SAN DIEGO – Induction therapy with obinutuzumab, a bioengineered CD20 inhibitor, induced a slightly higher overall response rate in induction therapy than did rituximab in patients with relapsed, CD20-positive indolent B-cell non-Hodgkin’s lymphoma, investigators reported at the annual meeting of the American Society of Hematology.

According to independent radiology reviewers who were blinded to treatment type, the overall response rate – a composite of complete responses (CR), CR-unconfirmed (CRu), and partial responses – was 44.6% at the end of induction among 74 patients with follicular lymphoma that was treated with obinutuzumab (Genentech’s GA101), compared with 26.7% of patients on rituximab (Rituxan) (P = .01), said Dr. Laurie H. Sehn, a medical oncologist at the University of British Columbia, Vancouver.

However, the overall response rate (ORR) by trial investigator ratings – the primary end point – showed a trend that was not significant, at 44.6% vs. 33.3% (P = .08). There is currently no difference in progression-free survival, said Dr. Sehn, on behalf of her colleagues in the phase II GAUSS trial, touted at the first head-to-head comparison of the two anti-CD20 antibodies.

Patients with other indolent lymphoma histologies were included in the trial, but Dr. Sehn reported full data on patients with follicular lymphomas only.

Obinutuzumab is considered to be a type II monoclonal antibody, shown in preclinical testing to have better ability than does rituximab to cause cell death and to invoke a cellular immune response, with lower complement-dependent cytotoxicity, Dr, Sehn said at a briefing on Dec. 11 in advance of presentation of the results on Dec. 12, 2011.

"As a single drug, rituximab really has had one of the most significant impacts in outcome in B-cell lymphomas in probably the last several decades, so there’s a real motivation to take it one step further and possibly develop a new anti-CD20 antibody that might work better than rituximab or one that may continue to work when rituximab stops working, so as to further improve outcomes," Dr, Sehn said.

A lymphoma specialist who was not involved in the GAUSS trial commented that despite rituximab’s significant benefits, new treatments still are needed, but whether obinutuzumab or another pretender is heir to rituximab’s throne is still unclear.

"We’ve been waiting for a better rituximab for some period of time. It has certainly been the major advance in the therapy of lymphomas in the last 10 to 12 years. The question is, can we do better? Genentech has made an attempt with obinutuzumab to improve the outcome for these patients who are still rituximab-sensitive," commented Dr. Ephraim P. Hochberg of the division of hematology/oncology at the Massachusetts General Hospital Cancer Center in Boston.

"The results are not overwhelming: there’s certainly a trend toward better progression-free survival, there’s a trend toward a slightly improved response rate, and a trend toward a slightly improved complete response rate, but this doesn’t look to be the home run that we might have hoped for with this patient population," he said.

The GAUSS trial is an ongoing, open-label, phase II study. Patients with relapsed CD20+ NHL who had a prior response lasting at least 6 months to a rituximab-containing regimen were randomly assigned to receive either rituximab 375 mg/m² IV weekly for 4 weeks or obinutuzumab 1 g IV weekly for 4 weeks. At the end of the induction phase, patients were assessed and those without disease progression continued with maintenance therapy on the same drug and dose every 2 months for up to 2 years.

In addition to the primary end point results shown above, they found that the best overall response rates by investigator determination occurred in 66.2% of patients on obinutuzumab (35.1% CR/Cru, and 31.1% partial response), and 64% among those on rituximab (18.7% CR/Cru, and 45.3% PR; P = .39). By independent review, the best ORR was 60.8% with obinutuzumab (27% CR/Cru, 33.8% PR), and 46.7% with rituximab (20% and 26.7%; P = .04).*

There were no differences in progression-survival with 39.2% of patients on obinutuzumab having an event at a median time to event of 17.3 months, compared with 34.7% of patients on rituximab with a median time to event of 17.4 months.

In the obinutuzumab arm, 93% of patients had at least one adverse event vs. 81% in the rituximab arm. There were no adverse events leading to death within 28 months of the last dose of obinutuzumab compared with 2 patients on rituximab. Adverse events leading to withdrawal occurred in 8% and 10%, respectively. The proportion of patients having at least one adverse event in each group was identical, at 14%.

Phase III trials with obinutuzumab are underway.

The study was supported by Roche. Dr. Sehn and three coauthors disclosed consulting and receiving honoraria and/or research funding from Roche/Genentech. Two coauthors are Roche employees. Dr. Hochberg has received consulting fees or research support from the company.

*Correction, 12/15/2011: The best overall response rate by independent review was incorrectly stated for rituximab. This version has been updated.

SAN DIEGO – Induction therapy with obinutuzumab, a bioengineered CD20 inhibitor, induced a slightly higher overall response rate in induction therapy than did rituximab in patients with relapsed, CD20-positive indolent B-cell non-Hodgkin’s lymphoma, investigators reported at the annual meeting of the American Society of Hematology.

According to independent radiology reviewers who were blinded to treatment type, the overall response rate – a composite of complete responses (CR), CR-unconfirmed (CRu), and partial responses – was 44.6% at the end of induction among 74 patients with follicular lymphoma that was treated with obinutuzumab (Genentech’s GA101), compared with 26.7% of patients on rituximab (Rituxan) (P = .01), said Dr. Laurie H. Sehn, a medical oncologist at the University of British Columbia, Vancouver.

However, the overall response rate (ORR) by trial investigator ratings – the primary end point – showed a trend that was not significant, at 44.6% vs. 33.3% (P = .08). There is currently no difference in progression-free survival, said Dr. Sehn, on behalf of her colleagues in the phase II GAUSS trial, touted at the first head-to-head comparison of the two anti-CD20 antibodies.

Patients with other indolent lymphoma histologies were included in the trial, but Dr. Sehn reported full data on patients with follicular lymphomas only.

Obinutuzumab is considered to be a type II monoclonal antibody, shown in preclinical testing to have better ability than does rituximab to cause cell death and to invoke a cellular immune response, with lower complement-dependent cytotoxicity, Dr, Sehn said at a briefing on Dec. 11 in advance of presentation of the results on Dec. 12, 2011.

"As a single drug, rituximab really has had one of the most significant impacts in outcome in B-cell lymphomas in probably the last several decades, so there’s a real motivation to take it one step further and possibly develop a new anti-CD20 antibody that might work better than rituximab or one that may continue to work when rituximab stops working, so as to further improve outcomes," Dr, Sehn said.

A lymphoma specialist who was not involved in the GAUSS trial commented that despite rituximab’s significant benefits, new treatments still are needed, but whether obinutuzumab or another pretender is heir to rituximab’s throne is still unclear.

"We’ve been waiting for a better rituximab for some period of time. It has certainly been the major advance in the therapy of lymphomas in the last 10 to 12 years. The question is, can we do better? Genentech has made an attempt with obinutuzumab to improve the outcome for these patients who are still rituximab-sensitive," commented Dr. Ephraim P. Hochberg of the division of hematology/oncology at the Massachusetts General Hospital Cancer Center in Boston.

"The results are not overwhelming: there’s certainly a trend toward better progression-free survival, there’s a trend toward a slightly improved response rate, and a trend toward a slightly improved complete response rate, but this doesn’t look to be the home run that we might have hoped for with this patient population," he said.

The GAUSS trial is an ongoing, open-label, phase II study. Patients with relapsed CD20+ NHL who had a prior response lasting at least 6 months to a rituximab-containing regimen were randomly assigned to receive either rituximab 375 mg/m² IV weekly for 4 weeks or obinutuzumab 1 g IV weekly for 4 weeks. At the end of the induction phase, patients were assessed and those without disease progression continued with maintenance therapy on the same drug and dose every 2 months for up to 2 years.

In addition to the primary end point results shown above, they found that the best overall response rates by investigator determination occurred in 66.2% of patients on obinutuzumab (35.1% CR/Cru, and 31.1% partial response), and 64% among those on rituximab (18.7% CR/Cru, and 45.3% PR; P = .39). By independent review, the best ORR was 60.8% with obinutuzumab (27% CR/Cru, 33.8% PR), and 46.7% with rituximab (20% and 26.7%; P = .04).*

There were no differences in progression-survival with 39.2% of patients on obinutuzumab having an event at a median time to event of 17.3 months, compared with 34.7% of patients on rituximab with a median time to event of 17.4 months.

In the obinutuzumab arm, 93% of patients had at least one adverse event vs. 81% in the rituximab arm. There were no adverse events leading to death within 28 months of the last dose of obinutuzumab compared with 2 patients on rituximab. Adverse events leading to withdrawal occurred in 8% and 10%, respectively. The proportion of patients having at least one adverse event in each group was identical, at 14%.

Phase III trials with obinutuzumab are underway.

The study was supported by Roche. Dr. Sehn and three coauthors disclosed consulting and receiving honoraria and/or research funding from Roche/Genentech. Two coauthors are Roche employees. Dr. Hochberg has received consulting fees or research support from the company.

*Correction, 12/15/2011: The best overall response rate by independent review was incorrectly stated for rituximab. This version has been updated.

SAN DIEGO – Induction therapy with obinutuzumab, a bioengineered CD20 inhibitor, induced a slightly higher overall response rate in induction therapy than did rituximab in patients with relapsed, CD20-positive indolent B-cell non-Hodgkin’s lymphoma, investigators reported at the annual meeting of the American Society of Hematology.

According to independent radiology reviewers who were blinded to treatment type, the overall response rate – a composite of complete responses (CR), CR-unconfirmed (CRu), and partial responses – was 44.6% at the end of induction among 74 patients with follicular lymphoma that was treated with obinutuzumab (Genentech’s GA101), compared with 26.7% of patients on rituximab (Rituxan) (P = .01), said Dr. Laurie H. Sehn, a medical oncologist at the University of British Columbia, Vancouver.

However, the overall response rate (ORR) by trial investigator ratings – the primary end point – showed a trend that was not significant, at 44.6% vs. 33.3% (P = .08). There is currently no difference in progression-free survival, said Dr. Sehn, on behalf of her colleagues in the phase II GAUSS trial, touted at the first head-to-head comparison of the two anti-CD20 antibodies.

Patients with other indolent lymphoma histologies were included in the trial, but Dr. Sehn reported full data on patients with follicular lymphomas only.

Obinutuzumab is considered to be a type II monoclonal antibody, shown in preclinical testing to have better ability than does rituximab to cause cell death and to invoke a cellular immune response, with lower complement-dependent cytotoxicity, Dr, Sehn said at a briefing on Dec. 11 in advance of presentation of the results on Dec. 12, 2011.

"As a single drug, rituximab really has had one of the most significant impacts in outcome in B-cell lymphomas in probably the last several decades, so there’s a real motivation to take it one step further and possibly develop a new anti-CD20 antibody that might work better than rituximab or one that may continue to work when rituximab stops working, so as to further improve outcomes," Dr, Sehn said.

A lymphoma specialist who was not involved in the GAUSS trial commented that despite rituximab’s significant benefits, new treatments still are needed, but whether obinutuzumab or another pretender is heir to rituximab’s throne is still unclear.

"We’ve been waiting for a better rituximab for some period of time. It has certainly been the major advance in the therapy of lymphomas in the last 10 to 12 years. The question is, can we do better? Genentech has made an attempt with obinutuzumab to improve the outcome for these patients who are still rituximab-sensitive," commented Dr. Ephraim P. Hochberg of the division of hematology/oncology at the Massachusetts General Hospital Cancer Center in Boston.

"The results are not overwhelming: there’s certainly a trend toward better progression-free survival, there’s a trend toward a slightly improved response rate, and a trend toward a slightly improved complete response rate, but this doesn’t look to be the home run that we might have hoped for with this patient population," he said.

The GAUSS trial is an ongoing, open-label, phase II study. Patients with relapsed CD20+ NHL who had a prior response lasting at least 6 months to a rituximab-containing regimen were randomly assigned to receive either rituximab 375 mg/m² IV weekly for 4 weeks or obinutuzumab 1 g IV weekly for 4 weeks. At the end of the induction phase, patients were assessed and those without disease progression continued with maintenance therapy on the same drug and dose every 2 months for up to 2 years.

In addition to the primary end point results shown above, they found that the best overall response rates by investigator determination occurred in 66.2% of patients on obinutuzumab (35.1% CR/Cru, and 31.1% partial response), and 64% among those on rituximab (18.7% CR/Cru, and 45.3% PR; P = .39). By independent review, the best ORR was 60.8% with obinutuzumab (27% CR/Cru, 33.8% PR), and 46.7% with rituximab (20% and 26.7%; P = .04).*

There were no differences in progression-survival with 39.2% of patients on obinutuzumab having an event at a median time to event of 17.3 months, compared with 34.7% of patients on rituximab with a median time to event of 17.4 months.

In the obinutuzumab arm, 93% of patients had at least one adverse event vs. 81% in the rituximab arm. There were no adverse events leading to death within 28 months of the last dose of obinutuzumab compared with 2 patients on rituximab. Adverse events leading to withdrawal occurred in 8% and 10%, respectively. The proportion of patients having at least one adverse event in each group was identical, at 14%.

Phase III trials with obinutuzumab are underway.

The study was supported by Roche. Dr. Sehn and three coauthors disclosed consulting and receiving honoraria and/or research funding from Roche/Genentech. Two coauthors are Roche employees. Dr. Hochberg has received consulting fees or research support from the company.

*Correction, 12/15/2011: The best overall response rate by independent review was incorrectly stated for rituximab. This version has been updated.

SAN DIEGO – In the long run, standard chemotherapy alone is more effective than radiation in keeping patients with limited-stage nonbulky Hodgkin’s lymphoma alive, according to updated results from an intergroup trial in 405 patients.

At 12 years, 94% of patients receiving ABVD – doxorubicin (Adriamycin), bleomycin (Blenoxane), vinblastine (Velbe), and dacarbazine – chemotherapy were alive, compared with 87% receiving subtotal nodal radiation with or without chemotherapy (hazard ratio for death, 0.50; P = .04).

Although 5-year data showed that patients treated with radiation experienced greater disease control, the survival advantage with chemotherapy resulted from a lower rate of death from other causes, Dr. Ralph M. Meyer said at the annual meeting of the American Society of Hematology.

A total of 12 patients in the ABVD arm died: six due to Hodgkin’s, four to a second cancer, and two due to cardiac causes. In contrast, 10 of the 24 deaths in the radiation arm were due to a second cancer. There were two deaths due to cardiac events, four to Hodgkin’s, three fatal infections, and five other deaths.

Dr. Meyer acknowledged that interpretation of the results is bound to be controversial because subtotal nodal radiation is no longer current practice as it is considered excessive. Patients today with low-risk stage IA or IIA nonbulky disease typically receive two cycles of ABVD with 20 Gy of involved-field radiation therapy. Although modern technology has reduced radiation exposure, radiation therapy would still include the coronary artery, heart, and substantial areas of the subdiaphragmatic, he said at a press briefing.

What is clear from the National Cancer Institute of Canada Clinical Trials Group and Eastern Cooperative Oncology Group study is that measures of disease control, like freedom from progressive disease, are not accurate surrogates for long-term overall survival in patients with stage I-II nonbulky Hodgkin’s lymphoma, said Dr. Meyer, director of the National Cancer Institute of Canada Clinical Trials Group.

"New proxies that predict for risks of late-treatment effects are needed," he said.

Trials are testing the use of PET scanning during therapy to identify patients who may receive chemotherapy alone. It is hypothesized that if PET scans are negative and patients are in remission after two cycles of chemotherapy, the cure rate will be high with further chemotherapy alone, whereas radiation therapy or some other form of chemotherapy should be considered if there is residual PET activity.

How the use of PET will alter current treatment management will be another contentious issue since results from ongoing trials are not expected for 2-3 years. Moreover, the trials are limited because they are using disease control and progression-free survival as end points, which the current trial has shown are not good proxies for overall survival, Dr. Meyer said.

"Thus it will cause issues and interpretation as to how to proceed with these results," he said.

Dr. Meyer and his associates randomly assigned 405 patients with previously untreated stage IA or IIA nonbulky Hodgkin’s lymphoma to receive ABVD chemotherapy alone or subtotal nodal radiation at a dose of 35 Gy in 20 daily fractions. Patients in the radiation group with a favorable risk profile received radiation only, while those with an unfavorable risk received two cycles of ABVD followed by radiation therapy. Median follow-up was 11.3 years.

At 12 years, freedom from disease progression was 92% with radiation vs. 87% with ABVD chemotherapy (HR, 1.91; P = .05,), Dr. Meyer said. Event-free survival was similar at 80% with radiation therapy and 85% with ABVD (HR, 0.88; P = .60).

The results were simultaneously published in the New England Journal of Medicine (N. Engl. J. Med. 2011 [doi:10.1056/NEJMoa1111961]).

Dr. Meyer reported honoraria from Lilly and Celgene.

SAN DIEGO – In the long run, standard chemotherapy alone is more effective than radiation in keeping patients with limited-stage nonbulky Hodgkin’s lymphoma alive, according to updated results from an intergroup trial in 405 patients.

At 12 years, 94% of patients receiving ABVD – doxorubicin (Adriamycin), bleomycin (Blenoxane), vinblastine (Velbe), and dacarbazine – chemotherapy were alive, compared with 87% receiving subtotal nodal radiation with or without chemotherapy (hazard ratio for death, 0.50; P = .04).

Although 5-year data showed that patients treated with radiation experienced greater disease control, the survival advantage with chemotherapy resulted from a lower rate of death from other causes, Dr. Ralph M. Meyer said at the annual meeting of the American Society of Hematology.

A total of 12 patients in the ABVD arm died: six due to Hodgkin’s, four to a second cancer, and two due to cardiac causes. In contrast, 10 of the 24 deaths in the radiation arm were due to a second cancer. There were two deaths due to cardiac events, four to Hodgkin’s, three fatal infections, and five other deaths.

Dr. Meyer acknowledged that interpretation of the results is bound to be controversial because subtotal nodal radiation is no longer current practice as it is considered excessive. Patients today with low-risk stage IA or IIA nonbulky disease typically receive two cycles of ABVD with 20 Gy of involved-field radiation therapy. Although modern technology has reduced radiation exposure, radiation therapy would still include the coronary artery, heart, and substantial areas of the subdiaphragmatic, he said at a press briefing.

What is clear from the National Cancer Institute of Canada Clinical Trials Group and Eastern Cooperative Oncology Group study is that measures of disease control, like freedom from progressive disease, are not accurate surrogates for long-term overall survival in patients with stage I-II nonbulky Hodgkin’s lymphoma, said Dr. Meyer, director of the National Cancer Institute of Canada Clinical Trials Group.

"New proxies that predict for risks of late-treatment effects are needed," he said.

Trials are testing the use of PET scanning during therapy to identify patients who may receive chemotherapy alone. It is hypothesized that if PET scans are negative and patients are in remission after two cycles of chemotherapy, the cure rate will be high with further chemotherapy alone, whereas radiation therapy or some other form of chemotherapy should be considered if there is residual PET activity.

How the use of PET will alter current treatment management will be another contentious issue since results from ongoing trials are not expected for 2-3 years. Moreover, the trials are limited because they are using disease control and progression-free survival as end points, which the current trial has shown are not good proxies for overall survival, Dr. Meyer said.

"Thus it will cause issues and interpretation as to how to proceed with these results," he said.

Dr. Meyer and his associates randomly assigned 405 patients with previously untreated stage IA or IIA nonbulky Hodgkin’s lymphoma to receive ABVD chemotherapy alone or subtotal nodal radiation at a dose of 35 Gy in 20 daily fractions. Patients in the radiation group with a favorable risk profile received radiation only, while those with an unfavorable risk received two cycles of ABVD followed by radiation therapy. Median follow-up was 11.3 years.

At 12 years, freedom from disease progression was 92% with radiation vs. 87% with ABVD chemotherapy (HR, 1.91; P = .05,), Dr. Meyer said. Event-free survival was similar at 80% with radiation therapy and 85% with ABVD (HR, 0.88; P = .60).

The results were simultaneously published in the New England Journal of Medicine (N. Engl. J. Med. 2011 [doi:10.1056/NEJMoa1111961]).

Dr. Meyer reported honoraria from Lilly and Celgene.

SAN DIEGO – In the long run, standard chemotherapy alone is more effective than radiation in keeping patients with limited-stage nonbulky Hodgkin’s lymphoma alive, according to updated results from an intergroup trial in 405 patients.

At 12 years, 94% of patients receiving ABVD – doxorubicin (Adriamycin), bleomycin (Blenoxane), vinblastine (Velbe), and dacarbazine – chemotherapy were alive, compared with 87% receiving subtotal nodal radiation with or without chemotherapy (hazard ratio for death, 0.50; P = .04).

Although 5-year data showed that patients treated with radiation experienced greater disease control, the survival advantage with chemotherapy resulted from a lower rate of death from other causes, Dr. Ralph M. Meyer said at the annual meeting of the American Society of Hematology.

A total of 12 patients in the ABVD arm died: six due to Hodgkin’s, four to a second cancer, and two due to cardiac causes. In contrast, 10 of the 24 deaths in the radiation arm were due to a second cancer. There were two deaths due to cardiac events, four to Hodgkin’s, three fatal infections, and five other deaths.

Dr. Meyer acknowledged that interpretation of the results is bound to be controversial because subtotal nodal radiation is no longer current practice as it is considered excessive. Patients today with low-risk stage IA or IIA nonbulky disease typically receive two cycles of ABVD with 20 Gy of involved-field radiation therapy. Although modern technology has reduced radiation exposure, radiation therapy would still include the coronary artery, heart, and substantial areas of the subdiaphragmatic, he said at a press briefing.

What is clear from the National Cancer Institute of Canada Clinical Trials Group and Eastern Cooperative Oncology Group study is that measures of disease control, like freedom from progressive disease, are not accurate surrogates for long-term overall survival in patients with stage I-II nonbulky Hodgkin’s lymphoma, said Dr. Meyer, director of the National Cancer Institute of Canada Clinical Trials Group.

"New proxies that predict for risks of late-treatment effects are needed," he said.

Trials are testing the use of PET scanning during therapy to identify patients who may receive chemotherapy alone. It is hypothesized that if PET scans are negative and patients are in remission after two cycles of chemotherapy, the cure rate will be high with further chemotherapy alone, whereas radiation therapy or some other form of chemotherapy should be considered if there is residual PET activity.

How the use of PET will alter current treatment management will be another contentious issue since results from ongoing trials are not expected for 2-3 years. Moreover, the trials are limited because they are using disease control and progression-free survival as end points, which the current trial has shown are not good proxies for overall survival, Dr. Meyer said.

"Thus it will cause issues and interpretation as to how to proceed with these results," he said.

Dr. Meyer and his associates randomly assigned 405 patients with previously untreated stage IA or IIA nonbulky Hodgkin’s lymphoma to receive ABVD chemotherapy alone or subtotal nodal radiation at a dose of 35 Gy in 20 daily fractions. Patients in the radiation group with a favorable risk profile received radiation only, while those with an unfavorable risk received two cycles of ABVD followed by radiation therapy. Median follow-up was 11.3 years.

At 12 years, freedom from disease progression was 92% with radiation vs. 87% with ABVD chemotherapy (HR, 1.91; P = .05,), Dr. Meyer said. Event-free survival was similar at 80% with radiation therapy and 85% with ABVD (HR, 0.88; P = .60).

The results were simultaneously published in the New England Journal of Medicine (N. Engl. J. Med. 2011 [doi:10.1056/NEJMoa1111961]).

Dr. Meyer reported honoraria from Lilly and Celgene.

SAN DIEGO – Maintain with more rituximab or re-treat? For patients with low tumor burden follicular lymphomas, the answer seems to be that it doesn’t much matter, said investigators at the annual meeting of the American Society of Hematology.

Following 4 weeks of induction with rituximab monotherapy, time to treatment failure (TTTF), the primary end point, was virtually identical between patients randomized to 12 weeks of rituximab (Rituxan) maintenance (3.9 years) or rituximab re-treatment at progression (3.6 years, P = .80) in the E4402 RESORT (Rituximab Extended Schedule or Re-Treatment Trial) study.

One year after randomization, there were no significant differences in patient quality of life or stress burden between the treatment strategies, said Dr. Brad S. Kahl of the University of Wisconsin, Madison, on behalf of coinvestigators a briefing in advance of his presentation of the results at a late-breaking abstracts session on Dec. 13.

For the end point of time to first cytotoxic therapy, however, maintenance was significantly better, with 95% of patients not on chemotherapy at 3 years, compared with 86% for the re-treatment strategy (hazard ratio, 2.5; P = .027).

"Both strategies performed extremely well," Dr. Kahl said.

The re-treatment strategy was less costly: Patients in the maintenance arm received a mean of 15.8 total doses of rituximab, compared with a mean 4.5 doses in the re-treatment arm, Dr. Kahl noted. "To get this very small improvement in time to chemotherapy took roughly 4 times more drug in the maintenance arm," he said,

"Given that there was no difference in time to treatment failure, and given the excellent results with re-treatment or time to first chemotherapy, given a slightly better toxicity profile [with re-treatment], given a lack of a quality-of-life benefit for maintenance, and given the resource utilization strategy, the re-treatment strategy would be our recommended strategy when you\'re administering single-agent rituximab in this patient population," he said.

Maintenance does, however, provide a progression-free survival advantage for patients with high tumor burden follicular lymphoma following induction with a combination immunochemotherapy regimen, as shown in the PRIMA trial, in which 2-years of rituximab maintenance was associated with significantly better progression-free survival compared with observation alone (Lancet 2011;377:42-51 [doi:10.1016/S0140-6736(10)62175-7]).

But some patients with low tumor burden may still be anxious about "doing nothing," and for them maintenance is still an appropriate option, said Dr. Ephraim P. Hochberg from the division of hematology/oncology at the Massachusetts General Hospital Cancer Center in Boston.

"In my practice, the patients who I think are going to be psychologically intolerant of relapse, or for whom relapse is a devastating personal event, those are patients for whom there is a benefit to maintenance rituximab that\'s not measured in this sort of analysis," he said in an interview. Dr. Hochberg was not involved in RESORT.

The RESORT trial enrolled 545 patients with non-Hodgkin’s lymphoma, 384 of whom (71%) had a follicular histology; patients with nonfollicular histologies are being analyzed separately. Among the 384 patients, 274 had a response to induction rituximab, and were then randomized to either re-treatment at progression (134) or to maintenance with rituximab 375 mg/m² every 12 weeks. Each strategy was continued until treatment failure.

Time to treatment failure was defined as progression within 6 months of the last rituximab infusion, no response to re-treatment, initiation of alternative therapy, or inability to complete the protocol therapy. Patients were evaluated every 3 months and had restaging CT scans every 6 months,

Grade 3 or 4 hematologic toxicities were seen in less than 5% of patients, and there were two on-study deaths, one in each treatment arm. Both strategies were "extremely well tolerated with minimal toxicities," Dr. Kahl said. There were more toxicities leading to a failure event in the maintenance arm, however.

"Our analysis so far shows that there is no quality-of-life benefit for the maintenance strategy relative to retreatment," he said.

The E4402 (RESORT) trial was sponsored by the Eastern Cooperative Oncology Group and the National Cancer Institute. Dr. Kahl disclosed being a consultant to Genentech and Roche, comarketer of rituximab. Two of his coauthors also are consultants to the company, and one is an employee. Dr. Hochberg has received consulting fees or research support from the company.

SAN DIEGO – Maintain with more rituximab or re-treat? For patients with low tumor burden follicular lymphomas, the answer seems to be that it doesn’t much matter, said investigators at the annual meeting of the American Society of Hematology.

Following 4 weeks of induction with rituximab monotherapy, time to treatment failure (TTTF), the primary end point, was virtually identical between patients randomized to 12 weeks of rituximab (Rituxan) maintenance (3.9 years) or rituximab re-treatment at progression (3.6 years, P = .80) in the E4402 RESORT (Rituximab Extended Schedule or Re-Treatment Trial) study.

One year after randomization, there were no significant differences in patient quality of life or stress burden between the treatment strategies, said Dr. Brad S. Kahl of the University of Wisconsin, Madison, on behalf of coinvestigators a briefing in advance of his presentation of the results at a late-breaking abstracts session on Dec. 13.

For the end point of time to first cytotoxic therapy, however, maintenance was significantly better, with 95% of patients not on chemotherapy at 3 years, compared with 86% for the re-treatment strategy (hazard ratio, 2.5; P = .027).

"Both strategies performed extremely well," Dr. Kahl said.

The re-treatment strategy was less costly: Patients in the maintenance arm received a mean of 15.8 total doses of rituximab, compared with a mean 4.5 doses in the re-treatment arm, Dr. Kahl noted. "To get this very small improvement in time to chemotherapy took roughly 4 times more drug in the maintenance arm," he said,

"Given that there was no difference in time to treatment failure, and given the excellent results with re-treatment or time to first chemotherapy, given a slightly better toxicity profile [with re-treatment], given a lack of a quality-of-life benefit for maintenance, and given the resource utilization strategy, the re-treatment strategy would be our recommended strategy when you\'re administering single-agent rituximab in this patient population," he said.

Maintenance does, however, provide a progression-free survival advantage for patients with high tumor burden follicular lymphoma following induction with a combination immunochemotherapy regimen, as shown in the PRIMA trial, in which 2-years of rituximab maintenance was associated with significantly better progression-free survival compared with observation alone (Lancet 2011;377:42-51 [doi:10.1016/S0140-6736(10)62175-7]).

But some patients with low tumor burden may still be anxious about "doing nothing," and for them maintenance is still an appropriate option, said Dr. Ephraim P. Hochberg from the division of hematology/oncology at the Massachusetts General Hospital Cancer Center in Boston.

"In my practice, the patients who I think are going to be psychologically intolerant of relapse, or for whom relapse is a devastating personal event, those are patients for whom there is a benefit to maintenance rituximab that\'s not measured in this sort of analysis," he said in an interview. Dr. Hochberg was not involved in RESORT.

The RESORT trial enrolled 545 patients with non-Hodgkin’s lymphoma, 384 of whom (71%) had a follicular histology; patients with nonfollicular histologies are being analyzed separately. Among the 384 patients, 274 had a response to induction rituximab, and were then randomized to either re-treatment at progression (134) or to maintenance with rituximab 375 mg/m² every 12 weeks. Each strategy was continued until treatment failure.

Time to treatment failure was defined as progression within 6 months of the last rituximab infusion, no response to re-treatment, initiation of alternative therapy, or inability to complete the protocol therapy. Patients were evaluated every 3 months and had restaging CT scans every 6 months,

Grade 3 or 4 hematologic toxicities were seen in less than 5% of patients, and there were two on-study deaths, one in each treatment arm. Both strategies were "extremely well tolerated with minimal toxicities," Dr. Kahl said. There were more toxicities leading to a failure event in the maintenance arm, however.

"Our analysis so far shows that there is no quality-of-life benefit for the maintenance strategy relative to retreatment," he said.

The E4402 (RESORT) trial was sponsored by the Eastern Cooperative Oncology Group and the National Cancer Institute. Dr. Kahl disclosed being a consultant to Genentech and Roche, comarketer of rituximab. Two of his coauthors also are consultants to the company, and one is an employee. Dr. Hochberg has received consulting fees or research support from the company.

SAN DIEGO – Maintain with more rituximab or re-treat? For patients with low tumor burden follicular lymphomas, the answer seems to be that it doesn’t much matter, said investigators at the annual meeting of the American Society of Hematology.

Following 4 weeks of induction with rituximab monotherapy, time to treatment failure (TTTF), the primary end point, was virtually identical between patients randomized to 12 weeks of rituximab (Rituxan) maintenance (3.9 years) or rituximab re-treatment at progression (3.6 years, P = .80) in the E4402 RESORT (Rituximab Extended Schedule or Re-Treatment Trial) study.

One year after randomization, there were no significant differences in patient quality of life or stress burden between the treatment strategies, said Dr. Brad S. Kahl of the University of Wisconsin, Madison, on behalf of coinvestigators a briefing in advance of his presentation of the results at a late-breaking abstracts session on Dec. 13.

For the end point of time to first cytotoxic therapy, however, maintenance was significantly better, with 95% of patients not on chemotherapy at 3 years, compared with 86% for the re-treatment strategy (hazard ratio, 2.5; P = .027).

"Both strategies performed extremely well," Dr. Kahl said.

The re-treatment strategy was less costly: Patients in the maintenance arm received a mean of 15.8 total doses of rituximab, compared with a mean 4.5 doses in the re-treatment arm, Dr. Kahl noted. "To get this very small improvement in time to chemotherapy took roughly 4 times more drug in the maintenance arm," he said,

"Given that there was no difference in time to treatment failure, and given the excellent results with re-treatment or time to first chemotherapy, given a slightly better toxicity profile [with re-treatment], given a lack of a quality-of-life benefit for maintenance, and given the resource utilization strategy, the re-treatment strategy would be our recommended strategy when you\'re administering single-agent rituximab in this patient population," he said.

Maintenance does, however, provide a progression-free survival advantage for patients with high tumor burden follicular lymphoma following induction with a combination immunochemotherapy regimen, as shown in the PRIMA trial, in which 2-years of rituximab maintenance was associated with significantly better progression-free survival compared with observation alone (Lancet 2011;377:42-51 [doi:10.1016/S0140-6736(10)62175-7]).

But some patients with low tumor burden may still be anxious about "doing nothing," and for them maintenance is still an appropriate option, said Dr. Ephraim P. Hochberg from the division of hematology/oncology at the Massachusetts General Hospital Cancer Center in Boston.

"In my practice, the patients who I think are going to be psychologically intolerant of relapse, or for whom relapse is a devastating personal event, those are patients for whom there is a benefit to maintenance rituximab that\'s not measured in this sort of analysis," he said in an interview. Dr. Hochberg was not involved in RESORT.

The RESORT trial enrolled 545 patients with non-Hodgkin’s lymphoma, 384 of whom (71%) had a follicular histology; patients with nonfollicular histologies are being analyzed separately. Among the 384 patients, 274 had a response to induction rituximab, and were then randomized to either re-treatment at progression (134) or to maintenance with rituximab 375 mg/m² every 12 weeks. Each strategy was continued until treatment failure.

Time to treatment failure was defined as progression within 6 months of the last rituximab infusion, no response to re-treatment, initiation of alternative therapy, or inability to complete the protocol therapy. Patients were evaluated every 3 months and had restaging CT scans every 6 months,

Grade 3 or 4 hematologic toxicities were seen in less than 5% of patients, and there were two on-study deaths, one in each treatment arm. Both strategies were "extremely well tolerated with minimal toxicities," Dr. Kahl said. There were more toxicities leading to a failure event in the maintenance arm, however.

"Our analysis so far shows that there is no quality-of-life benefit for the maintenance strategy relative to retreatment," he said.

The E4402 (RESORT) trial was sponsored by the Eastern Cooperative Oncology Group and the National Cancer Institute. Dr. Kahl disclosed being a consultant to Genentech and Roche, comarketer of rituximab. Two of his coauthors also are consultants to the company, and one is an employee. Dr. Hochberg has received consulting fees or research support from the company.

SAN DIEGO – A novel targeted agent was associated with high objective response rates at 10 months in patients with relapsed/refractory, heavily pretreated chronic lymphocytic leukemia/small lymphocytic lymphoma, investigators reported at the annual meeting of the American Society of Hematology.

At 10.2 months’ median follow-up, objective responses (combined complete and partial responses) were seen in 70% of 27 CLL/SLL patients assigned to a 420-mg daily dose of PCI-32765, an inhibitor of Bruton’s tyrosine kinase (BTK). Objective responses were seen at 6.5 months’ follow-up in 44% of 34 patients on an 840 mg daily dose, reported Dr. Susan O’Brien, professor in the department of leukemia at the University of Texas MD Anderson Cancer Center in Houston.

The researchers had previously reported a 48% objective response rate at 6.2 months median follow-up.

Among patients who did not have a complete or partial response, a nodal partial response was noted in 19% of those in the 420-mg cohort and in 35% of those in the 840-mg group. A nodal partial response was defined as a reduction of greater than 50% in aggregate lymph node size, but with residual lymphocytosis.

Progression-free survival at 6 months is 92% in the 27 patients in the 420-mg cohort, and 90% in the 34 patients in the 840-mg group.

Although it’s still too early to tell which dose will be more effective, the evidence to date suggests that the 420-mg dose completely inhibits activity of the targeted kinase. Thus, the 840-mg dose may not be necessary, Dr. O'Brien said.

Further, PC-32765 does not cause myelosuppression, a trait noted with imatinib (Gleevec) and other tyrosine kinase inhibitors that are effective in other leukemia subtypes.

"This is a big deal in CLL because all of the treatments that we have are pretty much chemo-based or antibody-based treatments. The biggest complication in treating CLL with pretty much every therapy we have is myelosuppression and infection, and of course these people are [already] immune suppressed. To have an agent that’s not myelosuppressive and this effective is very exciting," she said in a briefing prior to her presentation of the results at a session on Tuesday, Dec.13.

A leukemia specialist who was not involved in the study said that the results are particularly impressive given the nature of the patient population.

Patients also tolerated the drug well. The incidence of serious adverse events potentially related to PCI-32765 was 10%. The most common adverse event was diarrhea, which was generally mild, easily controlled, and self-limited, Dr. O’Brien said.

PCI-32765 binds selectively and irreversibly to BTK, an essential element of the B-cell antigen receptor signaling pathway, thereby blocking receptor signaling, inducing cell death via apoptosis, and inhibiting cellular migration and adhesion of malignant B cells.

"To have an agent that’s not myelo-suppressive and this effective is very exciting."

The investigators enrolled both treatment-naive patients with CLL and those who had relapsed/refractory disease following at least two prior therapies, including fludarabine. The patients were treated with PCI-32765 administered daily for 28-day cycles until disease progression. Treatment-naive patients and 27 patients with relapsed/refractory disease were assigned to the 420-mg dose; 34 patients with relapsed/refractory disease were assigned to the 840-mg dose.

In all, 72% of patients had one or more poor-risk molecular features. Of this group, 31% had the 17p deletion, 33% had the 11q deletion, and 57% had IgV_H un-mutated.

Two patients dropped out of the trial because of adverse events (dose group not specified), and six patients (two in the 420-mg group, four in the 840-mg group) required a dose reduction.

The most frequently reported grade 1 or 2 adverse events were diarrhea, fatigue, nausea, and ecchymosis. Serious adverse events were reported in 38% of patients. Serious events potentially related to the drug occurred in 10% of all patients.

The investigators noted that, in a majority of patients "a characteristic pattern of response, with a transient phase of lymphocytosis typically peaking within the first 2 months of therapy, followed by resolution over time."

At last follow-up, 22 of 27 patients on the 420-mg dose and 28 of 34 on the 840-mg dose were still on therapy. Phase-III trials are planned.

The trial was funded by Pharmacyclics. Dr. O’Brien disclosed serving on the board of directors or advisory committee, and has received research funding from the company. All of her coauthors disclosed either receiving research funding or consulting fees from the company, or being employees and receiving equity ownership in Phamacyclics.

SAN DIEGO – A novel targeted agent was associated with high objective response rates at 10 months in patients with relapsed/refractory, heavily pretreated chronic lymphocytic leukemia/small lymphocytic lymphoma, investigators reported at the annual meeting of the American Society of Hematology.

At 10.2 months’ median follow-up, objective responses (combined complete and partial responses) were seen in 70% of 27 CLL/SLL patients assigned to a 420-mg daily dose of PCI-32765, an inhibitor of Bruton’s tyrosine kinase (BTK). Objective responses were seen at 6.5 months’ follow-up in 44% of 34 patients on an 840 mg daily dose, reported Dr. Susan O’Brien, professor in the department of leukemia at the University of Texas MD Anderson Cancer Center in Houston.

The researchers had previously reported a 48% objective response rate at 6.2 months median follow-up.

Among patients who did not have a complete or partial response, a nodal partial response was noted in 19% of those in the 420-mg cohort and in 35% of those in the 840-mg group. A nodal partial response was defined as a reduction of greater than 50% in aggregate lymph node size, but with residual lymphocytosis.

Progression-free survival at 6 months is 92% in the 27 patients in the 420-mg cohort, and 90% in the 34 patients in the 840-mg group.

Although it’s still too early to tell which dose will be more effective, the evidence to date suggests that the 420-mg dose completely inhibits activity of the targeted kinase. Thus, the 840-mg dose may not be necessary, Dr. O'Brien said.

Further, PC-32765 does not cause myelosuppression, a trait noted with imatinib (Gleevec) and other tyrosine kinase inhibitors that are effective in other leukemia subtypes.

"This is a big deal in CLL because all of the treatments that we have are pretty much chemo-based or antibody-based treatments. The biggest complication in treating CLL with pretty much every therapy we have is myelosuppression and infection, and of course these people are [already] immune suppressed. To have an agent that’s not myelosuppressive and this effective is very exciting," she said in a briefing prior to her presentation of the results at a session on Tuesday, Dec.13.

A leukemia specialist who was not involved in the study said that the results are particularly impressive given the nature of the patient population.

Patients also tolerated the drug well. The incidence of serious adverse events potentially related to PCI-32765 was 10%. The most common adverse event was diarrhea, which was generally mild, easily controlled, and self-limited, Dr. O’Brien said.

PCI-32765 binds selectively and irreversibly to BTK, an essential element of the B-cell antigen receptor signaling pathway, thereby blocking receptor signaling, inducing cell death via apoptosis, and inhibiting cellular migration and adhesion of malignant B cells.

"To have an agent that’s not myelo-suppressive and this effective is very exciting."

The investigators enrolled both treatment-naive patients with CLL and those who had relapsed/refractory disease following at least two prior therapies, including fludarabine. The patients were treated with PCI-32765 administered daily for 28-day cycles until disease progression. Treatment-naive patients and 27 patients with relapsed/refractory disease were assigned to the 420-mg dose; 34 patients with relapsed/refractory disease were assigned to the 840-mg dose.

In all, 72% of patients had one or more poor-risk molecular features. Of this group, 31% had the 17p deletion, 33% had the 11q deletion, and 57% had IgV_H un-mutated.

Two patients dropped out of the trial because of adverse events (dose group not specified), and six patients (two in the 420-mg group, four in the 840-mg group) required a dose reduction.

The most frequently reported grade 1 or 2 adverse events were diarrhea, fatigue, nausea, and ecchymosis. Serious adverse events were reported in 38% of patients. Serious events potentially related to the drug occurred in 10% of all patients.

The investigators noted that, in a majority of patients "a characteristic pattern of response, with a transient phase of lymphocytosis typically peaking within the first 2 months of therapy, followed by resolution over time."

At last follow-up, 22 of 27 patients on the 420-mg dose and 28 of 34 on the 840-mg dose were still on therapy. Phase-III trials are planned.

The trial was funded by Pharmacyclics. Dr. O’Brien disclosed serving on the board of directors or advisory committee, and has received research funding from the company. All of her coauthors disclosed either receiving research funding or consulting fees from the company, or being employees and receiving equity ownership in Phamacyclics.

SAN DIEGO – A novel targeted agent was associated with high objective response rates at 10 months in patients with relapsed/refractory, heavily pretreated chronic lymphocytic leukemia/small lymphocytic lymphoma, investigators reported at the annual meeting of the American Society of Hematology.

At 10.2 months’ median follow-up, objective responses (combined complete and partial responses) were seen in 70% of 27 CLL/SLL patients assigned to a 420-mg daily dose of PCI-32765, an inhibitor of Bruton’s tyrosine kinase (BTK). Objective responses were seen at 6.5 months’ follow-up in 44% of 34 patients on an 840 mg daily dose, reported Dr. Susan O’Brien, professor in the department of leukemia at the University of Texas MD Anderson Cancer Center in Houston.

The researchers had previously reported a 48% objective response rate at 6.2 months median follow-up.

Among patients who did not have a complete or partial response, a nodal partial response was noted in 19% of those in the 420-mg cohort and in 35% of those in the 840-mg group. A nodal partial response was defined as a reduction of greater than 50% in aggregate lymph node size, but with residual lymphocytosis.

Progression-free survival at 6 months is 92% in the 27 patients in the 420-mg cohort, and 90% in the 34 patients in the 840-mg group.

Although it’s still too early to tell which dose will be more effective, the evidence to date suggests that the 420-mg dose completely inhibits activity of the targeted kinase. Thus, the 840-mg dose may not be necessary, Dr. O'Brien said.

Further, PC-32765 does not cause myelosuppression, a trait noted with imatinib (Gleevec) and other tyrosine kinase inhibitors that are effective in other leukemia subtypes.

"This is a big deal in CLL because all of the treatments that we have are pretty much chemo-based or antibody-based treatments. The biggest complication in treating CLL with pretty much every therapy we have is myelosuppression and infection, and of course these people are [already] immune suppressed. To have an agent that’s not myelosuppressive and this effective is very exciting," she said in a briefing prior to her presentation of the results at a session on Tuesday, Dec.13.

A leukemia specialist who was not involved in the study said that the results are particularly impressive given the nature of the patient population.

Patients also tolerated the drug well. The incidence of serious adverse events potentially related to PCI-32765 was 10%. The most common adverse event was diarrhea, which was generally mild, easily controlled, and self-limited, Dr. O’Brien said.

PCI-32765 binds selectively and irreversibly to BTK, an essential element of the B-cell antigen receptor signaling pathway, thereby blocking receptor signaling, inducing cell death via apoptosis, and inhibiting cellular migration and adhesion of malignant B cells.

"To have an agent that’s not myelo-suppressive and this effective is very exciting."

The investigators enrolled both treatment-naive patients with CLL and those who had relapsed/refractory disease following at least two prior therapies, including fludarabine. The patients were treated with PCI-32765 administered daily for 28-day cycles until disease progression. Treatment-naive patients and 27 patients with relapsed/refractory disease were assigned to the 420-mg dose; 34 patients with relapsed/refractory disease were assigned to the 840-mg dose.

In all, 72% of patients had one or more poor-risk molecular features. Of this group, 31% had the 17p deletion, 33% had the 11q deletion, and 57% had IgV_H un-mutated.

Two patients dropped out of the trial because of adverse events (dose group not specified), and six patients (two in the 420-mg group, four in the 840-mg group) required a dose reduction.

The most frequently reported grade 1 or 2 adverse events were diarrhea, fatigue, nausea, and ecchymosis. Serious adverse events were reported in 38% of patients. Serious events potentially related to the drug occurred in 10% of all patients.

The investigators noted that, in a majority of patients "a characteristic pattern of response, with a transient phase of lymphocytosis typically peaking within the first 2 months of therapy, followed by resolution over time."

At last follow-up, 22 of 27 patients on the 420-mg dose and 28 of 34 on the 840-mg dose were still on therapy. Phase-III trials are planned.

The trial was funded by Pharmacyclics. Dr. O’Brien disclosed serving on the board of directors or advisory committee, and has received research funding from the company. All of her coauthors disclosed either receiving research funding or consulting fees from the company, or being employees and receiving equity ownership in Phamacyclics.

SAN DIEGO – Adding low doses of gemtuzumab to standard chemotherapy extends survival in de novo acute myeloid leukemia without the toxicity that triggered the monoclonal antibody to be taken off the market in the United States last year, a study has shown.

Median event-free survival among 280 patients, aged 50-70 years, was increased from 11.9 months with standard daunorubicin (Cerubidine) and cytarabine (Ara-C) chemotherapy to 19.6 months with the addition of gemtuzumab ozogamicin (Mylotarg).

The 2-year estimate of event-free survival was 16.5% vs. 41.1% (log-rank P value = .00018; hazard ratio, 0.57).

This translated into an increase in median overall survival from 19.2 months to 34 months with the addition of gemtuzumab, Dr. Sylvie Castaigne reported on behalf of the Acute Leukemia French Association (ALFA) at the annual meeting of the American Society of Hematology. The 2-year overall survival estimate was 43.5% vs. 53.1% (log rank P = .046; HR, 0.70).

Notably, this improvement in survival was not present in patients with unfavorable cytogenetics, comprising 23% of the gemtuzumab group.

At the urging of the U.S. Food and Drug Administration, Pfizer voluntarily withdrew gemtuzumab from the market in June 2010, because of concerns about its toxicity and lack of clinical benefit in patients with acute myeloid leukemia (AML).

The drug remains available in Europe on a compassionate basis for relapsed AML, but not in the frontline setting, according to Dr. Castaigne, professor of hematology at Hôpital de Versailles (France).

When asked during a press briefing whether the current data could resurrect gemtuzumab in the United States or be parlayed into a new indication in Europe, she said, "I think many physicians will ask Pfizer to get the drug on the market."

Dr. Armand Keating, ASH president-elect, who moderated the presentation of the study, said in an interview that "I think it has the potential to change practice, but my concern is that there may be more side effects than are being reported in this particular study and certainly there were previous reports of veno-occlusive disease."

Dr. Castaigne reported three episodes of veno-occlusive disease, two of which were fatal. Prolonged grade 3 or greater thrombocytopenia occurred in 19 patients.

Dr. Martin Tallman, chief of the leukemia service at Memorial Sloan-Kettering Cancer Center in New York City, agreed that the data are impressive, but also expressed concern about the veno-occlusive disease events.

"Would I add gemtuzumab to my next patient Monday morning with favorable cytogenic risk, off study? No," he said in an interview. "Does it change standard of care? No.

"It is impressive, but I think we need more studies."

Still, Dr. Tallman said that he would advise Pfizer to bring gemtuzumab back on the market for clinical trials, and that a Pfizer executive told him during the presentation that Pfizer would see what it could do.

Dr. Keating, director of hematology at the University of Toronto, said the new data might lead to a consideration of putting gemtuzumab back on the market. "I think it would be very reasonable," he added.

Only 13,000 new patients are diagnosed each year in the United States with AML, but there are 9,000 deaths. Overall survival has improved among younger adults, but there is no evidence of improvement among older adults in 4 decades of investigation, Dr. Castaigne said.

The ALFA group opted to pursue gemtuzumab in AML based on phase I data suggesting that repeated lower-dose infusions would reduce the toxicity associated with the previous 9-mg/m² dose given on days 1 and 14, while enhancing the efficacy of gemtuzumab.

From January 2008 to November 2010, 280 patients were randomized to chemotherapy with daunorubicin 60 mg/m² on days 1-3 and cytarabine 200 mg/m² on days 1-7 with or without gemtuzumab 3 mg/m² on days 1, 4 and 7. Two patients withdrew consent, and were excluded from the analysis. Their median age was 62 years.

"Would I add gemtuzumab to my next patient Monday morning with favorable cytogenic risk, off study? No."

If bone marrow blasts were more than 10% at day 15, a second course of daunorubicin 60 mg/m² on days 1 and 2 and cytarabine 1 g/m² every 12 hours on days 1-3 was given.

Two rounds of consolidation chemotherapy were given to patients who experienced a complete response.

Median relapse-free survival among complete responders was 12.5 months in the control group and 28.1 months in the gemtuzumab group, with 21.7% vs. 50.8% alive at 2 years (log-rank P value = .00029; HR, 0.51), Dr. Castaigne said.

The rate of fatal events possibly related to treatment was similar at 6.7% in the chemotherapy group and 8.7% in the gemtuzumab group, she said.

The incidence of grade 3-4 sepsis was similar at 16% with chemotherapy and 20% with gemtuzumab, as was the rate of ICU admission (12% vs. 14%).

Additional data at the meeting also show a significant survival benefit with gemtuzumab among 806 older patients, with a median age of 67 years, according to Dr. Alan Burnett, head of hematology at Cardiff (Wales) University. Median overall survival increased from 39% to 47% with the addition of gemtuzumab to chemotherapy (P = .02). A lower benefit was observed in those with adverse cytogenetics or secondary disease, according to the study.

Dr. Castaigne reported financial relationships with Pfizer/Wyeth. Dr. Burnett reported financial relationships with Pfizer. Dr. Tallman reported consulting for Genzyme Oncology.

SAN DIEGO – Adding low doses of gemtuzumab to standard chemotherapy extends survival in de novo acute myeloid leukemia without the toxicity that triggered the monoclonal antibody to be taken off the market in the United States last year, a study has shown.

Median event-free survival among 280 patients, aged 50-70 years, was increased from 11.9 months with standard daunorubicin (Cerubidine) and cytarabine (Ara-C) chemotherapy to 19.6 months with the addition of gemtuzumab ozogamicin (Mylotarg).

The 2-year estimate of event-free survival was 16.5% vs. 41.1% (log-rank P value = .00018; hazard ratio, 0.57).

This translated into an increase in median overall survival from 19.2 months to 34 months with the addition of gemtuzumab, Dr. Sylvie Castaigne reported on behalf of the Acute Leukemia French Association (ALFA) at the annual meeting of the American Society of Hematology. The 2-year overall survival estimate was 43.5% vs. 53.1% (log rank P = .046; HR, 0.70).

Notably, this improvement in survival was not present in patients with unfavorable cytogenetics, comprising 23% of the gemtuzumab group.

At the urging of the U.S. Food and Drug Administration, Pfizer voluntarily withdrew gemtuzumab from the market in June 2010, because of concerns about its toxicity and lack of clinical benefit in patients with acute myeloid leukemia (AML).

The drug remains available in Europe on a compassionate basis for relapsed AML, but not in the frontline setting, according to Dr. Castaigne, professor of hematology at Hôpital de Versailles (France).

When asked during a press briefing whether the current data could resurrect gemtuzumab in the United States or be parlayed into a new indication in Europe, she said, "I think many physicians will ask Pfizer to get the drug on the market."

Dr. Armand Keating, ASH president-elect, who moderated the presentation of the study, said in an interview that "I think it has the potential to change practice, but my concern is that there may be more side effects than are being reported in this particular study and certainly there were previous reports of veno-occlusive disease."

Dr. Castaigne reported three episodes of veno-occlusive disease, two of which were fatal. Prolonged grade 3 or greater thrombocytopenia occurred in 19 patients.

Dr. Martin Tallman, chief of the leukemia service at Memorial Sloan-Kettering Cancer Center in New York City, agreed that the data are impressive, but also expressed concern about the veno-occlusive disease events.

"Would I add gemtuzumab to my next patient Monday morning with favorable cytogenic risk, off study? No," he said in an interview. "Does it change standard of care? No.

"It is impressive, but I think we need more studies."

Still, Dr. Tallman said that he would advise Pfizer to bring gemtuzumab back on the market for clinical trials, and that a Pfizer executive told him during the presentation that Pfizer would see what it could do.

Dr. Keating, director of hematology at the University of Toronto, said the new data might lead to a consideration of putting gemtuzumab back on the market. "I think it would be very reasonable," he added.

Only 13,000 new patients are diagnosed each year in the United States with AML, but there are 9,000 deaths. Overall survival has improved among younger adults, but there is no evidence of improvement among older adults in 4 decades of investigation, Dr. Castaigne said.

The ALFA group opted to pursue gemtuzumab in AML based on phase I data suggesting that repeated lower-dose infusions would reduce the toxicity associated with the previous 9-mg/m² dose given on days 1 and 14, while enhancing the efficacy of gemtuzumab.

From January 2008 to November 2010, 280 patients were randomized to chemotherapy with daunorubicin 60 mg/m² on days 1-3 and cytarabine 200 mg/m² on days 1-7 with or without gemtuzumab 3 mg/m² on days 1, 4 and 7. Two patients withdrew consent, and were excluded from the analysis. Their median age was 62 years.

"Would I add gemtuzumab to my next patient Monday morning with favorable cytogenic risk, off study? No."

If bone marrow blasts were more than 10% at day 15, a second course of daunorubicin 60 mg/m² on days 1 and 2 and cytarabine 1 g/m² every 12 hours on days 1-3 was given.

Two rounds of consolidation chemotherapy were given to patients who experienced a complete response.

Median relapse-free survival among complete responders was 12.5 months in the control group and 28.1 months in the gemtuzumab group, with 21.7% vs. 50.8% alive at 2 years (log-rank P value = .00029; HR, 0.51), Dr. Castaigne said.

The rate of fatal events possibly related to treatment was similar at 6.7% in the chemotherapy group and 8.7% in the gemtuzumab group, she said.

The incidence of grade 3-4 sepsis was similar at 16% with chemotherapy and 20% with gemtuzumab, as was the rate of ICU admission (12% vs. 14%).

Additional data at the meeting also show a significant survival benefit with gemtuzumab among 806 older patients, with a median age of 67 years, according to Dr. Alan Burnett, head of hematology at Cardiff (Wales) University. Median overall survival increased from 39% to 47% with the addition of gemtuzumab to chemotherapy (P = .02). A lower benefit was observed in those with adverse cytogenetics or secondary disease, according to the study.

Dr. Castaigne reported financial relationships with Pfizer/Wyeth. Dr. Burnett reported financial relationships with Pfizer. Dr. Tallman reported consulting for Genzyme Oncology.

SAN DIEGO – Adding low doses of gemtuzumab to standard chemotherapy extends survival in de novo acute myeloid leukemia without the toxicity that triggered the monoclonal antibody to be taken off the market in the United States last year, a study has shown.

Median event-free survival among 280 patients, aged 50-70 years, was increased from 11.9 months with standard daunorubicin (Cerubidine) and cytarabine (Ara-C) chemotherapy to 19.6 months with the addition of gemtuzumab ozogamicin (Mylotarg).

The 2-year estimate of event-free survival was 16.5% vs. 41.1% (log-rank P value = .00018; hazard ratio, 0.57).

This translated into an increase in median overall survival from 19.2 months to 34 months with the addition of gemtuzumab, Dr. Sylvie Castaigne reported on behalf of the Acute Leukemia French Association (ALFA) at the annual meeting of the American Society of Hematology. The 2-year overall survival estimate was 43.5% vs. 53.1% (log rank P = .046; HR, 0.70).

Notably, this improvement in survival was not present in patients with unfavorable cytogenetics, comprising 23% of the gemtuzumab group.

At the urging of the U.S. Food and Drug Administration, Pfizer voluntarily withdrew gemtuzumab from the market in June 2010, because of concerns about its toxicity and lack of clinical benefit in patients with acute myeloid leukemia (AML).

The drug remains available in Europe on a compassionate basis for relapsed AML, but not in the frontline setting, according to Dr. Castaigne, professor of hematology at Hôpital de Versailles (France).

When asked during a press briefing whether the current data could resurrect gemtuzumab in the United States or be parlayed into a new indication in Europe, she said, "I think many physicians will ask Pfizer to get the drug on the market."

Dr. Armand Keating, ASH president-elect, who moderated the presentation of the study, said in an interview that "I think it has the potential to change practice, but my concern is that there may be more side effects than are being reported in this particular study and certainly there were previous reports of veno-occlusive disease."

Dr. Castaigne reported three episodes of veno-occlusive disease, two of which were fatal. Prolonged grade 3 or greater thrombocytopenia occurred in 19 patients.

Dr. Martin Tallman, chief of the leukemia service at Memorial Sloan-Kettering Cancer Center in New York City, agreed that the data are impressive, but also expressed concern about the veno-occlusive disease events.

"Would I add gemtuzumab to my next patient Monday morning with favorable cytogenic risk, off study? No," he said in an interview. "Does it change standard of care? No.

"It is impressive, but I think we need more studies."

Still, Dr. Tallman said that he would advise Pfizer to bring gemtuzumab back on the market for clinical trials, and that a Pfizer executive told him during the presentation that Pfizer would see what it could do.

Dr. Keating, director of hematology at the University of Toronto, said the new data might lead to a consideration of putting gemtuzumab back on the market. "I think it would be very reasonable," he added.

Only 13,000 new patients are diagnosed each year in the United States with AML, but there are 9,000 deaths. Overall survival has improved among younger adults, but there is no evidence of improvement among older adults in 4 decades of investigation, Dr. Castaigne said.

The ALFA group opted to pursue gemtuzumab in AML based on phase I data suggesting that repeated lower-dose infusions would reduce the toxicity associated with the previous 9-mg/m² dose given on days 1 and 14, while enhancing the efficacy of gemtuzumab.

From January 2008 to November 2010, 280 patients were randomized to chemotherapy with daunorubicin 60 mg/m² on days 1-3 and cytarabine 200 mg/m² on days 1-7 with or without gemtuzumab 3 mg/m² on days 1, 4 and 7. Two patients withdrew consent, and were excluded from the analysis. Their median age was 62 years.

"Would I add gemtuzumab to my next patient Monday morning with favorable cytogenic risk, off study? No."

If bone marrow blasts were more than 10% at day 15, a second course of daunorubicin 60 mg/m² on days 1 and 2 and cytarabine 1 g/m² every 12 hours on days 1-3 was given.

Two rounds of consolidation chemotherapy were given to patients who experienced a complete response.

Median relapse-free survival among complete responders was 12.5 months in the control group and 28.1 months in the gemtuzumab group, with 21.7% vs. 50.8% alive at 2 years (log-rank P value = .00029; HR, 0.51), Dr. Castaigne said.

The rate of fatal events possibly related to treatment was similar at 6.7% in the chemotherapy group and 8.7% in the gemtuzumab group, she said.

The incidence of grade 3-4 sepsis was similar at 16% with chemotherapy and 20% with gemtuzumab, as was the rate of ICU admission (12% vs. 14%).

Additional data at the meeting also show a significant survival benefit with gemtuzumab among 806 older patients, with a median age of 67 years, according to Dr. Alan Burnett, head of hematology at Cardiff (Wales) University. Median overall survival increased from 39% to 47% with the addition of gemtuzumab to chemotherapy (P = .02). A lower benefit was observed in those with adverse cytogenetics or secondary disease, according to the study.

Dr. Castaigne reported financial relationships with Pfizer/Wyeth. Dr. Burnett reported financial relationships with Pfizer. Dr. Tallman reported consulting for Genzyme Oncology.

Researchers using massively parallel sequencing to characterize the spectrum of somatic mutations in chronic lymphocytic leukemia identified nine genes that are mutated at significant frequencies in the disease.

Of these nine "driver" genes, which were identified from DNA samples from normal tissues and tumors in 91 patients with chronic lymphocytic leukemia, four have previously established roles in the disease (TP53, ATM, MYD88, and NOTCH1), and five do not (SF3B1, ZMYM3, MAPK1, FBXW7, and DDX3X), Dr. Lili Wang of the Dana-Farber Cancer Institute, Boston, and her colleagues reported online in the Dec. 12 issue of the New England Journal of Medicine. The findings were reported simultaneously at the annual meeting of the American Society of Hematology.

"Strikingly, the second most frequently mutated gene in our cohort was splicing factor 3b, subunit 1 (SF3B1), with missense mutations occurring in 14 of 91 patients (15%). SF3B1 is a component of the SF3B complex, which is associated with the U2 small nuclear ribonucleoprotein (snRNP), at the catalytic center of the spliceosome," the investigators said (N. Engl. J. Med. 2011 Dec. 12 [doi:10.1056/NEJMoa1109016]).

The nine driver genes identified in this study appear in five core signaling pathways, and the genes each play different, though well-established roles in these pathways, such as DNA repair and cell-cycle control, Notch signaling, inflammatory pathways, and RNA splicing (in which SF3B1, in particular, was implicated). Furthermore, each driver mutation was found to be associated with different key abnormalities; for example, the findings indicate there may be an interaction between del(11q), which is associated with aggressive disease, and SF3B1 mutation in the pathogenesis of a clinical subgroup of chronic lymphocytic leukemia.

Overall, the investigators concluded that:

• Chronic lymphocytic leukemia has a lower rate of somatic mutation than most solid tumors.

• The rate of nonsynonymous mutation was not strongly affected by therapy.

• In addition to the expected mutations in cell-cycle and DNA-repair pathways, genetic alterations in Notch signaling, inflammatory pathways, and RNA splicing and processing also exist.

• Driver mutations showed striking associations with standard prognostic markers.

The latter suggests that "particular combinations of genetic alterations may act in concert to drive cancer," the investigators said.

The findings regarding the core spliceosome component SF3B1, which they described as a "major surprise," led to further analyses that suggested that SF3B1 mutations lead to "mistakes in the splicing of ... transcripts that affect the pathogenesis of chronic lymphocytic leukemia," they said, adding that ongoing studies will evaluate how mutations in SF3B1 alter its function in the processing of critical messenger RNAs.

The study, and in particular the findings regarding SF3B1 mutations, illustrate how identification of coding mutations in chronic lymphocytic leukemia can lead to the development of mechanistic hypotheses, novel prognostic markers, and potential therapeutic targets, Dr. Wang and her associates said.

They also noted the information provides a starting point for determining "which genes within chromosomal deletions and amplifications are essential, how each mutation alters cellular networks and phenotypes, which combinations of mutations are critical in the development of cancer, and how genetic events in the host may affect the importance of specific mutations and their combinations."

In an accompanying editorial, Dr. Benjamin Ebert and Olivier A. Bernard, Ph.D., commented that the study finding regarding mutations in genes involved in RNA splicing, although highly unexpected, converge remarkably with recent published findings from studies of myelodysplastic syndromes (N. Engl. J. Med. 2011;35:1384-95; Nature 2011;478:64-9).

SF3B1 mutations were found in 20% of patients with myelodysplastic syndromes, and in 65% of patients with refractory anemia and ring sideroblasts in one study (N. Engl. J. Med. 2011;35:1384-95).

"Moreover, mutations have been reported in multiple components of the spliceosome in 45%-85% of patients with myelodysplastic syndrome. SF3B1 mutations also occur in 1%-5% of samples from a wide range of tumor types, which indicates that mutations in RNA splicing factors are a widespread cause of oncogenic transformation," they added.

These and other findings, taken together, raise the "provocative possibility" that SF3B1 mutations may sometimes occur first in hematopoietic stem cells, with "additional mutations then being acquired in either the lymphoid or the myeloid lineages and causing chronic lymphocytic leukemia or myelodysplastic syndromes, respectively," Dr. Ebert of Brigham and Women’s Hospital, Boston, and Dr. Bernard, who is with INSERM at Institut Gustave Roussy, Villejuif, France, wrote (N. Engl. J. Med. 2011 Dec. 12 [doi:10.1056/NEJMe1111584]).

The findings have implications for determining prognosis, and for identifying targets for treatment. For example, the identification of mutations in genes encoding the RNA splicing machinery raises the possibility that spliceosome could be a therapeutic target, they said.

This study was supported by grants from the National Institutes of Health, the National Cancer Institute, the Melton and Rosenbach Funds, the Blavatnik Family Foundation, the Howard Hughes Medical Institute (via an Early Career Physician-Scientist Award), and the Damon Runyon Cancer Research Foundation. Dr. Wang said she had no relevant financial disclosures. Some of the coauthors said they were consultants to numerous pharmaceutical companies or owned stock in pharmaceutical companies. Other than employment by INSERM on the part of Dr. Bernard, neither he nor Dr. Ebert had any relevant financial disclosures to report.

Researchers using massively parallel sequencing to characterize the spectrum of somatic mutations in chronic lymphocytic leukemia identified nine genes that are mutated at significant frequencies in the disease.

Of these nine "driver" genes, which were identified from DNA samples from normal tissues and tumors in 91 patients with chronic lymphocytic leukemia, four have previously established roles in the disease (TP53, ATM, MYD88, and NOTCH1), and five do not (SF3B1, ZMYM3, MAPK1, FBXW7, and DDX3X), Dr. Lili Wang of the Dana-Farber Cancer Institute, Boston, and her colleagues reported online in the Dec. 12 issue of the New England Journal of Medicine. The findings were reported simultaneously at the annual meeting of the American Society of Hematology.

"Strikingly, the second most frequently mutated gene in our cohort was splicing factor 3b, subunit 1 (SF3B1), with missense mutations occurring in 14 of 91 patients (15%). SF3B1 is a component of the SF3B complex, which is associated with the U2 small nuclear ribonucleoprotein (snRNP), at the catalytic center of the spliceosome," the investigators said (N. Engl. J. Med. 2011 Dec. 12 [doi:10.1056/NEJMoa1109016]).

The nine driver genes identified in this study appear in five core signaling pathways, and the genes each play different, though well-established roles in these pathways, such as DNA repair and cell-cycle control, Notch signaling, inflammatory pathways, and RNA splicing (in which SF3B1, in particular, was implicated). Furthermore, each driver mutation was found to be associated with different key abnormalities; for example, the findings indicate there may be an interaction between del(11q), which is associated with aggressive disease, and SF3B1 mutation in the pathogenesis of a clinical subgroup of chronic lymphocytic leukemia.

Overall, the investigators concluded that:

• Chronic lymphocytic leukemia has a lower rate of somatic mutation than most solid tumors.

• The rate of nonsynonymous mutation was not strongly affected by therapy.

• In addition to the expected mutations in cell-cycle and DNA-repair pathways, genetic alterations in Notch signaling, inflammatory pathways, and RNA splicing and processing also exist.

• Driver mutations showed striking associations with standard prognostic markers.

The latter suggests that "particular combinations of genetic alterations may act in concert to drive cancer," the investigators said.

The findings regarding the core spliceosome component SF3B1, which they described as a "major surprise," led to further analyses that suggested that SF3B1 mutations lead to "mistakes in the splicing of ... transcripts that affect the pathogenesis of chronic lymphocytic leukemia," they said, adding that ongoing studies will evaluate how mutations in SF3B1 alter its function in the processing of critical messenger RNAs.

The study, and in particular the findings regarding SF3B1 mutations, illustrate how identification of coding mutations in chronic lymphocytic leukemia can lead to the development of mechanistic hypotheses, novel prognostic markers, and potential therapeutic targets, Dr. Wang and her associates said.

They also noted the information provides a starting point for determining "which genes within chromosomal deletions and amplifications are essential, how each mutation alters cellular networks and phenotypes, which combinations of mutations are critical in the development of cancer, and how genetic events in the host may affect the importance of specific mutations and their combinations."

In an accompanying editorial, Dr. Benjamin Ebert and Olivier A. Bernard, Ph.D., commented that the study finding regarding mutations in genes involved in RNA splicing, although highly unexpected, converge remarkably with recent published findings from studies of myelodysplastic syndromes (N. Engl. J. Med. 2011;35:1384-95; Nature 2011;478:64-9).

SF3B1 mutations were found in 20% of patients with myelodysplastic syndromes, and in 65% of patients with refractory anemia and ring sideroblasts in one study (N. Engl. J. Med. 2011;35:1384-95).

"Moreover, mutations have been reported in multiple components of the spliceosome in 45%-85% of patients with myelodysplastic syndrome. SF3B1 mutations also occur in 1%-5% of samples from a wide range of tumor types, which indicates that mutations in RNA splicing factors are a widespread cause of oncogenic transformation," they added.

These and other findings, taken together, raise the "provocative possibility" that SF3B1 mutations may sometimes occur first in hematopoietic stem cells, with "additional mutations then being acquired in either the lymphoid or the myeloid lineages and causing chronic lymphocytic leukemia or myelodysplastic syndromes, respectively," Dr. Ebert of Brigham and Women’s Hospital, Boston, and Dr. Bernard, who is with INSERM at Institut Gustave Roussy, Villejuif, France, wrote (N. Engl. J. Med. 2011 Dec. 12 [doi:10.1056/NEJMe1111584]).

The findings have implications for determining prognosis, and for identifying targets for treatment. For example, the identification of mutations in genes encoding the RNA splicing machinery raises the possibility that spliceosome could be a therapeutic target, they said.

This study was supported by grants from the National Institutes of Health, the National Cancer Institute, the Melton and Rosenbach Funds, the Blavatnik Family Foundation, the Howard Hughes Medical Institute (via an Early Career Physician-Scientist Award), and the Damon Runyon Cancer Research Foundation. Dr. Wang said she had no relevant financial disclosures. Some of the coauthors said they were consultants to numerous pharmaceutical companies or owned stock in pharmaceutical companies. Other than employment by INSERM on the part of Dr. Bernard, neither he nor Dr. Ebert had any relevant financial disclosures to report.

Researchers using massively parallel sequencing to characterize the spectrum of somatic mutations in chronic lymphocytic leukemia identified nine genes that are mutated at significant frequencies in the disease.

Of these nine "driver" genes, which were identified from DNA samples from normal tissues and tumors in 91 patients with chronic lymphocytic leukemia, four have previously established roles in the disease (TP53, ATM, MYD88, and NOTCH1), and five do not (SF3B1, ZMYM3, MAPK1, FBXW7, and DDX3X), Dr. Lili Wang of the Dana-Farber Cancer Institute, Boston, and her colleagues reported online in the Dec. 12 issue of the New England Journal of Medicine. The findings were reported simultaneously at the annual meeting of the American Society of Hematology.

"Strikingly, the second most frequently mutated gene in our cohort was splicing factor 3b, subunit 1 (SF3B1), with missense mutations occurring in 14 of 91 patients (15%). SF3B1 is a component of the SF3B complex, which is associated with the U2 small nuclear ribonucleoprotein (snRNP), at the catalytic center of the spliceosome," the investigators said (N. Engl. J. Med. 2011 Dec. 12 [doi:10.1056/NEJMoa1109016]).

The nine driver genes identified in this study appear in five core signaling pathways, and the genes each play different, though well-established roles in these pathways, such as DNA repair and cell-cycle control, Notch signaling, inflammatory pathways, and RNA splicing (in which SF3B1, in particular, was implicated). Furthermore, each driver mutation was found to be associated with different key abnormalities; for example, the findings indicate there may be an interaction between del(11q), which is associated with aggressive disease, and SF3B1 mutation in the pathogenesis of a clinical subgroup of chronic lymphocytic leukemia.

Overall, the investigators concluded that:

• Chronic lymphocytic leukemia has a lower rate of somatic mutation than most solid tumors.

• The rate of nonsynonymous mutation was not strongly affected by therapy.

• In addition to the expected mutations in cell-cycle and DNA-repair pathways, genetic alterations in Notch signaling, inflammatory pathways, and RNA splicing and processing also exist.

• Driver mutations showed striking associations with standard prognostic markers.

The latter suggests that "particular combinations of genetic alterations may act in concert to drive cancer," the investigators said.

The findings regarding the core spliceosome component SF3B1, which they described as a "major surprise," led to further analyses that suggested that SF3B1 mutations lead to "mistakes in the splicing of ... transcripts that affect the pathogenesis of chronic lymphocytic leukemia," they said, adding that ongoing studies will evaluate how mutations in SF3B1 alter its function in the processing of critical messenger RNAs.

The study, and in particular the findings regarding SF3B1 mutations, illustrate how identification of coding mutations in chronic lymphocytic leukemia can lead to the development of mechanistic hypotheses, novel prognostic markers, and potential therapeutic targets, Dr. Wang and her associates said.

They also noted the information provides a starting point for determining "which genes within chromosomal deletions and amplifications are essential, how each mutation alters cellular networks and phenotypes, which combinations of mutations are critical in the development of cancer, and how genetic events in the host may affect the importance of specific mutations and their combinations."

In an accompanying editorial, Dr. Benjamin Ebert and Olivier A. Bernard, Ph.D., commented that the study finding regarding mutations in genes involved in RNA splicing, although highly unexpected, converge remarkably with recent published findings from studies of myelodysplastic syndromes (N. Engl. J. Med. 2011;35:1384-95; Nature 2011;478:64-9).

SF3B1 mutations were found in 20% of patients with myelodysplastic syndromes, and in 65% of patients with refractory anemia and ring sideroblasts in one study (N. Engl. J. Med. 2011;35:1384-95).

"Moreover, mutations have been reported in multiple components of the spliceosome in 45%-85% of patients with myelodysplastic syndrome. SF3B1 mutations also occur in 1%-5% of samples from a wide range of tumor types, which indicates that mutations in RNA splicing factors are a widespread cause of oncogenic transformation," they added.

These and other findings, taken together, raise the "provocative possibility" that SF3B1 mutations may sometimes occur first in hematopoietic stem cells, with "additional mutations then being acquired in either the lymphoid or the myeloid lineages and causing chronic lymphocytic leukemia or myelodysplastic syndromes, respectively," Dr. Ebert of Brigham and Women’s Hospital, Boston, and Dr. Bernard, who is with INSERM at Institut Gustave Roussy, Villejuif, France, wrote (N. Engl. J. Med. 2011 Dec. 12 [doi:10.1056/NEJMe1111584]).

The findings have implications for determining prognosis, and for identifying targets for treatment. For example, the identification of mutations in genes encoding the RNA splicing machinery raises the possibility that spliceosome could be a therapeutic target, they said.

This study was supported by grants from the National Institutes of Health, the National Cancer Institute, the Melton and Rosenbach Funds, the Blavatnik Family Foundation, the Howard Hughes Medical Institute (via an Early Career Physician-Scientist Award), and the Damon Runyon Cancer Research Foundation. Dr. Wang said she had no relevant financial disclosures. Some of the coauthors said they were consultants to numerous pharmaceutical companies or owned stock in pharmaceutical companies. Other than employment by INSERM on the part of Dr. Bernard, neither he nor Dr. Ebert had any relevant financial disclosures to report.

SAN DIEGO – Data mined from several phase II studies of carfilzomib monotherapy confirm previous observations, but also raise new questions and insights into the use of the investigational proteasome inhibitor in relapsed and/or refractory multiple myeloma.

The first of three posters simultaneously presented at the American Society of Hematology used multivariate modeling to confirm a dose-response relationship for carfilzomib in bortezomib (Velcade)-naive and bortezomib-treated patients.

After study effect was adjusted for, the odds of achieving a partial response or better for a patient treated with 27 mg/m² were 4.08-fold higher than for a patient receiving only 20 mg/m² (P less than .001).

When using the average dose as a continuous variable and again adjusting for study effect, the odds of a response increased by 1.28-fold for each 1-mg/m² increase in average carfilzomib dose, equivalent to a 5.52-fold increase in the odds of a response if the average dose increased from 20 mg/m² to 27 mg/m² (P less than .001), reported Sunhee Ro, Ph.D., an employee of San Francisco–based Onyx Pharmaceuticals, which is developing the drug. Statistician Pierre Squifflet of the International Drug Development Institute in Belgium was the lead author.

The dose-effect relationship was observed not only on the primary end point of overall response rate, but also time to progression, progression-free survival, and overall survival.

The analysis included three study populations: 266 heavily pretreated patients who had received at least two prior therapies including bortezomib and either thalidomide or lenalidomide and who received carfilzomib 20 mg/m² in cycle one with escalation to 27 mg/m² if tolerable, 35 patients pretreated with one to three prior therapies including bortezomib who received carfilzomib 20 mg/m², and 129 bortezomib-naive patients treated at 20 mg/m² or the same dose with escalation to 27 mg/m² if tolerable.

A corresponding toxicity analysis is underway, as are clinical trials assessing higher-dose regimens. The analysis raises the obvious question of whether the 20- to-27-mg/m² dose schedule Onyx used in its recent accelerated review filing for carfilzomib is possibly too low.

Dr. Ro and other Onyx employees milling about the poster were hesitant to comment, with Ruben Sanchez, the associate director of publications at Onyx, saying only that the maximum tolerated dose of carfilzomib is 20-70 mg/m² and that studies are ongoing at an "experimental dose" of 20-56 mg/m².

Unfavorable Cytogenetics

The second poster confirmed that unfavorable cytogenetics did not significantly impact overall response rates or response duration, but found that median overall survival was shorter for those with cytogenetic abnormalities than for those with no detected abnormalities at 11.9 months vs. 19.2 months.

A similar trend was observed for median progression-free survival at 3.6 months vs. 4.6 months, reported Dr. Andrzej J. Jakubowiak of the University of Michigan Comprehensive Cancer Center in Ann Arbor.

When the researchers looked at specific cytogenetic abnormalities in the 234 evaluable patients dosed using the 20- to 27-mg/m² schedule, median overall survival was the lowest among those with deletion 17p3 at 7 months vs. 10.6 months with deletion 13, 10.4 months with hypodiploidy, and 11.8 months with translocation t(4:14).

 

Progression-free survival and time to progression also tended to be longer for patients with hypoploidy and translocation t(4:14) than for patients with deletion 13 and deletion 17p13. This observation is compatible with current thinking highlighted in an educational multiple myeloma program at the meeting, that cytogenetic abnormalities are becoming something of a moving target, coauthor Dr. Sundar Jagannath, director of the multiple myeloma program at Mt. Sinai Medical Center in New York, said in an interview.

"One area, 17p13 deletion, is still a challenge, but t4;14 translocation, hypodiploidy, and deletion 13 ... are all no longer considered as high risk in the presence of protease inhibitors," he said. "It is nothing unique to carfilzomib; it’s just the class of protease inhibitors."

Dr. Jagannath said that even in patients with the problematic 17p13 deletion, researchers have used gene expression profiling to further delineate those at high and low risk, and that data clearly show that outcomes are improved in low-risk 17p13 deletion patients with the inclusion of the protease inhibitor bortezomib therapy.

Safety Data

The third poster features integrated safety data from 526 heavily pretreated patients receiving carfilzomib 20 mg/m² or 20-27 mg/m², showing that grade 3/4 treatment adverse events occurred in 80% of patients, but were characterized as mostly reversible and primarily hematologic in nature.

The most common grade 3 adverse events were thrombocytopenia (23%), anemia (22%), lymphopenia (18%), and pneumonia (11%). There were no fatal hematologic events and no grade 4 or 5 bleeding reactions associated with thrombocytopenia, reported Dr. Seema Singhal, professor of medicine and director of the multiple myeloma program at Northwestern Memorial Hospital in Chicago, and her associates.

Cardiac events, some of which resulted in discontinuation or death, occurred. Cardiac failure events were reported in 7% with discontinuation due to heart failure in 2%, cardiac arrest in 1%, and myocardial ischemia in less than 1%.

"The extent to which these [events] were due to patients’ baseline comorbidities, toxicity from prior treatment, effects of multiple myeloma, carfilzomib itself, or a combination of these factors cannot be determined," the authors wrote.

Dr. Jagannath said the cardiac events do not represent a new signal.

The studies in the analyses were supported by Onyx. Dr. Ro is an employee of Onyx. Dr. Jakubowiak, Dr. Singhal, and Dr Jagannath reported financial relationships with several firms including Onyx.

SAN DIEGO – Data mined from several phase II studies of carfilzomib monotherapy confirm previous observations, but also raise new questions and insights into the use of the investigational proteasome inhibitor in relapsed and/or refractory multiple myeloma.

The first of three posters simultaneously presented at the American Society of Hematology used multivariate modeling to confirm a dose-response relationship for carfilzomib in bortezomib (Velcade)-naive and bortezomib-treated patients.

After study effect was adjusted for, the odds of achieving a partial response or better for a patient treated with 27 mg/m² were 4.08-fold higher than for a patient receiving only 20 mg/m² (P less than .001).

When using the average dose as a continuous variable and again adjusting for study effect, the odds of a response increased by 1.28-fold for each 1-mg/m² increase in average carfilzomib dose, equivalent to a 5.52-fold increase in the odds of a response if the average dose increased from 20 mg/m² to 27 mg/m² (P less than .001), reported Sunhee Ro, Ph.D., an employee of San Francisco–based Onyx Pharmaceuticals, which is developing the drug. Statistician Pierre Squifflet of the International Drug Development Institute in Belgium was the lead author.

The dose-effect relationship was observed not only on the primary end point of overall response rate, but also time to progression, progression-free survival, and overall survival.

The analysis included three study populations: 266 heavily pretreated patients who had received at least two prior therapies including bortezomib and either thalidomide or lenalidomide and who received carfilzomib 20 mg/m² in cycle one with escalation to 27 mg/m² if tolerable, 35 patients pretreated with one to three prior therapies including bortezomib who received carfilzomib 20 mg/m², and 129 bortezomib-naive patients treated at 20 mg/m² or the same dose with escalation to 27 mg/m² if tolerable.

A corresponding toxicity analysis is underway, as are clinical trials assessing higher-dose regimens. The analysis raises the obvious question of whether the 20- to-27-mg/m² dose schedule Onyx used in its recent accelerated review filing for carfilzomib is possibly too low.

Dr. Ro and other Onyx employees milling about the poster were hesitant to comment, with Ruben Sanchez, the associate director of publications at Onyx, saying only that the maximum tolerated dose of carfilzomib is 20-70 mg/m² and that studies are ongoing at an "experimental dose" of 20-56 mg/m².

Unfavorable Cytogenetics

The second poster confirmed that unfavorable cytogenetics did not significantly impact overall response rates or response duration, but found that median overall survival was shorter for those with cytogenetic abnormalities than for those with no detected abnormalities at 11.9 months vs. 19.2 months.

A similar trend was observed for median progression-free survival at 3.6 months vs. 4.6 months, reported Dr. Andrzej J. Jakubowiak of the University of Michigan Comprehensive Cancer Center in Ann Arbor.

When the researchers looked at specific cytogenetic abnormalities in the 234 evaluable patients dosed using the 20- to 27-mg/m² schedule, median overall survival was the lowest among those with deletion 17p3 at 7 months vs. 10.6 months with deletion 13, 10.4 months with hypodiploidy, and 11.8 months with translocation t(4:14).

 

Progression-free survival and time to progression also tended to be longer for patients with hypoploidy and translocation t(4:14) than for patients with deletion 13 and deletion 17p13. This observation is compatible with current thinking highlighted in an educational multiple myeloma program at the meeting, that cytogenetic abnormalities are becoming something of a moving target, coauthor Dr. Sundar Jagannath, director of the multiple myeloma program at Mt. Sinai Medical Center in New York, said in an interview.

"One area, 17p13 deletion, is still a challenge, but t4;14 translocation, hypodiploidy, and deletion 13 ... are all no longer considered as high risk in the presence of protease inhibitors," he said. "It is nothing unique to carfilzomib; it’s just the class of protease inhibitors."

Dr. Jagannath said that even in patients with the problematic 17p13 deletion, researchers have used gene expression profiling to further delineate those at high and low risk, and that data clearly show that outcomes are improved in low-risk 17p13 deletion patients with the inclusion of the protease inhibitor bortezomib therapy.

Safety Data

The third poster features integrated safety data from 526 heavily pretreated patients receiving carfilzomib 20 mg/m² or 20-27 mg/m², showing that grade 3/4 treatment adverse events occurred in 80% of patients, but were characterized as mostly reversible and primarily hematologic in nature.

The most common grade 3 adverse events were thrombocytopenia (23%), anemia (22%), lymphopenia (18%), and pneumonia (11%). There were no fatal hematologic events and no grade 4 or 5 bleeding reactions associated with thrombocytopenia, reported Dr. Seema Singhal, professor of medicine and director of the multiple myeloma program at Northwestern Memorial Hospital in Chicago, and her associates.

Cardiac events, some of which resulted in discontinuation or death, occurred. Cardiac failure events were reported in 7% with discontinuation due to heart failure in 2%, cardiac arrest in 1%, and myocardial ischemia in less than 1%.

"The extent to which these [events] were due to patients’ baseline comorbidities, toxicity from prior treatment, effects of multiple myeloma, carfilzomib itself, or a combination of these factors cannot be determined," the authors wrote.

Dr. Jagannath said the cardiac events do not represent a new signal.

The studies in the analyses were supported by Onyx. Dr. Ro is an employee of Onyx. Dr. Jakubowiak, Dr. Singhal, and Dr Jagannath reported financial relationships with several firms including Onyx.

SAN DIEGO – Data mined from several phase II studies of carfilzomib monotherapy confirm previous observations, but also raise new questions and insights into the use of the investigational proteasome inhibitor in relapsed and/or refractory multiple myeloma.

The first of three posters simultaneously presented at the American Society of Hematology used multivariate modeling to confirm a dose-response relationship for carfilzomib in bortezomib (Velcade)-naive and bortezomib-treated patients.

After study effect was adjusted for, the odds of achieving a partial response or better for a patient treated with 27 mg/m² were 4.08-fold higher than for a patient receiving only 20 mg/m² (P less than .001).

When using the average dose as a continuous variable and again adjusting for study effect, the odds of a response increased by 1.28-fold for each 1-mg/m² increase in average carfilzomib dose, equivalent to a 5.52-fold increase in the odds of a response if the average dose increased from 20 mg/m² to 27 mg/m² (P less than .001), reported Sunhee Ro, Ph.D., an employee of San Francisco–based Onyx Pharmaceuticals, which is developing the drug. Statistician Pierre Squifflet of the International Drug Development Institute in Belgium was the lead author.

The dose-effect relationship was observed not only on the primary end point of overall response rate, but also time to progression, progression-free survival, and overall survival.

The analysis included three study populations: 266 heavily pretreated patients who had received at least two prior therapies including bortezomib and either thalidomide or lenalidomide and who received carfilzomib 20 mg/m² in cycle one with escalation to 27 mg/m² if tolerable, 35 patients pretreated with one to three prior therapies including bortezomib who received carfilzomib 20 mg/m², and 129 bortezomib-naive patients treated at 20 mg/m² or the same dose with escalation to 27 mg/m² if tolerable.

A corresponding toxicity analysis is underway, as are clinical trials assessing higher-dose regimens. The analysis raises the obvious question of whether the 20- to-27-mg/m² dose schedule Onyx used in its recent accelerated review filing for carfilzomib is possibly too low.

Dr. Ro and other Onyx employees milling about the poster were hesitant to comment, with Ruben Sanchez, the associate director of publications at Onyx, saying only that the maximum tolerated dose of carfilzomib is 20-70 mg/m² and that studies are ongoing at an "experimental dose" of 20-56 mg/m².

Unfavorable Cytogenetics

The second poster confirmed that unfavorable cytogenetics did not significantly impact overall response rates or response duration, but found that median overall survival was shorter for those with cytogenetic abnormalities than for those with no detected abnormalities at 11.9 months vs. 19.2 months.

A similar trend was observed for median progression-free survival at 3.6 months vs. 4.6 months, reported Dr. Andrzej J. Jakubowiak of the University of Michigan Comprehensive Cancer Center in Ann Arbor.

When the researchers looked at specific cytogenetic abnormalities in the 234 evaluable patients dosed using the 20- to 27-mg/m² schedule, median overall survival was the lowest among those with deletion 17p3 at 7 months vs. 10.6 months with deletion 13, 10.4 months with hypodiploidy, and 11.8 months with translocation t(4:14).

 

Progression-free survival and time to progression also tended to be longer for patients with hypoploidy and translocation t(4:14) than for patients with deletion 13 and deletion 17p13. This observation is compatible with current thinking highlighted in an educational multiple myeloma program at the meeting, that cytogenetic abnormalities are becoming something of a moving target, coauthor Dr. Sundar Jagannath, director of the multiple myeloma program at Mt. Sinai Medical Center in New York, said in an interview.

"One area, 17p13 deletion, is still a challenge, but t4;14 translocation, hypodiploidy, and deletion 13 ... are all no longer considered as high risk in the presence of protease inhibitors," he said. "It is nothing unique to carfilzomib; it’s just the class of protease inhibitors."

Dr. Jagannath said that even in patients with the problematic 17p13 deletion, researchers have used gene expression profiling to further delineate those at high and low risk, and that data clearly show that outcomes are improved in low-risk 17p13 deletion patients with the inclusion of the protease inhibitor bortezomib therapy.

Safety Data

The third poster features integrated safety data from 526 heavily pretreated patients receiving carfilzomib 20 mg/m² or 20-27 mg/m², showing that grade 3/4 treatment adverse events occurred in 80% of patients, but were characterized as mostly reversible and primarily hematologic in nature.

The most common grade 3 adverse events were thrombocytopenia (23%), anemia (22%), lymphopenia (18%), and pneumonia (11%). There were no fatal hematologic events and no grade 4 or 5 bleeding reactions associated with thrombocytopenia, reported Dr. Seema Singhal, professor of medicine and director of the multiple myeloma program at Northwestern Memorial Hospital in Chicago, and her associates.

Cardiac events, some of which resulted in discontinuation or death, occurred. Cardiac failure events were reported in 7% with discontinuation due to heart failure in 2%, cardiac arrest in 1%, and myocardial ischemia in less than 1%.

"The extent to which these [events] were due to patients’ baseline comorbidities, toxicity from prior treatment, effects of multiple myeloma, carfilzomib itself, or a combination of these factors cannot be determined," the authors wrote.

Dr. Jagannath said the cardiac events do not represent a new signal.

The studies in the analyses were supported by Onyx. Dr. Ro is an employee of Onyx. Dr. Jakubowiak, Dr. Singhal, and Dr Jagannath reported financial relationships with several firms including Onyx.

SAN DIEGO – Mounting data from a federally funded follow-up to the BABY HUG study continue to demonstrate that hydroxyurea is a safe and effective treatment for young children with sickle cell anemia.

The results confirm findings published earlier this year from the Pediatric Hydroxyurea Phase III Clinical Trial (BABY HUG), a randomized, placebo-controlled study sponsored by the National Institutes of Health and by the Eunice Kennedy Shriver National Institute of Child Health and Human Development.

BABY HUG showed that hydroxyurea administered to 9- to 18-month-old children with sickle cell anemia provides significant clinical benefits, including a decrease in pain crises, acute chest syndrome events, and need for transfusion and hospital admission (Lancet 2011; 377:1663-72).

Hydroxyurea is approved to prevent sickle cell complications in adults with sickle cell anemia, but it is not currently indicated for use in children. Dr. Zora R. Rogers discussed the new data during a press briefing prior to a presentation at the annual meeting of the American Society of Hematology.

"We need to complete the data analysis and to critically examine the growth and development of this population with respect to hydroxyurea use," lead author Dr. Rogers said of the follow-up study, which terminates on Dec. 31, 2011. "But on a macroscopic level there [do] not appear to be any differences observed."

In 2008 Dr. Rogers, professor of pediatrics at the University of Texas Southwestern Medical Center, Dallas, and her associates at 14 centers launched the BABY HUG Follow-Up Study I to assess the safety and efficacy of continued treatment with hydroxyurea in infants with sickle cell anemia. The population consisted of 163 children aged 28-44 months who had participated in the original BABY HUG trial and who had completed at least 18 months of randomized treatment of either hydroxyurea or placebo. The researchers collected clinical and laboratory data every 6 months from patient medical records, including use and dosage of hydroxyurea, blood counts, clinical imaging, and frequency of sickle cell-related complications.

Of the 163 families that enrolled children in the follow-up study, 133 (82%) chose open-label hydroxyurea at the beginning of follow-up and every 6 months 65%-75% of the families reported that their children continued to take the drug. No patient developed intolerance or stopped permanently because of toxicity.

Dr. Rogers, clinical director of the bone marrow failure and general hematology program at Children’s Medical Center, Dallas, presented preliminary analyses as of Oct. 18, 2011, that amounted to 497 patient-years of follow-up. Compared with children who are not taking hydroxyurea, those who continue to take hydroxyurea have statistically lower rates of pain crises requiring emergency department visits (a rate of 29 vs. 54 per 100 patient-years, respectively), episodic transfusions (18 vs. 34 per 100 patient-years), and hospital admissions for any reason (73 vs. 132 per 100 patient-years), including acute chest syndrome or febrile illness.

In their abstract, the researchers pointed out that the decrease in acute chest syndrome episodes "is similar to the effect demonstrated with hydroxyurea use in the randomized BABY HUG trial in younger infants and consistent with published trials detailing the benefit of hydroxyurea therapy in older children and adults. The decrease in the rate of admission for febrile events in hydroxyurea-treated patients is also comparable to that in the randomized trial, but the reason for this benefit is uncertain."

There were no differences between the two groups in hospitalization rates for painful events, including dactylitis. Two patients in the non-hydroxyurea group each had a stroke. There were also no differences between the two groups in the frequency of a palpable spleen or rate of acute splenic sequestration crises. Through 36 months of follow up, children taking hydroxyurea had persistently higher hemoglobin and mean corpuscular volume and lower white blood cell count and absolute neutrophil count, compared with those not taking the drug.

Dr. Susan B. Shurin, acting director of the National Heart, Lung, and Blood Institute (NHLBI), characterized the findings as important in efforts to get an early handle on the burden of disease associated with sickle cell anemia.

"The internists who inherit the patients who have gone through pediatric practitioners have a powerful sense that they reach adolescence doing pretty well, and then things kind of fall apart," Dr. Shurin said. "The clear evidence that prevention of organ damage and prevention of complications of sickle cell anemia would be much preferable to trying to manage once they develop has been the motivation" for this work.

The BABY HUG investigators "believe that ongoing follow-up of this cohort is essential to continue to define the potential benefits as the children grow and to observe for late toxicity," Dr. Rogers said. "We are in final discussions with the NHLBI for an additional contract in support of 5 more years of follow-up."

The researchers intend to use the current findings "in support of an FDA application potentially to allow an indication for the use of hydroxyurea in very young children," Dr. Rogers said. "We are also hoping that there will be an interest for the use of this medication in a liquid format, because it’s very hard to get a 1-year-old to take a capsule."

The follow-up study is funded by the National Heart, Lung, and Blood Institute and by the Eunice Kennedy Shriver National Institute of Child Health and Human Development.

SAN DIEGO – Mounting data from a federally funded follow-up to the BABY HUG study continue to demonstrate that hydroxyurea is a safe and effective treatment for young children with sickle cell anemia.

The results confirm findings published earlier this year from the Pediatric Hydroxyurea Phase III Clinical Trial (BABY HUG), a randomized, placebo-controlled study sponsored by the National Institutes of Health and by the Eunice Kennedy Shriver National Institute of Child Health and Human Development.

BABY HUG showed that hydroxyurea administered to 9- to 18-month-old children with sickle cell anemia provides significant clinical benefits, including a decrease in pain crises, acute chest syndrome events, and need for transfusion and hospital admission (Lancet 2011; 377:1663-72).

Hydroxyurea is approved to prevent sickle cell complications in adults with sickle cell anemia, but it is not currently indicated for use in children. Dr. Zora R. Rogers discussed the new data during a press briefing prior to a presentation at the annual meeting of the American Society of Hematology.

"We need to complete the data analysis and to critically examine the growth and development of this population with respect to hydroxyurea use," lead author Dr. Rogers said of the follow-up study, which terminates on Dec. 31, 2011. "But on a macroscopic level there [do] not appear to be any differences observed."

In 2008 Dr. Rogers, professor of pediatrics at the University of Texas Southwestern Medical Center, Dallas, and her associates at 14 centers launched the BABY HUG Follow-Up Study I to assess the safety and efficacy of continued treatment with hydroxyurea in infants with sickle cell anemia. The population consisted of 163 children aged 28-44 months who had participated in the original BABY HUG trial and who had completed at least 18 months of randomized treatment of either hydroxyurea or placebo. The researchers collected clinical and laboratory data every 6 months from patient medical records, including use and dosage of hydroxyurea, blood counts, clinical imaging, and frequency of sickle cell-related complications.

Of the 163 families that enrolled children in the follow-up study, 133 (82%) chose open-label hydroxyurea at the beginning of follow-up and every 6 months 65%-75% of the families reported that their children continued to take the drug. No patient developed intolerance or stopped permanently because of toxicity.

Dr. Rogers, clinical director of the bone marrow failure and general hematology program at Children’s Medical Center, Dallas, presented preliminary analyses as of Oct. 18, 2011, that amounted to 497 patient-years of follow-up. Compared with children who are not taking hydroxyurea, those who continue to take hydroxyurea have statistically lower rates of pain crises requiring emergency department visits (a rate of 29 vs. 54 per 100 patient-years, respectively), episodic transfusions (18 vs. 34 per 100 patient-years), and hospital admissions for any reason (73 vs. 132 per 100 patient-years), including acute chest syndrome or febrile illness.

In their abstract, the researchers pointed out that the decrease in acute chest syndrome episodes "is similar to the effect demonstrated with hydroxyurea use in the randomized BABY HUG trial in younger infants and consistent with published trials detailing the benefit of hydroxyurea therapy in older children and adults. The decrease in the rate of admission for febrile events in hydroxyurea-treated patients is also comparable to that in the randomized trial, but the reason for this benefit is uncertain."

There were no differences between the two groups in hospitalization rates for painful events, including dactylitis. Two patients in the non-hydroxyurea group each had a stroke. There were also no differences between the two groups in the frequency of a palpable spleen or rate of acute splenic sequestration crises. Through 36 months of follow up, children taking hydroxyurea had persistently higher hemoglobin and mean corpuscular volume and lower white blood cell count and absolute neutrophil count, compared with those not taking the drug.

Dr. Susan B. Shurin, acting director of the National Heart, Lung, and Blood Institute (NHLBI), characterized the findings as important in efforts to get an early handle on the burden of disease associated with sickle cell anemia.

"The internists who inherit the patients who have gone through pediatric practitioners have a powerful sense that they reach adolescence doing pretty well, and then things kind of fall apart," Dr. Shurin said. "The clear evidence that prevention of organ damage and prevention of complications of sickle cell anemia would be much preferable to trying to manage once they develop has been the motivation" for this work.

The BABY HUG investigators "believe that ongoing follow-up of this cohort is essential to continue to define the potential benefits as the children grow and to observe for late toxicity," Dr. Rogers said. "We are in final discussions with the NHLBI for an additional contract in support of 5 more years of follow-up."

The researchers intend to use the current findings "in support of an FDA application potentially to allow an indication for the use of hydroxyurea in very young children," Dr. Rogers said. "We are also hoping that there will be an interest for the use of this medication in a liquid format, because it’s very hard to get a 1-year-old to take a capsule."

The follow-up study is funded by the National Heart, Lung, and Blood Institute and by the Eunice Kennedy Shriver National Institute of Child Health and Human Development.

SAN DIEGO – Mounting data from a federally funded follow-up to the BABY HUG study continue to demonstrate that hydroxyurea is a safe and effective treatment for young children with sickle cell anemia.

The results confirm findings published earlier this year from the Pediatric Hydroxyurea Phase III Clinical Trial (BABY HUG), a randomized, placebo-controlled study sponsored by the National Institutes of Health and by the Eunice Kennedy Shriver National Institute of Child Health and Human Development.

BABY HUG showed that hydroxyurea administered to 9- to 18-month-old children with sickle cell anemia provides significant clinical benefits, including a decrease in pain crises, acute chest syndrome events, and need for transfusion and hospital admission (Lancet 2011; 377:1663-72).

Hydroxyurea is approved to prevent sickle cell complications in adults with sickle cell anemia, but it is not currently indicated for use in children. Dr. Zora R. Rogers discussed the new data during a press briefing prior to a presentation at the annual meeting of the American Society of Hematology.

"We need to complete the data analysis and to critically examine the growth and development of this population with respect to hydroxyurea use," lead author Dr. Rogers said of the follow-up study, which terminates on Dec. 31, 2011. "But on a macroscopic level there [do] not appear to be any differences observed."

In 2008 Dr. Rogers, professor of pediatrics at the University of Texas Southwestern Medical Center, Dallas, and her associates at 14 centers launched the BABY HUG Follow-Up Study I to assess the safety and efficacy of continued treatment with hydroxyurea in infants with sickle cell anemia. The population consisted of 163 children aged 28-44 months who had participated in the original BABY HUG trial and who had completed at least 18 months of randomized treatment of either hydroxyurea or placebo. The researchers collected clinical and laboratory data every 6 months from patient medical records, including use and dosage of hydroxyurea, blood counts, clinical imaging, and frequency of sickle cell-related complications.

Of the 163 families that enrolled children in the follow-up study, 133 (82%) chose open-label hydroxyurea at the beginning of follow-up and every 6 months 65%-75% of the families reported that their children continued to take the drug. No patient developed intolerance or stopped permanently because of toxicity.

Dr. Rogers, clinical director of the bone marrow failure and general hematology program at Children’s Medical Center, Dallas, presented preliminary analyses as of Oct. 18, 2011, that amounted to 497 patient-years of follow-up. Compared with children who are not taking hydroxyurea, those who continue to take hydroxyurea have statistically lower rates of pain crises requiring emergency department visits (a rate of 29 vs. 54 per 100 patient-years, respectively), episodic transfusions (18 vs. 34 per 100 patient-years), and hospital admissions for any reason (73 vs. 132 per 100 patient-years), including acute chest syndrome or febrile illness.

In their abstract, the researchers pointed out that the decrease in acute chest syndrome episodes "is similar to the effect demonstrated with hydroxyurea use in the randomized BABY HUG trial in younger infants and consistent with published trials detailing the benefit of hydroxyurea therapy in older children and adults. The decrease in the rate of admission for febrile events in hydroxyurea-treated patients is also comparable to that in the randomized trial, but the reason for this benefit is uncertain."

There were no differences between the two groups in hospitalization rates for painful events, including dactylitis. Two patients in the non-hydroxyurea group each had a stroke. There were also no differences between the two groups in the frequency of a palpable spleen or rate of acute splenic sequestration crises. Through 36 months of follow up, children taking hydroxyurea had persistently higher hemoglobin and mean corpuscular volume and lower white blood cell count and absolute neutrophil count, compared with those not taking the drug.

Dr. Susan B. Shurin, acting director of the National Heart, Lung, and Blood Institute (NHLBI), characterized the findings as important in efforts to get an early handle on the burden of disease associated with sickle cell anemia.

"The internists who inherit the patients who have gone through pediatric practitioners have a powerful sense that they reach adolescence doing pretty well, and then things kind of fall apart," Dr. Shurin said. "The clear evidence that prevention of organ damage and prevention of complications of sickle cell anemia would be much preferable to trying to manage once they develop has been the motivation" for this work.

The BABY HUG investigators "believe that ongoing follow-up of this cohort is essential to continue to define the potential benefits as the children grow and to observe for late toxicity," Dr. Rogers said. "We are in final discussions with the NHLBI for an additional contract in support of 5 more years of follow-up."

The researchers intend to use the current findings "in support of an FDA application potentially to allow an indication for the use of hydroxyurea in very young children," Dr. Rogers said. "We are also hoping that there will be an interest for the use of this medication in a liquid format, because it’s very hard to get a 1-year-old to take a capsule."

The follow-up study is funded by the National Heart, Lung, and Blood Institute and by the Eunice Kennedy Shriver National Institute of Child Health and Human Development.

SAN DIEGO – Long after the event, hematopoietic stem cell recipients still bear a heavier burden of physical and emotional problems than do their siblings, and greater use of specialized health care, according to investigators at the annual meeting of the American Society of Hematology.

In all, 74% of transplant survivors reported having a chronic health condition at least 10 years on, compared with 39% of age-matched siblings in the Bone Marrow Transplant Survivor Study.

"The difference was especially prominent for severe or life-threatening conditions: 25% of the survivors versus 8% of the siblings reported having a severe, life threatening condition," said Dr. Can-Lan Sun, director of survey research at City of Hope Medical Center in Duarte, Calif., on behalf of coauthors at a press briefing.

"Survivors were five times more likely to report a severe life-threatening condition than siblings," she added.

The cumulative incidence of chronic health conditions over 15 years of follow-up was 71%, and the cumulative incidence of severe, life-threatening events was 40%, the authors found.

"We have many more survivors than we used to, and we’re very thankful for that, but I think it’s important to realize that once a transplant is over, it’s not really over – and that there are some long-term effects either because of the transplant procedure, or because of the chemotherapy that the patient had to get to the transplant," commented Dr. Stephanie J. Lee, professor of medicine at the University of Washington, and a transplant specialist at the Fred Hutchinson Cancer Research Center, both in Seattle.

Dr. Lee moderated the briefing but was not involved in the study.

The authors conducted a retrospective study that surveyed 366 hematopoietic cell transplantation (HCT) survivors of at least 10 years’ duration and compared outcomes of chronic health conditions and psychological health with those of 309 aged-matched siblings. The severe and/or life-threatening conditions they considered included:

• Impaired hearing (loss not corrected by hearing aids).

• Legal blindness.

• Dialysis support.

• Gastrointestinal problems (surgery for intestinal obstruction, rectal or anal strictures, or cirrhosis.

• Cardiovascular disease (coronary artery disease, congestive heart failure, stroke).

• Joint replacement.

• Diabetes.

• Subsequent cancers.

The majority of survivors (65%) had received allogeneic transplants from a relative, 27% had autologous transplants, and 8% received HCT from unrelated donors. In all, 72% of patients had a conditioning regimen with total body irradiation and cyclophosphamide or etoposide, or both.

Indications for transplant were acute myeloid leukemia (28%), chronic myeloid leukemia (17%), acute lymphocytic leukemia (17%), non-Hodgkin’s lymphoma (11%), Hodgkin’s lymphoma (7%), aplastic anemia, or others (10%).

In an analysis adjusted for age at questionnaire, sex, race/ethnicity, education level attained, income and insurance status, they found that the relative risk (RR) for survivors to have any grade 1-4 condition was 2.16. The RR for having a grade 1 or 2 condition was 2.24, and for having a grade 3 or 4 condition was 5.64 (P less than .001 for all comparisons).

In addition, an analysis of adverse psychological outcomes, adjusted for the same factors, showed that survivors had an RR for somatic distress (unexplained physical symptoms such as pain, fatigue, etc.) of 2.73 (P = .03).

"Among survivors, females, those with low income, and those with poor health status were more likely to report somatic distress," Dr. Sun said.

In contrast, there were no significant differences between survivors and siblings in risk for anxiety, depression, or global distress.

Survivors also reported high use of health care services, with 78% reporting receiving a general physical examination within the past 2 years, and nearly two-thirds reporting that they had returned to the cancer center for ongoing care.

"As HCT continues to be a curative option for a variety of hematological malignancies, the burden of long-term physical and emotional morbidity formed by HCT recipients who have survived at least 10 years is substantial," Dr. Sun concluded.

The study was supported by a National Institutes of Health grant and a Leukemia & Lymphoma Society Scholar award to Dr. Sun. Neither she nor Dr. Lee had reported conflicts of interest.

SAN DIEGO – Long after the event, hematopoietic stem cell recipients still bear a heavier burden of physical and emotional problems than do their siblings, and greater use of specialized health care, according to investigators at the annual meeting of the American Society of Hematology.

In all, 74% of transplant survivors reported having a chronic health condition at least 10 years on, compared with 39% of age-matched siblings in the Bone Marrow Transplant Survivor Study.

"The difference was especially prominent for severe or life-threatening conditions: 25% of the survivors versus 8% of the siblings reported having a severe, life threatening condition," said Dr. Can-Lan Sun, director of survey research at City of Hope Medical Center in Duarte, Calif., on behalf of coauthors at a press briefing.

"Survivors were five times more likely to report a severe life-threatening condition than siblings," she added.

The cumulative incidence of chronic health conditions over 15 years of follow-up was 71%, and the cumulative incidence of severe, life-threatening events was 40%, the authors found.

"We have many more survivors than we used to, and we’re very thankful for that, but I think it’s important to realize that once a transplant is over, it’s not really over – and that there are some long-term effects either because of the transplant procedure, or because of the chemotherapy that the patient had to get to the transplant," commented Dr. Stephanie J. Lee, professor of medicine at the University of Washington, and a transplant specialist at the Fred Hutchinson Cancer Research Center, both in Seattle.

Dr. Lee moderated the briefing but was not involved in the study.

The authors conducted a retrospective study that surveyed 366 hematopoietic cell transplantation (HCT) survivors of at least 10 years’ duration and compared outcomes of chronic health conditions and psychological health with those of 309 aged-matched siblings. The severe and/or life-threatening conditions they considered included:

• Impaired hearing (loss not corrected by hearing aids).

• Legal blindness.

• Dialysis support.

• Gastrointestinal problems (surgery for intestinal obstruction, rectal or anal strictures, or cirrhosis.

• Cardiovascular disease (coronary artery disease, congestive heart failure, stroke).

• Joint replacement.

• Diabetes.

• Subsequent cancers.

The majority of survivors (65%) had received allogeneic transplants from a relative, 27% had autologous transplants, and 8% received HCT from unrelated donors. In all, 72% of patients had a conditioning regimen with total body irradiation and cyclophosphamide or etoposide, or both.

Indications for transplant were acute myeloid leukemia (28%), chronic myeloid leukemia (17%), acute lymphocytic leukemia (17%), non-Hodgkin’s lymphoma (11%), Hodgkin’s lymphoma (7%), aplastic anemia, or others (10%).

In an analysis adjusted for age at questionnaire, sex, race/ethnicity, education level attained, income and insurance status, they found that the relative risk (RR) for survivors to have any grade 1-4 condition was 2.16. The RR for having a grade 1 or 2 condition was 2.24, and for having a grade 3 or 4 condition was 5.64 (P less than .001 for all comparisons).

In addition, an analysis of adverse psychological outcomes, adjusted for the same factors, showed that survivors had an RR for somatic distress (unexplained physical symptoms such as pain, fatigue, etc.) of 2.73 (P = .03).

"Among survivors, females, those with low income, and those with poor health status were more likely to report somatic distress," Dr. Sun said.

In contrast, there were no significant differences between survivors and siblings in risk for anxiety, depression, or global distress.

Survivors also reported high use of health care services, with 78% reporting receiving a general physical examination within the past 2 years, and nearly two-thirds reporting that they had returned to the cancer center for ongoing care.

"As HCT continues to be a curative option for a variety of hematological malignancies, the burden of long-term physical and emotional morbidity formed by HCT recipients who have survived at least 10 years is substantial," Dr. Sun concluded.

The study was supported by a National Institutes of Health grant and a Leukemia & Lymphoma Society Scholar award to Dr. Sun. Neither she nor Dr. Lee had reported conflicts of interest.

SAN DIEGO – Long after the event, hematopoietic stem cell recipients still bear a heavier burden of physical and emotional problems than do their siblings, and greater use of specialized health care, according to investigators at the annual meeting of the American Society of Hematology.

In all, 74% of transplant survivors reported having a chronic health condition at least 10 years on, compared with 39% of age-matched siblings in the Bone Marrow Transplant Survivor Study.

"The difference was especially prominent for severe or life-threatening conditions: 25% of the survivors versus 8% of the siblings reported having a severe, life threatening condition," said Dr. Can-Lan Sun, director of survey research at City of Hope Medical Center in Duarte, Calif., on behalf of coauthors at a press briefing.

"Survivors were five times more likely to report a severe life-threatening condition than siblings," she added.

The cumulative incidence of chronic health conditions over 15 years of follow-up was 71%, and the cumulative incidence of severe, life-threatening events was 40%, the authors found.

"We have many more survivors than we used to, and we’re very thankful for that, but I think it’s important to realize that once a transplant is over, it’s not really over – and that there are some long-term effects either because of the transplant procedure, or because of the chemotherapy that the patient had to get to the transplant," commented Dr. Stephanie J. Lee, professor of medicine at the University of Washington, and a transplant specialist at the Fred Hutchinson Cancer Research Center, both in Seattle.

Dr. Lee moderated the briefing but was not involved in the study.

The authors conducted a retrospective study that surveyed 366 hematopoietic cell transplantation (HCT) survivors of at least 10 years’ duration and compared outcomes of chronic health conditions and psychological health with those of 309 aged-matched siblings. The severe and/or life-threatening conditions they considered included:

• Impaired hearing (loss not corrected by hearing aids).

• Legal blindness.

• Dialysis support.

• Gastrointestinal problems (surgery for intestinal obstruction, rectal or anal strictures, or cirrhosis.

• Cardiovascular disease (coronary artery disease, congestive heart failure, stroke).

• Joint replacement.

• Diabetes.

• Subsequent cancers.

The majority of survivors (65%) had received allogeneic transplants from a relative, 27% had autologous transplants, and 8% received HCT from unrelated donors. In all, 72% of patients had a conditioning regimen with total body irradiation and cyclophosphamide or etoposide, or both.

Indications for transplant were acute myeloid leukemia (28%), chronic myeloid leukemia (17%), acute lymphocytic leukemia (17%), non-Hodgkin’s lymphoma (11%), Hodgkin’s lymphoma (7%), aplastic anemia, or others (10%).

In an analysis adjusted for age at questionnaire, sex, race/ethnicity, education level attained, income and insurance status, they found that the relative risk (RR) for survivors to have any grade 1-4 condition was 2.16. The RR for having a grade 1 or 2 condition was 2.24, and for having a grade 3 or 4 condition was 5.64 (P less than .001 for all comparisons).

In addition, an analysis of adverse psychological outcomes, adjusted for the same factors, showed that survivors had an RR for somatic distress (unexplained physical symptoms such as pain, fatigue, etc.) of 2.73 (P = .03).

"Among survivors, females, those with low income, and those with poor health status were more likely to report somatic distress," Dr. Sun said.

In contrast, there were no significant differences between survivors and siblings in risk for anxiety, depression, or global distress.

Survivors also reported high use of health care services, with 78% reporting receiving a general physical examination within the past 2 years, and nearly two-thirds reporting that they had returned to the cancer center for ongoing care.

"As HCT continues to be a curative option for a variety of hematological malignancies, the burden of long-term physical and emotional morbidity formed by HCT recipients who have survived at least 10 years is substantial," Dr. Sun concluded.

The study was supported by a National Institutes of Health grant and a Leukemia & Lymphoma Society Scholar award to Dr. Sun. Neither she nor Dr. Lee had reported conflicts of interest.