Leukemia, Myelodysplasia, Transplantation

GRAPEVINE, TEXAS—Administering radioimmunotherapy (RIT) prior to non-myeloablative allogeneic transplant (NMAT) can improve survival in patients with persistent disease, according to a speaker at the 2014 BMT Tandem Meetings.

Ryan Cassaday, MD, of the University of Washington in Seattle, noted that RIT-augmented NMAT can produce long-term remissions in patients with relapsed or refractory B-cell non-Hodgkin lymphoma (B-NHL) or chronic lymphocytic leukemia (CLL).

But outcomes for patients with persistent disease are “underdescribed.”

So he and his colleagues set out to describe outcomes of NMAT for patients with persistent indolent B-NHL or CLL and estimate the impact of RIT in these patients.

Treatment details

The researchers retrospectively analyzed data from 89 patients who underwent NMAT from December 1998 to April 2009 and were followed until September 2013. Eighteen of the patients had received RIT as part of a prospective study (AK Gopal et al, Blood 2011).

The remaining 71 patients did not receive RIT but met eligibility criteria for that study. Specifically, they had a CD20+ B-cell malignancy, an HLA-matched peripheral blood stem cell donor, and persistent disease at NMAT. These control subjects received fludarabine (30 mg/m² on days -7, -6, and -5) and 2 Gy of total body irradiation prior to NMAT.

Patients in the RIT group received the same treatment following RIT. On day -21, they received 250 mg/m² of rituximab before an imaging dose of ¹¹¹In-ibritumomab tiuxetan. And on day -14, they received 250 mg/m² of rituximab and 0.4 mCi/kg of ⁹⁰Y-ibritumomab tiuxetan.

Patient characteristics

In the RIT group, 10 patients had CLL/small lymphocytic lymphoma (SLL), 6 had follicular lymphoma (FL), 1 had marginal zone lymphoma (MZL), and 1 had hairy cell leukemia. As for controls, 52 had CLL/SLL, 18 had FL, and 1 had MZL.

“The majority of patients were male [74%] and a relatively young age, given the diseases being treated [median of 56 years],” Dr Cassaday said. “The majority of patients had previously received rituximab [88%], and patients were heavily pretreated [median of 4 prior therapies, range 1-12].”

There were no significant differences between the 2 treatment groups with regard to the aforementioned characteristics. However, there were some “striking differences” between the 2 groups, Dr Cassaday said, including characteristics that portend worse prognosis.

Specifically, RIT-treated patients had more bulky disease (> 5 cm) than controls (61% vs 15%, P<0.001) and more chemoresistant disease (81% vs 39%, P=0.003). And RIT patients were more likely to have HCT comorbidity index scores of 3 or higher (72% vs 37%, P=0.006), as well as pre-NMAT platelet counts less than 25k/μL (33% vs 7%, P=0.002).

RIT improves PFS, OS

The researchers conducted a multivariate analysis including the factors that differed significantly between the 2 treatment groups. And they found that only RIT was significantly associated with both progression-free survival (PFS) and overall survival (OS).

When calculating survival curves, the researchers adjusted for the imbalance in covariates between the treatment groups.

“[The adjusted survival rate] is essentially what one might expect had the RIT group had similar baseline characteristics as the control group,” Dr Cassaday explained.

Control subjects had a 3-year OS of 55%. For the RIT-treated patients, the unadjusted 3-year OS was 78% (P=0.20), and the adjusted OS was 87% (P=0.008).

The 3-year PFS was 44% for controls. For the RIT group, the unadjusted 3-year PFS was 56% (P=0.36), and the adjusted PFS was 71% (P=0.02).

The researchers also found that RIT did not increase the rate of non-relapse mortality. The unadjusted hazard ratio was 0.5 (P=0.32), and the adjusted hazard ratio was 0.4 (P=0.18).

“This analysis does have some limitations,” Dr Cassaday conceded. “Clearly, it does not replace the strength of evidence that would come from a randomized, controlled trial. And the relatively small sample size does limit our ability to look at a lot of different subgroups.”

In addition, the findings may not apply to other non-myeloablative regimens. And, due to the time frame of the study, the researchers could not account for the potential impact of newer agents.

Nevertheless, Dr Cassaday said the data suggest that RIT can improve the outcome of NMAT in patients with persistent indolent B-NHL or CLL. And a prospective, randomized study evaluating this approach is warranted.

Dr Cassaday presented this research at the 2014 BMT Tandem Meetings as abstract 75. Information in the abstract differs from that presented.

GRAPEVINE, TEXAS—Administering radioimmunotherapy (RIT) prior to non-myeloablative allogeneic transplant (NMAT) can improve survival in patients with persistent disease, according to a speaker at the 2014 BMT Tandem Meetings.

Ryan Cassaday, MD, of the University of Washington in Seattle, noted that RIT-augmented NMAT can produce long-term remissions in patients with relapsed or refractory B-cell non-Hodgkin lymphoma (B-NHL) or chronic lymphocytic leukemia (CLL).

But outcomes for patients with persistent disease are “underdescribed.”

So he and his colleagues set out to describe outcomes of NMAT for patients with persistent indolent B-NHL or CLL and estimate the impact of RIT in these patients.

Treatment details

The researchers retrospectively analyzed data from 89 patients who underwent NMAT from December 1998 to April 2009 and were followed until September 2013. Eighteen of the patients had received RIT as part of a prospective study (AK Gopal et al, Blood 2011).

The remaining 71 patients did not receive RIT but met eligibility criteria for that study. Specifically, they had a CD20+ B-cell malignancy, an HLA-matched peripheral blood stem cell donor, and persistent disease at NMAT. These control subjects received fludarabine (30 mg/m² on days -7, -6, and -5) and 2 Gy of total body irradiation prior to NMAT.

Patients in the RIT group received the same treatment following RIT. On day -21, they received 250 mg/m² of rituximab before an imaging dose of ¹¹¹In-ibritumomab tiuxetan. And on day -14, they received 250 mg/m² of rituximab and 0.4 mCi/kg of ⁹⁰Y-ibritumomab tiuxetan.

Patient characteristics

In the RIT group, 10 patients had CLL/small lymphocytic lymphoma (SLL), 6 had follicular lymphoma (FL), 1 had marginal zone lymphoma (MZL), and 1 had hairy cell leukemia. As for controls, 52 had CLL/SLL, 18 had FL, and 1 had MZL.

“The majority of patients were male [74%] and a relatively young age, given the diseases being treated [median of 56 years],” Dr Cassaday said. “The majority of patients had previously received rituximab [88%], and patients were heavily pretreated [median of 4 prior therapies, range 1-12].”

There were no significant differences between the 2 treatment groups with regard to the aforementioned characteristics. However, there were some “striking differences” between the 2 groups, Dr Cassaday said, including characteristics that portend worse prognosis.

Specifically, RIT-treated patients had more bulky disease (> 5 cm) than controls (61% vs 15%, P<0.001) and more chemoresistant disease (81% vs 39%, P=0.003). And RIT patients were more likely to have HCT comorbidity index scores of 3 or higher (72% vs 37%, P=0.006), as well as pre-NMAT platelet counts less than 25k/μL (33% vs 7%, P=0.002).

RIT improves PFS, OS

The researchers conducted a multivariate analysis including the factors that differed significantly between the 2 treatment groups. And they found that only RIT was significantly associated with both progression-free survival (PFS) and overall survival (OS).

When calculating survival curves, the researchers adjusted for the imbalance in covariates between the treatment groups.

“[The adjusted survival rate] is essentially what one might expect had the RIT group had similar baseline characteristics as the control group,” Dr Cassaday explained.

Control subjects had a 3-year OS of 55%. For the RIT-treated patients, the unadjusted 3-year OS was 78% (P=0.20), and the adjusted OS was 87% (P=0.008).

The 3-year PFS was 44% for controls. For the RIT group, the unadjusted 3-year PFS was 56% (P=0.36), and the adjusted PFS was 71% (P=0.02).

The researchers also found that RIT did not increase the rate of non-relapse mortality. The unadjusted hazard ratio was 0.5 (P=0.32), and the adjusted hazard ratio was 0.4 (P=0.18).

“This analysis does have some limitations,” Dr Cassaday conceded. “Clearly, it does not replace the strength of evidence that would come from a randomized, controlled trial. And the relatively small sample size does limit our ability to look at a lot of different subgroups.”

In addition, the findings may not apply to other non-myeloablative regimens. And, due to the time frame of the study, the researchers could not account for the potential impact of newer agents.

Nevertheless, Dr Cassaday said the data suggest that RIT can improve the outcome of NMAT in patients with persistent indolent B-NHL or CLL. And a prospective, randomized study evaluating this approach is warranted.

Dr Cassaday presented this research at the 2014 BMT Tandem Meetings as abstract 75. Information in the abstract differs from that presented.

GRAPEVINE, TEXAS—Administering radioimmunotherapy (RIT) prior to non-myeloablative allogeneic transplant (NMAT) can improve survival in patients with persistent disease, according to a speaker at the 2014 BMT Tandem Meetings.

Ryan Cassaday, MD, of the University of Washington in Seattle, noted that RIT-augmented NMAT can produce long-term remissions in patients with relapsed or refractory B-cell non-Hodgkin lymphoma (B-NHL) or chronic lymphocytic leukemia (CLL).

But outcomes for patients with persistent disease are “underdescribed.”

So he and his colleagues set out to describe outcomes of NMAT for patients with persistent indolent B-NHL or CLL and estimate the impact of RIT in these patients.

Treatment details

The researchers retrospectively analyzed data from 89 patients who underwent NMAT from December 1998 to April 2009 and were followed until September 2013. Eighteen of the patients had received RIT as part of a prospective study (AK Gopal et al, Blood 2011).

The remaining 71 patients did not receive RIT but met eligibility criteria for that study. Specifically, they had a CD20+ B-cell malignancy, an HLA-matched peripheral blood stem cell donor, and persistent disease at NMAT. These control subjects received fludarabine (30 mg/m² on days -7, -6, and -5) and 2 Gy of total body irradiation prior to NMAT.

Patients in the RIT group received the same treatment following RIT. On day -21, they received 250 mg/m² of rituximab before an imaging dose of ¹¹¹In-ibritumomab tiuxetan. And on day -14, they received 250 mg/m² of rituximab and 0.4 mCi/kg of ⁹⁰Y-ibritumomab tiuxetan.

Patient characteristics

In the RIT group, 10 patients had CLL/small lymphocytic lymphoma (SLL), 6 had follicular lymphoma (FL), 1 had marginal zone lymphoma (MZL), and 1 had hairy cell leukemia. As for controls, 52 had CLL/SLL, 18 had FL, and 1 had MZL.

“The majority of patients were male [74%] and a relatively young age, given the diseases being treated [median of 56 years],” Dr Cassaday said. “The majority of patients had previously received rituximab [88%], and patients were heavily pretreated [median of 4 prior therapies, range 1-12].”

There were no significant differences between the 2 treatment groups with regard to the aforementioned characteristics. However, there were some “striking differences” between the 2 groups, Dr Cassaday said, including characteristics that portend worse prognosis.

Specifically, RIT-treated patients had more bulky disease (> 5 cm) than controls (61% vs 15%, P<0.001) and more chemoresistant disease (81% vs 39%, P=0.003). And RIT patients were more likely to have HCT comorbidity index scores of 3 or higher (72% vs 37%, P=0.006), as well as pre-NMAT platelet counts less than 25k/μL (33% vs 7%, P=0.002).

RIT improves PFS, OS

The researchers conducted a multivariate analysis including the factors that differed significantly between the 2 treatment groups. And they found that only RIT was significantly associated with both progression-free survival (PFS) and overall survival (OS).

When calculating survival curves, the researchers adjusted for the imbalance in covariates between the treatment groups.

“[The adjusted survival rate] is essentially what one might expect had the RIT group had similar baseline characteristics as the control group,” Dr Cassaday explained.

Control subjects had a 3-year OS of 55%. For the RIT-treated patients, the unadjusted 3-year OS was 78% (P=0.20), and the adjusted OS was 87% (P=0.008).

The 3-year PFS was 44% for controls. For the RIT group, the unadjusted 3-year PFS was 56% (P=0.36), and the adjusted PFS was 71% (P=0.02).

The researchers also found that RIT did not increase the rate of non-relapse mortality. The unadjusted hazard ratio was 0.5 (P=0.32), and the adjusted hazard ratio was 0.4 (P=0.18).

“This analysis does have some limitations,” Dr Cassaday conceded. “Clearly, it does not replace the strength of evidence that would come from a randomized, controlled trial. And the relatively small sample size does limit our ability to look at a lot of different subgroups.”

In addition, the findings may not apply to other non-myeloablative regimens. And, due to the time frame of the study, the researchers could not account for the potential impact of newer agents.

Nevertheless, Dr Cassaday said the data suggest that RIT can improve the outcome of NMAT in patients with persistent indolent B-NHL or CLL. And a prospective, randomized study evaluating this approach is warranted.

Dr Cassaday presented this research at the 2014 BMT Tandem Meetings as abstract 75. Information in the abstract differs from that presented.

GRAPEVINE, TEXAS—Acute leukemia patients who undergo cord blood (CB) transplant have longer hospital stays than patients who receive other types of transplant, new research indicates.

The study also suggests the length of stay (LOS) is similar whether patients receive double or single CB grafts.

So it seems strategies are needed to decrease hospital stay after CB transplant, particularly as LOS drives the cost of care, said Karen K. Ballen, MD, of Massachusetts General Hospital in Boston.

Dr Ballen presented this research at the 2014 BMT Tandem Meetings as abstract 104.*

She and her colleagues studied patients diagnosed with acute leukemias who were transplanted at US centers and reported to the CIBMTR between 2008 and 2011.

Patients were eligible if they received an unrelated single or double CB transplant, an 8/8 matched unrelated donor (MUD) transplant with peripheral blood (PB) or bone marrow (BM), or a 7/8 MUD PB or BM graft.

In all, 1796 patients met these criteria. The researchers evaluated patients’ total hospital LOS in the first 100 days after transplant, compared LOS among graft sources, and looked for predictors of LOS in the first 100 days.

The team stratified patients according to age and conditioning regimen. Pediatric patients were classified as those aged 18 and younger, and they only received myeloablative conditioning (MAC). Adults received either MAC or reduced-intensity conditioning (RIC).

Pediatric patients

In a univariate analysis of the 368 pediatric patients, there was no significant difference in 100-day survival according to graft source (P=0.13).

However, patients who received single or double CB grafts had a significantly higher median total LOS by day 100 than patients who received 8/8 MUD BM, which was the only other graft source in this patient group (P=0.03).

Patients who received CB grafts also had significantly fewer days in which they were alive and not in the hospital (P=0.005).

“We wanted to account for patients whose length of stay was short because they actually died early after transplant,” Dr Ballen explained. “Therefore, we did an analysis of days alive and not in the hospital.”

In a multivariate analysis, pediatric patients who received CB grafts had significantly fewer days alive and out of the hospital than those who received 8/8 MUD BM (P=0.03).

Other factors associated with fewer days alive and out of the hospital were CMV positivity (P=0.01), black race (P=0.01), and a Karnofsky performance score of less than 80 (P=0.03).

Adults on MAC

In a univariate analysis of the 768 adults who received MAC, recipients of CB grafts had significantly worse 100-day survival than their peers (P<0.001), as well as a longer median LOS by day 100 (P<0.001) and fewer days alive and not in the hospital (P<0.001).

In a multivariate analysis, adults who received MAC had significantly fewer days alive and out of the hospital if they received CB grafts than if they received 8/8 MUD BM (P<0.001), 8/8 MUD PB (P<0.001), or 7/8 MUD PB (P=0.01), but not 7/8 MUD BM (P=0.49).

Other factors associated with fewer days alive and out of the hospital were black race (P=0.04), having acute lymphocytic leukemia rather than acute myeloid leukemia (P=0.01), and age 18-25 (P=0.01).

“We were a little surprised at these results—that the older patients actually spent more time alive and out of the hospital,” Dr Ballen said.

Adults on RIC

In a univariate analysis of the 660 adults who received RIC, recipients of CB grafts had significantly worse 100-day survival than their peers (P=0.017), as well as a longer median LOS by day 100 (P<0.001) and fewer days alive and not in the hospital (P<0.001).

In a multivariate analysis, adults who received RIC had significantly fewer days alive and out of the hospital if they received CB grafts than if they received 8/8 MUD PB (P<0.001) or 7/8 MUD PB (P<0.001).

No other factors were associated with the number of days these patients were alive and out of the hospital.

These results, when taken together, suggest that CB grafts are associated with longer hospital stays, independent of other factors.

“The majority of cost appears to be driven by the number of days in the hospital,” Dr Ballen noted. “So these data may be important for resource allocation, especially given the recent changes in the US healthcare system.”

*Information in the abstract differs from that presented at the meeting.

GRAPEVINE, TEXAS—Acute leukemia patients who undergo cord blood (CB) transplant have longer hospital stays than patients who receive other types of transplant, new research indicates.

The study also suggests the length of stay (LOS) is similar whether patients receive double or single CB grafts.

So it seems strategies are needed to decrease hospital stay after CB transplant, particularly as LOS drives the cost of care, said Karen K. Ballen, MD, of Massachusetts General Hospital in Boston.

Dr Ballen presented this research at the 2014 BMT Tandem Meetings as abstract 104.*

She and her colleagues studied patients diagnosed with acute leukemias who were transplanted at US centers and reported to the CIBMTR between 2008 and 2011.

Patients were eligible if they received an unrelated single or double CB transplant, an 8/8 matched unrelated donor (MUD) transplant with peripheral blood (PB) or bone marrow (BM), or a 7/8 MUD PB or BM graft.

In all, 1796 patients met these criteria. The researchers evaluated patients’ total hospital LOS in the first 100 days after transplant, compared LOS among graft sources, and looked for predictors of LOS in the first 100 days.

The team stratified patients according to age and conditioning regimen. Pediatric patients were classified as those aged 18 and younger, and they only received myeloablative conditioning (MAC). Adults received either MAC or reduced-intensity conditioning (RIC).

Pediatric patients

In a univariate analysis of the 368 pediatric patients, there was no significant difference in 100-day survival according to graft source (P=0.13).

However, patients who received single or double CB grafts had a significantly higher median total LOS by day 100 than patients who received 8/8 MUD BM, which was the only other graft source in this patient group (P=0.03).

Patients who received CB grafts also had significantly fewer days in which they were alive and not in the hospital (P=0.005).

“We wanted to account for patients whose length of stay was short because they actually died early after transplant,” Dr Ballen explained. “Therefore, we did an analysis of days alive and not in the hospital.”

In a multivariate analysis, pediatric patients who received CB grafts had significantly fewer days alive and out of the hospital than those who received 8/8 MUD BM (P=0.03).

Other factors associated with fewer days alive and out of the hospital were CMV positivity (P=0.01), black race (P=0.01), and a Karnofsky performance score of less than 80 (P=0.03).

Adults on MAC

In a univariate analysis of the 768 adults who received MAC, recipients of CB grafts had significantly worse 100-day survival than their peers (P<0.001), as well as a longer median LOS by day 100 (P<0.001) and fewer days alive and not in the hospital (P<0.001).

In a multivariate analysis, adults who received MAC had significantly fewer days alive and out of the hospital if they received CB grafts than if they received 8/8 MUD BM (P<0.001), 8/8 MUD PB (P<0.001), or 7/8 MUD PB (P=0.01), but not 7/8 MUD BM (P=0.49).

Other factors associated with fewer days alive and out of the hospital were black race (P=0.04), having acute lymphocytic leukemia rather than acute myeloid leukemia (P=0.01), and age 18-25 (P=0.01).

“We were a little surprised at these results—that the older patients actually spent more time alive and out of the hospital,” Dr Ballen said.

Adults on RIC

In a univariate analysis of the 660 adults who received RIC, recipients of CB grafts had significantly worse 100-day survival than their peers (P=0.017), as well as a longer median LOS by day 100 (P<0.001) and fewer days alive and not in the hospital (P<0.001).

In a multivariate analysis, adults who received RIC had significantly fewer days alive and out of the hospital if they received CB grafts than if they received 8/8 MUD PB (P<0.001) or 7/8 MUD PB (P<0.001).

No other factors were associated with the number of days these patients were alive and out of the hospital.

These results, when taken together, suggest that CB grafts are associated with longer hospital stays, independent of other factors.

“The majority of cost appears to be driven by the number of days in the hospital,” Dr Ballen noted. “So these data may be important for resource allocation, especially given the recent changes in the US healthcare system.”

*Information in the abstract differs from that presented at the meeting.

GRAPEVINE, TEXAS—Acute leukemia patients who undergo cord blood (CB) transplant have longer hospital stays than patients who receive other types of transplant, new research indicates.

The study also suggests the length of stay (LOS) is similar whether patients receive double or single CB grafts.

So it seems strategies are needed to decrease hospital stay after CB transplant, particularly as LOS drives the cost of care, said Karen K. Ballen, MD, of Massachusetts General Hospital in Boston.

Dr Ballen presented this research at the 2014 BMT Tandem Meetings as abstract 104.*

She and her colleagues studied patients diagnosed with acute leukemias who were transplanted at US centers and reported to the CIBMTR between 2008 and 2011.

Patients were eligible if they received an unrelated single or double CB transplant, an 8/8 matched unrelated donor (MUD) transplant with peripheral blood (PB) or bone marrow (BM), or a 7/8 MUD PB or BM graft.

In all, 1796 patients met these criteria. The researchers evaluated patients’ total hospital LOS in the first 100 days after transplant, compared LOS among graft sources, and looked for predictors of LOS in the first 100 days.

The team stratified patients according to age and conditioning regimen. Pediatric patients were classified as those aged 18 and younger, and they only received myeloablative conditioning (MAC). Adults received either MAC or reduced-intensity conditioning (RIC).

Pediatric patients

In a univariate analysis of the 368 pediatric patients, there was no significant difference in 100-day survival according to graft source (P=0.13).

However, patients who received single or double CB grafts had a significantly higher median total LOS by day 100 than patients who received 8/8 MUD BM, which was the only other graft source in this patient group (P=0.03).

Patients who received CB grafts also had significantly fewer days in which they were alive and not in the hospital (P=0.005).

“We wanted to account for patients whose length of stay was short because they actually died early after transplant,” Dr Ballen explained. “Therefore, we did an analysis of days alive and not in the hospital.”

In a multivariate analysis, pediatric patients who received CB grafts had significantly fewer days alive and out of the hospital than those who received 8/8 MUD BM (P=0.03).

Other factors associated with fewer days alive and out of the hospital were CMV positivity (P=0.01), black race (P=0.01), and a Karnofsky performance score of less than 80 (P=0.03).

Adults on MAC

In a univariate analysis of the 768 adults who received MAC, recipients of CB grafts had significantly worse 100-day survival than their peers (P<0.001), as well as a longer median LOS by day 100 (P<0.001) and fewer days alive and not in the hospital (P<0.001).

In a multivariate analysis, adults who received MAC had significantly fewer days alive and out of the hospital if they received CB grafts than if they received 8/8 MUD BM (P<0.001), 8/8 MUD PB (P<0.001), or 7/8 MUD PB (P=0.01), but not 7/8 MUD BM (P=0.49).

Other factors associated with fewer days alive and out of the hospital were black race (P=0.04), having acute lymphocytic leukemia rather than acute myeloid leukemia (P=0.01), and age 18-25 (P=0.01).

“We were a little surprised at these results—that the older patients actually spent more time alive and out of the hospital,” Dr Ballen said.

Adults on RIC

In a univariate analysis of the 660 adults who received RIC, recipients of CB grafts had significantly worse 100-day survival than their peers (P=0.017), as well as a longer median LOS by day 100 (P<0.001) and fewer days alive and not in the hospital (P<0.001).

In a multivariate analysis, adults who received RIC had significantly fewer days alive and out of the hospital if they received CB grafts than if they received 8/8 MUD PB (P<0.001) or 7/8 MUD PB (P<0.001).

No other factors were associated with the number of days these patients were alive and out of the hospital.

These results, when taken together, suggest that CB grafts are associated with longer hospital stays, independent of other factors.

“The majority of cost appears to be driven by the number of days in the hospital,” Dr Ballen noted. “So these data may be important for resource allocation, especially given the recent changes in the US healthcare system.”

*Information in the abstract differs from that presented at the meeting.

Patient consulting pharmacist

Credit: Rhoda Baer

Cancer patients in England are more likely to receive prescriptions for expensive drugs than patients in Wales, according to a study published in the British Journal of Cancer.

The research suggests this disparity is associated with the Cancer Drugs Fund (CDF), money set aside by the English government to pay for drugs that haven’t been approved by the National Institute for Health and Care Excellence (NICE) and aren’t available within the National Health Service (NHS).

The governments of Wales, Scotland, and Northern Ireland do not have access to the CDF or have similar programs of their own.

“There’s been much debate surrounding the Cancer Drugs Fund,” said study author Charlotte Chamberlain, MBBS, of the University of Bristol in the UK.

“The vast majority of Cancer Drugs Fund drugs do not cure the cancer but may extend life or improve symptoms in some people. The high cost of these drugs means that the NHS cannot afford other treatments, and, therefore, critics argue that public money is being spent inefficiently.”

To assess the impact of the CDF, Dr Chamberlain and her colleagues analyzed data from hospital pharmacies in England and Wales from August 2007 to December 2012. (The CDF was established in 2010, and the researchers wanted to capture data from before and after its introduction.)

The team evaluated 15 drugs that represent different categories of NICE approval—recommended, not recommended, and not yet appraised.

The results showed that, after the CDF was established, drugs recommended by NICE were not prescribed any more in England than in Wales.

However, drugs that were rejected by NICE because they were not cost-effective were prescribed up to 7 times more often in England than in Wales. For example, in the year before the CDF was introduced, prescription rates of imatinib (which is not recommended by NICE) were substantially higher in England than in Wales.

Immediately before the introduction of the CDF, following the first NICE rejection, imatinib prescribing declined in both countries. But it declined more slowly in England than in Wales, despite 2 additional NICE rejections. Regression analysis showed evidence of an association between the CDF and increased prescribing in England compared to Wales (P<0.001).

The research also revealed surprising information regarding the 3 most recently launched drugs—bendamustine, pazopanib, and abiraterone, which were awaiting NICE appraisal when the CDF was established but have since been approved.

These drugs were prescribed less often in England than in Wales. For instance, prescription rates of bendamustine were 25% lower in England.

This finding suggests that physicians in England have been slower to adopt newer drugs that are cost-effective, the researchers said.

“Our research has highlighted that the CDF has created an inequality between cancer sufferers in England and those in Wales,” Dr Chamberlain noted. “This raises ethical, moral, financial, and policy concerns.”

Patient consulting pharmacist

Credit: Rhoda Baer

Cancer patients in England are more likely to receive prescriptions for expensive drugs than patients in Wales, according to a study published in the British Journal of Cancer.

The research suggests this disparity is associated with the Cancer Drugs Fund (CDF), money set aside by the English government to pay for drugs that haven’t been approved by the National Institute for Health and Care Excellence (NICE) and aren’t available within the National Health Service (NHS).

The governments of Wales, Scotland, and Northern Ireland do not have access to the CDF or have similar programs of their own.

“There’s been much debate surrounding the Cancer Drugs Fund,” said study author Charlotte Chamberlain, MBBS, of the University of Bristol in the UK.

“The vast majority of Cancer Drugs Fund drugs do not cure the cancer but may extend life or improve symptoms in some people. The high cost of these drugs means that the NHS cannot afford other treatments, and, therefore, critics argue that public money is being spent inefficiently.”

To assess the impact of the CDF, Dr Chamberlain and her colleagues analyzed data from hospital pharmacies in England and Wales from August 2007 to December 2012. (The CDF was established in 2010, and the researchers wanted to capture data from before and after its introduction.)

The team evaluated 15 drugs that represent different categories of NICE approval—recommended, not recommended, and not yet appraised.

The results showed that, after the CDF was established, drugs recommended by NICE were not prescribed any more in England than in Wales.

However, drugs that were rejected by NICE because they were not cost-effective were prescribed up to 7 times more often in England than in Wales. For example, in the year before the CDF was introduced, prescription rates of imatinib (which is not recommended by NICE) were substantially higher in England than in Wales.

Immediately before the introduction of the CDF, following the first NICE rejection, imatinib prescribing declined in both countries. But it declined more slowly in England than in Wales, despite 2 additional NICE rejections. Regression analysis showed evidence of an association between the CDF and increased prescribing in England compared to Wales (P<0.001).

The research also revealed surprising information regarding the 3 most recently launched drugs—bendamustine, pazopanib, and abiraterone, which were awaiting NICE appraisal when the CDF was established but have since been approved.

These drugs were prescribed less often in England than in Wales. For instance, prescription rates of bendamustine were 25% lower in England.

This finding suggests that physicians in England have been slower to adopt newer drugs that are cost-effective, the researchers said.

“Our research has highlighted that the CDF has created an inequality between cancer sufferers in England and those in Wales,” Dr Chamberlain noted. “This raises ethical, moral, financial, and policy concerns.”

Patient consulting pharmacist

Credit: Rhoda Baer

Cancer patients in England are more likely to receive prescriptions for expensive drugs than patients in Wales, according to a study published in the British Journal of Cancer.

The research suggests this disparity is associated with the Cancer Drugs Fund (CDF), money set aside by the English government to pay for drugs that haven’t been approved by the National Institute for Health and Care Excellence (NICE) and aren’t available within the National Health Service (NHS).

The governments of Wales, Scotland, and Northern Ireland do not have access to the CDF or have similar programs of their own.

“There’s been much debate surrounding the Cancer Drugs Fund,” said study author Charlotte Chamberlain, MBBS, of the University of Bristol in the UK.

“The vast majority of Cancer Drugs Fund drugs do not cure the cancer but may extend life or improve symptoms in some people. The high cost of these drugs means that the NHS cannot afford other treatments, and, therefore, critics argue that public money is being spent inefficiently.”

To assess the impact of the CDF, Dr Chamberlain and her colleagues analyzed data from hospital pharmacies in England and Wales from August 2007 to December 2012. (The CDF was established in 2010, and the researchers wanted to capture data from before and after its introduction.)

The team evaluated 15 drugs that represent different categories of NICE approval—recommended, not recommended, and not yet appraised.

The results showed that, after the CDF was established, drugs recommended by NICE were not prescribed any more in England than in Wales.

However, drugs that were rejected by NICE because they were not cost-effective were prescribed up to 7 times more often in England than in Wales. For example, in the year before the CDF was introduced, prescription rates of imatinib (which is not recommended by NICE) were substantially higher in England than in Wales.

Immediately before the introduction of the CDF, following the first NICE rejection, imatinib prescribing declined in both countries. But it declined more slowly in England than in Wales, despite 2 additional NICE rejections. Regression analysis showed evidence of an association between the CDF and increased prescribing in England compared to Wales (P<0.001).

The research also revealed surprising information regarding the 3 most recently launched drugs—bendamustine, pazopanib, and abiraterone, which were awaiting NICE appraisal when the CDF was established but have since been approved.

These drugs were prescribed less often in England than in Wales. For instance, prescription rates of bendamustine were 25% lower in England.

This finding suggests that physicians in England have been slower to adopt newer drugs that are cost-effective, the researchers said.

“Our research has highlighted that the CDF has created an inequality between cancer sufferers in England and those in Wales,” Dr Chamberlain noted. “This raises ethical, moral, financial, and policy concerns.”

GRAPEVINE, TEXAS—Results of a large, retrospective study suggest that allogeneic stem cell transplant (allo-SCT) can overcome the poor prognosis associated with central nervous system (CNS) involvement in acute myeloid leukemia (AML).

By analyzing transplant outcomes in more than 5000 patients, researchers found that subjects with CNS AML had rates of relapse and survival that were similar to those of patients without CNS involvement.

The team also identified factors that can predict for survival in CNS AML, including cytogenetic risk group, the presence of chronic GVHD, and whether a patient was in complete response at transplant.

Jun Aoki, MD, of Tokyo Metropolitan Komagome Hospital in Japan, presented these findings at the 2014 BMT Tandem Meetings as abstract 68.

Dr Aoki pointed out that CNS involvement is rare in adult AML, occurring in about 5% of patients. However, these patients generally have poor prognosis. And although allo-SCT is one of the options used to treat CNS AML, exactly how CNS involvement impacts transplant outcomes remains unclear.

So Dr Aoki and his colleagues conducted a nationwide, retrospective study to gain some insight.  They collected data from the registry database of the Japan Society for Hematopoietic Cell Transplantation.

Patients had to be older than 15 years of age, have their first allo-SCT between 2006 and 2011, and not have acute promyelocytic leukemia.

The researchers identified 5068 patients who met these criteria, and 157 of them had CNS AML. CNS involvement was defined as infiltration of leukemia cells into CNS or myeloid sarcoma in CNS that were identified at any time from diagnosis to transplant.

No difference in relapse, survival

There were no significant differences between CNS patients and controls with regard to the estimated overall survival (OS), leukemia-free survival, cumulative incidence of relapse, or non-relapse mortality at 5 years.

OS was 39.9% among controls and 38.5% among CNS patients (P=0.847). Leukemia-free survival was 41.2% and 41.5%, respectively (P=0.82).

The cumulative incidence of relapse was 29.8% among controls and 31.8% among CNS patients (P=0.418). And non-relapse mortality was 22.5% and 26.5%, respectively (P=0.142).

Factors predicting OS

To determine the impact of patient and treatment characteristics on OS, the researchers conducted a multivariate analysis. This confirmed that CNS involvement was not a risk factor for OS.

But it revealed a number of other factors that adversely affect OS, including age of 50 or older (P<0.001), lack of a complete response at allo-SCT (P<0.001), a donor source of unrelated cord blood (P=0.005), having a prognostic score of 2-4 (P<0.001), unfavorable cytogenetics (P<0.001), and the absence of acute or chronic GVHD (P<0.001 for both).

When the researchers analyzed only CNS patients, they discovered that not all of these factors retained significance. Only the absence of chronic GVHD (P=0.002), lack of complete response at transplant (P<0.001), and having either intermediate (P=0.003) or unfavorable cytogenetics (P=0.011) were adversely associated with OS in these patients.

GRAPEVINE, TEXAS—Results of a large, retrospective study suggest that allogeneic stem cell transplant (allo-SCT) can overcome the poor prognosis associated with central nervous system (CNS) involvement in acute myeloid leukemia (AML).

By analyzing transplant outcomes in more than 5000 patients, researchers found that subjects with CNS AML had rates of relapse and survival that were similar to those of patients without CNS involvement.

The team also identified factors that can predict for survival in CNS AML, including cytogenetic risk group, the presence of chronic GVHD, and whether a patient was in complete response at transplant.

Jun Aoki, MD, of Tokyo Metropolitan Komagome Hospital in Japan, presented these findings at the 2014 BMT Tandem Meetings as abstract 68.

Dr Aoki pointed out that CNS involvement is rare in adult AML, occurring in about 5% of patients. However, these patients generally have poor prognosis. And although allo-SCT is one of the options used to treat CNS AML, exactly how CNS involvement impacts transplant outcomes remains unclear.

So Dr Aoki and his colleagues conducted a nationwide, retrospective study to gain some insight.  They collected data from the registry database of the Japan Society for Hematopoietic Cell Transplantation.

Patients had to be older than 15 years of age, have their first allo-SCT between 2006 and 2011, and not have acute promyelocytic leukemia.

The researchers identified 5068 patients who met these criteria, and 157 of them had CNS AML. CNS involvement was defined as infiltration of leukemia cells into CNS or myeloid sarcoma in CNS that were identified at any time from diagnosis to transplant.

No difference in relapse, survival

There were no significant differences between CNS patients and controls with regard to the estimated overall survival (OS), leukemia-free survival, cumulative incidence of relapse, or non-relapse mortality at 5 years.

OS was 39.9% among controls and 38.5% among CNS patients (P=0.847). Leukemia-free survival was 41.2% and 41.5%, respectively (P=0.82).

The cumulative incidence of relapse was 29.8% among controls and 31.8% among CNS patients (P=0.418). And non-relapse mortality was 22.5% and 26.5%, respectively (P=0.142).

Factors predicting OS

To determine the impact of patient and treatment characteristics on OS, the researchers conducted a multivariate analysis. This confirmed that CNS involvement was not a risk factor for OS.

But it revealed a number of other factors that adversely affect OS, including age of 50 or older (P<0.001), lack of a complete response at allo-SCT (P<0.001), a donor source of unrelated cord blood (P=0.005), having a prognostic score of 2-4 (P<0.001), unfavorable cytogenetics (P<0.001), and the absence of acute or chronic GVHD (P<0.001 for both).

When the researchers analyzed only CNS patients, they discovered that not all of these factors retained significance. Only the absence of chronic GVHD (P=0.002), lack of complete response at transplant (P<0.001), and having either intermediate (P=0.003) or unfavorable cytogenetics (P=0.011) were adversely associated with OS in these patients.

GRAPEVINE, TEXAS—Results of a large, retrospective study suggest that allogeneic stem cell transplant (allo-SCT) can overcome the poor prognosis associated with central nervous system (CNS) involvement in acute myeloid leukemia (AML).

By analyzing transplant outcomes in more than 5000 patients, researchers found that subjects with CNS AML had rates of relapse and survival that were similar to those of patients without CNS involvement.

The team also identified factors that can predict for survival in CNS AML, including cytogenetic risk group, the presence of chronic GVHD, and whether a patient was in complete response at transplant.

Jun Aoki, MD, of Tokyo Metropolitan Komagome Hospital in Japan, presented these findings at the 2014 BMT Tandem Meetings as abstract 68.

Dr Aoki pointed out that CNS involvement is rare in adult AML, occurring in about 5% of patients. However, these patients generally have poor prognosis. And although allo-SCT is one of the options used to treat CNS AML, exactly how CNS involvement impacts transplant outcomes remains unclear.

So Dr Aoki and his colleagues conducted a nationwide, retrospective study to gain some insight.  They collected data from the registry database of the Japan Society for Hematopoietic Cell Transplantation.

Patients had to be older than 15 years of age, have their first allo-SCT between 2006 and 2011, and not have acute promyelocytic leukemia.

The researchers identified 5068 patients who met these criteria, and 157 of them had CNS AML. CNS involvement was defined as infiltration of leukemia cells into CNS or myeloid sarcoma in CNS that were identified at any time from diagnosis to transplant.

No difference in relapse, survival

There were no significant differences between CNS patients and controls with regard to the estimated overall survival (OS), leukemia-free survival, cumulative incidence of relapse, or non-relapse mortality at 5 years.

OS was 39.9% among controls and 38.5% among CNS patients (P=0.847). Leukemia-free survival was 41.2% and 41.5%, respectively (P=0.82).

The cumulative incidence of relapse was 29.8% among controls and 31.8% among CNS patients (P=0.418). And non-relapse mortality was 22.5% and 26.5%, respectively (P=0.142).

Factors predicting OS

To determine the impact of patient and treatment characteristics on OS, the researchers conducted a multivariate analysis. This confirmed that CNS involvement was not a risk factor for OS.

But it revealed a number of other factors that adversely affect OS, including age of 50 or older (P<0.001), lack of a complete response at allo-SCT (P<0.001), a donor source of unrelated cord blood (P=0.005), having a prognostic score of 2-4 (P<0.001), unfavorable cytogenetics (P<0.001), and the absence of acute or chronic GVHD (P<0.001 for both).

When the researchers analyzed only CNS patients, they discovered that not all of these factors retained significance. Only the absence of chronic GVHD (P=0.002), lack of complete response at transplant (P<0.001), and having either intermediate (P=0.003) or unfavorable cytogenetics (P=0.011) were adversely associated with OS in these patients.

Patient receiving chemotherapy

Credit: Rhoda Baer

Palliative chemotherapy can negatively impact the end of life for terminally ill cancer patients, according to a paper published in BMJ.

Investigators found that patients who received palliative chemotherapy in their last months of life had an increased risk of requiring intensive medical care, such as resuscitation, and dying in a place they did not choose, such as an intensive care unit.

The researchers therefore suggested that end-of-life discussions may be particularly important for patients who want to receive palliative chemotherapy.

“The results highlight the need for more effective communication by doctors of terminal prognoses and the likely outcomes of chemotherapy for these patients,” said study author Holly Prigerson, PhD, of Weill Cornell Medical College in New York.

“For patients to make informed choices about their care, they need to know if they are incurable and understand what their life expectancy is, that palliative chemotherapy is not intended to cure them, that it may not appreciably prolong their life, and that it may result in the receipt of very aggressive, life-prolonging care at the expense of their quality of life.”

Data have suggested that between 20% and 50% of patients with incurable cancers undergo palliative chemotherapy within 30 days of death. But it has not been clear whether the use of chemotherapy in a patient’s last months is associated with the need for intensive medical care in the last week of life or with the patient’s death.

So Dr Prigerson and her colleagues decided to study the use of palliative chemotherapy in patients with 6 or fewer months to live. The researchers used data from “Coping with Cancer,” a 6-year study of 386 terminally ill patients.

The patients were interviewed around the time of their decision regarding palliative chemotherapy. In the month after each patient died, caregivers were asked to rate their loved ones’ care, quality of life, and place of death as being where the patient would have wanted to die. The investigators then reviewed patients’ medical charts to determine the type of care they actually received in their last week.

Effects of palliative chemo

In all, 56% of patients opted to receive palliative chemotherapy. They were more likely to be younger, married, and better educated than patients not on the treatment.

Patients on chemotherapy also had better performance status, overall quality of life, physical functioning, and psychological well-being at study enrollment.

However, patients who received palliative chemotherapy had a greater risk of requiring cardiopulmonary resuscitation and/or mechanical ventilation (14% vs 2%), and they were more likely to need a feeding tube (11% vs 5%) in their last weeks of life.

Patients on chemotherapy had a greater risk of being admitted to an intensive care unit (14% vs 8%) and of having a late hospice referral (54% vs 37%).

They were also less likely to die where they wanted to (65% vs 80%). They had a greater risk of dying in an intensive care unit (11% vs 2%) and were less likely than their peers to die at home (47% vs 66%).

“It’s hard to see in these data much of a silver lining to palliative chemotherapy for patients in the terminal stage of their cancer,” Dr Prigerson said. “Until now, there hasn’t been evidence of harmful effects of palliative chemotherapy in the last few months of life.”

“This study is a first step in providing evidence that specifically demonstrates what negative outcomes may result. Additional studies are needed to confirm these troubling findings.”

Explaining the negative effects

Dr Prigerson said the harmful effects of palliative chemotherapy may be a result of misunderstanding, a lack of communication, and denial. Patients may not comprehend the purpose and likely consequences of palliative chemotherapy, and they may not fully acknowledge their own prognoses.

In the study, patients receiving palliative chemotherapy were less likely than their peers to talk to their oncologists about end-of-life care (37% vs 48%), to complete Do-Not-Resuscitate orders (36% vs 49%), or to acknowledge that they were terminally ill (35% vs 47%).

“Our finding that patients with terminal cancers were at higher risk of receiving intensive end-of-life care if they were treated with palliative chemotherapy months earlier underscores the importance of oncologists asking patients about their end-of-life wishes,” said Alexi Wright, MD, of the Dana-Farber Cancer Institute in Boston.

“We often wait until patients stop chemotherapy before asking them about where and how they want to die, but this study shows we need to ask patients about their preferences while they are receiving chemotherapy to ensure they receive the kind of care they want near death.”

Moving forward

The investigators stressed that the study results do not suggest patients should be denied palliative chemotherapy.

“The vast majority of patients in this study wanted palliative chemotherapy if it might increase their survival by as little as a week,” Dr Wright said. “This study is a step towards understanding some of the human costs and benefits of palliative chemotherapy.”

The researchers said additional studies should examine whether patients who are aware that chemotherapy is not intended to cure them still want to receive the treatment, confirm the negative outcomes of palliative chemotherapy, and determine if end-of-life discussions promote more informed decision-making and receipt of value-consistent care.

In a related editorial, Mike Rabow, MD, of the University of California, San Francisco, noted that although most patients with metastatic cancer choose to receive chemotherapy, evidence suggests most do not understand its intent.

He said Dr Prigerson’s study suggests the need to “better identify patients who are likely to benefit from chemotherapy near the end of life.” And he encouraged oncologists to discuss with patients the broader implications of chemotherapy when making decisions about treatment.

Patient receiving chemotherapy

Credit: Rhoda Baer

Palliative chemotherapy can negatively impact the end of life for terminally ill cancer patients, according to a paper published in BMJ.

Investigators found that patients who received palliative chemotherapy in their last months of life had an increased risk of requiring intensive medical care, such as resuscitation, and dying in a place they did not choose, such as an intensive care unit.

The researchers therefore suggested that end-of-life discussions may be particularly important for patients who want to receive palliative chemotherapy.

“The results highlight the need for more effective communication by doctors of terminal prognoses and the likely outcomes of chemotherapy for these patients,” said study author Holly Prigerson, PhD, of Weill Cornell Medical College in New York.

“For patients to make informed choices about their care, they need to know if they are incurable and understand what their life expectancy is, that palliative chemotherapy is not intended to cure them, that it may not appreciably prolong their life, and that it may result in the receipt of very aggressive, life-prolonging care at the expense of their quality of life.”

Data have suggested that between 20% and 50% of patients with incurable cancers undergo palliative chemotherapy within 30 days of death. But it has not been clear whether the use of chemotherapy in a patient’s last months is associated with the need for intensive medical care in the last week of life or with the patient’s death.

So Dr Prigerson and her colleagues decided to study the use of palliative chemotherapy in patients with 6 or fewer months to live. The researchers used data from “Coping with Cancer,” a 6-year study of 386 terminally ill patients.

The patients were interviewed around the time of their decision regarding palliative chemotherapy. In the month after each patient died, caregivers were asked to rate their loved ones’ care, quality of life, and place of death as being where the patient would have wanted to die. The investigators then reviewed patients’ medical charts to determine the type of care they actually received in their last week.

Effects of palliative chemo

In all, 56% of patients opted to receive palliative chemotherapy. They were more likely to be younger, married, and better educated than patients not on the treatment.

Patients on chemotherapy also had better performance status, overall quality of life, physical functioning, and psychological well-being at study enrollment.

However, patients who received palliative chemotherapy had a greater risk of requiring cardiopulmonary resuscitation and/or mechanical ventilation (14% vs 2%), and they were more likely to need a feeding tube (11% vs 5%) in their last weeks of life.

Patients on chemotherapy had a greater risk of being admitted to an intensive care unit (14% vs 8%) and of having a late hospice referral (54% vs 37%).

They were also less likely to die where they wanted to (65% vs 80%). They had a greater risk of dying in an intensive care unit (11% vs 2%) and were less likely than their peers to die at home (47% vs 66%).

“It’s hard to see in these data much of a silver lining to palliative chemotherapy for patients in the terminal stage of their cancer,” Dr Prigerson said. “Until now, there hasn’t been evidence of harmful effects of palliative chemotherapy in the last few months of life.”

“This study is a first step in providing evidence that specifically demonstrates what negative outcomes may result. Additional studies are needed to confirm these troubling findings.”

Explaining the negative effects

Dr Prigerson said the harmful effects of palliative chemotherapy may be a result of misunderstanding, a lack of communication, and denial. Patients may not comprehend the purpose and likely consequences of palliative chemotherapy, and they may not fully acknowledge their own prognoses.

In the study, patients receiving palliative chemotherapy were less likely than their peers to talk to their oncologists about end-of-life care (37% vs 48%), to complete Do-Not-Resuscitate orders (36% vs 49%), or to acknowledge that they were terminally ill (35% vs 47%).

“Our finding that patients with terminal cancers were at higher risk of receiving intensive end-of-life care if they were treated with palliative chemotherapy months earlier underscores the importance of oncologists asking patients about their end-of-life wishes,” said Alexi Wright, MD, of the Dana-Farber Cancer Institute in Boston.

“We often wait until patients stop chemotherapy before asking them about where and how they want to die, but this study shows we need to ask patients about their preferences while they are receiving chemotherapy to ensure they receive the kind of care they want near death.”

Moving forward

The investigators stressed that the study results do not suggest patients should be denied palliative chemotherapy.

“The vast majority of patients in this study wanted palliative chemotherapy if it might increase their survival by as little as a week,” Dr Wright said. “This study is a step towards understanding some of the human costs and benefits of palliative chemotherapy.”

The researchers said additional studies should examine whether patients who are aware that chemotherapy is not intended to cure them still want to receive the treatment, confirm the negative outcomes of palliative chemotherapy, and determine if end-of-life discussions promote more informed decision-making and receipt of value-consistent care.

In a related editorial, Mike Rabow, MD, of the University of California, San Francisco, noted that although most patients with metastatic cancer choose to receive chemotherapy, evidence suggests most do not understand its intent.

He said Dr Prigerson’s study suggests the need to “better identify patients who are likely to benefit from chemotherapy near the end of life.” And he encouraged oncologists to discuss with patients the broader implications of chemotherapy when making decisions about treatment.

Patient receiving chemotherapy

Credit: Rhoda Baer

Palliative chemotherapy can negatively impact the end of life for terminally ill cancer patients, according to a paper published in BMJ.

Investigators found that patients who received palliative chemotherapy in their last months of life had an increased risk of requiring intensive medical care, such as resuscitation, and dying in a place they did not choose, such as an intensive care unit.

The researchers therefore suggested that end-of-life discussions may be particularly important for patients who want to receive palliative chemotherapy.

“The results highlight the need for more effective communication by doctors of terminal prognoses and the likely outcomes of chemotherapy for these patients,” said study author Holly Prigerson, PhD, of Weill Cornell Medical College in New York.

“For patients to make informed choices about their care, they need to know if they are incurable and understand what their life expectancy is, that palliative chemotherapy is not intended to cure them, that it may not appreciably prolong their life, and that it may result in the receipt of very aggressive, life-prolonging care at the expense of their quality of life.”

Data have suggested that between 20% and 50% of patients with incurable cancers undergo palliative chemotherapy within 30 days of death. But it has not been clear whether the use of chemotherapy in a patient’s last months is associated with the need for intensive medical care in the last week of life or with the patient’s death.

So Dr Prigerson and her colleagues decided to study the use of palliative chemotherapy in patients with 6 or fewer months to live. The researchers used data from “Coping with Cancer,” a 6-year study of 386 terminally ill patients.

The patients were interviewed around the time of their decision regarding palliative chemotherapy. In the month after each patient died, caregivers were asked to rate their loved ones’ care, quality of life, and place of death as being where the patient would have wanted to die. The investigators then reviewed patients’ medical charts to determine the type of care they actually received in their last week.

Effects of palliative chemo

In all, 56% of patients opted to receive palliative chemotherapy. They were more likely to be younger, married, and better educated than patients not on the treatment.

Patients on chemotherapy also had better performance status, overall quality of life, physical functioning, and psychological well-being at study enrollment.

However, patients who received palliative chemotherapy had a greater risk of requiring cardiopulmonary resuscitation and/or mechanical ventilation (14% vs 2%), and they were more likely to need a feeding tube (11% vs 5%) in their last weeks of life.

Patients on chemotherapy had a greater risk of being admitted to an intensive care unit (14% vs 8%) and of having a late hospice referral (54% vs 37%).

They were also less likely to die where they wanted to (65% vs 80%). They had a greater risk of dying in an intensive care unit (11% vs 2%) and were less likely than their peers to die at home (47% vs 66%).

“It’s hard to see in these data much of a silver lining to palliative chemotherapy for patients in the terminal stage of their cancer,” Dr Prigerson said. “Until now, there hasn’t been evidence of harmful effects of palliative chemotherapy in the last few months of life.”

“This study is a first step in providing evidence that specifically demonstrates what negative outcomes may result. Additional studies are needed to confirm these troubling findings.”

Explaining the negative effects

Dr Prigerson said the harmful effects of palliative chemotherapy may be a result of misunderstanding, a lack of communication, and denial. Patients may not comprehend the purpose and likely consequences of palliative chemotherapy, and they may not fully acknowledge their own prognoses.

In the study, patients receiving palliative chemotherapy were less likely than their peers to talk to their oncologists about end-of-life care (37% vs 48%), to complete Do-Not-Resuscitate orders (36% vs 49%), or to acknowledge that they were terminally ill (35% vs 47%).

“Our finding that patients with terminal cancers were at higher risk of receiving intensive end-of-life care if they were treated with palliative chemotherapy months earlier underscores the importance of oncologists asking patients about their end-of-life wishes,” said Alexi Wright, MD, of the Dana-Farber Cancer Institute in Boston.

“We often wait until patients stop chemotherapy before asking them about where and how they want to die, but this study shows we need to ask patients about their preferences while they are receiving chemotherapy to ensure they receive the kind of care they want near death.”

Moving forward

The investigators stressed that the study results do not suggest patients should be denied palliative chemotherapy.

“The vast majority of patients in this study wanted palliative chemotherapy if it might increase their survival by as little as a week,” Dr Wright said. “This study is a step towards understanding some of the human costs and benefits of palliative chemotherapy.”

The researchers said additional studies should examine whether patients who are aware that chemotherapy is not intended to cure them still want to receive the treatment, confirm the negative outcomes of palliative chemotherapy, and determine if end-of-life discussions promote more informed decision-making and receipt of value-consistent care.

In a related editorial, Mike Rabow, MD, of the University of California, San Francisco, noted that although most patients with metastatic cancer choose to receive chemotherapy, evidence suggests most do not understand its intent.

He said Dr Prigerson’s study suggests the need to “better identify patients who are likely to benefit from chemotherapy near the end of life.” And he encouraged oncologists to discuss with patients the broader implications of chemotherapy when making decisions about treatment.

Pill production

Credit: FDA

The US Food and Drug Administration (FDA) has granted orphan designation for the histone deacetylase (HDAC) inhibitor pracinostat to treat acute myeloid leukemia (AML) and the proteasome inhibitor marizomib to treat multiple myeloma (MM).

Orphan designation is available for drugs that treat or prevent rare diseases affecting fewer than 200,000 people in the US.

The designation qualifies the sponsor of a drug for development incentives, including tax credits for qualified clinical testing, prescription drug user fee exemptions, and 7-year marketing exclusivity upon FDA approval.

About pracinostat

The oral HDAC inhibitor pracinostat has been tested in phase 1 and 2 trials of adult and pediatric patients with advanced hematologic disorders and solid tumors.

The drug has been generally well tolerated in more than 200 patients to date, according to the drug’s maker, MEI Pharma.

In a dose-escalation phase 1 trial, pracinostat demonstrated single-agent activity in elderly AML patients. Two of 14 patients (14%) achieved a complete remission, with responses persisting more than 206 days and 362 days.

Researchers are currently conducting a phase 2 trial of pracinostat in combination with azacitidine in elderly patients with newly diagnosed AML. Preliminary data from this trial are expected to be available by December 2014.

About marizomib

The proteasome inhibitor marizomib is under development for the treatment of MM and other malignancies.

Intravenous marizomib has been evaluated in more than 230 patients across 4 phase 1/2 studies, as a single agent or in combination with dexamethasone or an HDAC inhibitor.

Researchers are currently evaluating marizomib in combination with dexamethasone in an ongoing phase 2 trial of highly refractory MM patients, including those who are refractory to carfilzomib.

Marizomib is also being tested in combination with pomalidomide and dexamethasone in a phase 1/2 study of patients with relapsed and refractory MM.

The drug’s maker, Triphase Accelerator Corporation, is currently developing an oral formulation of marizomib.

Pill production

Credit: FDA

The US Food and Drug Administration (FDA) has granted orphan designation for the histone deacetylase (HDAC) inhibitor pracinostat to treat acute myeloid leukemia (AML) and the proteasome inhibitor marizomib to treat multiple myeloma (MM).

Orphan designation is available for drugs that treat or prevent rare diseases affecting fewer than 200,000 people in the US.

The designation qualifies the sponsor of a drug for development incentives, including tax credits for qualified clinical testing, prescription drug user fee exemptions, and 7-year marketing exclusivity upon FDA approval.

About pracinostat

The oral HDAC inhibitor pracinostat has been tested in phase 1 and 2 trials of adult and pediatric patients with advanced hematologic disorders and solid tumors.

The drug has been generally well tolerated in more than 200 patients to date, according to the drug’s maker, MEI Pharma.

In a dose-escalation phase 1 trial, pracinostat demonstrated single-agent activity in elderly AML patients. Two of 14 patients (14%) achieved a complete remission, with responses persisting more than 206 days and 362 days.

Researchers are currently conducting a phase 2 trial of pracinostat in combination with azacitidine in elderly patients with newly diagnosed AML. Preliminary data from this trial are expected to be available by December 2014.

About marizomib

The proteasome inhibitor marizomib is under development for the treatment of MM and other malignancies.

Intravenous marizomib has been evaluated in more than 230 patients across 4 phase 1/2 studies, as a single agent or in combination with dexamethasone or an HDAC inhibitor.

Researchers are currently evaluating marizomib in combination with dexamethasone in an ongoing phase 2 trial of highly refractory MM patients, including those who are refractory to carfilzomib.

Marizomib is also being tested in combination with pomalidomide and dexamethasone in a phase 1/2 study of patients with relapsed and refractory MM.

The drug’s maker, Triphase Accelerator Corporation, is currently developing an oral formulation of marizomib.

Pill production

Credit: FDA

The US Food and Drug Administration (FDA) has granted orphan designation for the histone deacetylase (HDAC) inhibitor pracinostat to treat acute myeloid leukemia (AML) and the proteasome inhibitor marizomib to treat multiple myeloma (MM).

Orphan designation is available for drugs that treat or prevent rare diseases affecting fewer than 200,000 people in the US.

The designation qualifies the sponsor of a drug for development incentives, including tax credits for qualified clinical testing, prescription drug user fee exemptions, and 7-year marketing exclusivity upon FDA approval.

About pracinostat

The oral HDAC inhibitor pracinostat has been tested in phase 1 and 2 trials of adult and pediatric patients with advanced hematologic disorders and solid tumors.

The drug has been generally well tolerated in more than 200 patients to date, according to the drug’s maker, MEI Pharma.

In a dose-escalation phase 1 trial, pracinostat demonstrated single-agent activity in elderly AML patients. Two of 14 patients (14%) achieved a complete remission, with responses persisting more than 206 days and 362 days.

Researchers are currently conducting a phase 2 trial of pracinostat in combination with azacitidine in elderly patients with newly diagnosed AML. Preliminary data from this trial are expected to be available by December 2014.

About marizomib

The proteasome inhibitor marizomib is under development for the treatment of MM and other malignancies.

Intravenous marizomib has been evaluated in more than 230 patients across 4 phase 1/2 studies, as a single agent or in combination with dexamethasone or an HDAC inhibitor.

Researchers are currently evaluating marizomib in combination with dexamethasone in an ongoing phase 2 trial of highly refractory MM patients, including those who are refractory to carfilzomib.

Marizomib is also being tested in combination with pomalidomide and dexamethasone in a phase 1/2 study of patients with relapsed and refractory MM.

The drug’s maker, Triphase Accelerator Corporation, is currently developing an oral formulation of marizomib.

ALL in the bone marrow

Inhibiting two biosynthesis pathways can override treatment resistance in acute lymphoblastic leukemia (ALL), preclinical research suggests.

Researchers found that inhibiting only one pathway did not effectively kill ALL cells. The cells simply used another pathway to replicate their DNA and continue dividing.

But inhibiting both pathways induced apoptosis in human leukemia cells and reduced tumor burden in mouse models of T- and B-cell ALL.

“This new, dual-targeting approach shows that we can overcome the redundancy in DNA synthesis in ALL cells and identifies a potential target for metabolic intervention in ALL, and possibly in other hematological cancers,” said study author Caius Radu, MD, of the University of California, Los Angeles.

He and his colleagues described this approach in The Journal of Experimental Medicine.

The research began with the knowledge that deoxyribonucleotide triphosphates, including deoxycytidine triphosphate (dCTP), are required for DNA replication, which is necessary for cell division. And dCTP can be produced by the de novo pathway or the nucleoside salvage pathway.

Dr Radu and his colleagues discovered that inhibiting the de novo pathway with the compound thymidine caused leukemia cells to switch to the nucleoside salvage pathway for dCTP production.

However, inhibiting both the de novo and nucleoside salvage pathways prevented dCTP production and proved lethal for leukemia cells.

A number of experiments elicited these results. In one, the researchers knocked down the deoxycytidine kinase (dCK) in human T-ALL cells to inhibit the nucleoside salvage pathway. Then, they administered thymidine to inhibit the de novo pathway. This resulted in dCTP depletion, stalled DNA replication, replication stress, DNA damage, and apoptosis.

The researchers also used the small-molecule inhibitor DI-39 to target dCK. They found that co-administration of DI-39 and thymidine induced replication stress and apoptosis in several leukemia cell lines: CEM, Jurkat, MOLT-4, NALM-6 and RS4;116.

The team then tested DI-39 and thymidine in mice bearing CEM tumors. They found the combination reduced tumor growth in mice bearing established, subcutaneous CEM xenografts and in mice with systemic T-ALL.

In the systemic T-ALL model, treatment with thymidine alone resulted in a 7-fold reduction in tumor burden compared to vehicle control or DI-39 alone. But when thymidine and DI-39 were administered together, mice saw a 100-fold reduction in tumor burden compared to thymidine alone.

The thymidine-DI-39 combination also proved effective against B-ALL cells and in a mouse model of B-ALL. However, the effects were not as great as those observed in T-ALL.

Finally, the researchers evaluated the effects of thymidine and DI-39 in hematopoietic progenitor cells. They looked at the Lineage^- Sca-1⁺ c-Kit⁺ hematopoietic stem cell population, as well as short-term, long-term, and multipotent progenitor hematopoietic progenitor cells.

There was a minor decrease in the percentage of Lineage^- Sca-1⁺ c-Kit⁺ cells after thymidine treatment. However, there were no other significant changes in progenitor cells between the treatment and control groups. Why leukemic cells and normal hematopoietic progenitors respond so differently to this treatment requires further investigation, the researchers said.

But they also noted that this study advances our understanding of DNA synthesis in leukemic cells and suggests that targeted metabolic intervention could be a new therapeutic approach in ALL.

ALL in the bone marrow

Inhibiting two biosynthesis pathways can override treatment resistance in acute lymphoblastic leukemia (ALL), preclinical research suggests.

Researchers found that inhibiting only one pathway did not effectively kill ALL cells. The cells simply used another pathway to replicate their DNA and continue dividing.

But inhibiting both pathways induced apoptosis in human leukemia cells and reduced tumor burden in mouse models of T- and B-cell ALL.

“This new, dual-targeting approach shows that we can overcome the redundancy in DNA synthesis in ALL cells and identifies a potential target for metabolic intervention in ALL, and possibly in other hematological cancers,” said study author Caius Radu, MD, of the University of California, Los Angeles.

He and his colleagues described this approach in The Journal of Experimental Medicine.

The research began with the knowledge that deoxyribonucleotide triphosphates, including deoxycytidine triphosphate (dCTP), are required for DNA replication, which is necessary for cell division. And dCTP can be produced by the de novo pathway or the nucleoside salvage pathway.

Dr Radu and his colleagues discovered that inhibiting the de novo pathway with the compound thymidine caused leukemia cells to switch to the nucleoside salvage pathway for dCTP production.

However, inhibiting both the de novo and nucleoside salvage pathways prevented dCTP production and proved lethal for leukemia cells.

A number of experiments elicited these results. In one, the researchers knocked down the deoxycytidine kinase (dCK) in human T-ALL cells to inhibit the nucleoside salvage pathway. Then, they administered thymidine to inhibit the de novo pathway. This resulted in dCTP depletion, stalled DNA replication, replication stress, DNA damage, and apoptosis.

The researchers also used the small-molecule inhibitor DI-39 to target dCK. They found that co-administration of DI-39 and thymidine induced replication stress and apoptosis in several leukemia cell lines: CEM, Jurkat, MOLT-4, NALM-6 and RS4;116.

The team then tested DI-39 and thymidine in mice bearing CEM tumors. They found the combination reduced tumor growth in mice bearing established, subcutaneous CEM xenografts and in mice with systemic T-ALL.

In the systemic T-ALL model, treatment with thymidine alone resulted in a 7-fold reduction in tumor burden compared to vehicle control or DI-39 alone. But when thymidine and DI-39 were administered together, mice saw a 100-fold reduction in tumor burden compared to thymidine alone.

The thymidine-DI-39 combination also proved effective against B-ALL cells and in a mouse model of B-ALL. However, the effects were not as great as those observed in T-ALL.

Finally, the researchers evaluated the effects of thymidine and DI-39 in hematopoietic progenitor cells. They looked at the Lineage^- Sca-1⁺ c-Kit⁺ hematopoietic stem cell population, as well as short-term, long-term, and multipotent progenitor hematopoietic progenitor cells.

There was a minor decrease in the percentage of Lineage^- Sca-1⁺ c-Kit⁺ cells after thymidine treatment. However, there were no other significant changes in progenitor cells between the treatment and control groups. Why leukemic cells and normal hematopoietic progenitors respond so differently to this treatment requires further investigation, the researchers said.

But they also noted that this study advances our understanding of DNA synthesis in leukemic cells and suggests that targeted metabolic intervention could be a new therapeutic approach in ALL.

ALL in the bone marrow

Inhibiting two biosynthesis pathways can override treatment resistance in acute lymphoblastic leukemia (ALL), preclinical research suggests.

Researchers found that inhibiting only one pathway did not effectively kill ALL cells. The cells simply used another pathway to replicate their DNA and continue dividing.

But inhibiting both pathways induced apoptosis in human leukemia cells and reduced tumor burden in mouse models of T- and B-cell ALL.

“This new, dual-targeting approach shows that we can overcome the redundancy in DNA synthesis in ALL cells and identifies a potential target for metabolic intervention in ALL, and possibly in other hematological cancers,” said study author Caius Radu, MD, of the University of California, Los Angeles.

He and his colleagues described this approach in The Journal of Experimental Medicine.

The research began with the knowledge that deoxyribonucleotide triphosphates, including deoxycytidine triphosphate (dCTP), are required for DNA replication, which is necessary for cell division. And dCTP can be produced by the de novo pathway or the nucleoside salvage pathway.

Dr Radu and his colleagues discovered that inhibiting the de novo pathway with the compound thymidine caused leukemia cells to switch to the nucleoside salvage pathway for dCTP production.

However, inhibiting both the de novo and nucleoside salvage pathways prevented dCTP production and proved lethal for leukemia cells.

A number of experiments elicited these results. In one, the researchers knocked down the deoxycytidine kinase (dCK) in human T-ALL cells to inhibit the nucleoside salvage pathway. Then, they administered thymidine to inhibit the de novo pathway. This resulted in dCTP depletion, stalled DNA replication, replication stress, DNA damage, and apoptosis.

The researchers also used the small-molecule inhibitor DI-39 to target dCK. They found that co-administration of DI-39 and thymidine induced replication stress and apoptosis in several leukemia cell lines: CEM, Jurkat, MOLT-4, NALM-6 and RS4;116.

The team then tested DI-39 and thymidine in mice bearing CEM tumors. They found the combination reduced tumor growth in mice bearing established, subcutaneous CEM xenografts and in mice with systemic T-ALL.

In the systemic T-ALL model, treatment with thymidine alone resulted in a 7-fold reduction in tumor burden compared to vehicle control or DI-39 alone. But when thymidine and DI-39 were administered together, mice saw a 100-fold reduction in tumor burden compared to thymidine alone.

The thymidine-DI-39 combination also proved effective against B-ALL cells and in a mouse model of B-ALL. However, the effects were not as great as those observed in T-ALL.

Finally, the researchers evaluated the effects of thymidine and DI-39 in hematopoietic progenitor cells. They looked at the Lineage^- Sca-1⁺ c-Kit⁺ hematopoietic stem cell population, as well as short-term, long-term, and multipotent progenitor hematopoietic progenitor cells.

There was a minor decrease in the percentage of Lineage^- Sca-1⁺ c-Kit⁺ cells after thymidine treatment. However, there were no other significant changes in progenitor cells between the treatment and control groups. Why leukemic cells and normal hematopoietic progenitors respond so differently to this treatment requires further investigation, the researchers said.

But they also noted that this study advances our understanding of DNA synthesis in leukemic cells and suggests that targeted metabolic intervention could be a new therapeutic approach in ALL.

Lab mouse

Results of preclinical research point to a possible way of preventing mucositis, graft-vs-host disease, and other disorders associated with epithelial permeability.

Investigators created a mouse model of mucositis and discovered that interleukin-1 (IL-1) beta, a protein secreted by the stressed mucosa, played an important role in the condition.

But inhibiting IL-1 beta alleviated mucositis. So the researchers speculated that targeting IL-1 beta might prevent mucositis in humans.

Naama Kanarek, a doctoral student at Hebrew University Hadassah Medical School in Jerusalem, and her colleagues described this research in PNAS.

The investigators began by generating a mouse model deficient in a gene encoding the enzyme beta-TrCP. They chose this enzyme because it’s a major regulator of inflammatory cascades.

The team found that beta-TrCP deletion in the gut caused mucosal DNA damage in the mice, mimicking the effects of chemotherapy and irradiation. Similar to human patients, a severe mucositis reaction occurred in mice that were genetically engineered to be beta-TrCP-deficient.

Tracing the pathological basis of the mouse mucositis revealed that the source of the problem was IL-1 beta. IL-1 beta opened the gut lining, allowing gut bacteria to penetrate and destroy the gut interior.

To confirm this finding, the researchers treated mice with an antibody neutralizing IL-1 beta prior to deleting beta-TrCP. They found this prevented the onset of mucositis.

Therefore, the team has proposed that IL-1 receptor agonists should be tested as mucositis prophylaxis in humans. An example is anakinra (Kineret), which is used to treat chronic inflammatory conditions, such as rheumatoid arthritis and Crohn’s disease.

The investigators believe such treatments might also be used to prevent graft-vs-host disease, burn injuries, head and neck trauma, and other disorders associated with

epithelial permeability.

Lab mouse

Results of preclinical research point to a possible way of preventing mucositis, graft-vs-host disease, and other disorders associated with epithelial permeability.

Investigators created a mouse model of mucositis and discovered that interleukin-1 (IL-1) beta, a protein secreted by the stressed mucosa, played an important role in the condition.

But inhibiting IL-1 beta alleviated mucositis. So the researchers speculated that targeting IL-1 beta might prevent mucositis in humans.

Naama Kanarek, a doctoral student at Hebrew University Hadassah Medical School in Jerusalem, and her colleagues described this research in PNAS.

The investigators began by generating a mouse model deficient in a gene encoding the enzyme beta-TrCP. They chose this enzyme because it’s a major regulator of inflammatory cascades.

The team found that beta-TrCP deletion in the gut caused mucosal DNA damage in the mice, mimicking the effects of chemotherapy and irradiation. Similar to human patients, a severe mucositis reaction occurred in mice that were genetically engineered to be beta-TrCP-deficient.

Tracing the pathological basis of the mouse mucositis revealed that the source of the problem was IL-1 beta. IL-1 beta opened the gut lining, allowing gut bacteria to penetrate and destroy the gut interior.

To confirm this finding, the researchers treated mice with an antibody neutralizing IL-1 beta prior to deleting beta-TrCP. They found this prevented the onset of mucositis.

Therefore, the team has proposed that IL-1 receptor agonists should be tested as mucositis prophylaxis in humans. An example is anakinra (Kineret), which is used to treat chronic inflammatory conditions, such as rheumatoid arthritis and Crohn’s disease.

The investigators believe such treatments might also be used to prevent graft-vs-host disease, burn injuries, head and neck trauma, and other disorders associated with

epithelial permeability.

Lab mouse

Results of preclinical research point to a possible way of preventing mucositis, graft-vs-host disease, and other disorders associated with epithelial permeability.

Investigators created a mouse model of mucositis and discovered that interleukin-1 (IL-1) beta, a protein secreted by the stressed mucosa, played an important role in the condition.

But inhibiting IL-1 beta alleviated mucositis. So the researchers speculated that targeting IL-1 beta might prevent mucositis in humans.

Naama Kanarek, a doctoral student at Hebrew University Hadassah Medical School in Jerusalem, and her colleagues described this research in PNAS.

The investigators began by generating a mouse model deficient in a gene encoding the enzyme beta-TrCP. They chose this enzyme because it’s a major regulator of inflammatory cascades.

The team found that beta-TrCP deletion in the gut caused mucosal DNA damage in the mice, mimicking the effects of chemotherapy and irradiation. Similar to human patients, a severe mucositis reaction occurred in mice that were genetically engineered to be beta-TrCP-deficient.

Tracing the pathological basis of the mouse mucositis revealed that the source of the problem was IL-1 beta. IL-1 beta opened the gut lining, allowing gut bacteria to penetrate and destroy the gut interior.

To confirm this finding, the researchers treated mice with an antibody neutralizing IL-1 beta prior to deleting beta-TrCP. They found this prevented the onset of mucositis.

Therefore, the team has proposed that IL-1 receptor agonists should be tested as mucositis prophylaxis in humans. An example is anakinra (Kineret), which is used to treat chronic inflammatory conditions, such as rheumatoid arthritis and Crohn’s disease.

The investigators believe such treatments might also be used to prevent graft-vs-host disease, burn injuries, head and neck trauma, and other disorders associated with

epithelial permeability.

Infants who develop leukemia during the first year of life inherit a combination of genetic variations that can make them highly susceptible to the disease, according to a study published in Leukemia.

Results of whole-exome sequencing suggested that infants with leukemia inherited genetic variants from both parents that, by themselves, would not cause leukemia but, in combination, put the infants at high risk of developing the disease.

“We sequenced every single gene and found that infants with leukemia were born with an excess of damaging changes in genes known to be linked to leukemia,” said study author Todd Druley, MD, PhD, of Washington University School of Medicine in St Louis, Missouri.

“For each child, both parents carried a few harmful genetic variations in their DNA, and, just by chance, their child inherited all of these changes.”

However, it’s unlikely that the inherited variations alone cause leukemia, Dr Druley said. The infants likely needed to accumulate a few additional variations.

To uncover these findings, Dr Druley and his colleagues performed whole-exome sequencing in infants with acute myeloid leukemia (AML), infants with acute lymphoblastic leukemia (ALL), and the mothers of these children. The researchers used the process of elimination to determine a father’s contribution to a child’s DNA.

Among the 23 families studied, there was no history of pediatric cancers. As a comparison, the researchers also sequenced the DNA of 25 healthy children.

The team found the average amount of congenital coding variations was higher in infants with leukemia than in their mothers or the control subjects. The average total variants per exome was 1264.4 in infants with ALL, 1112.6 in their mothers, 2549.9 in infants with AML, 1225.0 in their mothers, and 582.8 in healthy controls.

The researchers then decided to home in on variants that were likely to impart a functional effect associated with leukemia. Using the COSMIC database, the team identified 126 ALL-associated genes and 655 AML-associated genes.

They found an average of 12.1 variants per ALL patient in the ALL-associated genes and 163.4 variants per AML patient in the AML-associated genes. There were 6.4 ALL-associated variants in the ALL patients’ mothers, 132.5 AML-associated variants in the AML patients’ mothers, 1.9 ALL variants in controls, and 27.5 AML variants in controls.

To prioritize genes that might be most relevant to infant leukemia, the researchers looked for compound heterozygous genes and the genes that were most commonly variant in all patients.

All of the infants with AML and 50% of the infants with ALL were compound heterozygotes for MLL3.  Sixty-seven percent of AML patients were compound heterozygotes for RYR1 and FLG, and 50% of ALL patients were compound heterozygotes for RBMX.

The most variant (but not necessarily compound heterozygous) AML-associated genes in infants with AML were TTN, MLL3, and FLG. But the ALL-associated genes MDN1, SYNE1, and MLL2 were frequently variable in AML patients as well.

For infants with ALL, MDN1 was the most variable ALL-associated gene. But these infants also had frequent variations in the AML-associated genes TTN, RBMX, and MLL3.

Dr Druley and his colleagues plan to study these variations in more detail to understand how they contribute to infant leukemia development.

Infants who develop leukemia during the first year of life inherit a combination of genetic variations that can make them highly susceptible to the disease, according to a study published in Leukemia.

Results of whole-exome sequencing suggested that infants with leukemia inherited genetic variants from both parents that, by themselves, would not cause leukemia but, in combination, put the infants at high risk of developing the disease.

“We sequenced every single gene and found that infants with leukemia were born with an excess of damaging changes in genes known to be linked to leukemia,” said study author Todd Druley, MD, PhD, of Washington University School of Medicine in St Louis, Missouri.

“For each child, both parents carried a few harmful genetic variations in their DNA, and, just by chance, their child inherited all of these changes.”

However, it’s unlikely that the inherited variations alone cause leukemia, Dr Druley said. The infants likely needed to accumulate a few additional variations.

To uncover these findings, Dr Druley and his colleagues performed whole-exome sequencing in infants with acute myeloid leukemia (AML), infants with acute lymphoblastic leukemia (ALL), and the mothers of these children. The researchers used the process of elimination to determine a father’s contribution to a child’s DNA.

Among the 23 families studied, there was no history of pediatric cancers. As a comparison, the researchers also sequenced the DNA of 25 healthy children.

The team found the average amount of congenital coding variations was higher in infants with leukemia than in their mothers or the control subjects. The average total variants per exome was 1264.4 in infants with ALL, 1112.6 in their mothers, 2549.9 in infants with AML, 1225.0 in their mothers, and 582.8 in healthy controls.

The researchers then decided to home in on variants that were likely to impart a functional effect associated with leukemia. Using the COSMIC database, the team identified 126 ALL-associated genes and 655 AML-associated genes.

They found an average of 12.1 variants per ALL patient in the ALL-associated genes and 163.4 variants per AML patient in the AML-associated genes. There were 6.4 ALL-associated variants in the ALL patients’ mothers, 132.5 AML-associated variants in the AML patients’ mothers, 1.9 ALL variants in controls, and 27.5 AML variants in controls.

To prioritize genes that might be most relevant to infant leukemia, the researchers looked for compound heterozygous genes and the genes that were most commonly variant in all patients.

All of the infants with AML and 50% of the infants with ALL were compound heterozygotes for MLL3.  Sixty-seven percent of AML patients were compound heterozygotes for RYR1 and FLG, and 50% of ALL patients were compound heterozygotes for RBMX.

The most variant (but not necessarily compound heterozygous) AML-associated genes in infants with AML were TTN, MLL3, and FLG. But the ALL-associated genes MDN1, SYNE1, and MLL2 were frequently variable in AML patients as well.

For infants with ALL, MDN1 was the most variable ALL-associated gene. But these infants also had frequent variations in the AML-associated genes TTN, RBMX, and MLL3.

Dr Druley and his colleagues plan to study these variations in more detail to understand how they contribute to infant leukemia development.

Infants who develop leukemia during the first year of life inherit a combination of genetic variations that can make them highly susceptible to the disease, according to a study published in Leukemia.

Results of whole-exome sequencing suggested that infants with leukemia inherited genetic variants from both parents that, by themselves, would not cause leukemia but, in combination, put the infants at high risk of developing the disease.

“We sequenced every single gene and found that infants with leukemia were born with an excess of damaging changes in genes known to be linked to leukemia,” said study author Todd Druley, MD, PhD, of Washington University School of Medicine in St Louis, Missouri.

“For each child, both parents carried a few harmful genetic variations in their DNA, and, just by chance, their child inherited all of these changes.”

However, it’s unlikely that the inherited variations alone cause leukemia, Dr Druley said. The infants likely needed to accumulate a few additional variations.

To uncover these findings, Dr Druley and his colleagues performed whole-exome sequencing in infants with acute myeloid leukemia (AML), infants with acute lymphoblastic leukemia (ALL), and the mothers of these children. The researchers used the process of elimination to determine a father’s contribution to a child’s DNA.

Among the 23 families studied, there was no history of pediatric cancers. As a comparison, the researchers also sequenced the DNA of 25 healthy children.

The team found the average amount of congenital coding variations was higher in infants with leukemia than in their mothers or the control subjects. The average total variants per exome was 1264.4 in infants with ALL, 1112.6 in their mothers, 2549.9 in infants with AML, 1225.0 in their mothers, and 582.8 in healthy controls.

The researchers then decided to home in on variants that were likely to impart a functional effect associated with leukemia. Using the COSMIC database, the team identified 126 ALL-associated genes and 655 AML-associated genes.

They found an average of 12.1 variants per ALL patient in the ALL-associated genes and 163.4 variants per AML patient in the AML-associated genes. There were 6.4 ALL-associated variants in the ALL patients’ mothers, 132.5 AML-associated variants in the AML patients’ mothers, 1.9 ALL variants in controls, and 27.5 AML variants in controls.

To prioritize genes that might be most relevant to infant leukemia, the researchers looked for compound heterozygous genes and the genes that were most commonly variant in all patients.

All of the infants with AML and 50% of the infants with ALL were compound heterozygotes for MLL3.  Sixty-seven percent of AML patients were compound heterozygotes for RYR1 and FLG, and 50% of ALL patients were compound heterozygotes for RBMX.

The most variant (but not necessarily compound heterozygous) AML-associated genes in infants with AML were TTN, MLL3, and FLG. But the ALL-associated genes MDN1, SYNE1, and MLL2 were frequently variable in AML patients as well.

For infants with ALL, MDN1 was the most variable ALL-associated gene. But these infants also had frequent variations in the AML-associated genes TTN, RBMX, and MLL3.

Dr Druley and his colleagues plan to study these variations in more detail to understand how they contribute to infant leukemia development.

Chronic lymphocytic leukemia

Researchers believe they’ve discovered how the Bcl-2 protein helps leukemia and lymphoma cells survive anticancer treatment.

The team found that Bcl-2 alters the level of calcium ions in cancer cells, and this promotes the cells’ survival.

The group thinks these findings, published in PNAS, could help spur the development of drugs that effectively inhibit Bcl-2 and produce better outcomes for cancer patients.

“Since 1993, our team has been conducting research on key mechanisms by which the protein Bcl-2 keeps cancer cells alive,” said study author Clark W. Distelhorst, MD, of Case Western Reserve School of Medicine in Cleveland, Ohio.

“Now, for the first time, we have evidence of how Bcl-2 is promoting abnormally long survival of the cancer cells by regulating calcium levels within cells, and [we] will use the discovery and data to deliver therapies designed to attack the Bcl-2 protein and inhibit its impact.”

More than a decade ago, researchers in Dr Distelhorst’s lab discovered that Bcl-2 binds to the inositol 1,4,5-trisphosphate receptor (InsP3R) channel and regulates the release of calcium ions.

In the current study, the team found that when Bcl-2 binds to the InsP3R channel, it initiates a complex feedback mechanism that blocks the release of calcium ions intended to induce cell death. Instead of dying, the cancer cells continue to proliferate.

Specifically, the researchers discovered that Bcl-2 interacts with the Ca2+-activated protein phosphatase calcineurin (CaN) and dopamine- and cAMP-regulated phosphoprotein of 32 kDa (DARPP-32), a CaN-regulated inhibitor of protein phosphatase 1.

Bcl-2 docks DARPP-32 and CaN on the InsP3R, creating a negative feedback loop that responds to InsP3R-mediated Ca2+ release by inhibiting InsP3R phosphorylation at Ser1755. And this prevents the excessive Ca2+ elevation that induces cell death.

The team theorized that cancer cells overexpressing Bcl-2 may exploit this mechanism to prevent apoptosis. And experiments in chronic lymphocytic leukemia cells appeared to confirm this theory.

The researchers treated the cells with the peptide TAT-IDPDD/AA, which inhibits Bcl-2–InsP3R interaction. This increased P-Ser1755 InsP3R-1 levels and elevated Ca2+, which induced apoptosis.

“We have recognized for decades that cancer cells grow and forget to die,” said Stanton Gerson, MD, director of the Case Comprehensive Cancer Center, who was not involved in this study.

“[N]ow, we understand why. I predict that this work will focus the discovery of new drugs against the Bcl-2-calcium-flow system.”

Chronic lymphocytic leukemia

Researchers believe they’ve discovered how the Bcl-2 protein helps leukemia and lymphoma cells survive anticancer treatment.

The team found that Bcl-2 alters the level of calcium ions in cancer cells, and this promotes the cells’ survival.

The group thinks these findings, published in PNAS, could help spur the development of drugs that effectively inhibit Bcl-2 and produce better outcomes for cancer patients.

“Since 1993, our team has been conducting research on key mechanisms by which the protein Bcl-2 keeps cancer cells alive,” said study author Clark W. Distelhorst, MD, of Case Western Reserve School of Medicine in Cleveland, Ohio.

“Now, for the first time, we have evidence of how Bcl-2 is promoting abnormally long survival of the cancer cells by regulating calcium levels within cells, and [we] will use the discovery and data to deliver therapies designed to attack the Bcl-2 protein and inhibit its impact.”

More than a decade ago, researchers in Dr Distelhorst’s lab discovered that Bcl-2 binds to the inositol 1,4,5-trisphosphate receptor (InsP3R) channel and regulates the release of calcium ions.

In the current study, the team found that when Bcl-2 binds to the InsP3R channel, it initiates a complex feedback mechanism that blocks the release of calcium ions intended to induce cell death. Instead of dying, the cancer cells continue to proliferate.

Specifically, the researchers discovered that Bcl-2 interacts with the Ca2+-activated protein phosphatase calcineurin (CaN) and dopamine- and cAMP-regulated phosphoprotein of 32 kDa (DARPP-32), a CaN-regulated inhibitor of protein phosphatase 1.

Bcl-2 docks DARPP-32 and CaN on the InsP3R, creating a negative feedback loop that responds to InsP3R-mediated Ca2+ release by inhibiting InsP3R phosphorylation at Ser1755. And this prevents the excessive Ca2+ elevation that induces cell death.

The team theorized that cancer cells overexpressing Bcl-2 may exploit this mechanism to prevent apoptosis. And experiments in chronic lymphocytic leukemia cells appeared to confirm this theory.

The researchers treated the cells with the peptide TAT-IDPDD/AA, which inhibits Bcl-2–InsP3R interaction. This increased P-Ser1755 InsP3R-1 levels and elevated Ca2+, which induced apoptosis.

“We have recognized for decades that cancer cells grow and forget to die,” said Stanton Gerson, MD, director of the Case Comprehensive Cancer Center, who was not involved in this study.

“[N]ow, we understand why. I predict that this work will focus the discovery of new drugs against the Bcl-2-calcium-flow system.”

Chronic lymphocytic leukemia

Researchers believe they’ve discovered how the Bcl-2 protein helps leukemia and lymphoma cells survive anticancer treatment.

The team found that Bcl-2 alters the level of calcium ions in cancer cells, and this promotes the cells’ survival.

The group thinks these findings, published in PNAS, could help spur the development of drugs that effectively inhibit Bcl-2 and produce better outcomes for cancer patients.

“Since 1993, our team has been conducting research on key mechanisms by which the protein Bcl-2 keeps cancer cells alive,” said study author Clark W. Distelhorst, MD, of Case Western Reserve School of Medicine in Cleveland, Ohio.

“Now, for the first time, we have evidence of how Bcl-2 is promoting abnormally long survival of the cancer cells by regulating calcium levels within cells, and [we] will use the discovery and data to deliver therapies designed to attack the Bcl-2 protein and inhibit its impact.”

More than a decade ago, researchers in Dr Distelhorst’s lab discovered that Bcl-2 binds to the inositol 1,4,5-trisphosphate receptor (InsP3R) channel and regulates the release of calcium ions.

In the current study, the team found that when Bcl-2 binds to the InsP3R channel, it initiates a complex feedback mechanism that blocks the release of calcium ions intended to induce cell death. Instead of dying, the cancer cells continue to proliferate.

Specifically, the researchers discovered that Bcl-2 interacts with the Ca2+-activated protein phosphatase calcineurin (CaN) and dopamine- and cAMP-regulated phosphoprotein of 32 kDa (DARPP-32), a CaN-regulated inhibitor of protein phosphatase 1.

Bcl-2 docks DARPP-32 and CaN on the InsP3R, creating a negative feedback loop that responds to InsP3R-mediated Ca2+ release by inhibiting InsP3R phosphorylation at Ser1755. And this prevents the excessive Ca2+ elevation that induces cell death.

The team theorized that cancer cells overexpressing Bcl-2 may exploit this mechanism to prevent apoptosis. And experiments in chronic lymphocytic leukemia cells appeared to confirm this theory.

The researchers treated the cells with the peptide TAT-IDPDD/AA, which inhibits Bcl-2–InsP3R interaction. This increased P-Ser1755 InsP3R-1 levels and elevated Ca2+, which induced apoptosis.

“We have recognized for decades that cancer cells grow and forget to die,” said Stanton Gerson, MD, director of the Case Comprehensive Cancer Center, who was not involved in this study.

“[N]ow, we understand why. I predict that this work will focus the discovery of new drugs against the Bcl-2-calcium-flow system.”