Leukemia, Myelodysplasia, Transplantation

Photo by Bill Branson

The US Food and Drug Administration(FDA) has accepted for priority review the biologics license application seeking approval for tagraxofusp (Elzonris, SL-401) to treat blastic plasmacytoid dendritic cell neoplasm (BPDCN).

The FDA expects to make a decision on this application by February 21, 2019.

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 intends to take action on a priority review application within 6 months of receiving it rather than the standard 10 months.

About tagraxofusp

Tagraxofusp is a targeted therapy directed to CD123, a cell surface receptor expressed on a range of malignancies. The drug is being developed by Stemline Therapeutics, Inc.

In addition to priority review, tagraxofusp has breakthrough therapy designation and orphan drug designation from the FDA.

Tagraxofusp has produced favorable early results in a phase 2 trial of patients with BPDCN. Results from this trial were presented at the 23rd Congress of the European Hematology Association (EHA) in June.

Results were presented for 45 patients—32 with previously untreated BPDCN and 13 with relapsed/refractory BPDCN.

Three patients received tagraxofusp at 7 μg/kg/day on days 1 to 5 of a 21-day cycle, and the rest received the drug at 12 μg/kg on days 1 to 5 of a 21-day cycle.

Among patients who received the 12 μg/kg/day dose, the overall response rate was 83% (35/42). The overall response rate was 90% (26/29) in the previously untreated patients and 69% (9/13) in relapsed/refractory patients.

The composite complete response rate was 62% (n=26) overall, 72% (n=21) in previously untreated patients, and 38% (n=5) in relapsed/refractory patients.

Fourteen patients went on to stem cell transplant, 1 of whom had relapsed/refractory disease at baseline.

Overall survival results were only available for the 29 previously untreated patients who received tagraxofusp at 12 μg/kg/day. In this group, the median overall survival had not been reached at a median follow-up of 13.8 months (range, 0.2 to 37.4 months).

Safety results were presented for 114 patients who have received tagraxofusp at 12 μg/kg/day on all trials of the drug. These data include patients with diseases other than BPDCN, although adverse events (AEs) were similar regardless of disease.

Common treatment-related AEs (of any grade, occurring in at least 15% of patients) included hypoalbuminemia (49%), ALT increase (48%), AST increase (48%), thrombocytopenia (29%), nausea (27%), pyrexia (25%), chills (23%), fatigue (23%), weight increase (19%), hypotension (18%), peripheral edema (17%), and vomiting (15%).

Another common AE was capillary leak syndrome (CLS), which occurred in 20% of patients (n=23). Most cases of CLS were grade 1 or 2, but there were grade 3 (n=5) and 4 (n=2) cases, as well as a single case of grade 5 CLS that occurred in a BPDCN patient.

Researchers found they could manage the CLS with monitoring and protocol adjustments.

Photo by Bill Branson

The US Food and Drug Administration(FDA) has accepted for priority review the biologics license application seeking approval for tagraxofusp (Elzonris, SL-401) to treat blastic plasmacytoid dendritic cell neoplasm (BPDCN).

The FDA expects to make a decision on this application by February 21, 2019.

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 intends to take action on a priority review application within 6 months of receiving it rather than the standard 10 months.

About tagraxofusp

Tagraxofusp is a targeted therapy directed to CD123, a cell surface receptor expressed on a range of malignancies. The drug is being developed by Stemline Therapeutics, Inc.

In addition to priority review, tagraxofusp has breakthrough therapy designation and orphan drug designation from the FDA.

Tagraxofusp has produced favorable early results in a phase 2 trial of patients with BPDCN. Results from this trial were presented at the 23rd Congress of the European Hematology Association (EHA) in June.

Results were presented for 45 patients—32 with previously untreated BPDCN and 13 with relapsed/refractory BPDCN.

Three patients received tagraxofusp at 7 μg/kg/day on days 1 to 5 of a 21-day cycle, and the rest received the drug at 12 μg/kg on days 1 to 5 of a 21-day cycle.

Among patients who received the 12 μg/kg/day dose, the overall response rate was 83% (35/42). The overall response rate was 90% (26/29) in the previously untreated patients and 69% (9/13) in relapsed/refractory patients.

The composite complete response rate was 62% (n=26) overall, 72% (n=21) in previously untreated patients, and 38% (n=5) in relapsed/refractory patients.

Fourteen patients went on to stem cell transplant, 1 of whom had relapsed/refractory disease at baseline.

Overall survival results were only available for the 29 previously untreated patients who received tagraxofusp at 12 μg/kg/day. In this group, the median overall survival had not been reached at a median follow-up of 13.8 months (range, 0.2 to 37.4 months).

Safety results were presented for 114 patients who have received tagraxofusp at 12 μg/kg/day on all trials of the drug. These data include patients with diseases other than BPDCN, although adverse events (AEs) were similar regardless of disease.

Common treatment-related AEs (of any grade, occurring in at least 15% of patients) included hypoalbuminemia (49%), ALT increase (48%), AST increase (48%), thrombocytopenia (29%), nausea (27%), pyrexia (25%), chills (23%), fatigue (23%), weight increase (19%), hypotension (18%), peripheral edema (17%), and vomiting (15%).

Another common AE was capillary leak syndrome (CLS), which occurred in 20% of patients (n=23). Most cases of CLS were grade 1 or 2, but there were grade 3 (n=5) and 4 (n=2) cases, as well as a single case of grade 5 CLS that occurred in a BPDCN patient.

Researchers found they could manage the CLS with monitoring and protocol adjustments.

Photo by Bill Branson

The US Food and Drug Administration(FDA) has accepted for priority review the biologics license application seeking approval for tagraxofusp (Elzonris, SL-401) to treat blastic plasmacytoid dendritic cell neoplasm (BPDCN).

The FDA expects to make a decision on this application by February 21, 2019.

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 intends to take action on a priority review application within 6 months of receiving it rather than the standard 10 months.

About tagraxofusp

Tagraxofusp is a targeted therapy directed to CD123, a cell surface receptor expressed on a range of malignancies. The drug is being developed by Stemline Therapeutics, Inc.

In addition to priority review, tagraxofusp has breakthrough therapy designation and orphan drug designation from the FDA.

Tagraxofusp has produced favorable early results in a phase 2 trial of patients with BPDCN. Results from this trial were presented at the 23rd Congress of the European Hematology Association (EHA) in June.

Results were presented for 45 patients—32 with previously untreated BPDCN and 13 with relapsed/refractory BPDCN.

Three patients received tagraxofusp at 7 μg/kg/day on days 1 to 5 of a 21-day cycle, and the rest received the drug at 12 μg/kg on days 1 to 5 of a 21-day cycle.

Among patients who received the 12 μg/kg/day dose, the overall response rate was 83% (35/42). The overall response rate was 90% (26/29) in the previously untreated patients and 69% (9/13) in relapsed/refractory patients.

The composite complete response rate was 62% (n=26) overall, 72% (n=21) in previously untreated patients, and 38% (n=5) in relapsed/refractory patients.

Fourteen patients went on to stem cell transplant, 1 of whom had relapsed/refractory disease at baseline.

Overall survival results were only available for the 29 previously untreated patients who received tagraxofusp at 12 μg/kg/day. In this group, the median overall survival had not been reached at a median follow-up of 13.8 months (range, 0.2 to 37.4 months).

Safety results were presented for 114 patients who have received tagraxofusp at 12 μg/kg/day on all trials of the drug. These data include patients with diseases other than BPDCN, although adverse events (AEs) were similar regardless of disease.

Common treatment-related AEs (of any grade, occurring in at least 15% of patients) included hypoalbuminemia (49%), ALT increase (48%), AST increase (48%), thrombocytopenia (29%), nausea (27%), pyrexia (25%), chills (23%), fatigue (23%), weight increase (19%), hypotension (18%), peripheral edema (17%), and vomiting (15%).

Another common AE was capillary leak syndrome (CLS), which occurred in 20% of patients (n=23). Most cases of CLS were grade 1 or 2, but there were grade 3 (n=5) and 4 (n=2) cases, as well as a single case of grade 5 CLS that occurred in a BPDCN patient.

Researchers found they could manage the CLS with monitoring and protocol adjustments.

Photo by Luis Alvaz

Patients undergoing autologous hematopoietic stem cell transplant (auto-HSCT) for lymphoma or myeloma have an increased risk of acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS), according to a retrospective study.

The study suggested these patients have 10 to 100 times the risk of AML or MDS as the general population.

The elevated risk also exceeds that of similar lymphoma and myeloma patients largely untreated with auto-HSCT.

Tomas Radivoyevitch, PhD, of the Cleveland Clinic Foundation in Ohio, and his colleagues reported these findings in Leukemia Research.

The investigators noted that exposure to DNA-damaging drugs and ionizing radiation—both used in auto-HSCT—is known to increase the risk of AML and MDS.

With this in mind, the team analyzed data on auto-HSCT recipients reported to the Center for International Blood and Marrow Transplant Research (CIBMTR).

Analyses were based on 9028 patients undergoing auto-HSCT from 1995 to 2010 for Hodgkin lymphoma (n=916), non-Hodgkin lymphoma (NHL, n=3546), or plasma cell myeloma (n=4566). Their median duration of follow-up was 90 months, 110 months, and 97 months, respectively.

Overall, 3.7% of the cohort developed AML or MDS after their transplant.

More aggressive transplant protocols increased the likelihood of this outcome. The risk of developing AML or MDS was higher for:

• Hodgkin lymphoma patients who received conditioning with total body radiation versus chemotherapy alone (hazard ratio [HR], 4.0)
• NHL patients who received conditioning with total body radiation (HR, 1.7) or with busulfan and melphalan or cyclophosphamide (HR, 1.8) versus the BEAM regimen (bischloroethylnitrosourea, etoposide, cytarabine, and melphalan)
• NHL or myeloma patients who received 3 or more lines of chemotherapy versus 1 line (HR, 1.9 for NHL and 1.8 for myeloma)
• NHL patients who underwent transplant in 2005 to 2010 versus 1995 to 1999 (HR, 2.1).

Patients reported to the Surveillance, Epidemiology and End Results database with the same lymphoma and myeloma diagnoses, few of whom underwent auto-HSCT, had risks of AML and MDS that were 5 to 10 times higher than the background level in the population.

However, the study auto-HSCT cohort had a risk of AML that was 10 to 50 times higher and a relative risk of MDS that was roughly 100 times higher than the background level.

“These increases may be related to exposure to high doses of DNA-damaging drugs given for [auto-HSCT], but this hypothesis can only be tested in a prospective study,” Dr Radivoyevitch and his coinvestigators wrote.

The reason for the greater elevation of MDS risk, compared with AML risk, is unknown.

“One possible explanation is that many cases of MDS evolve to AML, and that earlier diagnosis from increased post-transplant surveillance resulted in a deficiency of AML,” the investigators wrote. “A second is based on steeper MDS versus AML incidences versus age . . . and the possibility that transplantation recipient marrow ages (ie, marrow biological ages) are perhaps decades older than calendar ages.”

The study authors said they had no relevant conflicts of interest. The CIBMTR is supported by several US government agencies and numerous pharmaceutical companies. 

Photo by Luis Alvaz

Patients undergoing autologous hematopoietic stem cell transplant (auto-HSCT) for lymphoma or myeloma have an increased risk of acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS), according to a retrospective study.

The study suggested these patients have 10 to 100 times the risk of AML or MDS as the general population.

The elevated risk also exceeds that of similar lymphoma and myeloma patients largely untreated with auto-HSCT.

Tomas Radivoyevitch, PhD, of the Cleveland Clinic Foundation in Ohio, and his colleagues reported these findings in Leukemia Research.

The investigators noted that exposure to DNA-damaging drugs and ionizing radiation—both used in auto-HSCT—is known to increase the risk of AML and MDS.

With this in mind, the team analyzed data on auto-HSCT recipients reported to the Center for International Blood and Marrow Transplant Research (CIBMTR).

Analyses were based on 9028 patients undergoing auto-HSCT from 1995 to 2010 for Hodgkin lymphoma (n=916), non-Hodgkin lymphoma (NHL, n=3546), or plasma cell myeloma (n=4566). Their median duration of follow-up was 90 months, 110 months, and 97 months, respectively.

Overall, 3.7% of the cohort developed AML or MDS after their transplant.

More aggressive transplant protocols increased the likelihood of this outcome. The risk of developing AML or MDS was higher for:

• Hodgkin lymphoma patients who received conditioning with total body radiation versus chemotherapy alone (hazard ratio [HR], 4.0)
• NHL patients who received conditioning with total body radiation (HR, 1.7) or with busulfan and melphalan or cyclophosphamide (HR, 1.8) versus the BEAM regimen (bischloroethylnitrosourea, etoposide, cytarabine, and melphalan)
• NHL or myeloma patients who received 3 or more lines of chemotherapy versus 1 line (HR, 1.9 for NHL and 1.8 for myeloma)
• NHL patients who underwent transplant in 2005 to 2010 versus 1995 to 1999 (HR, 2.1).

Patients reported to the Surveillance, Epidemiology and End Results database with the same lymphoma and myeloma diagnoses, few of whom underwent auto-HSCT, had risks of AML and MDS that were 5 to 10 times higher than the background level in the population.

However, the study auto-HSCT cohort had a risk of AML that was 10 to 50 times higher and a relative risk of MDS that was roughly 100 times higher than the background level.

“These increases may be related to exposure to high doses of DNA-damaging drugs given for [auto-HSCT], but this hypothesis can only be tested in a prospective study,” Dr Radivoyevitch and his coinvestigators wrote.

The reason for the greater elevation of MDS risk, compared with AML risk, is unknown.

“One possible explanation is that many cases of MDS evolve to AML, and that earlier diagnosis from increased post-transplant surveillance resulted in a deficiency of AML,” the investigators wrote. “A second is based on steeper MDS versus AML incidences versus age . . . and the possibility that transplantation recipient marrow ages (ie, marrow biological ages) are perhaps decades older than calendar ages.”

The study authors said they had no relevant conflicts of interest. The CIBMTR is supported by several US government agencies and numerous pharmaceutical companies. 

Photo by Luis Alvaz

Patients undergoing autologous hematopoietic stem cell transplant (auto-HSCT) for lymphoma or myeloma have an increased risk of acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS), according to a retrospective study.

The study suggested these patients have 10 to 100 times the risk of AML or MDS as the general population.

The elevated risk also exceeds that of similar lymphoma and myeloma patients largely untreated with auto-HSCT.

Tomas Radivoyevitch, PhD, of the Cleveland Clinic Foundation in Ohio, and his colleagues reported these findings in Leukemia Research.

The investigators noted that exposure to DNA-damaging drugs and ionizing radiation—both used in auto-HSCT—is known to increase the risk of AML and MDS.

With this in mind, the team analyzed data on auto-HSCT recipients reported to the Center for International Blood and Marrow Transplant Research (CIBMTR).

Analyses were based on 9028 patients undergoing auto-HSCT from 1995 to 2010 for Hodgkin lymphoma (n=916), non-Hodgkin lymphoma (NHL, n=3546), or plasma cell myeloma (n=4566). Their median duration of follow-up was 90 months, 110 months, and 97 months, respectively.

Overall, 3.7% of the cohort developed AML or MDS after their transplant.

More aggressive transplant protocols increased the likelihood of this outcome. The risk of developing AML or MDS was higher for:

• Hodgkin lymphoma patients who received conditioning with total body radiation versus chemotherapy alone (hazard ratio [HR], 4.0)
• NHL patients who received conditioning with total body radiation (HR, 1.7) or with busulfan and melphalan or cyclophosphamide (HR, 1.8) versus the BEAM regimen (bischloroethylnitrosourea, etoposide, cytarabine, and melphalan)
• NHL or myeloma patients who received 3 or more lines of chemotherapy versus 1 line (HR, 1.9 for NHL and 1.8 for myeloma)
• NHL patients who underwent transplant in 2005 to 2010 versus 1995 to 1999 (HR, 2.1).

Patients reported to the Surveillance, Epidemiology and End Results database with the same lymphoma and myeloma diagnoses, few of whom underwent auto-HSCT, had risks of AML and MDS that were 5 to 10 times higher than the background level in the population.

However, the study auto-HSCT cohort had a risk of AML that was 10 to 50 times higher and a relative risk of MDS that was roughly 100 times higher than the background level.

“These increases may be related to exposure to high doses of DNA-damaging drugs given for [auto-HSCT], but this hypothesis can only be tested in a prospective study,” Dr Radivoyevitch and his coinvestigators wrote.

The reason for the greater elevation of MDS risk, compared with AML risk, is unknown.

“One possible explanation is that many cases of MDS evolve to AML, and that earlier diagnosis from increased post-transplant surveillance resulted in a deficiency of AML,” the investigators wrote. “A second is based on steeper MDS versus AML incidences versus age . . . and the possibility that transplantation recipient marrow ages (ie, marrow biological ages) are perhaps decades older than calendar ages.”

The study authors said they had no relevant conflicts of interest. The CIBMTR is supported by several US government agencies and numerous pharmaceutical companies. 

Three generations of women in a family

A large study has revealed “the strongest evidence yet” supporting genetic susceptibility to myeloid malignancies, according to a researcher.

The study showed that first-degree relatives of patients with myeloid malignancies had double the risk of developing a myeloid malignancy themselves, when compared to the general population.

The researchers observed significant risks for developing acute myeloid leukemia (AML), myelodysplastic syndromes (MDS), essential thrombocythemia (ET), and polycythemia vera (PV).

“Our study provides the strongest evidence yet for inherited risk for these diseases—evidence that has proved evasive before, in part, because these cancers are relatively uncommon, and our ability to characterize these diseases has, until recently, been limited,” said Amit Sud, MBChB, PhD, of The Institute of Cancer Research in London, UK.

Dr Sud and his colleagues described their research in a letter to Blood.

The researchers analyzed data from the Swedish Family-Cancer Database, which included 93,199 first-degree relatives of 35,037 patients with myeloid malignancies. The patients had been diagnosed between 1958 and 2015.

First-degree relatives of the patients had an increased risk of all myeloid malignancies, with a standardized incidence ratio (SIR) of 1.99 (95% CI 1.12-2.04).

For individual diseases, there was a significant association between family history and increased risk for:

• AML—SIR=1.53 (95% CI 1.21-2.17)
• ET—SIR=6.30 (95% CI 3.95-9.54)
• MDS—SIR=6.87 (95% CI 4.07-10.86)
• PV—SIR=7.66 (95% CI 5.74-10.02).

Dr Sud and his colleagues noted that the strongest familial relative risks tended to occur for the same disease, but there were significant associations between different myeloid malignancies as well.

Risk by age group

The researchers also looked at familial relative risk for the same disease by patients’ age at diagnosis and observed a significantly increased risk for younger cases for all myeloproliferative neoplasms (MPNs) combined, PV, and MDS.

The SIRs for MPNs were 6.46 (95% CI 5.12-8.04) for patients age 59 or younger and 4.15 (95% CI 3.38-5.04) for patients older than 59.

The SIRs for PV were 10.90 (95% CI 7.12-15.97) for patients age 59 or younger and 5.96 (95% CI 3.93-8.67) for patients older than 59.

The SIRs for MDS were 11.95 (95% CI 6.36-20.43) for patients age 68 or younger and 3.27 (95% CI 1.06-7.63) for patients older than 68.

Risk by number of relatives

Dr Sud and his colleagues also discovered that familial relative risks of all myeloid malignancies and MPNs were significantly associated with the number of first-degree relatives affected by myeloid malignancies or MPNs.

The SIRs for first-degree relatives with 2 or more affected relatives were 4.55 (95% CI 2.08-8.64) for all myeloid malignancies and 17.82 (95% CI 5.79-24.89) for MPNs.

The SIRs for first-degree relatives with 1 affected relative were 1.96 (95% CI 1.79-2.15) for all myeloid malignancies and 4.83 (95% CI 4.14-5.60) for MPNs.

The researchers said these results suggest inherited genetic changes increase the risk of myeloid malignancies, although environmental factors shared in families could also play a role.

“In the future, our findings could help identify people at higher risk than normal because of their family background who could be prioritized for medical help like screening to catch the disease earlier if it arises,” Dr Sud said.

This study was funded by German Cancer Aid, the Swedish Research Council, ALF funding from Region Skåne, DKFZ, and Bloodwise.

Three generations of women in a family

A large study has revealed “the strongest evidence yet” supporting genetic susceptibility to myeloid malignancies, according to a researcher.

The study showed that first-degree relatives of patients with myeloid malignancies had double the risk of developing a myeloid malignancy themselves, when compared to the general population.

The researchers observed significant risks for developing acute myeloid leukemia (AML), myelodysplastic syndromes (MDS), essential thrombocythemia (ET), and polycythemia vera (PV).

“Our study provides the strongest evidence yet for inherited risk for these diseases—evidence that has proved evasive before, in part, because these cancers are relatively uncommon, and our ability to characterize these diseases has, until recently, been limited,” said Amit Sud, MBChB, PhD, of The Institute of Cancer Research in London, UK.

Dr Sud and his colleagues described their research in a letter to Blood.

The researchers analyzed data from the Swedish Family-Cancer Database, which included 93,199 first-degree relatives of 35,037 patients with myeloid malignancies. The patients had been diagnosed between 1958 and 2015.

First-degree relatives of the patients had an increased risk of all myeloid malignancies, with a standardized incidence ratio (SIR) of 1.99 (95% CI 1.12-2.04).

For individual diseases, there was a significant association between family history and increased risk for:

• AML—SIR=1.53 (95% CI 1.21-2.17)
• ET—SIR=6.30 (95% CI 3.95-9.54)
• MDS—SIR=6.87 (95% CI 4.07-10.86)
• PV—SIR=7.66 (95% CI 5.74-10.02).

Dr Sud and his colleagues noted that the strongest familial relative risks tended to occur for the same disease, but there were significant associations between different myeloid malignancies as well.

Risk by age group

The researchers also looked at familial relative risk for the same disease by patients’ age at diagnosis and observed a significantly increased risk for younger cases for all myeloproliferative neoplasms (MPNs) combined, PV, and MDS.

The SIRs for MPNs were 6.46 (95% CI 5.12-8.04) for patients age 59 or younger and 4.15 (95% CI 3.38-5.04) for patients older than 59.

The SIRs for PV were 10.90 (95% CI 7.12-15.97) for patients age 59 or younger and 5.96 (95% CI 3.93-8.67) for patients older than 59.

The SIRs for MDS were 11.95 (95% CI 6.36-20.43) for patients age 68 or younger and 3.27 (95% CI 1.06-7.63) for patients older than 68.

Risk by number of relatives

Dr Sud and his colleagues also discovered that familial relative risks of all myeloid malignancies and MPNs were significantly associated with the number of first-degree relatives affected by myeloid malignancies or MPNs.

The SIRs for first-degree relatives with 2 or more affected relatives were 4.55 (95% CI 2.08-8.64) for all myeloid malignancies and 17.82 (95% CI 5.79-24.89) for MPNs.

The SIRs for first-degree relatives with 1 affected relative were 1.96 (95% CI 1.79-2.15) for all myeloid malignancies and 4.83 (95% CI 4.14-5.60) for MPNs.

The researchers said these results suggest inherited genetic changes increase the risk of myeloid malignancies, although environmental factors shared in families could also play a role.

“In the future, our findings could help identify people at higher risk than normal because of their family background who could be prioritized for medical help like screening to catch the disease earlier if it arises,” Dr Sud said.

This study was funded by German Cancer Aid, the Swedish Research Council, ALF funding from Region Skåne, DKFZ, and Bloodwise.

Three generations of women in a family

A large study has revealed “the strongest evidence yet” supporting genetic susceptibility to myeloid malignancies, according to a researcher.

The study showed that first-degree relatives of patients with myeloid malignancies had double the risk of developing a myeloid malignancy themselves, when compared to the general population.

The researchers observed significant risks for developing acute myeloid leukemia (AML), myelodysplastic syndromes (MDS), essential thrombocythemia (ET), and polycythemia vera (PV).

“Our study provides the strongest evidence yet for inherited risk for these diseases—evidence that has proved evasive before, in part, because these cancers are relatively uncommon, and our ability to characterize these diseases has, until recently, been limited,” said Amit Sud, MBChB, PhD, of The Institute of Cancer Research in London, UK.

Dr Sud and his colleagues described their research in a letter to Blood.

The researchers analyzed data from the Swedish Family-Cancer Database, which included 93,199 first-degree relatives of 35,037 patients with myeloid malignancies. The patients had been diagnosed between 1958 and 2015.

First-degree relatives of the patients had an increased risk of all myeloid malignancies, with a standardized incidence ratio (SIR) of 1.99 (95% CI 1.12-2.04).

For individual diseases, there was a significant association between family history and increased risk for:

• AML—SIR=1.53 (95% CI 1.21-2.17)
• ET—SIR=6.30 (95% CI 3.95-9.54)
• MDS—SIR=6.87 (95% CI 4.07-10.86)
• PV—SIR=7.66 (95% CI 5.74-10.02).

Dr Sud and his colleagues noted that the strongest familial relative risks tended to occur for the same disease, but there were significant associations between different myeloid malignancies as well.

Risk by age group

The researchers also looked at familial relative risk for the same disease by patients’ age at diagnosis and observed a significantly increased risk for younger cases for all myeloproliferative neoplasms (MPNs) combined, PV, and MDS.

The SIRs for MPNs were 6.46 (95% CI 5.12-8.04) for patients age 59 or younger and 4.15 (95% CI 3.38-5.04) for patients older than 59.

The SIRs for PV were 10.90 (95% CI 7.12-15.97) for patients age 59 or younger and 5.96 (95% CI 3.93-8.67) for patients older than 59.

The SIRs for MDS were 11.95 (95% CI 6.36-20.43) for patients age 68 or younger and 3.27 (95% CI 1.06-7.63) for patients older than 68.

Risk by number of relatives

Dr Sud and his colleagues also discovered that familial relative risks of all myeloid malignancies and MPNs were significantly associated with the number of first-degree relatives affected by myeloid malignancies or MPNs.

The SIRs for first-degree relatives with 2 or more affected relatives were 4.55 (95% CI 2.08-8.64) for all myeloid malignancies and 17.82 (95% CI 5.79-24.89) for MPNs.

The SIRs for first-degree relatives with 1 affected relative were 1.96 (95% CI 1.79-2.15) for all myeloid malignancies and 4.83 (95% CI 4.14-5.60) for MPNs.

The researchers said these results suggest inherited genetic changes increase the risk of myeloid malignancies, although environmental factors shared in families could also play a role.

“In the future, our findings could help identify people at higher risk than normal because of their family background who could be prioritized for medical help like screening to catch the disease earlier if it arises,” Dr Sud said.

This study was funded by German Cancer Aid, the Swedish Research Council, ALF funding from Region Skåne, DKFZ, and Bloodwise.

Photo by Bill Branson

Fludarabine, cyclophosphamide, and rituximab are recommended as initial therapy for fit patients with chronic lymphocytic leukemia (CLL) who do not have TP53 disruption, according to new guidelines from the British Society for Haematology.

The guidelines update the 2012 recommendations on CLL to include “significant” developments in treatment.

The new guidelines were published in the British Journal of Haematology.

Anna H. Schuh, MD, of the University of Oxford in the UK, and her coauthors noted that, while these guidelines apply to treatments available outside clinical trials, wherever possible, patients with CLL should be treated within the clinical trial setting.

While recommending fludarabine, cyclophosphamide, and rituximab as first-line therapy, the guideline authors acknowledged that the combination of bendamustine and rituximab is an acceptable alternative for patients who cannot take the triple therapy because of comorbidities such as advanced age, renal impairment, or issues with marrow capacity.

Similarly, less-fit patients can also be considered for chlorambucil-obinutuzumab or chlorambucil-ofatumumab combinations.

All patients diagnosed with CLL should be tested for TP53 deletions and mutations before each line of therapy, the guideline committee recommended.

TP53 disruption makes chemoimmunotherapy ineffective because of either a deletion of chromosome 17p or a mutation in the TP53 gene. However, there is compelling evidence for the efficacy of ibrutinib in these patients, or idelalisib and rituximab for those with cardiac disease or receiving vitamin K antagonists.

With respect to maintenance therapy, the guidelines noted that this was not routinely recommended in CLL as “it is unclear to what extent the progression-free survival benefit is offset by long-term toxicity.”

Patients who are refractory to chemoimmunotherapy, who have relapsed, or who cannot be retreated with chemoimmunotherapy should be treated with idelalisib plus rituximab or ibrutinib monotherapy, the guidelines suggested.

“Deciding whether ibrutinib or idelalisib with rituximab is most appropriate for an individual patient depends on a range of factors, including toxicity profile and convenience of delivery,” the authors wrote.

However, they noted that the value of adding bendamustine to either option was unclear as research had not shown significant, associated gains in median progression-free survival.

Allogeneic stem cell transplant should be considered as an option for patients who have failed chemotherapy, have a TP53 disruption and have not responded to B-cell receptor signaling pathway inhibitors such as ibrutinib, or have Richter’s transformation.

The guidelines also addressed the issue of autoimmune cytopenias, which occur in 5% to 10% of patients with CLL and can actually precede the diagnosis of CLL in about 9% of cases.

In patients where autoimmune cytopenia is the dominant clinical feature, they should be treated with corticosteroids, intravenous immunoglobulin, or rituximab. However, for patients where the cytopenia is triggered by CLL therapy, the guidelines recommended halting treatment and beginning immunosuppression.

The guideline development was supported by the British Society for Haematology. The UK CLL Forum, which was involved in development as well, is a registered charity that receives funding from a number of pharmaceutical companies.

Photo by Bill Branson

Fludarabine, cyclophosphamide, and rituximab are recommended as initial therapy for fit patients with chronic lymphocytic leukemia (CLL) who do not have TP53 disruption, according to new guidelines from the British Society for Haematology.

The guidelines update the 2012 recommendations on CLL to include “significant” developments in treatment.

The new guidelines were published in the British Journal of Haematology.

Anna H. Schuh, MD, of the University of Oxford in the UK, and her coauthors noted that, while these guidelines apply to treatments available outside clinical trials, wherever possible, patients with CLL should be treated within the clinical trial setting.

While recommending fludarabine, cyclophosphamide, and rituximab as first-line therapy, the guideline authors acknowledged that the combination of bendamustine and rituximab is an acceptable alternative for patients who cannot take the triple therapy because of comorbidities such as advanced age, renal impairment, or issues with marrow capacity.

Similarly, less-fit patients can also be considered for chlorambucil-obinutuzumab or chlorambucil-ofatumumab combinations.

All patients diagnosed with CLL should be tested for TP53 deletions and mutations before each line of therapy, the guideline committee recommended.

TP53 disruption makes chemoimmunotherapy ineffective because of either a deletion of chromosome 17p or a mutation in the TP53 gene. However, there is compelling evidence for the efficacy of ibrutinib in these patients, or idelalisib and rituximab for those with cardiac disease or receiving vitamin K antagonists.

With respect to maintenance therapy, the guidelines noted that this was not routinely recommended in CLL as “it is unclear to what extent the progression-free survival benefit is offset by long-term toxicity.”

Patients who are refractory to chemoimmunotherapy, who have relapsed, or who cannot be retreated with chemoimmunotherapy should be treated with idelalisib plus rituximab or ibrutinib monotherapy, the guidelines suggested.

“Deciding whether ibrutinib or idelalisib with rituximab is most appropriate for an individual patient depends on a range of factors, including toxicity profile and convenience of delivery,” the authors wrote.

However, they noted that the value of adding bendamustine to either option was unclear as research had not shown significant, associated gains in median progression-free survival.

Allogeneic stem cell transplant should be considered as an option for patients who have failed chemotherapy, have a TP53 disruption and have not responded to B-cell receptor signaling pathway inhibitors such as ibrutinib, or have Richter’s transformation.

The guidelines also addressed the issue of autoimmune cytopenias, which occur in 5% to 10% of patients with CLL and can actually precede the diagnosis of CLL in about 9% of cases.

In patients where autoimmune cytopenia is the dominant clinical feature, they should be treated with corticosteroids, intravenous immunoglobulin, or rituximab. However, for patients where the cytopenia is triggered by CLL therapy, the guidelines recommended halting treatment and beginning immunosuppression.

The guideline development was supported by the British Society for Haematology. The UK CLL Forum, which was involved in development as well, is a registered charity that receives funding from a number of pharmaceutical companies.

Photo by Bill Branson

Fludarabine, cyclophosphamide, and rituximab are recommended as initial therapy for fit patients with chronic lymphocytic leukemia (CLL) who do not have TP53 disruption, according to new guidelines from the British Society for Haematology.

The guidelines update the 2012 recommendations on CLL to include “significant” developments in treatment.

The new guidelines were published in the British Journal of Haematology.

Anna H. Schuh, MD, of the University of Oxford in the UK, and her coauthors noted that, while these guidelines apply to treatments available outside clinical trials, wherever possible, patients with CLL should be treated within the clinical trial setting.

While recommending fludarabine, cyclophosphamide, and rituximab as first-line therapy, the guideline authors acknowledged that the combination of bendamustine and rituximab is an acceptable alternative for patients who cannot take the triple therapy because of comorbidities such as advanced age, renal impairment, or issues with marrow capacity.

Similarly, less-fit patients can also be considered for chlorambucil-obinutuzumab or chlorambucil-ofatumumab combinations.

All patients diagnosed with CLL should be tested for TP53 deletions and mutations before each line of therapy, the guideline committee recommended.

TP53 disruption makes chemoimmunotherapy ineffective because of either a deletion of chromosome 17p or a mutation in the TP53 gene. However, there is compelling evidence for the efficacy of ibrutinib in these patients, or idelalisib and rituximab for those with cardiac disease or receiving vitamin K antagonists.

With respect to maintenance therapy, the guidelines noted that this was not routinely recommended in CLL as “it is unclear to what extent the progression-free survival benefit is offset by long-term toxicity.”

Patients who are refractory to chemoimmunotherapy, who have relapsed, or who cannot be retreated with chemoimmunotherapy should be treated with idelalisib plus rituximab or ibrutinib monotherapy, the guidelines suggested.

“Deciding whether ibrutinib or idelalisib with rituximab is most appropriate for an individual patient depends on a range of factors, including toxicity profile and convenience of delivery,” the authors wrote.

However, they noted that the value of adding bendamustine to either option was unclear as research had not shown significant, associated gains in median progression-free survival.

Allogeneic stem cell transplant should be considered as an option for patients who have failed chemotherapy, have a TP53 disruption and have not responded to B-cell receptor signaling pathway inhibitors such as ibrutinib, or have Richter’s transformation.

The guidelines also addressed the issue of autoimmune cytopenias, which occur in 5% to 10% of patients with CLL and can actually precede the diagnosis of CLL in about 9% of cases.

In patients where autoimmune cytopenia is the dominant clinical feature, they should be treated with corticosteroids, intravenous immunoglobulin, or rituximab. However, for patients where the cytopenia is triggered by CLL therapy, the guidelines recommended halting treatment and beginning immunosuppression.

The guideline development was supported by the British Society for Haematology. The UK CLL Forum, which was involved in development as well, is a registered charity that receives funding from a number of pharmaceutical companies.

Lab mouse

New research suggests the FOXM1 protein plays an important role in acute myeloid leukemia (AML) progression, and targeting FOXM1 could improve AML treatment.

With a retrospective study, researchers showed that overexpression of FOXM1 was associated with increased resistance to chemotherapy and inferior overall survival.

Subsequent preclinical research showed that ixazomib inhibits FOXM1, exhibits antileukemic activity, and sensitizes AML cells to chemotherapy.

Irum Khan, MD, of the University of Illinois in Chicago, and her colleagues reported these findings in JCI Insight.

Previous research showed that AML patients with NPM1 mutations have a higher rate of remission with chemotherapy, and the NPM1 protein affects the location and activity of FOXM1. NPM1 keeps FOXM1 in the nucleus where it can activate other cancer-promoting genes.

When the NPM1 gene is mutated, FOXM1 migrates out of the nucleus and into the cell’s cytoplasm, where it can’t interact with DNA. This may explain why AML patients with NPM1 mutations have a better response to chemotherapy and are less likely to relapse.

With the current research, Dr Khan and her colleagues further explored the role of FOXM1 in AML.

Retrospective analysis

The multicenter, retrospective study began with data from 111 adults with AML. They had intermediate-risk cytogenetics and a median age of 61.

Eighty-eight patients received induction with cytarabine and an anthracycline, and 80 achieved a complete remission with or without count recovery.

FOXM1 expression data were available for 74 of these patients. Fifty patients achieved remission with 1 cycle of induction, and 24 required more than 1 cycle.

“[Patients] with FOXM1 present in the nucleus of their cancer cells had worse treatment outcomes, higher rates of chemotherapy resistance, and lower survival rates compared to patients without FOXM1 present in the nucleus,” Dr Khan said.

The patients who failed their first line of induction had a more than 2-fold increase in the percentage of nuclei expressing FOXM1 in their bone marrow (P=0.004). And the average nuclear intensity of FOXM1 was significantly higher in the patients who failed their first line of induction (P=0.02).

The percentage of FOXM1-positive nuclei and the average nuclear intensity of FOXM1 both significantly predicted resistance to first-line chemotherapy. The odds ratio was 1.80 for a 10% increase in FOXM1-positive nuclei (P=0.005) and 2.5 for a 0.1 unit increase in nuclear intensity (P=0.02).

A multivariate analysis showed that the FOXM1 nuclear/cytoplasmic (N:C) ratio and nuclear FOXM1 intensity predicted inferior overall survival in a single institution. (Institutions were analyzed separately for survival). The hazard ratio was 4.7 for every 0.1 unit increase in N:C ratio (P=0.03) and 4.27 for every 0.1 unit increase in nuclear intensity (P=0.06).

Confirming the role of FOXM1

The researchers set out to confirm the role of FOXM1 via experiments in mice.

The team induced a FLT3-ITD-driven myeloproliferative neoplasm in a FOXM1-overexpressing transgenic mouse model.

These mice had more residual disease after treatment with cytarabine than control mice with normal levels of FOXM1.

“Our finding suggests that overexpression of FOXM1 directly induces chemoresistance, which matches what we saw in our analysis of patients’ FOXM1 levels and their treatment outcomes,” Dr Khan said.

Targeting FOXM1 with ixazomib

Next, the researchers showed they could produce a therapeutic response by inhibiting FOXM1 in AML. The team used ixazomib, which was shown to suppress FOXM1.

There was a 2-fold increase in apoptosis when AML patient cells were treated with ixazomib (compared to DMSO).

Ixazomib also exhibited antitumor activity in a xenograft model of AML (HL-60 cells) and reduced leukemic burden in an orthotopic model of AML (KG-1 cells).

Finally, the researchers found that ixazomib sensitized AML cells to chemotherapy. The team observed synergistic activity between ixazomib and cytarabine or 5-azacitidine.

“There is a real unmet need for new ways to get around the resistance to chemotherapy that patients who don’t have this beneficial [NPM1] mutation often face,” Dr Khan said.

“Drugs that suppress FOXM1 in combination with the standard treatment, such as ixazomib, should result in better outcomes, but clinical trials will ultimately be needed to prove this theory.”

This research was supported by grants from the National Institutes of Health and Takeda.

Lab mouse

New research suggests the FOXM1 protein plays an important role in acute myeloid leukemia (AML) progression, and targeting FOXM1 could improve AML treatment.

With a retrospective study, researchers showed that overexpression of FOXM1 was associated with increased resistance to chemotherapy and inferior overall survival.

Subsequent preclinical research showed that ixazomib inhibits FOXM1, exhibits antileukemic activity, and sensitizes AML cells to chemotherapy.

Irum Khan, MD, of the University of Illinois in Chicago, and her colleagues reported these findings in JCI Insight.

Previous research showed that AML patients with NPM1 mutations have a higher rate of remission with chemotherapy, and the NPM1 protein affects the location and activity of FOXM1. NPM1 keeps FOXM1 in the nucleus where it can activate other cancer-promoting genes.

When the NPM1 gene is mutated, FOXM1 migrates out of the nucleus and into the cell’s cytoplasm, where it can’t interact with DNA. This may explain why AML patients with NPM1 mutations have a better response to chemotherapy and are less likely to relapse.

With the current research, Dr Khan and her colleagues further explored the role of FOXM1 in AML.

Retrospective analysis

The multicenter, retrospective study began with data from 111 adults with AML. They had intermediate-risk cytogenetics and a median age of 61.

Eighty-eight patients received induction with cytarabine and an anthracycline, and 80 achieved a complete remission with or without count recovery.

FOXM1 expression data were available for 74 of these patients. Fifty patients achieved remission with 1 cycle of induction, and 24 required more than 1 cycle.

“[Patients] with FOXM1 present in the nucleus of their cancer cells had worse treatment outcomes, higher rates of chemotherapy resistance, and lower survival rates compared to patients without FOXM1 present in the nucleus,” Dr Khan said.

The patients who failed their first line of induction had a more than 2-fold increase in the percentage of nuclei expressing FOXM1 in their bone marrow (P=0.004). And the average nuclear intensity of FOXM1 was significantly higher in the patients who failed their first line of induction (P=0.02).

The percentage of FOXM1-positive nuclei and the average nuclear intensity of FOXM1 both significantly predicted resistance to first-line chemotherapy. The odds ratio was 1.80 for a 10% increase in FOXM1-positive nuclei (P=0.005) and 2.5 for a 0.1 unit increase in nuclear intensity (P=0.02).

A multivariate analysis showed that the FOXM1 nuclear/cytoplasmic (N:C) ratio and nuclear FOXM1 intensity predicted inferior overall survival in a single institution. (Institutions were analyzed separately for survival). The hazard ratio was 4.7 for every 0.1 unit increase in N:C ratio (P=0.03) and 4.27 for every 0.1 unit increase in nuclear intensity (P=0.06).

Confirming the role of FOXM1

The researchers set out to confirm the role of FOXM1 via experiments in mice.

The team induced a FLT3-ITD-driven myeloproliferative neoplasm in a FOXM1-overexpressing transgenic mouse model.

These mice had more residual disease after treatment with cytarabine than control mice with normal levels of FOXM1.

“Our finding suggests that overexpression of FOXM1 directly induces chemoresistance, which matches what we saw in our analysis of patients’ FOXM1 levels and their treatment outcomes,” Dr Khan said.

Targeting FOXM1 with ixazomib

Next, the researchers showed they could produce a therapeutic response by inhibiting FOXM1 in AML. The team used ixazomib, which was shown to suppress FOXM1.

There was a 2-fold increase in apoptosis when AML patient cells were treated with ixazomib (compared to DMSO).

Ixazomib also exhibited antitumor activity in a xenograft model of AML (HL-60 cells) and reduced leukemic burden in an orthotopic model of AML (KG-1 cells).

Finally, the researchers found that ixazomib sensitized AML cells to chemotherapy. The team observed synergistic activity between ixazomib and cytarabine or 5-azacitidine.

“There is a real unmet need for new ways to get around the resistance to chemotherapy that patients who don’t have this beneficial [NPM1] mutation often face,” Dr Khan said.

“Drugs that suppress FOXM1 in combination with the standard treatment, such as ixazomib, should result in better outcomes, but clinical trials will ultimately be needed to prove this theory.”

This research was supported by grants from the National Institutes of Health and Takeda.

Lab mouse

New research suggests the FOXM1 protein plays an important role in acute myeloid leukemia (AML) progression, and targeting FOXM1 could improve AML treatment.

With a retrospective study, researchers showed that overexpression of FOXM1 was associated with increased resistance to chemotherapy and inferior overall survival.

Subsequent preclinical research showed that ixazomib inhibits FOXM1, exhibits antileukemic activity, and sensitizes AML cells to chemotherapy.

Irum Khan, MD, of the University of Illinois in Chicago, and her colleagues reported these findings in JCI Insight.

Previous research showed that AML patients with NPM1 mutations have a higher rate of remission with chemotherapy, and the NPM1 protein affects the location and activity of FOXM1. NPM1 keeps FOXM1 in the nucleus where it can activate other cancer-promoting genes.

When the NPM1 gene is mutated, FOXM1 migrates out of the nucleus and into the cell’s cytoplasm, where it can’t interact with DNA. This may explain why AML patients with NPM1 mutations have a better response to chemotherapy and are less likely to relapse.

With the current research, Dr Khan and her colleagues further explored the role of FOXM1 in AML.

Retrospective analysis

The multicenter, retrospective study began with data from 111 adults with AML. They had intermediate-risk cytogenetics and a median age of 61.

Eighty-eight patients received induction with cytarabine and an anthracycline, and 80 achieved a complete remission with or without count recovery.

FOXM1 expression data were available for 74 of these patients. Fifty patients achieved remission with 1 cycle of induction, and 24 required more than 1 cycle.

“[Patients] with FOXM1 present in the nucleus of their cancer cells had worse treatment outcomes, higher rates of chemotherapy resistance, and lower survival rates compared to patients without FOXM1 present in the nucleus,” Dr Khan said.

The patients who failed their first line of induction had a more than 2-fold increase in the percentage of nuclei expressing FOXM1 in their bone marrow (P=0.004). And the average nuclear intensity of FOXM1 was significantly higher in the patients who failed their first line of induction (P=0.02).

The percentage of FOXM1-positive nuclei and the average nuclear intensity of FOXM1 both significantly predicted resistance to first-line chemotherapy. The odds ratio was 1.80 for a 10% increase in FOXM1-positive nuclei (P=0.005) and 2.5 for a 0.1 unit increase in nuclear intensity (P=0.02).

A multivariate analysis showed that the FOXM1 nuclear/cytoplasmic (N:C) ratio and nuclear FOXM1 intensity predicted inferior overall survival in a single institution. (Institutions were analyzed separately for survival). The hazard ratio was 4.7 for every 0.1 unit increase in N:C ratio (P=0.03) and 4.27 for every 0.1 unit increase in nuclear intensity (P=0.06).

Confirming the role of FOXM1

The researchers set out to confirm the role of FOXM1 via experiments in mice.

The team induced a FLT3-ITD-driven myeloproliferative neoplasm in a FOXM1-overexpressing transgenic mouse model.

These mice had more residual disease after treatment with cytarabine than control mice with normal levels of FOXM1.

“Our finding suggests that overexpression of FOXM1 directly induces chemoresistance, which matches what we saw in our analysis of patients’ FOXM1 levels and their treatment outcomes,” Dr Khan said.

Targeting FOXM1 with ixazomib

Next, the researchers showed they could produce a therapeutic response by inhibiting FOXM1 in AML. The team used ixazomib, which was shown to suppress FOXM1.

There was a 2-fold increase in apoptosis when AML patient cells were treated with ixazomib (compared to DMSO).

Ixazomib also exhibited antitumor activity in a xenograft model of AML (HL-60 cells) and reduced leukemic burden in an orthotopic model of AML (KG-1 cells).

Finally, the researchers found that ixazomib sensitized AML cells to chemotherapy. The team observed synergistic activity between ixazomib and cytarabine or 5-azacitidine.

“There is a real unmet need for new ways to get around the resistance to chemotherapy that patients who don’t have this beneficial [NPM1] mutation often face,” Dr Khan said.

“Drugs that suppress FOXM1 in combination with the standard treatment, such as ixazomib, should result in better outcomes, but clinical trials will ultimately be needed to prove this theory.”

This research was supported by grants from the National Institutes of Health and Takeda.

Micrograph showing CLL

Patients with chronic lymphocytic leukemia (CLL) should be routinely monitored for melanoma, according to researchers.

A study of 470 CLL patients showed they have a significantly higher risk of invasive melanoma than the general population.

Most of the melanomas reported in this study were detected via routine surveillance, and most were discovered before they reached an advanced stage.

Clive Zent, MD, of Wilmot Cancer Institute at the University of Rochester Medical Center in Rochester, New York, and his colleagues described this study in Leukemia Research.

The researchers analyzed data on 470 CLL patients followed for 2849 person-years. Eighteen of these patients developed 22 melanomas. This included 14 cases of invasive melanoma in 13 patients.

The rate of invasive melanoma was significantly higher in this CLL cohort than the rate observed in the age- and sex-matched general population. The standardized incidence ratio was 6.32.

“We do not for sure know why CLL patients are more susceptible to melanoma, but the most likely cause is a suppressed immune system,” Dr Zent noted.

“Normally, in people with healthy immune systems, malignant skin cells might be detected and destroyed before they become a problem. But in CLL patients, failure of this control system increases the rate at which cancer cells can grow into tumors and also the likelihood that they will become invasive or spread to distant sites.”

Detection and management

Fifteen of the 22 melanomas (68.2%) in the CLL cohort were detected via surveillance in a dermatology clinic, and 2 (9.1%) were detected at the CLL/lymphoma clinic.

Three cases of melanoma (14.3%) were detected within the first year of a patient’s CLL diagnosis.

Seven melanomas (33.3%) were detected at pathologic stage 0, 8 (38.1%) at stage I, 2 (9.5%) at stage II, 3 (14.3%) at stage III, and 1 (4.8%) at stage IV. Detailed data were not available for the remaining case.

Melanomas were managed with wide local excision (n=19), sentinel node biopsies (n=6), Mohs surgery (n=1), drugs (n=2), palliative care (n=1), and comfort care (n=1).

The 4 patients who received drugs, palliative care, or comfort care had advanced melanoma.

The patient who received palliative care was still alive at 2.4 years of follow-up. The patient who received comfort care died of metastatic melanoma 1.4 years after diagnosis.

The third patient with advanced melanoma received 2 cycles of dacarbazine and palliative radiation to lung and brain metastases. This patient died 3.6 years after melanoma diagnosis.

The fourth patient received ipilimumab for the melanoma while also receiving ibrutinib to treat her CLL. When the ipilimumab failed, the patient proceeded to pembrolizumab and achieved a near-complete response within 3 months. Then, an intensely hypermetabolic abdominal node was detected and successfully treated with radiation.

The patient continued on pembrolizumab, and her melanoma was in sustained remission at last follow-up, after 23 cycles of pembrolizumab. Her CLL was still responding to ibrutinib at that point as well.

Based on these data, Dr Zent and his colleagues recommend routine melanoma screening for CLL patients. The team believes such surveillance might decrease morbidity and mortality in these patients, although more research is needed to confirm this theory.

Micrograph showing CLL

Patients with chronic lymphocytic leukemia (CLL) should be routinely monitored for melanoma, according to researchers.

A study of 470 CLL patients showed they have a significantly higher risk of invasive melanoma than the general population.

Most of the melanomas reported in this study were detected via routine surveillance, and most were discovered before they reached an advanced stage.

Clive Zent, MD, of Wilmot Cancer Institute at the University of Rochester Medical Center in Rochester, New York, and his colleagues described this study in Leukemia Research.

The researchers analyzed data on 470 CLL patients followed for 2849 person-years. Eighteen of these patients developed 22 melanomas. This included 14 cases of invasive melanoma in 13 patients.

The rate of invasive melanoma was significantly higher in this CLL cohort than the rate observed in the age- and sex-matched general population. The standardized incidence ratio was 6.32.

“We do not for sure know why CLL patients are more susceptible to melanoma, but the most likely cause is a suppressed immune system,” Dr Zent noted.

“Normally, in people with healthy immune systems, malignant skin cells might be detected and destroyed before they become a problem. But in CLL patients, failure of this control system increases the rate at which cancer cells can grow into tumors and also the likelihood that they will become invasive or spread to distant sites.”

Detection and management

Fifteen of the 22 melanomas (68.2%) in the CLL cohort were detected via surveillance in a dermatology clinic, and 2 (9.1%) were detected at the CLL/lymphoma clinic.

Three cases of melanoma (14.3%) were detected within the first year of a patient’s CLL diagnosis.

Seven melanomas (33.3%) were detected at pathologic stage 0, 8 (38.1%) at stage I, 2 (9.5%) at stage II, 3 (14.3%) at stage III, and 1 (4.8%) at stage IV. Detailed data were not available for the remaining case.

Melanomas were managed with wide local excision (n=19), sentinel node biopsies (n=6), Mohs surgery (n=1), drugs (n=2), palliative care (n=1), and comfort care (n=1).

The 4 patients who received drugs, palliative care, or comfort care had advanced melanoma.

The patient who received palliative care was still alive at 2.4 years of follow-up. The patient who received comfort care died of metastatic melanoma 1.4 years after diagnosis.

The third patient with advanced melanoma received 2 cycles of dacarbazine and palliative radiation to lung and brain metastases. This patient died 3.6 years after melanoma diagnosis.

The fourth patient received ipilimumab for the melanoma while also receiving ibrutinib to treat her CLL. When the ipilimumab failed, the patient proceeded to pembrolizumab and achieved a near-complete response within 3 months. Then, an intensely hypermetabolic abdominal node was detected and successfully treated with radiation.

The patient continued on pembrolizumab, and her melanoma was in sustained remission at last follow-up, after 23 cycles of pembrolizumab. Her CLL was still responding to ibrutinib at that point as well.

Based on these data, Dr Zent and his colleagues recommend routine melanoma screening for CLL patients. The team believes such surveillance might decrease morbidity and mortality in these patients, although more research is needed to confirm this theory.

Micrograph showing CLL

Patients with chronic lymphocytic leukemia (CLL) should be routinely monitored for melanoma, according to researchers.

A study of 470 CLL patients showed they have a significantly higher risk of invasive melanoma than the general population.

Most of the melanomas reported in this study were detected via routine surveillance, and most were discovered before they reached an advanced stage.

Clive Zent, MD, of Wilmot Cancer Institute at the University of Rochester Medical Center in Rochester, New York, and his colleagues described this study in Leukemia Research.

The researchers analyzed data on 470 CLL patients followed for 2849 person-years. Eighteen of these patients developed 22 melanomas. This included 14 cases of invasive melanoma in 13 patients.

The rate of invasive melanoma was significantly higher in this CLL cohort than the rate observed in the age- and sex-matched general population. The standardized incidence ratio was 6.32.

“We do not for sure know why CLL patients are more susceptible to melanoma, but the most likely cause is a suppressed immune system,” Dr Zent noted.

“Normally, in people with healthy immune systems, malignant skin cells might be detected and destroyed before they become a problem. But in CLL patients, failure of this control system increases the rate at which cancer cells can grow into tumors and also the likelihood that they will become invasive or spread to distant sites.”

Detection and management

Fifteen of the 22 melanomas (68.2%) in the CLL cohort were detected via surveillance in a dermatology clinic, and 2 (9.1%) were detected at the CLL/lymphoma clinic.

Three cases of melanoma (14.3%) were detected within the first year of a patient’s CLL diagnosis.

Seven melanomas (33.3%) were detected at pathologic stage 0, 8 (38.1%) at stage I, 2 (9.5%) at stage II, 3 (14.3%) at stage III, and 1 (4.8%) at stage IV. Detailed data were not available for the remaining case.

Melanomas were managed with wide local excision (n=19), sentinel node biopsies (n=6), Mohs surgery (n=1), drugs (n=2), palliative care (n=1), and comfort care (n=1).

The 4 patients who received drugs, palliative care, or comfort care had advanced melanoma.

The patient who received palliative care was still alive at 2.4 years of follow-up. The patient who received comfort care died of metastatic melanoma 1.4 years after diagnosis.

The third patient with advanced melanoma received 2 cycles of dacarbazine and palliative radiation to lung and brain metastases. This patient died 3.6 years after melanoma diagnosis.

The fourth patient received ipilimumab for the melanoma while also receiving ibrutinib to treat her CLL. When the ipilimumab failed, the patient proceeded to pembrolizumab and achieved a near-complete response within 3 months. Then, an intensely hypermetabolic abdominal node was detected and successfully treated with radiation.

The patient continued on pembrolizumab, and her melanoma was in sustained remission at last follow-up, after 23 cycles of pembrolizumab. Her CLL was still responding to ibrutinib at that point as well.

Based on these data, Dr Zent and his colleagues recommend routine melanoma screening for CLL patients. The team believes such surveillance might decrease morbidity and mortality in these patients, although more research is needed to confirm this theory.

Woman sunbathing

New research suggests people who develop frequent cases of basal cell carcinoma (BCC) have an increased risk of leukemias, lymphomas, and other cancers.

“We discovered that people who develop 6 or more basal cell carcinomas during a 10-year period are about 3 times more likely than the general population to develop other, unrelated cancers,” said Kavita Sarin, MD, PhD, of Stanford University School of Medicine in California.

“We’re hopeful that this finding could be a way to identify people at an increased risk for a life-threatening malignancy before those cancers develop.”

Dr Sarin and her colleagues reported their findings in JCI Insight.

Stanford cohort

The researchers first studied 61 patients treated at Stanford Health Care for unusually frequent BCCs—an average of 11 per patient over a 10-year period. The team investigated whether these patients may have mutations in 29 genes that code for DNA damage repair proteins.

“We found that about 20% of the people with frequent basal cell carcinomas have a mutation in one of the genes responsible for repairing DNA damage, versus about 3% of the general population,” Dr Sarin said. “That’s shockingly high.”

Specifically, there were 12 BCC patients (19.7%) who had 13 pathogenic mutations in 12 genes—APC, BARD1, BRCA1, BRCA2, CDH1, CHEK2, MLH1, MSH2, MSH6, MUTYH, NBN, and PALB2. And 3.0% of non-Finnish European subjects in the Exome Aggregation Consortium had pathogenic mutations in these 12 genes.

Furthermore, 21 of the 61 BCC patients (64.4%) had a history of additional cancers. This included 5 hematologic malignancies (leukemia/lymphoma), 5 invasive melanomas, and 2 breast, 2 colon, and 5 prostate cancers.

When the researchers compared the cancer prevalence in these patients to the Surveillance, Epidemiology, and End Results-estimated prevalence of cancer in the 60- to 69-year-old population of European descent, the BCC cohort had an increased risk of any cancer—a relative risk (RR) of 3.5 (P<0.001).

The RR was 3.5 for leukemia and lymphoma (P=0.004), 11.9 for invasive melanoma (P<0.001), 4.5 for colon cancer (P=0.030), 5.6 for breast cancer (P=0.009), and 4.7 for prostate cancer (P<0.001).

Insurance cohort

To confirm the findings in the Stanford cohort, the researchers applied a similar analysis to a large medical insurance claims database, Truven MarketScan.

The database contained 111,562 patients with 1 case of BCC, 13,264 patients with 6 or more BCCs, and 2920 patients with 12 or more BCCs. Truven patients with no history of BCC served as controls.

The researchers adjusted for age and sex and found that patients with 1 BCC, 6 or more BCCs, and 12 or more BCCs had an increased risk of any cancer compared to controls.

The odds ratio (OR) for any cancer was 1.61 for patients with 1 BCC, 3.12 for those with 6 or more BCCs, and 4.15 for patients with 12 or more BCCs.

The OR for Hodgkin lymphoma was 2.27 for patients with 1 BCC, 8.94 for patients with 6 or more BCCs, and 15.41 for patients with 12 or more BCCs.

The OR for non-Hodgkin lymphoma was 1.40 for patients with 1 BCC, 2.59 for patients with 6 or more BCCs, and 3.10 for patients with 12 or more BCCs.

The OR for leukemia was 1.76 for patients with 1 BCC, 3.23 for patients with 6 or more BCCs, and 5.78 for patients with 12 or more BCCs.

The researchers pointed out that, the more BCCs an individual had, the more likely that person was to have had other cancers as well.

“I was surprised to see such a strong correlation, but it’s also very gratifying,” Dr Sarin said. “Now, we can ask patients with repeated basal cell carcinomas whether they have family members with other types of cancers and perhaps suggest that they consider genetic testing and increased screening.”

The researchers are continuing to enroll Stanford patients in their study to learn whether particular mutations in genes responsible for repairing DNA damage are linked to the development of specific malignancies. The team would also like to conduct a similar study in patients with frequent melanomas.

The current study was supported by the Dermatology Foundation, the Stanford Society of Physician Scholars, the American Skin Association, and Pellepharm Inc.

Woman sunbathing

New research suggests people who develop frequent cases of basal cell carcinoma (BCC) have an increased risk of leukemias, lymphomas, and other cancers.

“We discovered that people who develop 6 or more basal cell carcinomas during a 10-year period are about 3 times more likely than the general population to develop other, unrelated cancers,” said Kavita Sarin, MD, PhD, of Stanford University School of Medicine in California.

“We’re hopeful that this finding could be a way to identify people at an increased risk for a life-threatening malignancy before those cancers develop.”

Dr Sarin and her colleagues reported their findings in JCI Insight.

Stanford cohort

The researchers first studied 61 patients treated at Stanford Health Care for unusually frequent BCCs—an average of 11 per patient over a 10-year period. The team investigated whether these patients may have mutations in 29 genes that code for DNA damage repair proteins.

“We found that about 20% of the people with frequent basal cell carcinomas have a mutation in one of the genes responsible for repairing DNA damage, versus about 3% of the general population,” Dr Sarin said. “That’s shockingly high.”

Specifically, there were 12 BCC patients (19.7%) who had 13 pathogenic mutations in 12 genes—APC, BARD1, BRCA1, BRCA2, CDH1, CHEK2, MLH1, MSH2, MSH6, MUTYH, NBN, and PALB2. And 3.0% of non-Finnish European subjects in the Exome Aggregation Consortium had pathogenic mutations in these 12 genes.

Furthermore, 21 of the 61 BCC patients (64.4%) had a history of additional cancers. This included 5 hematologic malignancies (leukemia/lymphoma), 5 invasive melanomas, and 2 breast, 2 colon, and 5 prostate cancers.

When the researchers compared the cancer prevalence in these patients to the Surveillance, Epidemiology, and End Results-estimated prevalence of cancer in the 60- to 69-year-old population of European descent, the BCC cohort had an increased risk of any cancer—a relative risk (RR) of 3.5 (P<0.001).

The RR was 3.5 for leukemia and lymphoma (P=0.004), 11.9 for invasive melanoma (P<0.001), 4.5 for colon cancer (P=0.030), 5.6 for breast cancer (P=0.009), and 4.7 for prostate cancer (P<0.001).

Insurance cohort

To confirm the findings in the Stanford cohort, the researchers applied a similar analysis to a large medical insurance claims database, Truven MarketScan.

The database contained 111,562 patients with 1 case of BCC, 13,264 patients with 6 or more BCCs, and 2920 patients with 12 or more BCCs. Truven patients with no history of BCC served as controls.

The researchers adjusted for age and sex and found that patients with 1 BCC, 6 or more BCCs, and 12 or more BCCs had an increased risk of any cancer compared to controls.

The odds ratio (OR) for any cancer was 1.61 for patients with 1 BCC, 3.12 for those with 6 or more BCCs, and 4.15 for patients with 12 or more BCCs.

The OR for Hodgkin lymphoma was 2.27 for patients with 1 BCC, 8.94 for patients with 6 or more BCCs, and 15.41 for patients with 12 or more BCCs.

The OR for non-Hodgkin lymphoma was 1.40 for patients with 1 BCC, 2.59 for patients with 6 or more BCCs, and 3.10 for patients with 12 or more BCCs.

The OR for leukemia was 1.76 for patients with 1 BCC, 3.23 for patients with 6 or more BCCs, and 5.78 for patients with 12 or more BCCs.

The researchers pointed out that, the more BCCs an individual had, the more likely that person was to have had other cancers as well.

“I was surprised to see such a strong correlation, but it’s also very gratifying,” Dr Sarin said. “Now, we can ask patients with repeated basal cell carcinomas whether they have family members with other types of cancers and perhaps suggest that they consider genetic testing and increased screening.”

The researchers are continuing to enroll Stanford patients in their study to learn whether particular mutations in genes responsible for repairing DNA damage are linked to the development of specific malignancies. The team would also like to conduct a similar study in patients with frequent melanomas.

The current study was supported by the Dermatology Foundation, the Stanford Society of Physician Scholars, the American Skin Association, and Pellepharm Inc.

Woman sunbathing

New research suggests people who develop frequent cases of basal cell carcinoma (BCC) have an increased risk of leukemias, lymphomas, and other cancers.

“We discovered that people who develop 6 or more basal cell carcinomas during a 10-year period are about 3 times more likely than the general population to develop other, unrelated cancers,” said Kavita Sarin, MD, PhD, of Stanford University School of Medicine in California.

“We’re hopeful that this finding could be a way to identify people at an increased risk for a life-threatening malignancy before those cancers develop.”

Dr Sarin and her colleagues reported their findings in JCI Insight.

Stanford cohort

The researchers first studied 61 patients treated at Stanford Health Care for unusually frequent BCCs—an average of 11 per patient over a 10-year period. The team investigated whether these patients may have mutations in 29 genes that code for DNA damage repair proteins.

“We found that about 20% of the people with frequent basal cell carcinomas have a mutation in one of the genes responsible for repairing DNA damage, versus about 3% of the general population,” Dr Sarin said. “That’s shockingly high.”

Specifically, there were 12 BCC patients (19.7%) who had 13 pathogenic mutations in 12 genes—APC, BARD1, BRCA1, BRCA2, CDH1, CHEK2, MLH1, MSH2, MSH6, MUTYH, NBN, and PALB2. And 3.0% of non-Finnish European subjects in the Exome Aggregation Consortium had pathogenic mutations in these 12 genes.

Furthermore, 21 of the 61 BCC patients (64.4%) had a history of additional cancers. This included 5 hematologic malignancies (leukemia/lymphoma), 5 invasive melanomas, and 2 breast, 2 colon, and 5 prostate cancers.

When the researchers compared the cancer prevalence in these patients to the Surveillance, Epidemiology, and End Results-estimated prevalence of cancer in the 60- to 69-year-old population of European descent, the BCC cohort had an increased risk of any cancer—a relative risk (RR) of 3.5 (P<0.001).

The RR was 3.5 for leukemia and lymphoma (P=0.004), 11.9 for invasive melanoma (P<0.001), 4.5 for colon cancer (P=0.030), 5.6 for breast cancer (P=0.009), and 4.7 for prostate cancer (P<0.001).

Insurance cohort

To confirm the findings in the Stanford cohort, the researchers applied a similar analysis to a large medical insurance claims database, Truven MarketScan.

The database contained 111,562 patients with 1 case of BCC, 13,264 patients with 6 or more BCCs, and 2920 patients with 12 or more BCCs. Truven patients with no history of BCC served as controls.

The researchers adjusted for age and sex and found that patients with 1 BCC, 6 or more BCCs, and 12 or more BCCs had an increased risk of any cancer compared to controls.

The odds ratio (OR) for any cancer was 1.61 for patients with 1 BCC, 3.12 for those with 6 or more BCCs, and 4.15 for patients with 12 or more BCCs.

The OR for Hodgkin lymphoma was 2.27 for patients with 1 BCC, 8.94 for patients with 6 or more BCCs, and 15.41 for patients with 12 or more BCCs.

The OR for non-Hodgkin lymphoma was 1.40 for patients with 1 BCC, 2.59 for patients with 6 or more BCCs, and 3.10 for patients with 12 or more BCCs.

The OR for leukemia was 1.76 for patients with 1 BCC, 3.23 for patients with 6 or more BCCs, and 5.78 for patients with 12 or more BCCs.

The researchers pointed out that, the more BCCs an individual had, the more likely that person was to have had other cancers as well.

“I was surprised to see such a strong correlation, but it’s also very gratifying,” Dr Sarin said. “Now, we can ask patients with repeated basal cell carcinomas whether they have family members with other types of cancers and perhaps suggest that they consider genetic testing and increased screening.”

The researchers are continuing to enroll Stanford patients in their study to learn whether particular mutations in genes responsible for repairing DNA damage are linked to the development of specific malignancies. The team would also like to conduct a similar study in patients with frequent melanomas.

The current study was supported by the Dermatology Foundation, the Stanford Society of Physician Scholars, the American Skin Association, and Pellepharm Inc.

Fludarabine, cyclophosphamide, and rituximab are recommended as initial therapy for patients with chronic lymphocytic leukemia who do not have TP53 disruption, according to new guidelines from the British Society for Haematology.

The guidelines update the 2012 recommendations on chronic lymphocytic leukemia (CLL) to include “significant” developments in treatment. They were published in the British Journal of Haematology.

Anna H. Schuh, MD, of the department of oncology at the University of Oxford (England), and her coauthors noted that, while these guidelines apply to treatments available outside clinical trials, wherever possible patients with CLL should be treated within the clinical trial setting.

While recommending fludarabine, cyclophosphamide, and rituximab as first-line therapy, the guideline authors acknowledged that the combination of bendamustine and rituximab is an acceptable alternative for patients who could not take the triple therapy because of comorbidities such as advanced age, renal impairment, or issues with marrow capacity.

Similarly, less-fit patients could also be considered for chlorambucil-obinutuzumab or chlorambucil-ofatumumab combinations.

All patients diagnosed with CLL should be tested for TP53 deletions and mutations before each line of therapy, the guideline committee recommended. TP53 disruption makes chemoimmunotherapy ineffective because of either a deletion of chromosome 17p or a mutation in the TP53 gene. However, there is compelling evidence for the efficacy of ibrutinib in these patients, or idelalisib and rituximab for those with cardiac disease or receiving vitamin K antagonists.

With respect to maintenance therapy, the guidelines noted that this was not routinely recommended in CLL as “it is unclear to what extent the progression-free survival benefit is offset by long-term toxicity.”

Patients who are refractory to chemoimmunotherapy, who have relapsed, or who cannot be retreated with chemoimmunotherapy should be treated with idelalisib with rituximab or ibrutinib monotherapy, the guidelines suggested.

“Deciding whether ibrutinib or idelalisib with rituximab is most appropriate for an individual patient depends on a range of factors, including toxicity profile and convenience of delivery,” the authors wrote. However, they noted that the value of adding bendamustine to either option was unclear as research had not shown significant, associated gains in median progression-free survival.

Allogeneic stem cell transplantation should be considered as a treatment option for patients who have either failed chemotherapy, have a TP53 disruption and have not responded to B-cell receptor signaling pathway inhibitors such as ibrutinib, or have a Richter transformation.

The guidelines also addressed the issue of autoimmune cytopenias, which occur in 5%-10% of patients with CLL and can actually precede the diagnosis of CLL in about 9% of cases.

In patients where autoimmune cytopenia is the dominant clinical feature, they should be treated with corticosteroids, intravenous immunoglobulin, or rituximab. However, for patients where the cytopenia is triggered by CLL therapy, the guidelines recommended halting treatment and beginning immunosuppression.

The guideline development was supported by the British Society for Haematology. The UK CLL Forum is a registered charity that receives funding from a number of pharmaceutical companies.

SOURCE: Schuh AH et al. Br J Haematol. 2018 Jul 15. doi: 10.1111/bjh.15460.

Fludarabine, cyclophosphamide, and rituximab are recommended as initial therapy for patients with chronic lymphocytic leukemia who do not have TP53 disruption, according to new guidelines from the British Society for Haematology.

The guidelines update the 2012 recommendations on chronic lymphocytic leukemia (CLL) to include “significant” developments in treatment. They were published in the British Journal of Haematology.

Anna H. Schuh, MD, of the department of oncology at the University of Oxford (England), and her coauthors noted that, while these guidelines apply to treatments available outside clinical trials, wherever possible patients with CLL should be treated within the clinical trial setting.

While recommending fludarabine, cyclophosphamide, and rituximab as first-line therapy, the guideline authors acknowledged that the combination of bendamustine and rituximab is an acceptable alternative for patients who could not take the triple therapy because of comorbidities such as advanced age, renal impairment, or issues with marrow capacity.

Similarly, less-fit patients could also be considered for chlorambucil-obinutuzumab or chlorambucil-ofatumumab combinations.

All patients diagnosed with CLL should be tested for TP53 deletions and mutations before each line of therapy, the guideline committee recommended. TP53 disruption makes chemoimmunotherapy ineffective because of either a deletion of chromosome 17p or a mutation in the TP53 gene. However, there is compelling evidence for the efficacy of ibrutinib in these patients, or idelalisib and rituximab for those with cardiac disease or receiving vitamin K antagonists.

With respect to maintenance therapy, the guidelines noted that this was not routinely recommended in CLL as “it is unclear to what extent the progression-free survival benefit is offset by long-term toxicity.”

Patients who are refractory to chemoimmunotherapy, who have relapsed, or who cannot be retreated with chemoimmunotherapy should be treated with idelalisib with rituximab or ibrutinib monotherapy, the guidelines suggested.

“Deciding whether ibrutinib or idelalisib with rituximab is most appropriate for an individual patient depends on a range of factors, including toxicity profile and convenience of delivery,” the authors wrote. However, they noted that the value of adding bendamustine to either option was unclear as research had not shown significant, associated gains in median progression-free survival.

Allogeneic stem cell transplantation should be considered as a treatment option for patients who have either failed chemotherapy, have a TP53 disruption and have not responded to B-cell receptor signaling pathway inhibitors such as ibrutinib, or have a Richter transformation.

The guidelines also addressed the issue of autoimmune cytopenias, which occur in 5%-10% of patients with CLL and can actually precede the diagnosis of CLL in about 9% of cases.

In patients where autoimmune cytopenia is the dominant clinical feature, they should be treated with corticosteroids, intravenous immunoglobulin, or rituximab. However, for patients where the cytopenia is triggered by CLL therapy, the guidelines recommended halting treatment and beginning immunosuppression.

The guideline development was supported by the British Society for Haematology. The UK CLL Forum is a registered charity that receives funding from a number of pharmaceutical companies.

SOURCE: Schuh AH et al. Br J Haematol. 2018 Jul 15. doi: 10.1111/bjh.15460.

Fludarabine, cyclophosphamide, and rituximab are recommended as initial therapy for patients with chronic lymphocytic leukemia who do not have TP53 disruption, according to new guidelines from the British Society for Haematology.

The guidelines update the 2012 recommendations on chronic lymphocytic leukemia (CLL) to include “significant” developments in treatment. They were published in the British Journal of Haematology.

Anna H. Schuh, MD, of the department of oncology at the University of Oxford (England), and her coauthors noted that, while these guidelines apply to treatments available outside clinical trials, wherever possible patients with CLL should be treated within the clinical trial setting.

While recommending fludarabine, cyclophosphamide, and rituximab as first-line therapy, the guideline authors acknowledged that the combination of bendamustine and rituximab is an acceptable alternative for patients who could not take the triple therapy because of comorbidities such as advanced age, renal impairment, or issues with marrow capacity.

Similarly, less-fit patients could also be considered for chlorambucil-obinutuzumab or chlorambucil-ofatumumab combinations.

All patients diagnosed with CLL should be tested for TP53 deletions and mutations before each line of therapy, the guideline committee recommended. TP53 disruption makes chemoimmunotherapy ineffective because of either a deletion of chromosome 17p or a mutation in the TP53 gene. However, there is compelling evidence for the efficacy of ibrutinib in these patients, or idelalisib and rituximab for those with cardiac disease or receiving vitamin K antagonists.

With respect to maintenance therapy, the guidelines noted that this was not routinely recommended in CLL as “it is unclear to what extent the progression-free survival benefit is offset by long-term toxicity.”

Patients who are refractory to chemoimmunotherapy, who have relapsed, or who cannot be retreated with chemoimmunotherapy should be treated with idelalisib with rituximab or ibrutinib monotherapy, the guidelines suggested.

“Deciding whether ibrutinib or idelalisib with rituximab is most appropriate for an individual patient depends on a range of factors, including toxicity profile and convenience of delivery,” the authors wrote. However, they noted that the value of adding bendamustine to either option was unclear as research had not shown significant, associated gains in median progression-free survival.

Allogeneic stem cell transplantation should be considered as a treatment option for patients who have either failed chemotherapy, have a TP53 disruption and have not responded to B-cell receptor signaling pathway inhibitors such as ibrutinib, or have a Richter transformation.

The guidelines also addressed the issue of autoimmune cytopenias, which occur in 5%-10% of patients with CLL and can actually precede the diagnosis of CLL in about 9% of cases.

In patients where autoimmune cytopenia is the dominant clinical feature, they should be treated with corticosteroids, intravenous immunoglobulin, or rituximab. However, for patients where the cytopenia is triggered by CLL therapy, the guidelines recommended halting treatment and beginning immunosuppression.

The guideline development was supported by the British Society for Haematology. The UK CLL Forum is a registered charity that receives funding from a number of pharmaceutical companies.

SOURCE: Schuh AH et al. Br J Haematol. 2018 Jul 15. doi: 10.1111/bjh.15460.

Cancer Research Center

Venetoclax might improve the treatment of certain patients with T-cell acute lymphoblastic leukemia (T-ALL), according to preclinical research published in Leukemia.

Researchers found that a ribosomal defect—the R98S mutation in ribosomal protein L10 (RPL10 R98S)—causes overexpression of BCL-2 in T-ALL.

The BCL-2 inhibitor venetoclax induced apoptosis of RPL10 R98S T-ALL cells and inhibited leukemia progression in mouse models of RPL10 R98S T-ALL.

The researchers therefore believe venetoclax could be used, in combination with other drugs, to treat T-ALL patients with RPL10 R98S.

“In the past couple of years, it has become clear that ribosome defects play a role in different types of cancer,” said study author Kim De Keersmaecker, PhD, of KU Leuven in Leuven, Belgium.

“In the case of a ribosome defect, the cells still produce proteins, but the balance between their quantities is slightly off, which leads to cancer.”

Dr De Keersmaecker and her colleagues noted that RPL10 R98S affects 8% of pediatric patients with T-ALL.

With this study, the researchers found that RPL10 R98S mutant cells were more resilient than wild-type (WT) cells. In overgrowth condition, Ba/F3 RPL10 R98S mutant cells “displayed a clear survival benefit” over RPL10 WT cells.

Likewise, RPL10 R98S Jurkat cells exhibited a survival benefit over WT Jurkat cells in overgrowth condition. And RPL10 R98S Jurkat cells were more resistant to treatment with doxorubicin.

Dr De Keersmaecker and her colleagues said the increased survival they observed in RPL10 R98S mutant cells is associated with enhanced BCL-2 expression. So the team decided to test a BCL-2 inhibitor in RPL10 R98S leukemic cells.

In vitro, venetoclax induced slightly more apoptosis in Jurkat RPL10 R98S cells than WT Jurkat cells. In vivo, venetoclax induced apoptosis in RPL10 R98S T-ALL cells but not WT T-ALL cells.

The researchers also found that venetoclax could re-sensitize RPL10 R98S cells to doxorubicin.

Finally, the team injected RPL10 WT and R98S samples from pediatric T-ALL patients into mice and treated the animals with DMSO or venetoclax (50 mg/kg) once a week.

Venetoclax had very little effect on the RPL10 WT mice. Percentages of human CD45 T-ALL cells in the peripheral blood were similar whether mice received DMSO or venetoclax.

However, in the RPL10 R98S mice, those that received DMSO experienced disease progression, while there were no signs of leukemia progression in the peripheral blood of mice that received venetoclax.

The splenomegaly observed in DMSO-treated mice was “almost completely suppressed” in mice that received venetoclax, according to the researchers.

The team also said they observed a 30% to 50% suppression of human CD45 leukemia cell engraftment in the bone marrow and the presence of 30% to 40% mouse CD45 cells in mice treated with venetoclax.

On the other hand, mice treated with DMSO had more than 95% human leukemia infiltration in the bone marrow and no mouse CD45-expressing cells.

Dr De Keersmaecker and her colleagues said these results suggest RPL10 R98S pediatric T-ALL is sensitive to BCL-2 targeted therapies such as venetoclax. However, venetoclax alone would not be sufficient to treat this type of T-ALL.

“Patients with leukemia often get a drug cocktail, while our study only tested the BCL-2 inhibitor,” Dr De Keersmaecker said. “That’s why our follow-up study will focus on a cocktail of this BCL-2 inhibitor and other drugs. For patients with the ribosome defect analyzed in our study, this avenue is definitely worth examining in greater detail.”

Cancer Research Center

Venetoclax might improve the treatment of certain patients with T-cell acute lymphoblastic leukemia (T-ALL), according to preclinical research published in Leukemia.

Researchers found that a ribosomal defect—the R98S mutation in ribosomal protein L10 (RPL10 R98S)—causes overexpression of BCL-2 in T-ALL.

The BCL-2 inhibitor venetoclax induced apoptosis of RPL10 R98S T-ALL cells and inhibited leukemia progression in mouse models of RPL10 R98S T-ALL.

The researchers therefore believe venetoclax could be used, in combination with other drugs, to treat T-ALL patients with RPL10 R98S.

“In the past couple of years, it has become clear that ribosome defects play a role in different types of cancer,” said study author Kim De Keersmaecker, PhD, of KU Leuven in Leuven, Belgium.

“In the case of a ribosome defect, the cells still produce proteins, but the balance between their quantities is slightly off, which leads to cancer.”

Dr De Keersmaecker and her colleagues noted that RPL10 R98S affects 8% of pediatric patients with T-ALL.

With this study, the researchers found that RPL10 R98S mutant cells were more resilient than wild-type (WT) cells. In overgrowth condition, Ba/F3 RPL10 R98S mutant cells “displayed a clear survival benefit” over RPL10 WT cells.

Likewise, RPL10 R98S Jurkat cells exhibited a survival benefit over WT Jurkat cells in overgrowth condition. And RPL10 R98S Jurkat cells were more resistant to treatment with doxorubicin.

Dr De Keersmaecker and her colleagues said the increased survival they observed in RPL10 R98S mutant cells is associated with enhanced BCL-2 expression. So the team decided to test a BCL-2 inhibitor in RPL10 R98S leukemic cells.

In vitro, venetoclax induced slightly more apoptosis in Jurkat RPL10 R98S cells than WT Jurkat cells. In vivo, venetoclax induced apoptosis in RPL10 R98S T-ALL cells but not WT T-ALL cells.

The researchers also found that venetoclax could re-sensitize RPL10 R98S cells to doxorubicin.

Finally, the team injected RPL10 WT and R98S samples from pediatric T-ALL patients into mice and treated the animals with DMSO or venetoclax (50 mg/kg) once a week.

Venetoclax had very little effect on the RPL10 WT mice. Percentages of human CD45 T-ALL cells in the peripheral blood were similar whether mice received DMSO or venetoclax.

However, in the RPL10 R98S mice, those that received DMSO experienced disease progression, while there were no signs of leukemia progression in the peripheral blood of mice that received venetoclax.

The splenomegaly observed in DMSO-treated mice was “almost completely suppressed” in mice that received venetoclax, according to the researchers.

The team also said they observed a 30% to 50% suppression of human CD45 leukemia cell engraftment in the bone marrow and the presence of 30% to 40% mouse CD45 cells in mice treated with venetoclax.

On the other hand, mice treated with DMSO had more than 95% human leukemia infiltration in the bone marrow and no mouse CD45-expressing cells.

Dr De Keersmaecker and her colleagues said these results suggest RPL10 R98S pediatric T-ALL is sensitive to BCL-2 targeted therapies such as venetoclax. However, venetoclax alone would not be sufficient to treat this type of T-ALL.

“Patients with leukemia often get a drug cocktail, while our study only tested the BCL-2 inhibitor,” Dr De Keersmaecker said. “That’s why our follow-up study will focus on a cocktail of this BCL-2 inhibitor and other drugs. For patients with the ribosome defect analyzed in our study, this avenue is definitely worth examining in greater detail.”

Cancer Research Center

Venetoclax might improve the treatment of certain patients with T-cell acute lymphoblastic leukemia (T-ALL), according to preclinical research published in Leukemia.

Researchers found that a ribosomal defect—the R98S mutation in ribosomal protein L10 (RPL10 R98S)—causes overexpression of BCL-2 in T-ALL.

The BCL-2 inhibitor venetoclax induced apoptosis of RPL10 R98S T-ALL cells and inhibited leukemia progression in mouse models of RPL10 R98S T-ALL.

The researchers therefore believe venetoclax could be used, in combination with other drugs, to treat T-ALL patients with RPL10 R98S.

“In the past couple of years, it has become clear that ribosome defects play a role in different types of cancer,” said study author Kim De Keersmaecker, PhD, of KU Leuven in Leuven, Belgium.

“In the case of a ribosome defect, the cells still produce proteins, but the balance between their quantities is slightly off, which leads to cancer.”

Dr De Keersmaecker and her colleagues noted that RPL10 R98S affects 8% of pediatric patients with T-ALL.

With this study, the researchers found that RPL10 R98S mutant cells were more resilient than wild-type (WT) cells. In overgrowth condition, Ba/F3 RPL10 R98S mutant cells “displayed a clear survival benefit” over RPL10 WT cells.

Likewise, RPL10 R98S Jurkat cells exhibited a survival benefit over WT Jurkat cells in overgrowth condition. And RPL10 R98S Jurkat cells were more resistant to treatment with doxorubicin.

Dr De Keersmaecker and her colleagues said the increased survival they observed in RPL10 R98S mutant cells is associated with enhanced BCL-2 expression. So the team decided to test a BCL-2 inhibitor in RPL10 R98S leukemic cells.

In vitro, venetoclax induced slightly more apoptosis in Jurkat RPL10 R98S cells than WT Jurkat cells. In vivo, venetoclax induced apoptosis in RPL10 R98S T-ALL cells but not WT T-ALL cells.

The researchers also found that venetoclax could re-sensitize RPL10 R98S cells to doxorubicin.

Finally, the team injected RPL10 WT and R98S samples from pediatric T-ALL patients into mice and treated the animals with DMSO or venetoclax (50 mg/kg) once a week.

Venetoclax had very little effect on the RPL10 WT mice. Percentages of human CD45 T-ALL cells in the peripheral blood were similar whether mice received DMSO or venetoclax.

However, in the RPL10 R98S mice, those that received DMSO experienced disease progression, while there were no signs of leukemia progression in the peripheral blood of mice that received venetoclax.

The splenomegaly observed in DMSO-treated mice was “almost completely suppressed” in mice that received venetoclax, according to the researchers.

The team also said they observed a 30% to 50% suppression of human CD45 leukemia cell engraftment in the bone marrow and the presence of 30% to 40% mouse CD45 cells in mice treated with venetoclax.

On the other hand, mice treated with DMSO had more than 95% human leukemia infiltration in the bone marrow and no mouse CD45-expressing cells.

Dr De Keersmaecker and her colleagues said these results suggest RPL10 R98S pediatric T-ALL is sensitive to BCL-2 targeted therapies such as venetoclax. However, venetoclax alone would not be sufficient to treat this type of T-ALL.

“Patients with leukemia often get a drug cocktail, while our study only tested the BCL-2 inhibitor,” Dr De Keersmaecker said. “That’s why our follow-up study will focus on a cocktail of this BCL-2 inhibitor and other drugs. For patients with the ribosome defect analyzed in our study, this avenue is definitely worth examining in greater detail.”