Leukemia, Myelodysplasia, Transplantation

Micrograph showing DLBCL

MAINZ/FRANKFURT, GERMANY—Outcomes of treatment with a third-generation chimeric antigen receptor (CAR) T-cell therapy are associated with a patient’s immune status, according to a phase 1/2a trial.

The CD19-specific CAR T-cell therapy produced a complete response (CR) in 6 of 15 patients with relapsed/refractory CD19-positive leukemia or lymphoma.

Though all responders eventually relapsed, 4 patients—including 2 with stable disease (SD) after treatment—responded to subsequent therapy and are still alive, 1 of them beyond 36 months.

An analysis of blood samples taken throughout the study revealed that a patient’s immune status was associated with treatment failure and overall survival.

Tanja Lövgren, PhD, of Uppsala University in Sweden, and her colleagues presented these findings at the Third CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival (abstract B156).

“CD19-specific CAR T-cell therapy has yielded remarkable response rates for patients who have B-cell acute lymphoblastic leukemia,” Dr Lövgren said. “However, many patients relapse.”

“In addition, response rates are more variable for patients who have other CD19-positive B-cell malignancies, and many patients experience serious adverse events. We set out to investigate the safety and effectiveness of a third-generation CD19-specific CAR T-cell therapy and to identify potential biomarkers of treatment outcome.”

Dr Lövgren and her colleagues studied 15 patients (ages 24-72) who had relapsed or refractory CD19-positive B-cell malignancies:

• Six patients with diffuse large B-cell lymphoma (DLBCL), including 3 cases that were transformed from follicular lymphoma (FL)
• Four patients with pre-B acute lymphoblastic leukemia (ALL)
• Two patients with mantle cell lymphoma (MCL)
• Two patients with chronic lymphocytic leukemia (CLL)
• One patient with FL transformed from Burkitt lymphoma.

Eleven patients received preconditioning with cyclophosphamide (500 mg/m²) and fludarabine (3 doses at 25 mg/m²).

All patients received CAR T cells at 1 x 10⁸, 2 x 10⁷, or 2 x 10⁸ cells/m². These were autologous, CD19-targeting CAR T cells with 3 intracellular signaling domains derived from CD3 zeta, CD28, and 4-1BB.

The researchers assessed tumor responses via bone marrow/blood analysis and/or radiology, depending on the type of malignancy. The team also collected blood samples before CAR T-cell infusion and at multiple times after infusion.

Efficacy and safety

Six patients achieved a CR to treatment—3 with DLBCL (1 transformed), 2 with ALL, and 1 with CLL. Two patients had SD—1 with MCL and 1 with CLL. The remaining patients progressed.

All patients with a CR eventually relapsed. The median duration of CR was 5 months (range, 3-24 months).

Four patients—2 complete responders and 2 with SD—responded well to subsequent therapy and are still alive with 27 to 36 months of follow-up. This includes 1 patient with DLBCL, 1 with MCL, and 2 with CLL.

Four patients had serious adverse events. Three had cytokine-release syndrome, and 2 had neurological toxicity.

All cases of cytokine-release syndrome resolved after treatment with corticosteroids/anti-IL6R therapy. The neurological toxicity resolved spontaneously.

Immune status

An analysis of the blood samples taken throughout the study showed that high levels of monocytic myeloid-derived suppressor cells (MDSCs) prior to treatment was associated with decreased overall survival. In addition, increased levels of MDSCs after treatment preceded treatment failure.

Furthermore, high plasma levels of immunosuppressive factors—such as PD-L1 and PD-L2—after treatment were associated with decreased overall survival.

High plasma levels of biomarkers of an immunostimulatory environment—including IL-12, DC-LAMP, TRAIL, and FasL—before the administration of CAR T-cell therapy was associated with increased overall survival.

“[A]n immunostimulatory environment was associated with improved overall survival, while immunosuppressive cells and factors were associated with treatment failure and decreased overall survival,” Dr Lövgren said.

“We are hoping to follow up this study with another clinical trial that will combine CAR T-cell therapy with chemotherapy known to decrease the number of monocytic myeloid-derived suppressive cells. We are also looking to further optimize the CAR T-cell therapy.”

Dr Lövgren said the main limitations of this study are that it only included 15 patients, the patients had several different malignancies, and some patients may have been too sick to respond to any treatment.

This study was supported by funds from AFA Insurance AB, the Swedish Cancer Society, the Swedish Research Council, the Lions Fund at Uppsala University Hospital, and the Swedish State Support for Clinical Research. Dr Lövgren declared no conflicts of interest.

Micrograph showing DLBCL

MAINZ/FRANKFURT, GERMANY—Outcomes of treatment with a third-generation chimeric antigen receptor (CAR) T-cell therapy are associated with a patient’s immune status, according to a phase 1/2a trial.

The CD19-specific CAR T-cell therapy produced a complete response (CR) in 6 of 15 patients with relapsed/refractory CD19-positive leukemia or lymphoma.

Though all responders eventually relapsed, 4 patients—including 2 with stable disease (SD) after treatment—responded to subsequent therapy and are still alive, 1 of them beyond 36 months.

An analysis of blood samples taken throughout the study revealed that a patient’s immune status was associated with treatment failure and overall survival.

Tanja Lövgren, PhD, of Uppsala University in Sweden, and her colleagues presented these findings at the Third CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival (abstract B156).

“CD19-specific CAR T-cell therapy has yielded remarkable response rates for patients who have B-cell acute lymphoblastic leukemia,” Dr Lövgren said. “However, many patients relapse.”

“In addition, response rates are more variable for patients who have other CD19-positive B-cell malignancies, and many patients experience serious adverse events. We set out to investigate the safety and effectiveness of a third-generation CD19-specific CAR T-cell therapy and to identify potential biomarkers of treatment outcome.”

Dr Lövgren and her colleagues studied 15 patients (ages 24-72) who had relapsed or refractory CD19-positive B-cell malignancies:

• Six patients with diffuse large B-cell lymphoma (DLBCL), including 3 cases that were transformed from follicular lymphoma (FL)
• Four patients with pre-B acute lymphoblastic leukemia (ALL)
• Two patients with mantle cell lymphoma (MCL)
• Two patients with chronic lymphocytic leukemia (CLL)
• One patient with FL transformed from Burkitt lymphoma.

Eleven patients received preconditioning with cyclophosphamide (500 mg/m²) and fludarabine (3 doses at 25 mg/m²).

All patients received CAR T cells at 1 x 10⁸, 2 x 10⁷, or 2 x 10⁸ cells/m². These were autologous, CD19-targeting CAR T cells with 3 intracellular signaling domains derived from CD3 zeta, CD28, and 4-1BB.

The researchers assessed tumor responses via bone marrow/blood analysis and/or radiology, depending on the type of malignancy. The team also collected blood samples before CAR T-cell infusion and at multiple times after infusion.

Efficacy and safety

Six patients achieved a CR to treatment—3 with DLBCL (1 transformed), 2 with ALL, and 1 with CLL. Two patients had SD—1 with MCL and 1 with CLL. The remaining patients progressed.

All patients with a CR eventually relapsed. The median duration of CR was 5 months (range, 3-24 months).

Four patients—2 complete responders and 2 with SD—responded well to subsequent therapy and are still alive with 27 to 36 months of follow-up. This includes 1 patient with DLBCL, 1 with MCL, and 2 with CLL.

Four patients had serious adverse events. Three had cytokine-release syndrome, and 2 had neurological toxicity.

All cases of cytokine-release syndrome resolved after treatment with corticosteroids/anti-IL6R therapy. The neurological toxicity resolved spontaneously.

Immune status

An analysis of the blood samples taken throughout the study showed that high levels of monocytic myeloid-derived suppressor cells (MDSCs) prior to treatment was associated with decreased overall survival. In addition, increased levels of MDSCs after treatment preceded treatment failure.

Furthermore, high plasma levels of immunosuppressive factors—such as PD-L1 and PD-L2—after treatment were associated with decreased overall survival.

High plasma levels of biomarkers of an immunostimulatory environment—including IL-12, DC-LAMP, TRAIL, and FasL—before the administration of CAR T-cell therapy was associated with increased overall survival.

“[A]n immunostimulatory environment was associated with improved overall survival, while immunosuppressive cells and factors were associated with treatment failure and decreased overall survival,” Dr Lövgren said.

“We are hoping to follow up this study with another clinical trial that will combine CAR T-cell therapy with chemotherapy known to decrease the number of monocytic myeloid-derived suppressive cells. We are also looking to further optimize the CAR T-cell therapy.”

Dr Lövgren said the main limitations of this study are that it only included 15 patients, the patients had several different malignancies, and some patients may have been too sick to respond to any treatment.

This study was supported by funds from AFA Insurance AB, the Swedish Cancer Society, the Swedish Research Council, the Lions Fund at Uppsala University Hospital, and the Swedish State Support for Clinical Research. Dr Lövgren declared no conflicts of interest.

Micrograph showing DLBCL

MAINZ/FRANKFURT, GERMANY—Outcomes of treatment with a third-generation chimeric antigen receptor (CAR) T-cell therapy are associated with a patient’s immune status, according to a phase 1/2a trial.

The CD19-specific CAR T-cell therapy produced a complete response (CR) in 6 of 15 patients with relapsed/refractory CD19-positive leukemia or lymphoma.

Though all responders eventually relapsed, 4 patients—including 2 with stable disease (SD) after treatment—responded to subsequent therapy and are still alive, 1 of them beyond 36 months.

An analysis of blood samples taken throughout the study revealed that a patient’s immune status was associated with treatment failure and overall survival.

Tanja Lövgren, PhD, of Uppsala University in Sweden, and her colleagues presented these findings at the Third CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival (abstract B156).

“CD19-specific CAR T-cell therapy has yielded remarkable response rates for patients who have B-cell acute lymphoblastic leukemia,” Dr Lövgren said. “However, many patients relapse.”

“In addition, response rates are more variable for patients who have other CD19-positive B-cell malignancies, and many patients experience serious adverse events. We set out to investigate the safety and effectiveness of a third-generation CD19-specific CAR T-cell therapy and to identify potential biomarkers of treatment outcome.”

Dr Lövgren and her colleagues studied 15 patients (ages 24-72) who had relapsed or refractory CD19-positive B-cell malignancies:

• Six patients with diffuse large B-cell lymphoma (DLBCL), including 3 cases that were transformed from follicular lymphoma (FL)
• Four patients with pre-B acute lymphoblastic leukemia (ALL)
• Two patients with mantle cell lymphoma (MCL)
• Two patients with chronic lymphocytic leukemia (CLL)
• One patient with FL transformed from Burkitt lymphoma.

Eleven patients received preconditioning with cyclophosphamide (500 mg/m²) and fludarabine (3 doses at 25 mg/m²).

All patients received CAR T cells at 1 x 10⁸, 2 x 10⁷, or 2 x 10⁸ cells/m². These were autologous, CD19-targeting CAR T cells with 3 intracellular signaling domains derived from CD3 zeta, CD28, and 4-1BB.

The researchers assessed tumor responses via bone marrow/blood analysis and/or radiology, depending on the type of malignancy. The team also collected blood samples before CAR T-cell infusion and at multiple times after infusion.

Efficacy and safety

Six patients achieved a CR to treatment—3 with DLBCL (1 transformed), 2 with ALL, and 1 with CLL. Two patients had SD—1 with MCL and 1 with CLL. The remaining patients progressed.

All patients with a CR eventually relapsed. The median duration of CR was 5 months (range, 3-24 months).

Four patients—2 complete responders and 2 with SD—responded well to subsequent therapy and are still alive with 27 to 36 months of follow-up. This includes 1 patient with DLBCL, 1 with MCL, and 2 with CLL.

Four patients had serious adverse events. Three had cytokine-release syndrome, and 2 had neurological toxicity.

All cases of cytokine-release syndrome resolved after treatment with corticosteroids/anti-IL6R therapy. The neurological toxicity resolved spontaneously.

Immune status

An analysis of the blood samples taken throughout the study showed that high levels of monocytic myeloid-derived suppressor cells (MDSCs) prior to treatment was associated with decreased overall survival. In addition, increased levels of MDSCs after treatment preceded treatment failure.

Furthermore, high plasma levels of immunosuppressive factors—such as PD-L1 and PD-L2—after treatment were associated with decreased overall survival.

High plasma levels of biomarkers of an immunostimulatory environment—including IL-12, DC-LAMP, TRAIL, and FasL—before the administration of CAR T-cell therapy was associated with increased overall survival.

“[A]n immunostimulatory environment was associated with improved overall survival, while immunosuppressive cells and factors were associated with treatment failure and decreased overall survival,” Dr Lövgren said.

“We are hoping to follow up this study with another clinical trial that will combine CAR T-cell therapy with chemotherapy known to decrease the number of monocytic myeloid-derived suppressive cells. We are also looking to further optimize the CAR T-cell therapy.”

Dr Lövgren said the main limitations of this study are that it only included 15 patients, the patients had several different malignancies, and some patients may have been too sick to respond to any treatment.

This study was supported by funds from AFA Insurance AB, the Swedish Cancer Society, the Swedish Research Council, the Lions Fund at Uppsala University Hospital, and the Swedish State Support for Clinical Research. Dr Lövgren declared no conflicts of interest.

Photo by Rhoda Baer

MADRID—New research indicates there is a lack of specialized care in Europe for adolescents and young adults (AYAs) with cancer.

In a survey of more than 200 European healthcare professionals, more than two-thirds of respondents said they did not have access to specialized services where adult and pediatric cancer specialists work together to plan treatment and deliver care to AYAs with cancer.

This lack of services was more pronounced in Eastern and Southern Europe than Western and Northern Europe.

“The survey found gaps and disparities in cancer care for adolescents and young adults across Europe,” said study author Emmanouil Saloustros, MD, a consultant medical oncologist at General Hospital of Heraklion “Venizelio” in Heraklion, Crete, Greece.

Dr Saloustros and his colleagues presented these findings at the ESMO 2017 Congress (abstract 1438O_PR) and reported them in ESMO Open.

The researchers sent an online survey on the status of care and research in AYAs (ages 15-39) to members of the European Society for Medical Oncology (ESMO) and the European Society for Paediatric Oncology (SIOPE).

The team received responses from 266 healthcare professionals across Europe—55% of them female. Eleven percent were age 20–29, 29% were age 30–39, 26% were age 40–49, 25% were age 50–59, and 9% were age 60 and older.

Forty-eight percent were medical oncologists, 21% were pediatric oncologists, 8% were in training, 5% were hematologists, 4% were radiation oncologists, and 2% were surgical oncologists. The rest were other types of healthcare professionals, such as oncology nurses.

Fifty-two percent of respondents worked in general academic centers, 19% in specialized cancer hospitals, and 11% in pediatric hospitals. Sixty percent of respondents had been trained to treat adults with cancer, 25% to treat pediatric cancer patients, and 15% were trained to treat both.

In the past year, 32% of respondents had treated between 1 and 10 AYAs, 28% had treated 11 to 20, 17% had treated between 21 and 50, and 16% had treated more than 50 AYAs.

Results

The following results are based on data from 242 survey respondents. (The other respondents did not provide complete information.)

More than two-thirds (67%) of the respondents said they did not have access to specialized services for AYAs with cancer. This was true for 88% of respondents in Southern Europe, 87% in Eastern Europe, 55% in Western Europe, and 40% in Northern Europe.

Sixty-two percent of hematologists said they had access to AYA services, as did 44% of pediatric oncologists and 27% of medical oncologists.

Eighty-six percent of respondents said their AYA patients had access to professional psychological support. This was true for 97% of respondents in Western Europe, 82% in Southern Europe, 81% in Northern Europe, and 74% in Eastern Europe.

Fifty-four percent of all respondents said their AYAs had access to a support group with other young people. This was true for 81% of respondents in Northern Europe, 60% in Western Europe, 48% in Eastern Europe, and 34% in Southern Europe.

Thirty-six percent of all respondents said their AYAs had access to an age-specific specialist nurse. This was true for 53% of respondents in Western Europe, 51% in Northern Europe, 32% in Eastern Europe, and 10% in Southern Europe.

Sixty-two percent of respondents said their institution provided AYAs with access to a fertility specialist. This was true for 78% of respondents in Western Europe, 72% in Northern Europe, 52% in Southern Europe, and 24% in Eastern Europe.

“These patients have specific needs that are not covered by pediatric or general oncology centers or classical medical oncology centers, and this survey shows that most do not have access to the recommended special care,” said Gilles Vassal, director of clinical research at Gustave Roussy in Villejuif, France, and past president of SIOPE (who was not involved in this study).

“Countries without these services can look at existing examples—such as in the UK and France—to build teams equipped to improve survival and survivorship for adolescents and young adults with cancer.”

Photo by Rhoda Baer

MADRID—New research indicates there is a lack of specialized care in Europe for adolescents and young adults (AYAs) with cancer.

In a survey of more than 200 European healthcare professionals, more than two-thirds of respondents said they did not have access to specialized services where adult and pediatric cancer specialists work together to plan treatment and deliver care to AYAs with cancer.

This lack of services was more pronounced in Eastern and Southern Europe than Western and Northern Europe.

“The survey found gaps and disparities in cancer care for adolescents and young adults across Europe,” said study author Emmanouil Saloustros, MD, a consultant medical oncologist at General Hospital of Heraklion “Venizelio” in Heraklion, Crete, Greece.

Dr Saloustros and his colleagues presented these findings at the ESMO 2017 Congress (abstract 1438O_PR) and reported them in ESMO Open.

The researchers sent an online survey on the status of care and research in AYAs (ages 15-39) to members of the European Society for Medical Oncology (ESMO) and the European Society for Paediatric Oncology (SIOPE).

The team received responses from 266 healthcare professionals across Europe—55% of them female. Eleven percent were age 20–29, 29% were age 30–39, 26% were age 40–49, 25% were age 50–59, and 9% were age 60 and older.

Forty-eight percent were medical oncologists, 21% were pediatric oncologists, 8% were in training, 5% were hematologists, 4% were radiation oncologists, and 2% were surgical oncologists. The rest were other types of healthcare professionals, such as oncology nurses.

Fifty-two percent of respondents worked in general academic centers, 19% in specialized cancer hospitals, and 11% in pediatric hospitals. Sixty percent of respondents had been trained to treat adults with cancer, 25% to treat pediatric cancer patients, and 15% were trained to treat both.

In the past year, 32% of respondents had treated between 1 and 10 AYAs, 28% had treated 11 to 20, 17% had treated between 21 and 50, and 16% had treated more than 50 AYAs.

Results

The following results are based on data from 242 survey respondents. (The other respondents did not provide complete information.)

More than two-thirds (67%) of the respondents said they did not have access to specialized services for AYAs with cancer. This was true for 88% of respondents in Southern Europe, 87% in Eastern Europe, 55% in Western Europe, and 40% in Northern Europe.

Sixty-two percent of hematologists said they had access to AYA services, as did 44% of pediatric oncologists and 27% of medical oncologists.

Eighty-six percent of respondents said their AYA patients had access to professional psychological support. This was true for 97% of respondents in Western Europe, 82% in Southern Europe, 81% in Northern Europe, and 74% in Eastern Europe.

Fifty-four percent of all respondents said their AYAs had access to a support group with other young people. This was true for 81% of respondents in Northern Europe, 60% in Western Europe, 48% in Eastern Europe, and 34% in Southern Europe.

Thirty-six percent of all respondents said their AYAs had access to an age-specific specialist nurse. This was true for 53% of respondents in Western Europe, 51% in Northern Europe, 32% in Eastern Europe, and 10% in Southern Europe.

Sixty-two percent of respondents said their institution provided AYAs with access to a fertility specialist. This was true for 78% of respondents in Western Europe, 72% in Northern Europe, 52% in Southern Europe, and 24% in Eastern Europe.

“These patients have specific needs that are not covered by pediatric or general oncology centers or classical medical oncology centers, and this survey shows that most do not have access to the recommended special care,” said Gilles Vassal, director of clinical research at Gustave Roussy in Villejuif, France, and past president of SIOPE (who was not involved in this study).

“Countries without these services can look at existing examples—such as in the UK and France—to build teams equipped to improve survival and survivorship for adolescents and young adults with cancer.”

Photo by Rhoda Baer

MADRID—New research indicates there is a lack of specialized care in Europe for adolescents and young adults (AYAs) with cancer.

In a survey of more than 200 European healthcare professionals, more than two-thirds of respondents said they did not have access to specialized services where adult and pediatric cancer specialists work together to plan treatment and deliver care to AYAs with cancer.

This lack of services was more pronounced in Eastern and Southern Europe than Western and Northern Europe.

“The survey found gaps and disparities in cancer care for adolescents and young adults across Europe,” said study author Emmanouil Saloustros, MD, a consultant medical oncologist at General Hospital of Heraklion “Venizelio” in Heraklion, Crete, Greece.

Dr Saloustros and his colleagues presented these findings at the ESMO 2017 Congress (abstract 1438O_PR) and reported them in ESMO Open.

The researchers sent an online survey on the status of care and research in AYAs (ages 15-39) to members of the European Society for Medical Oncology (ESMO) and the European Society for Paediatric Oncology (SIOPE).

The team received responses from 266 healthcare professionals across Europe—55% of them female. Eleven percent were age 20–29, 29% were age 30–39, 26% were age 40–49, 25% were age 50–59, and 9% were age 60 and older.

Forty-eight percent were medical oncologists, 21% were pediatric oncologists, 8% were in training, 5% were hematologists, 4% were radiation oncologists, and 2% were surgical oncologists. The rest were other types of healthcare professionals, such as oncology nurses.

Fifty-two percent of respondents worked in general academic centers, 19% in specialized cancer hospitals, and 11% in pediatric hospitals. Sixty percent of respondents had been trained to treat adults with cancer, 25% to treat pediatric cancer patients, and 15% were trained to treat both.

In the past year, 32% of respondents had treated between 1 and 10 AYAs, 28% had treated 11 to 20, 17% had treated between 21 and 50, and 16% had treated more than 50 AYAs.

Results

The following results are based on data from 242 survey respondents. (The other respondents did not provide complete information.)

More than two-thirds (67%) of the respondents said they did not have access to specialized services for AYAs with cancer. This was true for 88% of respondents in Southern Europe, 87% in Eastern Europe, 55% in Western Europe, and 40% in Northern Europe.

Sixty-two percent of hematologists said they had access to AYA services, as did 44% of pediatric oncologists and 27% of medical oncologists.

Eighty-six percent of respondents said their AYA patients had access to professional psychological support. This was true for 97% of respondents in Western Europe, 82% in Southern Europe, 81% in Northern Europe, and 74% in Eastern Europe.

Fifty-four percent of all respondents said their AYAs had access to a support group with other young people. This was true for 81% of respondents in Northern Europe, 60% in Western Europe, 48% in Eastern Europe, and 34% in Southern Europe.

Thirty-six percent of all respondents said their AYAs had access to an age-specific specialist nurse. This was true for 53% of respondents in Western Europe, 51% in Northern Europe, 32% in Eastern Europe, and 10% in Southern Europe.

Sixty-two percent of respondents said their institution provided AYAs with access to a fertility specialist. This was true for 78% of respondents in Western Europe, 72% in Northern Europe, 52% in Southern Europe, and 24% in Eastern Europe.

“These patients have specific needs that are not covered by pediatric or general oncology centers or classical medical oncology centers, and this survey shows that most do not have access to the recommended special care,” said Gilles Vassal, director of clinical research at Gustave Roussy in Villejuif, France, and past president of SIOPE (who was not involved in this study).

“Countries without these services can look at existing examples—such as in the UK and France—to build teams equipped to improve survival and survivorship for adolescents and young adults with cancer.”

Photo by Rhoda Baer

Deaths from cancer are on the decline in the US, but new cases of cancer are on the rise, according to the 7th annual American Association for Cancer Research (AACR) Cancer Progress Report.

The data suggest the cancer death rate declined by 35% from 1991 to 2014 for children and by 25% for adults, a reduction that translates to 2.1 million cancer deaths avoided.

However, 600,920 people in the US are projected to die from cancer in 2017.

And the number of new cancer cases is predicted to rise from 1.7 million in 2017 to 2.3 million in 2030.

The report also estimates there will be 62,130 new cases of leukemia in 2017 and 24,500 leukemia deaths this year.

This includes:

• 5970 cases of acute lymphocytic leukemia and 1440 deaths
• 20,110 cases of chronic lymphocytic leukemia and 4660 deaths
• 21,380 cases of acute myeloid leukemia (AML) and 10,590 deaths
• 8950 cases of chronic myeloid leukemia and 1080 deaths.

The estimate for lymphomas is 80,500 new cases and 21,210 deaths.

This includes:

• 8260 cases of Hodgkin lymphoma (HL) and 1070 deaths
• 72,240 cases of non-Hodgkin lymphoma and 20,140 deaths.

The estimate for myeloma is 30,280 new cases and 12,590 deaths.

The report says the estimated new cases of cancer are based on cancer incidence rates from 49 states and the District of Columbia from 1995 through 2013, as reported by the North American Association of Central Cancer Registries. This represents about 98% of the US population.

The estimated deaths are based on US mortality data from 1997 through 2013, taken from the National Center for Health Statistics of the Centers for Disease Control and Prevention.

Drug approvals

The AACR report notes that, between August 1, 2016, and July 31, 2017, the US Food and Drug Administration (FDA) approved new uses for 15 anticancer agents, 9 of which had no previous FDA approval.

Five of the agents are immunotherapies, which the report dubs “revolutionary treatments that are increasing survival and improving quality of life for patients.”

Among the recently approved therapies are 3 used for hematology indications:

• Ibrutinib (Imbruvica), approved to treat patients with relapsed/refractory marginal zone lymphoma who require systemic therapy and have received at least 1 prior anti-CD20-based therapy
• Midostaurin (Rydapt), approved as monotherapy for adults with advanced systemic mastocytosis and for use in combination with standard cytarabine and daunorubicin induction, followed by cytarabine consolidation, in adults with newly diagnosed AML who are FLT3 mutation-positive, as detected by an FDA-approved test.
• Pembrolizumab (Keytruda), approved to treat adult and pediatric patients with refractory classical HL or those with classical HL who have relapsed after 3 or more prior lines of therapy.

Disparities and costs

The AACR report points out that advances against cancer have not benefited everyone equally, and cancer health disparities are some of the most pressing challenges.

Among the disparities listed is the fact that adolescents and young adults (ages 15 to 39) with AML have a 5-year relative survival rate that is 22% lower than that of children (ages 1 to 14) with AML.

And Hispanic children are 24% more likely to develop leukemia than non-Hispanic children.

Another concern mentioned in the report is the cost of cancer care. The direct medical costs of cancer care in 2014 were estimated to be nearly $87.6 billion. This number does not include the indirect costs of lost productivity due to cancer-related morbidity and mortality.

With this in mind, the AACR is calling for a $2 billion increase in funding for the National Institutes of Health in fiscal year 2018, for a total funding level of $36.2 billion.

The AACR also recommends an $80 million increase in the FDA budget, bringing it to $2.8 billion for fiscal year 2018.

Photo by Rhoda Baer

Deaths from cancer are on the decline in the US, but new cases of cancer are on the rise, according to the 7th annual American Association for Cancer Research (AACR) Cancer Progress Report.

The data suggest the cancer death rate declined by 35% from 1991 to 2014 for children and by 25% for adults, a reduction that translates to 2.1 million cancer deaths avoided.

However, 600,920 people in the US are projected to die from cancer in 2017.

And the number of new cancer cases is predicted to rise from 1.7 million in 2017 to 2.3 million in 2030.

The report also estimates there will be 62,130 new cases of leukemia in 2017 and 24,500 leukemia deaths this year.

This includes:

• 5970 cases of acute lymphocytic leukemia and 1440 deaths
• 20,110 cases of chronic lymphocytic leukemia and 4660 deaths
• 21,380 cases of acute myeloid leukemia (AML) and 10,590 deaths
• 8950 cases of chronic myeloid leukemia and 1080 deaths.

The estimate for lymphomas is 80,500 new cases and 21,210 deaths.

This includes:

• 8260 cases of Hodgkin lymphoma (HL) and 1070 deaths
• 72,240 cases of non-Hodgkin lymphoma and 20,140 deaths.

The estimate for myeloma is 30,280 new cases and 12,590 deaths.

The report says the estimated new cases of cancer are based on cancer incidence rates from 49 states and the District of Columbia from 1995 through 2013, as reported by the North American Association of Central Cancer Registries. This represents about 98% of the US population.

The estimated deaths are based on US mortality data from 1997 through 2013, taken from the National Center for Health Statistics of the Centers for Disease Control and Prevention.

Drug approvals

The AACR report notes that, between August 1, 2016, and July 31, 2017, the US Food and Drug Administration (FDA) approved new uses for 15 anticancer agents, 9 of which had no previous FDA approval.

Five of the agents are immunotherapies, which the report dubs “revolutionary treatments that are increasing survival and improving quality of life for patients.”

Among the recently approved therapies are 3 used for hematology indications:

• Ibrutinib (Imbruvica), approved to treat patients with relapsed/refractory marginal zone lymphoma who require systemic therapy and have received at least 1 prior anti-CD20-based therapy
• Midostaurin (Rydapt), approved as monotherapy for adults with advanced systemic mastocytosis and for use in combination with standard cytarabine and daunorubicin induction, followed by cytarabine consolidation, in adults with newly diagnosed AML who are FLT3 mutation-positive, as detected by an FDA-approved test.
• Pembrolizumab (Keytruda), approved to treat adult and pediatric patients with refractory classical HL or those with classical HL who have relapsed after 3 or more prior lines of therapy.

Disparities and costs

The AACR report points out that advances against cancer have not benefited everyone equally, and cancer health disparities are some of the most pressing challenges.

Among the disparities listed is the fact that adolescents and young adults (ages 15 to 39) with AML have a 5-year relative survival rate that is 22% lower than that of children (ages 1 to 14) with AML.

And Hispanic children are 24% more likely to develop leukemia than non-Hispanic children.

Another concern mentioned in the report is the cost of cancer care. The direct medical costs of cancer care in 2014 were estimated to be nearly $87.6 billion. This number does not include the indirect costs of lost productivity due to cancer-related morbidity and mortality.

With this in mind, the AACR is calling for a $2 billion increase in funding for the National Institutes of Health in fiscal year 2018, for a total funding level of $36.2 billion.

The AACR also recommends an $80 million increase in the FDA budget, bringing it to $2.8 billion for fiscal year 2018.

Photo by Rhoda Baer

Deaths from cancer are on the decline in the US, but new cases of cancer are on the rise, according to the 7th annual American Association for Cancer Research (AACR) Cancer Progress Report.

The data suggest the cancer death rate declined by 35% from 1991 to 2014 for children and by 25% for adults, a reduction that translates to 2.1 million cancer deaths avoided.

However, 600,920 people in the US are projected to die from cancer in 2017.

And the number of new cancer cases is predicted to rise from 1.7 million in 2017 to 2.3 million in 2030.

The report also estimates there will be 62,130 new cases of leukemia in 2017 and 24,500 leukemia deaths this year.

This includes:

• 5970 cases of acute lymphocytic leukemia and 1440 deaths
• 20,110 cases of chronic lymphocytic leukemia and 4660 deaths
• 21,380 cases of acute myeloid leukemia (AML) and 10,590 deaths
• 8950 cases of chronic myeloid leukemia and 1080 deaths.

The estimate for lymphomas is 80,500 new cases and 21,210 deaths.

This includes:

• 8260 cases of Hodgkin lymphoma (HL) and 1070 deaths
• 72,240 cases of non-Hodgkin lymphoma and 20,140 deaths.

The estimate for myeloma is 30,280 new cases and 12,590 deaths.

The report says the estimated new cases of cancer are based on cancer incidence rates from 49 states and the District of Columbia from 1995 through 2013, as reported by the North American Association of Central Cancer Registries. This represents about 98% of the US population.

The estimated deaths are based on US mortality data from 1997 through 2013, taken from the National Center for Health Statistics of the Centers for Disease Control and Prevention.

Drug approvals

The AACR report notes that, between August 1, 2016, and July 31, 2017, the US Food and Drug Administration (FDA) approved new uses for 15 anticancer agents, 9 of which had no previous FDA approval.

Five of the agents are immunotherapies, which the report dubs “revolutionary treatments that are increasing survival and improving quality of life for patients.”

Among the recently approved therapies are 3 used for hematology indications:

• Ibrutinib (Imbruvica), approved to treat patients with relapsed/refractory marginal zone lymphoma who require systemic therapy and have received at least 1 prior anti-CD20-based therapy
• Midostaurin (Rydapt), approved as monotherapy for adults with advanced systemic mastocytosis and for use in combination with standard cytarabine and daunorubicin induction, followed by cytarabine consolidation, in adults with newly diagnosed AML who are FLT3 mutation-positive, as detected by an FDA-approved test.
• Pembrolizumab (Keytruda), approved to treat adult and pediatric patients with refractory classical HL or those with classical HL who have relapsed after 3 or more prior lines of therapy.

Disparities and costs

The AACR report points out that advances against cancer have not benefited everyone equally, and cancer health disparities are some of the most pressing challenges.

Among the disparities listed is the fact that adolescents and young adults (ages 15 to 39) with AML have a 5-year relative survival rate that is 22% lower than that of children (ages 1 to 14) with AML.

And Hispanic children are 24% more likely to develop leukemia than non-Hispanic children.

Another concern mentioned in the report is the cost of cancer care. The direct medical costs of cancer care in 2014 were estimated to be nearly $87.6 billion. This number does not include the indirect costs of lost productivity due to cancer-related morbidity and mortality.

With this in mind, the AACR is calling for a $2 billion increase in funding for the National Institutes of Health in fiscal year 2018, for a total funding level of $36.2 billion.

The AACR also recommends an $80 million increase in the FDA budget, bringing it to $2.8 billion for fiscal year 2018.

Institute of Pathology

The US Food and Drug Administration (FDA) has accepted for priority review a supplemental new drug application (sNDA) for arsenic trioxide (TRISENOX®) injection.

With this sNDA, Teva Pharmaceutical Industries Ltd. is seeking approval for arsenic trioxide to be used in combination with all-trans retinoic acid (ATRA) for induction of remission and consolidation in patients with newly diagnosed, low- or intermediate-risk acute promyelocytic leukemia (APL) characterized by the presence of the t(15;17) translocation or PML/RAR-alpha gene expression.

Currently, arsenic trioxide is FDA-approved as monotherapy for induction of remission and consolidation in patients with APL who are refractory to, or have relapsed from, retinoid and anthracycline chemotherapy, and whose APL is characterized by the presence of the t(15;17) translocation or PML/RAR-alpha gene expression.

For more details, see the full prescribing information.

The FDA has accepted the arsenic trioxide sNDA for priority review and expects to make a decision on the application in the first quarter of 2018.

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

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

Phase 3 study results

The sNDA for arsenic trioxide is supported by results from the APL0406 study. Updated results from this phase 3 study were published in the Journal of Clinical Oncology in February.

The study included 276 adults (ages 18 to 71) with newly diagnosed, low- or intermediate-risk APL. Patients were randomized to receive ATRA plus arsenic trioxide or ATRA plus chemotherapy.

A total of 263 patients were evaluable for response to induction. One hundred percent of patients in the arsenic trioxide arm (127/127) achieved a complete response (CR), as did 97% (132/136) of patients in the chemotherapy arm (P=0.12).

After a median follow-up of 40.6 months, the event-free survival was 97.3% in the arsenic trioxide arm and 80% in the chemotherapy arm (P<0.001). The cumulative incidence of relapse was 1.9% and 13.9%, respectively (P=0.0013).

At 50 months, the overall survival was 99.2% in the arsenic trioxide arm and 92.6% in the chemotherapy arm (P=0.0073).

After induction, there were 2 relapses and 1 death in CR in the arsenic trioxide arm.

In the chemotherapy arm, there were 2 instances of molecular resistance after third consolidation, 15 relapses, 5 deaths in CR, and 2 patients who developed a therapy-related myeloid neoplasm.

Institute of Pathology

The US Food and Drug Administration (FDA) has accepted for priority review a supplemental new drug application (sNDA) for arsenic trioxide (TRISENOX®) injection.

With this sNDA, Teva Pharmaceutical Industries Ltd. is seeking approval for arsenic trioxide to be used in combination with all-trans retinoic acid (ATRA) for induction of remission and consolidation in patients with newly diagnosed, low- or intermediate-risk acute promyelocytic leukemia (APL) characterized by the presence of the t(15;17) translocation or PML/RAR-alpha gene expression.

Currently, arsenic trioxide is FDA-approved as monotherapy for induction of remission and consolidation in patients with APL who are refractory to, or have relapsed from, retinoid and anthracycline chemotherapy, and whose APL is characterized by the presence of the t(15;17) translocation or PML/RAR-alpha gene expression.

For more details, see the full prescribing information.

The FDA has accepted the arsenic trioxide sNDA for priority review and expects to make a decision on the application in the first quarter of 2018.

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

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

Phase 3 study results

The sNDA for arsenic trioxide is supported by results from the APL0406 study. Updated results from this phase 3 study were published in the Journal of Clinical Oncology in February.

The study included 276 adults (ages 18 to 71) with newly diagnosed, low- or intermediate-risk APL. Patients were randomized to receive ATRA plus arsenic trioxide or ATRA plus chemotherapy.

A total of 263 patients were evaluable for response to induction. One hundred percent of patients in the arsenic trioxide arm (127/127) achieved a complete response (CR), as did 97% (132/136) of patients in the chemotherapy arm (P=0.12).

After a median follow-up of 40.6 months, the event-free survival was 97.3% in the arsenic trioxide arm and 80% in the chemotherapy arm (P<0.001). The cumulative incidence of relapse was 1.9% and 13.9%, respectively (P=0.0013).

At 50 months, the overall survival was 99.2% in the arsenic trioxide arm and 92.6% in the chemotherapy arm (P=0.0073).

After induction, there were 2 relapses and 1 death in CR in the arsenic trioxide arm.

In the chemotherapy arm, there were 2 instances of molecular resistance after third consolidation, 15 relapses, 5 deaths in CR, and 2 patients who developed a therapy-related myeloid neoplasm.

Institute of Pathology

The US Food and Drug Administration (FDA) has accepted for priority review a supplemental new drug application (sNDA) for arsenic trioxide (TRISENOX®) injection.

With this sNDA, Teva Pharmaceutical Industries Ltd. is seeking approval for arsenic trioxide to be used in combination with all-trans retinoic acid (ATRA) for induction of remission and consolidation in patients with newly diagnosed, low- or intermediate-risk acute promyelocytic leukemia (APL) characterized by the presence of the t(15;17) translocation or PML/RAR-alpha gene expression.

Currently, arsenic trioxide is FDA-approved as monotherapy for induction of remission and consolidation in patients with APL who are refractory to, or have relapsed from, retinoid and anthracycline chemotherapy, and whose APL is characterized by the presence of the t(15;17) translocation or PML/RAR-alpha gene expression.

For more details, see the full prescribing information.

The FDA has accepted the arsenic trioxide sNDA for priority review and expects to make a decision on the application in the first quarter of 2018.

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

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

Phase 3 study results

The sNDA for arsenic trioxide is supported by results from the APL0406 study. Updated results from this phase 3 study were published in the Journal of Clinical Oncology in February.

The study included 276 adults (ages 18 to 71) with newly diagnosed, low- or intermediate-risk APL. Patients were randomized to receive ATRA plus arsenic trioxide or ATRA plus chemotherapy.

A total of 263 patients were evaluable for response to induction. One hundred percent of patients in the arsenic trioxide arm (127/127) achieved a complete response (CR), as did 97% (132/136) of patients in the chemotherapy arm (P=0.12).

After a median follow-up of 40.6 months, the event-free survival was 97.3% in the arsenic trioxide arm and 80% in the chemotherapy arm (P<0.001). The cumulative incidence of relapse was 1.9% and 13.9%, respectively (P=0.0013).

At 50 months, the overall survival was 99.2% in the arsenic trioxide arm and 92.6% in the chemotherapy arm (P=0.0073).

After induction, there were 2 relapses and 1 death in CR in the arsenic trioxide arm.

In the chemotherapy arm, there were 2 instances of molecular resistance after third consolidation, 15 relapses, 5 deaths in CR, and 2 patients who developed a therapy-related myeloid neoplasm.

Photo courtesy of ESMO

MADRID—New research suggests patients with well-differentiated thyroid cancer (WDTC) are more likely to develop acute myeloid leukemia (AML) if they receive radioactive iodine (RAI) after surgery.

Of the WDTC patients studied, those who only underwent surgery were less likely to develop AML.

WDTC patients who did develop AML had a far worse prognosis than WDTC patients without AML and patients with de novo AML.

These results were presented at the ESMO 2017 Congress (abstract 996O).

Researchers already knew that the risk of developing leukemia is increased after radiation and RAI treatment for WDTC.

However, the risk of AML following RAI treatment in WDTC survivors had not been fully characterized, according to Remco J. Molenaar, an MD/PhD candidate at Academic Medical Centre in Amsterdam, Netherlands.

Therefore, Molenaar and colleagues reviewed data from all 18 registries in the Surveillance Epidemiology and End Results database for WDTC cases treated solely with surgery or by surgery and RAI.

The researchers identified 148,215 patients who were diagnosed with WDTC from 1973 to 2014. Fifty-five percent were treated with surgery alone, and 45% were treated with surgery and RAI.

The median follow-up was 4.3 person-years. AML occurred in 44 patients in the surgery-only arm and 56 patients in the RAI arm.

A comparison to the background rates in the general population showed that patients receiving surgery plus RAI had an increased risk of developing AML (relative risk=5.6; 95% confidence interval [CI] 3.8, 8.1; P<0.0001), after correcting for age, sex, and year of WDTC diagnosis.

This risk peaked within the first 3 years following RAI and subsequently regressed to baseline rates.

In multivariate analysis that corrected for sex and WDTC tumor size, 3 variables emerged as independent predictors of AML development. There was an increased risk of AML associated with:

• Patient age (hazard ratio [HR]=1.03; 95% CI 1.02, 1.05; P<0.001)
• WDTC tumor stage (HR=1.36; 95% CI 1.04, 1.79; P=0.03)
• Receiving RAI after thyroidectomy vs thyroidectomy alone (HR=1.38; 95% CI 1.09, 1.75; P=0.007).

The researchers also found prognosis is significantly poorer in WDTC patients who develop AML following RAI and in patients with spontaneous AML development.

Case-control analyses revealed that WDTC patients who developed AML after surgery and RAI survived one-third as long as matched control patients who were successfully treated for WDTC but did not develop AML. The median overall survival was 7.4 years and 24.4 years, respectively (P<0.0001).

Patients who were diagnosed with AML after RAI treatment also had a significantly worse prognosis than patients with de novo AML. The median overall survival was 1.2 years and 3.5 years, respectively (P=0.004).

The researchers noted that rates of AML in WDTC survivors will likely continue to rise due to the increasing incidence of WDTC, the young ages at which most WDTC diagnoses are made, and the otherwise high survival rates of patients with WDTC.

Photo courtesy of ESMO

MADRID—New research suggests patients with well-differentiated thyroid cancer (WDTC) are more likely to develop acute myeloid leukemia (AML) if they receive radioactive iodine (RAI) after surgery.

Of the WDTC patients studied, those who only underwent surgery were less likely to develop AML.

WDTC patients who did develop AML had a far worse prognosis than WDTC patients without AML and patients with de novo AML.

These results were presented at the ESMO 2017 Congress (abstract 996O).

Researchers already knew that the risk of developing leukemia is increased after radiation and RAI treatment for WDTC.

However, the risk of AML following RAI treatment in WDTC survivors had not been fully characterized, according to Remco J. Molenaar, an MD/PhD candidate at Academic Medical Centre in Amsterdam, Netherlands.

Therefore, Molenaar and colleagues reviewed data from all 18 registries in the Surveillance Epidemiology and End Results database for WDTC cases treated solely with surgery or by surgery and RAI.

The researchers identified 148,215 patients who were diagnosed with WDTC from 1973 to 2014. Fifty-five percent were treated with surgery alone, and 45% were treated with surgery and RAI.

The median follow-up was 4.3 person-years. AML occurred in 44 patients in the surgery-only arm and 56 patients in the RAI arm.

A comparison to the background rates in the general population showed that patients receiving surgery plus RAI had an increased risk of developing AML (relative risk=5.6; 95% confidence interval [CI] 3.8, 8.1; P<0.0001), after correcting for age, sex, and year of WDTC diagnosis.

This risk peaked within the first 3 years following RAI and subsequently regressed to baseline rates.

In multivariate analysis that corrected for sex and WDTC tumor size, 3 variables emerged as independent predictors of AML development. There was an increased risk of AML associated with:

• Patient age (hazard ratio [HR]=1.03; 95% CI 1.02, 1.05; P<0.001)
• WDTC tumor stage (HR=1.36; 95% CI 1.04, 1.79; P=0.03)
• Receiving RAI after thyroidectomy vs thyroidectomy alone (HR=1.38; 95% CI 1.09, 1.75; P=0.007).

The researchers also found prognosis is significantly poorer in WDTC patients who develop AML following RAI and in patients with spontaneous AML development.

Case-control analyses revealed that WDTC patients who developed AML after surgery and RAI survived one-third as long as matched control patients who were successfully treated for WDTC but did not develop AML. The median overall survival was 7.4 years and 24.4 years, respectively (P<0.0001).

Patients who were diagnosed with AML after RAI treatment also had a significantly worse prognosis than patients with de novo AML. The median overall survival was 1.2 years and 3.5 years, respectively (P=0.004).

The researchers noted that rates of AML in WDTC survivors will likely continue to rise due to the increasing incidence of WDTC, the young ages at which most WDTC diagnoses are made, and the otherwise high survival rates of patients with WDTC.

Photo courtesy of ESMO

MADRID—New research suggests patients with well-differentiated thyroid cancer (WDTC) are more likely to develop acute myeloid leukemia (AML) if they receive radioactive iodine (RAI) after surgery.

Of the WDTC patients studied, those who only underwent surgery were less likely to develop AML.

WDTC patients who did develop AML had a far worse prognosis than WDTC patients without AML and patients with de novo AML.

These results were presented at the ESMO 2017 Congress (abstract 996O).

Researchers already knew that the risk of developing leukemia is increased after radiation and RAI treatment for WDTC.

However, the risk of AML following RAI treatment in WDTC survivors had not been fully characterized, according to Remco J. Molenaar, an MD/PhD candidate at Academic Medical Centre in Amsterdam, Netherlands.

Therefore, Molenaar and colleagues reviewed data from all 18 registries in the Surveillance Epidemiology and End Results database for WDTC cases treated solely with surgery or by surgery and RAI.

The researchers identified 148,215 patients who were diagnosed with WDTC from 1973 to 2014. Fifty-five percent were treated with surgery alone, and 45% were treated with surgery and RAI.

The median follow-up was 4.3 person-years. AML occurred in 44 patients in the surgery-only arm and 56 patients in the RAI arm.

A comparison to the background rates in the general population showed that patients receiving surgery plus RAI had an increased risk of developing AML (relative risk=5.6; 95% confidence interval [CI] 3.8, 8.1; P<0.0001), after correcting for age, sex, and year of WDTC diagnosis.

This risk peaked within the first 3 years following RAI and subsequently regressed to baseline rates.

In multivariate analysis that corrected for sex and WDTC tumor size, 3 variables emerged as independent predictors of AML development. There was an increased risk of AML associated with:

• Patient age (hazard ratio [HR]=1.03; 95% CI 1.02, 1.05; P<0.001)
• WDTC tumor stage (HR=1.36; 95% CI 1.04, 1.79; P=0.03)
• Receiving RAI after thyroidectomy vs thyroidectomy alone (HR=1.38; 95% CI 1.09, 1.75; P=0.007).

The researchers also found prognosis is significantly poorer in WDTC patients who develop AML following RAI and in patients with spontaneous AML development.

Case-control analyses revealed that WDTC patients who developed AML after surgery and RAI survived one-third as long as matched control patients who were successfully treated for WDTC but did not develop AML. The median overall survival was 7.4 years and 24.4 years, respectively (P<0.0001).

Patients who were diagnosed with AML after RAI treatment also had a significantly worse prognosis than patients with de novo AML. The median overall survival was 1.2 years and 3.5 years, respectively (P=0.004).

The researchers noted that rates of AML in WDTC survivors will likely continue to rise due to the increasing incidence of WDTC, the young ages at which most WDTC diagnoses are made, and the otherwise high survival rates of patients with WDTC.

Photo by Esther Dyson

MADRID—Results of a nationwide study suggest many cancer patients in Ireland don’t understand key aspects of clinical trial methodology.

Most of the patients surveyed, which included individuals who had participated in a clinical trial, did not understand the concepts of randomization or equipoise.

“Over half of previous medical trial participants and 73% of those who had never been on a cancer clinical trial did not understand that, in a randomized trial, the treatment given was decided by chance,” said study investigator Catherine Kelly, MB BCh, of Mater Misericordiae University Hospital in Dublin, Ireland.

“We also found that most patients did not understand clinical equipoise—the fact that no one knows which treatment is best. Surprisingly, this was more marked in previous clinical trial participants, 60% of whom believed that their doctor would know which study arm was best.”

Dr Kelly and her colleagues presented these findings at the ESMO 2017 Congress (abstract 1465P_PR).

The researchers surveyed 1090 adult cancer patients treated at 1 of 14 participating oncology centers across Ireland.

The patients’ median age was 60 (range, 50-69), 64.4% were female, and 66% were diagnosed between 2014 and 2016. The most common cancer types were breast (31.4%), colorectal (15.6%), hematologic (12.6%), genitourinary (11.6%), and lung (6.8%).

The patients filled out anonymized questionnaires in which they were asked to evaluate statements about clinical trials. The patients had to determine whether a statement is true or false, or they could indicate that they didn’t know an answer.

A majority of the patients (82.3%) said they understood what a medical or cancer clinical trial is. And 27.8% of patients said they had previously participated in a cancer trial.

However, many patients didn’t know when clinical trials may be an option. Twenty-two percent of patients said it is true that “clinical trials are only used when standard treatments have not worked,” and 26.6% said they didn’t know if this statement is true or false.

Roughly a third (33.5%) of patients said it is true that, in a randomized trial, treatment is decided by chance, but 41.4% of patients said this is false, and 25% said they didn’t know.

More than half of patients (56.5%) said their doctor would know which treatment was superior in a clinical trial, and 23.2% of patients said they didn’t know if their doctor would know.

About 61% of all patients said their doctor would make sure they received the superior treatment in a clinical trial. An even greater percentage—63.6%—of patients who had previously participated in a clinical trial said the same.

“To provide informed consent when participating in a trial, patients need to understand these key concepts, and doctors explaining them well is essential to alleviating any fears that might prevent patients from participating,” Dr Kelly said.

“Doctors have a responsibility to properly inform their patients in this regard because they are the ones patients trust the most. As we analyze the data further, we will be able to offer physicians a more detailed picture of the questions patients need answered and the factors that influence their decision-making according to age group, cancer type, educational background, and other demographics.”

Funding for this research was provided to Cancer Trials Ireland by Amgen, Abbvie, Bayor, and Inveva.

Photo by Esther Dyson

MADRID—Results of a nationwide study suggest many cancer patients in Ireland don’t understand key aspects of clinical trial methodology.

Most of the patients surveyed, which included individuals who had participated in a clinical trial, did not understand the concepts of randomization or equipoise.

“Over half of previous medical trial participants and 73% of those who had never been on a cancer clinical trial did not understand that, in a randomized trial, the treatment given was decided by chance,” said study investigator Catherine Kelly, MB BCh, of Mater Misericordiae University Hospital in Dublin, Ireland.

“We also found that most patients did not understand clinical equipoise—the fact that no one knows which treatment is best. Surprisingly, this was more marked in previous clinical trial participants, 60% of whom believed that their doctor would know which study arm was best.”

Dr Kelly and her colleagues presented these findings at the ESMO 2017 Congress (abstract 1465P_PR).

The researchers surveyed 1090 adult cancer patients treated at 1 of 14 participating oncology centers across Ireland.

The patients’ median age was 60 (range, 50-69), 64.4% were female, and 66% were diagnosed between 2014 and 2016. The most common cancer types were breast (31.4%), colorectal (15.6%), hematologic (12.6%), genitourinary (11.6%), and lung (6.8%).

The patients filled out anonymized questionnaires in which they were asked to evaluate statements about clinical trials. The patients had to determine whether a statement is true or false, or they could indicate that they didn’t know an answer.

A majority of the patients (82.3%) said they understood what a medical or cancer clinical trial is. And 27.8% of patients said they had previously participated in a cancer trial.

However, many patients didn’t know when clinical trials may be an option. Twenty-two percent of patients said it is true that “clinical trials are only used when standard treatments have not worked,” and 26.6% said they didn’t know if this statement is true or false.

Roughly a third (33.5%) of patients said it is true that, in a randomized trial, treatment is decided by chance, but 41.4% of patients said this is false, and 25% said they didn’t know.

More than half of patients (56.5%) said their doctor would know which treatment was superior in a clinical trial, and 23.2% of patients said they didn’t know if their doctor would know.

About 61% of all patients said their doctor would make sure they received the superior treatment in a clinical trial. An even greater percentage—63.6%—of patients who had previously participated in a clinical trial said the same.

“To provide informed consent when participating in a trial, patients need to understand these key concepts, and doctors explaining them well is essential to alleviating any fears that might prevent patients from participating,” Dr Kelly said.

“Doctors have a responsibility to properly inform their patients in this regard because they are the ones patients trust the most. As we analyze the data further, we will be able to offer physicians a more detailed picture of the questions patients need answered and the factors that influence their decision-making according to age group, cancer type, educational background, and other demographics.”

Funding for this research was provided to Cancer Trials Ireland by Amgen, Abbvie, Bayor, and Inveva.

Photo by Esther Dyson

MADRID—Results of a nationwide study suggest many cancer patients in Ireland don’t understand key aspects of clinical trial methodology.

Most of the patients surveyed, which included individuals who had participated in a clinical trial, did not understand the concepts of randomization or equipoise.

“Over half of previous medical trial participants and 73% of those who had never been on a cancer clinical trial did not understand that, in a randomized trial, the treatment given was decided by chance,” said study investigator Catherine Kelly, MB BCh, of Mater Misericordiae University Hospital in Dublin, Ireland.

“We also found that most patients did not understand clinical equipoise—the fact that no one knows which treatment is best. Surprisingly, this was more marked in previous clinical trial participants, 60% of whom believed that their doctor would know which study arm was best.”

Dr Kelly and her colleagues presented these findings at the ESMO 2017 Congress (abstract 1465P_PR).

The researchers surveyed 1090 adult cancer patients treated at 1 of 14 participating oncology centers across Ireland.

The patients’ median age was 60 (range, 50-69), 64.4% were female, and 66% were diagnosed between 2014 and 2016. The most common cancer types were breast (31.4%), colorectal (15.6%), hematologic (12.6%), genitourinary (11.6%), and lung (6.8%).

The patients filled out anonymized questionnaires in which they were asked to evaluate statements about clinical trials. The patients had to determine whether a statement is true or false, or they could indicate that they didn’t know an answer.

A majority of the patients (82.3%) said they understood what a medical or cancer clinical trial is. And 27.8% of patients said they had previously participated in a cancer trial.

However, many patients didn’t know when clinical trials may be an option. Twenty-two percent of patients said it is true that “clinical trials are only used when standard treatments have not worked,” and 26.6% said they didn’t know if this statement is true or false.

Roughly a third (33.5%) of patients said it is true that, in a randomized trial, treatment is decided by chance, but 41.4% of patients said this is false, and 25% said they didn’t know.

More than half of patients (56.5%) said their doctor would know which treatment was superior in a clinical trial, and 23.2% of patients said they didn’t know if their doctor would know.

About 61% of all patients said their doctor would make sure they received the superior treatment in a clinical trial. An even greater percentage—63.6%—of patients who had previously participated in a clinical trial said the same.

“To provide informed consent when participating in a trial, patients need to understand these key concepts, and doctors explaining them well is essential to alleviating any fears that might prevent patients from participating,” Dr Kelly said.

“Doctors have a responsibility to properly inform their patients in this regard because they are the ones patients trust the most. As we analyze the data further, we will be able to offer physicians a more detailed picture of the questions patients need answered and the factors that influence their decision-making according to age group, cancer type, educational background, and other demographics.”

Funding for this research was provided to Cancer Trials Ireland by Amgen, Abbvie, Bayor, and Inveva.

A commonly-used intensive induction regimen was associated with higher rates of hematopoietic progenitor cell mobilization failure in patients with mantle cell lymphoma, even when plerixafor rescue was attempted, based on a study by Amandeep Salhotra, MD, and his colleagues at City of Hope, Duarte, Calif.

Patients who received rituximab and hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone (R-hyperCVAD) in the era after plerixafor came into use experienced significantly higher rates of peripheral blood stem cell (PBSC) collection failure than did patients receiving other induction regimens (17% vs. 4% failure rate, P = .04).

Courtesy Wikimedia Commons/Nephron/Creative Commons

“Plerixafor does not overcome the negative impact of R-hyperCVAD on PBSC mobilization, and caution is warranted in using R-hyperCVAD in patients with newly diagnosed MCL who are candidates for ASCT (autologous stem cell transplant),” wrote Dr. Salhotra and his colleagues.

The higher rate of hematopoietic progenitor cell collection failure for R-hyperCVAD patients could not be attributed to their age at time of mantle cell lymphoma diagnosis or to the amount of time between diagnosis and collection.

Treatment records for 181 consecutive mantle cell lymphoma patients were examined for a 10 year period in the retrospective single-site study. Plerixafor, a C-X-C chemokine receptor agonist that reduces hematopoietic progenitor cells’ ability to bind to bone marrow stroma, was introduced on August 16, 2009; a total of 71 patients were treated before this point, and 110 were treated afterward.

The R-hyperCVAD regimen was received by 34 pre-plerixafor patients (45%) and by 42 of the post-plerixafor era patients (55%). Other regimens were received by 37 (35%) and 68 (65%) of the pre- and post-plerixafor era patients, respectively.

Before plerixafor came into use, Dr. Salhotra, of City of Hope’s department of hematology and hematopoietic cell transplantation, and his coinvestigators saw no significant difference among their study population in the rates of PBSC collection failure between those receiving R-hyperCVAD (11%) and those receiving other regimens (12%). The findings were reported in Biology of Blood and Marrow Transplantation.

The study was conducted in the context of other recent work that showed higher rates of PBSC collection failure and fewer CD34+ cells collected with the use of an R-hyperCVAD conditioning regimen. The fact that PBSC mobilization rates were significantly lower in R-hyperCVAD patients post-plerixafor surprised the investigators, who had hypothesized that the use of plerixafor would overcome PBSC mobilization failures without regard to the conditioning regimen used.

“It may be worthwhile to consider using a more aggressive strategy for [hematopoetic progenitor cell] mobilization in patients who have received R-hyperCVAD chemotherapy upfront or as salvage for aggressive lymphomas,” the researchers wrote. This might include the use of plerixafor upfront when patients have low CD34 counts before apheresis.

The researchers plan to examine their data to see how the choice of induction regimen and plerixafor usage impact patient survival.

The study authors reported no conflicts of interest.
 

Source: Amandeep Salhotra, et al. Hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone chemotherapy in mantle cell lymphoma patients is associated with higher rates of hematopoietic progenitor cell mobilization failure despite plerixafor rescue. Biol Blood Marrow Transplant 2017; 23:1264-1268.

[email protected]

SOURCE: Biol Blood Marrow Transplant 2017; 23:1264-1268. http://dx.doi.org/10.1016/j.bbmt.2017.04.011
 

A commonly-used intensive induction regimen was associated with higher rates of hematopoietic progenitor cell mobilization failure in patients with mantle cell lymphoma, even when plerixafor rescue was attempted, based on a study by Amandeep Salhotra, MD, and his colleagues at City of Hope, Duarte, Calif.

Patients who received rituximab and hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone (R-hyperCVAD) in the era after plerixafor came into use experienced significantly higher rates of peripheral blood stem cell (PBSC) collection failure than did patients receiving other induction regimens (17% vs. 4% failure rate, P = .04).

Courtesy Wikimedia Commons/Nephron/Creative Commons

“Plerixafor does not overcome the negative impact of R-hyperCVAD on PBSC mobilization, and caution is warranted in using R-hyperCVAD in patients with newly diagnosed MCL who are candidates for ASCT (autologous stem cell transplant),” wrote Dr. Salhotra and his colleagues.

The higher rate of hematopoietic progenitor cell collection failure for R-hyperCVAD patients could not be attributed to their age at time of mantle cell lymphoma diagnosis or to the amount of time between diagnosis and collection.

Treatment records for 181 consecutive mantle cell lymphoma patients were examined for a 10 year period in the retrospective single-site study. Plerixafor, a C-X-C chemokine receptor agonist that reduces hematopoietic progenitor cells’ ability to bind to bone marrow stroma, was introduced on August 16, 2009; a total of 71 patients were treated before this point, and 110 were treated afterward.

The R-hyperCVAD regimen was received by 34 pre-plerixafor patients (45%) and by 42 of the post-plerixafor era patients (55%). Other regimens were received by 37 (35%) and 68 (65%) of the pre- and post-plerixafor era patients, respectively.

Before plerixafor came into use, Dr. Salhotra, of City of Hope’s department of hematology and hematopoietic cell transplantation, and his coinvestigators saw no significant difference among their study population in the rates of PBSC collection failure between those receiving R-hyperCVAD (11%) and those receiving other regimens (12%). The findings were reported in Biology of Blood and Marrow Transplantation.

The study was conducted in the context of other recent work that showed higher rates of PBSC collection failure and fewer CD34+ cells collected with the use of an R-hyperCVAD conditioning regimen. The fact that PBSC mobilization rates were significantly lower in R-hyperCVAD patients post-plerixafor surprised the investigators, who had hypothesized that the use of plerixafor would overcome PBSC mobilization failures without regard to the conditioning regimen used.

“It may be worthwhile to consider using a more aggressive strategy for [hematopoetic progenitor cell] mobilization in patients who have received R-hyperCVAD chemotherapy upfront or as salvage for aggressive lymphomas,” the researchers wrote. This might include the use of plerixafor upfront when patients have low CD34 counts before apheresis.

The researchers plan to examine their data to see how the choice of induction regimen and plerixafor usage impact patient survival.

The study authors reported no conflicts of interest.
 

Source: Amandeep Salhotra, et al. Hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone chemotherapy in mantle cell lymphoma patients is associated with higher rates of hematopoietic progenitor cell mobilization failure despite plerixafor rescue. Biol Blood Marrow Transplant 2017; 23:1264-1268.

[email protected]

SOURCE: Biol Blood Marrow Transplant 2017; 23:1264-1268. http://dx.doi.org/10.1016/j.bbmt.2017.04.011
 

A commonly-used intensive induction regimen was associated with higher rates of hematopoietic progenitor cell mobilization failure in patients with mantle cell lymphoma, even when plerixafor rescue was attempted, based on a study by Amandeep Salhotra, MD, and his colleagues at City of Hope, Duarte, Calif.

Patients who received rituximab and hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone (R-hyperCVAD) in the era after plerixafor came into use experienced significantly higher rates of peripheral blood stem cell (PBSC) collection failure than did patients receiving other induction regimens (17% vs. 4% failure rate, P = .04).

Courtesy Wikimedia Commons/Nephron/Creative Commons

“Plerixafor does not overcome the negative impact of R-hyperCVAD on PBSC mobilization, and caution is warranted in using R-hyperCVAD in patients with newly diagnosed MCL who are candidates for ASCT (autologous stem cell transplant),” wrote Dr. Salhotra and his colleagues.

The higher rate of hematopoietic progenitor cell collection failure for R-hyperCVAD patients could not be attributed to their age at time of mantle cell lymphoma diagnosis or to the amount of time between diagnosis and collection.

Treatment records for 181 consecutive mantle cell lymphoma patients were examined for a 10 year period in the retrospective single-site study. Plerixafor, a C-X-C chemokine receptor agonist that reduces hematopoietic progenitor cells’ ability to bind to bone marrow stroma, was introduced on August 16, 2009; a total of 71 patients were treated before this point, and 110 were treated afterward.

The R-hyperCVAD regimen was received by 34 pre-plerixafor patients (45%) and by 42 of the post-plerixafor era patients (55%). Other regimens were received by 37 (35%) and 68 (65%) of the pre- and post-plerixafor era patients, respectively.

Before plerixafor came into use, Dr. Salhotra, of City of Hope’s department of hematology and hematopoietic cell transplantation, and his coinvestigators saw no significant difference among their study population in the rates of PBSC collection failure between those receiving R-hyperCVAD (11%) and those receiving other regimens (12%). The findings were reported in Biology of Blood and Marrow Transplantation.

The study was conducted in the context of other recent work that showed higher rates of PBSC collection failure and fewer CD34+ cells collected with the use of an R-hyperCVAD conditioning regimen. The fact that PBSC mobilization rates were significantly lower in R-hyperCVAD patients post-plerixafor surprised the investigators, who had hypothesized that the use of plerixafor would overcome PBSC mobilization failures without regard to the conditioning regimen used.

“It may be worthwhile to consider using a more aggressive strategy for [hematopoetic progenitor cell] mobilization in patients who have received R-hyperCVAD chemotherapy upfront or as salvage for aggressive lymphomas,” the researchers wrote. This might include the use of plerixafor upfront when patients have low CD34 counts before apheresis.

The researchers plan to examine their data to see how the choice of induction regimen and plerixafor usage impact patient survival.

The study authors reported no conflicts of interest.
 

Source: Amandeep Salhotra, et al. Hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone chemotherapy in mantle cell lymphoma patients is associated with higher rates of hematopoietic progenitor cell mobilization failure despite plerixafor rescue. Biol Blood Marrow Transplant 2017; 23:1264-1268.

[email protected]

SOURCE: Biol Blood Marrow Transplant 2017; 23:1264-1268. http://dx.doi.org/10.1016/j.bbmt.2017.04.011
 

A first-in-class oral inhibitor of valosin-containing protein (VCP) p97 showed significant activity against human B acute lymphoblastic leukemia (B-ALL) cells, including those with the most common fusion genes seen in pediatric and adult B-ALL, researchers reported.

The drug, dubbed CB-5083 (Cleave Biosciences), induces cell death by causing endoplasmic reticulum stress, to which B-ALL cells are “distinctly vulnerable,” wrote Gabriele Gugliotta, MD, PhD, of Cedars-Sinai Medical Center in Los Angeles, Calif., and her coinvestigators. In their study, CB-5083 significantly reduced the viability of 10 B-ALL cell lines tested, and did so at blood concentrations that caused no significant toxicities in mice. Human B-ALL cells also showed no signs of upfront drug resistance, the researchers wrote in Neoplasia.

CB-5083 received an FDA orphan drug designation in 2015 for treating multiple myeloma, and also has shown activity against solid tumors. In the study, exposing BALL1 and OP1 B-ALL cell lines to CB-5083 triggered “early and strong” apoptosis, along with a “robust” cleavage of PARP, the researchers reported (Neoplasia. 2017 Aug 24. doi: 10.1016/j.neo.2017.08.001). http://www.neoplasia.com/article/S1476-5586(17)30258-0/fulltext

The drug also reduced the viability of human B-ALL cells without genes for GRP78, GRP94, or XBP1, suggesting that CB-5083 does not require the presence of these proteins to work, the investigators said. Deficiency of X-box binding protein 1 (XBP1) predicted greater sensitivity to CB-5083, which might mean that XBP1 splicing counteracts drug activity by mitigating endoplasmic reticulum stress, they added. “Finally, vincristine was synergistic with CB-5083 in both BALL1 and OP1 [cell lines],” they wrote. “In summary, the targeting of p97 with CB-5083 is a novel promising therapeutic approach that should be further evaluated in B-ALL.”

The investigators acknowledged support from the Melamed family, Reuben Yeroushalmi, National Research Foundation Singapore, Singapore Ministry of Education, Leukemia Lymphoma Society of America, and University of Bologna, Italy. They did not report having conflicts of interest.

A first-in-class oral inhibitor of valosin-containing protein (VCP) p97 showed significant activity against human B acute lymphoblastic leukemia (B-ALL) cells, including those with the most common fusion genes seen in pediatric and adult B-ALL, researchers reported.

The drug, dubbed CB-5083 (Cleave Biosciences), induces cell death by causing endoplasmic reticulum stress, to which B-ALL cells are “distinctly vulnerable,” wrote Gabriele Gugliotta, MD, PhD, of Cedars-Sinai Medical Center in Los Angeles, Calif., and her coinvestigators. In their study, CB-5083 significantly reduced the viability of 10 B-ALL cell lines tested, and did so at blood concentrations that caused no significant toxicities in mice. Human B-ALL cells also showed no signs of upfront drug resistance, the researchers wrote in Neoplasia.

CB-5083 received an FDA orphan drug designation in 2015 for treating multiple myeloma, and also has shown activity against solid tumors. In the study, exposing BALL1 and OP1 B-ALL cell lines to CB-5083 triggered “early and strong” apoptosis, along with a “robust” cleavage of PARP, the researchers reported (Neoplasia. 2017 Aug 24. doi: 10.1016/j.neo.2017.08.001). http://www.neoplasia.com/article/S1476-5586(17)30258-0/fulltext

The drug also reduced the viability of human B-ALL cells without genes for GRP78, GRP94, or XBP1, suggesting that CB-5083 does not require the presence of these proteins to work, the investigators said. Deficiency of X-box binding protein 1 (XBP1) predicted greater sensitivity to CB-5083, which might mean that XBP1 splicing counteracts drug activity by mitigating endoplasmic reticulum stress, they added. “Finally, vincristine was synergistic with CB-5083 in both BALL1 and OP1 [cell lines],” they wrote. “In summary, the targeting of p97 with CB-5083 is a novel promising therapeutic approach that should be further evaluated in B-ALL.”

The investigators acknowledged support from the Melamed family, Reuben Yeroushalmi, National Research Foundation Singapore, Singapore Ministry of Education, Leukemia Lymphoma Society of America, and University of Bologna, Italy. They did not report having conflicts of interest.

A first-in-class oral inhibitor of valosin-containing protein (VCP) p97 showed significant activity against human B acute lymphoblastic leukemia (B-ALL) cells, including those with the most common fusion genes seen in pediatric and adult B-ALL, researchers reported.

The drug, dubbed CB-5083 (Cleave Biosciences), induces cell death by causing endoplasmic reticulum stress, to which B-ALL cells are “distinctly vulnerable,” wrote Gabriele Gugliotta, MD, PhD, of Cedars-Sinai Medical Center in Los Angeles, Calif., and her coinvestigators. In their study, CB-5083 significantly reduced the viability of 10 B-ALL cell lines tested, and did so at blood concentrations that caused no significant toxicities in mice. Human B-ALL cells also showed no signs of upfront drug resistance, the researchers wrote in Neoplasia.

CB-5083 received an FDA orphan drug designation in 2015 for treating multiple myeloma, and also has shown activity against solid tumors. In the study, exposing BALL1 and OP1 B-ALL cell lines to CB-5083 triggered “early and strong” apoptosis, along with a “robust” cleavage of PARP, the researchers reported (Neoplasia. 2017 Aug 24. doi: 10.1016/j.neo.2017.08.001). http://www.neoplasia.com/article/S1476-5586(17)30258-0/fulltext

The drug also reduced the viability of human B-ALL cells without genes for GRP78, GRP94, or XBP1, suggesting that CB-5083 does not require the presence of these proteins to work, the investigators said. Deficiency of X-box binding protein 1 (XBP1) predicted greater sensitivity to CB-5083, which might mean that XBP1 splicing counteracts drug activity by mitigating endoplasmic reticulum stress, they added. “Finally, vincristine was synergistic with CB-5083 in both BALL1 and OP1 [cell lines],” they wrote. “In summary, the targeting of p97 with CB-5083 is a novel promising therapeutic approach that should be further evaluated in B-ALL.”

The investigators acknowledged support from the Melamed family, Reuben Yeroushalmi, National Research Foundation Singapore, Singapore Ministry of Education, Leukemia Lymphoma Society of America, and University of Bologna, Italy. They did not report having conflicts of interest.

Photo courtesy of NIH

Adult survivors of childhood cancer have a greater cumulative burden of chronic health conditions than the general public, according to research published in The Lancet.

The study showed that, by age 50, childhood cancer survivors (CCSs) had experienced, on average, 17.1 chronic health conditions, and matched control subjects had experienced 9.2.

“The cumulative burden of chronic disease revealed in this analysis, along with the complexity and severity of chronic conditions some survivors experience, found childhood cancer survivors to be a vulnerable, medically complex population,” said study author Nickhill Bhakta, MD, of St. Jude Children’s Research Hospital in Memphis, Tennessee.

For this study, Dr Bhakta and his colleagues assessed the lifelong impact of 168 chronic health conditions—such as hepatic, thyroid, ocular, and reproductive disorders—on CCSs and control subjects.

The 3010 evaluable CCSs had survived 10 years or longer from their initial cancer diagnosis and were 18 years or older as of June 30, 2015. The 272 controls had no history of pediatric cancer and were matched to CCSs by age and sex.

At age 50, the cumulative incidence of chronic health conditions (of any grade) was 99.9% in CCSs and 96.0% in controls (P<0.0001). The cumulative incidence of grade 3 to 5 chronic health conditions was 96.0% and 84.9%, respectively (P<0.0001).

The cumulative burden for CCSs was 17.1 chronic health conditions, including 4.7 that were grade 3 to 5. For controls, the cumulative burden was 9.2 chronic health conditions, including 2.3 that were grade 3 to 5 (P<0.0001 for both comparisons).

The researchers said second neoplasms, spinal disorders, and pulmonary disease were major contributors to the excess total cumulative burden observed in CCSs. However, there was “notable heterogeneity” in burden according to the patients’ primary cancer diagnosis.

For instance, growth hormone deficiency was in the top 10th percentile of chronic health conditions for survivors of acute lymphoblastic leukemia but not for controls.

And pulmonary function deficits were in the top 10th percentile for survivors of acute myeloid leukemia and Hodgkin lymphoma but not for controls or survivors of acute lymphoblastic leukemia or non-Hodgkin lymphoma.

“This study found that the average childhood cancer survivor has a cumulative burden of chronic disease that requires a significant time investment by healthcare providers to disentangle and manage—time that community providers are unlikely to have,” Dr Bhakta said.

“The results suggest that childhood cancer survivors may benefit from the integrated, specialized healthcare delivery that is being tried for individuals infected with HIV or those with other complex, chronic health problems.”

Photo courtesy of NIH

Adult survivors of childhood cancer have a greater cumulative burden of chronic health conditions than the general public, according to research published in The Lancet.

The study showed that, by age 50, childhood cancer survivors (CCSs) had experienced, on average, 17.1 chronic health conditions, and matched control subjects had experienced 9.2.

“The cumulative burden of chronic disease revealed in this analysis, along with the complexity and severity of chronic conditions some survivors experience, found childhood cancer survivors to be a vulnerable, medically complex population,” said study author Nickhill Bhakta, MD, of St. Jude Children’s Research Hospital in Memphis, Tennessee.

For this study, Dr Bhakta and his colleagues assessed the lifelong impact of 168 chronic health conditions—such as hepatic, thyroid, ocular, and reproductive disorders—on CCSs and control subjects.

The 3010 evaluable CCSs had survived 10 years or longer from their initial cancer diagnosis and were 18 years or older as of June 30, 2015. The 272 controls had no history of pediatric cancer and were matched to CCSs by age and sex.

At age 50, the cumulative incidence of chronic health conditions (of any grade) was 99.9% in CCSs and 96.0% in controls (P<0.0001). The cumulative incidence of grade 3 to 5 chronic health conditions was 96.0% and 84.9%, respectively (P<0.0001).

The cumulative burden for CCSs was 17.1 chronic health conditions, including 4.7 that were grade 3 to 5. For controls, the cumulative burden was 9.2 chronic health conditions, including 2.3 that were grade 3 to 5 (P<0.0001 for both comparisons).

The researchers said second neoplasms, spinal disorders, and pulmonary disease were major contributors to the excess total cumulative burden observed in CCSs. However, there was “notable heterogeneity” in burden according to the patients’ primary cancer diagnosis.

For instance, growth hormone deficiency was in the top 10th percentile of chronic health conditions for survivors of acute lymphoblastic leukemia but not for controls.

And pulmonary function deficits were in the top 10th percentile for survivors of acute myeloid leukemia and Hodgkin lymphoma but not for controls or survivors of acute lymphoblastic leukemia or non-Hodgkin lymphoma.

“This study found that the average childhood cancer survivor has a cumulative burden of chronic disease that requires a significant time investment by healthcare providers to disentangle and manage—time that community providers are unlikely to have,” Dr Bhakta said.

“The results suggest that childhood cancer survivors may benefit from the integrated, specialized healthcare delivery that is being tried for individuals infected with HIV or those with other complex, chronic health problems.”

Photo courtesy of NIH

Adult survivors of childhood cancer have a greater cumulative burden of chronic health conditions than the general public, according to research published in The Lancet.

The study showed that, by age 50, childhood cancer survivors (CCSs) had experienced, on average, 17.1 chronic health conditions, and matched control subjects had experienced 9.2.

“The cumulative burden of chronic disease revealed in this analysis, along with the complexity and severity of chronic conditions some survivors experience, found childhood cancer survivors to be a vulnerable, medically complex population,” said study author Nickhill Bhakta, MD, of St. Jude Children’s Research Hospital in Memphis, Tennessee.

For this study, Dr Bhakta and his colleagues assessed the lifelong impact of 168 chronic health conditions—such as hepatic, thyroid, ocular, and reproductive disorders—on CCSs and control subjects.

The 3010 evaluable CCSs had survived 10 years or longer from their initial cancer diagnosis and were 18 years or older as of June 30, 2015. The 272 controls had no history of pediatric cancer and were matched to CCSs by age and sex.

At age 50, the cumulative incidence of chronic health conditions (of any grade) was 99.9% in CCSs and 96.0% in controls (P<0.0001). The cumulative incidence of grade 3 to 5 chronic health conditions was 96.0% and 84.9%, respectively (P<0.0001).

The cumulative burden for CCSs was 17.1 chronic health conditions, including 4.7 that were grade 3 to 5. For controls, the cumulative burden was 9.2 chronic health conditions, including 2.3 that were grade 3 to 5 (P<0.0001 for both comparisons).

The researchers said second neoplasms, spinal disorders, and pulmonary disease were major contributors to the excess total cumulative burden observed in CCSs. However, there was “notable heterogeneity” in burden according to the patients’ primary cancer diagnosis.

For instance, growth hormone deficiency was in the top 10th percentile of chronic health conditions for survivors of acute lymphoblastic leukemia but not for controls.

And pulmonary function deficits were in the top 10th percentile for survivors of acute myeloid leukemia and Hodgkin lymphoma but not for controls or survivors of acute lymphoblastic leukemia or non-Hodgkin lymphoma.

“This study found that the average childhood cancer survivor has a cumulative burden of chronic disease that requires a significant time investment by healthcare providers to disentangle and manage—time that community providers are unlikely to have,” Dr Bhakta said.

“The results suggest that childhood cancer survivors may benefit from the integrated, specialized healthcare delivery that is being tried for individuals infected with HIV or those with other complex, chronic health problems.”

With a recent flurry of new drug approvals, the treatment landscape for acute myeloid leukemia has expanded, raising new questions about how to incorporate those drugs into patient care.

Until about a decade ago, advances in AML therapy centered mainly around iterations of daunorubicin and cytarabine. Now, novel and targeted agents, many specifically going after mutational byproducts, are yielding some great results and raising hopes for better survival outcomes, Jeffrey Lancet, MD, said in an interview.

“When I go to sleep at night, I often dream about ... 10-year survival rates in the 80% range. And then I wake up ... and I realize this is actually [the survival curve for chronic myeloid leukemia]. This is where we’d like to be [with AML].” Those outcomes are a long way off, but appreciable incremental gains may lie ahead with the recent advances in AML therapy, said Dr. Lancet, chair of the department of malignant hematology at Moffitt Cancer Center in Tampa.

In addition to the new approvals, 16 drugs are in late stage clinical development and will likely contribute to an AML market that is expected to surpass $1.5 billion by 2026, according to projections by the market intelligence company GlobalData.

Vyxeos

The liposome-encapsulated combination of daunorubicin and cytarabine (Vyxeos) was approved in August by the Food and Drug Administration for the treatment of therapy-related AML and AML with myelodysplasia-related changes.

In a phase 3 randomized trial, the fixed-dose combination product was associated with median overall survival of 9.6 months, compared with 5.9 months with a standard combination of cytarabine and daunorubicin (7+3).

“I would envision that Vyxeos will hold and become the primary standard of care for fit chemotherapy-suitable older patients, or any patients for that matter, who are dealing with secondary-like AML or high-risk AML, based on the phase 3 results that we demonstrated,” Dr. Lancet, the principal investigator for the trial, said in an interview.

Asked whether the improved survival with Vyxeos is primarily related to more patients becoming transplant eligible or to significant reductions in disease burden, Dr. Lancet remarked that it’s likely a mixture of both.

The high remission rate with Vyxeos vs. standard 7+3 therapy means Vyxeos has the ability to stand on its own, and “the potential to send more patients to transplant and to get better results.”

“Transplant is part of the continuum of care of AML, including in older patients, and Vyxeos is going to become a standard part of that care,” he remarked. But transplant outcomes were not a predesignated component of the phase 3 trial, and further study will be needed to determine Vyxeos’ role as a bridge to transplant. “At this stage I can reasonably state that it has a role in the upfront therapy of secondary and high-risk AML, regardless of whether the patient is being considered for transplant.”

The early stages of working Vyxeos into the therapeutic mix come with some challenges, however, according to Donna Capozzi, PharmD.

Oral targeted therapies

Enasidenib (Idhifa) was approved under priority review in August in conjunction with a companion diagnostic IDH2 assay for patients with relapsed or refractory disease and specific mutations in the IDH2 gene. Midostaurin (Rydapt) was approved in April for use in conjunction with standard daunorubicin and cytarabine induction and cytarabine consolidation in adults with FLT3 mutation-positive AML.

In a phase 1 dose escalation study reported at the annual meeting of the European Hematology Association, enasidenib was associated with an overall response rate of 37% in patients with relapsed/refractory AML, including 20.1% complete responses and 7.9% complete responses with incomplete recovery of platelets or incomplete hematologic recovery, 3.7% with partial responses, and 5.1% with a morphologic leukemia-free state. Patients who had a CR had a median overall survival of 22.9 months. For patients with responses other than CR, the median OS was 15.1 months. For patients with no response to the drug, the median OS was 5.6 months, Dr. Eytan M. Stein, of Memorial Sloan Kettering Cancer Center in New York, reported.

Additionally, need for transfusions was reduced in 34% of 157 patients who required transfusions at study entry.

“In a relapsed or refractory group of patients where there’s no true standard of care, this drug definitely represents a major breakthrough and has a lot of utility as a single agent, as a potential bridge to a transplant, and in combination with new or even old drugs – including regular old induction chemotherapy as a way to improve responses and outcomes in the future,” Dr. Lancet said, adding that as an oral agent it has potential for development as a maintenance strategy.

This agent could have a large impact, he said, adding: “I think this sets the paradigm for novel targeted therapies.”

Midostaurin has also emerged as a new standard of care, particularly for younger patients, Dr. Lancet said.

The approval of the multitargeted kinase inhibitor was based on the results of the randomized, placebo-controlled phase 3 RATIFY trial, which demonstrated significantly longer overall and event-free survival vs. placebo and standard chemotherapy in newly diagnosed AML patients with FLT3 gene mutations.

“I think this will be the new comparator for future studies, whatever they may be, for this patient population,” he said.

Dr. Capozzi noted that she has had some difficulty obtaining prior authorization for enasidenib due to its high cost (about $1,000/day).

The drug is taken orally on days 8-21 of a 28-day treatment cycle. In RATIFY, patients who achieved complete remission after induction therapy received four 28-day cycles of consolidation therapy.

Dr. Capozzi noted that the dosing regimen can be confusing, as it changes depending on whether it is used for induction or consolidation. It remains to be seen how these agents will fit into the treatment setting, she said.

Targeted therapies in development

Other targeted therapies in development for AML include an IDH1 inhibitor, the BCL2 inhibitor venetoclax, and several second-generation FLT3 inhibitors such as gilteritinib, Dr. Lancet said.

Venetoclax, which is currently approved for chronic lymphocytic leukemia, has shown single agent activity, but is even more promising in combination with low-dose cytarabine or aza-nucleosides, he noted.

For example, in one recent study reported at the annual congress of the European Hematology Association, response rates in older, newly diagnosed AML patients were as high as 72% for azacitidine plus venetoclax, and 76% for decitabine plus venetoclax.

“So there’s a lot of interest and promise,” Dr. Lancet said, adding that venetoclax may have broad application in AML. “We’ll be seeing a lot more data in the next year or two.”

An unusual aspect of venetoclax, which is used often for CLL, is the need for observation during dose escalation, Dr. Capozzi noted. Patients tend to question the need for admission for observation with the use of an oral agent, thus efforts are underway to develop criteria for outpatient observation.

Otherwise, venetoclax is fairly easy to access and use, and is well tolerated, she said.

“I expect as we learn more about where (venetoclax) fits in, it will be a much more commonplace agent” as part of AML therapy, she said.

Gilteritinib, as well as the second generation FLT3 inhibitors quizartinib and crenolanib, are also of interest in AML. With midostaurin already on the market, however, different strategies are being pursued, Dr. Lancet said.

“I believe gilteritinib is entering the fray in relapsed/refractory disease, and crenolanib is being looked at in the upfront FLT3 AML-positive setting and ultimately will be compared to midostaurin in combination with chemotherapy in that setting,” he added, noting that these drugs have the advantage of being more potent and selective inhibitors of FLT3, and some appear to have the ability to target resistance-conferring mutations.

“It still remains to be determined what the ultimate role will be, especially now that midostaurin is approved as frontline therapy and, in my opinion, will likely be entrenched there for awhile,” he said. “It’s a fairly competitive field right now, but certainly one where there’s a lot of excitement. The encouraging part is the second generation inhibitors, especially crenolanib and gilteritinib, are able to rescue some patients who may have failed primary therapy with an FLT3 inhibitor.”

Future direction and outcomes

So how should one go about selecting therapies, in the absence of data on combining therapies, for patients with multiple mutations?

Ideally, that means teasing out which of the AML patient’s mutations is clonal and the driver of their disease, and which one is subclonal. There are no guarantees, but that seems like a rational way to begin and move the field forward to studies of combination therapies, Dr. Lancet said.

“I think with the right combinations that target leukemias that are mutationally driven, there is potential to treat subsets of patient with very targeted therapies that will lead to prolonged survival. Right now, for the most part, we don’t have drugs for many of the targets that are very important in AML, and we don’t always know which target is driving the disease ... these are considerations that remain to be discovered,” he said. “But I do think that in 10 years we will have the ability with novel drugs and increased understanding of the clinical relevance of these targets to really personalize the approach more so than we are today, and to increase response rates significantly and improve survival as a result.”

Dr. Lancet is a consultant for Jazz Pharmaceuticals, Daiichi Sankyo, and Celgene. Dr. Capozzi reported having no disclosures.

[email protected]

With a recent flurry of new drug approvals, the treatment landscape for acute myeloid leukemia has expanded, raising new questions about how to incorporate those drugs into patient care.

Until about a decade ago, advances in AML therapy centered mainly around iterations of daunorubicin and cytarabine. Now, novel and targeted agents, many specifically going after mutational byproducts, are yielding some great results and raising hopes for better survival outcomes, Jeffrey Lancet, MD, said in an interview.

“When I go to sleep at night, I often dream about ... 10-year survival rates in the 80% range. And then I wake up ... and I realize this is actually [the survival curve for chronic myeloid leukemia]. This is where we’d like to be [with AML].” Those outcomes are a long way off, but appreciable incremental gains may lie ahead with the recent advances in AML therapy, said Dr. Lancet, chair of the department of malignant hematology at Moffitt Cancer Center in Tampa.

In addition to the new approvals, 16 drugs are in late stage clinical development and will likely contribute to an AML market that is expected to surpass $1.5 billion by 2026, according to projections by the market intelligence company GlobalData.

Vyxeos

The liposome-encapsulated combination of daunorubicin and cytarabine (Vyxeos) was approved in August by the Food and Drug Administration for the treatment of therapy-related AML and AML with myelodysplasia-related changes.

In a phase 3 randomized trial, the fixed-dose combination product was associated with median overall survival of 9.6 months, compared with 5.9 months with a standard combination of cytarabine and daunorubicin (7+3).

“I would envision that Vyxeos will hold and become the primary standard of care for fit chemotherapy-suitable older patients, or any patients for that matter, who are dealing with secondary-like AML or high-risk AML, based on the phase 3 results that we demonstrated,” Dr. Lancet, the principal investigator for the trial, said in an interview.

Asked whether the improved survival with Vyxeos is primarily related to more patients becoming transplant eligible or to significant reductions in disease burden, Dr. Lancet remarked that it’s likely a mixture of both.

The high remission rate with Vyxeos vs. standard 7+3 therapy means Vyxeos has the ability to stand on its own, and “the potential to send more patients to transplant and to get better results.”

“Transplant is part of the continuum of care of AML, including in older patients, and Vyxeos is going to become a standard part of that care,” he remarked. But transplant outcomes were not a predesignated component of the phase 3 trial, and further study will be needed to determine Vyxeos’ role as a bridge to transplant. “At this stage I can reasonably state that it has a role in the upfront therapy of secondary and high-risk AML, regardless of whether the patient is being considered for transplant.”

The early stages of working Vyxeos into the therapeutic mix come with some challenges, however, according to Donna Capozzi, PharmD.

Oral targeted therapies

Enasidenib (Idhifa) was approved under priority review in August in conjunction with a companion diagnostic IDH2 assay for patients with relapsed or refractory disease and specific mutations in the IDH2 gene. Midostaurin (Rydapt) was approved in April for use in conjunction with standard daunorubicin and cytarabine induction and cytarabine consolidation in adults with FLT3 mutation-positive AML.

In a phase 1 dose escalation study reported at the annual meeting of the European Hematology Association, enasidenib was associated with an overall response rate of 37% in patients with relapsed/refractory AML, including 20.1% complete responses and 7.9% complete responses with incomplete recovery of platelets or incomplete hematologic recovery, 3.7% with partial responses, and 5.1% with a morphologic leukemia-free state. Patients who had a CR had a median overall survival of 22.9 months. For patients with responses other than CR, the median OS was 15.1 months. For patients with no response to the drug, the median OS was 5.6 months, Dr. Eytan M. Stein, of Memorial Sloan Kettering Cancer Center in New York, reported.

Additionally, need for transfusions was reduced in 34% of 157 patients who required transfusions at study entry.

“In a relapsed or refractory group of patients where there’s no true standard of care, this drug definitely represents a major breakthrough and has a lot of utility as a single agent, as a potential bridge to a transplant, and in combination with new or even old drugs – including regular old induction chemotherapy as a way to improve responses and outcomes in the future,” Dr. Lancet said, adding that as an oral agent it has potential for development as a maintenance strategy.

This agent could have a large impact, he said, adding: “I think this sets the paradigm for novel targeted therapies.”

Midostaurin has also emerged as a new standard of care, particularly for younger patients, Dr. Lancet said.

The approval of the multitargeted kinase inhibitor was based on the results of the randomized, placebo-controlled phase 3 RATIFY trial, which demonstrated significantly longer overall and event-free survival vs. placebo and standard chemotherapy in newly diagnosed AML patients with FLT3 gene mutations.

“I think this will be the new comparator for future studies, whatever they may be, for this patient population,” he said.

Dr. Capozzi noted that she has had some difficulty obtaining prior authorization for enasidenib due to its high cost (about $1,000/day).

The drug is taken orally on days 8-21 of a 28-day treatment cycle. In RATIFY, patients who achieved complete remission after induction therapy received four 28-day cycles of consolidation therapy.

Dr. Capozzi noted that the dosing regimen can be confusing, as it changes depending on whether it is used for induction or consolidation. It remains to be seen how these agents will fit into the treatment setting, she said.

Targeted therapies in development

Other targeted therapies in development for AML include an IDH1 inhibitor, the BCL2 inhibitor venetoclax, and several second-generation FLT3 inhibitors such as gilteritinib, Dr. Lancet said.

Venetoclax, which is currently approved for chronic lymphocytic leukemia, has shown single agent activity, but is even more promising in combination with low-dose cytarabine or aza-nucleosides, he noted.

For example, in one recent study reported at the annual congress of the European Hematology Association, response rates in older, newly diagnosed AML patients were as high as 72% for azacitidine plus venetoclax, and 76% for decitabine plus venetoclax.

“So there’s a lot of interest and promise,” Dr. Lancet said, adding that venetoclax may have broad application in AML. “We’ll be seeing a lot more data in the next year or two.”

An unusual aspect of venetoclax, which is used often for CLL, is the need for observation during dose escalation, Dr. Capozzi noted. Patients tend to question the need for admission for observation with the use of an oral agent, thus efforts are underway to develop criteria for outpatient observation.

Otherwise, venetoclax is fairly easy to access and use, and is well tolerated, she said.

“I expect as we learn more about where (venetoclax) fits in, it will be a much more commonplace agent” as part of AML therapy, she said.

Gilteritinib, as well as the second generation FLT3 inhibitors quizartinib and crenolanib, are also of interest in AML. With midostaurin already on the market, however, different strategies are being pursued, Dr. Lancet said.

“I believe gilteritinib is entering the fray in relapsed/refractory disease, and crenolanib is being looked at in the upfront FLT3 AML-positive setting and ultimately will be compared to midostaurin in combination with chemotherapy in that setting,” he added, noting that these drugs have the advantage of being more potent and selective inhibitors of FLT3, and some appear to have the ability to target resistance-conferring mutations.

“It still remains to be determined what the ultimate role will be, especially now that midostaurin is approved as frontline therapy and, in my opinion, will likely be entrenched there for awhile,” he said. “It’s a fairly competitive field right now, but certainly one where there’s a lot of excitement. The encouraging part is the second generation inhibitors, especially crenolanib and gilteritinib, are able to rescue some patients who may have failed primary therapy with an FLT3 inhibitor.”

Future direction and outcomes

So how should one go about selecting therapies, in the absence of data on combining therapies, for patients with multiple mutations?

Ideally, that means teasing out which of the AML patient’s mutations is clonal and the driver of their disease, and which one is subclonal. There are no guarantees, but that seems like a rational way to begin and move the field forward to studies of combination therapies, Dr. Lancet said.

“I think with the right combinations that target leukemias that are mutationally driven, there is potential to treat subsets of patient with very targeted therapies that will lead to prolonged survival. Right now, for the most part, we don’t have drugs for many of the targets that are very important in AML, and we don’t always know which target is driving the disease ... these are considerations that remain to be discovered,” he said. “But I do think that in 10 years we will have the ability with novel drugs and increased understanding of the clinical relevance of these targets to really personalize the approach more so than we are today, and to increase response rates significantly and improve survival as a result.”

Dr. Lancet is a consultant for Jazz Pharmaceuticals, Daiichi Sankyo, and Celgene. Dr. Capozzi reported having no disclosures.

[email protected]

With a recent flurry of new drug approvals, the treatment landscape for acute myeloid leukemia has expanded, raising new questions about how to incorporate those drugs into patient care.

Until about a decade ago, advances in AML therapy centered mainly around iterations of daunorubicin and cytarabine. Now, novel and targeted agents, many specifically going after mutational byproducts, are yielding some great results and raising hopes for better survival outcomes, Jeffrey Lancet, MD, said in an interview.

“When I go to sleep at night, I often dream about ... 10-year survival rates in the 80% range. And then I wake up ... and I realize this is actually [the survival curve for chronic myeloid leukemia]. This is where we’d like to be [with AML].” Those outcomes are a long way off, but appreciable incremental gains may lie ahead with the recent advances in AML therapy, said Dr. Lancet, chair of the department of malignant hematology at Moffitt Cancer Center in Tampa.

In addition to the new approvals, 16 drugs are in late stage clinical development and will likely contribute to an AML market that is expected to surpass $1.5 billion by 2026, according to projections by the market intelligence company GlobalData.

Vyxeos

The liposome-encapsulated combination of daunorubicin and cytarabine (Vyxeos) was approved in August by the Food and Drug Administration for the treatment of therapy-related AML and AML with myelodysplasia-related changes.

In a phase 3 randomized trial, the fixed-dose combination product was associated with median overall survival of 9.6 months, compared with 5.9 months with a standard combination of cytarabine and daunorubicin (7+3).

“I would envision that Vyxeos will hold and become the primary standard of care for fit chemotherapy-suitable older patients, or any patients for that matter, who are dealing with secondary-like AML or high-risk AML, based on the phase 3 results that we demonstrated,” Dr. Lancet, the principal investigator for the trial, said in an interview.

Asked whether the improved survival with Vyxeos is primarily related to more patients becoming transplant eligible or to significant reductions in disease burden, Dr. Lancet remarked that it’s likely a mixture of both.

The high remission rate with Vyxeos vs. standard 7+3 therapy means Vyxeos has the ability to stand on its own, and “the potential to send more patients to transplant and to get better results.”

“Transplant is part of the continuum of care of AML, including in older patients, and Vyxeos is going to become a standard part of that care,” he remarked. But transplant outcomes were not a predesignated component of the phase 3 trial, and further study will be needed to determine Vyxeos’ role as a bridge to transplant. “At this stage I can reasonably state that it has a role in the upfront therapy of secondary and high-risk AML, regardless of whether the patient is being considered for transplant.”

The early stages of working Vyxeos into the therapeutic mix come with some challenges, however, according to Donna Capozzi, PharmD.

Oral targeted therapies

Enasidenib (Idhifa) was approved under priority review in August in conjunction with a companion diagnostic IDH2 assay for patients with relapsed or refractory disease and specific mutations in the IDH2 gene. Midostaurin (Rydapt) was approved in April for use in conjunction with standard daunorubicin and cytarabine induction and cytarabine consolidation in adults with FLT3 mutation-positive AML.

In a phase 1 dose escalation study reported at the annual meeting of the European Hematology Association, enasidenib was associated with an overall response rate of 37% in patients with relapsed/refractory AML, including 20.1% complete responses and 7.9% complete responses with incomplete recovery of platelets or incomplete hematologic recovery, 3.7% with partial responses, and 5.1% with a morphologic leukemia-free state. Patients who had a CR had a median overall survival of 22.9 months. For patients with responses other than CR, the median OS was 15.1 months. For patients with no response to the drug, the median OS was 5.6 months, Dr. Eytan M. Stein, of Memorial Sloan Kettering Cancer Center in New York, reported.

Additionally, need for transfusions was reduced in 34% of 157 patients who required transfusions at study entry.

“In a relapsed or refractory group of patients where there’s no true standard of care, this drug definitely represents a major breakthrough and has a lot of utility as a single agent, as a potential bridge to a transplant, and in combination with new or even old drugs – including regular old induction chemotherapy as a way to improve responses and outcomes in the future,” Dr. Lancet said, adding that as an oral agent it has potential for development as a maintenance strategy.

This agent could have a large impact, he said, adding: “I think this sets the paradigm for novel targeted therapies.”

Midostaurin has also emerged as a new standard of care, particularly for younger patients, Dr. Lancet said.

The approval of the multitargeted kinase inhibitor was based on the results of the randomized, placebo-controlled phase 3 RATIFY trial, which demonstrated significantly longer overall and event-free survival vs. placebo and standard chemotherapy in newly diagnosed AML patients with FLT3 gene mutations.

“I think this will be the new comparator for future studies, whatever they may be, for this patient population,” he said.

Dr. Capozzi noted that she has had some difficulty obtaining prior authorization for enasidenib due to its high cost (about $1,000/day).

The drug is taken orally on days 8-21 of a 28-day treatment cycle. In RATIFY, patients who achieved complete remission after induction therapy received four 28-day cycles of consolidation therapy.

Dr. Capozzi noted that the dosing regimen can be confusing, as it changes depending on whether it is used for induction or consolidation. It remains to be seen how these agents will fit into the treatment setting, she said.

Targeted therapies in development

Other targeted therapies in development for AML include an IDH1 inhibitor, the BCL2 inhibitor venetoclax, and several second-generation FLT3 inhibitors such as gilteritinib, Dr. Lancet said.

Venetoclax, which is currently approved for chronic lymphocytic leukemia, has shown single agent activity, but is even more promising in combination with low-dose cytarabine or aza-nucleosides, he noted.

For example, in one recent study reported at the annual congress of the European Hematology Association, response rates in older, newly diagnosed AML patients were as high as 72% for azacitidine plus venetoclax, and 76% for decitabine plus venetoclax.

“So there’s a lot of interest and promise,” Dr. Lancet said, adding that venetoclax may have broad application in AML. “We’ll be seeing a lot more data in the next year or two.”

An unusual aspect of venetoclax, which is used often for CLL, is the need for observation during dose escalation, Dr. Capozzi noted. Patients tend to question the need for admission for observation with the use of an oral agent, thus efforts are underway to develop criteria for outpatient observation.

Otherwise, venetoclax is fairly easy to access and use, and is well tolerated, she said.

“I expect as we learn more about where (venetoclax) fits in, it will be a much more commonplace agent” as part of AML therapy, she said.

Gilteritinib, as well as the second generation FLT3 inhibitors quizartinib and crenolanib, are also of interest in AML. With midostaurin already on the market, however, different strategies are being pursued, Dr. Lancet said.

“I believe gilteritinib is entering the fray in relapsed/refractory disease, and crenolanib is being looked at in the upfront FLT3 AML-positive setting and ultimately will be compared to midostaurin in combination with chemotherapy in that setting,” he added, noting that these drugs have the advantage of being more potent and selective inhibitors of FLT3, and some appear to have the ability to target resistance-conferring mutations.

“It still remains to be determined what the ultimate role will be, especially now that midostaurin is approved as frontline therapy and, in my opinion, will likely be entrenched there for awhile,” he said. “It’s a fairly competitive field right now, but certainly one where there’s a lot of excitement. The encouraging part is the second generation inhibitors, especially crenolanib and gilteritinib, are able to rescue some patients who may have failed primary therapy with an FLT3 inhibitor.”

Future direction and outcomes

So how should one go about selecting therapies, in the absence of data on combining therapies, for patients with multiple mutations?

Ideally, that means teasing out which of the AML patient’s mutations is clonal and the driver of their disease, and which one is subclonal. There are no guarantees, but that seems like a rational way to begin and move the field forward to studies of combination therapies, Dr. Lancet said.

“I think with the right combinations that target leukemias that are mutationally driven, there is potential to treat subsets of patient with very targeted therapies that will lead to prolonged survival. Right now, for the most part, we don’t have drugs for many of the targets that are very important in AML, and we don’t always know which target is driving the disease ... these are considerations that remain to be discovered,” he said. “But I do think that in 10 years we will have the ability with novel drugs and increased understanding of the clinical relevance of these targets to really personalize the approach more so than we are today, and to increase response rates significantly and improve survival as a result.”

Dr. Lancet is a consultant for Jazz Pharmaceuticals, Daiichi Sankyo, and Celgene. Dr. Capozzi reported having no disclosures.

[email protected]