injection.
Mylan NV and Aspen have partnered to develop Myleran (busulfan) Injection, 60 mg/10 mL (6 mg/mL) Single-dose Vial, a generic version of Otsuka Pharmaceutical’s Busulfex® Injection.
The US Food and Drug Administration approved Myleran Injection for use in combination with cyclophosphamide as a conditioning regimen prior to allogeneic hematopoietic stem cell transplant in patients with chronic myeloid leukemia.
Nilotinib approved to treat kids with CML in EU
The European Commission has approved nilotinib (Tasigna®) for the treatment of pediatric patients.
The drug is now approved to treat children age 2 and older with newly diagnosed, Philadelphia chromosome-positive (Ph+), chronic phase (CP) chronic myeloid leukemia (CML) or Ph+ CP-CML with resistance or intolerance to prior therapy, including imatinib.
Nilotinib is the only second-generation tyrosine kinase inhibitor currently approved in the European Union (EU) for the treatment of Ph+ CP-CML in children. The approval applies to all EU member states.
According to Novartis, the expanded indication for nilotinib is based on 2 prospective studies of the drug in children with Ph+ CP-CML, which were part of a formal “pediatric investigation plan” agreed upon with the European Medicines Agency.
The company said 69 patients received nilotinib in these studies. The patients ranged in age from 2 to 18. They had either newly diagnosed Ph+ CP-CML or Ph+ CP-CML with resistance or intolerance to prior therapy, including imatinib.
In the newly diagnosed patients, the major molecular response (MMR) rate was 60.0% (95% CI: 38.7, 78.9) at 12 cycles, with 15 patients achieving MMR.
In patients with resistance or intolerance to prior therapy, the MMR rate was 40.9% (95% CI: 26.3, 56.8) at 12 cycles, with 18 patients being in MMR.
In newly diagnosed patients, the cumulative MMR rate was 64.0% by cycle 12. In patients with resistance or intolerance to prior therapy, the cumulative MMR rate was 47.7% by cycle 12.
Adverse events were generally consistent with those observed in adults, with the exception of hyperbilirubinemia and transaminase elevation, which were reported at a higher frequency than in adults.
The rate of grade 3/4 hyperbilirubinemia was 13.0%, the rate of grade 3/4 AST elevation was 1.4%, and the rate of grade 3/4 ALT elevation was 8.7%.
There were no deaths on treatment or after treatment discontinuation.
The European Commission has approved nilotinib (Tasigna®) for the treatment of pediatric patients.
The drug is now approved to treat children age 2 and older with newly diagnosed, Philadelphia chromosome-positive (Ph+), chronic phase (CP) chronic myeloid leukemia (CML) or Ph+ CP-CML with resistance or intolerance to prior therapy, including imatinib.
Nilotinib is the only second-generation tyrosine kinase inhibitor currently approved in the European Union (EU) for the treatment of Ph+ CP-CML in children. The approval applies to all EU member states.
According to Novartis, the expanded indication for nilotinib is based on 2 prospective studies of the drug in children with Ph+ CP-CML, which were part of a formal “pediatric investigation plan” agreed upon with the European Medicines Agency.
The company said 69 patients received nilotinib in these studies. The patients ranged in age from 2 to 18. They had either newly diagnosed Ph+ CP-CML or Ph+ CP-CML with resistance or intolerance to prior therapy, including imatinib.
In the newly diagnosed patients, the major molecular response (MMR) rate was 60.0% (95% CI: 38.7, 78.9) at 12 cycles, with 15 patients achieving MMR.
In patients with resistance or intolerance to prior therapy, the MMR rate was 40.9% (95% CI: 26.3, 56.8) at 12 cycles, with 18 patients being in MMR.
In newly diagnosed patients, the cumulative MMR rate was 64.0% by cycle 12. In patients with resistance or intolerance to prior therapy, the cumulative MMR rate was 47.7% by cycle 12.
Adverse events were generally consistent with those observed in adults, with the exception of hyperbilirubinemia and transaminase elevation, which were reported at a higher frequency than in adults.
The rate of grade 3/4 hyperbilirubinemia was 13.0%, the rate of grade 3/4 AST elevation was 1.4%, and the rate of grade 3/4 ALT elevation was 8.7%.
There were no deaths on treatment or after treatment discontinuation.
The European Commission has approved nilotinib (Tasigna®) for the treatment of pediatric patients.
The drug is now approved to treat children age 2 and older with newly diagnosed, Philadelphia chromosome-positive (Ph+), chronic phase (CP) chronic myeloid leukemia (CML) or Ph+ CP-CML with resistance or intolerance to prior therapy, including imatinib.
Nilotinib is the only second-generation tyrosine kinase inhibitor currently approved in the European Union (EU) for the treatment of Ph+ CP-CML in children. The approval applies to all EU member states.
According to Novartis, the expanded indication for nilotinib is based on 2 prospective studies of the drug in children with Ph+ CP-CML, which were part of a formal “pediatric investigation plan” agreed upon with the European Medicines Agency.
The company said 69 patients received nilotinib in these studies. The patients ranged in age from 2 to 18. They had either newly diagnosed Ph+ CP-CML or Ph+ CP-CML with resistance or intolerance to prior therapy, including imatinib.
In the newly diagnosed patients, the major molecular response (MMR) rate was 60.0% (95% CI: 38.7, 78.9) at 12 cycles, with 15 patients achieving MMR.
In patients with resistance or intolerance to prior therapy, the MMR rate was 40.9% (95% CI: 26.3, 56.8) at 12 cycles, with 18 patients being in MMR.
In newly diagnosed patients, the cumulative MMR rate was 64.0% by cycle 12. In patients with resistance or intolerance to prior therapy, the cumulative MMR rate was 47.7% by cycle 12.
Adverse events were generally consistent with those observed in adults, with the exception of hyperbilirubinemia and transaminase elevation, which were reported at a higher frequency than in adults.
The rate of grade 3/4 hyperbilirubinemia was 13.0%, the rate of grade 3/4 AST elevation was 1.4%, and the rate of grade 3/4 ALT elevation was 8.7%.
There were no deaths on treatment or after treatment discontinuation.
Cancer patients with TKI-induced hypothyroidism had better survival rates
VICTORIA, B.C. – When it comes to the adverse effects of tyrosine kinase inhibitors (TKIs), hypothyroidism appears to have a bright side, according to a retrospective cohort study among patients with nonthyroid cancers.
While taking one of these targeted agents, roughly a quarter of patients became overtly hypothyroid, an adverse effect that appears to be due in part to immune destruction. Risk was higher for women and earlier in therapy.
Relative to counterparts who remained euthyroid, overtly hypothyroid patients were 44% less likely to die after other factors were taken into account.
Hypothyroidism may reflect changes in immune activation, Dr. Angell proposed. “Additional studies may be helpful, both prospectively looking at the clinical importance of this finding [of survival benefit], and also potentially mechanistically, to understand the relationship between hypothyroidism and survival in these patients.”
“This is an innovative study that looked at an interesting clinical question,” observed session cochair Angela M. Leung, MD, of the University of California, Los Angeles, and an endocrinologist at both UCLA and the VA Greater Los Angeles Healthcare System.
Thyroid dysfunction is a well-known, common side effect of TKI therapy, Dr. Angell noted. “The possible mechanisms that have been suggested for this are direct toxicity on the thyroid gland, destructive thyroiditis, increased thyroid hormone clearance, and vascular endothelial growth factor (VEGF) inhibition, among others.”
Some previous research has suggested a possible survival benefit of TKI-induced hypothyroidism. But “there are limitations in our understanding of hypothyroidism in this setting, including the timing of onset, what risk factors there may be, and the effect of additional clinical variables on the survival effect seen,” Dr. Angell pointed out.
He and his coinvestigators studied 538 adult patients with nonthyroid cancers (mostly stage III or IV) who received a first TKI during 2000-2013 and were followed up through 2017. They excluded those who had preexisting thyroid disease or were on thyroid-related medications.
During TKI therapy, 26.7% of patients developed overt hypothyroidism, and another 13.2% developed subclinical hypothyroidism.
“For a given drug, patients were less likely to develop hypothyroidism when they were given it subsequent to another TKI, as opposed to it being the initial TKI,” Dr. Angell reported. But median time to onset of hypothyroidism was about 2.5 months, regardless.
Cumulative months of all TKI exposure during cancer treatment were not significantly associated with development of hypothyroidism.
In a multivariate analysis, patients were significantly more likely to develop hypothyroidism if they were female (odds ratio, 1.99) and significantly less likely if they had a longer total time on treatment (OR, 0.98) or received a non-TKI VEGF inhibitor (OR, 0.43). Age, race, and cumulative TKI exposure did not influence the outcome.
In a second multivariate analysis, patients’ risk of death was significantly lower if they developed overt hypothyroidism (hazard ratio, 0.56; P less than .0001), but not if they developed subclinical hypothyroidism (HR, 0.79; P = .1655).
Treatment of hypothyroidism did not appear to influence survival, according to Dr. Angell. However, “there wasn’t a specific decision on who was treated, how they were treated, [or] when they were treated,” he said. “So, it is difficult within this cohort to look specifically at which cutoff would be ideal” for initiating treatment.
Similarly, thyroid function testing was not standardized in this retrospectively identified cohort, so it was not possible to determine how long patients were hypothyroid and whether that had an impact, according to Dr. Angell.
Dr. Angell had no relevant conflicts of interest.
VICTORIA, B.C. – When it comes to the adverse effects of tyrosine kinase inhibitors (TKIs), hypothyroidism appears to have a bright side, according to a retrospective cohort study among patients with nonthyroid cancers.
While taking one of these targeted agents, roughly a quarter of patients became overtly hypothyroid, an adverse effect that appears to be due in part to immune destruction. Risk was higher for women and earlier in therapy.
Relative to counterparts who remained euthyroid, overtly hypothyroid patients were 44% less likely to die after other factors were taken into account.
Hypothyroidism may reflect changes in immune activation, Dr. Angell proposed. “Additional studies may be helpful, both prospectively looking at the clinical importance of this finding [of survival benefit], and also potentially mechanistically, to understand the relationship between hypothyroidism and survival in these patients.”
“This is an innovative study that looked at an interesting clinical question,” observed session cochair Angela M. Leung, MD, of the University of California, Los Angeles, and an endocrinologist at both UCLA and the VA Greater Los Angeles Healthcare System.
Thyroid dysfunction is a well-known, common side effect of TKI therapy, Dr. Angell noted. “The possible mechanisms that have been suggested for this are direct toxicity on the thyroid gland, destructive thyroiditis, increased thyroid hormone clearance, and vascular endothelial growth factor (VEGF) inhibition, among others.”
Some previous research has suggested a possible survival benefit of TKI-induced hypothyroidism. But “there are limitations in our understanding of hypothyroidism in this setting, including the timing of onset, what risk factors there may be, and the effect of additional clinical variables on the survival effect seen,” Dr. Angell pointed out.
He and his coinvestigators studied 538 adult patients with nonthyroid cancers (mostly stage III or IV) who received a first TKI during 2000-2013 and were followed up through 2017. They excluded those who had preexisting thyroid disease or were on thyroid-related medications.
During TKI therapy, 26.7% of patients developed overt hypothyroidism, and another 13.2% developed subclinical hypothyroidism.
“For a given drug, patients were less likely to develop hypothyroidism when they were given it subsequent to another TKI, as opposed to it being the initial TKI,” Dr. Angell reported. But median time to onset of hypothyroidism was about 2.5 months, regardless.
Cumulative months of all TKI exposure during cancer treatment were not significantly associated with development of hypothyroidism.
In a multivariate analysis, patients were significantly more likely to develop hypothyroidism if they were female (odds ratio, 1.99) and significantly less likely if they had a longer total time on treatment (OR, 0.98) or received a non-TKI VEGF inhibitor (OR, 0.43). Age, race, and cumulative TKI exposure did not influence the outcome.
In a second multivariate analysis, patients’ risk of death was significantly lower if they developed overt hypothyroidism (hazard ratio, 0.56; P less than .0001), but not if they developed subclinical hypothyroidism (HR, 0.79; P = .1655).
Treatment of hypothyroidism did not appear to influence survival, according to Dr. Angell. However, “there wasn’t a specific decision on who was treated, how they were treated, [or] when they were treated,” he said. “So, it is difficult within this cohort to look specifically at which cutoff would be ideal” for initiating treatment.
Similarly, thyroid function testing was not standardized in this retrospectively identified cohort, so it was not possible to determine how long patients were hypothyroid and whether that had an impact, according to Dr. Angell.
Dr. Angell had no relevant conflicts of interest.
VICTORIA, B.C. – When it comes to the adverse effects of tyrosine kinase inhibitors (TKIs), hypothyroidism appears to have a bright side, according to a retrospective cohort study among patients with nonthyroid cancers.
While taking one of these targeted agents, roughly a quarter of patients became overtly hypothyroid, an adverse effect that appears to be due in part to immune destruction. Risk was higher for women and earlier in therapy.
Relative to counterparts who remained euthyroid, overtly hypothyroid patients were 44% less likely to die after other factors were taken into account.
Hypothyroidism may reflect changes in immune activation, Dr. Angell proposed. “Additional studies may be helpful, both prospectively looking at the clinical importance of this finding [of survival benefit], and also potentially mechanistically, to understand the relationship between hypothyroidism and survival in these patients.”
“This is an innovative study that looked at an interesting clinical question,” observed session cochair Angela M. Leung, MD, of the University of California, Los Angeles, and an endocrinologist at both UCLA and the VA Greater Los Angeles Healthcare System.
Thyroid dysfunction is a well-known, common side effect of TKI therapy, Dr. Angell noted. “The possible mechanisms that have been suggested for this are direct toxicity on the thyroid gland, destructive thyroiditis, increased thyroid hormone clearance, and vascular endothelial growth factor (VEGF) inhibition, among others.”
Some previous research has suggested a possible survival benefit of TKI-induced hypothyroidism. But “there are limitations in our understanding of hypothyroidism in this setting, including the timing of onset, what risk factors there may be, and the effect of additional clinical variables on the survival effect seen,” Dr. Angell pointed out.
He and his coinvestigators studied 538 adult patients with nonthyroid cancers (mostly stage III or IV) who received a first TKI during 2000-2013 and were followed up through 2017. They excluded those who had preexisting thyroid disease or were on thyroid-related medications.
During TKI therapy, 26.7% of patients developed overt hypothyroidism, and another 13.2% developed subclinical hypothyroidism.
“For a given drug, patients were less likely to develop hypothyroidism when they were given it subsequent to another TKI, as opposed to it being the initial TKI,” Dr. Angell reported. But median time to onset of hypothyroidism was about 2.5 months, regardless.
Cumulative months of all TKI exposure during cancer treatment were not significantly associated with development of hypothyroidism.
In a multivariate analysis, patients were significantly more likely to develop hypothyroidism if they were female (odds ratio, 1.99) and significantly less likely if they had a longer total time on treatment (OR, 0.98) or received a non-TKI VEGF inhibitor (OR, 0.43). Age, race, and cumulative TKI exposure did not influence the outcome.
In a second multivariate analysis, patients’ risk of death was significantly lower if they developed overt hypothyroidism (hazard ratio, 0.56; P less than .0001), but not if they developed subclinical hypothyroidism (HR, 0.79; P = .1655).
Treatment of hypothyroidism did not appear to influence survival, according to Dr. Angell. However, “there wasn’t a specific decision on who was treated, how they were treated, [or] when they were treated,” he said. “So, it is difficult within this cohort to look specifically at which cutoff would be ideal” for initiating treatment.
Similarly, thyroid function testing was not standardized in this retrospectively identified cohort, so it was not possible to determine how long patients were hypothyroid and whether that had an impact, according to Dr. Angell.
Dr. Angell had no relevant conflicts of interest.
AT ATA 2017
Key clinical point:
Major finding: Relative to peers who remained euthyroid, patients who developed overt hypothyroidism had a reduced risk of death (HR, 0.56; P less than .0001).
Data source: A retrospective cohort study of 538 adult patients with mainly advanced nonthyroid cancers treated with a tyrosine kinase inhibitor.
Disclosures: Dr. Angell had no relevant conflicts of interest.
FDA approves dasatinib for pediatric Ph+ CML
(CML).
The tyrosine kinase inhibitor was approved for the treatment of newly diagnosed adult patients with chronic phase Ph+ CML in 2010.
Median follow-up was 4.5 years for newly diagnosed patients and 5.2 years for patients who were resistant to or intolerant of imatinib, the FDA reported. Because more than half of the responding patients had not progressed at the time of data cutoff, the investigators could not estimate median durations of complete cytogenetic response, major cytogenetic response, and major molecular response.
Adverse reactions to dasatinib included headache, nausea, diarrhea, skin rash, vomiting, pain in extremities, abdominal pain, fatigue, and arthralgia; these side effects were reported in approximately 10% of patients.
Dasatinib is marketed as Sprycel by Bristol-Myers Squibb.
The recommended dose of dasatinib for pediatric patients is based on their body weight. Full prescribing information is available here.
[email protected]
On Twitter @nikolaideslaura
(CML).
The tyrosine kinase inhibitor was approved for the treatment of newly diagnosed adult patients with chronic phase Ph+ CML in 2010.
Median follow-up was 4.5 years for newly diagnosed patients and 5.2 years for patients who were resistant to or intolerant of imatinib, the FDA reported. Because more than half of the responding patients had not progressed at the time of data cutoff, the investigators could not estimate median durations of complete cytogenetic response, major cytogenetic response, and major molecular response.
Adverse reactions to dasatinib included headache, nausea, diarrhea, skin rash, vomiting, pain in extremities, abdominal pain, fatigue, and arthralgia; these side effects were reported in approximately 10% of patients.
Dasatinib is marketed as Sprycel by Bristol-Myers Squibb.
The recommended dose of dasatinib for pediatric patients is based on their body weight. Full prescribing information is available here.
[email protected]
On Twitter @nikolaideslaura
(CML).
The tyrosine kinase inhibitor was approved for the treatment of newly diagnosed adult patients with chronic phase Ph+ CML in 2010.
Median follow-up was 4.5 years for newly diagnosed patients and 5.2 years for patients who were resistant to or intolerant of imatinib, the FDA reported. Because more than half of the responding patients had not progressed at the time of data cutoff, the investigators could not estimate median durations of complete cytogenetic response, major cytogenetic response, and major molecular response.
Adverse reactions to dasatinib included headache, nausea, diarrhea, skin rash, vomiting, pain in extremities, abdominal pain, fatigue, and arthralgia; these side effects were reported in approximately 10% of patients.
Dasatinib is marketed as Sprycel by Bristol-Myers Squibb.
The recommended dose of dasatinib for pediatric patients is based on their body weight. Full prescribing information is available here.
[email protected]
On Twitter @nikolaideslaura
Dasatinib approved to treat kids with CML
The US Food and Drug Administration (FDA) has expanded the approved use of dasatinib (Sprycel®).
The drug is now approved to treat children with Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia (CML) in chronic phase.
This approval was granted under priority review, and the drug received orphan designation for this indication.
The recommended starting dosage for dasatinib in pediatric patients with chronic phase, Ph+ CML is based on body weight.
The recommended dose should be administered orally once daily, and the dose should be recalculated every 3 months based on changes in body weight or more often if necessary.
For more details, see the full prescribing information.
Dasatinib is also approved by the FDA to treat adults with newly diagnosed chronic phase, Ph+ CML; chronic, accelerated, or myeloid/lymphoid blast phase Ph+ CML with resistance or intolerance to prior therapy including imatinib; and Ph+ acute lymphoblastic leukemia with resistance or intolerance to prior therapy.
Pediatric studies
The approval of dasatinib in pediatric CML patients was supported by 2 studies. Results from the phase 1 study (NCT00306202) were published in the Journal of Clinical Oncology in 2013. Phase 2 (NCT00777036) results were presented at the 2017 ASCO Annual Meeting.
There were 97 patients in the 2 studies who had chronic phase CML and received oral dasatinib—17 from phase 1 and 80 from phase 2. Fifty-one of the patients had newly diagnosed CML, and 46 patients were resistant or intolerant to previous treatment with imatinib.
Ninety-one patients received dasatinib at 60 mg/m2 once daily (maximum dose of 100 mg once daily for patients with high body surface area). Patients were treated until disease progression or unacceptable toxicity.
The median duration of treatment was 51.1 months, or 4.3 years (range, 1.9 to 99.6 months). The median follow-up was 4.5 years in the newly diagnosed patients and 5.2 years in patients who had previously received imatinib.
The efficacy endpoints were complete cytogenetic response (CCyR), major cytogenetic response (MCyR), and major molecular response (MMR).
At 12 months, the CCyR rate was 96.1% in newly diagnosed patients and 78.3% in patients who had prior treatment with imatinib. The MCyR rate was 98.0% and 89.1%, respectively. And the MMR rate was 56.9% and 39.1%, respectively.
At 24 months, the CCyR rate was 96.1% in newly diagnosed patients and 82.6% in patients who had prior treatment with imatinib. The MCyR rate was 98.0% and 89.1%, respectively. And the MMR rate was 74.5% and 52.2%, respectively.
The median durations of CCyR, MCyR and MMR could not be estimated, as more than half of the responding patients had not progressed at the time of data cut-off.
Drug-related serious adverse events were reported in 14.4% of dasatinib-treated patients. The most common adverse events (≥15%) were headache (28%), nausea (20%), diarrhea (21%), skin rash (19%), pain in extremity (19%), and abdominal pain (16%).
The US Food and Drug Administration (FDA) has expanded the approved use of dasatinib (Sprycel®).
The drug is now approved to treat children with Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia (CML) in chronic phase.
This approval was granted under priority review, and the drug received orphan designation for this indication.
The recommended starting dosage for dasatinib in pediatric patients with chronic phase, Ph+ CML is based on body weight.
The recommended dose should be administered orally once daily, and the dose should be recalculated every 3 months based on changes in body weight or more often if necessary.
For more details, see the full prescribing information.
Dasatinib is also approved by the FDA to treat adults with newly diagnosed chronic phase, Ph+ CML; chronic, accelerated, or myeloid/lymphoid blast phase Ph+ CML with resistance or intolerance to prior therapy including imatinib; and Ph+ acute lymphoblastic leukemia with resistance or intolerance to prior therapy.
Pediatric studies
The approval of dasatinib in pediatric CML patients was supported by 2 studies. Results from the phase 1 study (NCT00306202) were published in the Journal of Clinical Oncology in 2013. Phase 2 (NCT00777036) results were presented at the 2017 ASCO Annual Meeting.
There were 97 patients in the 2 studies who had chronic phase CML and received oral dasatinib—17 from phase 1 and 80 from phase 2. Fifty-one of the patients had newly diagnosed CML, and 46 patients were resistant or intolerant to previous treatment with imatinib.
Ninety-one patients received dasatinib at 60 mg/m2 once daily (maximum dose of 100 mg once daily for patients with high body surface area). Patients were treated until disease progression or unacceptable toxicity.
The median duration of treatment was 51.1 months, or 4.3 years (range, 1.9 to 99.6 months). The median follow-up was 4.5 years in the newly diagnosed patients and 5.2 years in patients who had previously received imatinib.
The efficacy endpoints were complete cytogenetic response (CCyR), major cytogenetic response (MCyR), and major molecular response (MMR).
At 12 months, the CCyR rate was 96.1% in newly diagnosed patients and 78.3% in patients who had prior treatment with imatinib. The MCyR rate was 98.0% and 89.1%, respectively. And the MMR rate was 56.9% and 39.1%, respectively.
At 24 months, the CCyR rate was 96.1% in newly diagnosed patients and 82.6% in patients who had prior treatment with imatinib. The MCyR rate was 98.0% and 89.1%, respectively. And the MMR rate was 74.5% and 52.2%, respectively.
The median durations of CCyR, MCyR and MMR could not be estimated, as more than half of the responding patients had not progressed at the time of data cut-off.
Drug-related serious adverse events were reported in 14.4% of dasatinib-treated patients. The most common adverse events (≥15%) were headache (28%), nausea (20%), diarrhea (21%), skin rash (19%), pain in extremity (19%), and abdominal pain (16%).
The US Food and Drug Administration (FDA) has expanded the approved use of dasatinib (Sprycel®).
The drug is now approved to treat children with Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia (CML) in chronic phase.
This approval was granted under priority review, and the drug received orphan designation for this indication.
The recommended starting dosage for dasatinib in pediatric patients with chronic phase, Ph+ CML is based on body weight.
The recommended dose should be administered orally once daily, and the dose should be recalculated every 3 months based on changes in body weight or more often if necessary.
For more details, see the full prescribing information.
Dasatinib is also approved by the FDA to treat adults with newly diagnosed chronic phase, Ph+ CML; chronic, accelerated, or myeloid/lymphoid blast phase Ph+ CML with resistance or intolerance to prior therapy including imatinib; and Ph+ acute lymphoblastic leukemia with resistance or intolerance to prior therapy.
Pediatric studies
The approval of dasatinib in pediatric CML patients was supported by 2 studies. Results from the phase 1 study (NCT00306202) were published in the Journal of Clinical Oncology in 2013. Phase 2 (NCT00777036) results were presented at the 2017 ASCO Annual Meeting.
There were 97 patients in the 2 studies who had chronic phase CML and received oral dasatinib—17 from phase 1 and 80 from phase 2. Fifty-one of the patients had newly diagnosed CML, and 46 patients were resistant or intolerant to previous treatment with imatinib.
Ninety-one patients received dasatinib at 60 mg/m2 once daily (maximum dose of 100 mg once daily for patients with high body surface area). Patients were treated until disease progression or unacceptable toxicity.
The median duration of treatment was 51.1 months, or 4.3 years (range, 1.9 to 99.6 months). The median follow-up was 4.5 years in the newly diagnosed patients and 5.2 years in patients who had previously received imatinib.
The efficacy endpoints were complete cytogenetic response (CCyR), major cytogenetic response (MCyR), and major molecular response (MMR).
At 12 months, the CCyR rate was 96.1% in newly diagnosed patients and 78.3% in patients who had prior treatment with imatinib. The MCyR rate was 98.0% and 89.1%, respectively. And the MMR rate was 56.9% and 39.1%, respectively.
At 24 months, the CCyR rate was 96.1% in newly diagnosed patients and 82.6% in patients who had prior treatment with imatinib. The MCyR rate was 98.0% and 89.1%, respectively. And the MMR rate was 74.5% and 52.2%, respectively.
The median durations of CCyR, MCyR and MMR could not be estimated, as more than half of the responding patients had not progressed at the time of data cut-off.
Drug-related serious adverse events were reported in 14.4% of dasatinib-treated patients. The most common adverse events (≥15%) were headache (28%), nausea (20%), diarrhea (21%), skin rash (19%), pain in extremity (19%), and abdominal pain (16%).