Aggressive Lymphomas

Photo courtesy of the CDC

New research provides an explanation for the fact that US patients with hematologic malignancies are less likely to enroll in hospice care than patients with solid tumor malignancies.

Results of a national survey suggest that concerns about the adequacy of hospice may prevent hematologic oncologists from referring their patients.

Researchers say this finding, published in Cancer, points to potential means of improving end-of-life care for patients with hematologic malignancies.

Oreofe Odejide, MD, of the Dana-Farber Cancer Institute in Boston, Massachusetts, and her colleagues carried out this study.

The team conducted a survey of a national sample of hematologic oncologists listed in the publicly available clinical directory of the American Society of Hematology.

More than 57% of physicians who were contacted provided responses, for a total of 349 respondents.

The survey included questions about views regarding the helpfulness and adequacy of home hospice services for patients with hematologic malignancies, as well as factors that would impact oncologists’ likelihood of referring patients to hospice.

More than 68% of hematologic oncologists strongly agreed that hospice care is “helpful” for patients with hematologic malignancies.

However, 46% of the oncologists felt that home hospice is “inadequate” for the needs of patients with hematologic malignancies, when compared to inpatient hospice.

Still, most of the respondents who believed home hospice is inadequate said they would be more likely to refer patients if platelet and red blood cell transfusions were readily available.

“Our findings are important as they shed light on factors that are potential barriers to hospice referrals,” Dr Odejide said. “These findings can be employed to develop targeted interventions to address hospice underuse for patients with blood cancers.” 

Photo courtesy of the CDC

New research provides an explanation for the fact that US patients with hematologic malignancies are less likely to enroll in hospice care than patients with solid tumor malignancies.

Results of a national survey suggest that concerns about the adequacy of hospice may prevent hematologic oncologists from referring their patients.

Researchers say this finding, published in Cancer, points to potential means of improving end-of-life care for patients with hematologic malignancies.

Oreofe Odejide, MD, of the Dana-Farber Cancer Institute in Boston, Massachusetts, and her colleagues carried out this study.

The team conducted a survey of a national sample of hematologic oncologists listed in the publicly available clinical directory of the American Society of Hematology.

More than 57% of physicians who were contacted provided responses, for a total of 349 respondents.

The survey included questions about views regarding the helpfulness and adequacy of home hospice services for patients with hematologic malignancies, as well as factors that would impact oncologists’ likelihood of referring patients to hospice.

More than 68% of hematologic oncologists strongly agreed that hospice care is “helpful” for patients with hematologic malignancies.

However, 46% of the oncologists felt that home hospice is “inadequate” for the needs of patients with hematologic malignancies, when compared to inpatient hospice.

Still, most of the respondents who believed home hospice is inadequate said they would be more likely to refer patients if platelet and red blood cell transfusions were readily available.

“Our findings are important as they shed light on factors that are potential barriers to hospice referrals,” Dr Odejide said. “These findings can be employed to develop targeted interventions to address hospice underuse for patients with blood cancers.” 

Photo courtesy of the CDC

New research provides an explanation for the fact that US patients with hematologic malignancies are less likely to enroll in hospice care than patients with solid tumor malignancies.

Results of a national survey suggest that concerns about the adequacy of hospice may prevent hematologic oncologists from referring their patients.

Researchers say this finding, published in Cancer, points to potential means of improving end-of-life care for patients with hematologic malignancies.

Oreofe Odejide, MD, of the Dana-Farber Cancer Institute in Boston, Massachusetts, and her colleagues carried out this study.

The team conducted a survey of a national sample of hematologic oncologists listed in the publicly available clinical directory of the American Society of Hematology.

More than 57% of physicians who were contacted provided responses, for a total of 349 respondents.

The survey included questions about views regarding the helpfulness and adequacy of home hospice services for patients with hematologic malignancies, as well as factors that would impact oncologists’ likelihood of referring patients to hospice.

More than 68% of hematologic oncologists strongly agreed that hospice care is “helpful” for patients with hematologic malignancies.

However, 46% of the oncologists felt that home hospice is “inadequate” for the needs of patients with hematologic malignancies, when compared to inpatient hospice.

Still, most of the respondents who believed home hospice is inadequate said they would be more likely to refer patients if platelet and red blood cell transfusions were readily available.

“Our findings are important as they shed light on factors that are potential barriers to hospice referrals,” Dr Odejide said. “These findings can be employed to develop targeted interventions to address hospice underuse for patients with blood cancers.” 

Follicular lymphoma

The US Food and Drug Administration (FDA) has granted priority review to the new drug application (NDA) for copanlisib, an intravenous PI3K inhibitor.

The NDA is for copanlisib as a treatment for patients with relapsed or refractory follicular lymphoma (FL) who have received at least 2 prior therapies.

The FDA grants priority review to applications for products that may provide significant improvements in the treatment, diagnosis, or prevention of serious conditions.

The agency’s goal is to take action on a priority review application within 6 months of receiving it, rather than the standard 10 months.

The application for copanlisib is supported by data from the CHRONOS-1 trial. This phase 2 trial enrolled 141 patients with relapsed/refractory, indolent non-Hodgkin lymphoma. Most of these patients had FL (n=104).

In all patients, copanlisib produced an objective response rate of 59.2%, with a complete response rate of 12%. The median duration of response exceeded 98 weeks.

In the FL subset, copanlisib produced an overall response rate of 58.7%, with a complete response rate of 14.4%. The median duration of response exceeded 52 weeks.

In the entire cohort, there were 3 deaths considered related to copanlisib.

The most common treatment-related adverse events were transient hyperglycemia (all grades: 49%/grade 3-4: 40%) and hypertension (all grades: 29%/grade 3: 23%).

“Patients with relapsed or refractory follicular lymphoma have a poor prognosis, and new treatment options which are well tolerated and effective are needed to prolong progression-free survival and improve quality of life for these patients,” said Martin Dreyling, MD, a professor at the University of Munich Hospital (Grosshadern) in Germany and lead investigator of the CHRONOS-1 study.

“Based on the CHRONOS-1 results, where copanlisib showed durable efficacy with a manageable and distinct safety profile, the compound may have the potential to address this unmet medical need.”

Data from CHRONOS-1 were presented at the AACR Annual Meeting 2017.

Data from the FL subset of the trial are scheduled to be presented at the 2017 ASCO Annual Meeting in June.

Copanlisib is being developed by Bayer. The compound has fast track and orphan drug designations from the FDA.

The FDA grants orphan designation to products intended to treat, diagnose, or prevent diseases/disorders that affect fewer than 200,000 people in the US.

The designation provides incentives for sponsors to develop products for rare diseases. This may include tax credits toward the cost of clinical trials, prescription drug user fee waivers, and 7 years of market exclusivity if the product is approved.

The FDA’s fast track program is designed to facilitate the development and expedite the review of products intended to treat or prevent serious or life-threatening conditions and address unmet medical need.

Through the fast track program, a product may be eligible for priority review. In addition, the company developing the product may be allowed to submit sections of the NDA or biologic license application on a rolling basis as data become available.

Fast track designation also provides the company with opportunities for more frequent meetings and written communications with the FDA. 

Follicular lymphoma

The US Food and Drug Administration (FDA) has granted priority review to the new drug application (NDA) for copanlisib, an intravenous PI3K inhibitor.

The NDA is for copanlisib as a treatment for patients with relapsed or refractory follicular lymphoma (FL) who have received at least 2 prior therapies.

The FDA grants priority review to applications for products that may provide significant improvements in the treatment, diagnosis, or prevention of serious conditions.

The agency’s goal is to take action on a priority review application within 6 months of receiving it, rather than the standard 10 months.

The application for copanlisib is supported by data from the CHRONOS-1 trial. This phase 2 trial enrolled 141 patients with relapsed/refractory, indolent non-Hodgkin lymphoma. Most of these patients had FL (n=104).

In all patients, copanlisib produced an objective response rate of 59.2%, with a complete response rate of 12%. The median duration of response exceeded 98 weeks.

In the FL subset, copanlisib produced an overall response rate of 58.7%, with a complete response rate of 14.4%. The median duration of response exceeded 52 weeks.

In the entire cohort, there were 3 deaths considered related to copanlisib.

The most common treatment-related adverse events were transient hyperglycemia (all grades: 49%/grade 3-4: 40%) and hypertension (all grades: 29%/grade 3: 23%).

“Patients with relapsed or refractory follicular lymphoma have a poor prognosis, and new treatment options which are well tolerated and effective are needed to prolong progression-free survival and improve quality of life for these patients,” said Martin Dreyling, MD, a professor at the University of Munich Hospital (Grosshadern) in Germany and lead investigator of the CHRONOS-1 study.

“Based on the CHRONOS-1 results, where copanlisib showed durable efficacy with a manageable and distinct safety profile, the compound may have the potential to address this unmet medical need.”

Data from CHRONOS-1 were presented at the AACR Annual Meeting 2017.

Data from the FL subset of the trial are scheduled to be presented at the 2017 ASCO Annual Meeting in June.

Copanlisib is being developed by Bayer. The compound has fast track and orphan drug designations from the FDA.

The FDA grants orphan designation to products intended to treat, diagnose, or prevent diseases/disorders that affect fewer than 200,000 people in the US.

The designation provides incentives for sponsors to develop products for rare diseases. This may include tax credits toward the cost of clinical trials, prescription drug user fee waivers, and 7 years of market exclusivity if the product is approved.

The FDA’s fast track program is designed to facilitate the development and expedite the review of products intended to treat or prevent serious or life-threatening conditions and address unmet medical need.

Through the fast track program, a product may be eligible for priority review. In addition, the company developing the product may be allowed to submit sections of the NDA or biologic license application on a rolling basis as data become available.

Fast track designation also provides the company with opportunities for more frequent meetings and written communications with the FDA. 

Follicular lymphoma

The US Food and Drug Administration (FDA) has granted priority review to the new drug application (NDA) for copanlisib, an intravenous PI3K inhibitor.

The NDA is for copanlisib as a treatment for patients with relapsed or refractory follicular lymphoma (FL) who have received at least 2 prior therapies.

The FDA grants priority review to applications for products that may provide significant improvements in the treatment, diagnosis, or prevention of serious conditions.

The agency’s goal is to take action on a priority review application within 6 months of receiving it, rather than the standard 10 months.

The application for copanlisib is supported by data from the CHRONOS-1 trial. This phase 2 trial enrolled 141 patients with relapsed/refractory, indolent non-Hodgkin lymphoma. Most of these patients had FL (n=104).

In all patients, copanlisib produced an objective response rate of 59.2%, with a complete response rate of 12%. The median duration of response exceeded 98 weeks.

In the FL subset, copanlisib produced an overall response rate of 58.7%, with a complete response rate of 14.4%. The median duration of response exceeded 52 weeks.

In the entire cohort, there were 3 deaths considered related to copanlisib.

The most common treatment-related adverse events were transient hyperglycemia (all grades: 49%/grade 3-4: 40%) and hypertension (all grades: 29%/grade 3: 23%).

“Patients with relapsed or refractory follicular lymphoma have a poor prognosis, and new treatment options which are well tolerated and effective are needed to prolong progression-free survival and improve quality of life for these patients,” said Martin Dreyling, MD, a professor at the University of Munich Hospital (Grosshadern) in Germany and lead investigator of the CHRONOS-1 study.

“Based on the CHRONOS-1 results, where copanlisib showed durable efficacy with a manageable and distinct safety profile, the compound may have the potential to address this unmet medical need.”

Data from CHRONOS-1 were presented at the AACR Annual Meeting 2017.

Data from the FL subset of the trial are scheduled to be presented at the 2017 ASCO Annual Meeting in June.

Copanlisib is being developed by Bayer. The compound has fast track and orphan drug designations from the FDA.

The FDA grants orphan designation to products intended to treat, diagnose, or prevent diseases/disorders that affect fewer than 200,000 people in the US.

The designation provides incentives for sponsors to develop products for rare diseases. This may include tax credits toward the cost of clinical trials, prescription drug user fee waivers, and 7 years of market exclusivity if the product is approved.

The FDA’s fast track program is designed to facilitate the development and expedite the review of products intended to treat or prevent serious or life-threatening conditions and address unmet medical need.

Through the fast track program, a product may be eligible for priority review. In addition, the company developing the product may be allowed to submit sections of the NDA or biologic license application on a rolling basis as data become available.

Fast track designation also provides the company with opportunities for more frequent meetings and written communications with the FDA. 

Lab mouse

A nucleoside analog has shown potential for treating primary effusion lymphoma (PEL) and multiple myeloma (MM), according to researchers.

The compound, 6-ethylthioinosine (6-ETI), killed both PEL and MM cells in vitro.

6-ETI also reduced tumor burden and prolonged survival in mouse models of MM and PEL.

Ethel Cesarman, MD, PhD, of Weill Cornell Medicine in New York, New York, and her colleagues conducted this research and disclosed their results in the Journal of Clinical Investigation.

The researchers identified 6-ETI via high-throughput screening, and they initially tested the compound in PEL cell lines. 6-ETI induced necrosis, apoptosis, and autophagy in these cells.

In a xenograft model of PEL, mice treated with 6-ETI experienced “striking and immediate regression of the implanted xenograft within 3 days of treatment,” according to the researchers.

In addition, mice that received 6-ETI had significantly longer progression-free and overall survival than control mice (P<0.0001 for both), and the researchers said there were no obvious toxicities from the treatment.

Looking into the mechanism of 6-ETI, the researchers found that adenosine kinase (ADK) is required to phosphorylate and activate the compound, and PEL cells have high levels of ADK.

Because PEL cells closely resemble plasma cells, the researchers theorized that MM might produce high levels of ADK as well. Experiments in MM cells proved this theory correct.

So the researchers tested 6-ETI in MM cell lines and samples from MM patients. The compound induced apoptosis and autophagy, and it activated a DNA damage response in MM cells.

In a mouse model of MM, 6-ETI treatment significantly reduced tumor burden but did not result in weight loss. And treated mice had significantly longer overall survival than control mice (P<0.005).

Dr Cesarman and her colleagues are now trying to better understand how 6-ETI works and determine what other cancers expressing high levels of ADK might respond to the drug.

“This compound could provide a much-needed approach to treat people with some forms of plasma malignancies as well as other cancers that express ADK,” Dr Cesarman said. 

Lab mouse

A nucleoside analog has shown potential for treating primary effusion lymphoma (PEL) and multiple myeloma (MM), according to researchers.

The compound, 6-ethylthioinosine (6-ETI), killed both PEL and MM cells in vitro.

6-ETI also reduced tumor burden and prolonged survival in mouse models of MM and PEL.

Ethel Cesarman, MD, PhD, of Weill Cornell Medicine in New York, New York, and her colleagues conducted this research and disclosed their results in the Journal of Clinical Investigation.

The researchers identified 6-ETI via high-throughput screening, and they initially tested the compound in PEL cell lines. 6-ETI induced necrosis, apoptosis, and autophagy in these cells.

In a xenograft model of PEL, mice treated with 6-ETI experienced “striking and immediate regression of the implanted xenograft within 3 days of treatment,” according to the researchers.

In addition, mice that received 6-ETI had significantly longer progression-free and overall survival than control mice (P<0.0001 for both), and the researchers said there were no obvious toxicities from the treatment.

Looking into the mechanism of 6-ETI, the researchers found that adenosine kinase (ADK) is required to phosphorylate and activate the compound, and PEL cells have high levels of ADK.

Because PEL cells closely resemble plasma cells, the researchers theorized that MM might produce high levels of ADK as well. Experiments in MM cells proved this theory correct.

So the researchers tested 6-ETI in MM cell lines and samples from MM patients. The compound induced apoptosis and autophagy, and it activated a DNA damage response in MM cells.

In a mouse model of MM, 6-ETI treatment significantly reduced tumor burden but did not result in weight loss. And treated mice had significantly longer overall survival than control mice (P<0.005).

Dr Cesarman and her colleagues are now trying to better understand how 6-ETI works and determine what other cancers expressing high levels of ADK might respond to the drug.

“This compound could provide a much-needed approach to treat people with some forms of plasma malignancies as well as other cancers that express ADK,” Dr Cesarman said. 

Lab mouse

A nucleoside analog has shown potential for treating primary effusion lymphoma (PEL) and multiple myeloma (MM), according to researchers.

The compound, 6-ethylthioinosine (6-ETI), killed both PEL and MM cells in vitro.

6-ETI also reduced tumor burden and prolonged survival in mouse models of MM and PEL.

Ethel Cesarman, MD, PhD, of Weill Cornell Medicine in New York, New York, and her colleagues conducted this research and disclosed their results in the Journal of Clinical Investigation.

The researchers identified 6-ETI via high-throughput screening, and they initially tested the compound in PEL cell lines. 6-ETI induced necrosis, apoptosis, and autophagy in these cells.

In a xenograft model of PEL, mice treated with 6-ETI experienced “striking and immediate regression of the implanted xenograft within 3 days of treatment,” according to the researchers.

In addition, mice that received 6-ETI had significantly longer progression-free and overall survival than control mice (P<0.0001 for both), and the researchers said there were no obvious toxicities from the treatment.

Looking into the mechanism of 6-ETI, the researchers found that adenosine kinase (ADK) is required to phosphorylate and activate the compound, and PEL cells have high levels of ADK.

Because PEL cells closely resemble plasma cells, the researchers theorized that MM might produce high levels of ADK as well. Experiments in MM cells proved this theory correct.

So the researchers tested 6-ETI in MM cell lines and samples from MM patients. The compound induced apoptosis and autophagy, and it activated a DNA damage response in MM cells.

In a mouse model of MM, 6-ETI treatment significantly reduced tumor burden but did not result in weight loss. And treated mice had significantly longer overall survival than control mice (P<0.005).

Dr Cesarman and her colleagues are now trying to better understand how 6-ETI works and determine what other cancers expressing high levels of ADK might respond to the drug.

“This compound could provide a much-needed approach to treat people with some forms of plasma malignancies as well as other cancers that express ADK,” Dr Cesarman said. 

Photo by Rhoda Baer

A new study suggests that patients with double-hit lymphoma (DHL) in first remission only benefit from an autologous hematopoietic stem cell transplant (auto-HSCT) if they received standard frontline chemotherapy.

Researchers looked at long-term outcomes for DHL patients who achieved remission and, overall, found that auto-HSCT did not significantly prolong remission or survival.

However, patients who received standard chemotherapy as frontline treatment did appear to benefit from auto-HSCT, as these patients had worse outcomes than patients who received intensive frontline chemotherapy.

This finding led the researchers to recommend that DHL patients receive intensive chemotherapy upfront and forgo subsequent auto-HSCT.

Daniel J. Landsburg, MD, of the University of Pennsylvania in Philadelphia, and his colleagues made these recommendations in the Journal of Clinical Oncology.

“A major dilemma for oncologists who treat [DHL] was whether or not to recommend the potentially harmful therapy of auto-[H]SCT to patients with this disease as a strategy to help keep them in remission,” Dr Landsburg said.

To gain some insight into the issue, Dr Landsburg and his colleagues looked at data on 159 patients from 19 academic medical centers across the US.

Patients were diagnosed with DHL between 2006 and 2015, and all achieved remission following frontline chemotherapy.

Thirty-five patients received standard frontline therapy—R-CHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone).

The remaining patients received intensive frontline chemotherapy:

• 81 received DA-EPOCH-R (etoposide, prednisone, vincristine, cyclophos­phamide, doxorubicin, and rituximab)
• 32 received R-hyperCVAD (rituximab, cyclophos­phamide, vincristine, doxorubicin, dexamethasone, methotrexate, and cytarabine)
• 11 received R-CODOX-M/IVAC (rituximab, cyclophosphamide, doxorubicin, vincristine, methotrexate/ifosfamide, etoposide, high-dose cytarabine).

Sixty-two patients underwent auto-HSCT, and 97 patients did not. There were no significant differences between these 2 patient groups at baseline.

“Our result is not explained by differences in patients’ overall health or disease features,” Dr Landsburg said. “The transplant and non-transplant arms of this study were very well-matched.”

Relapse and survival

For the entire patient cohort, the 3-year relapse-free survival (RFS) rate was 80%, and the 3-year overall survival (OS) rate was 87%.

There was no significant difference in RFS or OS between patients who underwent auto-HSCT and those who did not.

The RFS rate was 89% in patients who underwent auto-HSCT and 75% in patients who did not (P=0.12). The OS rate was 91% and 85%, respectively (P=0.74).

“Once these patients achieve remission, the data show they are likely to stay in remission,” Dr Landsburg said.

“In the absence of a large, randomized, controlled trial, which would be very challenging to carry out in this case, this is the best evidence we have, and it shows there’s no clear benefit to these patients undergoing auto-[H]SCT.”

Impact of frontline therapy

Patients who received R-CHOP upfront had worse RFS and OS than those who received intensive chemotherapy, although the OS difference was not significant.

RFS rates were 56% in patients who received R-CHOP, 88% in those who received DA-EPOCH-R, 87% in those who received R-hyperCVAD, and 91% in those who received R-CODOX-M/IVAC (P=0.003).

OS rates were 77% in patients who received R-CHOP, 87% in those who received DA-EPOCH-R, 90% in those who received R-hyperCVAD, and 100% in those who received R-CODOX-M/IVAC, respectively (P=0.36).

When the 3 intensive regimens were combined, the RFS rate was 88% (vs 56% for R-CHOP, P=0.002), and the OS rate was 90% (vs 77% for R-CHOP, P=0.13).

Frontline therapy and HSCT

Patients who received R-CHOP upfront benefited from auto-HSCT, but patients who received intensive chemotherapy did not.

The RFS was 51% for patients who received R-CHOP and did not undergo auto-HSCT, and it was 75% for patients who received R-CHOP followed by auto-HSCT.

The OS was 75% for patients who received R-CHOP and did not undergo auto-HSCT, and it was 83% for patients who received R-CHOP followed by auto-HSCT.

The RFS was 86% for patients who received intensive chemotherapy and did not undergo auto-HSCT, and it was 91% for patients who received intensive chemotherapy followed by auto-HSCT.

The OS was 89% for patients who received intensive chemotherapy and did not undergo auto-HSCT, and it was 92% for patients who received intensive chemotherapy followed by auto-HSCT.

An intergroup comparison showed a significant difference in RFS (P=0.003), which was driven by a significantly lower rate of RFS for patients who received R-CHOP without auto-HSCT, compared with patients who received intensive chemotherapy without auto-HSCT (P=0.003) or intensive chemotherapy with auto-HSCT (P=0.001).

“[I]f patients do go into remission with R-CHOP, it appears to be less durable, so, in these cases, going forward with auto-[H]SCT may still make sense,” Dr Landsburg said.

On the other hand, there was no significant difference between the groups with regard to OS (P=0.50).

Dr Landsburg said the next step for this research will be to study features of patients who don’t go into remission in order to understand why their disease is resistant to therapy and if that can be overcome with different treatment strategies. He also said it’s important to try to find more effective therapies for DHL patients who relapse. 

Photo by Rhoda Baer

A new study suggests that patients with double-hit lymphoma (DHL) in first remission only benefit from an autologous hematopoietic stem cell transplant (auto-HSCT) if they received standard frontline chemotherapy.

Researchers looked at long-term outcomes for DHL patients who achieved remission and, overall, found that auto-HSCT did not significantly prolong remission or survival.

However, patients who received standard chemotherapy as frontline treatment did appear to benefit from auto-HSCT, as these patients had worse outcomes than patients who received intensive frontline chemotherapy.

This finding led the researchers to recommend that DHL patients receive intensive chemotherapy upfront and forgo subsequent auto-HSCT.

Daniel J. Landsburg, MD, of the University of Pennsylvania in Philadelphia, and his colleagues made these recommendations in the Journal of Clinical Oncology.

“A major dilemma for oncologists who treat [DHL] was whether or not to recommend the potentially harmful therapy of auto-[H]SCT to patients with this disease as a strategy to help keep them in remission,” Dr Landsburg said.

To gain some insight into the issue, Dr Landsburg and his colleagues looked at data on 159 patients from 19 academic medical centers across the US.

Patients were diagnosed with DHL between 2006 and 2015, and all achieved remission following frontline chemotherapy.

Thirty-five patients received standard frontline therapy—R-CHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone).

The remaining patients received intensive frontline chemotherapy:

• 81 received DA-EPOCH-R (etoposide, prednisone, vincristine, cyclophos­phamide, doxorubicin, and rituximab)
• 32 received R-hyperCVAD (rituximab, cyclophos­phamide, vincristine, doxorubicin, dexamethasone, methotrexate, and cytarabine)
• 11 received R-CODOX-M/IVAC (rituximab, cyclophosphamide, doxorubicin, vincristine, methotrexate/ifosfamide, etoposide, high-dose cytarabine).

Sixty-two patients underwent auto-HSCT, and 97 patients did not. There were no significant differences between these 2 patient groups at baseline.

“Our result is not explained by differences in patients’ overall health or disease features,” Dr Landsburg said. “The transplant and non-transplant arms of this study were very well-matched.”

Relapse and survival

For the entire patient cohort, the 3-year relapse-free survival (RFS) rate was 80%, and the 3-year overall survival (OS) rate was 87%.

There was no significant difference in RFS or OS between patients who underwent auto-HSCT and those who did not.

The RFS rate was 89% in patients who underwent auto-HSCT and 75% in patients who did not (P=0.12). The OS rate was 91% and 85%, respectively (P=0.74).

“Once these patients achieve remission, the data show they are likely to stay in remission,” Dr Landsburg said.

“In the absence of a large, randomized, controlled trial, which would be very challenging to carry out in this case, this is the best evidence we have, and it shows there’s no clear benefit to these patients undergoing auto-[H]SCT.”

Impact of frontline therapy

Patients who received R-CHOP upfront had worse RFS and OS than those who received intensive chemotherapy, although the OS difference was not significant.

RFS rates were 56% in patients who received R-CHOP, 88% in those who received DA-EPOCH-R, 87% in those who received R-hyperCVAD, and 91% in those who received R-CODOX-M/IVAC (P=0.003).

OS rates were 77% in patients who received R-CHOP, 87% in those who received DA-EPOCH-R, 90% in those who received R-hyperCVAD, and 100% in those who received R-CODOX-M/IVAC, respectively (P=0.36).

When the 3 intensive regimens were combined, the RFS rate was 88% (vs 56% for R-CHOP, P=0.002), and the OS rate was 90% (vs 77% for R-CHOP, P=0.13).

Frontline therapy and HSCT

Patients who received R-CHOP upfront benefited from auto-HSCT, but patients who received intensive chemotherapy did not.

The RFS was 51% for patients who received R-CHOP and did not undergo auto-HSCT, and it was 75% for patients who received R-CHOP followed by auto-HSCT.

The OS was 75% for patients who received R-CHOP and did not undergo auto-HSCT, and it was 83% for patients who received R-CHOP followed by auto-HSCT.

The RFS was 86% for patients who received intensive chemotherapy and did not undergo auto-HSCT, and it was 91% for patients who received intensive chemotherapy followed by auto-HSCT.

The OS was 89% for patients who received intensive chemotherapy and did not undergo auto-HSCT, and it was 92% for patients who received intensive chemotherapy followed by auto-HSCT.

An intergroup comparison showed a significant difference in RFS (P=0.003), which was driven by a significantly lower rate of RFS for patients who received R-CHOP without auto-HSCT, compared with patients who received intensive chemotherapy without auto-HSCT (P=0.003) or intensive chemotherapy with auto-HSCT (P=0.001).

“[I]f patients do go into remission with R-CHOP, it appears to be less durable, so, in these cases, going forward with auto-[H]SCT may still make sense,” Dr Landsburg said.

On the other hand, there was no significant difference between the groups with regard to OS (P=0.50).

Dr Landsburg said the next step for this research will be to study features of patients who don’t go into remission in order to understand why their disease is resistant to therapy and if that can be overcome with different treatment strategies. He also said it’s important to try to find more effective therapies for DHL patients who relapse. 

Photo by Rhoda Baer

A new study suggests that patients with double-hit lymphoma (DHL) in first remission only benefit from an autologous hematopoietic stem cell transplant (auto-HSCT) if they received standard frontline chemotherapy.

Researchers looked at long-term outcomes for DHL patients who achieved remission and, overall, found that auto-HSCT did not significantly prolong remission or survival.

However, patients who received standard chemotherapy as frontline treatment did appear to benefit from auto-HSCT, as these patients had worse outcomes than patients who received intensive frontline chemotherapy.

This finding led the researchers to recommend that DHL patients receive intensive chemotherapy upfront and forgo subsequent auto-HSCT.

Daniel J. Landsburg, MD, of the University of Pennsylvania in Philadelphia, and his colleagues made these recommendations in the Journal of Clinical Oncology.

“A major dilemma for oncologists who treat [DHL] was whether or not to recommend the potentially harmful therapy of auto-[H]SCT to patients with this disease as a strategy to help keep them in remission,” Dr Landsburg said.

To gain some insight into the issue, Dr Landsburg and his colleagues looked at data on 159 patients from 19 academic medical centers across the US.

Patients were diagnosed with DHL between 2006 and 2015, and all achieved remission following frontline chemotherapy.

Thirty-five patients received standard frontline therapy—R-CHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone).

The remaining patients received intensive frontline chemotherapy:

• 81 received DA-EPOCH-R (etoposide, prednisone, vincristine, cyclophos­phamide, doxorubicin, and rituximab)
• 32 received R-hyperCVAD (rituximab, cyclophos­phamide, vincristine, doxorubicin, dexamethasone, methotrexate, and cytarabine)
• 11 received R-CODOX-M/IVAC (rituximab, cyclophosphamide, doxorubicin, vincristine, methotrexate/ifosfamide, etoposide, high-dose cytarabine).

Sixty-two patients underwent auto-HSCT, and 97 patients did not. There were no significant differences between these 2 patient groups at baseline.

“Our result is not explained by differences in patients’ overall health or disease features,” Dr Landsburg said. “The transplant and non-transplant arms of this study were very well-matched.”

Relapse and survival

For the entire patient cohort, the 3-year relapse-free survival (RFS) rate was 80%, and the 3-year overall survival (OS) rate was 87%.

There was no significant difference in RFS or OS between patients who underwent auto-HSCT and those who did not.

The RFS rate was 89% in patients who underwent auto-HSCT and 75% in patients who did not (P=0.12). The OS rate was 91% and 85%, respectively (P=0.74).

“Once these patients achieve remission, the data show they are likely to stay in remission,” Dr Landsburg said.

“In the absence of a large, randomized, controlled trial, which would be very challenging to carry out in this case, this is the best evidence we have, and it shows there’s no clear benefit to these patients undergoing auto-[H]SCT.”

Impact of frontline therapy

Patients who received R-CHOP upfront had worse RFS and OS than those who received intensive chemotherapy, although the OS difference was not significant.

RFS rates were 56% in patients who received R-CHOP, 88% in those who received DA-EPOCH-R, 87% in those who received R-hyperCVAD, and 91% in those who received R-CODOX-M/IVAC (P=0.003).

OS rates were 77% in patients who received R-CHOP, 87% in those who received DA-EPOCH-R, 90% in those who received R-hyperCVAD, and 100% in those who received R-CODOX-M/IVAC, respectively (P=0.36).

When the 3 intensive regimens were combined, the RFS rate was 88% (vs 56% for R-CHOP, P=0.002), and the OS rate was 90% (vs 77% for R-CHOP, P=0.13).

Frontline therapy and HSCT

Patients who received R-CHOP upfront benefited from auto-HSCT, but patients who received intensive chemotherapy did not.

The RFS was 51% for patients who received R-CHOP and did not undergo auto-HSCT, and it was 75% for patients who received R-CHOP followed by auto-HSCT.

The OS was 75% for patients who received R-CHOP and did not undergo auto-HSCT, and it was 83% for patients who received R-CHOP followed by auto-HSCT.

The RFS was 86% for patients who received intensive chemotherapy and did not undergo auto-HSCT, and it was 91% for patients who received intensive chemotherapy followed by auto-HSCT.

The OS was 89% for patients who received intensive chemotherapy and did not undergo auto-HSCT, and it was 92% for patients who received intensive chemotherapy followed by auto-HSCT.

An intergroup comparison showed a significant difference in RFS (P=0.003), which was driven by a significantly lower rate of RFS for patients who received R-CHOP without auto-HSCT, compared with patients who received intensive chemotherapy without auto-HSCT (P=0.003) or intensive chemotherapy with auto-HSCT (P=0.001).

“[I]f patients do go into remission with R-CHOP, it appears to be less durable, so, in these cases, going forward with auto-[H]SCT may still make sense,” Dr Landsburg said.

On the other hand, there was no significant difference between the groups with regard to OS (P=0.50).

Dr Landsburg said the next step for this research will be to study features of patients who don’t go into remission in order to understand why their disease is resistant to therapy and if that can be overcome with different treatment strategies. He also said it’s important to try to find more effective therapies for DHL patients who relapse. 

Photo by Rhoda Baer

VIENNA, AUSTRIA—Hodgkin lymphoma (HL) survivors who received chest irradiation should be screened for coronary artery disease (CAD), according to researchers.

The team evaluated HL survivors who underwent mediastinal irradiation 20 years prior to study initiation.

These individuals were more likely to have CAD and to have more severe CAD than matched control subjects.

The researchers presented these findings at ICNC 2017, the International Conference on Nuclear Cardiology and Cardiac CT (abstract P118).

“Patients with Hodgkin lymphoma receive high-dose mediastinal irradiation at a young age as part of their treatment,” said Alexander van Rosendael, MD, of Leiden University Medical Centre in the Netherlands.

“There is an ongoing debate about whether to screen patients who get chest irradiation for coronary artery disease.”

Therefore, Dr van Rosendael and his colleagues assessed the extent, severity, and location of CAD in HL survivors who had received chest irradiation.

The study included 79 patients who had been free of HL for at least 10 years and had received mediastinal irradiation 20 years ago, plus 273 control subjects without HL or irradiation.

CAD was assessed using coronary computed tomography angiography (CTA). To assess differences in CAD between patients and controls, they were matched in a 1:3 fashion by age, gender, diabetes, hypertension, hypercholesterolemia, family history of CAD, and smoking status.

Patients were 45 years old, on average, and the presence of cardiovascular risk factors was low overall.

Forty-two percent of patients had no atherosclerosis on coronary CTA, compared to 64% of controls (P<0.001).

Regarding the extent and severity of CAD, HL patients had significantly more multi-vessel CAD than controls. Ten percent of patients had 2-vessel disease, and 24% had 3-vessel disease, compared to 6% and 9% of controls, respectively (P=0.001).

The segment involvement score (which measures overall coronary plaque distribution) and the segment stenosis score (which measures overall coronary plaque extent and severity) were significantly higher for patients than for controls (P<0.001 and P=0.034, respectively).

Regarding the location of CAD, patients had significantly more coronary plaques in the left main (17% vs 6%, P=0.004), proximal left anterior descending (30% vs 16%, P=0.004), proximal right coronary artery (25% vs 10%, P<0.001), and proximal left circumflex (14% vs 6%, P=0.022), but not in non-proximal coronary segments.

Patients had about a 4-fold higher risk of proximal plaque and about 3-fold higher risk of proximal obstructive stenosis compared to controls (odds ratios, 4.1 and 2.9, respectively; P values, <0.001 and 0.025, respectively).

“Hodgkin patients who have chest irradiation have much more CAD than people of the same age who did not have irradiation,” Dr van Rosendael said.

“The CAD occurred at a young age—patients were 45 years old, on average—and was probably caused by the irradiation. The CTA was done about 20 years after chest irradiation, so there was time for CAD to develop.”

“What was remarkable was that irradiated patients had all the features of high-risk CAD, including high stenosis severity, proximal location, and extensive disease. We know that the proximal location of the disease is much riskier, and this may explain why Hodgkin patients have such poor cardiovascular outcomes when they get older.”

Dr van Rosendael explained that irradiation of the chest can cause inflammation of the coronary arteries, making patients more vulnerable to developing CAD. But it is not known why the CAD in irradiated patients tends to be proximally located.

He said the finding of more, and more severe, CAD in irradiated patients supports the argument for screening.

“When you see CAD in patients who received chest irradiation, it is high-risk CAD,” he said. “Such patients should be screened at regular intervals after irradiation so that CAD can be spotted early and early treatment can be initiated.”

“These patients are around 45 years old, and they are almost all asymptomatic. If you see a severe left main stenosis by screening with CTA (which occurred in 4%), then you can start statin therapy and perform revascularization, which may improve outcome. We know such treatment reduces the risk of events in non-irradiated patients, so it seems likely that it would benefit Hodgkin patients.” 

Photo by Rhoda Baer

VIENNA, AUSTRIA—Hodgkin lymphoma (HL) survivors who received chest irradiation should be screened for coronary artery disease (CAD), according to researchers.

The team evaluated HL survivors who underwent mediastinal irradiation 20 years prior to study initiation.

These individuals were more likely to have CAD and to have more severe CAD than matched control subjects.

The researchers presented these findings at ICNC 2017, the International Conference on Nuclear Cardiology and Cardiac CT (abstract P118).

“Patients with Hodgkin lymphoma receive high-dose mediastinal irradiation at a young age as part of their treatment,” said Alexander van Rosendael, MD, of Leiden University Medical Centre in the Netherlands.

“There is an ongoing debate about whether to screen patients who get chest irradiation for coronary artery disease.”

Therefore, Dr van Rosendael and his colleagues assessed the extent, severity, and location of CAD in HL survivors who had received chest irradiation.

The study included 79 patients who had been free of HL for at least 10 years and had received mediastinal irradiation 20 years ago, plus 273 control subjects without HL or irradiation.

CAD was assessed using coronary computed tomography angiography (CTA). To assess differences in CAD between patients and controls, they were matched in a 1:3 fashion by age, gender, diabetes, hypertension, hypercholesterolemia, family history of CAD, and smoking status.

Patients were 45 years old, on average, and the presence of cardiovascular risk factors was low overall.

Forty-two percent of patients had no atherosclerosis on coronary CTA, compared to 64% of controls (P<0.001).

Regarding the extent and severity of CAD, HL patients had significantly more multi-vessel CAD than controls. Ten percent of patients had 2-vessel disease, and 24% had 3-vessel disease, compared to 6% and 9% of controls, respectively (P=0.001).

The segment involvement score (which measures overall coronary plaque distribution) and the segment stenosis score (which measures overall coronary plaque extent and severity) were significantly higher for patients than for controls (P<0.001 and P=0.034, respectively).

Regarding the location of CAD, patients had significantly more coronary plaques in the left main (17% vs 6%, P=0.004), proximal left anterior descending (30% vs 16%, P=0.004), proximal right coronary artery (25% vs 10%, P<0.001), and proximal left circumflex (14% vs 6%, P=0.022), but not in non-proximal coronary segments.

Patients had about a 4-fold higher risk of proximal plaque and about 3-fold higher risk of proximal obstructive stenosis compared to controls (odds ratios, 4.1 and 2.9, respectively; P values, <0.001 and 0.025, respectively).

“Hodgkin patients who have chest irradiation have much more CAD than people of the same age who did not have irradiation,” Dr van Rosendael said.

“The CAD occurred at a young age—patients were 45 years old, on average—and was probably caused by the irradiation. The CTA was done about 20 years after chest irradiation, so there was time for CAD to develop.”

“What was remarkable was that irradiated patients had all the features of high-risk CAD, including high stenosis severity, proximal location, and extensive disease. We know that the proximal location of the disease is much riskier, and this may explain why Hodgkin patients have such poor cardiovascular outcomes when they get older.”

Dr van Rosendael explained that irradiation of the chest can cause inflammation of the coronary arteries, making patients more vulnerable to developing CAD. But it is not known why the CAD in irradiated patients tends to be proximally located.

He said the finding of more, and more severe, CAD in irradiated patients supports the argument for screening.

“When you see CAD in patients who received chest irradiation, it is high-risk CAD,” he said. “Such patients should be screened at regular intervals after irradiation so that CAD can be spotted early and early treatment can be initiated.”

“These patients are around 45 years old, and they are almost all asymptomatic. If you see a severe left main stenosis by screening with CTA (which occurred in 4%), then you can start statin therapy and perform revascularization, which may improve outcome. We know such treatment reduces the risk of events in non-irradiated patients, so it seems likely that it would benefit Hodgkin patients.” 

Photo by Rhoda Baer

VIENNA, AUSTRIA—Hodgkin lymphoma (HL) survivors who received chest irradiation should be screened for coronary artery disease (CAD), according to researchers.

The team evaluated HL survivors who underwent mediastinal irradiation 20 years prior to study initiation.

These individuals were more likely to have CAD and to have more severe CAD than matched control subjects.

The researchers presented these findings at ICNC 2017, the International Conference on Nuclear Cardiology and Cardiac CT (abstract P118).

“Patients with Hodgkin lymphoma receive high-dose mediastinal irradiation at a young age as part of their treatment,” said Alexander van Rosendael, MD, of Leiden University Medical Centre in the Netherlands.

“There is an ongoing debate about whether to screen patients who get chest irradiation for coronary artery disease.”

Therefore, Dr van Rosendael and his colleagues assessed the extent, severity, and location of CAD in HL survivors who had received chest irradiation.

The study included 79 patients who had been free of HL for at least 10 years and had received mediastinal irradiation 20 years ago, plus 273 control subjects without HL or irradiation.

CAD was assessed using coronary computed tomography angiography (CTA). To assess differences in CAD between patients and controls, they were matched in a 1:3 fashion by age, gender, diabetes, hypertension, hypercholesterolemia, family history of CAD, and smoking status.

Patients were 45 years old, on average, and the presence of cardiovascular risk factors was low overall.

Forty-two percent of patients had no atherosclerosis on coronary CTA, compared to 64% of controls (P<0.001).

Regarding the extent and severity of CAD, HL patients had significantly more multi-vessel CAD than controls. Ten percent of patients had 2-vessel disease, and 24% had 3-vessel disease, compared to 6% and 9% of controls, respectively (P=0.001).

The segment involvement score (which measures overall coronary plaque distribution) and the segment stenosis score (which measures overall coronary plaque extent and severity) were significantly higher for patients than for controls (P<0.001 and P=0.034, respectively).

Regarding the location of CAD, patients had significantly more coronary plaques in the left main (17% vs 6%, P=0.004), proximal left anterior descending (30% vs 16%, P=0.004), proximal right coronary artery (25% vs 10%, P<0.001), and proximal left circumflex (14% vs 6%, P=0.022), but not in non-proximal coronary segments.

Patients had about a 4-fold higher risk of proximal plaque and about 3-fold higher risk of proximal obstructive stenosis compared to controls (odds ratios, 4.1 and 2.9, respectively; P values, <0.001 and 0.025, respectively).

“Hodgkin patients who have chest irradiation have much more CAD than people of the same age who did not have irradiation,” Dr van Rosendael said.

“The CAD occurred at a young age—patients were 45 years old, on average—and was probably caused by the irradiation. The CTA was done about 20 years after chest irradiation, so there was time for CAD to develop.”

“What was remarkable was that irradiated patients had all the features of high-risk CAD, including high stenosis severity, proximal location, and extensive disease. We know that the proximal location of the disease is much riskier, and this may explain why Hodgkin patients have such poor cardiovascular outcomes when they get older.”

Dr van Rosendael explained that irradiation of the chest can cause inflammation of the coronary arteries, making patients more vulnerable to developing CAD. But it is not known why the CAD in irradiated patients tends to be proximally located.

He said the finding of more, and more severe, CAD in irradiated patients supports the argument for screening.

“When you see CAD in patients who received chest irradiation, it is high-risk CAD,” he said. “Such patients should be screened at regular intervals after irradiation so that CAD can be spotted early and early treatment can be initiated.”

“These patients are around 45 years old, and they are almost all asymptomatic. If you see a severe left main stenosis by screening with CTA (which occurred in 4%), then you can start statin therapy and perform revascularization, which may improve outcome. We know such treatment reduces the risk of events in non-irradiated patients, so it seems likely that it would benefit Hodgkin patients.” 

Photo by Rhoda Baer

BOSTON—A pair of preclinical studies suggest the FLT3/BTK inhibitor CG’806 is active in a range of hematologic malignancies.

In one of the studies, CG’806 proved particularly effective against acute myeloid leukemia (AML) cells harboring mutant forms of FLT3, and the compound was able to eradicate AML in mice.

In another study, researchers found CG’806 exhibited “broad potency” against leukemias, lymphomas, myelodysplastic syndromes (MDS), and myeloproliferative neoplasms (MPNs).

Both studies were presented as posters at Hematologic Malignancies: Translating Discoveries to Novel Therapies (poster 25 and poster 44).

Both studies involved researchers from Aptose Biosciences, the company developing CG’806.

Poster 25

Weiguo Zhang, MD, PhD, of The University of Texas MD Anderson Cancer Center in Houston, and his colleagues presented poster 25, “CG’806, a first-in-class FLT3/BTK inhibitor, exerts superior potency against AML cells harboring ITD, TKD and gatekeeper mutated FLT3 or wild-type FLT3.”

The researchers tested CG’806 and other FLT3 inhibitors in human or murine leukemia cell lines with wild-type (WT) FLT3, FLT3-ITD mutations, FLT3 TKD domain mutations, or ITD plus TKD mutations.

Compared to second-generation FLT3 inhibitors (quizartinib, gilteritinib, or crenolanib), CG’806 showed more pronounced anti-proliferative effects in leukemia cells with ITD mutations, D835 mutations, ITD plus F691I/Y842D/D835 mutations, or in FLT3 WT cells.

With CG’086, the IC50s in human AML cell lines were 0.17 nM for MV4-11 (FLT3-ITD) and 0.82 nM for MOLM13 (FLT3-ITD).

The IC50s in the murine leukemia cell lines were 9.49 nM for Ba/F3 (FLT3-WT), 0.30 nM for Ba/F3 (FLT3-ITD), 8.26 nM for Ba/F3 (FLT3-D835Y), 9.72 nM for Ba/F3 (FLT3-ITD+D835Y), and 0.43 nM for Ba/F3 (FLT3-ITD+F691L).

The researchers also found that CG’806 “triggers marked apoptosis” in FLT3-ITD-mutated primary AML samples but minimal apoptosis in normal bone marrow cells.

Another finding was that once-daily oral dosing of CG’806 in a murine model of AML (MV4-11) resulted in sustained micromolar plasma concentration over a 24-hour period.

This was accompanied by complete elimination of AML FLT3-ITD tumors without toxicity, the researchers said.

Poster 44

Stephen E. Kurtz, PhD, of Oregon Health & Science University in Portland, and his colleagues presented poster 44, “CG’806, a First-in-Class FLT3/BTK Inhibitor, Exhibits Potent Activity against AML Patient Samples with Mutant or Wild-Type FLT3, as well as Other Hematologic Malignancy Subtypes.”

The researchers tested CG’806 in samples from patients with AML (n=82), MDS/MPNs (n=15), acute lymphoblastic leukemia (ALL, n=17), chronic lymphocytic leukemia (CLL, n=58), and chronic myeloid leukemia (CML, n=4).

The team observed “broad sensitivity” to CG’806, with 59% (48/82) of AML, 53% (8/15) of MDS/MPN, 40% (23/58) of CLL, 29% (5/17) of ALL, and 25% (1/4) of CML cases exhibiting an IC50 of less than 100 nM.

Among the 38 tested AML samples with known FLT3 mutational status, the FLT3-ITD+ AML samples tended to have enhanced sensitivity to CG’806 (median IC50 = 20 nM, n=8) relative to the FLT3-WT samples (median IC50 = 120 nM, n=30).

The researchers also found that CG’806 exerted potent anti-proliferative activity against human AML, B-ALL, mantle cell lymphoma, Burkitt lymphoma, and diffuse large B-cell lymphoma cell lines.

“The analyses of CG’806 against primary hematologic malignancy patient samples and cultured cell lines show evidence of potent and broad drug activity in AML and other disease subtypes and support further development of this agent for hematologic malignancies,” Dr Kurtz said. 

Photo by Rhoda Baer

BOSTON—A pair of preclinical studies suggest the FLT3/BTK inhibitor CG’806 is active in a range of hematologic malignancies.

In one of the studies, CG’806 proved particularly effective against acute myeloid leukemia (AML) cells harboring mutant forms of FLT3, and the compound was able to eradicate AML in mice.

In another study, researchers found CG’806 exhibited “broad potency” against leukemias, lymphomas, myelodysplastic syndromes (MDS), and myeloproliferative neoplasms (MPNs).

Both studies were presented as posters at Hematologic Malignancies: Translating Discoveries to Novel Therapies (poster 25 and poster 44).

Both studies involved researchers from Aptose Biosciences, the company developing CG’806.

Poster 25

Weiguo Zhang, MD, PhD, of The University of Texas MD Anderson Cancer Center in Houston, and his colleagues presented poster 25, “CG’806, a first-in-class FLT3/BTK inhibitor, exerts superior potency against AML cells harboring ITD, TKD and gatekeeper mutated FLT3 or wild-type FLT3.”

The researchers tested CG’806 and other FLT3 inhibitors in human or murine leukemia cell lines with wild-type (WT) FLT3, FLT3-ITD mutations, FLT3 TKD domain mutations, or ITD plus TKD mutations.

Compared to second-generation FLT3 inhibitors (quizartinib, gilteritinib, or crenolanib), CG’806 showed more pronounced anti-proliferative effects in leukemia cells with ITD mutations, D835 mutations, ITD plus F691I/Y842D/D835 mutations, or in FLT3 WT cells.

With CG’086, the IC50s in human AML cell lines were 0.17 nM for MV4-11 (FLT3-ITD) and 0.82 nM for MOLM13 (FLT3-ITD).

The IC50s in the murine leukemia cell lines were 9.49 nM for Ba/F3 (FLT3-WT), 0.30 nM for Ba/F3 (FLT3-ITD), 8.26 nM for Ba/F3 (FLT3-D835Y), 9.72 nM for Ba/F3 (FLT3-ITD+D835Y), and 0.43 nM for Ba/F3 (FLT3-ITD+F691L).

The researchers also found that CG’806 “triggers marked apoptosis” in FLT3-ITD-mutated primary AML samples but minimal apoptosis in normal bone marrow cells.

Another finding was that once-daily oral dosing of CG’806 in a murine model of AML (MV4-11) resulted in sustained micromolar plasma concentration over a 24-hour period.

This was accompanied by complete elimination of AML FLT3-ITD tumors without toxicity, the researchers said.

Poster 44

Stephen E. Kurtz, PhD, of Oregon Health & Science University in Portland, and his colleagues presented poster 44, “CG’806, a First-in-Class FLT3/BTK Inhibitor, Exhibits Potent Activity against AML Patient Samples with Mutant or Wild-Type FLT3, as well as Other Hematologic Malignancy Subtypes.”

The researchers tested CG’806 in samples from patients with AML (n=82), MDS/MPNs (n=15), acute lymphoblastic leukemia (ALL, n=17), chronic lymphocytic leukemia (CLL, n=58), and chronic myeloid leukemia (CML, n=4).

The team observed “broad sensitivity” to CG’806, with 59% (48/82) of AML, 53% (8/15) of MDS/MPN, 40% (23/58) of CLL, 29% (5/17) of ALL, and 25% (1/4) of CML cases exhibiting an IC50 of less than 100 nM.

Among the 38 tested AML samples with known FLT3 mutational status, the FLT3-ITD+ AML samples tended to have enhanced sensitivity to CG’806 (median IC50 = 20 nM, n=8) relative to the FLT3-WT samples (median IC50 = 120 nM, n=30).

The researchers also found that CG’806 exerted potent anti-proliferative activity against human AML, B-ALL, mantle cell lymphoma, Burkitt lymphoma, and diffuse large B-cell lymphoma cell lines.

“The analyses of CG’806 against primary hematologic malignancy patient samples and cultured cell lines show evidence of potent and broad drug activity in AML and other disease subtypes and support further development of this agent for hematologic malignancies,” Dr Kurtz said. 

Photo by Rhoda Baer

BOSTON—A pair of preclinical studies suggest the FLT3/BTK inhibitor CG’806 is active in a range of hematologic malignancies.

In one of the studies, CG’806 proved particularly effective against acute myeloid leukemia (AML) cells harboring mutant forms of FLT3, and the compound was able to eradicate AML in mice.

In another study, researchers found CG’806 exhibited “broad potency” against leukemias, lymphomas, myelodysplastic syndromes (MDS), and myeloproliferative neoplasms (MPNs).

Both studies were presented as posters at Hematologic Malignancies: Translating Discoveries to Novel Therapies (poster 25 and poster 44).

Both studies involved researchers from Aptose Biosciences, the company developing CG’806.

Poster 25

Weiguo Zhang, MD, PhD, of The University of Texas MD Anderson Cancer Center in Houston, and his colleagues presented poster 25, “CG’806, a first-in-class FLT3/BTK inhibitor, exerts superior potency against AML cells harboring ITD, TKD and gatekeeper mutated FLT3 or wild-type FLT3.”

The researchers tested CG’806 and other FLT3 inhibitors in human or murine leukemia cell lines with wild-type (WT) FLT3, FLT3-ITD mutations, FLT3 TKD domain mutations, or ITD plus TKD mutations.

Compared to second-generation FLT3 inhibitors (quizartinib, gilteritinib, or crenolanib), CG’806 showed more pronounced anti-proliferative effects in leukemia cells with ITD mutations, D835 mutations, ITD plus F691I/Y842D/D835 mutations, or in FLT3 WT cells.

With CG’086, the IC50s in human AML cell lines were 0.17 nM for MV4-11 (FLT3-ITD) and 0.82 nM for MOLM13 (FLT3-ITD).

The IC50s in the murine leukemia cell lines were 9.49 nM for Ba/F3 (FLT3-WT), 0.30 nM for Ba/F3 (FLT3-ITD), 8.26 nM for Ba/F3 (FLT3-D835Y), 9.72 nM for Ba/F3 (FLT3-ITD+D835Y), and 0.43 nM for Ba/F3 (FLT3-ITD+F691L).

The researchers also found that CG’806 “triggers marked apoptosis” in FLT3-ITD-mutated primary AML samples but minimal apoptosis in normal bone marrow cells.

Another finding was that once-daily oral dosing of CG’806 in a murine model of AML (MV4-11) resulted in sustained micromolar plasma concentration over a 24-hour period.

This was accompanied by complete elimination of AML FLT3-ITD tumors without toxicity, the researchers said.

Poster 44

Stephen E. Kurtz, PhD, of Oregon Health & Science University in Portland, and his colleagues presented poster 44, “CG’806, a First-in-Class FLT3/BTK Inhibitor, Exhibits Potent Activity against AML Patient Samples with Mutant or Wild-Type FLT3, as well as Other Hematologic Malignancy Subtypes.”

The researchers tested CG’806 in samples from patients with AML (n=82), MDS/MPNs (n=15), acute lymphoblastic leukemia (ALL, n=17), chronic lymphocytic leukemia (CLL, n=58), and chronic myeloid leukemia (CML, n=4).

The team observed “broad sensitivity” to CG’806, with 59% (48/82) of AML, 53% (8/15) of MDS/MPN, 40% (23/58) of CLL, 29% (5/17) of ALL, and 25% (1/4) of CML cases exhibiting an IC50 of less than 100 nM.

Among the 38 tested AML samples with known FLT3 mutational status, the FLT3-ITD+ AML samples tended to have enhanced sensitivity to CG’806 (median IC50 = 20 nM, n=8) relative to the FLT3-WT samples (median IC50 = 120 nM, n=30).

The researchers also found that CG’806 exerted potent anti-proliferative activity against human AML, B-ALL, mantle cell lymphoma, Burkitt lymphoma, and diffuse large B-cell lymphoma cell lines.

“The analyses of CG’806 against primary hematologic malignancy patient samples and cultured cell lines show evidence of potent and broad drug activity in AML and other disease subtypes and support further development of this agent for hematologic malignancies,” Dr Kurtz said. 

Vials and a syringe

In a phase 3 trial, subcutaneous (SC) and intravenous (IV) rituximab produced comparable results as part of a first-line treatment regimen for follicular lymphoma (FL).

Overall response rates (ORR) were similar in patients who received SC rituximab and those who received IV rituximab, first in combination with chemotherapy and then alone as maintenance therapy.

Although patients who received SC rituximab had administration-related reactions that weren’t observed in the IV rituximab group, these events were largely mild-to-moderate local injection-site reactions.

Andrew Davies, PhD, of the University of Southampton in the UK, and his colleagues reported these results in The Lancet Haematology.

Data from stage 1 of this study, known as SABRINA, were previously published in The Lancet Oncology. The current publication includes stage 2 data.

The study was funded by Roche, which markets rituximab as Rituxan and MabThera.

The trial enrolled 410 patients with previously untreated, grade 1-3a, CD20-positive FL.

Patients were randomized to receive IV rituximab at 375 mg/m² (n=205) or SC rituximab at 1400 mg (n=205) plus chemotherapy.

Chemotherapy consisted of 6 to 8 cycles of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) or 8 cycles of cyclophosphamide, vincristine, and prednisone (CVP) every 3 weeks during induction.

Patients then received rituximab maintenance every 8 weeks.

The researchers said baseline characteristics were balanced between the treatment arms, although there were more females in the SC arm than the IV arm—120 (59%) and 99 (48%), respectively.

Efficacy

In stage 1 of this study, the primary endpoint was the ratio of observed rituximab serum trough concentrations (C_trough) between the treatment arms at cycle 7.

The results suggested SC rituximab was non-inferior to the IV formulation. The geometric mean C_trough was 83.13 μg/mL in the IV arm and 134.58 μg/mL in the SC arm (ratio=1.62).

In stage 2, the primary endpoint was efficacy, or ORR, at the end of induction based on the researchers’ assessments and confirmed by an independent review panel of radiologists.

At the end of induction, the ORR was 84.9% (174/205) in the IV arm and 84.4% (173/205) in the SC arm. The complete response rate was 32.2% (n=66) in both arms.

At the end of maintenance therapy, the ORR was 78.1% (139/178) in the IV arm and 77.9% (134/172) in the SC arm. The complete response rates were 56.2% (n=100) and 50.6% (n=87), respectively.

At a median follow-up of 37 months, there was no significant difference between the arms with regard to progression-free survival (hazard ratio[HR]=0.84), event-free survival (HR=0.91), or overall survival (HR=0.81).

Safety

The incidence of adverse events (AEs) was similar between the treatment arms—95% in the IV arm and 96% in the SC arm. The incidence of grade 3 or higher AEs was 55% and 56%, respectively, and the incidence of serious AEs was 34% and 37%, respectively.

Overall, the most common AEs were gastrointestinal disorders (60% in the IV arm and 66% in the SC arm), infections and infestations (64% and 67%, respectively), and general or administration site conditions (50% and 60%, respectively).

Administration-related reactions were more common in the SC arm than the IV arm—48% and 35%, respectively. The most common of these reactions were chills (7%) and pruritus (6%) in the IV arm and injection-site erythema (11%), pruritus (6%), rash (5%), and injection-site pain (5%) in the SC arm.

Neutropenia was the most common grade 3 or higher AE, occurring in 34% of patients in the IV arm and 37% in the SC arm. Febrile neutropenia was the most frequent serious AE, occurring in 5% and 6%, respectively.

The researchers said these results suggest the SC formulation of rituximab has similar efficacy and a similar safety profile as IV rituximab in the first-line treatment of FL. 

Vials and a syringe

In a phase 3 trial, subcutaneous (SC) and intravenous (IV) rituximab produced comparable results as part of a first-line treatment regimen for follicular lymphoma (FL).

Overall response rates (ORR) were similar in patients who received SC rituximab and those who received IV rituximab, first in combination with chemotherapy and then alone as maintenance therapy.

Although patients who received SC rituximab had administration-related reactions that weren’t observed in the IV rituximab group, these events were largely mild-to-moderate local injection-site reactions.

Andrew Davies, PhD, of the University of Southampton in the UK, and his colleagues reported these results in The Lancet Haematology.

Data from stage 1 of this study, known as SABRINA, were previously published in The Lancet Oncology. The current publication includes stage 2 data.

The study was funded by Roche, which markets rituximab as Rituxan and MabThera.

The trial enrolled 410 patients with previously untreated, grade 1-3a, CD20-positive FL.

Patients were randomized to receive IV rituximab at 375 mg/m² (n=205) or SC rituximab at 1400 mg (n=205) plus chemotherapy.

Chemotherapy consisted of 6 to 8 cycles of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) or 8 cycles of cyclophosphamide, vincristine, and prednisone (CVP) every 3 weeks during induction.

Patients then received rituximab maintenance every 8 weeks.

The researchers said baseline characteristics were balanced between the treatment arms, although there were more females in the SC arm than the IV arm—120 (59%) and 99 (48%), respectively.

Efficacy

In stage 1 of this study, the primary endpoint was the ratio of observed rituximab serum trough concentrations (C_trough) between the treatment arms at cycle 7.

The results suggested SC rituximab was non-inferior to the IV formulation. The geometric mean C_trough was 83.13 μg/mL in the IV arm and 134.58 μg/mL in the SC arm (ratio=1.62).

In stage 2, the primary endpoint was efficacy, or ORR, at the end of induction based on the researchers’ assessments and confirmed by an independent review panel of radiologists.

At the end of induction, the ORR was 84.9% (174/205) in the IV arm and 84.4% (173/205) in the SC arm. The complete response rate was 32.2% (n=66) in both arms.

At the end of maintenance therapy, the ORR was 78.1% (139/178) in the IV arm and 77.9% (134/172) in the SC arm. The complete response rates were 56.2% (n=100) and 50.6% (n=87), respectively.

At a median follow-up of 37 months, there was no significant difference between the arms with regard to progression-free survival (hazard ratio[HR]=0.84), event-free survival (HR=0.91), or overall survival (HR=0.81).

Safety

The incidence of adverse events (AEs) was similar between the treatment arms—95% in the IV arm and 96% in the SC arm. The incidence of grade 3 or higher AEs was 55% and 56%, respectively, and the incidence of serious AEs was 34% and 37%, respectively.

Overall, the most common AEs were gastrointestinal disorders (60% in the IV arm and 66% in the SC arm), infections and infestations (64% and 67%, respectively), and general or administration site conditions (50% and 60%, respectively).

Administration-related reactions were more common in the SC arm than the IV arm—48% and 35%, respectively. The most common of these reactions were chills (7%) and pruritus (6%) in the IV arm and injection-site erythema (11%), pruritus (6%), rash (5%), and injection-site pain (5%) in the SC arm.

Neutropenia was the most common grade 3 or higher AE, occurring in 34% of patients in the IV arm and 37% in the SC arm. Febrile neutropenia was the most frequent serious AE, occurring in 5% and 6%, respectively.

The researchers said these results suggest the SC formulation of rituximab has similar efficacy and a similar safety profile as IV rituximab in the first-line treatment of FL. 

Vials and a syringe

In a phase 3 trial, subcutaneous (SC) and intravenous (IV) rituximab produced comparable results as part of a first-line treatment regimen for follicular lymphoma (FL).

Overall response rates (ORR) were similar in patients who received SC rituximab and those who received IV rituximab, first in combination with chemotherapy and then alone as maintenance therapy.

Although patients who received SC rituximab had administration-related reactions that weren’t observed in the IV rituximab group, these events were largely mild-to-moderate local injection-site reactions.

Andrew Davies, PhD, of the University of Southampton in the UK, and his colleagues reported these results in The Lancet Haematology.

Data from stage 1 of this study, known as SABRINA, were previously published in The Lancet Oncology. The current publication includes stage 2 data.

The study was funded by Roche, which markets rituximab as Rituxan and MabThera.

The trial enrolled 410 patients with previously untreated, grade 1-3a, CD20-positive FL.

Patients were randomized to receive IV rituximab at 375 mg/m² (n=205) or SC rituximab at 1400 mg (n=205) plus chemotherapy.

Chemotherapy consisted of 6 to 8 cycles of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) or 8 cycles of cyclophosphamide, vincristine, and prednisone (CVP) every 3 weeks during induction.

Patients then received rituximab maintenance every 8 weeks.

The researchers said baseline characteristics were balanced between the treatment arms, although there were more females in the SC arm than the IV arm—120 (59%) and 99 (48%), respectively.

Efficacy

In stage 1 of this study, the primary endpoint was the ratio of observed rituximab serum trough concentrations (C_trough) between the treatment arms at cycle 7.

The results suggested SC rituximab was non-inferior to the IV formulation. The geometric mean C_trough was 83.13 μg/mL in the IV arm and 134.58 μg/mL in the SC arm (ratio=1.62).

In stage 2, the primary endpoint was efficacy, or ORR, at the end of induction based on the researchers’ assessments and confirmed by an independent review panel of radiologists.

At the end of induction, the ORR was 84.9% (174/205) in the IV arm and 84.4% (173/205) in the SC arm. The complete response rate was 32.2% (n=66) in both arms.

At the end of maintenance therapy, the ORR was 78.1% (139/178) in the IV arm and 77.9% (134/172) in the SC arm. The complete response rates were 56.2% (n=100) and 50.6% (n=87), respectively.

At a median follow-up of 37 months, there was no significant difference between the arms with regard to progression-free survival (hazard ratio[HR]=0.84), event-free survival (HR=0.91), or overall survival (HR=0.81).

Safety

The incidence of adverse events (AEs) was similar between the treatment arms—95% in the IV arm and 96% in the SC arm. The incidence of grade 3 or higher AEs was 55% and 56%, respectively, and the incidence of serious AEs was 34% and 37%, respectively.

Overall, the most common AEs were gastrointestinal disorders (60% in the IV arm and 66% in the SC arm), infections and infestations (64% and 67%, respectively), and general or administration site conditions (50% and 60%, respectively).

Administration-related reactions were more common in the SC arm than the IV arm—48% and 35%, respectively. The most common of these reactions were chills (7%) and pruritus (6%) in the IV arm and injection-site erythema (11%), pruritus (6%), rash (5%), and injection-site pain (5%) in the SC arm.

Neutropenia was the most common grade 3 or higher AE, occurring in 34% of patients in the IV arm and 37% in the SC arm. Febrile neutropenia was the most frequent serious AE, occurring in 5% and 6%, respectively.

The researchers said these results suggest the SC formulation of rituximab has similar efficacy and a similar safety profile as IV rituximab in the first-line treatment of FL. 

Photo courtesy of Merck

The European Commission (EC) has approved the anti-PD-1 therapy pembrolizumab (Keytruda) for use in patients with classical Hodgkin lymphoma (cHL).

The drug is now approved to treat adults with relapsed or refractory cHL who have failed autologous stem cell transplant (auto-SCT) and brentuximab vedotin (BV) or who are transplant-ineligible and have failed treatment with BV.

The approval allows marketing of pembrolizumab for this indication in the European Economic Area (EEA).

This is the first approval for pembrolizumab in a hematologic malignancy in the EEA. The drug was previously approved there as a treatment for melanoma and non-small-cell lung cancer.

The new approval for pembrolizumab was based on data from the KEYNOTE-087 and KEYNOTE-013 trials.

Results from KEYNOTE-013 were presented at the 2016 ASH Annual Meeting (abstract 1108), and results from KEYNOTE-087 were recently published in the Journal of Clinical Oncology.

KEYNOTE-087

In this phase 2 trial, researchers evaluated pembrolizumab (a 200 mg fixed dose every 3 weeks) in patients with relapsed or refractory cHL across 3 cohorts:

• Cohort 1: Patients who progressed after auto-HSCT and subsequent treatment with BV
• Cohort 2: Patients who failed salvage chemotherapy, were ineligible for a transplant, and progressed after BV
• Cohort 3: Patients who progressed after auto-HSCT and did not receive BV after transplant.

Across all 210 enrolled patients, the overall response rate (ORR) was 69.0%, and the complete response (CR) rate was 22.4%.

In Cohort 1 (n=69), the ORR was 73.9%, and the CR rate was 21.7%.

In Cohort 2 (n=81), the ORR was 64.2%, and the CR rate was 24.7%.

In Cohort 3 (n=60), the ORR was 70.0%, and the CR rate was 20%.

For the entire study cohort, the median duration of response was not reached, and the median overall survival (OS) was not reached. At 9 months, the OS was 97.5%, and the progression-free survival (PFS) was 63.4%.

The most common treatment-related adverse events (AEs) were hypothyroidism (12.4%), pyrexia (10.5%), fatigue (9.0%), rash (7.6%), diarrhea (7.1%), headache (6.2%), nausea (5.7%), cough (5.7%), and neutropenia (5.2%).

The most common grade 3/4 treatment-related AEs were neutropenia (2.4%), diarrhea (1.0%), and dyspnea (1.0%). Immune-mediated AEs included pneumonitis (2.9%), hyperthyroidism (2.9%), colitis (1.0%), and myositis (1.0%).

There were 9 discontinuations because of treatment-related AEs and no treatment-related deaths.

KEYNOTE-013

KEYNOTE-013 is a phase 1b trial that has enrolled 31 patients with relapsed or refractory cHL who failed auto-HSCT and subsequent BV or who were transplant-ineligible.

Patients received pembrolizumab at 10 mg/kg every 2 weeks. The median duration of follow-up was 29 months.

The ORR was 58%, and the CR rate was 19%. The median duration of response had not been reached at last follow-up (range, 0.0+ to 26.1+ months), and 70% of responding patients had a response lasting 12 months or more.

The median PFS was 11.4 months (range, 4.9-27.8 months). The 6-month PFS rate was 66%, and the 12-month PFS rate was 48%.

The median OS was not reached. Six-month and 12-month OS rates were 100% and 87%, respectively.

The most common treatment-related AEs were diarrhea (19%), hypothyroidism (13%), pneumonitis (13%), nausea (13%), fatigue (10%), and dyspnea (10%).

The most common grade 3/4 treatment-related AEs were colitis (3%), axillary pain (3%), AST increase (3%), joint swelling (3%), nephrotic syndrome back pain (3%), and dyspnea (3%).

AEs leading to discontinuation were nephrotic syndrome (grade 3), interstitial lung disease (grade 2), and pneumonitis (grade 2). There were no treatment-related deaths. 

Photo courtesy of Merck

The European Commission (EC) has approved the anti-PD-1 therapy pembrolizumab (Keytruda) for use in patients with classical Hodgkin lymphoma (cHL).

The drug is now approved to treat adults with relapsed or refractory cHL who have failed autologous stem cell transplant (auto-SCT) and brentuximab vedotin (BV) or who are transplant-ineligible and have failed treatment with BV.

The approval allows marketing of pembrolizumab for this indication in the European Economic Area (EEA).

This is the first approval for pembrolizumab in a hematologic malignancy in the EEA. The drug was previously approved there as a treatment for melanoma and non-small-cell lung cancer.

The new approval for pembrolizumab was based on data from the KEYNOTE-087 and KEYNOTE-013 trials.

Results from KEYNOTE-013 were presented at the 2016 ASH Annual Meeting (abstract 1108), and results from KEYNOTE-087 were recently published in the Journal of Clinical Oncology.

KEYNOTE-087

In this phase 2 trial, researchers evaluated pembrolizumab (a 200 mg fixed dose every 3 weeks) in patients with relapsed or refractory cHL across 3 cohorts:

• Cohort 1: Patients who progressed after auto-HSCT and subsequent treatment with BV
• Cohort 2: Patients who failed salvage chemotherapy, were ineligible for a transplant, and progressed after BV
• Cohort 3: Patients who progressed after auto-HSCT and did not receive BV after transplant.

Across all 210 enrolled patients, the overall response rate (ORR) was 69.0%, and the complete response (CR) rate was 22.4%.

In Cohort 1 (n=69), the ORR was 73.9%, and the CR rate was 21.7%.

In Cohort 2 (n=81), the ORR was 64.2%, and the CR rate was 24.7%.

In Cohort 3 (n=60), the ORR was 70.0%, and the CR rate was 20%.

For the entire study cohort, the median duration of response was not reached, and the median overall survival (OS) was not reached. At 9 months, the OS was 97.5%, and the progression-free survival (PFS) was 63.4%.

The most common treatment-related adverse events (AEs) were hypothyroidism (12.4%), pyrexia (10.5%), fatigue (9.0%), rash (7.6%), diarrhea (7.1%), headache (6.2%), nausea (5.7%), cough (5.7%), and neutropenia (5.2%).

The most common grade 3/4 treatment-related AEs were neutropenia (2.4%), diarrhea (1.0%), and dyspnea (1.0%). Immune-mediated AEs included pneumonitis (2.9%), hyperthyroidism (2.9%), colitis (1.0%), and myositis (1.0%).

There were 9 discontinuations because of treatment-related AEs and no treatment-related deaths.

KEYNOTE-013

KEYNOTE-013 is a phase 1b trial that has enrolled 31 patients with relapsed or refractory cHL who failed auto-HSCT and subsequent BV or who were transplant-ineligible.

Patients received pembrolizumab at 10 mg/kg every 2 weeks. The median duration of follow-up was 29 months.

The ORR was 58%, and the CR rate was 19%. The median duration of response had not been reached at last follow-up (range, 0.0+ to 26.1+ months), and 70% of responding patients had a response lasting 12 months or more.

The median PFS was 11.4 months (range, 4.9-27.8 months). The 6-month PFS rate was 66%, and the 12-month PFS rate was 48%.

The median OS was not reached. Six-month and 12-month OS rates were 100% and 87%, respectively.

The most common treatment-related AEs were diarrhea (19%), hypothyroidism (13%), pneumonitis (13%), nausea (13%), fatigue (10%), and dyspnea (10%).

The most common grade 3/4 treatment-related AEs were colitis (3%), axillary pain (3%), AST increase (3%), joint swelling (3%), nephrotic syndrome back pain (3%), and dyspnea (3%).

AEs leading to discontinuation were nephrotic syndrome (grade 3), interstitial lung disease (grade 2), and pneumonitis (grade 2). There were no treatment-related deaths. 

Photo courtesy of Merck

The European Commission (EC) has approved the anti-PD-1 therapy pembrolizumab (Keytruda) for use in patients with classical Hodgkin lymphoma (cHL).

The drug is now approved to treat adults with relapsed or refractory cHL who have failed autologous stem cell transplant (auto-SCT) and brentuximab vedotin (BV) or who are transplant-ineligible and have failed treatment with BV.

The approval allows marketing of pembrolizumab for this indication in the European Economic Area (EEA).

This is the first approval for pembrolizumab in a hematologic malignancy in the EEA. The drug was previously approved there as a treatment for melanoma and non-small-cell lung cancer.

The new approval for pembrolizumab was based on data from the KEYNOTE-087 and KEYNOTE-013 trials.

Results from KEYNOTE-013 were presented at the 2016 ASH Annual Meeting (abstract 1108), and results from KEYNOTE-087 were recently published in the Journal of Clinical Oncology.

KEYNOTE-087

In this phase 2 trial, researchers evaluated pembrolizumab (a 200 mg fixed dose every 3 weeks) in patients with relapsed or refractory cHL across 3 cohorts:

• Cohort 1: Patients who progressed after auto-HSCT and subsequent treatment with BV
• Cohort 2: Patients who failed salvage chemotherapy, were ineligible for a transplant, and progressed after BV
• Cohort 3: Patients who progressed after auto-HSCT and did not receive BV after transplant.

Across all 210 enrolled patients, the overall response rate (ORR) was 69.0%, and the complete response (CR) rate was 22.4%.

In Cohort 1 (n=69), the ORR was 73.9%, and the CR rate was 21.7%.

In Cohort 2 (n=81), the ORR was 64.2%, and the CR rate was 24.7%.

In Cohort 3 (n=60), the ORR was 70.0%, and the CR rate was 20%.

For the entire study cohort, the median duration of response was not reached, and the median overall survival (OS) was not reached. At 9 months, the OS was 97.5%, and the progression-free survival (PFS) was 63.4%.

The most common treatment-related adverse events (AEs) were hypothyroidism (12.4%), pyrexia (10.5%), fatigue (9.0%), rash (7.6%), diarrhea (7.1%), headache (6.2%), nausea (5.7%), cough (5.7%), and neutropenia (5.2%).

The most common grade 3/4 treatment-related AEs were neutropenia (2.4%), diarrhea (1.0%), and dyspnea (1.0%). Immune-mediated AEs included pneumonitis (2.9%), hyperthyroidism (2.9%), colitis (1.0%), and myositis (1.0%).

There were 9 discontinuations because of treatment-related AEs and no treatment-related deaths.

KEYNOTE-013

KEYNOTE-013 is a phase 1b trial that has enrolled 31 patients with relapsed or refractory cHL who failed auto-HSCT and subsequent BV or who were transplant-ineligible.

Patients received pembrolizumab at 10 mg/kg every 2 weeks. The median duration of follow-up was 29 months.

The ORR was 58%, and the CR rate was 19%. The median duration of response had not been reached at last follow-up (range, 0.0+ to 26.1+ months), and 70% of responding patients had a response lasting 12 months or more.

The median PFS was 11.4 months (range, 4.9-27.8 months). The 6-month PFS rate was 66%, and the 12-month PFS rate was 48%.

The median OS was not reached. Six-month and 12-month OS rates were 100% and 87%, respectively.

The most common treatment-related AEs were diarrhea (19%), hypothyroidism (13%), pneumonitis (13%), nausea (13%), fatigue (10%), and dyspnea (10%).

The most common grade 3/4 treatment-related AEs were colitis (3%), axillary pain (3%), AST increase (3%), joint swelling (3%), nephrotic syndrome back pain (3%), and dyspnea (3%).

AEs leading to discontinuation were nephrotic syndrome (grade 3), interstitial lung disease (grade 2), and pneumonitis (grade 2). There were no treatment-related deaths. 

Micrograph showing CLL

Long-term follow-up of a phase 1 study suggests the BTK inhibitor ONO/GS-4059 can stave off progression in patients with relapsed or refractory chronic lymphocytic leukemia (CLL).

Roughly 60% of the patients studied were progression-free and still taking ONO/GS-4059 at last follow-up, with the longest time on treatment exceeding 3 years.

In addition, researchers said the extended follow-up revealed no new safety concerns, and the maximum tolerated dose of ONO/GS-4059 has not been reached.

Martin Dyer, DPhil, of the University of Leicester in the UK, and his colleagues reported these results in Blood.

The research was funded by Gilead Sciences, Inc., and ONO Pharmaceuticals helped with data analysis.

The study enrolled 90 patients with relapsed or refractory B-cell malignancies, 28 of whom had CLL. Dr Dyer and his colleagues reported follow-up results in CLL patients only.

The patients’ median number of prior treatments was 4 (range, 2-9), and 11 patients were refractory to their last line of therapy. None had received prior treatment with a BTK inhibitor.

The patients received ONO/GS-4059 at varying doses, from 20 mg once daily (QD) to 600 mg QD and a twice-daily (BID) regimen of 300 mg. Six patients were also taking anticoagulant therapy while on study.

Patients were allowed to continue treatment with ONO/GS-4059 if they responded to the drug or maintained stable disease.

Initially, 25 patients were evaluable for response, and 24 of them responded to ONO/GS-4059, for an overall response rate of 96%.

At last follow-up on June 8, 2016, 17 patients were still receiving ONO/GS-4059, and all had a very good partial response.

Dr Dyer said the responses have been similar to those seen with other irreversible BTK inhibitors. Most have involved rapid and almost complete resolution of lymph node masses and rapid improvement in hematological indexes.

“It is clear . . . that the major responses occur rapidly, within the first 3 months of drug, and that, thereafter, improvement occurs at a much slower rate,” Dr Dyer said. “It will be of interest, I think, to look at the remaining patients on study to assess whether responses deepen with time on drug.”

The duration of treatment for these patients ranged from 302 days to 1160 days at last follow-up. They were receiving ONO/GS-4059 at doses ranging from 40 mg QD to 600 mg QD or 300 mg BID, and no maximum tolerated dose had been identified.

Eleven patients (39.3%) discontinued ONO/GS-4059 due to death (n=3), disease progression (n=4), adverse events (AEs, n=3), and sponsor decision due to extended drug interruption (n=1). One of the patients included in the AE group also had concurrent disease progression.

The median progression-free survival was 38.5 months, and the median overall survival was 44.9 months. The median time on study was 32.5 months.

The most common treatment-emergent AEs were bruising (35.7%), neutropenia (35.7%), anemia (32.1%), nasopharyngitis (32.1%), fall (32.1%), cough (28.6%), arthralgia (28.6%), and basal cell carcinoma (28.6%).

The most common grade 3/4 AEs included neutropenia (25%), thrombocytopenia (14.3%), lower respiratory tract infection (14.3%), and anemia (10.7%).

“Our long-term follow-up shows maintained efficacy without toxicity,” Dr Dyer said. “This study is the first report of long-term follow-up of a selective BTK inhibitor, and it is excellent news for patients. We are now doing studies of ONO/GS-4059 in combination with other precision medicines to assess whether these results can be enhanced in patients with CLL and other B-cell malignancies.” 

Micrograph showing CLL

Long-term follow-up of a phase 1 study suggests the BTK inhibitor ONO/GS-4059 can stave off progression in patients with relapsed or refractory chronic lymphocytic leukemia (CLL).

Roughly 60% of the patients studied were progression-free and still taking ONO/GS-4059 at last follow-up, with the longest time on treatment exceeding 3 years.

In addition, researchers said the extended follow-up revealed no new safety concerns, and the maximum tolerated dose of ONO/GS-4059 has not been reached.

Martin Dyer, DPhil, of the University of Leicester in the UK, and his colleagues reported these results in Blood.

The research was funded by Gilead Sciences, Inc., and ONO Pharmaceuticals helped with data analysis.

The study enrolled 90 patients with relapsed or refractory B-cell malignancies, 28 of whom had CLL. Dr Dyer and his colleagues reported follow-up results in CLL patients only.

The patients’ median number of prior treatments was 4 (range, 2-9), and 11 patients were refractory to their last line of therapy. None had received prior treatment with a BTK inhibitor.

The patients received ONO/GS-4059 at varying doses, from 20 mg once daily (QD) to 600 mg QD and a twice-daily (BID) regimen of 300 mg. Six patients were also taking anticoagulant therapy while on study.

Patients were allowed to continue treatment with ONO/GS-4059 if they responded to the drug or maintained stable disease.

Initially, 25 patients were evaluable for response, and 24 of them responded to ONO/GS-4059, for an overall response rate of 96%.

At last follow-up on June 8, 2016, 17 patients were still receiving ONO/GS-4059, and all had a very good partial response.

Dr Dyer said the responses have been similar to those seen with other irreversible BTK inhibitors. Most have involved rapid and almost complete resolution of lymph node masses and rapid improvement in hematological indexes.

“It is clear . . . that the major responses occur rapidly, within the first 3 months of drug, and that, thereafter, improvement occurs at a much slower rate,” Dr Dyer said. “It will be of interest, I think, to look at the remaining patients on study to assess whether responses deepen with time on drug.”

The duration of treatment for these patients ranged from 302 days to 1160 days at last follow-up. They were receiving ONO/GS-4059 at doses ranging from 40 mg QD to 600 mg QD or 300 mg BID, and no maximum tolerated dose had been identified.

Eleven patients (39.3%) discontinued ONO/GS-4059 due to death (n=3), disease progression (n=4), adverse events (AEs, n=3), and sponsor decision due to extended drug interruption (n=1). One of the patients included in the AE group also had concurrent disease progression.

The median progression-free survival was 38.5 months, and the median overall survival was 44.9 months. The median time on study was 32.5 months.

The most common treatment-emergent AEs were bruising (35.7%), neutropenia (35.7%), anemia (32.1%), nasopharyngitis (32.1%), fall (32.1%), cough (28.6%), arthralgia (28.6%), and basal cell carcinoma (28.6%).

The most common grade 3/4 AEs included neutropenia (25%), thrombocytopenia (14.3%), lower respiratory tract infection (14.3%), and anemia (10.7%).

“Our long-term follow-up shows maintained efficacy without toxicity,” Dr Dyer said. “This study is the first report of long-term follow-up of a selective BTK inhibitor, and it is excellent news for patients. We are now doing studies of ONO/GS-4059 in combination with other precision medicines to assess whether these results can be enhanced in patients with CLL and other B-cell malignancies.” 

Micrograph showing CLL

Long-term follow-up of a phase 1 study suggests the BTK inhibitor ONO/GS-4059 can stave off progression in patients with relapsed or refractory chronic lymphocytic leukemia (CLL).

Roughly 60% of the patients studied were progression-free and still taking ONO/GS-4059 at last follow-up, with the longest time on treatment exceeding 3 years.

In addition, researchers said the extended follow-up revealed no new safety concerns, and the maximum tolerated dose of ONO/GS-4059 has not been reached.

Martin Dyer, DPhil, of the University of Leicester in the UK, and his colleagues reported these results in Blood.

The research was funded by Gilead Sciences, Inc., and ONO Pharmaceuticals helped with data analysis.

The study enrolled 90 patients with relapsed or refractory B-cell malignancies, 28 of whom had CLL. Dr Dyer and his colleagues reported follow-up results in CLL patients only.

The patients’ median number of prior treatments was 4 (range, 2-9), and 11 patients were refractory to their last line of therapy. None had received prior treatment with a BTK inhibitor.

The patients received ONO/GS-4059 at varying doses, from 20 mg once daily (QD) to 600 mg QD and a twice-daily (BID) regimen of 300 mg. Six patients were also taking anticoagulant therapy while on study.

Patients were allowed to continue treatment with ONO/GS-4059 if they responded to the drug or maintained stable disease.

Initially, 25 patients were evaluable for response, and 24 of them responded to ONO/GS-4059, for an overall response rate of 96%.

At last follow-up on June 8, 2016, 17 patients were still receiving ONO/GS-4059, and all had a very good partial response.

Dr Dyer said the responses have been similar to those seen with other irreversible BTK inhibitors. Most have involved rapid and almost complete resolution of lymph node masses and rapid improvement in hematological indexes.

“It is clear . . . that the major responses occur rapidly, within the first 3 months of drug, and that, thereafter, improvement occurs at a much slower rate,” Dr Dyer said. “It will be of interest, I think, to look at the remaining patients on study to assess whether responses deepen with time on drug.”

The duration of treatment for these patients ranged from 302 days to 1160 days at last follow-up. They were receiving ONO/GS-4059 at doses ranging from 40 mg QD to 600 mg QD or 300 mg BID, and no maximum tolerated dose had been identified.

Eleven patients (39.3%) discontinued ONO/GS-4059 due to death (n=3), disease progression (n=4), adverse events (AEs, n=3), and sponsor decision due to extended drug interruption (n=1). One of the patients included in the AE group also had concurrent disease progression.

The median progression-free survival was 38.5 months, and the median overall survival was 44.9 months. The median time on study was 32.5 months.

The most common treatment-emergent AEs were bruising (35.7%), neutropenia (35.7%), anemia (32.1%), nasopharyngitis (32.1%), fall (32.1%), cough (28.6%), arthralgia (28.6%), and basal cell carcinoma (28.6%).

The most common grade 3/4 AEs included neutropenia (25%), thrombocytopenia (14.3%), lower respiratory tract infection (14.3%), and anemia (10.7%).

“Our long-term follow-up shows maintained efficacy without toxicity,” Dr Dyer said. “This study is the first report of long-term follow-up of a selective BTK inhibitor, and it is excellent news for patients. We are now doing studies of ONO/GS-4059 in combination with other precision medicines to assess whether these results can be enhanced in patients with CLL and other B-cell malignancies.” 

MONTREAL – A combination of placenta-derived stem cells and umbilical cord blood was associated with early engraftment and high degrees of cord blood donor chimerism in the treatment of children with both malignant and nonmalignant hematologic conditions requiring stem cell transplantation, updated results of a pilot study show.

Among 16 children treated with the combination, the probability of neutrophil engraftment was 87.5%, and all patients who had neutrophil engraftment went on to have platelet engraftment. The probability of 12-month overall survival was 81.2%, reported Allyson Flower, MD, from Boston Children’s Health Physicians in Hawthorne, N.Y. “The probability of grade II-IV acute graft vs. host disease was 12.5%, compared with 32.5% seen with unrelated cord blood in our group’s previous studies. Cellular immune reconstitution was robust,” she said at the annual meeting of the American Society of Pediatric Hematology/Oncology.

Augmenting cord blood

Although unrelated donor cord blood transplantation expands the donor pool, is rapidly available, and is associated with decreases in both severe acute graft vs. host disease (GVHD) and chronic GVHD, compared with other stem cell sources, the technique is hampered by limited cell doses, prolonged immune reconstitution time, delays in hematopoietic recovery, and a higher incidence of graft failure.

Early studies of myeloablative conditioning followed by unrelated umbilical or placental blood transplantation showed a median of 22-24 days to neutrophil engraftment (Blood 1996 88:795-802; N Engl J Med. 1996;335:157-66), Dr. Flower noted.

More recently, a multivariate analysis of patients who underwent reduced-intensity conditioning followed by hematopoietic stem cell transplant with unrelated cord blood showed that graft failure was an independent risk factor for worse overall survival (Biol Blood Marrow Transplant. 2013 Apr;19:4;552-61).

Multiple groups have shown that adding human placenta–derived stem cells (HPDSC) to cord blood transplantation can facilitate more rapid hematopoietic engraftment by increasing the number of stem cells, increasing the proportion of hematopoietic progenitor cells, and providing additional, immature CD34+/CD45– progenitor cells.

In a single-arm, nonrandomized study, the investigators enrolled 16 patients ranging in age from 0.3 to 15.7 years with inborn errors of metabolism, marrow failure syndromes, severe immunodeficiency states, or hematologic malignancies.

Malignant conditions included B-cell precursor acute lymphoblastic leukemia (B-ALL; four patients), acute myeloid leukemia (AML; two), and T-cell ALL (one) in first complete remission, and T-cell lymphoblastic lymphoma following induction failure (one). Nonmalignant conditions included adrenoleukodystrophy (two patients), amegakaryotic thrombocytopenia (one), severe combined immunodeficiency (SCID; two), dyskeratosis congenita (one), chronic granulomatous disease (one), and severe congenital neutropenia (one).

The patients first underwent either myeloablative or reduced-intensity conditioning, followed 10 days later by infusion of unrelated cord blood and HPDSCs. Prior to HPDSC infusion, patients were medicated with diphenhydramine and hydrocortisone to prevent or reduce potential sensitivity reactions. HPDSCs were infused no sooner than 4 hours after the end of the cord blood infusion.

Patients received GVHD prophylaxis with either tacrolimus or cyclosporine, plus mycophenolate mofetil.

The combination appeared to be safe, with no cases of grade 3 or 4 toxicity secondary to HPDSC infusion.

The probability of neutrophil engraftment was 87.5%, with engraftment occurring at a median of 23 days (range 13-53). As noted before, all patients who had neutrophil engraftment had platelet engraftment, which was achieved at a median of 47 days (range, 20-98). In the group’s previous studies, median time to platelet engraftment was 53 days for patients who had undergone reduced-intensity conditioning, and 118 days for patients who had undergone myeloablation.

The probability of grade 2-4 acute GVHD within 100 days was 12.5%, and there were no cases of chronic GVHD.

Respective percentages of cord blood donor chimerism at days 30, 60, 100, and 180 were 88%, 98%, 99%, and 99%.

Immune reconstitution was strong, with normalization of mean CD3+, CD19+, and CD56+ cells occurring by day 100, CD8+ cells by day 180, and CD4+ cells by day 270.

There were three patient deaths: one from adenoviremia in a patient with B-ALL and CNS relapse, who had neutrophil engraftment at day 21; one in a patient with SCID, from adenoviremia and multiple system organ failure, who did not have engraftment before death; and one in a patient with severe congenital neutrophilia, who also did not have neutrophil engraftment.

None of the eight patients with malignant disease have experienced relapse to date, Dr. Flower noted.

The study was funded by a grant from Celgene Cellular Therapeutics. Dr. Flower reported having no conflicts of interest.

[email protected]

MONTREAL – A combination of placenta-derived stem cells and umbilical cord blood was associated with early engraftment and high degrees of cord blood donor chimerism in the treatment of children with both malignant and nonmalignant hematologic conditions requiring stem cell transplantation, updated results of a pilot study show.

Among 16 children treated with the combination, the probability of neutrophil engraftment was 87.5%, and all patients who had neutrophil engraftment went on to have platelet engraftment. The probability of 12-month overall survival was 81.2%, reported Allyson Flower, MD, from Boston Children’s Health Physicians in Hawthorne, N.Y. “The probability of grade II-IV acute graft vs. host disease was 12.5%, compared with 32.5% seen with unrelated cord blood in our group’s previous studies. Cellular immune reconstitution was robust,” she said at the annual meeting of the American Society of Pediatric Hematology/Oncology.

Augmenting cord blood

Although unrelated donor cord blood transplantation expands the donor pool, is rapidly available, and is associated with decreases in both severe acute graft vs. host disease (GVHD) and chronic GVHD, compared with other stem cell sources, the technique is hampered by limited cell doses, prolonged immune reconstitution time, delays in hematopoietic recovery, and a higher incidence of graft failure.

Early studies of myeloablative conditioning followed by unrelated umbilical or placental blood transplantation showed a median of 22-24 days to neutrophil engraftment (Blood 1996 88:795-802; N Engl J Med. 1996;335:157-66), Dr. Flower noted.

More recently, a multivariate analysis of patients who underwent reduced-intensity conditioning followed by hematopoietic stem cell transplant with unrelated cord blood showed that graft failure was an independent risk factor for worse overall survival (Biol Blood Marrow Transplant. 2013 Apr;19:4;552-61).

Multiple groups have shown that adding human placenta–derived stem cells (HPDSC) to cord blood transplantation can facilitate more rapid hematopoietic engraftment by increasing the number of stem cells, increasing the proportion of hematopoietic progenitor cells, and providing additional, immature CD34+/CD45– progenitor cells.

In a single-arm, nonrandomized study, the investigators enrolled 16 patients ranging in age from 0.3 to 15.7 years with inborn errors of metabolism, marrow failure syndromes, severe immunodeficiency states, or hematologic malignancies.

Malignant conditions included B-cell precursor acute lymphoblastic leukemia (B-ALL; four patients), acute myeloid leukemia (AML; two), and T-cell ALL (one) in first complete remission, and T-cell lymphoblastic lymphoma following induction failure (one). Nonmalignant conditions included adrenoleukodystrophy (two patients), amegakaryotic thrombocytopenia (one), severe combined immunodeficiency (SCID; two), dyskeratosis congenita (one), chronic granulomatous disease (one), and severe congenital neutropenia (one).

The patients first underwent either myeloablative or reduced-intensity conditioning, followed 10 days later by infusion of unrelated cord blood and HPDSCs. Prior to HPDSC infusion, patients were medicated with diphenhydramine and hydrocortisone to prevent or reduce potential sensitivity reactions. HPDSCs were infused no sooner than 4 hours after the end of the cord blood infusion.

Patients received GVHD prophylaxis with either tacrolimus or cyclosporine, plus mycophenolate mofetil.

The combination appeared to be safe, with no cases of grade 3 or 4 toxicity secondary to HPDSC infusion.

The probability of neutrophil engraftment was 87.5%, with engraftment occurring at a median of 23 days (range 13-53). As noted before, all patients who had neutrophil engraftment had platelet engraftment, which was achieved at a median of 47 days (range, 20-98). In the group’s previous studies, median time to platelet engraftment was 53 days for patients who had undergone reduced-intensity conditioning, and 118 days for patients who had undergone myeloablation.

The probability of grade 2-4 acute GVHD within 100 days was 12.5%, and there were no cases of chronic GVHD.

Respective percentages of cord blood donor chimerism at days 30, 60, 100, and 180 were 88%, 98%, 99%, and 99%.

Immune reconstitution was strong, with normalization of mean CD3+, CD19+, and CD56+ cells occurring by day 100, CD8+ cells by day 180, and CD4+ cells by day 270.

There were three patient deaths: one from adenoviremia in a patient with B-ALL and CNS relapse, who had neutrophil engraftment at day 21; one in a patient with SCID, from adenoviremia and multiple system organ failure, who did not have engraftment before death; and one in a patient with severe congenital neutrophilia, who also did not have neutrophil engraftment.

None of the eight patients with malignant disease have experienced relapse to date, Dr. Flower noted.

The study was funded by a grant from Celgene Cellular Therapeutics. Dr. Flower reported having no conflicts of interest.

[email protected]

MONTREAL – A combination of placenta-derived stem cells and umbilical cord blood was associated with early engraftment and high degrees of cord blood donor chimerism in the treatment of children with both malignant and nonmalignant hematologic conditions requiring stem cell transplantation, updated results of a pilot study show.

Among 16 children treated with the combination, the probability of neutrophil engraftment was 87.5%, and all patients who had neutrophil engraftment went on to have platelet engraftment. The probability of 12-month overall survival was 81.2%, reported Allyson Flower, MD, from Boston Children’s Health Physicians in Hawthorne, N.Y. “The probability of grade II-IV acute graft vs. host disease was 12.5%, compared with 32.5% seen with unrelated cord blood in our group’s previous studies. Cellular immune reconstitution was robust,” she said at the annual meeting of the American Society of Pediatric Hematology/Oncology.

Augmenting cord blood

Although unrelated donor cord blood transplantation expands the donor pool, is rapidly available, and is associated with decreases in both severe acute graft vs. host disease (GVHD) and chronic GVHD, compared with other stem cell sources, the technique is hampered by limited cell doses, prolonged immune reconstitution time, delays in hematopoietic recovery, and a higher incidence of graft failure.

Early studies of myeloablative conditioning followed by unrelated umbilical or placental blood transplantation showed a median of 22-24 days to neutrophil engraftment (Blood 1996 88:795-802; N Engl J Med. 1996;335:157-66), Dr. Flower noted.

More recently, a multivariate analysis of patients who underwent reduced-intensity conditioning followed by hematopoietic stem cell transplant with unrelated cord blood showed that graft failure was an independent risk factor for worse overall survival (Biol Blood Marrow Transplant. 2013 Apr;19:4;552-61).

Multiple groups have shown that adding human placenta–derived stem cells (HPDSC) to cord blood transplantation can facilitate more rapid hematopoietic engraftment by increasing the number of stem cells, increasing the proportion of hematopoietic progenitor cells, and providing additional, immature CD34+/CD45– progenitor cells.

In a single-arm, nonrandomized study, the investigators enrolled 16 patients ranging in age from 0.3 to 15.7 years with inborn errors of metabolism, marrow failure syndromes, severe immunodeficiency states, or hematologic malignancies.

Malignant conditions included B-cell precursor acute lymphoblastic leukemia (B-ALL; four patients), acute myeloid leukemia (AML; two), and T-cell ALL (one) in first complete remission, and T-cell lymphoblastic lymphoma following induction failure (one). Nonmalignant conditions included adrenoleukodystrophy (two patients), amegakaryotic thrombocytopenia (one), severe combined immunodeficiency (SCID; two), dyskeratosis congenita (one), chronic granulomatous disease (one), and severe congenital neutropenia (one).

The patients first underwent either myeloablative or reduced-intensity conditioning, followed 10 days later by infusion of unrelated cord blood and HPDSCs. Prior to HPDSC infusion, patients were medicated with diphenhydramine and hydrocortisone to prevent or reduce potential sensitivity reactions. HPDSCs were infused no sooner than 4 hours after the end of the cord blood infusion.

Patients received GVHD prophylaxis with either tacrolimus or cyclosporine, plus mycophenolate mofetil.

The combination appeared to be safe, with no cases of grade 3 or 4 toxicity secondary to HPDSC infusion.

The probability of neutrophil engraftment was 87.5%, with engraftment occurring at a median of 23 days (range 13-53). As noted before, all patients who had neutrophil engraftment had platelet engraftment, which was achieved at a median of 47 days (range, 20-98). In the group’s previous studies, median time to platelet engraftment was 53 days for patients who had undergone reduced-intensity conditioning, and 118 days for patients who had undergone myeloablation.

The probability of grade 2-4 acute GVHD within 100 days was 12.5%, and there were no cases of chronic GVHD.

Respective percentages of cord blood donor chimerism at days 30, 60, 100, and 180 were 88%, 98%, 99%, and 99%.

Immune reconstitution was strong, with normalization of mean CD3+, CD19+, and CD56+ cells occurring by day 100, CD8+ cells by day 180, and CD4+ cells by day 270.

There were three patient deaths: one from adenoviremia in a patient with B-ALL and CNS relapse, who had neutrophil engraftment at day 21; one in a patient with SCID, from adenoviremia and multiple system organ failure, who did not have engraftment before death; and one in a patient with severe congenital neutrophilia, who also did not have neutrophil engraftment.

None of the eight patients with malignant disease have experienced relapse to date, Dr. Flower noted.

The study was funded by a grant from Celgene Cellular Therapeutics. Dr. Flower reported having no conflicts of interest.

[email protected]