ASH 2012

ATLANTA – Cytotoxic chemotherapy is not needed to achieve excellent results in the first-line treatment of acute promyelocytic leukemia, a most aggressive form of acute leukemia.

A phase III trial achieved a 2-year event-free survival rate of 86.7% with all-trans retinoic acid (ATRA) and chemotherapy, the current standard, and 97% with ATRA plus arsenic trioxide (ATO), a small-molecule arsenic compound (P = .03).

The new chemotherapy-free regimen represents "the demolition of a dogma" by showing that cancer is not an irreversible condition and that malignant cells can be transformed rather than killed with chemotherapy, Dr. Francesco Lo-Coco said at a press briefing during the annual meeting of the American Society of Hematology.

ASH president Armand Keating said that the groundbreaking study highlights novel approaches – in this case a targeted combination with roots in ancient Chinese medicine – that can produce comparable efficacy with far less toxicity than chemotherapy.

"This, I think, is an exciting development because it is a shift in the way we think of treating potentially fatal diseases, quite remarkable," Dr. Keating said during a teleconference with reporters.

He pointed out that, 30-40 years ago, before ATRA and chemotherapy transformed the treatment of acute promyelocytic leukemia (APL), mortality was 100%, with most patients dying within a week.

ATRA and cytotoxic chemotherapy, typically containing anthracyclines, produce remission rates of 85%-90% in APL, but early death and relapse among high-risk groups such as the elderly remain problematic in the management of APL.

"I found this study amazing, frankly. ... This [disease] used to be the worst of the worst," ASH Secretary Charles Abrahms said during the teleconference.

Both men remarked that the results will spur further research to elucidate how ATO works, not just in APL but in other diseases.

The current trial is the first randomized, prospective phase III trial to compare ATRA plus ATO against the standard of care, although earlier phase II trials have reported encouraging responses to ATO in combination with other drugs.

As for how the combination works, the altered protein present in APL has specific binding sites for ATO and ATRA, explained Dr. Lo-Coco of the University of Tor Vergata, Rome. ATRA, a derivative developed from Chinese herbal medicine, is thought to induce leukemia cell differentiation, whereas ATO, well known for its activity in treating relapsed APL, produces remissions at least in part by inducing apoptosis.

Dr. Lo-Coco and his coinvestigators in Italy and Germany enrolled 162 patients with newly diagnosed, non–high-risk APL; the median age was 45 years (range 18-70) and the median white blood cell count was 1.50 × 10⁹/L.

Patients in the experimental arm received arsenic trioxide 0.15/kg plus oral ATRA 45 mg/m² daily until complete remission, then ATO given 5 days per week, 4 weeks on and 4 weeks off, for a total of four courses and ATRA given 2 weeks on and 2 weeks off for a total of seven courses. Patients in the control arm received standard ATRA plus 12 mg/m² idarubicin as induction, followed by three cycles of anthracycline-based chemotherapy plus ATRA consolidation and maintenance with low-dose chemotherapy and ATRA.

Of the 154 patients evaluable for response to induction, all 75 patients in the experimental arm and 75 of 79 in the control arm achieved complete remission, Dr. Lo-Coco reported in the plenary session.

Molecular complete remission per central review was seen in 141 of 142 evaluable patients after completing the third round of consolidation therapy.

After a median follow-up of 31 months, overall survival was 98.7% with ATRA plus ATO and 91.1% with ATRA plus chemotherapy (P = .02), he said.

Patients receiving ATRA and chemotherapy had significantly more episodes of fever lasting more than 15 days and grade 3 or higher neutropenia and thrombocytopenia than those receiving ATRA and ATO (P less than .001 for all differences).

The ATRA/ATO combination, however, induced QTc prolongation in two patients, requiring ATO discontinuation and study withdrawal for one of them, Dr. Lo-Coco reported.

Rates of APL differentiation syndrome and increased liver enzymes were similar in both groups. There was one death and two relapses in the experimental arm vs. seven deaths and four relapses in the control arm.

The success achieved with ATRA and ATO therapy is likely to raise new questions regarding use of ATO monotherapy in the first-line treatment of APL. The first study to take this approach reported a complete remission rate of 86% in treatment-naive patients (J. Clin. Oncol. 2011;29:2753-7), but the phase II study conducted in Iran prompted a backlash of criticism that it violated medical ethics by failing to provide standard treatment. An accompanying editorial, however, pointed out that treatment with ATRA, anthracyclines, and cytarabine is often "prohibitively expensive in the developing world" (J. Clin. Oncol. 2011;29:2743-6)

A more recent Chinese study pointed to benefits with single-agent ATO in the hard-to-treat elderly, with 88% of patients, aged 60 years or older, achieving a complete remission. The 10-year cumulative incidence of relapse was 10.3% after a median follow-up of 99 months, during which time no patient died of ATO-related toxicities (Cancer 2013;119:115-25).

Dr. Lo-Coco reported serving on the board of directors or advisory committees for Boehringer Ingelheim and as a speaker for Cephalon, the maker of Trisenox (arsenic trioxide). His coauthors reported relationships with several pharmaceutical firms.

[email protected]

ATLANTA – Cytotoxic chemotherapy is not needed to achieve excellent results in the first-line treatment of acute promyelocytic leukemia, a most aggressive form of acute leukemia.

A phase III trial achieved a 2-year event-free survival rate of 86.7% with all-trans retinoic acid (ATRA) and chemotherapy, the current standard, and 97% with ATRA plus arsenic trioxide (ATO), a small-molecule arsenic compound (P = .03).

The new chemotherapy-free regimen represents "the demolition of a dogma" by showing that cancer is not an irreversible condition and that malignant cells can be transformed rather than killed with chemotherapy, Dr. Francesco Lo-Coco said at a press briefing during the annual meeting of the American Society of Hematology.

ASH president Armand Keating said that the groundbreaking study highlights novel approaches – in this case a targeted combination with roots in ancient Chinese medicine – that can produce comparable efficacy with far less toxicity than chemotherapy.

"This, I think, is an exciting development because it is a shift in the way we think of treating potentially fatal diseases, quite remarkable," Dr. Keating said during a teleconference with reporters.

He pointed out that, 30-40 years ago, before ATRA and chemotherapy transformed the treatment of acute promyelocytic leukemia (APL), mortality was 100%, with most patients dying within a week.

ATRA and cytotoxic chemotherapy, typically containing anthracyclines, produce remission rates of 85%-90% in APL, but early death and relapse among high-risk groups such as the elderly remain problematic in the management of APL.

"I found this study amazing, frankly. ... This [disease] used to be the worst of the worst," ASH Secretary Charles Abrahms said during the teleconference.

Both men remarked that the results will spur further research to elucidate how ATO works, not just in APL but in other diseases.

The current trial is the first randomized, prospective phase III trial to compare ATRA plus ATO against the standard of care, although earlier phase II trials have reported encouraging responses to ATO in combination with other drugs.

As for how the combination works, the altered protein present in APL has specific binding sites for ATO and ATRA, explained Dr. Lo-Coco of the University of Tor Vergata, Rome. ATRA, a derivative developed from Chinese herbal medicine, is thought to induce leukemia cell differentiation, whereas ATO, well known for its activity in treating relapsed APL, produces remissions at least in part by inducing apoptosis.

Dr. Lo-Coco and his coinvestigators in Italy and Germany enrolled 162 patients with newly diagnosed, non–high-risk APL; the median age was 45 years (range 18-70) and the median white blood cell count was 1.50 × 10⁹/L.

Patients in the experimental arm received arsenic trioxide 0.15/kg plus oral ATRA 45 mg/m² daily until complete remission, then ATO given 5 days per week, 4 weeks on and 4 weeks off, for a total of four courses and ATRA given 2 weeks on and 2 weeks off for a total of seven courses. Patients in the control arm received standard ATRA plus 12 mg/m² idarubicin as induction, followed by three cycles of anthracycline-based chemotherapy plus ATRA consolidation and maintenance with low-dose chemotherapy and ATRA.

Of the 154 patients evaluable for response to induction, all 75 patients in the experimental arm and 75 of 79 in the control arm achieved complete remission, Dr. Lo-Coco reported in the plenary session.

Molecular complete remission per central review was seen in 141 of 142 evaluable patients after completing the third round of consolidation therapy.

After a median follow-up of 31 months, overall survival was 98.7% with ATRA plus ATO and 91.1% with ATRA plus chemotherapy (P = .02), he said.

Patients receiving ATRA and chemotherapy had significantly more episodes of fever lasting more than 15 days and grade 3 or higher neutropenia and thrombocytopenia than those receiving ATRA and ATO (P less than .001 for all differences).

The ATRA/ATO combination, however, induced QTc prolongation in two patients, requiring ATO discontinuation and study withdrawal for one of them, Dr. Lo-Coco reported.

Rates of APL differentiation syndrome and increased liver enzymes were similar in both groups. There was one death and two relapses in the experimental arm vs. seven deaths and four relapses in the control arm.

The success achieved with ATRA and ATO therapy is likely to raise new questions regarding use of ATO monotherapy in the first-line treatment of APL. The first study to take this approach reported a complete remission rate of 86% in treatment-naive patients (J. Clin. Oncol. 2011;29:2753-7), but the phase II study conducted in Iran prompted a backlash of criticism that it violated medical ethics by failing to provide standard treatment. An accompanying editorial, however, pointed out that treatment with ATRA, anthracyclines, and cytarabine is often "prohibitively expensive in the developing world" (J. Clin. Oncol. 2011;29:2743-6)

A more recent Chinese study pointed to benefits with single-agent ATO in the hard-to-treat elderly, with 88% of patients, aged 60 years or older, achieving a complete remission. The 10-year cumulative incidence of relapse was 10.3% after a median follow-up of 99 months, during which time no patient died of ATO-related toxicities (Cancer 2013;119:115-25).

Dr. Lo-Coco reported serving on the board of directors or advisory committees for Boehringer Ingelheim and as a speaker for Cephalon, the maker of Trisenox (arsenic trioxide). His coauthors reported relationships with several pharmaceutical firms.

[email protected]

ATLANTA – Cytotoxic chemotherapy is not needed to achieve excellent results in the first-line treatment of acute promyelocytic leukemia, a most aggressive form of acute leukemia.

A phase III trial achieved a 2-year event-free survival rate of 86.7% with all-trans retinoic acid (ATRA) and chemotherapy, the current standard, and 97% with ATRA plus arsenic trioxide (ATO), a small-molecule arsenic compound (P = .03).

The new chemotherapy-free regimen represents "the demolition of a dogma" by showing that cancer is not an irreversible condition and that malignant cells can be transformed rather than killed with chemotherapy, Dr. Francesco Lo-Coco said at a press briefing during the annual meeting of the American Society of Hematology.

ASH president Armand Keating said that the groundbreaking study highlights novel approaches – in this case a targeted combination with roots in ancient Chinese medicine – that can produce comparable efficacy with far less toxicity than chemotherapy.

"This, I think, is an exciting development because it is a shift in the way we think of treating potentially fatal diseases, quite remarkable," Dr. Keating said during a teleconference with reporters.

He pointed out that, 30-40 years ago, before ATRA and chemotherapy transformed the treatment of acute promyelocytic leukemia (APL), mortality was 100%, with most patients dying within a week.

ATRA and cytotoxic chemotherapy, typically containing anthracyclines, produce remission rates of 85%-90% in APL, but early death and relapse among high-risk groups such as the elderly remain problematic in the management of APL.

"I found this study amazing, frankly. ... This [disease] used to be the worst of the worst," ASH Secretary Charles Abrahms said during the teleconference.

Both men remarked that the results will spur further research to elucidate how ATO works, not just in APL but in other diseases.

The current trial is the first randomized, prospective phase III trial to compare ATRA plus ATO against the standard of care, although earlier phase II trials have reported encouraging responses to ATO in combination with other drugs.

As for how the combination works, the altered protein present in APL has specific binding sites for ATO and ATRA, explained Dr. Lo-Coco of the University of Tor Vergata, Rome. ATRA, a derivative developed from Chinese herbal medicine, is thought to induce leukemia cell differentiation, whereas ATO, well known for its activity in treating relapsed APL, produces remissions at least in part by inducing apoptosis.

Dr. Lo-Coco and his coinvestigators in Italy and Germany enrolled 162 patients with newly diagnosed, non–high-risk APL; the median age was 45 years (range 18-70) and the median white blood cell count was 1.50 × 10⁹/L.

Patients in the experimental arm received arsenic trioxide 0.15/kg plus oral ATRA 45 mg/m² daily until complete remission, then ATO given 5 days per week, 4 weeks on and 4 weeks off, for a total of four courses and ATRA given 2 weeks on and 2 weeks off for a total of seven courses. Patients in the control arm received standard ATRA plus 12 mg/m² idarubicin as induction, followed by three cycles of anthracycline-based chemotherapy plus ATRA consolidation and maintenance with low-dose chemotherapy and ATRA.

Of the 154 patients evaluable for response to induction, all 75 patients in the experimental arm and 75 of 79 in the control arm achieved complete remission, Dr. Lo-Coco reported in the plenary session.

Molecular complete remission per central review was seen in 141 of 142 evaluable patients after completing the third round of consolidation therapy.

After a median follow-up of 31 months, overall survival was 98.7% with ATRA plus ATO and 91.1% with ATRA plus chemotherapy (P = .02), he said.

Patients receiving ATRA and chemotherapy had significantly more episodes of fever lasting more than 15 days and grade 3 or higher neutropenia and thrombocytopenia than those receiving ATRA and ATO (P less than .001 for all differences).

The ATRA/ATO combination, however, induced QTc prolongation in two patients, requiring ATO discontinuation and study withdrawal for one of them, Dr. Lo-Coco reported.

Rates of APL differentiation syndrome and increased liver enzymes were similar in both groups. There was one death and two relapses in the experimental arm vs. seven deaths and four relapses in the control arm.

The success achieved with ATRA and ATO therapy is likely to raise new questions regarding use of ATO monotherapy in the first-line treatment of APL. The first study to take this approach reported a complete remission rate of 86% in treatment-naive patients (J. Clin. Oncol. 2011;29:2753-7), but the phase II study conducted in Iran prompted a backlash of criticism that it violated medical ethics by failing to provide standard treatment. An accompanying editorial, however, pointed out that treatment with ATRA, anthracyclines, and cytarabine is often "prohibitively expensive in the developing world" (J. Clin. Oncol. 2011;29:2743-6)

A more recent Chinese study pointed to benefits with single-agent ATO in the hard-to-treat elderly, with 88% of patients, aged 60 years or older, achieving a complete remission. The 10-year cumulative incidence of relapse was 10.3% after a median follow-up of 99 months, during which time no patient died of ATO-related toxicities (Cancer 2013;119:115-25).

Dr. Lo-Coco reported serving on the board of directors or advisory committees for Boehringer Ingelheim and as a speaker for Cephalon, the maker of Trisenox (arsenic trioxide). His coauthors reported relationships with several pharmaceutical firms.

[email protected]

ATLANTA – The experimental drug ARRY-520, the first kinesin spindle protein inhibitor in multiple myeloma, prompted responses in nearly one-fourth of heavily pretreated and triple-refractory patients in a phase II study.

The overall response rate to single-agent ARRY-520 was 16% in patients with a median of six prior regimens. It reached 22% when combined with dexamethasone in patients with a median of 10 prior regimens – all but one of whom was refractory to lenalidomide (Revlimid), bortezomib (Velcade), and dexamethasone (Decadron), Dr. Jatin Shah reported at the annual meeting of the American Society of Hematology.

Kinesin spindle protein (KSP) is a microtubule motor protein required for mitosis and separation of the mitotic spindle pole into a bipolar spindle pole. Inhibition of KSP prevents formation of the bipolar spindle, leading to cell death. Preclinical work shows that ARRY-520 also down-regulates myeloid cell leukemia-1 levels, a mechanism for dexamethasone resistance.

Patrice Wendling/IMNG Medical Media

The investigators also identified a potential biomarker called alpha 1-acid glycoprotein (AAG) that may predict how well patients respond to ARRY-520.

Selecting patients by AAG serum results increased the response rate to 33% in the combination group, a population with an unmet clinical need, said Dr. Shah of the University of Texas M.D. Anderson Cancer Center in Houston.

"The assay isn’t a fancy test; it can be done actually at any commercial lab," he said in an interview. "The key is to validate that the labs are doing the assay in the same way."

Duration of response noted

Dr. Antonio Palumbo, chief of the myeloma unit at the University Hospital of Torino, Italy, who comoderated the session, said in an interview that ARRY-520 is "certainly an exciting new agent" in multiple myeloma, given its novel therapeutic target, partial responses of 20%-30% in such advanced disease and a potential biomarker.

"I think the biomarker was important and probably also the durability because this type of drug may have a major role in durability, more than on response," he said.

Median duration of response was 8.6 months with ARRY-520 monotherapy (range 1.4-20 months) and 5.4 months with combination therapy (2.5-9 months).

Dr. Angela Dispenzieri, hematologist and professor of medicine at Mayo Clinic, Rochester, Minn., and a member of the meeting’s scientific committee, was more effusive in her assessment of the results.

"Actually, I think it’s the best thing so far at ASH," she said after the session on the penultimate day of the meeting. "It’s novel.

"This is a new class and it actually has single-agent activity. That’s the beginning and that is very important. I was really impressed, and I’m really cynical."

Both Dr. Dispenzieri and Dr. Palumbo said results should be better if ARRY-520 is combined with other agents such as bortezomib, proteasome inhibitors or immunomodulatory drugs (IMiDs).

Preliminary results reported in a poster at the meeting show that one of six evaluable patients achieved a near complete response and four had stable disease after completing at least one cycle of ARRY-520 plus the proteasome inhibitor carfilzomib (Kyprolis), Dr. Shah reported.

Patrice Wendling/IMNG Medical Media

"We’re already starting to see a signal there, and we’re going to go with IMiDs next," he said.

A phase Ib combination trial with bortezomib is also underway.

Fifty patients in two cohorts

The current phase II study included 32 patients who received single-agent ARRY-520 at 1.5 mg/m² on days 1 and 2 every 2 weeks and 18 patients who also received low-dose dexamethasone 40 mg once weekly. Both groups received granulocyte–colony stimulating factor support.

The first cohort had relapsed and/or refractory multiple myeloma after receiving at least two prior rounds of therapy (range 2-19) that included bortezomib and an IMiD. Roughly half were bortezomib refractory (53%) and 41% were triple refractory.

Cohort two had also received at least two prior regimens (range 5-13), but progressed during or within 60 days of their last regimen, was refractory to lenalidomide, bortezomib, and dexamethasone (except one dexamethasone-refractory patient) and had received adequate prior alkylator therapy. High-risk cytogenetics were present in 17% vs. 9% of cohort one.

In cohort one, there were 5 partial responses, 6 minor plus partial responses, and 14 cases of stable disease, Dr. Shah said. The median time to response was 4.4 months and median progression-free survival was 3.7 months. The cohort had very durable responses at a median of 8.6 months (range 1.4-20 months), and an overall survival of 19 months, he said.

In cohort two, there were 4 partial responses, 6 minimal plus partial responses and 5 patients with stable disease. The median time on treatment about doubled from 2.1 in cohort one to 3.9 months, with a shorter time to response of 3.4 months. The median duration of response was shorter at 5.4 months, "but again this was a very different patient population," Dr. Shah said.

An analysis of baseline AAG levels in 45 patients revealed that patients with low AAG remained on study longer than did those with high AAG in both cohort one (3.4 months vs. 1.7 months) and cohort two (6.2 months vs. 1.6 months). Moreover, 24% of low-AAG patients on monotherapy and 22% on combination therapy achieved at least a partial response, whereas no patient with high AAG levels did so.

In vitro work has shown that increasing levels of AAG result in increased half maximal inhibitory concentration (IC₅₀) of ARRY-520, suggesting that patients with elevated AAG may have subtherapeutic exposure to the drug, Dr. Shah explained. AAG does not bind to other standard multiple myeloma agents on the market, and is not correlated with prognostic markers in myeloma.

Nonhematologic adverse events were very low, including one case each of grade 4 fatigue and hypokalemia, and two cases of grade 4 pneumonia.

As expected from the biology of the drug, grade 3/4 hematologic events were more common, but generally reversible and not observed to be cumulative out to 3 years of therapy, Dr. Shah said. Grade 4 neutropenia, thrombocytopenia, and anemia were present in 28%, 25%, and 6% of patients in cohort one and in 38%, 19% and 5% of cohort two, respectively. Febrile neutropenia was grade 3 only, and reported in just one patient in each group, he noted.

Dr. Shah and coauthors reported relationships with study sponsor Array BioPharma, which is developing ARRY-520. Dr. Palumbo disclosed relationships with other companies.

ATLANTA – The experimental drug ARRY-520, the first kinesin spindle protein inhibitor in multiple myeloma, prompted responses in nearly one-fourth of heavily pretreated and triple-refractory patients in a phase II study.

The overall response rate to single-agent ARRY-520 was 16% in patients with a median of six prior regimens. It reached 22% when combined with dexamethasone in patients with a median of 10 prior regimens – all but one of whom was refractory to lenalidomide (Revlimid), bortezomib (Velcade), and dexamethasone (Decadron), Dr. Jatin Shah reported at the annual meeting of the American Society of Hematology.

Kinesin spindle protein (KSP) is a microtubule motor protein required for mitosis and separation of the mitotic spindle pole into a bipolar spindle pole. Inhibition of KSP prevents formation of the bipolar spindle, leading to cell death. Preclinical work shows that ARRY-520 also down-regulates myeloid cell leukemia-1 levels, a mechanism for dexamethasone resistance.

Patrice Wendling/IMNG Medical Media

The investigators also identified a potential biomarker called alpha 1-acid glycoprotein (AAG) that may predict how well patients respond to ARRY-520.

Selecting patients by AAG serum results increased the response rate to 33% in the combination group, a population with an unmet clinical need, said Dr. Shah of the University of Texas M.D. Anderson Cancer Center in Houston.

"The assay isn’t a fancy test; it can be done actually at any commercial lab," he said in an interview. "The key is to validate that the labs are doing the assay in the same way."

Duration of response noted

Dr. Antonio Palumbo, chief of the myeloma unit at the University Hospital of Torino, Italy, who comoderated the session, said in an interview that ARRY-520 is "certainly an exciting new agent" in multiple myeloma, given its novel therapeutic target, partial responses of 20%-30% in such advanced disease and a potential biomarker.

"I think the biomarker was important and probably also the durability because this type of drug may have a major role in durability, more than on response," he said.

Median duration of response was 8.6 months with ARRY-520 monotherapy (range 1.4-20 months) and 5.4 months with combination therapy (2.5-9 months).

Dr. Angela Dispenzieri, hematologist and professor of medicine at Mayo Clinic, Rochester, Minn., and a member of the meeting’s scientific committee, was more effusive in her assessment of the results.

"Actually, I think it’s the best thing so far at ASH," she said after the session on the penultimate day of the meeting. "It’s novel.

"This is a new class and it actually has single-agent activity. That’s the beginning and that is very important. I was really impressed, and I’m really cynical."

Both Dr. Dispenzieri and Dr. Palumbo said results should be better if ARRY-520 is combined with other agents such as bortezomib, proteasome inhibitors or immunomodulatory drugs (IMiDs).

Preliminary results reported in a poster at the meeting show that one of six evaluable patients achieved a near complete response and four had stable disease after completing at least one cycle of ARRY-520 plus the proteasome inhibitor carfilzomib (Kyprolis), Dr. Shah reported.

Patrice Wendling/IMNG Medical Media

"We’re already starting to see a signal there, and we’re going to go with IMiDs next," he said.

A phase Ib combination trial with bortezomib is also underway.

Fifty patients in two cohorts

The current phase II study included 32 patients who received single-agent ARRY-520 at 1.5 mg/m² on days 1 and 2 every 2 weeks and 18 patients who also received low-dose dexamethasone 40 mg once weekly. Both groups received granulocyte–colony stimulating factor support.

The first cohort had relapsed and/or refractory multiple myeloma after receiving at least two prior rounds of therapy (range 2-19) that included bortezomib and an IMiD. Roughly half were bortezomib refractory (53%) and 41% were triple refractory.

Cohort two had also received at least two prior regimens (range 5-13), but progressed during or within 60 days of their last regimen, was refractory to lenalidomide, bortezomib, and dexamethasone (except one dexamethasone-refractory patient) and had received adequate prior alkylator therapy. High-risk cytogenetics were present in 17% vs. 9% of cohort one.

In cohort one, there were 5 partial responses, 6 minor plus partial responses, and 14 cases of stable disease, Dr. Shah said. The median time to response was 4.4 months and median progression-free survival was 3.7 months. The cohort had very durable responses at a median of 8.6 months (range 1.4-20 months), and an overall survival of 19 months, he said.

In cohort two, there were 4 partial responses, 6 minimal plus partial responses and 5 patients with stable disease. The median time on treatment about doubled from 2.1 in cohort one to 3.9 months, with a shorter time to response of 3.4 months. The median duration of response was shorter at 5.4 months, "but again this was a very different patient population," Dr. Shah said.

An analysis of baseline AAG levels in 45 patients revealed that patients with low AAG remained on study longer than did those with high AAG in both cohort one (3.4 months vs. 1.7 months) and cohort two (6.2 months vs. 1.6 months). Moreover, 24% of low-AAG patients on monotherapy and 22% on combination therapy achieved at least a partial response, whereas no patient with high AAG levels did so.

In vitro work has shown that increasing levels of AAG result in increased half maximal inhibitory concentration (IC₅₀) of ARRY-520, suggesting that patients with elevated AAG may have subtherapeutic exposure to the drug, Dr. Shah explained. AAG does not bind to other standard multiple myeloma agents on the market, and is not correlated with prognostic markers in myeloma.

Nonhematologic adverse events were very low, including one case each of grade 4 fatigue and hypokalemia, and two cases of grade 4 pneumonia.

As expected from the biology of the drug, grade 3/4 hematologic events were more common, but generally reversible and not observed to be cumulative out to 3 years of therapy, Dr. Shah said. Grade 4 neutropenia, thrombocytopenia, and anemia were present in 28%, 25%, and 6% of patients in cohort one and in 38%, 19% and 5% of cohort two, respectively. Febrile neutropenia was grade 3 only, and reported in just one patient in each group, he noted.

Dr. Shah and coauthors reported relationships with study sponsor Array BioPharma, which is developing ARRY-520. Dr. Palumbo disclosed relationships with other companies.

ATLANTA – The experimental drug ARRY-520, the first kinesin spindle protein inhibitor in multiple myeloma, prompted responses in nearly one-fourth of heavily pretreated and triple-refractory patients in a phase II study.

The overall response rate to single-agent ARRY-520 was 16% in patients with a median of six prior regimens. It reached 22% when combined with dexamethasone in patients with a median of 10 prior regimens – all but one of whom was refractory to lenalidomide (Revlimid), bortezomib (Velcade), and dexamethasone (Decadron), Dr. Jatin Shah reported at the annual meeting of the American Society of Hematology.

Kinesin spindle protein (KSP) is a microtubule motor protein required for mitosis and separation of the mitotic spindle pole into a bipolar spindle pole. Inhibition of KSP prevents formation of the bipolar spindle, leading to cell death. Preclinical work shows that ARRY-520 also down-regulates myeloid cell leukemia-1 levels, a mechanism for dexamethasone resistance.

Patrice Wendling/IMNG Medical Media

The investigators also identified a potential biomarker called alpha 1-acid glycoprotein (AAG) that may predict how well patients respond to ARRY-520.

Selecting patients by AAG serum results increased the response rate to 33% in the combination group, a population with an unmet clinical need, said Dr. Shah of the University of Texas M.D. Anderson Cancer Center in Houston.

"The assay isn’t a fancy test; it can be done actually at any commercial lab," he said in an interview. "The key is to validate that the labs are doing the assay in the same way."

Duration of response noted

Dr. Antonio Palumbo, chief of the myeloma unit at the University Hospital of Torino, Italy, who comoderated the session, said in an interview that ARRY-520 is "certainly an exciting new agent" in multiple myeloma, given its novel therapeutic target, partial responses of 20%-30% in such advanced disease and a potential biomarker.

"I think the biomarker was important and probably also the durability because this type of drug may have a major role in durability, more than on response," he said.

Median duration of response was 8.6 months with ARRY-520 monotherapy (range 1.4-20 months) and 5.4 months with combination therapy (2.5-9 months).

Dr. Angela Dispenzieri, hematologist and professor of medicine at Mayo Clinic, Rochester, Minn., and a member of the meeting’s scientific committee, was more effusive in her assessment of the results.

"Actually, I think it’s the best thing so far at ASH," she said after the session on the penultimate day of the meeting. "It’s novel.

"This is a new class and it actually has single-agent activity. That’s the beginning and that is very important. I was really impressed, and I’m really cynical."

Both Dr. Dispenzieri and Dr. Palumbo said results should be better if ARRY-520 is combined with other agents such as bortezomib, proteasome inhibitors or immunomodulatory drugs (IMiDs).

Preliminary results reported in a poster at the meeting show that one of six evaluable patients achieved a near complete response and four had stable disease after completing at least one cycle of ARRY-520 plus the proteasome inhibitor carfilzomib (Kyprolis), Dr. Shah reported.

Patrice Wendling/IMNG Medical Media

"We’re already starting to see a signal there, and we’re going to go with IMiDs next," he said.

A phase Ib combination trial with bortezomib is also underway.

Fifty patients in two cohorts

The current phase II study included 32 patients who received single-agent ARRY-520 at 1.5 mg/m² on days 1 and 2 every 2 weeks and 18 patients who also received low-dose dexamethasone 40 mg once weekly. Both groups received granulocyte–colony stimulating factor support.

The first cohort had relapsed and/or refractory multiple myeloma after receiving at least two prior rounds of therapy (range 2-19) that included bortezomib and an IMiD. Roughly half were bortezomib refractory (53%) and 41% were triple refractory.

Cohort two had also received at least two prior regimens (range 5-13), but progressed during or within 60 days of their last regimen, was refractory to lenalidomide, bortezomib, and dexamethasone (except one dexamethasone-refractory patient) and had received adequate prior alkylator therapy. High-risk cytogenetics were present in 17% vs. 9% of cohort one.

In cohort one, there were 5 partial responses, 6 minor plus partial responses, and 14 cases of stable disease, Dr. Shah said. The median time to response was 4.4 months and median progression-free survival was 3.7 months. The cohort had very durable responses at a median of 8.6 months (range 1.4-20 months), and an overall survival of 19 months, he said.

In cohort two, there were 4 partial responses, 6 minimal plus partial responses and 5 patients with stable disease. The median time on treatment about doubled from 2.1 in cohort one to 3.9 months, with a shorter time to response of 3.4 months. The median duration of response was shorter at 5.4 months, "but again this was a very different patient population," Dr. Shah said.

An analysis of baseline AAG levels in 45 patients revealed that patients with low AAG remained on study longer than did those with high AAG in both cohort one (3.4 months vs. 1.7 months) and cohort two (6.2 months vs. 1.6 months). Moreover, 24% of low-AAG patients on monotherapy and 22% on combination therapy achieved at least a partial response, whereas no patient with high AAG levels did so.

In vitro work has shown that increasing levels of AAG result in increased half maximal inhibitory concentration (IC₅₀) of ARRY-520, suggesting that patients with elevated AAG may have subtherapeutic exposure to the drug, Dr. Shah explained. AAG does not bind to other standard multiple myeloma agents on the market, and is not correlated with prognostic markers in myeloma.

Nonhematologic adverse events were very low, including one case each of grade 4 fatigue and hypokalemia, and two cases of grade 4 pneumonia.

As expected from the biology of the drug, grade 3/4 hematologic events were more common, but generally reversible and not observed to be cumulative out to 3 years of therapy, Dr. Shah said. Grade 4 neutropenia, thrombocytopenia, and anemia were present in 28%, 25%, and 6% of patients in cohort one and in 38%, 19% and 5% of cohort two, respectively. Febrile neutropenia was grade 3 only, and reported in just one patient in each group, he noted.

Dr. Shah and coauthors reported relationships with study sponsor Array BioPharma, which is developing ARRY-520. Dr. Palumbo disclosed relationships with other companies.

ATLANTA – Like many of their fellow physicians, oncologists and hematologists are concerned about the across-the-board federal budget cuts looming on the other side of the fiscal cliff.

At its recently concluded annual meeting, the American Society of Hematology surveyed abstract presenters and found that two-thirds are reliant on the National Institutes of Health for some or all of their research funding.

Should sequestration go into effect in January, the NIH budget is expected to be cut by about $2.5 billion. The agency "would have to halt or curtail scientific research, including needed research into cancer and childhood diseases," according to a report from the federal Office of Management and Budget.

Such cuts, according to ASH leaders, will discourage young scientists from pursuing a career in research, and if left in place would eventually dismantle the teaching support structure.

A total of 86% of U.S.-based survey respondents reported that they had referenced NIH-funded studies in their research. Three-quarters said they were "extremely concerned" about the threat of NIH budget cuts and the impact on their careers.

"We could lose a generation of scientists," Dr. Janis L. Abkowitz, president of ASH, said in an interview. The research field may not look any different for a few years, but "eventually, we will lose the competitive edge in research. It’s as if we’re giving up on science."

In 2011, roughly 18% of projects received R01 grant funding, the major funding mechanism for individual projects. That’s compared with 22% in 2010, 25%-32% in 1993-2003, and 45%-58% in 1962-1966, according to an article coauthored by Dr. Abkowitz (JAMA 2012;308:2343-4).

The article also challenges other professional societies to bring the issue to the forefront and create programs such as the ASH bridge grant program to help fund researchers caught in sequestration’s grip that otherwise would lose their funding.

Dr. Abkowitz, head of the division of hematology at the University of Washington, Seattle, said that funding from pharmaceutical companies doesn’t fill the gap for cuts in NIH funding, because drug companies invest in ideas that are developed and that have commercial possibilities, she said.

NIH grants, on the other hand, "invest in individuals who have great ideas. Some ideas work out, some fail, and some take 10 years to come to fruition," she said. "But it’s the idea that’s the revolutionary piece that eventually could lead to a discovery that could cure a disease or find a new test, and is the economic driver. That’s why we have prominence economically and in health care. It\'s because of these novel ideas."

If the country goes over the fiscal cliff in January, 2,300 new grants won’t receive funding. Some 33,000 jobs depend on those grants, Dr. Robert Hromas, chair of ASH’s Committee on Scientific Affairs, said in an interview (see video). "It’s as if we’re turning off the spigot for future grants."

NIH issued a statement this month, proposing a "critical initiative" to help sustain the future of U.S. biomedical research.

ATLANTA – Like many of their fellow physicians, oncologists and hematologists are concerned about the across-the-board federal budget cuts looming on the other side of the fiscal cliff.

At its recently concluded annual meeting, the American Society of Hematology surveyed abstract presenters and found that two-thirds are reliant on the National Institutes of Health for some or all of their research funding.

Should sequestration go into effect in January, the NIH budget is expected to be cut by about $2.5 billion. The agency "would have to halt or curtail scientific research, including needed research into cancer and childhood diseases," according to a report from the federal Office of Management and Budget.

Such cuts, according to ASH leaders, will discourage young scientists from pursuing a career in research, and if left in place would eventually dismantle the teaching support structure.

A total of 86% of U.S.-based survey respondents reported that they had referenced NIH-funded studies in their research. Three-quarters said they were "extremely concerned" about the threat of NIH budget cuts and the impact on their careers.

"We could lose a generation of scientists," Dr. Janis L. Abkowitz, president of ASH, said in an interview. The research field may not look any different for a few years, but "eventually, we will lose the competitive edge in research. It’s as if we’re giving up on science."

In 2011, roughly 18% of projects received R01 grant funding, the major funding mechanism for individual projects. That’s compared with 22% in 2010, 25%-32% in 1993-2003, and 45%-58% in 1962-1966, according to an article coauthored by Dr. Abkowitz (JAMA 2012;308:2343-4).

The article also challenges other professional societies to bring the issue to the forefront and create programs such as the ASH bridge grant program to help fund researchers caught in sequestration’s grip that otherwise would lose their funding.

Dr. Abkowitz, head of the division of hematology at the University of Washington, Seattle, said that funding from pharmaceutical companies doesn’t fill the gap for cuts in NIH funding, because drug companies invest in ideas that are developed and that have commercial possibilities, she said.

NIH grants, on the other hand, "invest in individuals who have great ideas. Some ideas work out, some fail, and some take 10 years to come to fruition," she said. "But it’s the idea that’s the revolutionary piece that eventually could lead to a discovery that could cure a disease or find a new test, and is the economic driver. That’s why we have prominence economically and in health care. It\'s because of these novel ideas."

If the country goes over the fiscal cliff in January, 2,300 new grants won’t receive funding. Some 33,000 jobs depend on those grants, Dr. Robert Hromas, chair of ASH’s Committee on Scientific Affairs, said in an interview (see video). "It’s as if we’re turning off the spigot for future grants."

NIH issued a statement this month, proposing a "critical initiative" to help sustain the future of U.S. biomedical research.

ATLANTA – Like many of their fellow physicians, oncologists and hematologists are concerned about the across-the-board federal budget cuts looming on the other side of the fiscal cliff.

At its recently concluded annual meeting, the American Society of Hematology surveyed abstract presenters and found that two-thirds are reliant on the National Institutes of Health for some or all of their research funding.

Should sequestration go into effect in January, the NIH budget is expected to be cut by about $2.5 billion. The agency "would have to halt or curtail scientific research, including needed research into cancer and childhood diseases," according to a report from the federal Office of Management and Budget.

Such cuts, according to ASH leaders, will discourage young scientists from pursuing a career in research, and if left in place would eventually dismantle the teaching support structure.

A total of 86% of U.S.-based survey respondents reported that they had referenced NIH-funded studies in their research. Three-quarters said they were "extremely concerned" about the threat of NIH budget cuts and the impact on their careers.

"We could lose a generation of scientists," Dr. Janis L. Abkowitz, president of ASH, said in an interview. The research field may not look any different for a few years, but "eventually, we will lose the competitive edge in research. It’s as if we’re giving up on science."

In 2011, roughly 18% of projects received R01 grant funding, the major funding mechanism for individual projects. That’s compared with 22% in 2010, 25%-32% in 1993-2003, and 45%-58% in 1962-1966, according to an article coauthored by Dr. Abkowitz (JAMA 2012;308:2343-4).

The article also challenges other professional societies to bring the issue to the forefront and create programs such as the ASH bridge grant program to help fund researchers caught in sequestration’s grip that otherwise would lose their funding.

Dr. Abkowitz, head of the division of hematology at the University of Washington, Seattle, said that funding from pharmaceutical companies doesn’t fill the gap for cuts in NIH funding, because drug companies invest in ideas that are developed and that have commercial possibilities, she said.

NIH grants, on the other hand, "invest in individuals who have great ideas. Some ideas work out, some fail, and some take 10 years to come to fruition," she said. "But it’s the idea that’s the revolutionary piece that eventually could lead to a discovery that could cure a disease or find a new test, and is the economic driver. That’s why we have prominence economically and in health care. It\'s because of these novel ideas."

If the country goes over the fiscal cliff in January, 2,300 new grants won’t receive funding. Some 33,000 jobs depend on those grants, Dr. Robert Hromas, chair of ASH’s Committee on Scientific Affairs, said in an interview (see video). "It’s as if we’re turning off the spigot for future grants."

NIH issued a statement this month, proposing a "critical initiative" to help sustain the future of U.S. biomedical research.

ATLANTA – The experimental drug quizartinib bought significant time for some patients with acute myeloid leukemia bearing a high-risk FLT3-ITD mutation, investigators reported at the annual meeting of the American Society of Hematology.

Among patients positive for FLT3-ITD, the composite complete remission rate (CRc) was 46%, and 27% of patients had a partial response. Both rates were higher than in patients without the mutation, of whom 32% had a CRc, and 16% a partial response.

The median duration of the remissions was 12.1 weeks for FLT3-ITD–positive patients, and 7.0 weeks for those lacking the mutation, reported Dr. Mark J. Levis of the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University in Baltimore.

Although median overall survival was not significantly different among all patients in the open-label trial, it improved significantly among FLT3-ITD–positive patients for whom quizartinib served as bridge to hematopoietic stem cell transplant (HSCT). Median survival in FLT3-ITD–positive patients who received a transplant was 33.3 weeks, compared with 17.7 weeks for those not transplanted.

"Our focus for this drug is to clear the leukemia out of the patient's bone marrow to a sufficient degree to allow them to go for a bone marrow transplant," said Dr. Levis at a press briefing. More than a third of patients were bridged to transplant, with 18 long-term survivors, he said.

In a separate presentation looking at a separate cohort of patients aged 60 years and older, another high-risk population in the study, Dr. Jorge Cortes of the University of Texas M.D. Anderson Cancer Center in Houston reported a 54% CRc rate, with 13% of patients surviving more than 1 year and 8% still alive at last follow-up.

Patients tolerated the drug, a tyrosine kinase inhibitor (TKI), very well, and had toxicities that could generally be managed well, Dr. Cortes and Dr. Levis said in their presentations.

New Era Foreseen in Relapsed /Refractory AML

A leukemia specialist who was not involved in the trial said that quizartinib, which is specifically targeted against FLT3, may be ushering in a new era of treatment options for patients with relapsed or refractory AML.

"We see these patients, they come to us having relapsed after standard therapy, they have this mutation, and there’s nothing we can offer that’s standard therapy – their survival is measured in weeks," said Dr. Aaron Schimmer of the Princess Margaret Cancer Centre of the University Health Network in Toronto.

"Now, they can receive a targeted agent that is exceptionally well tolerated and in large number of patients is producing responses that allow them to on to potentially curative bone marrow transplant," he said.

Dr. Schimmer moderated a press briefing at which Dr. Levis presented data on one of the study cohorts.

Tenfold Higher Potency Than Other Agents

FLT3 has been an attractive target for drug developers because it is expressed in hematopoietic progenitor cells and its signals promote proliferation and differentiation of cells. It is found to be overexpressed in the majority of AML cases, and the FLT3-ITD mutation is found in up to one-third of patients with AML, Dr. Levis said.

Quizartinib is the latest in a line of agents aimed squarely at FLT3, with the ability to selective inhibit FLT3 while avoiding other targets at much smaller concentrations than that required for agents such lestaurtinib, midostaurin, and sorafenib (Nexavar) – giving the drug about a 10-fold higher potency than the other agents, Dr. Levis said.

In the phase II AC220-002 trial, investigators enrolled 271 patients with primary AML or AML secondary to the myelodysplastic syndrome.

One cohort enrolled 133 patients aged 60 years and older who had had their first relapse within the previous year or were refractory to first-line therapy. In this cohort, 90 patients were FLT3-ITD positive.

The other cohort included 138 patients 18 and older (100 FLT3-ITD–positive) who had relapsed after or were refractory to second-line treatment or HSCT.

In the older-patient cohort described by Dr. Cortes, the CRc rate (a composite of complete remissions plus complete remissions with incomplete platelet and/or hematologic recovery) in FLT3-ITD–positive patients was 50%, and the partial response rate was 21%. Among FLT3-ITD–negative patients, the CRc rate was 36%, and the PR rate was 10%.

In these patients, 70% of those carrying the mutation and 55% of those without the mutation who had been refractory to their last prior therapy achieved at least a partial response. The median duration of remission was 10.4 weeks for FLT3-ITD–positive patients, and 9.3 weeks for –negative patients.

Patients tolerated the drug very well, with the most serious event being a reversible prolongation of the QT interval, and dose-limiting myelosuppression, possibly related to inhibition of the KIT kinase, said Dr. Levis.

The study was funded by Ambit Biosciences, maker of quizartinib (AC220). Dr. Levis disclosed serving as a consultant to the company. Dr. Cortes disclosed serving as a consultant to Novartis.

ATLANTA – The experimental drug quizartinib bought significant time for some patients with acute myeloid leukemia bearing a high-risk FLT3-ITD mutation, investigators reported at the annual meeting of the American Society of Hematology.

Among patients positive for FLT3-ITD, the composite complete remission rate (CRc) was 46%, and 27% of patients had a partial response. Both rates were higher than in patients without the mutation, of whom 32% had a CRc, and 16% a partial response.

The median duration of the remissions was 12.1 weeks for FLT3-ITD–positive patients, and 7.0 weeks for those lacking the mutation, reported Dr. Mark J. Levis of the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University in Baltimore.

Although median overall survival was not significantly different among all patients in the open-label trial, it improved significantly among FLT3-ITD–positive patients for whom quizartinib served as bridge to hematopoietic stem cell transplant (HSCT). Median survival in FLT3-ITD–positive patients who received a transplant was 33.3 weeks, compared with 17.7 weeks for those not transplanted.

"Our focus for this drug is to clear the leukemia out of the patient's bone marrow to a sufficient degree to allow them to go for a bone marrow transplant," said Dr. Levis at a press briefing. More than a third of patients were bridged to transplant, with 18 long-term survivors, he said.

In a separate presentation looking at a separate cohort of patients aged 60 years and older, another high-risk population in the study, Dr. Jorge Cortes of the University of Texas M.D. Anderson Cancer Center in Houston reported a 54% CRc rate, with 13% of patients surviving more than 1 year and 8% still alive at last follow-up.

Patients tolerated the drug, a tyrosine kinase inhibitor (TKI), very well, and had toxicities that could generally be managed well, Dr. Cortes and Dr. Levis said in their presentations.

New Era Foreseen in Relapsed /Refractory AML

A leukemia specialist who was not involved in the trial said that quizartinib, which is specifically targeted against FLT3, may be ushering in a new era of treatment options for patients with relapsed or refractory AML.

"We see these patients, they come to us having relapsed after standard therapy, they have this mutation, and there’s nothing we can offer that’s standard therapy – their survival is measured in weeks," said Dr. Aaron Schimmer of the Princess Margaret Cancer Centre of the University Health Network in Toronto.

"Now, they can receive a targeted agent that is exceptionally well tolerated and in large number of patients is producing responses that allow them to on to potentially curative bone marrow transplant," he said.

Dr. Schimmer moderated a press briefing at which Dr. Levis presented data on one of the study cohorts.

Tenfold Higher Potency Than Other Agents

FLT3 has been an attractive target for drug developers because it is expressed in hematopoietic progenitor cells and its signals promote proliferation and differentiation of cells. It is found to be overexpressed in the majority of AML cases, and the FLT3-ITD mutation is found in up to one-third of patients with AML, Dr. Levis said.

Quizartinib is the latest in a line of agents aimed squarely at FLT3, with the ability to selective inhibit FLT3 while avoiding other targets at much smaller concentrations than that required for agents such lestaurtinib, midostaurin, and sorafenib (Nexavar) – giving the drug about a 10-fold higher potency than the other agents, Dr. Levis said.

In the phase II AC220-002 trial, investigators enrolled 271 patients with primary AML or AML secondary to the myelodysplastic syndrome.

One cohort enrolled 133 patients aged 60 years and older who had had their first relapse within the previous year or were refractory to first-line therapy. In this cohort, 90 patients were FLT3-ITD positive.

The other cohort included 138 patients 18 and older (100 FLT3-ITD–positive) who had relapsed after or were refractory to second-line treatment or HSCT.

In the older-patient cohort described by Dr. Cortes, the CRc rate (a composite of complete remissions plus complete remissions with incomplete platelet and/or hematologic recovery) in FLT3-ITD–positive patients was 50%, and the partial response rate was 21%. Among FLT3-ITD–negative patients, the CRc rate was 36%, and the PR rate was 10%.

In these patients, 70% of those carrying the mutation and 55% of those without the mutation who had been refractory to their last prior therapy achieved at least a partial response. The median duration of remission was 10.4 weeks for FLT3-ITD–positive patients, and 9.3 weeks for –negative patients.

Patients tolerated the drug very well, with the most serious event being a reversible prolongation of the QT interval, and dose-limiting myelosuppression, possibly related to inhibition of the KIT kinase, said Dr. Levis.

The study was funded by Ambit Biosciences, maker of quizartinib (AC220). Dr. Levis disclosed serving as a consultant to the company. Dr. Cortes disclosed serving as a consultant to Novartis.

ATLANTA – The experimental drug quizartinib bought significant time for some patients with acute myeloid leukemia bearing a high-risk FLT3-ITD mutation, investigators reported at the annual meeting of the American Society of Hematology.

Among patients positive for FLT3-ITD, the composite complete remission rate (CRc) was 46%, and 27% of patients had a partial response. Both rates were higher than in patients without the mutation, of whom 32% had a CRc, and 16% a partial response.

The median duration of the remissions was 12.1 weeks for FLT3-ITD–positive patients, and 7.0 weeks for those lacking the mutation, reported Dr. Mark J. Levis of the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University in Baltimore.

Although median overall survival was not significantly different among all patients in the open-label trial, it improved significantly among FLT3-ITD–positive patients for whom quizartinib served as bridge to hematopoietic stem cell transplant (HSCT). Median survival in FLT3-ITD–positive patients who received a transplant was 33.3 weeks, compared with 17.7 weeks for those not transplanted.

"Our focus for this drug is to clear the leukemia out of the patient's bone marrow to a sufficient degree to allow them to go for a bone marrow transplant," said Dr. Levis at a press briefing. More than a third of patients were bridged to transplant, with 18 long-term survivors, he said.

In a separate presentation looking at a separate cohort of patients aged 60 years and older, another high-risk population in the study, Dr. Jorge Cortes of the University of Texas M.D. Anderson Cancer Center in Houston reported a 54% CRc rate, with 13% of patients surviving more than 1 year and 8% still alive at last follow-up.

Patients tolerated the drug, a tyrosine kinase inhibitor (TKI), very well, and had toxicities that could generally be managed well, Dr. Cortes and Dr. Levis said in their presentations.

New Era Foreseen in Relapsed /Refractory AML

A leukemia specialist who was not involved in the trial said that quizartinib, which is specifically targeted against FLT3, may be ushering in a new era of treatment options for patients with relapsed or refractory AML.

"We see these patients, they come to us having relapsed after standard therapy, they have this mutation, and there’s nothing we can offer that’s standard therapy – their survival is measured in weeks," said Dr. Aaron Schimmer of the Princess Margaret Cancer Centre of the University Health Network in Toronto.

"Now, they can receive a targeted agent that is exceptionally well tolerated and in large number of patients is producing responses that allow them to on to potentially curative bone marrow transplant," he said.

Dr. Schimmer moderated a press briefing at which Dr. Levis presented data on one of the study cohorts.

Tenfold Higher Potency Than Other Agents

FLT3 has been an attractive target for drug developers because it is expressed in hematopoietic progenitor cells and its signals promote proliferation and differentiation of cells. It is found to be overexpressed in the majority of AML cases, and the FLT3-ITD mutation is found in up to one-third of patients with AML, Dr. Levis said.

Quizartinib is the latest in a line of agents aimed squarely at FLT3, with the ability to selective inhibit FLT3 while avoiding other targets at much smaller concentrations than that required for agents such lestaurtinib, midostaurin, and sorafenib (Nexavar) – giving the drug about a 10-fold higher potency than the other agents, Dr. Levis said.

In the phase II AC220-002 trial, investigators enrolled 271 patients with primary AML or AML secondary to the myelodysplastic syndrome.

One cohort enrolled 133 patients aged 60 years and older who had had their first relapse within the previous year or were refractory to first-line therapy. In this cohort, 90 patients were FLT3-ITD positive.

The other cohort included 138 patients 18 and older (100 FLT3-ITD–positive) who had relapsed after or were refractory to second-line treatment or HSCT.

In the older-patient cohort described by Dr. Cortes, the CRc rate (a composite of complete remissions plus complete remissions with incomplete platelet and/or hematologic recovery) in FLT3-ITD–positive patients was 50%, and the partial response rate was 21%. Among FLT3-ITD–negative patients, the CRc rate was 36%, and the PR rate was 10%.

In these patients, 70% of those carrying the mutation and 55% of those without the mutation who had been refractory to their last prior therapy achieved at least a partial response. The median duration of remission was 10.4 weeks for FLT3-ITD–positive patients, and 9.3 weeks for –negative patients.

Patients tolerated the drug very well, with the most serious event being a reversible prolongation of the QT interval, and dose-limiting myelosuppression, possibly related to inhibition of the KIT kinase, said Dr. Levis.

The study was funded by Ambit Biosciences, maker of quizartinib (AC220). Dr. Levis disclosed serving as a consultant to the company. Dr. Cortes disclosed serving as a consultant to Novartis.

ATLANTA – It took a randomized clinical trial to show that current treatment recommendations for polycythemia vera are right on target, investigators from Italy reported at the annual meeting of the American Society of Hematology.

Patients with JAK2-positive polycythemia vera who were randomized to an intensive hematocrit management strategy (target below 45%) had a fourfold lower risk of death, major cardiovascular complications, or major thrombotic events than patients treated to a target of 45% to 50%, reported Dr. Tiziano Barbui, professor of hematology at the Ospedali Riuniti di Bergamo, Italy.

When superficial vein thrombosis, a secondary endpoint, was added into the primary endpoint (a composite of cardiovascular deaths and thrombosis), the death rate for the less-than-45% target was 4.4%, compared with 10.9% in the 45%-50% group, Dr. Barbui said.

"We confirm that hematocrit less than 45% should be the target of therapy in polycythemia vera," Dr. Barbui said.

The findings were also published online in the New England Journal of Medicine (2012 Dec. 8 [doi: 10.1056/NEJMoa1208500]).

Polycythemia vera is a rare neoplasm in which there is overproliferation of bone marrow progenitor cells, leading in turn to overproduction of erythroid cells and increased red cell mass. Patients are at significantly elevated risk for cardiovascular complications and death from thrombosis and bleeding, as well as from hematologic transformation into acute leukemia or overt myelofibrosis.

It is typically treated with phlebotomy, cytoreductive drugs, or both.

The incidence of polycythemia vera is about 2-3 per 100,000, presenting most commonly in individuals aged 50-70 years, Dr. Barbui said, and is slightly higher among Jews of eastern European descent.

Optimal Approach Was Uncertain

Dr. Barbui and his colleagues undertook the study because of the uncertainty of the science behind the recommendations, which were based on studies showing proportional increases in thrombotic events among patients with higher hematocrit levels and platelet counts. But there was also concern that more intensive therapy needed to reach the hematocrit target could come at the cost of poor tolerability and adverse events, Dr. Barbui said.

The study enrolled 365 patients with a polycythemia vera diagnosis according to World Health Organization 2008 criteria, and assigned them to either a less-than-45% hematocrit target or the 45%-50% range. Treatment was at the investigators’ discretion, although they were encouraged to give hydroxyurea to high-risk patients (those over age 65 or with a history of thrombosis).

The trial was closed earlier than planned, in February 2012, because of competition for patients from clinical trials of JAK-2 inhibitors.

Dr. Barbui presented data from an intention-to-treat analysis.

At a median follow-up of 31 months, 2.8% of patients in the less-than-45% group had experienced one or more of the events in the composite primary endpoint (stroke, acute coronary syndrome, transient ischemic attack, pulmonary embolism, abdominal thrombosis, deep vein thrombosis, or peripheral arterial thrombosis), compared with 9.8% of those in the 45-50% group. The hazard ratio for the primary endpoint with the less intensive targeting strategy was 3.91 (P = .005).

The HR for total cardiovascular events (with superficial vein thrombosis thrown in for good measure) was 2.69 (P = .012).

Gender Disparity Noted

In an editorial accompanying the NEJM article, Dr. Jerry L. Spivak of the hematology/oncology division at Johns Hopkins University in Baltimore noted that women normally have a lower red-cell mass and hematocrit than men, putting women with polycythemia vera at risk for intra-abdominal venous thrombosis, even when their hematocrit appears to be normal.

"Therefore the hematocrit target described by [the investigators] is adequate for men but inadequate for women, who on the basis of other studies should have a target hematocrit of less than 42%," he wrote.

Dr. Barbui and Dr. Spivak reported no relevant conflicts of interest.

ATLANTA – It took a randomized clinical trial to show that current treatment recommendations for polycythemia vera are right on target, investigators from Italy reported at the annual meeting of the American Society of Hematology.

Patients with JAK2-positive polycythemia vera who were randomized to an intensive hematocrit management strategy (target below 45%) had a fourfold lower risk of death, major cardiovascular complications, or major thrombotic events than patients treated to a target of 45% to 50%, reported Dr. Tiziano Barbui, professor of hematology at the Ospedali Riuniti di Bergamo, Italy.

When superficial vein thrombosis, a secondary endpoint, was added into the primary endpoint (a composite of cardiovascular deaths and thrombosis), the death rate for the less-than-45% target was 4.4%, compared with 10.9% in the 45%-50% group, Dr. Barbui said.

"We confirm that hematocrit less than 45% should be the target of therapy in polycythemia vera," Dr. Barbui said.

The findings were also published online in the New England Journal of Medicine (2012 Dec. 8 [doi: 10.1056/NEJMoa1208500]).

Polycythemia vera is a rare neoplasm in which there is overproliferation of bone marrow progenitor cells, leading in turn to overproduction of erythroid cells and increased red cell mass. Patients are at significantly elevated risk for cardiovascular complications and death from thrombosis and bleeding, as well as from hematologic transformation into acute leukemia or overt myelofibrosis.

It is typically treated with phlebotomy, cytoreductive drugs, or both.

The incidence of polycythemia vera is about 2-3 per 100,000, presenting most commonly in individuals aged 50-70 years, Dr. Barbui said, and is slightly higher among Jews of eastern European descent.

Optimal Approach Was Uncertain

Dr. Barbui and his colleagues undertook the study because of the uncertainty of the science behind the recommendations, which were based on studies showing proportional increases in thrombotic events among patients with higher hematocrit levels and platelet counts. But there was also concern that more intensive therapy needed to reach the hematocrit target could come at the cost of poor tolerability and adverse events, Dr. Barbui said.

The study enrolled 365 patients with a polycythemia vera diagnosis according to World Health Organization 2008 criteria, and assigned them to either a less-than-45% hematocrit target or the 45%-50% range. Treatment was at the investigators’ discretion, although they were encouraged to give hydroxyurea to high-risk patients (those over age 65 or with a history of thrombosis).

The trial was closed earlier than planned, in February 2012, because of competition for patients from clinical trials of JAK-2 inhibitors.

Dr. Barbui presented data from an intention-to-treat analysis.

At a median follow-up of 31 months, 2.8% of patients in the less-than-45% group had experienced one or more of the events in the composite primary endpoint (stroke, acute coronary syndrome, transient ischemic attack, pulmonary embolism, abdominal thrombosis, deep vein thrombosis, or peripheral arterial thrombosis), compared with 9.8% of those in the 45-50% group. The hazard ratio for the primary endpoint with the less intensive targeting strategy was 3.91 (P = .005).

The HR for total cardiovascular events (with superficial vein thrombosis thrown in for good measure) was 2.69 (P = .012).

Gender Disparity Noted

In an editorial accompanying the NEJM article, Dr. Jerry L. Spivak of the hematology/oncology division at Johns Hopkins University in Baltimore noted that women normally have a lower red-cell mass and hematocrit than men, putting women with polycythemia vera at risk for intra-abdominal venous thrombosis, even when their hematocrit appears to be normal.

"Therefore the hematocrit target described by [the investigators] is adequate for men but inadequate for women, who on the basis of other studies should have a target hematocrit of less than 42%," he wrote.

Dr. Barbui and Dr. Spivak reported no relevant conflicts of interest.

ATLANTA – It took a randomized clinical trial to show that current treatment recommendations for polycythemia vera are right on target, investigators from Italy reported at the annual meeting of the American Society of Hematology.

Patients with JAK2-positive polycythemia vera who were randomized to an intensive hematocrit management strategy (target below 45%) had a fourfold lower risk of death, major cardiovascular complications, or major thrombotic events than patients treated to a target of 45% to 50%, reported Dr. Tiziano Barbui, professor of hematology at the Ospedali Riuniti di Bergamo, Italy.

When superficial vein thrombosis, a secondary endpoint, was added into the primary endpoint (a composite of cardiovascular deaths and thrombosis), the death rate for the less-than-45% target was 4.4%, compared with 10.9% in the 45%-50% group, Dr. Barbui said.

"We confirm that hematocrit less than 45% should be the target of therapy in polycythemia vera," Dr. Barbui said.

The findings were also published online in the New England Journal of Medicine (2012 Dec. 8 [doi: 10.1056/NEJMoa1208500]).

Polycythemia vera is a rare neoplasm in which there is overproliferation of bone marrow progenitor cells, leading in turn to overproduction of erythroid cells and increased red cell mass. Patients are at significantly elevated risk for cardiovascular complications and death from thrombosis and bleeding, as well as from hematologic transformation into acute leukemia or overt myelofibrosis.

It is typically treated with phlebotomy, cytoreductive drugs, or both.

The incidence of polycythemia vera is about 2-3 per 100,000, presenting most commonly in individuals aged 50-70 years, Dr. Barbui said, and is slightly higher among Jews of eastern European descent.

Optimal Approach Was Uncertain

Dr. Barbui and his colleagues undertook the study because of the uncertainty of the science behind the recommendations, which were based on studies showing proportional increases in thrombotic events among patients with higher hematocrit levels and platelet counts. But there was also concern that more intensive therapy needed to reach the hematocrit target could come at the cost of poor tolerability and adverse events, Dr. Barbui said.

The study enrolled 365 patients with a polycythemia vera diagnosis according to World Health Organization 2008 criteria, and assigned them to either a less-than-45% hematocrit target or the 45%-50% range. Treatment was at the investigators’ discretion, although they were encouraged to give hydroxyurea to high-risk patients (those over age 65 or with a history of thrombosis).

The trial was closed earlier than planned, in February 2012, because of competition for patients from clinical trials of JAK-2 inhibitors.

Dr. Barbui presented data from an intention-to-treat analysis.

At a median follow-up of 31 months, 2.8% of patients in the less-than-45% group had experienced one or more of the events in the composite primary endpoint (stroke, acute coronary syndrome, transient ischemic attack, pulmonary embolism, abdominal thrombosis, deep vein thrombosis, or peripheral arterial thrombosis), compared with 9.8% of those in the 45-50% group. The hazard ratio for the primary endpoint with the less intensive targeting strategy was 3.91 (P = .005).

The HR for total cardiovascular events (with superficial vein thrombosis thrown in for good measure) was 2.69 (P = .012).

Gender Disparity Noted

In an editorial accompanying the NEJM article, Dr. Jerry L. Spivak of the hematology/oncology division at Johns Hopkins University in Baltimore noted that women normally have a lower red-cell mass and hematocrit than men, putting women with polycythemia vera at risk for intra-abdominal venous thrombosis, even when their hematocrit appears to be normal.

"Therefore the hematocrit target described by [the investigators] is adequate for men but inadequate for women, who on the basis of other studies should have a target hematocrit of less than 42%," he wrote.

Dr. Barbui and Dr. Spivak reported no relevant conflicts of interest.

ATLANTA – Ponatinib succeeds when other drugs for chronic myeloid leukemia begin to fail, investigators reported at the annual meeting of the American Society of Hematology.

In heavily pretreated patients with relapsed or refractory chronic-phase chronic myeloid leukemia (CML), the investigational drug produced a major cytogenetic response (MCyR) in 56% of patients, and a complete cytogenetic response (CCyR) in 46% of patients – many of whom were resistant or intolerant to second- or third-line therapy with dasatinib (Sprycel) and nilotinib (Tasigna).

Approximately half of the patients carried the notorious T315I mutation that confers resistance to multiple tyrosine kinase inhibitors (TKIs), but not, evidently, to ponatinib, said Dr. Jorge Cortes from the University of Texas M.D. Anderson Cancer Center in Houston.

"These results suggest that ponatinib has outstanding clinical activity in patients with chronic myeloid leukemia, or Philadelphia [chromosome]-positive patients with acute lymphoblastic leukemia. These responses have been regardless of the stage of disease and regardless of the presence or absence of mutations. And the responses are very deep, rapid, and sustained to the extent of the follow-up we have so far, with a drug that is very well tolerated," he said at a press briefing.

Major responses, the primary endpoint, were also seen in patients with every other mutation commonly seen in clinic, Dr. Cortes said in an interview.

"This is potentially really huge," commented Dr. Aaron Schimmer, a clinician scientist at the Princess Margaret Cancer Centre of the University Health Network in Toronto.

"From a broad scientific perspective, when you think about it, we’ve identified the cause of resistance in a mutation in patients receiving standard therapy, and now they’ve actually designed a drug that specifically works on that mutation," he said in an interview.

"From a patient’s standpoint, think of the patients who no longer respond to standard tyrosine kinase inhibitors: Their options at this point are exceptionally limited, survival rates are not good, and now we’ve got a new drug that’s very well tolerated and is producing response rates in a high percentage of these patients, and that’s really amazing at that individual level," he added.

Ponatinib Blocks T315I

Dr. Cortes reported on 12-month follow-up data from the PACE (Ponatinib Ph+ ALL and CML Evaluation) trial, a single-arm study of oral ponatinib in 449 patients with chronic phase, accelerated phase, or blast phase CML and Ph-positive acute lymphocytic leukemia (ALL) who are resistant or intolerant to dasatinib or nilotinib or have the T315I mutation in BCR-ABL kinase.

Ponatinib is an oral pan-BCR-ABL tyrosine kinase inhibitor with potent activity against native and mutated BCR-ABL and other kinases, and was specially designed to thwart T315I’s ability to block other TKIs. Dr. Cortes explained.

Approximately 92% of patients in each of the three CML phase groups (patients with Ph-positive ALL were included in the blast-phase CML [BP-CML] group) had received at least two prior TKIs, and more than half (53%-60%) had received at least three.

Best MCyR rates to recent therapies were 26% in patients with chronic phase CML (CP-CML), 15% in those in accelerated phase (AP-CML), and 16% of those in BP-CML.

Among patients with CP-CML, those who were resistant to dasatinib or nilotinib 51% had a major cytogenetic response, as did 70% of patients with the T315I mutation. Among patients with AP-CML, 58% of resistant/intolerant patients and half of those with the mutation had a major hematologic response (MaHR). Among patients in the BP-CML group, the respective MaHR rates were 35% and 33%.

Among the 267 patients in CP-CML, 67% had any cytogenetic response, 56% had a MCyR, 46% had a CCyR, and 34% had a major molecular response (MMR). The median time to MCyR was 2.8 months, and to MMR was 5.5 months.

Responses Durable at 1 Year

In all, 91% of patients with CP-CML and a MCyR were estimated to remain in response at 12 months.

As with other TKIs, the drug was well tolerated with the most common side effects being dry skin or skin rash, mostly mild and manageable. Grade 3 pancreatitis occurred in 6% of patients but was well managed, and only one patient had to discontinue because of this adverse event, Dr. Cortes said.

Dr. Cortes disclosed receiving research support and serving as a consultant to Aria, maker of ponatinib. Dr. Schimmer reported no relevant disclosures.

ATLANTA – Ponatinib succeeds when other drugs for chronic myeloid leukemia begin to fail, investigators reported at the annual meeting of the American Society of Hematology.

In heavily pretreated patients with relapsed or refractory chronic-phase chronic myeloid leukemia (CML), the investigational drug produced a major cytogenetic response (MCyR) in 56% of patients, and a complete cytogenetic response (CCyR) in 46% of patients – many of whom were resistant or intolerant to second- or third-line therapy with dasatinib (Sprycel) and nilotinib (Tasigna).

Approximately half of the patients carried the notorious T315I mutation that confers resistance to multiple tyrosine kinase inhibitors (TKIs), but not, evidently, to ponatinib, said Dr. Jorge Cortes from the University of Texas M.D. Anderson Cancer Center in Houston.

"These results suggest that ponatinib has outstanding clinical activity in patients with chronic myeloid leukemia, or Philadelphia [chromosome]-positive patients with acute lymphoblastic leukemia. These responses have been regardless of the stage of disease and regardless of the presence or absence of mutations. And the responses are very deep, rapid, and sustained to the extent of the follow-up we have so far, with a drug that is very well tolerated," he said at a press briefing.

Major responses, the primary endpoint, were also seen in patients with every other mutation commonly seen in clinic, Dr. Cortes said in an interview.

"This is potentially really huge," commented Dr. Aaron Schimmer, a clinician scientist at the Princess Margaret Cancer Centre of the University Health Network in Toronto.

"From a broad scientific perspective, when you think about it, we’ve identified the cause of resistance in a mutation in patients receiving standard therapy, and now they’ve actually designed a drug that specifically works on that mutation," he said in an interview.

"From a patient’s standpoint, think of the patients who no longer respond to standard tyrosine kinase inhibitors: Their options at this point are exceptionally limited, survival rates are not good, and now we’ve got a new drug that’s very well tolerated and is producing response rates in a high percentage of these patients, and that’s really amazing at that individual level," he added.

Ponatinib Blocks T315I

Dr. Cortes reported on 12-month follow-up data from the PACE (Ponatinib Ph+ ALL and CML Evaluation) trial, a single-arm study of oral ponatinib in 449 patients with chronic phase, accelerated phase, or blast phase CML and Ph-positive acute lymphocytic leukemia (ALL) who are resistant or intolerant to dasatinib or nilotinib or have the T315I mutation in BCR-ABL kinase.

Ponatinib is an oral pan-BCR-ABL tyrosine kinase inhibitor with potent activity against native and mutated BCR-ABL and other kinases, and was specially designed to thwart T315I’s ability to block other TKIs. Dr. Cortes explained.

Approximately 92% of patients in each of the three CML phase groups (patients with Ph-positive ALL were included in the blast-phase CML [BP-CML] group) had received at least two prior TKIs, and more than half (53%-60%) had received at least three.

Best MCyR rates to recent therapies were 26% in patients with chronic phase CML (CP-CML), 15% in those in accelerated phase (AP-CML), and 16% of those in BP-CML.

Among patients with CP-CML, those who were resistant to dasatinib or nilotinib 51% had a major cytogenetic response, as did 70% of patients with the T315I mutation. Among patients with AP-CML, 58% of resistant/intolerant patients and half of those with the mutation had a major hematologic response (MaHR). Among patients in the BP-CML group, the respective MaHR rates were 35% and 33%.

Among the 267 patients in CP-CML, 67% had any cytogenetic response, 56% had a MCyR, 46% had a CCyR, and 34% had a major molecular response (MMR). The median time to MCyR was 2.8 months, and to MMR was 5.5 months.

Responses Durable at 1 Year

In all, 91% of patients with CP-CML and a MCyR were estimated to remain in response at 12 months.

As with other TKIs, the drug was well tolerated with the most common side effects being dry skin or skin rash, mostly mild and manageable. Grade 3 pancreatitis occurred in 6% of patients but was well managed, and only one patient had to discontinue because of this adverse event, Dr. Cortes said.

Dr. Cortes disclosed receiving research support and serving as a consultant to Aria, maker of ponatinib. Dr. Schimmer reported no relevant disclosures.

ATLANTA – Ponatinib succeeds when other drugs for chronic myeloid leukemia begin to fail, investigators reported at the annual meeting of the American Society of Hematology.

In heavily pretreated patients with relapsed or refractory chronic-phase chronic myeloid leukemia (CML), the investigational drug produced a major cytogenetic response (MCyR) in 56% of patients, and a complete cytogenetic response (CCyR) in 46% of patients – many of whom were resistant or intolerant to second- or third-line therapy with dasatinib (Sprycel) and nilotinib (Tasigna).

Approximately half of the patients carried the notorious T315I mutation that confers resistance to multiple tyrosine kinase inhibitors (TKIs), but not, evidently, to ponatinib, said Dr. Jorge Cortes from the University of Texas M.D. Anderson Cancer Center in Houston.

"These results suggest that ponatinib has outstanding clinical activity in patients with chronic myeloid leukemia, or Philadelphia [chromosome]-positive patients with acute lymphoblastic leukemia. These responses have been regardless of the stage of disease and regardless of the presence or absence of mutations. And the responses are very deep, rapid, and sustained to the extent of the follow-up we have so far, with a drug that is very well tolerated," he said at a press briefing.

Major responses, the primary endpoint, were also seen in patients with every other mutation commonly seen in clinic, Dr. Cortes said in an interview.

"This is potentially really huge," commented Dr. Aaron Schimmer, a clinician scientist at the Princess Margaret Cancer Centre of the University Health Network in Toronto.

"From a broad scientific perspective, when you think about it, we’ve identified the cause of resistance in a mutation in patients receiving standard therapy, and now they’ve actually designed a drug that specifically works on that mutation," he said in an interview.

"From a patient’s standpoint, think of the patients who no longer respond to standard tyrosine kinase inhibitors: Their options at this point are exceptionally limited, survival rates are not good, and now we’ve got a new drug that’s very well tolerated and is producing response rates in a high percentage of these patients, and that’s really amazing at that individual level," he added.

Ponatinib Blocks T315I

Dr. Cortes reported on 12-month follow-up data from the PACE (Ponatinib Ph+ ALL and CML Evaluation) trial, a single-arm study of oral ponatinib in 449 patients with chronic phase, accelerated phase, or blast phase CML and Ph-positive acute lymphocytic leukemia (ALL) who are resistant or intolerant to dasatinib or nilotinib or have the T315I mutation in BCR-ABL kinase.

Ponatinib is an oral pan-BCR-ABL tyrosine kinase inhibitor with potent activity against native and mutated BCR-ABL and other kinases, and was specially designed to thwart T315I’s ability to block other TKIs. Dr. Cortes explained.

Approximately 92% of patients in each of the three CML phase groups (patients with Ph-positive ALL were included in the blast-phase CML [BP-CML] group) had received at least two prior TKIs, and more than half (53%-60%) had received at least three.

Best MCyR rates to recent therapies were 26% in patients with chronic phase CML (CP-CML), 15% in those in accelerated phase (AP-CML), and 16% of those in BP-CML.

Among patients with CP-CML, those who were resistant to dasatinib or nilotinib 51% had a major cytogenetic response, as did 70% of patients with the T315I mutation. Among patients with AP-CML, 58% of resistant/intolerant patients and half of those with the mutation had a major hematologic response (MaHR). Among patients in the BP-CML group, the respective MaHR rates were 35% and 33%.

Among the 267 patients in CP-CML, 67% had any cytogenetic response, 56% had a MCyR, 46% had a CCyR, and 34% had a major molecular response (MMR). The median time to MCyR was 2.8 months, and to MMR was 5.5 months.

Responses Durable at 1 Year

In all, 91% of patients with CP-CML and a MCyR were estimated to remain in response at 12 months.

As with other TKIs, the drug was well tolerated with the most common side effects being dry skin or skin rash, mostly mild and manageable. Grade 3 pancreatitis occurred in 6% of patients but was well managed, and only one patient had to discontinue because of this adverse event, Dr. Cortes said.

Dr. Cortes disclosed receiving research support and serving as a consultant to Aria, maker of ponatinib. Dr. Schimmer reported no relevant disclosures.

ATLANTA – Children with standard-risk B-lineage acute lymphoblastic leukemia can be safely spared from at least some of the toxicity associated with anthracyclines, the results of a randomized clinical trial suggest.

The 5-year overall survival rate among children with B-cell lineage acute lymphoblastic leukemia (ALL) treated without daunorubicin in the induction regimen was 98%, compared with 97.3% of those who received the anthracycline, Dr. Andre Baruchel reported at the annual meeting of the American Society of Hematology.

Event-free survival rates 5 years after randomization were also virtually identical, at 92.8% without daunorubicin and 92.6% with daunorubicin, said Dr. Baruchel, head of the pediatric hematology department at Robert Debré University Hospital (Assistance Publique Hôpitaux) in Paris.

"There was no difference in terms of complete remission rate, MRD [minimal residual disease] levels, event-free survival, overall survival, [and] cumulative incidence of relapse, secondary malignancy. Whatever the criteria you choose for trying to capture any difference between receiving or not receiving daunorubicin in these patients, you cannot find it," he said.

By cutting daunorubicin out of the induction phase, the investigators were able to reduce the total cumulative dose from 155 mg/m² to 75 mg/m².

Children with standard-risk B-cell lineage ALL comprise about 55%-60% of all cases, and generally have the best prognosis with modern chemotherapy, with overall survival rates hovering around 90%.

Anthracyclines were introduced in the late 1970s, and have become a mainstay for ALL therapy in both children and adults, but the evidence for including them in induction regimens has been weak, Dr. Baruchel said. He noted that a recent Cochrane Review of randomized studies of anthracyclines in leukemia found only three studies with sufficiently robust evidence, and none had been performed within the last 20 years.

Furthermore, anthracycline use varies with different protocols and risk groups, making it difficult to get a clear picture of their efficacy up front in ALL. What is clear, however, is that anthracyclines carry significant risk of both myelosuppression and cardiotoxicity, Dr. Baruchel said.

Hold the Daunorubicin?

To see whether they could safely eliminate daunorubicin from the induction regimen, the authors looked at 1,195 patients with standard-risk B-cell lineage ALL treated in the FRALLE 2000-A trial. The children, who ranged from 1 to 9 years in age, were treated with an induction regimen of prednisone prephase plus intrathecal methotrexate, dexamethasone 6 mg/m² per day, vincristine, and L-asparaginase 6000 IU/m² for nine infusions. Children were assessed for blood response on day 8, with a good response defined as less than 1000 blasts/mm³, and for an M1 bone marrow response on day 21 (less than 5% blasts).

In all, 94.7% of patients had a day 21 bone marrow morphology response, and 1,128 of these children were then randomized to either daunorubicin 40 mg/m² on day 22 and day 29 (560 patients) or no daunorubicin (568).

The children were also assessed on day 35 for an end-of-induction response with bone marrow morphology and DNA-based polymerase chain reaction for MRD. The 61 patients who were not randomized because of inadequate bone marrow morphology received two infusions of daunorubicin.

Patients in the randomized phase went on to a 12-week-consolidation phase with vincristine, dexamethasone, mercaptopurine, and oral methotrexate. Consolidation was followed by a first delayed intensification phase, up to a total cumulative dose of daunorubicin of 75 mg/m², interphase therapy, second delayed intensification, and a 24-month maintenance phase. Details of the regimen can be found in the abstract.

A molecular analysis showed that there was no difference in minimal residual disease measured at either 10^-2 or 10^-3 thresholds. Dr. Baruchel commented that there could possibly be a difference detected with more sensitive thresholds.

Similar Results in 1980s

Dr. William G. Woods, director of hematology/oncology at the Aflac Cancer Center and Blood Disorders Service at Children’s Healthcare of Atlanta, commented that similar trials were conducted in the United States in the late 1980s in standard-risk ALL, which showed that it was possible to safely eliminate daunorubicin from induction regimens.

Dr. Woods was not involved in the study, but moderated the briefing at which the data were presented.

Dr. Baruchel and Dr. Woods declared that they have no relevant conflicts of interest.

ATLANTA – Children with standard-risk B-lineage acute lymphoblastic leukemia can be safely spared from at least some of the toxicity associated with anthracyclines, the results of a randomized clinical trial suggest.

The 5-year overall survival rate among children with B-cell lineage acute lymphoblastic leukemia (ALL) treated without daunorubicin in the induction regimen was 98%, compared with 97.3% of those who received the anthracycline, Dr. Andre Baruchel reported at the annual meeting of the American Society of Hematology.

Event-free survival rates 5 years after randomization were also virtually identical, at 92.8% without daunorubicin and 92.6% with daunorubicin, said Dr. Baruchel, head of the pediatric hematology department at Robert Debré University Hospital (Assistance Publique Hôpitaux) in Paris.

"There was no difference in terms of complete remission rate, MRD [minimal residual disease] levels, event-free survival, overall survival, [and] cumulative incidence of relapse, secondary malignancy. Whatever the criteria you choose for trying to capture any difference between receiving or not receiving daunorubicin in these patients, you cannot find it," he said.

By cutting daunorubicin out of the induction phase, the investigators were able to reduce the total cumulative dose from 155 mg/m² to 75 mg/m².

Children with standard-risk B-cell lineage ALL comprise about 55%-60% of all cases, and generally have the best prognosis with modern chemotherapy, with overall survival rates hovering around 90%.

Anthracyclines were introduced in the late 1970s, and have become a mainstay for ALL therapy in both children and adults, but the evidence for including them in induction regimens has been weak, Dr. Baruchel said. He noted that a recent Cochrane Review of randomized studies of anthracyclines in leukemia found only three studies with sufficiently robust evidence, and none had been performed within the last 20 years.

Furthermore, anthracycline use varies with different protocols and risk groups, making it difficult to get a clear picture of their efficacy up front in ALL. What is clear, however, is that anthracyclines carry significant risk of both myelosuppression and cardiotoxicity, Dr. Baruchel said.

Hold the Daunorubicin?

To see whether they could safely eliminate daunorubicin from the induction regimen, the authors looked at 1,195 patients with standard-risk B-cell lineage ALL treated in the FRALLE 2000-A trial. The children, who ranged from 1 to 9 years in age, were treated with an induction regimen of prednisone prephase plus intrathecal methotrexate, dexamethasone 6 mg/m² per day, vincristine, and L-asparaginase 6000 IU/m² for nine infusions. Children were assessed for blood response on day 8, with a good response defined as less than 1000 blasts/mm³, and for an M1 bone marrow response on day 21 (less than 5% blasts).

In all, 94.7% of patients had a day 21 bone marrow morphology response, and 1,128 of these children were then randomized to either daunorubicin 40 mg/m² on day 22 and day 29 (560 patients) or no daunorubicin (568).

The children were also assessed on day 35 for an end-of-induction response with bone marrow morphology and DNA-based polymerase chain reaction for MRD. The 61 patients who were not randomized because of inadequate bone marrow morphology received two infusions of daunorubicin.

Patients in the randomized phase went on to a 12-week-consolidation phase with vincristine, dexamethasone, mercaptopurine, and oral methotrexate. Consolidation was followed by a first delayed intensification phase, up to a total cumulative dose of daunorubicin of 75 mg/m², interphase therapy, second delayed intensification, and a 24-month maintenance phase. Details of the regimen can be found in the abstract.

A molecular analysis showed that there was no difference in minimal residual disease measured at either 10^-2 or 10^-3 thresholds. Dr. Baruchel commented that there could possibly be a difference detected with more sensitive thresholds.

Similar Results in 1980s

Dr. William G. Woods, director of hematology/oncology at the Aflac Cancer Center and Blood Disorders Service at Children’s Healthcare of Atlanta, commented that similar trials were conducted in the United States in the late 1980s in standard-risk ALL, which showed that it was possible to safely eliminate daunorubicin from induction regimens.

Dr. Woods was not involved in the study, but moderated the briefing at which the data were presented.

Dr. Baruchel and Dr. Woods declared that they have no relevant conflicts of interest.

ATLANTA – Children with standard-risk B-lineage acute lymphoblastic leukemia can be safely spared from at least some of the toxicity associated with anthracyclines, the results of a randomized clinical trial suggest.

The 5-year overall survival rate among children with B-cell lineage acute lymphoblastic leukemia (ALL) treated without daunorubicin in the induction regimen was 98%, compared with 97.3% of those who received the anthracycline, Dr. Andre Baruchel reported at the annual meeting of the American Society of Hematology.

Event-free survival rates 5 years after randomization were also virtually identical, at 92.8% without daunorubicin and 92.6% with daunorubicin, said Dr. Baruchel, head of the pediatric hematology department at Robert Debré University Hospital (Assistance Publique Hôpitaux) in Paris.

"There was no difference in terms of complete remission rate, MRD [minimal residual disease] levels, event-free survival, overall survival, [and] cumulative incidence of relapse, secondary malignancy. Whatever the criteria you choose for trying to capture any difference between receiving or not receiving daunorubicin in these patients, you cannot find it," he said.

By cutting daunorubicin out of the induction phase, the investigators were able to reduce the total cumulative dose from 155 mg/m² to 75 mg/m².

Children with standard-risk B-cell lineage ALL comprise about 55%-60% of all cases, and generally have the best prognosis with modern chemotherapy, with overall survival rates hovering around 90%.

Anthracyclines were introduced in the late 1970s, and have become a mainstay for ALL therapy in both children and adults, but the evidence for including them in induction regimens has been weak, Dr. Baruchel said. He noted that a recent Cochrane Review of randomized studies of anthracyclines in leukemia found only three studies with sufficiently robust evidence, and none had been performed within the last 20 years.

Furthermore, anthracycline use varies with different protocols and risk groups, making it difficult to get a clear picture of their efficacy up front in ALL. What is clear, however, is that anthracyclines carry significant risk of both myelosuppression and cardiotoxicity, Dr. Baruchel said.

Hold the Daunorubicin?

To see whether they could safely eliminate daunorubicin from the induction regimen, the authors looked at 1,195 patients with standard-risk B-cell lineage ALL treated in the FRALLE 2000-A trial. The children, who ranged from 1 to 9 years in age, were treated with an induction regimen of prednisone prephase plus intrathecal methotrexate, dexamethasone 6 mg/m² per day, vincristine, and L-asparaginase 6000 IU/m² for nine infusions. Children were assessed for blood response on day 8, with a good response defined as less than 1000 blasts/mm³, and for an M1 bone marrow response on day 21 (less than 5% blasts).

In all, 94.7% of patients had a day 21 bone marrow morphology response, and 1,128 of these children were then randomized to either daunorubicin 40 mg/m² on day 22 and day 29 (560 patients) or no daunorubicin (568).

The children were also assessed on day 35 for an end-of-induction response with bone marrow morphology and DNA-based polymerase chain reaction for MRD. The 61 patients who were not randomized because of inadequate bone marrow morphology received two infusions of daunorubicin.

Patients in the randomized phase went on to a 12-week-consolidation phase with vincristine, dexamethasone, mercaptopurine, and oral methotrexate. Consolidation was followed by a first delayed intensification phase, up to a total cumulative dose of daunorubicin of 75 mg/m², interphase therapy, second delayed intensification, and a 24-month maintenance phase. Details of the regimen can be found in the abstract.

A molecular analysis showed that there was no difference in minimal residual disease measured at either 10^-2 or 10^-3 thresholds. Dr. Baruchel commented that there could possibly be a difference detected with more sensitive thresholds.

Similar Results in 1980s

Dr. William G. Woods, director of hematology/oncology at the Aflac Cancer Center and Blood Disorders Service at Children’s Healthcare of Atlanta, commented that similar trials were conducted in the United States in the late 1980s in standard-risk ALL, which showed that it was possible to safely eliminate daunorubicin from induction regimens.

Dr. Woods was not involved in the study, but moderated the briefing at which the data were presented.

Dr. Baruchel and Dr. Woods declared that they have no relevant conflicts of interest.

ATLANTA – The experimental oral therapy ibrutinib produces dramatic responses but dodges the significant toxicity seen in conventional treatments for chronic lymphocytic leukemia and small lymphocytic lymphoma.

In one of two phase II trials, the overall response rate was 68% in previously untreated patients and 71% in patients with relapsed or refractory chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL).

The outcome was similar in patients with high-risk relapsed or refractory disease, with the possible exception of those with chromosome 17p deletion. However, with more than half responding, these patients still do better with ibrutinib than with any other therapy explored to date, said Dr. John C. Byrd, director of hematology at Ohio State Comprehensive Cancer Center in Columbus.

"Ibrutinib offers great potential to significantly change the treatment landscape of CLL," he said at a press briefing at the annual meeting of the American Society of Hematology.

In the second trial, combining ibrutinib with the anti-CD20 antibody rituximab (Rituxan) pushed the overall response rate to 83% in high-risk CLL and SLL, said Dr. Jan A. Burger, of the University of Texas M.D. Anderson Cancer Center in Houston.

He noted that several ongoing phase III trials are underway that should accelerate the development of ibrutinib for high-risk patients, who have a high unmet need for alternative treatments.

Ibrutinib is currently not available, even under compassionate use. Despite this, the drug is generating much enthusiasm among clinicians and patients, with some traveling great distances to get into these ongoing trials despite only a 50-50 chance of receiving the drug, said press briefing moderator Dr. Claire Dearden, head of the CLL unit at the Royal Marsden NHS Foundation Trust in London.

"It’s orally active, it’s well tolerated, it’s not chemo, and it produces excellent responses, particularly in patients who are elderly and frail and not necessarily suitable for the more intensive chemotherapy regimens that have become the first-line treatment for the younger, fitter patients," she said.

Ibrutinib, formerly known as PCI-32765, is the first irreversible inhibitor of Bruton’s tyrosine kinase (BTK) to enter clinical development. BTK is essential for B-cell receptor signaling, chemokine-mediated migration and adhesion, and toll-like receptor signaling.

96% Survival Estimates at 22 Months

Dr. Byrd reported new and updated results from 31 patients with treatment naive CLL or SLL, 61 with relapsed or refractory disease, and 24 with high-risk relapsed or refractory disease (defined as progression within 24 months of starting a regimen containing at least a nucleoside analogue or bendamustine in combination with a monoclonal antibody or failure to respond to such a regimen).

Patients were given ibrutinib 420 mg or 840 mg daily 2 hours before food until disease progression or intolerable toxicity. Their median age was 72.

After follow-up ranging from 14.7 months to 22.1 months, complete responses occurred in 10% of treatment-naive patients and 2% of relapsed or refractory patients, Dr. Byrd said. Partial responses occurred in 58% and 68%.

At 22 months, progression-free and overall survival estimates were both 96% among previously untreated patients. To put these results in perspective, he said, that with standard cytotoxic chemotherapy, one would expect this number to be 70% or less if patients are young and 50% or less if elderly. "So these are really dramatic results," he added.

In the relapsed or refractory group, progression-free survival was 76% and overall survival 85%.

Longer follow-up is needed to determine whether the remissions are durable once ibrutinib is stopped – something currently being studied more than a decade after clinicians began using another kinase inhibitor, imatinib (Gleevec), to treat chronic myeloid leukemia, Dr. Byrd said.

He reported 3 grade 3 and no grade 4 infections in treatment-naive patients, and 26 grade 3 infections and 4 grade 4 events in relapsed/refractory patients.

Nearly All Still on Study in Combination Trial

In the second trial, 40 patients received continuous ibrutinib 420 mg daily plus weekly rituximab 365 mg/m² for 4 weeks, followed by daily ibrutinib plus monthly rituximab until month 6, followed by single-agent ibrutinib. High-risk CLL/SLL was defined as deletion 17p, TP53 mutation, deletion 11q, or less than 3 years remission after first-line chemo-immunotherapy. More than half of patients (58%) had stage IV disease.

After 3-6 months’ follow-up, there were 1 complete response, 32 partial responses, and 3 partial responses with lymphocytosis, Dr. Burger said. In all, 84% of patients experienced more than a 50% reduction in lymph node size.

At the time of the analysis, 95% of all patients and 90% with del 17p continued on therapy without disease progression.

Two patients came off study; one with pneumonia and an intracranial abscess, who died, and another who discontinued due to mucositis/ulcers after four cycles.

Severe toxicities were uncommon in both studies, particularly the considerable immunosuppression and serious infections associated with standard chemo-immunotherapy, the investigators said. The most common event was diarrhea, which was experienced by 54% of patients receiving ibrutinib monotherapy and was largely grade 1 or 2 and resolved after the first couple of cycles, Dr. Byrd said.

Other events included fatigue (29%), upper respiratory infection (29%), rash (28%), nausea (26%) and bone pain (25%). Rates were similar in the combination therapy trial, with bruising also seen in both trials

One of the ongoing phase III trials is the 350-patient RESONATE study evaluating ibrutinib versus ofatumumab (Arzerra) in patients with relapsed or refractory CLL or SLL.

Dr. Byrd disclosed research funding from the study sponsor Pharmacyclics, which is developing ibrutinib. Dr. Burger reported consulting for and research funding from Pharmacyclics. Co-authors of both studies are Pharmacyclics employees. Dr. Dearden disclosed no conflicts of interest.

ATLANTA – The experimental oral therapy ibrutinib produces dramatic responses but dodges the significant toxicity seen in conventional treatments for chronic lymphocytic leukemia and small lymphocytic lymphoma.

In one of two phase II trials, the overall response rate was 68% in previously untreated patients and 71% in patients with relapsed or refractory chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL).

The outcome was similar in patients with high-risk relapsed or refractory disease, with the possible exception of those with chromosome 17p deletion. However, with more than half responding, these patients still do better with ibrutinib than with any other therapy explored to date, said Dr. John C. Byrd, director of hematology at Ohio State Comprehensive Cancer Center in Columbus.

"Ibrutinib offers great potential to significantly change the treatment landscape of CLL," he said at a press briefing at the annual meeting of the American Society of Hematology.

In the second trial, combining ibrutinib with the anti-CD20 antibody rituximab (Rituxan) pushed the overall response rate to 83% in high-risk CLL and SLL, said Dr. Jan A. Burger, of the University of Texas M.D. Anderson Cancer Center in Houston.

He noted that several ongoing phase III trials are underway that should accelerate the development of ibrutinib for high-risk patients, who have a high unmet need for alternative treatments.

Ibrutinib is currently not available, even under compassionate use. Despite this, the drug is generating much enthusiasm among clinicians and patients, with some traveling great distances to get into these ongoing trials despite only a 50-50 chance of receiving the drug, said press briefing moderator Dr. Claire Dearden, head of the CLL unit at the Royal Marsden NHS Foundation Trust in London.

"It’s orally active, it’s well tolerated, it’s not chemo, and it produces excellent responses, particularly in patients who are elderly and frail and not necessarily suitable for the more intensive chemotherapy regimens that have become the first-line treatment for the younger, fitter patients," she said.

Ibrutinib, formerly known as PCI-32765, is the first irreversible inhibitor of Bruton’s tyrosine kinase (BTK) to enter clinical development. BTK is essential for B-cell receptor signaling, chemokine-mediated migration and adhesion, and toll-like receptor signaling.

96% Survival Estimates at 22 Months

Dr. Byrd reported new and updated results from 31 patients with treatment naive CLL or SLL, 61 with relapsed or refractory disease, and 24 with high-risk relapsed or refractory disease (defined as progression within 24 months of starting a regimen containing at least a nucleoside analogue or bendamustine in combination with a monoclonal antibody or failure to respond to such a regimen).

Patients were given ibrutinib 420 mg or 840 mg daily 2 hours before food until disease progression or intolerable toxicity. Their median age was 72.

After follow-up ranging from 14.7 months to 22.1 months, complete responses occurred in 10% of treatment-naive patients and 2% of relapsed or refractory patients, Dr. Byrd said. Partial responses occurred in 58% and 68%.

At 22 months, progression-free and overall survival estimates were both 96% among previously untreated patients. To put these results in perspective, he said, that with standard cytotoxic chemotherapy, one would expect this number to be 70% or less if patients are young and 50% or less if elderly. "So these are really dramatic results," he added.

In the relapsed or refractory group, progression-free survival was 76% and overall survival 85%.

Longer follow-up is needed to determine whether the remissions are durable once ibrutinib is stopped – something currently being studied more than a decade after clinicians began using another kinase inhibitor, imatinib (Gleevec), to treat chronic myeloid leukemia, Dr. Byrd said.

He reported 3 grade 3 and no grade 4 infections in treatment-naive patients, and 26 grade 3 infections and 4 grade 4 events in relapsed/refractory patients.

Nearly All Still on Study in Combination Trial

In the second trial, 40 patients received continuous ibrutinib 420 mg daily plus weekly rituximab 365 mg/m² for 4 weeks, followed by daily ibrutinib plus monthly rituximab until month 6, followed by single-agent ibrutinib. High-risk CLL/SLL was defined as deletion 17p, TP53 mutation, deletion 11q, or less than 3 years remission after first-line chemo-immunotherapy. More than half of patients (58%) had stage IV disease.

After 3-6 months’ follow-up, there were 1 complete response, 32 partial responses, and 3 partial responses with lymphocytosis, Dr. Burger said. In all, 84% of patients experienced more than a 50% reduction in lymph node size.

At the time of the analysis, 95% of all patients and 90% with del 17p continued on therapy without disease progression.

Two patients came off study; one with pneumonia and an intracranial abscess, who died, and another who discontinued due to mucositis/ulcers after four cycles.

Severe toxicities were uncommon in both studies, particularly the considerable immunosuppression and serious infections associated with standard chemo-immunotherapy, the investigators said. The most common event was diarrhea, which was experienced by 54% of patients receiving ibrutinib monotherapy and was largely grade 1 or 2 and resolved after the first couple of cycles, Dr. Byrd said.

Other events included fatigue (29%), upper respiratory infection (29%), rash (28%), nausea (26%) and bone pain (25%). Rates were similar in the combination therapy trial, with bruising also seen in both trials

One of the ongoing phase III trials is the 350-patient RESONATE study evaluating ibrutinib versus ofatumumab (Arzerra) in patients with relapsed or refractory CLL or SLL.

Dr. Byrd disclosed research funding from the study sponsor Pharmacyclics, which is developing ibrutinib. Dr. Burger reported consulting for and research funding from Pharmacyclics. Co-authors of both studies are Pharmacyclics employees. Dr. Dearden disclosed no conflicts of interest.

ATLANTA – The experimental oral therapy ibrutinib produces dramatic responses but dodges the significant toxicity seen in conventional treatments for chronic lymphocytic leukemia and small lymphocytic lymphoma.

In one of two phase II trials, the overall response rate was 68% in previously untreated patients and 71% in patients with relapsed or refractory chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL).

The outcome was similar in patients with high-risk relapsed or refractory disease, with the possible exception of those with chromosome 17p deletion. However, with more than half responding, these patients still do better with ibrutinib than with any other therapy explored to date, said Dr. John C. Byrd, director of hematology at Ohio State Comprehensive Cancer Center in Columbus.

"Ibrutinib offers great potential to significantly change the treatment landscape of CLL," he said at a press briefing at the annual meeting of the American Society of Hematology.

In the second trial, combining ibrutinib with the anti-CD20 antibody rituximab (Rituxan) pushed the overall response rate to 83% in high-risk CLL and SLL, said Dr. Jan A. Burger, of the University of Texas M.D. Anderson Cancer Center in Houston.

He noted that several ongoing phase III trials are underway that should accelerate the development of ibrutinib for high-risk patients, who have a high unmet need for alternative treatments.

Ibrutinib is currently not available, even under compassionate use. Despite this, the drug is generating much enthusiasm among clinicians and patients, with some traveling great distances to get into these ongoing trials despite only a 50-50 chance of receiving the drug, said press briefing moderator Dr. Claire Dearden, head of the CLL unit at the Royal Marsden NHS Foundation Trust in London.

"It’s orally active, it’s well tolerated, it’s not chemo, and it produces excellent responses, particularly in patients who are elderly and frail and not necessarily suitable for the more intensive chemotherapy regimens that have become the first-line treatment for the younger, fitter patients," she said.

Ibrutinib, formerly known as PCI-32765, is the first irreversible inhibitor of Bruton’s tyrosine kinase (BTK) to enter clinical development. BTK is essential for B-cell receptor signaling, chemokine-mediated migration and adhesion, and toll-like receptor signaling.

96% Survival Estimates at 22 Months

Dr. Byrd reported new and updated results from 31 patients with treatment naive CLL or SLL, 61 with relapsed or refractory disease, and 24 with high-risk relapsed or refractory disease (defined as progression within 24 months of starting a regimen containing at least a nucleoside analogue or bendamustine in combination with a monoclonal antibody or failure to respond to such a regimen).

Patients were given ibrutinib 420 mg or 840 mg daily 2 hours before food until disease progression or intolerable toxicity. Their median age was 72.

After follow-up ranging from 14.7 months to 22.1 months, complete responses occurred in 10% of treatment-naive patients and 2% of relapsed or refractory patients, Dr. Byrd said. Partial responses occurred in 58% and 68%.

At 22 months, progression-free and overall survival estimates were both 96% among previously untreated patients. To put these results in perspective, he said, that with standard cytotoxic chemotherapy, one would expect this number to be 70% or less if patients are young and 50% or less if elderly. "So these are really dramatic results," he added.

In the relapsed or refractory group, progression-free survival was 76% and overall survival 85%.

Longer follow-up is needed to determine whether the remissions are durable once ibrutinib is stopped – something currently being studied more than a decade after clinicians began using another kinase inhibitor, imatinib (Gleevec), to treat chronic myeloid leukemia, Dr. Byrd said.

He reported 3 grade 3 and no grade 4 infections in treatment-naive patients, and 26 grade 3 infections and 4 grade 4 events in relapsed/refractory patients.

Nearly All Still on Study in Combination Trial

In the second trial, 40 patients received continuous ibrutinib 420 mg daily plus weekly rituximab 365 mg/m² for 4 weeks, followed by daily ibrutinib plus monthly rituximab until month 6, followed by single-agent ibrutinib. High-risk CLL/SLL was defined as deletion 17p, TP53 mutation, deletion 11q, or less than 3 years remission after first-line chemo-immunotherapy. More than half of patients (58%) had stage IV disease.

After 3-6 months’ follow-up, there were 1 complete response, 32 partial responses, and 3 partial responses with lymphocytosis, Dr. Burger said. In all, 84% of patients experienced more than a 50% reduction in lymph node size.

At the time of the analysis, 95% of all patients and 90% with del 17p continued on therapy without disease progression.

Two patients came off study; one with pneumonia and an intracranial abscess, who died, and another who discontinued due to mucositis/ulcers after four cycles.

Severe toxicities were uncommon in both studies, particularly the considerable immunosuppression and serious infections associated with standard chemo-immunotherapy, the investigators said. The most common event was diarrhea, which was experienced by 54% of patients receiving ibrutinib monotherapy and was largely grade 1 or 2 and resolved after the first couple of cycles, Dr. Byrd said.

Other events included fatigue (29%), upper respiratory infection (29%), rash (28%), nausea (26%) and bone pain (25%). Rates were similar in the combination therapy trial, with bruising also seen in both trials

One of the ongoing phase III trials is the 350-patient RESONATE study evaluating ibrutinib versus ofatumumab (Arzerra) in patients with relapsed or refractory CLL or SLL.

Dr. Byrd disclosed research funding from the study sponsor Pharmacyclics, which is developing ibrutinib. Dr. Burger reported consulting for and research funding from Pharmacyclics. Co-authors of both studies are Pharmacyclics employees. Dr. Dearden disclosed no conflicts of interest.