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Photo courtesy of EHA
MILAN—The BCL-2 inhibitor ABT-199 may be a feasible treatment option for patients with chronic lymphocyctic leukemia/small lymphocytic lymphoma (CLL/SLL), according to research presented at the 19th Congress of the European Hematology Association (EHA).
Previous results showed that ABT-199 can elicit responses in patients with CLL/SLL, but it can also induce tumor lysis syndrome (TLS).
In fact, 2 TLS-related deaths prompted the temporary suspension of enrollment in trials of ABT-199.
But now, researchers have reported that a modified dosing schedule, prophylaxis, and patient monitoring can reduce, and perhaps even eliminate, the risk of TLS.
And ABT-199 can produce solid responses, even in high-risk CLL/SLL patients.
John Seymour, MBBS, PhD, of the Peter MacCallum Cancer Center in Victoria, Australia, and his colleagues presented results observed with a TLS prophylactic regimen at the EHA Congress as abstract P868.
Dr Seymour also presented data from a phase 1 study of ABT-199 monotherapy as abstract S702. Both studies were supported by AbbVie and Genentech, the companies developing ABT-199.
Assessing the risk of TLS
To identify pre-treatment risk factors for TLS and appropriate prophylactic measures, Dr Seymour and his colleagues analyzed 77 CLL/SLL patients who were treated with ABT-199 prior to the identification of TLS (from June 2011 to March 2013).
Twenty-four of these patients had values meeting Cairo-Bishop criteria for TLS, and medical adjudication suggested 19 (25%) of them had TLS.
Comparing these patients to those who did not develop TLS, the researchers found that patients were at low risk of developing TLS if they had a nodal mass measuring less than 5 cm and an absolute lymphocyte count (ALC) less than 25,000.
Patients were at medium risk of TLS if they had a nodal mass of 5 cm to 9 cm or an ALC of at least 25,000. And patients were at high risk of TLS if they had a nodal mass of 10 cm or greater or a nodal mass of 5 cm to 9 cm and an ALC of 25,000 or greater.
Dose modification
The researchers also found that TLS events tended to occur within 24 hours of the first dose of ABT-199. And the initial exposure (median Cmax value) for patients who had a TLS incident was higher than patients without TLS (0.49 μg/mL vs 0.23 μg/mL).
However, simulations suggested that, at a 20 mg starting dose, 98% of patients will achieve initial peak exposures similar to patients without TLS (Cmax below 0.23 ug/mL).
So the researchers modified the dosing schedule of ABT-199 in subsequently treated patients. The patients received a 20 mg starting dose, then 50 mg for the rest of week 1, 100 mg in week 2, 200 mg in week 3, and 400 mg in week 4.
However, if 1 or more electrolytes met Cairo-Bishop criteria and/or there was a 30% or greater decrease in ALC with the first dose, patients received the drug at 20 mg in week 1, 50 mg in week 2, 100 mg in week 3, 200 mg in week 4, and 400 mg in week 5.
Prophylactic measures
Dr Seymour and his colleagues also recommended several other steps to minimize the risk of TLS. They said their findings support hospitalizing and monitoring patients for the first dose of 20 mg and 50 mg, regardless of their risk of TLS.
High-risk patients should be hospitalized for all subsequent dose escalations until they are re-categorized to medium- or low-risk groups. The researchers also said hospitalization should be considered at subsequent dose escalation for medium-risk patients with creatinine clearance of 80 mL/min or less.
All patients should receive oral hydration prior to receiving ABT-199, and hospitalized patients should receive intravenous hydration (150-200 cc/hour, as tolerated).
All patients should receive a uric-acid-reducing agent at least 72 hours before their first dose of ABT-199. Rasburicase is strongly suggested for high-risk patients with high baseline uric acid and for patients who develop rapid rises in uric acid values.
The researchers also recommended laboratory assessment at 8 hours and 24 hours in an outpatient setting and at 4, 8, 12, and 24 hours in hospitalized patients.
Approach reduces TLS risk
Lastly, Dr Seymour and his colleagues analyzed the effect of the modified dosing schedule and the aforementioned prophylactic measures on a cohort of 58 CLL/SLL patients treated with ABT-199.
The TLS risk stratification was similar in this cohort and the pre-modification cohort of 77 patients. There was, however, a higher proportion of patients in the post-modification cohort who fell into the high-risk category.
According to Cairo-Bishop criteria, 3 patients (3.9%) had clinical TLS in the pre-modification cohort and 16 (20.8%) had laboratory TLS. In the post-modification cohort, none of the patients had clinical TLS, and 8 (13.8%) had laboratory TLS.
According to the Howard definition of TLS, 3 patients (3.9%) in the pre-modification cohort had clinical TLS, and 7 (9.1%) had laboratory TLS. But none of the patients in the post-modification cohort had clinical or laboratory TLS.
Phase 1 trial of ABT-199 monotherapy
In another presentation at the EHA Congress, Dr Seymour reported results from a phase 1 study of ABT-199 monotherapy in 105 patients with high-risk CLL/SLL.
Following the identification of TLS, patients received treatment according to the modified schedule, as well as TLS prophylaxis.
In all, 7 patients developed TLS. One of these patients died, and 1 required dialysis. As of April 9, 2014, there were no cases of TLS among the 49 patients who received ABT-199 according to the modified dosing schedule, as well as TLS prophylaxis.
Other common treatment-emergent adverse events included diarrhea (40%), neutropenia (36%), and nausea (35%). Grade 3/4 neutropenia occurred in 33% of patients, and febrile neutropenia occurred in 4%.
Thirty-seven patients discontinued treatment—22 due to progressive disease, 12 due to adverse events, and 3 for other reasons (1 required warfarin, and 2 proceeded to transplant).
Seventy-eight patients were evaluable for treatment response. Nineteen of these patients had del (17p), 41 were fludarabine-refractory, and 24 had unmutated IGHV.
The response rate was 77% overall, 79% among patients with del (17p), 76% in those who were fludarabine-refractory, and 75% in those with unmutated IGHV. The complete response rates were 23% 26%, 22%, and 29%, respectively.
As of April 9, the median progression-free survival was about 18 months. The median progression-free survival had not been reached for patients treated at or above 400 mg. 
Photo courtesy of EHA
MILAN—The BCL-2 inhibitor ABT-199 may be a feasible treatment option for patients with chronic lymphocyctic leukemia/small lymphocytic lymphoma (CLL/SLL), according to research presented at the 19th Congress of the European Hematology Association (EHA).
Previous results showed that ABT-199 can elicit responses in patients with CLL/SLL, but it can also induce tumor lysis syndrome (TLS).
In fact, 2 TLS-related deaths prompted the temporary suspension of enrollment in trials of ABT-199.
But now, researchers have reported that a modified dosing schedule, prophylaxis, and patient monitoring can reduce, and perhaps even eliminate, the risk of TLS.
And ABT-199 can produce solid responses, even in high-risk CLL/SLL patients.
John Seymour, MBBS, PhD, of the Peter MacCallum Cancer Center in Victoria, Australia, and his colleagues presented results observed with a TLS prophylactic regimen at the EHA Congress as abstract P868.
Dr Seymour also presented data from a phase 1 study of ABT-199 monotherapy as abstract S702. Both studies were supported by AbbVie and Genentech, the companies developing ABT-199.
Assessing the risk of TLS
To identify pre-treatment risk factors for TLS and appropriate prophylactic measures, Dr Seymour and his colleagues analyzed 77 CLL/SLL patients who were treated with ABT-199 prior to the identification of TLS (from June 2011 to March 2013).
Twenty-four of these patients had values meeting Cairo-Bishop criteria for TLS, and medical adjudication suggested 19 (25%) of them had TLS.
Comparing these patients to those who did not develop TLS, the researchers found that patients were at low risk of developing TLS if they had a nodal mass measuring less than 5 cm and an absolute lymphocyte count (ALC) less than 25,000.
Patients were at medium risk of TLS if they had a nodal mass of 5 cm to 9 cm or an ALC of at least 25,000. And patients were at high risk of TLS if they had a nodal mass of 10 cm or greater or a nodal mass of 5 cm to 9 cm and an ALC of 25,000 or greater.
Dose modification
The researchers also found that TLS events tended to occur within 24 hours of the first dose of ABT-199. And the initial exposure (median Cmax value) for patients who had a TLS incident was higher than patients without TLS (0.49 μg/mL vs 0.23 μg/mL).
However, simulations suggested that, at a 20 mg starting dose, 98% of patients will achieve initial peak exposures similar to patients without TLS (Cmax below 0.23 ug/mL).
So the researchers modified the dosing schedule of ABT-199 in subsequently treated patients. The patients received a 20 mg starting dose, then 50 mg for the rest of week 1, 100 mg in week 2, 200 mg in week 3, and 400 mg in week 4.
However, if 1 or more electrolytes met Cairo-Bishop criteria and/or there was a 30% or greater decrease in ALC with the first dose, patients received the drug at 20 mg in week 1, 50 mg in week 2, 100 mg in week 3, 200 mg in week 4, and 400 mg in week 5.
Prophylactic measures
Dr Seymour and his colleagues also recommended several other steps to minimize the risk of TLS. They said their findings support hospitalizing and monitoring patients for the first dose of 20 mg and 50 mg, regardless of their risk of TLS.
High-risk patients should be hospitalized for all subsequent dose escalations until they are re-categorized to medium- or low-risk groups. The researchers also said hospitalization should be considered at subsequent dose escalation for medium-risk patients with creatinine clearance of 80 mL/min or less.
All patients should receive oral hydration prior to receiving ABT-199, and hospitalized patients should receive intravenous hydration (150-200 cc/hour, as tolerated).
All patients should receive a uric-acid-reducing agent at least 72 hours before their first dose of ABT-199. Rasburicase is strongly suggested for high-risk patients with high baseline uric acid and for patients who develop rapid rises in uric acid values.
The researchers also recommended laboratory assessment at 8 hours and 24 hours in an outpatient setting and at 4, 8, 12, and 24 hours in hospitalized patients.
Approach reduces TLS risk
Lastly, Dr Seymour and his colleagues analyzed the effect of the modified dosing schedule and the aforementioned prophylactic measures on a cohort of 58 CLL/SLL patients treated with ABT-199.
The TLS risk stratification was similar in this cohort and the pre-modification cohort of 77 patients. There was, however, a higher proportion of patients in the post-modification cohort who fell into the high-risk category.
According to Cairo-Bishop criteria, 3 patients (3.9%) had clinical TLS in the pre-modification cohort and 16 (20.8%) had laboratory TLS. In the post-modification cohort, none of the patients had clinical TLS, and 8 (13.8%) had laboratory TLS.
According to the Howard definition of TLS, 3 patients (3.9%) in the pre-modification cohort had clinical TLS, and 7 (9.1%) had laboratory TLS. But none of the patients in the post-modification cohort had clinical or laboratory TLS.
Phase 1 trial of ABT-199 monotherapy
In another presentation at the EHA Congress, Dr Seymour reported results from a phase 1 study of ABT-199 monotherapy in 105 patients with high-risk CLL/SLL.
Following the identification of TLS, patients received treatment according to the modified schedule, as well as TLS prophylaxis.
In all, 7 patients developed TLS. One of these patients died, and 1 required dialysis. As of April 9, 2014, there were no cases of TLS among the 49 patients who received ABT-199 according to the modified dosing schedule, as well as TLS prophylaxis.
Other common treatment-emergent adverse events included diarrhea (40%), neutropenia (36%), and nausea (35%). Grade 3/4 neutropenia occurred in 33% of patients, and febrile neutropenia occurred in 4%.
Thirty-seven patients discontinued treatment—22 due to progressive disease, 12 due to adverse events, and 3 for other reasons (1 required warfarin, and 2 proceeded to transplant).
Seventy-eight patients were evaluable for treatment response. Nineteen of these patients had del (17p), 41 were fludarabine-refractory, and 24 had unmutated IGHV.
The response rate was 77% overall, 79% among patients with del (17p), 76% in those who were fludarabine-refractory, and 75% in those with unmutated IGHV. The complete response rates were 23% 26%, 22%, and 29%, respectively.
As of April 9, the median progression-free survival was about 18 months. The median progression-free survival had not been reached for patients treated at or above 400 mg.
Photo courtesy of EHA
MILAN—The BCL-2 inhibitor ABT-199 may be a feasible treatment option for patients with chronic lymphocyctic leukemia/small lymphocytic lymphoma (CLL/SLL), according to research presented at the 19th Congress of the European Hematology Association (EHA).
Previous results showed that ABT-199 can elicit responses in patients with CLL/SLL, but it can also induce tumor lysis syndrome (TLS).
In fact, 2 TLS-related deaths prompted the temporary suspension of enrollment in trials of ABT-199.
But now, researchers have reported that a modified dosing schedule, prophylaxis, and patient monitoring can reduce, and perhaps even eliminate, the risk of TLS.
And ABT-199 can produce solid responses, even in high-risk CLL/SLL patients.
John Seymour, MBBS, PhD, of the Peter MacCallum Cancer Center in Victoria, Australia, and his colleagues presented results observed with a TLS prophylactic regimen at the EHA Congress as abstract P868.
Dr Seymour also presented data from a phase 1 study of ABT-199 monotherapy as abstract S702. Both studies were supported by AbbVie and Genentech, the companies developing ABT-199.
Assessing the risk of TLS
To identify pre-treatment risk factors for TLS and appropriate prophylactic measures, Dr Seymour and his colleagues analyzed 77 CLL/SLL patients who were treated with ABT-199 prior to the identification of TLS (from June 2011 to March 2013).
Twenty-four of these patients had values meeting Cairo-Bishop criteria for TLS, and medical adjudication suggested 19 (25%) of them had TLS.
Comparing these patients to those who did not develop TLS, the researchers found that patients were at low risk of developing TLS if they had a nodal mass measuring less than 5 cm and an absolute lymphocyte count (ALC) less than 25,000.
Patients were at medium risk of TLS if they had a nodal mass of 5 cm to 9 cm or an ALC of at least 25,000. And patients were at high risk of TLS if they had a nodal mass of 10 cm or greater or a nodal mass of 5 cm to 9 cm and an ALC of 25,000 or greater.
Dose modification
The researchers also found that TLS events tended to occur within 24 hours of the first dose of ABT-199. And the initial exposure (median Cmax value) for patients who had a TLS incident was higher than patients without TLS (0.49 μg/mL vs 0.23 μg/mL).
However, simulations suggested that, at a 20 mg starting dose, 98% of patients will achieve initial peak exposures similar to patients without TLS (Cmax below 0.23 ug/mL).
So the researchers modified the dosing schedule of ABT-199 in subsequently treated patients. The patients received a 20 mg starting dose, then 50 mg for the rest of week 1, 100 mg in week 2, 200 mg in week 3, and 400 mg in week 4.
However, if 1 or more electrolytes met Cairo-Bishop criteria and/or there was a 30% or greater decrease in ALC with the first dose, patients received the drug at 20 mg in week 1, 50 mg in week 2, 100 mg in week 3, 200 mg in week 4, and 400 mg in week 5.
Prophylactic measures
Dr Seymour and his colleagues also recommended several other steps to minimize the risk of TLS. They said their findings support hospitalizing and monitoring patients for the first dose of 20 mg and 50 mg, regardless of their risk of TLS.
High-risk patients should be hospitalized for all subsequent dose escalations until they are re-categorized to medium- or low-risk groups. The researchers also said hospitalization should be considered at subsequent dose escalation for medium-risk patients with creatinine clearance of 80 mL/min or less.
All patients should receive oral hydration prior to receiving ABT-199, and hospitalized patients should receive intravenous hydration (150-200 cc/hour, as tolerated).
All patients should receive a uric-acid-reducing agent at least 72 hours before their first dose of ABT-199. Rasburicase is strongly suggested for high-risk patients with high baseline uric acid and for patients who develop rapid rises in uric acid values.
The researchers also recommended laboratory assessment at 8 hours and 24 hours in an outpatient setting and at 4, 8, 12, and 24 hours in hospitalized patients.
Approach reduces TLS risk
Lastly, Dr Seymour and his colleagues analyzed the effect of the modified dosing schedule and the aforementioned prophylactic measures on a cohort of 58 CLL/SLL patients treated with ABT-199.
The TLS risk stratification was similar in this cohort and the pre-modification cohort of 77 patients. There was, however, a higher proportion of patients in the post-modification cohort who fell into the high-risk category.
According to Cairo-Bishop criteria, 3 patients (3.9%) had clinical TLS in the pre-modification cohort and 16 (20.8%) had laboratory TLS. In the post-modification cohort, none of the patients had clinical TLS, and 8 (13.8%) had laboratory TLS.
According to the Howard definition of TLS, 3 patients (3.9%) in the pre-modification cohort had clinical TLS, and 7 (9.1%) had laboratory TLS. But none of the patients in the post-modification cohort had clinical or laboratory TLS.
Phase 1 trial of ABT-199 monotherapy
In another presentation at the EHA Congress, Dr Seymour reported results from a phase 1 study of ABT-199 monotherapy in 105 patients with high-risk CLL/SLL.
Following the identification of TLS, patients received treatment according to the modified schedule, as well as TLS prophylaxis.
In all, 7 patients developed TLS. One of these patients died, and 1 required dialysis. As of April 9, 2014, there were no cases of TLS among the 49 patients who received ABT-199 according to the modified dosing schedule, as well as TLS prophylaxis.
Other common treatment-emergent adverse events included diarrhea (40%), neutropenia (36%), and nausea (35%). Grade 3/4 neutropenia occurred in 33% of patients, and febrile neutropenia occurred in 4%.
Thirty-seven patients discontinued treatment—22 due to progressive disease, 12 due to adverse events, and 3 for other reasons (1 required warfarin, and 2 proceeded to transplant).
Seventy-eight patients were evaluable for treatment response. Nineteen of these patients had del (17p), 41 were fludarabine-refractory, and 24 had unmutated IGHV.
The response rate was 77% overall, 79% among patients with del (17p), 76% in those who were fludarabine-refractory, and 75% in those with unmutated IGHV. The complete response rates were 23% 26%, 22%, and 29%, respectively.
As of April 9, the median progression-free survival was about 18 months. The median progression-free survival had not been reached for patients treated at or above 400 mg.