Myelodysplastic Syndrome

Coadministration with entinostat – a cell-cycle inhibitor – appears to decrease hematologic responsiveness to azacitidine treatment for high-risk myelodysplastic syndrome, according to data from an open-label, phase II randomized trial.

An earlier, phase I pilot study had suggested that the combination was effective and tolerable, however this phase II study in 149 patients (97 patients with myelodysplastic syndrome and 52 patients with acute myeloid leukemia) showed a lower overall hematologic response and lower median overall survival in the combination arm, compared with the azacitidine-only arm, said Dr. Thomas Prebet, who was at the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University, Baltimore, when the work was done, but is now at Institut Paoli Calmettes, Marseille, France, and his colleagues.

They also performed genome-wide methylation studies on 99 specimens, finding that while demethylation in the combination arm was trending toward overall demethylation, it was significantly reduced, compared with the single agent arm, suggesting the entinostat was actually blocking the action of the azacitidine (J. Clin. Oncol. 2014 March 24 [doi:10.1200/JCO.2013.50.3102]).

The authors did note that the lower-dose, 10-day schedule of azacitidine, which was developed specifically for this phase II trial, appeared to double the rate of hematologic normalization, compared with that observed in a previous study using the standard 7-day schedule, suggesting that the longer schedule was more effective.

Some authors reported being consultants for and/or receiving research funding from various pharmaceutical companies. The study was partly supported by grants from the Leukemia and Lymphoma Society of America and Fulbright Franco-American Commission/Foundation.

[email protected]

Coadministration with entinostat – a cell-cycle inhibitor – appears to decrease hematologic responsiveness to azacitidine treatment for high-risk myelodysplastic syndrome, according to data from an open-label, phase II randomized trial.

An earlier, phase I pilot study had suggested that the combination was effective and tolerable, however this phase II study in 149 patients (97 patients with myelodysplastic syndrome and 52 patients with acute myeloid leukemia) showed a lower overall hematologic response and lower median overall survival in the combination arm, compared with the azacitidine-only arm, said Dr. Thomas Prebet, who was at the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University, Baltimore, when the work was done, but is now at Institut Paoli Calmettes, Marseille, France, and his colleagues.

They also performed genome-wide methylation studies on 99 specimens, finding that while demethylation in the combination arm was trending toward overall demethylation, it was significantly reduced, compared with the single agent arm, suggesting the entinostat was actually blocking the action of the azacitidine (J. Clin. Oncol. 2014 March 24 [doi:10.1200/JCO.2013.50.3102]).

The authors did note that the lower-dose, 10-day schedule of azacitidine, which was developed specifically for this phase II trial, appeared to double the rate of hematologic normalization, compared with that observed in a previous study using the standard 7-day schedule, suggesting that the longer schedule was more effective.

Some authors reported being consultants for and/or receiving research funding from various pharmaceutical companies. The study was partly supported by grants from the Leukemia and Lymphoma Society of America and Fulbright Franco-American Commission/Foundation.

[email protected]

Coadministration with entinostat – a cell-cycle inhibitor – appears to decrease hematologic responsiveness to azacitidine treatment for high-risk myelodysplastic syndrome, according to data from an open-label, phase II randomized trial.

An earlier, phase I pilot study had suggested that the combination was effective and tolerable, however this phase II study in 149 patients (97 patients with myelodysplastic syndrome and 52 patients with acute myeloid leukemia) showed a lower overall hematologic response and lower median overall survival in the combination arm, compared with the azacitidine-only arm, said Dr. Thomas Prebet, who was at the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University, Baltimore, when the work was done, but is now at Institut Paoli Calmettes, Marseille, France, and his colleagues.

They also performed genome-wide methylation studies on 99 specimens, finding that while demethylation in the combination arm was trending toward overall demethylation, it was significantly reduced, compared with the single agent arm, suggesting the entinostat was actually blocking the action of the azacitidine (J. Clin. Oncol. 2014 March 24 [doi:10.1200/JCO.2013.50.3102]).

The authors did note that the lower-dose, 10-day schedule of azacitidine, which was developed specifically for this phase II trial, appeared to double the rate of hematologic normalization, compared with that observed in a previous study using the standard 7-day schedule, suggesting that the longer schedule was more effective.

Some authors reported being consultants for and/or receiving research funding from various pharmaceutical companies. The study was partly supported by grants from the Leukemia and Lymphoma Society of America and Fulbright Franco-American Commission/Foundation.

[email protected]

NEW ORLEANS – Lower doses of quizartinib reduced worrisome QT-interval prolongation events without a loss of efficacy in patients with FLT3-ITD–positive relapsed or refractory acute myeloid leukemia, a phase II study shows.

In a 76-patient study, grade 2 QT-interval prolongation (QTcF) of more than 480-500 msec occurred in two patients (5%) on oral quizartinib 30 mg/day and in five patients (14%) on 60 mg/day, with no differences between groups in QTcF events of more than 500 msec (5% vs. 3%).

In addition, an increase in QTcF from baseline of more than 60 msec was seen in 19% of patients on the 60-mg dose and in 3% of those on the 30-mg dose, Dr. Jorge Cortes reported at the annual meeting of the American Society of Hematology.

About a third of patients with acute myeloid leukemia (AML) will have FLT3 internal tandem duplications (FLT3-ITD), which are associated with early relapse and poor survival in AML. Quizartinib has shown the highest single-agent activity among FMS-like tyrosine kinase 3 (FLT3)-targeted agents in this population, according to Dr. Cortes.

At last year’s ASH meeting, investigators presented results from a phase II study in which the investigational agent elicited responses in both FLT3-positive and -negative relapsed/refractory AML. The unprecedented results at doses of 90, 135, and 200 mg were partially eclipsed, however, by respective 46%, 39%, and 92% increases in QTcF from baseline of more than 60 msec, noted Dr. Cortes, chair of the AML section, department of leukemia, University of Texas M.D. Anderson Cancer Center, Houston.

The current study randomized 76 patients to quizartinib 30 mg or 60 mg continuous daily dosing for primary AML or AML secondary to myelodysplastic syndrome that relapsed or was refractory to first-line salvage therapy or prior hematopoietic stem cell transplantation. The coprimary endpoints were rate of grade 2 QTc prolongation and the composite complete remission rate, which included complete remission (CR), CR with incomplete platelet recovery, and CR with incomplete hematologic recovery.

In all, 92% of patients had FLT3 internal tandem duplications, and 58 of 60 evaluable patients had intermediate or poor cytogenetic risk. Their mean age was 55 years. Two patients were randomized but not treated.

Treatment with the 30-mg and 60-mg doses resulted in a composite CR rate of 47%, Dr. Cortes said. The median duration of response was 4.1 weeks in the 30-mg group and 20 weeks in the 60-mg group.

Two patients (5%) on the 30-mg dose and 1 patient (3%) on the 60-mg dose achieved CR; 1 patient (3%) in the 60-mg group had a CR with incomplete platelet recovery; and 16 patients (42%) in each arm had a CR with incomplete hematologic recovery.

Partial responses were also seen in 5 patients (13%) in the 30-mg group and 9 (24%) in the 60-mg group.

These results compare favorably with composite CR rates of 47%, 45%, and 42% with the 90-, 135-, and 200-mg doses used in the earlier study, Dr. Cortes observed.

Median overall survival in the current study was 20.7 weeks in the lower-dose group and 25.4 weeks with the 60-mg dose.

Importantly, 34% of patients were successfully bridged to transplant, extending median survival to 31 weeks for those on 30 mg of quizartinib and to 28.1 weeks for those given 60 mg.

"This study demonstrates there is certainly sustained efficacy with these lower doses of quizartinib and a decreased QT signal at doses of 30 and 60 mg compared with the higher doses we’ve tested in the past," Dr. Cortes concluded.

Grade 3/4 adverse events were mainly anemia (39%) in the 30-mg group and febrile neutropenia (36%) in the 60-mg group. Three patients required dose reductions due to QTc prolongation.

A global phase III randomized study of quizartinib in FLT3-ITD–positive patients in first relapse is planned to start in early 2014, he said.

Development of quizartinib has been somewhat rocky, with Astellas Pharma announcing in March 2013 it was ending its collaboration with Ambit Biosciences to develop FLT3 inhibitors including quizartinib.

Dr. Cortes reported research funding from Astellas Pharma, Arog, Novartis, and Ambit Biosciences, which is developing quizartinib, and consulting for Astellas, Arog, and Ambit.

[email protected]

NEW ORLEANS – Lower doses of quizartinib reduced worrisome QT-interval prolongation events without a loss of efficacy in patients with FLT3-ITD–positive relapsed or refractory acute myeloid leukemia, a phase II study shows.

In a 76-patient study, grade 2 QT-interval prolongation (QTcF) of more than 480-500 msec occurred in two patients (5%) on oral quizartinib 30 mg/day and in five patients (14%) on 60 mg/day, with no differences between groups in QTcF events of more than 500 msec (5% vs. 3%).

In addition, an increase in QTcF from baseline of more than 60 msec was seen in 19% of patients on the 60-mg dose and in 3% of those on the 30-mg dose, Dr. Jorge Cortes reported at the annual meeting of the American Society of Hematology.

About a third of patients with acute myeloid leukemia (AML) will have FLT3 internal tandem duplications (FLT3-ITD), which are associated with early relapse and poor survival in AML. Quizartinib has shown the highest single-agent activity among FMS-like tyrosine kinase 3 (FLT3)-targeted agents in this population, according to Dr. Cortes.

At last year’s ASH meeting, investigators presented results from a phase II study in which the investigational agent elicited responses in both FLT3-positive and -negative relapsed/refractory AML. The unprecedented results at doses of 90, 135, and 200 mg were partially eclipsed, however, by respective 46%, 39%, and 92% increases in QTcF from baseline of more than 60 msec, noted Dr. Cortes, chair of the AML section, department of leukemia, University of Texas M.D. Anderson Cancer Center, Houston.

The current study randomized 76 patients to quizartinib 30 mg or 60 mg continuous daily dosing for primary AML or AML secondary to myelodysplastic syndrome that relapsed or was refractory to first-line salvage therapy or prior hematopoietic stem cell transplantation. The coprimary endpoints were rate of grade 2 QTc prolongation and the composite complete remission rate, which included complete remission (CR), CR with incomplete platelet recovery, and CR with incomplete hematologic recovery.

In all, 92% of patients had FLT3 internal tandem duplications, and 58 of 60 evaluable patients had intermediate or poor cytogenetic risk. Their mean age was 55 years. Two patients were randomized but not treated.

Treatment with the 30-mg and 60-mg doses resulted in a composite CR rate of 47%, Dr. Cortes said. The median duration of response was 4.1 weeks in the 30-mg group and 20 weeks in the 60-mg group.

Two patients (5%) on the 30-mg dose and 1 patient (3%) on the 60-mg dose achieved CR; 1 patient (3%) in the 60-mg group had a CR with incomplete platelet recovery; and 16 patients (42%) in each arm had a CR with incomplete hematologic recovery.

Partial responses were also seen in 5 patients (13%) in the 30-mg group and 9 (24%) in the 60-mg group.

These results compare favorably with composite CR rates of 47%, 45%, and 42% with the 90-, 135-, and 200-mg doses used in the earlier study, Dr. Cortes observed.

Median overall survival in the current study was 20.7 weeks in the lower-dose group and 25.4 weeks with the 60-mg dose.

Importantly, 34% of patients were successfully bridged to transplant, extending median survival to 31 weeks for those on 30 mg of quizartinib and to 28.1 weeks for those given 60 mg.

"This study demonstrates there is certainly sustained efficacy with these lower doses of quizartinib and a decreased QT signal at doses of 30 and 60 mg compared with the higher doses we’ve tested in the past," Dr. Cortes concluded.

Grade 3/4 adverse events were mainly anemia (39%) in the 30-mg group and febrile neutropenia (36%) in the 60-mg group. Three patients required dose reductions due to QTc prolongation.

A global phase III randomized study of quizartinib in FLT3-ITD–positive patients in first relapse is planned to start in early 2014, he said.

Development of quizartinib has been somewhat rocky, with Astellas Pharma announcing in March 2013 it was ending its collaboration with Ambit Biosciences to develop FLT3 inhibitors including quizartinib.

Dr. Cortes reported research funding from Astellas Pharma, Arog, Novartis, and Ambit Biosciences, which is developing quizartinib, and consulting for Astellas, Arog, and Ambit.

[email protected]

NEW ORLEANS – Lower doses of quizartinib reduced worrisome QT-interval prolongation events without a loss of efficacy in patients with FLT3-ITD–positive relapsed or refractory acute myeloid leukemia, a phase II study shows.

In a 76-patient study, grade 2 QT-interval prolongation (QTcF) of more than 480-500 msec occurred in two patients (5%) on oral quizartinib 30 mg/day and in five patients (14%) on 60 mg/day, with no differences between groups in QTcF events of more than 500 msec (5% vs. 3%).

In addition, an increase in QTcF from baseline of more than 60 msec was seen in 19% of patients on the 60-mg dose and in 3% of those on the 30-mg dose, Dr. Jorge Cortes reported at the annual meeting of the American Society of Hematology.

About a third of patients with acute myeloid leukemia (AML) will have FLT3 internal tandem duplications (FLT3-ITD), which are associated with early relapse and poor survival in AML. Quizartinib has shown the highest single-agent activity among FMS-like tyrosine kinase 3 (FLT3)-targeted agents in this population, according to Dr. Cortes.

At last year’s ASH meeting, investigators presented results from a phase II study in which the investigational agent elicited responses in both FLT3-positive and -negative relapsed/refractory AML. The unprecedented results at doses of 90, 135, and 200 mg were partially eclipsed, however, by respective 46%, 39%, and 92% increases in QTcF from baseline of more than 60 msec, noted Dr. Cortes, chair of the AML section, department of leukemia, University of Texas M.D. Anderson Cancer Center, Houston.

The current study randomized 76 patients to quizartinib 30 mg or 60 mg continuous daily dosing for primary AML or AML secondary to myelodysplastic syndrome that relapsed or was refractory to first-line salvage therapy or prior hematopoietic stem cell transplantation. The coprimary endpoints were rate of grade 2 QTc prolongation and the composite complete remission rate, which included complete remission (CR), CR with incomplete platelet recovery, and CR with incomplete hematologic recovery.

In all, 92% of patients had FLT3 internal tandem duplications, and 58 of 60 evaluable patients had intermediate or poor cytogenetic risk. Their mean age was 55 years. Two patients were randomized but not treated.

Treatment with the 30-mg and 60-mg doses resulted in a composite CR rate of 47%, Dr. Cortes said. The median duration of response was 4.1 weeks in the 30-mg group and 20 weeks in the 60-mg group.

Two patients (5%) on the 30-mg dose and 1 patient (3%) on the 60-mg dose achieved CR; 1 patient (3%) in the 60-mg group had a CR with incomplete platelet recovery; and 16 patients (42%) in each arm had a CR with incomplete hematologic recovery.

Partial responses were also seen in 5 patients (13%) in the 30-mg group and 9 (24%) in the 60-mg group.

These results compare favorably with composite CR rates of 47%, 45%, and 42% with the 90-, 135-, and 200-mg doses used in the earlier study, Dr. Cortes observed.

Median overall survival in the current study was 20.7 weeks in the lower-dose group and 25.4 weeks with the 60-mg dose.

Importantly, 34% of patients were successfully bridged to transplant, extending median survival to 31 weeks for those on 30 mg of quizartinib and to 28.1 weeks for those given 60 mg.

"This study demonstrates there is certainly sustained efficacy with these lower doses of quizartinib and a decreased QT signal at doses of 30 and 60 mg compared with the higher doses we’ve tested in the past," Dr. Cortes concluded.

Grade 3/4 adverse events were mainly anemia (39%) in the 30-mg group and febrile neutropenia (36%) in the 60-mg group. Three patients required dose reductions due to QTc prolongation.

A global phase III randomized study of quizartinib in FLT3-ITD–positive patients in first relapse is planned to start in early 2014, he said.

Development of quizartinib has been somewhat rocky, with Astellas Pharma announcing in March 2013 it was ending its collaboration with Ambit Biosciences to develop FLT3 inhibitors including quizartinib.

Dr. Cortes reported research funding from Astellas Pharma, Arog, Novartis, and Ambit Biosciences, which is developing quizartinib, and consulting for Astellas, Arog, and Ambit.

[email protected]

The US Food and Drug Administration (FDA) has granted orphan designation to an investigational drug for the treatment of myelodysplastic syndromes (MDS).

The drug, CPI-613, targets metabolic changes that are thought to occur in many cancer cells.

It has demonstrated activity and tolerability in a phase 1 trial of patients with advanced, relapsed/refractory hematologic malignancies.

CPI-613 previously received orphan designation for acute myeloid leukemia (AML) and pancreatic carcinoma.

Orphan designation is granted for drugs intended to treat diseases that affect fewer than 200,000 individuals in the US. This designation gives the makers of CPI-613, Cornerstone Pharmaceuticals, 7 years of US marketing exclusivity once the drug is approved.

The designation also allows the company to apply for government funding to defray trial costs, tax credits for clinical research expenses, and a potential waiver of the FDA’s application user fee.

CPI-613: Mechanism and phase 1 results

CPI-613 induces cancer-specific inhibition of the mitochondrial enzymes pyruvate dehydrogenase (PDH) and alpha ketoglutarate dehydrogenase (KGDH).

Disrupting the function of PDH and KGDH disrupts tumor mitochondrial metabolism. As a result, tumor cells are starved of energy and biosynthetic intermediates, which leads to cell death.

Researchers evaluated CPI-613 in a phase 1 study of patients with advanced, relapsed/refractory hematologic malignancies.

The team, led by Timothy S. Pardee, MD, of Wake Forest Baptist Medical Center in Winston-Salem, North Carolina, presented the results at the 2013 ASCO Annual Meeting as abstract 2516. (Information in the abstract differs slightly from that presented at the meeting.)

The trial was designed to determine the maximum tolerated dose, safety, and anticancer activity of CPI-613 as a single agent.

Twenty-one evaluable patients received CPI-613 on days 1 and 4 for 3 weeks every 28 days. Ten patients received more than 1 cycle of therapy.

The starting dose was 420 mg/m². Treatment could be continued if the patient experienced clinical benefit. Doses were escalated to a final dose of 3780 mg/m².

CPI-613 was generally well-tolerated when infused over 2 hours. Patients did not experience worsening cytopenias at any dose level. However, 1-hour infusions led to grade 3 renal failure in 2 patients.

At a dose of 3780 mg/m², 1 patient had prolonged grade 3 nausea, and 1 patient had grade 3 renal failure. Six patients received a 2-hour infusion of 2940 mg/m² without dose-limiting toxicities, so the researchers considered this the maximum tolerated dose.

Of the 21 patients, 9 achieved a response of stable disease or better. One MDS patient achieved a complete remission and maintained it over 23 cycles. One AML patient achieved a morphologic leukemia-free state.

A Burkitt lymphoma patient and a cutaneous T-cell lymphoma patient maintained partial responses over 16 and 15 cycles, respectively. Two multiple myeloma patients, 2 MDS patients, and 1 AML patient had stable disease.

“We are very encouraged by the tolerability and signals of activity seen in several patients in this phase 1 study for whom there is no available therapy shown to provide clinical benefit,” Dr Pardee said.

“We look forward to further evaluating CPI-613 in the early relapsed/refractory AML patient setting when administered in combination with a standard chemotherapeutic regimen, as well as in early relapsed or refractory MDS patients, with the hope of improving the outcomes and the quality of life for these patients through the combined use of this mechanistically novel agent.”

The AML study is a phase 1 trial investigating CPI-613 in combination with high-dose cytarabine and mitoxantrone, and the MDS study is a phase 2 trial investigating single-agent CPI-613.

The US Food and Drug Administration (FDA) has granted orphan designation to an investigational drug for the treatment of myelodysplastic syndromes (MDS).

The drug, CPI-613, targets metabolic changes that are thought to occur in many cancer cells.

It has demonstrated activity and tolerability in a phase 1 trial of patients with advanced, relapsed/refractory hematologic malignancies.

CPI-613 previously received orphan designation for acute myeloid leukemia (AML) and pancreatic carcinoma.

Orphan designation is granted for drugs intended to treat diseases that affect fewer than 200,000 individuals in the US. This designation gives the makers of CPI-613, Cornerstone Pharmaceuticals, 7 years of US marketing exclusivity once the drug is approved.

The designation also allows the company to apply for government funding to defray trial costs, tax credits for clinical research expenses, and a potential waiver of the FDA’s application user fee.

CPI-613: Mechanism and phase 1 results

CPI-613 induces cancer-specific inhibition of the mitochondrial enzymes pyruvate dehydrogenase (PDH) and alpha ketoglutarate dehydrogenase (KGDH).

Disrupting the function of PDH and KGDH disrupts tumor mitochondrial metabolism. As a result, tumor cells are starved of energy and biosynthetic intermediates, which leads to cell death.

Researchers evaluated CPI-613 in a phase 1 study of patients with advanced, relapsed/refractory hematologic malignancies.

The team, led by Timothy S. Pardee, MD, of Wake Forest Baptist Medical Center in Winston-Salem, North Carolina, presented the results at the 2013 ASCO Annual Meeting as abstract 2516. (Information in the abstract differs slightly from that presented at the meeting.)

The trial was designed to determine the maximum tolerated dose, safety, and anticancer activity of CPI-613 as a single agent.

Twenty-one evaluable patients received CPI-613 on days 1 and 4 for 3 weeks every 28 days. Ten patients received more than 1 cycle of therapy.

The starting dose was 420 mg/m². Treatment could be continued if the patient experienced clinical benefit. Doses were escalated to a final dose of 3780 mg/m².

CPI-613 was generally well-tolerated when infused over 2 hours. Patients did not experience worsening cytopenias at any dose level. However, 1-hour infusions led to grade 3 renal failure in 2 patients.

At a dose of 3780 mg/m², 1 patient had prolonged grade 3 nausea, and 1 patient had grade 3 renal failure. Six patients received a 2-hour infusion of 2940 mg/m² without dose-limiting toxicities, so the researchers considered this the maximum tolerated dose.

Of the 21 patients, 9 achieved a response of stable disease or better. One MDS patient achieved a complete remission and maintained it over 23 cycles. One AML patient achieved a morphologic leukemia-free state.

A Burkitt lymphoma patient and a cutaneous T-cell lymphoma patient maintained partial responses over 16 and 15 cycles, respectively. Two multiple myeloma patients, 2 MDS patients, and 1 AML patient had stable disease.

“We are very encouraged by the tolerability and signals of activity seen in several patients in this phase 1 study for whom there is no available therapy shown to provide clinical benefit,” Dr Pardee said.

“We look forward to further evaluating CPI-613 in the early relapsed/refractory AML patient setting when administered in combination with a standard chemotherapeutic regimen, as well as in early relapsed or refractory MDS patients, with the hope of improving the outcomes and the quality of life for these patients through the combined use of this mechanistically novel agent.”

The AML study is a phase 1 trial investigating CPI-613 in combination with high-dose cytarabine and mitoxantrone, and the MDS study is a phase 2 trial investigating single-agent CPI-613.

The US Food and Drug Administration (FDA) has granted orphan designation to an investigational drug for the treatment of myelodysplastic syndromes (MDS).

The drug, CPI-613, targets metabolic changes that are thought to occur in many cancer cells.

It has demonstrated activity and tolerability in a phase 1 trial of patients with advanced, relapsed/refractory hematologic malignancies.

CPI-613 previously received orphan designation for acute myeloid leukemia (AML) and pancreatic carcinoma.

Orphan designation is granted for drugs intended to treat diseases that affect fewer than 200,000 individuals in the US. This designation gives the makers of CPI-613, Cornerstone Pharmaceuticals, 7 years of US marketing exclusivity once the drug is approved.

The designation also allows the company to apply for government funding to defray trial costs, tax credits for clinical research expenses, and a potential waiver of the FDA’s application user fee.

CPI-613: Mechanism and phase 1 results

CPI-613 induces cancer-specific inhibition of the mitochondrial enzymes pyruvate dehydrogenase (PDH) and alpha ketoglutarate dehydrogenase (KGDH).

Disrupting the function of PDH and KGDH disrupts tumor mitochondrial metabolism. As a result, tumor cells are starved of energy and biosynthetic intermediates, which leads to cell death.

Researchers evaluated CPI-613 in a phase 1 study of patients with advanced, relapsed/refractory hematologic malignancies.

The team, led by Timothy S. Pardee, MD, of Wake Forest Baptist Medical Center in Winston-Salem, North Carolina, presented the results at the 2013 ASCO Annual Meeting as abstract 2516. (Information in the abstract differs slightly from that presented at the meeting.)

The trial was designed to determine the maximum tolerated dose, safety, and anticancer activity of CPI-613 as a single agent.

Twenty-one evaluable patients received CPI-613 on days 1 and 4 for 3 weeks every 28 days. Ten patients received more than 1 cycle of therapy.

The starting dose was 420 mg/m². Treatment could be continued if the patient experienced clinical benefit. Doses were escalated to a final dose of 3780 mg/m².

CPI-613 was generally well-tolerated when infused over 2 hours. Patients did not experience worsening cytopenias at any dose level. However, 1-hour infusions led to grade 3 renal failure in 2 patients.

At a dose of 3780 mg/m², 1 patient had prolonged grade 3 nausea, and 1 patient had grade 3 renal failure. Six patients received a 2-hour infusion of 2940 mg/m² without dose-limiting toxicities, so the researchers considered this the maximum tolerated dose.

Of the 21 patients, 9 achieved a response of stable disease or better. One MDS patient achieved a complete remission and maintained it over 23 cycles. One AML patient achieved a morphologic leukemia-free state.

A Burkitt lymphoma patient and a cutaneous T-cell lymphoma patient maintained partial responses over 16 and 15 cycles, respectively. Two multiple myeloma patients, 2 MDS patients, and 1 AML patient had stable disease.

“We are very encouraged by the tolerability and signals of activity seen in several patients in this phase 1 study for whom there is no available therapy shown to provide clinical benefit,” Dr Pardee said.

“We look forward to further evaluating CPI-613 in the early relapsed/refractory AML patient setting when administered in combination with a standard chemotherapeutic regimen, as well as in early relapsed or refractory MDS patients, with the hope of improving the outcomes and the quality of life for these patients through the combined use of this mechanistically novel agent.”

The AML study is a phase 1 trial investigating CPI-613 in combination with high-dose cytarabine and mitoxantrone, and the MDS study is a phase 2 trial investigating single-agent CPI-613.

Blood smear showing MDS

In a multicenter trial, deferasirox reduced serum ferritin and labile plasma iron (LPI) in transfusion-dependent patients with myelodysplastic syndrome (MDS). A subset of patients also experienced improvements in hematologic parameters.

In spite of these results, nearly 80% of patients discontinued therapy. But researchers said only about 40% of the discontinuations were drug-related; ie, a result of adverse events, abnormal lab values, or drug inefficacy.

Alan F. List, MD, of the Moffitt Cancer Center in Tampa, Florida, and his colleagues reported these results in the Journal of Clinical Oncology. The team’s research was supported by Novartis Pharmaceuticals, the maker of deferasirox.

The researchers analyzed the effects of the drug in 173 patients with low- or intermediate-1-risk MDS. The median patient age was 71 years (range, 21 to 90 years).

Patients had serum ferritin of at least 1000 μg/L, had received at least 20 units of red blood cells, and had ongoing transfusion requirements. The starting dose of deferasirox was 20 mg/kg per day, with dose escalation up to 40 mg/kg per day.

Patients who completed 1 year of therapy (n=91) experienced a median decrease in serum ferritin of 23%. Serum ferritin decreased by 36.7% in patients who completed 2 years of therapy (n=49) and 36.5% in patients who completed 3 years of therapy (n=33).

The investigators measured LPI quarterly during the first year of the study. Nearly 40% of patients (n=68) had elevated LPI at baseline. But, by week 13, LPI levels had normalized in all of the patients.

Twenty-eight percent of patients (n=51) experienced hematologic improvements according to International Working Group 2006 criteria. However, 7 of these patients had received growth factors or MDS therapy.

By the end of the study period, 79.8% of patients (n=138) had discontinued therapy. The reasons included adverse events in 24.8% (n=43), death in 16.1% (n=28), administrative problems in 15.4% (n=27), and abnormal lab values in 13.2% (n=23).

In addition, 6.9% of patients (n=12) chose not to enroll in the extension phase of the study, and 1.7% of patients (n=3) reported an unsatisfactory therapeutic effect. In 1.1% of cases (n=2), the patient no longer required the drug.

The most common drug-related adverse events were gastrointestinal disturbances and increased serum creatinine. Of the 28 patient deaths, none were linked to deferasirox.

“Overall, this study demonstrated improvements in iron parameters in a group of heavily transfused, lower-risk patients with MDS,” Dr List said. “A randomized trial is warranted to better ascertain the clinical impact of deferasirox therapy in lower-risk patients with MDS.”

Blood smear showing MDS

In a multicenter trial, deferasirox reduced serum ferritin and labile plasma iron (LPI) in transfusion-dependent patients with myelodysplastic syndrome (MDS). A subset of patients also experienced improvements in hematologic parameters.

In spite of these results, nearly 80% of patients discontinued therapy. But researchers said only about 40% of the discontinuations were drug-related; ie, a result of adverse events, abnormal lab values, or drug inefficacy.

Alan F. List, MD, of the Moffitt Cancer Center in Tampa, Florida, and his colleagues reported these results in the Journal of Clinical Oncology. The team’s research was supported by Novartis Pharmaceuticals, the maker of deferasirox.

The researchers analyzed the effects of the drug in 173 patients with low- or intermediate-1-risk MDS. The median patient age was 71 years (range, 21 to 90 years).

Patients had serum ferritin of at least 1000 μg/L, had received at least 20 units of red blood cells, and had ongoing transfusion requirements. The starting dose of deferasirox was 20 mg/kg per day, with dose escalation up to 40 mg/kg per day.

Patients who completed 1 year of therapy (n=91) experienced a median decrease in serum ferritin of 23%. Serum ferritin decreased by 36.7% in patients who completed 2 years of therapy (n=49) and 36.5% in patients who completed 3 years of therapy (n=33).

The investigators measured LPI quarterly during the first year of the study. Nearly 40% of patients (n=68) had elevated LPI at baseline. But, by week 13, LPI levels had normalized in all of the patients.

Twenty-eight percent of patients (n=51) experienced hematologic improvements according to International Working Group 2006 criteria. However, 7 of these patients had received growth factors or MDS therapy.

By the end of the study period, 79.8% of patients (n=138) had discontinued therapy. The reasons included adverse events in 24.8% (n=43), death in 16.1% (n=28), administrative problems in 15.4% (n=27), and abnormal lab values in 13.2% (n=23).

In addition, 6.9% of patients (n=12) chose not to enroll in the extension phase of the study, and 1.7% of patients (n=3) reported an unsatisfactory therapeutic effect. In 1.1% of cases (n=2), the patient no longer required the drug.

The most common drug-related adverse events were gastrointestinal disturbances and increased serum creatinine. Of the 28 patient deaths, none were linked to deferasirox.

“Overall, this study demonstrated improvements in iron parameters in a group of heavily transfused, lower-risk patients with MDS,” Dr List said. “A randomized trial is warranted to better ascertain the clinical impact of deferasirox therapy in lower-risk patients with MDS.”

Blood smear showing MDS

In a multicenter trial, deferasirox reduced serum ferritin and labile plasma iron (LPI) in transfusion-dependent patients with myelodysplastic syndrome (MDS). A subset of patients also experienced improvements in hematologic parameters.

In spite of these results, nearly 80% of patients discontinued therapy. But researchers said only about 40% of the discontinuations were drug-related; ie, a result of adverse events, abnormal lab values, or drug inefficacy.

Alan F. List, MD, of the Moffitt Cancer Center in Tampa, Florida, and his colleagues reported these results in the Journal of Clinical Oncology. The team’s research was supported by Novartis Pharmaceuticals, the maker of deferasirox.

The researchers analyzed the effects of the drug in 173 patients with low- or intermediate-1-risk MDS. The median patient age was 71 years (range, 21 to 90 years).

Patients had serum ferritin of at least 1000 μg/L, had received at least 20 units of red blood cells, and had ongoing transfusion requirements. The starting dose of deferasirox was 20 mg/kg per day, with dose escalation up to 40 mg/kg per day.

Patients who completed 1 year of therapy (n=91) experienced a median decrease in serum ferritin of 23%. Serum ferritin decreased by 36.7% in patients who completed 2 years of therapy (n=49) and 36.5% in patients who completed 3 years of therapy (n=33).

The investigators measured LPI quarterly during the first year of the study. Nearly 40% of patients (n=68) had elevated LPI at baseline. But, by week 13, LPI levels had normalized in all of the patients.

Twenty-eight percent of patients (n=51) experienced hematologic improvements according to International Working Group 2006 criteria. However, 7 of these patients had received growth factors or MDS therapy.

By the end of the study period, 79.8% of patients (n=138) had discontinued therapy. The reasons included adverse events in 24.8% (n=43), death in 16.1% (n=28), administrative problems in 15.4% (n=27), and abnormal lab values in 13.2% (n=23).

In addition, 6.9% of patients (n=12) chose not to enroll in the extension phase of the study, and 1.7% of patients (n=3) reported an unsatisfactory therapeutic effect. In 1.1% of cases (n=2), the patient no longer required the drug.

The most common drug-related adverse events were gastrointestinal disturbances and increased serum creatinine. Of the 28 patient deaths, none were linked to deferasirox.

“Overall, this study demonstrated improvements in iron parameters in a group of heavily transfused, lower-risk patients with MDS,” Dr List said. “A randomized trial is warranted to better ascertain the clinical impact of deferasirox therapy in lower-risk patients with MDS.”

More detailed genetic profiling of patients with acute myeloid leukemia and of those with precursor myelodysplastic syndromes is likely to improve prognostic and therapeutic decision making, according to two separate studies published online March 14 in the New England Journal of Medicine.

In one study, investigators found that the presence of DNMT3A and NPM1 mutations and MLL translocations predicted an improved outcome when patients received high-dose daunorubicin instead of the standard dose in induction chemotherapy for acute myeloid leukemia (AML).

The results suggest that "mutational profiling can be used to determine which patients will benefit from dose-intensive induction therapy," wrote Jay P. Patel of the human oncology and pathogenesis program at Memorial Sloan-Kettering Cancer Center, New York, and his associates.

In the other study, researchers reported that "nearly all" of the bone marrow cells were clonally derived in paired samples of skin and bone marrow from seven patients with myelodysplastic syndromes (MDS) and secondary AML. Founding clones and daughter subclones in all seven paired samples had recurrent gene mutations, including at least one mutation in a coding gene.

"Although clonality is not sufficient to define malignant transformation, it is a cardinal manifestation of most human cancers, and our findings suggest that the myelodysplastic syndromes and secondary AML are both highly clonal hematologic cancers," said Dr. Matthew J. Walter of the departments of internal medicine and genetics at the Siteman Cancer Center, Washington University, St. Louis, and his associates.

Mutational Analysis of Trial Results

In the first study, researchers performed a more-extensive mutational analysis than is typically done to better discriminate among patients with different prognoses.

"Previous studies have suggested that mutational analysis of [the genes] CEBPA, NPM1, and FLT3-ITD can be used to stratify risk among patients with intermediate-risk AML," wrote Mr. Patel and his colleagues.

"We hypothesized that integrated mutational analysis of all known molecular alterations occurring in more than 5% of patients with AML would allow us to identify novel molecular markers of outcome ... and to identify molecularly defined subgroups of patients who would benefit from dose-intensified induction therapy."

For DNA extraction and profiling, the investigators used diagnostic samples of bone marrow and peripheral blood from 398 patients who were participating in the phase III ECOG (Eastern Cooperative Oncology Group) E1900 clinical trial in which two doses of induction therapy were tested. They found that 97.3% of the study subjects had mutations in 18 genes, and performed extensive mutational analysis of these 18 candidate genes.

The results led them to identify three distinct risk groups. Patients with favorable genetic profiles had a 3-year overall survival of 64% and had not yet reached a median survival; those with intermediate-risk genetic profiles had a 3-year survival of 42% and a median survival of 25 months; and those with unfavorable genetic profiles had a 3-year overall survival of 12% and a median survival of 10 months.

These findings were then validated in a separate group of 104 patients from the same clinical trial. The value of the genetic risk profiles was confirmed, with the favorable, intermediate, and unfavorable profiles accurately predicting patient outcomes independently of patient age, white cell count, induction dose, transplantation status, and type of postremission therapy, Mr. Patel and his colleagues said (N. Engl. J. Med. 2012 March 14 [doi:10.1056/NEJMoa1112304]).

Moreover, the 3-year overall survival rate in patients with a mutation in the DNMT3A or NPM1 genes or a MLL translocation was 44% with high-dose chemotherapy vs. 25% with the standard dose. In patients with other genotypes, it was 35% with the high-dose regimen and 39% with the standard dose.

"These data indicate that more detailed genetic analysis may lead to improved risk stratification and identification of patients who can benefit from more intensive induction chemotherapy. The challenge is to provide genetic information in a timely and affordable way and show that this information could prospectively influence treatment decisions," they noted.

Founding MDS Clones Persist in AML

In the second study, Dr. Walter and his associates used bone marrow biopsy specimens from seven patients who progressed from MDS to AML to define changes in the proportion of clonal cells and the genetic architecture that took place during that progression.

Several genes have already been identified that show recurrent mutations during this process, "but our understanding of the total number and clonal distribution of mutations in this disease is limited," they noted.

For each subject, DNA sequences were obtained from samples of normal skin, bone marrow obtained during the MDS stage, and bone marrow obtained during the secondary AML stage, to analyze mutations. In all seven samples, the founding clones (containing 182-660 mutations) persisted in the secondary samples, while acquiring at least one new mutation predicting translational consequences.

"We have found that the proportion of neoplastic bone marrow cells is indistinguishable [between] myelodysplastic-syndrome and secondary-AML samples, suggesting that the myelodysplastic syndromes are as clonal as secondary AML," Dr. Walter and his colleagues said (N. Engl. J. Med. 2012 March 14 [doi:10.1056/NEJMoa1106968]).

There are three major clinical implications, according to the authors.

First, MDS is currently distinguished from secondary AML based on hand counting of bone marrow myeloblasts – a method prone to inaccuracy but nonetheless relied upon to drive major treatment decisions. "Ultimately, identifying the patterns of pathogenic mutations and their clonality in bone marrow samples ... should lead to greater diagnostic certainty and improved prognostic algorithms," the investigators said.

Second, the dominant AML clone was derived from a founding MDS clone in every case, suggesting that "therapies targeted to these early mutations might be the most effective strategy for eliminating disease-propagating cells and improving the rate of response to traditional chemotherapy."

Third, it is possible that progression from MDS to AML "is driven not only by the presence of recurrent mutations ... but also by the clone ([that is], founding vs. daughter) in which they arise." Combining genotyping of samples with analysis of the clonal architecture "may yield more informative biomarkers and a better understanding of the pathogenesis of the myelodysplastic syndrome," Dr. Walter and his associates said.

Dr. Patel’s study was supported by the National Cancer Institute Physical Sciences Oncology Center, Gabrielle’s Angel Fund, the Starr Cancer Consortium, the Peter Solomon Fund, the American Society of Hematology, the Leukemia and Lymphoma Society, the Fund for Scientific Research Flanders, Burroughs Wellcome, the Sackler Center for Biomedical and Research Sciences, and the Howard Hughes Medical Institute. One of Dr. Patel’s associates reported ties to Agios, Incyte, and Novartis. Dr. Walter’s study was supported by the National Institutes of Health, the Howard Hughes Medical Institute, and the National Center for Research Resources. He and his associates reported no financial conflicts of interest.

More detailed genetic profiling of patients with acute myeloid leukemia and of those with precursor myelodysplastic syndromes is likely to improve prognostic and therapeutic decision making, according to two separate studies published online March 14 in the New England Journal of Medicine.

In one study, investigators found that the presence of DNMT3A and NPM1 mutations and MLL translocations predicted an improved outcome when patients received high-dose daunorubicin instead of the standard dose in induction chemotherapy for acute myeloid leukemia (AML).

The results suggest that "mutational profiling can be used to determine which patients will benefit from dose-intensive induction therapy," wrote Jay P. Patel of the human oncology and pathogenesis program at Memorial Sloan-Kettering Cancer Center, New York, and his associates.

In the other study, researchers reported that "nearly all" of the bone marrow cells were clonally derived in paired samples of skin and bone marrow from seven patients with myelodysplastic syndromes (MDS) and secondary AML. Founding clones and daughter subclones in all seven paired samples had recurrent gene mutations, including at least one mutation in a coding gene.

"Although clonality is not sufficient to define malignant transformation, it is a cardinal manifestation of most human cancers, and our findings suggest that the myelodysplastic syndromes and secondary AML are both highly clonal hematologic cancers," said Dr. Matthew J. Walter of the departments of internal medicine and genetics at the Siteman Cancer Center, Washington University, St. Louis, and his associates.

Mutational Analysis of Trial Results

In the first study, researchers performed a more-extensive mutational analysis than is typically done to better discriminate among patients with different prognoses.

"Previous studies have suggested that mutational analysis of [the genes] CEBPA, NPM1, and FLT3-ITD can be used to stratify risk among patients with intermediate-risk AML," wrote Mr. Patel and his colleagues.

"We hypothesized that integrated mutational analysis of all known molecular alterations occurring in more than 5% of patients with AML would allow us to identify novel molecular markers of outcome ... and to identify molecularly defined subgroups of patients who would benefit from dose-intensified induction therapy."

For DNA extraction and profiling, the investigators used diagnostic samples of bone marrow and peripheral blood from 398 patients who were participating in the phase III ECOG (Eastern Cooperative Oncology Group) E1900 clinical trial in which two doses of induction therapy were tested. They found that 97.3% of the study subjects had mutations in 18 genes, and performed extensive mutational analysis of these 18 candidate genes.

The results led them to identify three distinct risk groups. Patients with favorable genetic profiles had a 3-year overall survival of 64% and had not yet reached a median survival; those with intermediate-risk genetic profiles had a 3-year survival of 42% and a median survival of 25 months; and those with unfavorable genetic profiles had a 3-year overall survival of 12% and a median survival of 10 months.

These findings were then validated in a separate group of 104 patients from the same clinical trial. The value of the genetic risk profiles was confirmed, with the favorable, intermediate, and unfavorable profiles accurately predicting patient outcomes independently of patient age, white cell count, induction dose, transplantation status, and type of postremission therapy, Mr. Patel and his colleagues said (N. Engl. J. Med. 2012 March 14 [doi:10.1056/NEJMoa1112304]).

Moreover, the 3-year overall survival rate in patients with a mutation in the DNMT3A or NPM1 genes or a MLL translocation was 44% with high-dose chemotherapy vs. 25% with the standard dose. In patients with other genotypes, it was 35% with the high-dose regimen and 39% with the standard dose.

"These data indicate that more detailed genetic analysis may lead to improved risk stratification and identification of patients who can benefit from more intensive induction chemotherapy. The challenge is to provide genetic information in a timely and affordable way and show that this information could prospectively influence treatment decisions," they noted.

Founding MDS Clones Persist in AML

In the second study, Dr. Walter and his associates used bone marrow biopsy specimens from seven patients who progressed from MDS to AML to define changes in the proportion of clonal cells and the genetic architecture that took place during that progression.

Several genes have already been identified that show recurrent mutations during this process, "but our understanding of the total number and clonal distribution of mutations in this disease is limited," they noted.

For each subject, DNA sequences were obtained from samples of normal skin, bone marrow obtained during the MDS stage, and bone marrow obtained during the secondary AML stage, to analyze mutations. In all seven samples, the founding clones (containing 182-660 mutations) persisted in the secondary samples, while acquiring at least one new mutation predicting translational consequences.

"We have found that the proportion of neoplastic bone marrow cells is indistinguishable [between] myelodysplastic-syndrome and secondary-AML samples, suggesting that the myelodysplastic syndromes are as clonal as secondary AML," Dr. Walter and his colleagues said (N. Engl. J. Med. 2012 March 14 [doi:10.1056/NEJMoa1106968]).

There are three major clinical implications, according to the authors.

First, MDS is currently distinguished from secondary AML based on hand counting of bone marrow myeloblasts – a method prone to inaccuracy but nonetheless relied upon to drive major treatment decisions. "Ultimately, identifying the patterns of pathogenic mutations and their clonality in bone marrow samples ... should lead to greater diagnostic certainty and improved prognostic algorithms," the investigators said.

Second, the dominant AML clone was derived from a founding MDS clone in every case, suggesting that "therapies targeted to these early mutations might be the most effective strategy for eliminating disease-propagating cells and improving the rate of response to traditional chemotherapy."

Third, it is possible that progression from MDS to AML "is driven not only by the presence of recurrent mutations ... but also by the clone ([that is], founding vs. daughter) in which they arise." Combining genotyping of samples with analysis of the clonal architecture "may yield more informative biomarkers and a better understanding of the pathogenesis of the myelodysplastic syndrome," Dr. Walter and his associates said.

Dr. Patel’s study was supported by the National Cancer Institute Physical Sciences Oncology Center, Gabrielle’s Angel Fund, the Starr Cancer Consortium, the Peter Solomon Fund, the American Society of Hematology, the Leukemia and Lymphoma Society, the Fund for Scientific Research Flanders, Burroughs Wellcome, the Sackler Center for Biomedical and Research Sciences, and the Howard Hughes Medical Institute. One of Dr. Patel’s associates reported ties to Agios, Incyte, and Novartis. Dr. Walter’s study was supported by the National Institutes of Health, the Howard Hughes Medical Institute, and the National Center for Research Resources. He and his associates reported no financial conflicts of interest.

More detailed genetic profiling of patients with acute myeloid leukemia and of those with precursor myelodysplastic syndromes is likely to improve prognostic and therapeutic decision making, according to two separate studies published online March 14 in the New England Journal of Medicine.

In one study, investigators found that the presence of DNMT3A and NPM1 mutations and MLL translocations predicted an improved outcome when patients received high-dose daunorubicin instead of the standard dose in induction chemotherapy for acute myeloid leukemia (AML).

The results suggest that "mutational profiling can be used to determine which patients will benefit from dose-intensive induction therapy," wrote Jay P. Patel of the human oncology and pathogenesis program at Memorial Sloan-Kettering Cancer Center, New York, and his associates.

In the other study, researchers reported that "nearly all" of the bone marrow cells were clonally derived in paired samples of skin and bone marrow from seven patients with myelodysplastic syndromes (MDS) and secondary AML. Founding clones and daughter subclones in all seven paired samples had recurrent gene mutations, including at least one mutation in a coding gene.

"Although clonality is not sufficient to define malignant transformation, it is a cardinal manifestation of most human cancers, and our findings suggest that the myelodysplastic syndromes and secondary AML are both highly clonal hematologic cancers," said Dr. Matthew J. Walter of the departments of internal medicine and genetics at the Siteman Cancer Center, Washington University, St. Louis, and his associates.

Mutational Analysis of Trial Results

In the first study, researchers performed a more-extensive mutational analysis than is typically done to better discriminate among patients with different prognoses.

"Previous studies have suggested that mutational analysis of [the genes] CEBPA, NPM1, and FLT3-ITD can be used to stratify risk among patients with intermediate-risk AML," wrote Mr. Patel and his colleagues.

"We hypothesized that integrated mutational analysis of all known molecular alterations occurring in more than 5% of patients with AML would allow us to identify novel molecular markers of outcome ... and to identify molecularly defined subgroups of patients who would benefit from dose-intensified induction therapy."

For DNA extraction and profiling, the investigators used diagnostic samples of bone marrow and peripheral blood from 398 patients who were participating in the phase III ECOG (Eastern Cooperative Oncology Group) E1900 clinical trial in which two doses of induction therapy were tested. They found that 97.3% of the study subjects had mutations in 18 genes, and performed extensive mutational analysis of these 18 candidate genes.

The results led them to identify three distinct risk groups. Patients with favorable genetic profiles had a 3-year overall survival of 64% and had not yet reached a median survival; those with intermediate-risk genetic profiles had a 3-year survival of 42% and a median survival of 25 months; and those with unfavorable genetic profiles had a 3-year overall survival of 12% and a median survival of 10 months.

These findings were then validated in a separate group of 104 patients from the same clinical trial. The value of the genetic risk profiles was confirmed, with the favorable, intermediate, and unfavorable profiles accurately predicting patient outcomes independently of patient age, white cell count, induction dose, transplantation status, and type of postremission therapy, Mr. Patel and his colleagues said (N. Engl. J. Med. 2012 March 14 [doi:10.1056/NEJMoa1112304]).

Moreover, the 3-year overall survival rate in patients with a mutation in the DNMT3A or NPM1 genes or a MLL translocation was 44% with high-dose chemotherapy vs. 25% with the standard dose. In patients with other genotypes, it was 35% with the high-dose regimen and 39% with the standard dose.

"These data indicate that more detailed genetic analysis may lead to improved risk stratification and identification of patients who can benefit from more intensive induction chemotherapy. The challenge is to provide genetic information in a timely and affordable way and show that this information could prospectively influence treatment decisions," they noted.

Founding MDS Clones Persist in AML

In the second study, Dr. Walter and his associates used bone marrow biopsy specimens from seven patients who progressed from MDS to AML to define changes in the proportion of clonal cells and the genetic architecture that took place during that progression.

Several genes have already been identified that show recurrent mutations during this process, "but our understanding of the total number and clonal distribution of mutations in this disease is limited," they noted.

For each subject, DNA sequences were obtained from samples of normal skin, bone marrow obtained during the MDS stage, and bone marrow obtained during the secondary AML stage, to analyze mutations. In all seven samples, the founding clones (containing 182-660 mutations) persisted in the secondary samples, while acquiring at least one new mutation predicting translational consequences.

"We have found that the proportion of neoplastic bone marrow cells is indistinguishable [between] myelodysplastic-syndrome and secondary-AML samples, suggesting that the myelodysplastic syndromes are as clonal as secondary AML," Dr. Walter and his colleagues said (N. Engl. J. Med. 2012 March 14 [doi:10.1056/NEJMoa1106968]).

There are three major clinical implications, according to the authors.

First, MDS is currently distinguished from secondary AML based on hand counting of bone marrow myeloblasts – a method prone to inaccuracy but nonetheless relied upon to drive major treatment decisions. "Ultimately, identifying the patterns of pathogenic mutations and their clonality in bone marrow samples ... should lead to greater diagnostic certainty and improved prognostic algorithms," the investigators said.

Second, the dominant AML clone was derived from a founding MDS clone in every case, suggesting that "therapies targeted to these early mutations might be the most effective strategy for eliminating disease-propagating cells and improving the rate of response to traditional chemotherapy."

Third, it is possible that progression from MDS to AML "is driven not only by the presence of recurrent mutations ... but also by the clone ([that is], founding vs. daughter) in which they arise." Combining genotyping of samples with analysis of the clonal architecture "may yield more informative biomarkers and a better understanding of the pathogenesis of the myelodysplastic syndrome," Dr. Walter and his associates said.

Dr. Patel’s study was supported by the National Cancer Institute Physical Sciences Oncology Center, Gabrielle’s Angel Fund, the Starr Cancer Consortium, the Peter Solomon Fund, the American Society of Hematology, the Leukemia and Lymphoma Society, the Fund for Scientific Research Flanders, Burroughs Wellcome, the Sackler Center for Biomedical and Research Sciences, and the Howard Hughes Medical Institute. One of Dr. Patel’s associates reported ties to Agios, Incyte, and Novartis. Dr. Walter’s study was supported by the National Institutes of Health, the Howard Hughes Medical Institute, and the National Center for Research Resources. He and his associates reported no financial conflicts of interest.