CML

Prescription drugs

Photo by Steven Harbour

The US Food and Drug Administration (FDA) has approved the use of imatinib mesylate, a generic version of Novartis’s Gleevec being developed by a subsidiary of Sun Pharmaceuticals Limited.

Under the terms of a settlement agreement with Novartis, the Sun Pharma subsidiary is allowed to launch its generic imatinib in the US on February 1, 2016.

The drug will be available in 100 mg and 400 mg tablets.

The Sun Pharma subsidiary was the first company to file an abbreviated new drug application for generic imatinib with a para IV certification and is therefore eligible for 180 days of marketing exclusivity in the US.

Sun Pharma’s imatinib mesylate is approved for the following indications:

• Newly diagnosed adult and pediatric patients with Philadelphia chromosome positive chronic myeloid leukemia (Ph+ CML) in chronic phase
• Patients with (Ph+ CML) in blast crisis, accelerated phase, or in chronic phase after failure of interferon-alpha therapy
• Adult patients with relapsed or refractory Ph+ acute lymphoblastic leukemia
• Adult patients with myelodysplastic/myeloproliferative diseases associated with PDGFR gene re-arrangements
• Adult patients with aggressive systemic mastocytosis without the D816V c-Kit mutation or with c-Kit mutational status unknown
•  Adult patients with hypereosinophilic syndrome (HES) and/or chronic eosinophilic leukemia (CEL) who have the FIP1L1-PDGFRα fusion kinase and for patients with HES and/or CEL who are FIP1L1- PDGFRα fusion kinase negative or unknown
• Adult patients with unresectable, recurrent and/or metastatic dermatofibrosarcoma protuberans.

The drug is not approved to treat patients with KIT (CD117)-positive unresectable and/or metastatic malignant gastrointestinal stromal tumors.

Prescription drugs

Photo by Steven Harbour

The US Food and Drug Administration (FDA) has approved the use of imatinib mesylate, a generic version of Novartis’s Gleevec being developed by a subsidiary of Sun Pharmaceuticals Limited.

Under the terms of a settlement agreement with Novartis, the Sun Pharma subsidiary is allowed to launch its generic imatinib in the US on February 1, 2016.

The drug will be available in 100 mg and 400 mg tablets.

The Sun Pharma subsidiary was the first company to file an abbreviated new drug application for generic imatinib with a para IV certification and is therefore eligible for 180 days of marketing exclusivity in the US.

Sun Pharma’s imatinib mesylate is approved for the following indications:

• Newly diagnosed adult and pediatric patients with Philadelphia chromosome positive chronic myeloid leukemia (Ph+ CML) in chronic phase
• Patients with (Ph+ CML) in blast crisis, accelerated phase, or in chronic phase after failure of interferon-alpha therapy
• Adult patients with relapsed or refractory Ph+ acute lymphoblastic leukemia
• Adult patients with myelodysplastic/myeloproliferative diseases associated with PDGFR gene re-arrangements
• Adult patients with aggressive systemic mastocytosis without the D816V c-Kit mutation or with c-Kit mutational status unknown
•  Adult patients with hypereosinophilic syndrome (HES) and/or chronic eosinophilic leukemia (CEL) who have the FIP1L1-PDGFRα fusion kinase and for patients with HES and/or CEL who are FIP1L1- PDGFRα fusion kinase negative or unknown
• Adult patients with unresectable, recurrent and/or metastatic dermatofibrosarcoma protuberans.

The drug is not approved to treat patients with KIT (CD117)-positive unresectable and/or metastatic malignant gastrointestinal stromal tumors.

Prescription drugs

Photo by Steven Harbour

The US Food and Drug Administration (FDA) has approved the use of imatinib mesylate, a generic version of Novartis’s Gleevec being developed by a subsidiary of Sun Pharmaceuticals Limited.

Under the terms of a settlement agreement with Novartis, the Sun Pharma subsidiary is allowed to launch its generic imatinib in the US on February 1, 2016.

The drug will be available in 100 mg and 400 mg tablets.

The Sun Pharma subsidiary was the first company to file an abbreviated new drug application for generic imatinib with a para IV certification and is therefore eligible for 180 days of marketing exclusivity in the US.

Sun Pharma’s imatinib mesylate is approved for the following indications:

• Newly diagnosed adult and pediatric patients with Philadelphia chromosome positive chronic myeloid leukemia (Ph+ CML) in chronic phase
• Patients with (Ph+ CML) in blast crisis, accelerated phase, or in chronic phase after failure of interferon-alpha therapy
• Adult patients with relapsed or refractory Ph+ acute lymphoblastic leukemia
• Adult patients with myelodysplastic/myeloproliferative diseases associated with PDGFR gene re-arrangements
• Adult patients with aggressive systemic mastocytosis without the D816V c-Kit mutation or with c-Kit mutational status unknown
•  Adult patients with hypereosinophilic syndrome (HES) and/or chronic eosinophilic leukemia (CEL) who have the FIP1L1-PDGFRα fusion kinase and for patients with HES and/or CEL who are FIP1L1- PDGFRα fusion kinase negative or unknown
• Adult patients with unresectable, recurrent and/or metastatic dermatofibrosarcoma protuberans.

The drug is not approved to treat patients with KIT (CD117)-positive unresectable and/or metastatic malignant gastrointestinal stromal tumors.

CML cells

Image by Difu Wu

Researchers say they have identified a mechanism governing malignant reprogramming of progenitors into self-renewing leukemia stem cells (LSCs).

And their discovery has revealed a potential new therapeutic approach for chronic myeloid leukemia (CML).

Experiments in mice showed that a targeted monoclonal antibody could impair LSCs’ ability to regenerate and made them easier to eradicate with a tyrosine kinase inhibitor.

Catriona Jamieson, MD, PhD, of the University of California, San Diego, and her colleagues described this research in PNAS.

The researchers found that downregulation of Muscleblind-like 3 (MBNL3) RNA binding proteins resulted in re-expression of a human embryonic stem cell-specific alternative splicing gene regulatory network—a mechanism that controls embryonic stem cell pluripotency and fate. One effect of this was reprogramming of progenitor cells into LSCs in blast crisis CML.

“This is the first description of cancer stem cell generation through decreased expression of a transcriptional repressor of an embryonic pattern of alternative splicing that enhances stem cell self-renewal and survival,” Dr Jamieson said.

“Rather than acquiring multiple DNA mutations, as was previously thought, cancer stem cells in chronic myeloid leukemia switch to embryonic RNA splicing, which enhances their capacity to self-renew or clone themselves.”

“If we can detect and turn off embryonic splicing, we may be able to prevent cancer stem cells from propagating themselves. Also, if we target embryonic versions of proteins that are re-expressed by cancer, like CD44 variant 3, with specific antibodies together with tyrosine kinase inhibitors, we may be able to circumvent cancer relapse—a leading cause of cancer-related mortality.”

The researchers tested this theory in mice. They found that treatment with a humanized pan-CD44 monoclonal antibody and a targeted tyrosine kinase antagonist disrupted the development of LSCs in their protected microenvironment.

This forced the cells to enter the bloodstream, where dasatinib could effectively target them.

CML cells

Image by Difu Wu

Researchers say they have identified a mechanism governing malignant reprogramming of progenitors into self-renewing leukemia stem cells (LSCs).

And their discovery has revealed a potential new therapeutic approach for chronic myeloid leukemia (CML).

Experiments in mice showed that a targeted monoclonal antibody could impair LSCs’ ability to regenerate and made them easier to eradicate with a tyrosine kinase inhibitor.

Catriona Jamieson, MD, PhD, of the University of California, San Diego, and her colleagues described this research in PNAS.

The researchers found that downregulation of Muscleblind-like 3 (MBNL3) RNA binding proteins resulted in re-expression of a human embryonic stem cell-specific alternative splicing gene regulatory network—a mechanism that controls embryonic stem cell pluripotency and fate. One effect of this was reprogramming of progenitor cells into LSCs in blast crisis CML.

“This is the first description of cancer stem cell generation through decreased expression of a transcriptional repressor of an embryonic pattern of alternative splicing that enhances stem cell self-renewal and survival,” Dr Jamieson said.

“Rather than acquiring multiple DNA mutations, as was previously thought, cancer stem cells in chronic myeloid leukemia switch to embryonic RNA splicing, which enhances their capacity to self-renew or clone themselves.”

“If we can detect and turn off embryonic splicing, we may be able to prevent cancer stem cells from propagating themselves. Also, if we target embryonic versions of proteins that are re-expressed by cancer, like CD44 variant 3, with specific antibodies together with tyrosine kinase inhibitors, we may be able to circumvent cancer relapse—a leading cause of cancer-related mortality.”

The researchers tested this theory in mice. They found that treatment with a humanized pan-CD44 monoclonal antibody and a targeted tyrosine kinase antagonist disrupted the development of LSCs in their protected microenvironment.

This forced the cells to enter the bloodstream, where dasatinib could effectively target them.

CML cells

Image by Difu Wu

Researchers say they have identified a mechanism governing malignant reprogramming of progenitors into self-renewing leukemia stem cells (LSCs).

And their discovery has revealed a potential new therapeutic approach for chronic myeloid leukemia (CML).

Experiments in mice showed that a targeted monoclonal antibody could impair LSCs’ ability to regenerate and made them easier to eradicate with a tyrosine kinase inhibitor.

Catriona Jamieson, MD, PhD, of the University of California, San Diego, and her colleagues described this research in PNAS.

The researchers found that downregulation of Muscleblind-like 3 (MBNL3) RNA binding proteins resulted in re-expression of a human embryonic stem cell-specific alternative splicing gene regulatory network—a mechanism that controls embryonic stem cell pluripotency and fate. One effect of this was reprogramming of progenitor cells into LSCs in blast crisis CML.

“This is the first description of cancer stem cell generation through decreased expression of a transcriptional repressor of an embryonic pattern of alternative splicing that enhances stem cell self-renewal and survival,” Dr Jamieson said.

“Rather than acquiring multiple DNA mutations, as was previously thought, cancer stem cells in chronic myeloid leukemia switch to embryonic RNA splicing, which enhances their capacity to self-renew or clone themselves.”

“If we can detect and turn off embryonic splicing, we may be able to prevent cancer stem cells from propagating themselves. Also, if we target embryonic versions of proteins that are re-expressed by cancer, like CD44 variant 3, with specific antibodies together with tyrosine kinase inhibitors, we may be able to circumvent cancer relapse—a leading cause of cancer-related mortality.”

The researchers tested this theory in mice. They found that treatment with a humanized pan-CD44 monoclonal antibody and a targeted tyrosine kinase antagonist disrupted the development of LSCs in their protected microenvironment.

This forced the cells to enter the bloodstream, where dasatinib could effectively target them.

Consensus guidelines for the perinatal management of hematologic malignancies detected during pregnancy have been issued by a panel of international experts.

The guidelines, published online in the Journal of Clinical Oncology, aim to ensure that timely treatment of the cancers is not delayed in pregnant women (doi: 10.1200/JCO.2015.62.4445).

While rare, hematologic malignancies in pregnancy introduce clinical, social, ethical, and moral dilemmas. Evidence-based data are scarce, according to the researchers, who note the International Network on Cancer, Infertility and Pregnancy registers all cancers occurring during gestation.

“Patient accrual is ongoing and essential, because registration of new cases and long-term follow-up will improve clinical knowledge and increase the level of evidence,” Dr. Michael Lishner of Tel Aviv University and Meir Medical Center, Kfar Saba, Israel, and his fellow panelists wrote.

Hodgkin lymphoma

The researchers note that Hodgkin lymphoma is the most common hematologic cancer in pregnancy, and the prognosis for these patients is excellent. When diagnosed during the first trimester, a regimen based on vinblastine monotherapy has been used. ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine) therapy can be used postpartum and has been used in cases of progression during pregnancy, the panelists wrote.

“The limited data available suggest that ABVD may be administered safely and effectively during the latter phases of pregnancy,” the panel wrote. “Although it may be associated with prematurity and lower birth weights, studies have not reported significant disadvantages.”

Non-Hodgkin lymphoma

The second most common cancer in pregnancy is non-Hodgkin lymphoma. In the case of indolent disease, watchful waiting is possible, with the intent to treat with monoclonal antibodies – with or without chemotherapy – if symptoms or evidence of disease progression are noted. Steroids can be administered during the first trimester as a bridge to the second trimester, when chemotherapy can be used with relatively greater safety, the panelists noted.

Aggressive lymphomas diagnosed before 20 weeks’ gestation warrant pregnancy termination and treatment, they recommend. When diagnosed after 20 weeks, therapy should be comparable to that given a nonpregnant woman, including monoclonal antibodies (R-CHOP).

Chronic myeloid leukemia

Chronic myeloid leukemia occurs in approximately 1 in 100,000 pregnancies and is typically diagnosed during routine blood testing in an asymptomatic patient. As a result, treatment may not be needed until the patient’s white count or platelet count have risen to levels associated with the onset of symptoms. An approximate guideline is a white cell count greater than 100 X 10⁹/L and a platelet count greater than 500 X 10⁹/L.

Therapeutic approaches in pregnancy include interferon-a (INF-a), which does not inhibit DNA synthesis or readily cross the placenta, and leukapheresis, which is frequently required two to three times per week during the first and second trimesters. Counts tend to drop during the third trimester, allowing less frequent intervention.

Consideration should be given to adding aspirin or low-molecular-weight heparin (LMWH) when the platelet count exceeds 1,000 X 10⁹/L.

Myeloproliferative neoplasms

The most common myeloproliferative neoplasm seen in women of childbearing age is essential thrombocytosis.

“A large meta-analysis of pregnant women with essential thrombocytosis reported a live birth rate of 50%-70%, first trimester loss in 25%-40%, late pregnancy loss in 10%, placental abruption in 3.6%, and intrauterine growth restriction in 4.5%. Maternal morbidity is rare, but stroke has been reported,” according to the panelists.

Limited literature suggests similar outcomes for pregnant women with polycythemia vera and primary myelofibrosis.

In low-risk pregnancies, aspirin (75 mg/day) should be offered unless clearly contraindicated. For women with polycythemia vera, venesection may be continued when tolerated to maintain the hematocrit within the gestation-appropriate range.

Fetal ultrasound scans should be performed at 20, 26, and 34 weeks of gestation and uterine artery Doppler should be performed at 20 weeks’ gestation. If the mean pulsatility index exceeds 1.4, the pregnancy may be considered high risk, and treatment and monitoring should be increased.

In high-risk pregnancies, additional treatment includes cytoreductive therapy with or without LMWH. If cytoreductive therapy is required, INF-a should be titrated to maintain a platelet count of less than 400 X 10⁹/L and hematocrit within appropriate range.

Local protocols regarding interruption of LMWH should be adhered to during labor, and dehydration should be avoided. Platelet count and hematocrit may increase postpartum, requiring cytoreductive therapy. Thromboprophylaxis should be considered at 6 weeks’ postpartum because of the increased risk of thrombosis, the guidelines note.

Acute leukemia

“The remarkable anemia, thrombocytopenia, and neutropenia that characterize acute myeloid and lymphoblastic leukemia” require prompt treatment. Leukapheresis in the presence of clinically significant evidence of leukostasis can be considered, regardless of gestational stage. When patients are diagnosed with acute myeloid leukemia during the first trimester, pregnancy termination followed by conventional induction therapy (cytarabine/anthracycline) is recommended.

Those diagnosed later in pregnancy can receive conventional induction therapy, although this seems to be associated with increased risk of fetal growth restriction and even fetal loss. “Notably, neonates rarely experience neutropenia and cardiac impairment unless exposed to lipophilic idarubicin, which should not be used,” the panelists wrote.

When acute promyelocytic leukemia is diagnosed in the first trimester, pregnancy termination is recommended before initiating conventional ATRA-anthracycline therapy. Later in pregnancy, the regimen demonstrates low teratogenicity and can be used in women diagnosed after that stage. Arsenic treatment is highly teratogenic and is prohibited throughout gestation.

Acute lymphocytic leukemia (ALL) requires prophylactic CNS therapy, including methotrexate and L-asparaginase, which are fetotoxic. Methotrexate interferes with organogenesis and is prohibited before week 20 of gestation. L-asparaginase may increase the high risk for thromboembolic events attributed to the combination of pregnancy and malignancy.

Notably, tyrosine kinase inhibitors, essential for patients with Philadelphia chromosome–positive ALL, are teratogenic. Given these limitations, women diagnosed with ALL before 20 weeks’ gestation should undergo termination of the pregnancy and start conventional treatment. After week 20, conventional chemotherapy can be administered during pregnancy. Tyrosine kinase inhibitors can be initiated postpartum.

The guidelines also contain recommendations on diagnostic testing and radiotherapy, maternal supportive care, and perinatal and pediatric aspects of hematologic malignancies in pregnancy. An online appendix offers recommendations on the treatment of rare hematologic malignancies, including hairy cell leukemia, multiple myeloma, and myelodysplastic syndromes.

Dr. Lishner and nine of his coauthors had no financial relationships to disclose. Three coauthors received honoraria and research funding or are consultants to a wide variety of drug makers.

[email protected]

On Twitter @maryjodales

Consensus guidelines for the perinatal management of hematologic malignancies detected during pregnancy have been issued by a panel of international experts.

The guidelines, published online in the Journal of Clinical Oncology, aim to ensure that timely treatment of the cancers is not delayed in pregnant women (doi: 10.1200/JCO.2015.62.4445).

While rare, hematologic malignancies in pregnancy introduce clinical, social, ethical, and moral dilemmas. Evidence-based data are scarce, according to the researchers, who note the International Network on Cancer, Infertility and Pregnancy registers all cancers occurring during gestation.

“Patient accrual is ongoing and essential, because registration of new cases and long-term follow-up will improve clinical knowledge and increase the level of evidence,” Dr. Michael Lishner of Tel Aviv University and Meir Medical Center, Kfar Saba, Israel, and his fellow panelists wrote.

Hodgkin lymphoma

The researchers note that Hodgkin lymphoma is the most common hematologic cancer in pregnancy, and the prognosis for these patients is excellent. When diagnosed during the first trimester, a regimen based on vinblastine monotherapy has been used. ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine) therapy can be used postpartum and has been used in cases of progression during pregnancy, the panelists wrote.

“The limited data available suggest that ABVD may be administered safely and effectively during the latter phases of pregnancy,” the panel wrote. “Although it may be associated with prematurity and lower birth weights, studies have not reported significant disadvantages.”

Non-Hodgkin lymphoma

The second most common cancer in pregnancy is non-Hodgkin lymphoma. In the case of indolent disease, watchful waiting is possible, with the intent to treat with monoclonal antibodies – with or without chemotherapy – if symptoms or evidence of disease progression are noted. Steroids can be administered during the first trimester as a bridge to the second trimester, when chemotherapy can be used with relatively greater safety, the panelists noted.

Aggressive lymphomas diagnosed before 20 weeks’ gestation warrant pregnancy termination and treatment, they recommend. When diagnosed after 20 weeks, therapy should be comparable to that given a nonpregnant woman, including monoclonal antibodies (R-CHOP).

Chronic myeloid leukemia

Chronic myeloid leukemia occurs in approximately 1 in 100,000 pregnancies and is typically diagnosed during routine blood testing in an asymptomatic patient. As a result, treatment may not be needed until the patient’s white count or platelet count have risen to levels associated with the onset of symptoms. An approximate guideline is a white cell count greater than 100 X 10⁹/L and a platelet count greater than 500 X 10⁹/L.

Therapeutic approaches in pregnancy include interferon-a (INF-a), which does not inhibit DNA synthesis or readily cross the placenta, and leukapheresis, which is frequently required two to three times per week during the first and second trimesters. Counts tend to drop during the third trimester, allowing less frequent intervention.

Consideration should be given to adding aspirin or low-molecular-weight heparin (LMWH) when the platelet count exceeds 1,000 X 10⁹/L.

Myeloproliferative neoplasms

The most common myeloproliferative neoplasm seen in women of childbearing age is essential thrombocytosis.

“A large meta-analysis of pregnant women with essential thrombocytosis reported a live birth rate of 50%-70%, first trimester loss in 25%-40%, late pregnancy loss in 10%, placental abruption in 3.6%, and intrauterine growth restriction in 4.5%. Maternal morbidity is rare, but stroke has been reported,” according to the panelists.

Limited literature suggests similar outcomes for pregnant women with polycythemia vera and primary myelofibrosis.

In low-risk pregnancies, aspirin (75 mg/day) should be offered unless clearly contraindicated. For women with polycythemia vera, venesection may be continued when tolerated to maintain the hematocrit within the gestation-appropriate range.

Fetal ultrasound scans should be performed at 20, 26, and 34 weeks of gestation and uterine artery Doppler should be performed at 20 weeks’ gestation. If the mean pulsatility index exceeds 1.4, the pregnancy may be considered high risk, and treatment and monitoring should be increased.

In high-risk pregnancies, additional treatment includes cytoreductive therapy with or without LMWH. If cytoreductive therapy is required, INF-a should be titrated to maintain a platelet count of less than 400 X 10⁹/L and hematocrit within appropriate range.

Local protocols regarding interruption of LMWH should be adhered to during labor, and dehydration should be avoided. Platelet count and hematocrit may increase postpartum, requiring cytoreductive therapy. Thromboprophylaxis should be considered at 6 weeks’ postpartum because of the increased risk of thrombosis, the guidelines note.

Acute leukemia

“The remarkable anemia, thrombocytopenia, and neutropenia that characterize acute myeloid and lymphoblastic leukemia” require prompt treatment. Leukapheresis in the presence of clinically significant evidence of leukostasis can be considered, regardless of gestational stage. When patients are diagnosed with acute myeloid leukemia during the first trimester, pregnancy termination followed by conventional induction therapy (cytarabine/anthracycline) is recommended.

Those diagnosed later in pregnancy can receive conventional induction therapy, although this seems to be associated with increased risk of fetal growth restriction and even fetal loss. “Notably, neonates rarely experience neutropenia and cardiac impairment unless exposed to lipophilic idarubicin, which should not be used,” the panelists wrote.

When acute promyelocytic leukemia is diagnosed in the first trimester, pregnancy termination is recommended before initiating conventional ATRA-anthracycline therapy. Later in pregnancy, the regimen demonstrates low teratogenicity and can be used in women diagnosed after that stage. Arsenic treatment is highly teratogenic and is prohibited throughout gestation.

Acute lymphocytic leukemia (ALL) requires prophylactic CNS therapy, including methotrexate and L-asparaginase, which are fetotoxic. Methotrexate interferes with organogenesis and is prohibited before week 20 of gestation. L-asparaginase may increase the high risk for thromboembolic events attributed to the combination of pregnancy and malignancy.

Notably, tyrosine kinase inhibitors, essential for patients with Philadelphia chromosome–positive ALL, are teratogenic. Given these limitations, women diagnosed with ALL before 20 weeks’ gestation should undergo termination of the pregnancy and start conventional treatment. After week 20, conventional chemotherapy can be administered during pregnancy. Tyrosine kinase inhibitors can be initiated postpartum.

The guidelines also contain recommendations on diagnostic testing and radiotherapy, maternal supportive care, and perinatal and pediatric aspects of hematologic malignancies in pregnancy. An online appendix offers recommendations on the treatment of rare hematologic malignancies, including hairy cell leukemia, multiple myeloma, and myelodysplastic syndromes.

Dr. Lishner and nine of his coauthors had no financial relationships to disclose. Three coauthors received honoraria and research funding or are consultants to a wide variety of drug makers.

[email protected]

On Twitter @maryjodales

Consensus guidelines for the perinatal management of hematologic malignancies detected during pregnancy have been issued by a panel of international experts.

The guidelines, published online in the Journal of Clinical Oncology, aim to ensure that timely treatment of the cancers is not delayed in pregnant women (doi: 10.1200/JCO.2015.62.4445).

While rare, hematologic malignancies in pregnancy introduce clinical, social, ethical, and moral dilemmas. Evidence-based data are scarce, according to the researchers, who note the International Network on Cancer, Infertility and Pregnancy registers all cancers occurring during gestation.

“Patient accrual is ongoing and essential, because registration of new cases and long-term follow-up will improve clinical knowledge and increase the level of evidence,” Dr. Michael Lishner of Tel Aviv University and Meir Medical Center, Kfar Saba, Israel, and his fellow panelists wrote.

Hodgkin lymphoma

The researchers note that Hodgkin lymphoma is the most common hematologic cancer in pregnancy, and the prognosis for these patients is excellent. When diagnosed during the first trimester, a regimen based on vinblastine monotherapy has been used. ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine) therapy can be used postpartum and has been used in cases of progression during pregnancy, the panelists wrote.

“The limited data available suggest that ABVD may be administered safely and effectively during the latter phases of pregnancy,” the panel wrote. “Although it may be associated with prematurity and lower birth weights, studies have not reported significant disadvantages.”

Non-Hodgkin lymphoma

The second most common cancer in pregnancy is non-Hodgkin lymphoma. In the case of indolent disease, watchful waiting is possible, with the intent to treat with monoclonal antibodies – with or without chemotherapy – if symptoms or evidence of disease progression are noted. Steroids can be administered during the first trimester as a bridge to the second trimester, when chemotherapy can be used with relatively greater safety, the panelists noted.

Aggressive lymphomas diagnosed before 20 weeks’ gestation warrant pregnancy termination and treatment, they recommend. When diagnosed after 20 weeks, therapy should be comparable to that given a nonpregnant woman, including monoclonal antibodies (R-CHOP).

Chronic myeloid leukemia

Chronic myeloid leukemia occurs in approximately 1 in 100,000 pregnancies and is typically diagnosed during routine blood testing in an asymptomatic patient. As a result, treatment may not be needed until the patient’s white count or platelet count have risen to levels associated with the onset of symptoms. An approximate guideline is a white cell count greater than 100 X 10⁹/L and a platelet count greater than 500 X 10⁹/L.

Therapeutic approaches in pregnancy include interferon-a (INF-a), which does not inhibit DNA synthesis or readily cross the placenta, and leukapheresis, which is frequently required two to three times per week during the first and second trimesters. Counts tend to drop during the third trimester, allowing less frequent intervention.

Consideration should be given to adding aspirin or low-molecular-weight heparin (LMWH) when the platelet count exceeds 1,000 X 10⁹/L.

Myeloproliferative neoplasms

The most common myeloproliferative neoplasm seen in women of childbearing age is essential thrombocytosis.

“A large meta-analysis of pregnant women with essential thrombocytosis reported a live birth rate of 50%-70%, first trimester loss in 25%-40%, late pregnancy loss in 10%, placental abruption in 3.6%, and intrauterine growth restriction in 4.5%. Maternal morbidity is rare, but stroke has been reported,” according to the panelists.

Limited literature suggests similar outcomes for pregnant women with polycythemia vera and primary myelofibrosis.

In low-risk pregnancies, aspirin (75 mg/day) should be offered unless clearly contraindicated. For women with polycythemia vera, venesection may be continued when tolerated to maintain the hematocrit within the gestation-appropriate range.

Fetal ultrasound scans should be performed at 20, 26, and 34 weeks of gestation and uterine artery Doppler should be performed at 20 weeks’ gestation. If the mean pulsatility index exceeds 1.4, the pregnancy may be considered high risk, and treatment and monitoring should be increased.

In high-risk pregnancies, additional treatment includes cytoreductive therapy with or without LMWH. If cytoreductive therapy is required, INF-a should be titrated to maintain a platelet count of less than 400 X 10⁹/L and hematocrit within appropriate range.

Local protocols regarding interruption of LMWH should be adhered to during labor, and dehydration should be avoided. Platelet count and hematocrit may increase postpartum, requiring cytoreductive therapy. Thromboprophylaxis should be considered at 6 weeks’ postpartum because of the increased risk of thrombosis, the guidelines note.

Acute leukemia

“The remarkable anemia, thrombocytopenia, and neutropenia that characterize acute myeloid and lymphoblastic leukemia” require prompt treatment. Leukapheresis in the presence of clinically significant evidence of leukostasis can be considered, regardless of gestational stage. When patients are diagnosed with acute myeloid leukemia during the first trimester, pregnancy termination followed by conventional induction therapy (cytarabine/anthracycline) is recommended.

Those diagnosed later in pregnancy can receive conventional induction therapy, although this seems to be associated with increased risk of fetal growth restriction and even fetal loss. “Notably, neonates rarely experience neutropenia and cardiac impairment unless exposed to lipophilic idarubicin, which should not be used,” the panelists wrote.

When acute promyelocytic leukemia is diagnosed in the first trimester, pregnancy termination is recommended before initiating conventional ATRA-anthracycline therapy. Later in pregnancy, the regimen demonstrates low teratogenicity and can be used in women diagnosed after that stage. Arsenic treatment is highly teratogenic and is prohibited throughout gestation.

Acute lymphocytic leukemia (ALL) requires prophylactic CNS therapy, including methotrexate and L-asparaginase, which are fetotoxic. Methotrexate interferes with organogenesis and is prohibited before week 20 of gestation. L-asparaginase may increase the high risk for thromboembolic events attributed to the combination of pregnancy and malignancy.

Notably, tyrosine kinase inhibitors, essential for patients with Philadelphia chromosome–positive ALL, are teratogenic. Given these limitations, women diagnosed with ALL before 20 weeks’ gestation should undergo termination of the pregnancy and start conventional treatment. After week 20, conventional chemotherapy can be administered during pregnancy. Tyrosine kinase inhibitors can be initiated postpartum.

The guidelines also contain recommendations on diagnostic testing and radiotherapy, maternal supportive care, and perinatal and pediatric aspects of hematologic malignancies in pregnancy. An online appendix offers recommendations on the treatment of rare hematologic malignancies, including hairy cell leukemia, multiple myeloma, and myelodysplastic syndromes.

Dr. Lishner and nine of his coauthors had no financial relationships to disclose. Three coauthors received honoraria and research funding or are consultants to a wide variety of drug makers.

[email protected]

On Twitter @maryjodales

FROM A TELECONFERENCE – The American Society of Hematology’s (ASH) 57th annual meeting in Orlando is chock-full of much-anticipated results in cancer immunotherapies such as CAR T cell therapies and checkpoint inhibitors, advances in sickle cell disease, and practical advice on managing the latest drugs in the clinic, ASH officials said in a teleconference. Here are some of the day-by-day picks selected by ASH president Dr. David Williams and ASH secretary Dr. Stephanie J. Lee, who gave their recommendations during a conference call for the press. Meeting abstracts are now available online.

Saturday, Dec. 5

Clinical applications of newly approved drugs

The popular special education session on clinical applications of newly approved drugs returns on Saturday, Dec. 5 at 9:30 a.m., with didactic presentations that address issues clinicians may face such as drug-drug interactions, side effects, and adverse events. The three drugs to be discussed this year are: idarucizumab (Praxbind), the first specific reversal agent approved for dabigatran reversal; blinatumomab (Blincyto), approved for second-line treatment of Philadelphia chromosomenegative acute lymphoblastic leukemia; and the histone deacetylase (HDAC) inhibitor panobinostat (Farydak), approved for the treatment of multiple myeloma.

Adoptive immunotherapy

One presentation to look out for next month is abstract 99at 12:30 p.m. on Saturday, Dec. 5 in the adoptive immunotherapy session, Dr. Williams told reporters. The chimeric antigen receptor (CAR)-T-cell approach has relied on genetically engineering the patient’s own T cells to rev up the immune system. This group’s approach is to treat B-cell malignancies after allogeneic hematopoietic stem cell transplantation using a single infusion of anti-CD19 CAR-T cells from the patient’s transplant donor.

Eight of 20 patients treated with this strategy achieved remission, including six complete remissions and two partial remissions. Importantly, none of these patients developed acute graft-versus-host disease, a potential consequence of using allogeneic rather than autologous T cells, he said. The authors also noted that patients who responded and went into remission were marked by higher numbers of these infused CAR-T cells in their circulation, suggesting a biomarker of response.

Checkpoint, please?

Immunotherapy is a “very hot area,” so ASH has put together a special session at 4 p.m. Saturday called “Checkpoint, Please?” Dr. Williams said. Topics include the role of programmed death (PD)-1 and PD-ligand 1 in acute and chronic graft-versus-host disease, checkpoint blockade with neoantigen cancer vaccines, and insights into the mechanisms of action of anti-CTLA-4 (cytotoxic T-lymphocyte–associated protein 4) antibody therapy.

Sunday, Dec. 6

Precision medicine

Sunday’s plenary scientific session will include several noteworthy personalized medicine abstracts featuring emerging therapies targeted to specific genetic subtypes, Dr. Lee, from the University of Washington, Seattle, said.

Plenary abstract 6 is a large, multinational study looking at whether adding the multikinase inhibitor midostaurin to standard induction therapy and carried through 1 year of maintenance would improve outcomes in newly diagnosed acute myeloid leukemia with FLT3 mutations. Patients with these deleterious mutations do enter remission with chemotherapy, but often relapse.

Overall and event-free survival were better at 5 years by about 7% to 8% in the experimental arm using midostaurin, she said. Caveats are that complete response rates were similar in both arms and lower than reported in other trials.

“Because we know that patients with this FLT3 mutation have a very poor prognosis with standard chemotherapy, more than half of the patients in this trial received an allogeneic transplant,” Dr. Lee noted. “But the abstract does say that the results are similar if you censor at the time of the transplant.”

In this same vein of precision medicine is plenary abstract 1, testing whether adding rituximab to standard chemotherapy improves outcomes in adults with CD-20–positive, Philadelphia chromosome–negative, B-cell precursor acute lymphoblastic leukemia (ALL). Rituximab (Rituxan) binds to CD-20, which is found in about 30% to 50% of adult B-cell ALL, she said.

At 2 years, patients treated with rituximab had longer event-free survival than controls (65% vs. 52%; P = .038), but similar overall survival (71% vs. 64%; P = .09), according to the abstract. The rituximab arm also received more allogeneic transplants, but again, after censoring the data, the abstract states that both event-free and overall survival were longer with rituximab, Dr. Lee said.

Sickle cell anemia

Sunday’s plenary session will also feature the very important TWiTCH (TCD with Transfusions Changing to Hydroxyurea) study evaluating hydroxyurea therapy as an alternative to chronic blood transfusions to prevent stroke. Stroke is one of the most dreaded complications of sickle cell disease, occurring in up to 10% of children, Dr. Williams said. Though transfusions are effective, they have to be continued indefinitely and lead to iron overload. Hydroxyurea increases the amount of fetal hemoglobin and fetal red blood cells and has become a standard therapy to attenuate the complications of sickle cell.

The phase III noninferiority study, which used Transcranial Doppler (TCD) screening to identify children at elevated risk for stroke, showed that hydroxyurea “was as good as current therapy with red cell transfusions and there was some indication, although not significant, that it might even be superior in lowering the TCD levels,” Dr. Williams said. An added benefit of the hydroxyurea was that it improved the patients’ iron overload status. There were no strokes in either group.

Sunday’s abstract 202 is another presentation “that I’m sure will get a lot of attention,” Dr. Williams said. It offers updated details on outcomes from patients with sickle cell disease (SCD) treated with a novel gene therapy transduced with the LentiGlobin BB305 (Bluebird Bio) lentiviral vector. Patients with beta thalassemia major have remained transfusion-independent for more than a year after this treatment, with results now available from four patients with SCD. One patient with a severe phenotype has had no sickle cell complications and has been able to stop his transfusion therapy, while two of the other four patients are also transfusion-independent.

“This is an early study showing what appears to be efficacy of the gene therapy approach not in thalassemia, but in sickle cell disease,” Dr. Williams said, noting that abstract 3233 will also feature results using LentiGlobin gene therapy in severe SCD.

ASH/EHA joint symposium

Also noteworthy is a special joint ASH/European Hematology Association symposium looking at how well genomic data are being incorporated into practice in the U.S. and Europe.

Monday, Dec. 7

ASH/FDA joint symposium

A joint ASH/FDA symposium on late-breaking drug approvals is new this year and features drugs that gained approval in November 2015. FDA product-reviewers will discuss safety and efficacy issues in the clinical approval trials and toxicity studies, while clinicians will share their experiences in the real-world use of these drugs.

“This is information that is really going to be very hot off the press and presented in conjunction with the FDA,” Dr. Lee said.

Dr. Williams reported research funding from Bluebird Bio. Dr. Lee reported having no conflicts of interest.

[email protected]

FROM A TELECONFERENCE – The American Society of Hematology’s (ASH) 57th annual meeting in Orlando is chock-full of much-anticipated results in cancer immunotherapies such as CAR T cell therapies and checkpoint inhibitors, advances in sickle cell disease, and practical advice on managing the latest drugs in the clinic, ASH officials said in a teleconference. Here are some of the day-by-day picks selected by ASH president Dr. David Williams and ASH secretary Dr. Stephanie J. Lee, who gave their recommendations during a conference call for the press. Meeting abstracts are now available online.

Saturday, Dec. 5

Clinical applications of newly approved drugs

The popular special education session on clinical applications of newly approved drugs returns on Saturday, Dec. 5 at 9:30 a.m., with didactic presentations that address issues clinicians may face such as drug-drug interactions, side effects, and adverse events. The three drugs to be discussed this year are: idarucizumab (Praxbind), the first specific reversal agent approved for dabigatran reversal; blinatumomab (Blincyto), approved for second-line treatment of Philadelphia chromosomenegative acute lymphoblastic leukemia; and the histone deacetylase (HDAC) inhibitor panobinostat (Farydak), approved for the treatment of multiple myeloma.

Adoptive immunotherapy

One presentation to look out for next month is abstract 99at 12:30 p.m. on Saturday, Dec. 5 in the adoptive immunotherapy session, Dr. Williams told reporters. The chimeric antigen receptor (CAR)-T-cell approach has relied on genetically engineering the patient’s own T cells to rev up the immune system. This group’s approach is to treat B-cell malignancies after allogeneic hematopoietic stem cell transplantation using a single infusion of anti-CD19 CAR-T cells from the patient’s transplant donor.

Eight of 20 patients treated with this strategy achieved remission, including six complete remissions and two partial remissions. Importantly, none of these patients developed acute graft-versus-host disease, a potential consequence of using allogeneic rather than autologous T cells, he said. The authors also noted that patients who responded and went into remission were marked by higher numbers of these infused CAR-T cells in their circulation, suggesting a biomarker of response.

Checkpoint, please?

Immunotherapy is a “very hot area,” so ASH has put together a special session at 4 p.m. Saturday called “Checkpoint, Please?” Dr. Williams said. Topics include the role of programmed death (PD)-1 and PD-ligand 1 in acute and chronic graft-versus-host disease, checkpoint blockade with neoantigen cancer vaccines, and insights into the mechanisms of action of anti-CTLA-4 (cytotoxic T-lymphocyte–associated protein 4) antibody therapy.

Sunday, Dec. 6

Precision medicine

Sunday’s plenary scientific session will include several noteworthy personalized medicine abstracts featuring emerging therapies targeted to specific genetic subtypes, Dr. Lee, from the University of Washington, Seattle, said.

Plenary abstract 6 is a large, multinational study looking at whether adding the multikinase inhibitor midostaurin to standard induction therapy and carried through 1 year of maintenance would improve outcomes in newly diagnosed acute myeloid leukemia with FLT3 mutations. Patients with these deleterious mutations do enter remission with chemotherapy, but often relapse.

Overall and event-free survival were better at 5 years by about 7% to 8% in the experimental arm using midostaurin, she said. Caveats are that complete response rates were similar in both arms and lower than reported in other trials.

“Because we know that patients with this FLT3 mutation have a very poor prognosis with standard chemotherapy, more than half of the patients in this trial received an allogeneic transplant,” Dr. Lee noted. “But the abstract does say that the results are similar if you censor at the time of the transplant.”

In this same vein of precision medicine is plenary abstract 1, testing whether adding rituximab to standard chemotherapy improves outcomes in adults with CD-20–positive, Philadelphia chromosome–negative, B-cell precursor acute lymphoblastic leukemia (ALL). Rituximab (Rituxan) binds to CD-20, which is found in about 30% to 50% of adult B-cell ALL, she said.

At 2 years, patients treated with rituximab had longer event-free survival than controls (65% vs. 52%; P = .038), but similar overall survival (71% vs. 64%; P = .09), according to the abstract. The rituximab arm also received more allogeneic transplants, but again, after censoring the data, the abstract states that both event-free and overall survival were longer with rituximab, Dr. Lee said.

Sickle cell anemia

Sunday’s plenary session will also feature the very important TWiTCH (TCD with Transfusions Changing to Hydroxyurea) study evaluating hydroxyurea therapy as an alternative to chronic blood transfusions to prevent stroke. Stroke is one of the most dreaded complications of sickle cell disease, occurring in up to 10% of children, Dr. Williams said. Though transfusions are effective, they have to be continued indefinitely and lead to iron overload. Hydroxyurea increases the amount of fetal hemoglobin and fetal red blood cells and has become a standard therapy to attenuate the complications of sickle cell.

The phase III noninferiority study, which used Transcranial Doppler (TCD) screening to identify children at elevated risk for stroke, showed that hydroxyurea “was as good as current therapy with red cell transfusions and there was some indication, although not significant, that it might even be superior in lowering the TCD levels,” Dr. Williams said. An added benefit of the hydroxyurea was that it improved the patients’ iron overload status. There were no strokes in either group.

Sunday’s abstract 202 is another presentation “that I’m sure will get a lot of attention,” Dr. Williams said. It offers updated details on outcomes from patients with sickle cell disease (SCD) treated with a novel gene therapy transduced with the LentiGlobin BB305 (Bluebird Bio) lentiviral vector. Patients with beta thalassemia major have remained transfusion-independent for more than a year after this treatment, with results now available from four patients with SCD. One patient with a severe phenotype has had no sickle cell complications and has been able to stop his transfusion therapy, while two of the other four patients are also transfusion-independent.

“This is an early study showing what appears to be efficacy of the gene therapy approach not in thalassemia, but in sickle cell disease,” Dr. Williams said, noting that abstract 3233 will also feature results using LentiGlobin gene therapy in severe SCD.

ASH/EHA joint symposium

Also noteworthy is a special joint ASH/European Hematology Association symposium looking at how well genomic data are being incorporated into practice in the U.S. and Europe.

Monday, Dec. 7

ASH/FDA joint symposium

A joint ASH/FDA symposium on late-breaking drug approvals is new this year and features drugs that gained approval in November 2015. FDA product-reviewers will discuss safety and efficacy issues in the clinical approval trials and toxicity studies, while clinicians will share their experiences in the real-world use of these drugs.

“This is information that is really going to be very hot off the press and presented in conjunction with the FDA,” Dr. Lee said.

Dr. Williams reported research funding from Bluebird Bio. Dr. Lee reported having no conflicts of interest.

[email protected]

FROM A TELECONFERENCE – The American Society of Hematology’s (ASH) 57th annual meeting in Orlando is chock-full of much-anticipated results in cancer immunotherapies such as CAR T cell therapies and checkpoint inhibitors, advances in sickle cell disease, and practical advice on managing the latest drugs in the clinic, ASH officials said in a teleconference. Here are some of the day-by-day picks selected by ASH president Dr. David Williams and ASH secretary Dr. Stephanie J. Lee, who gave their recommendations during a conference call for the press. Meeting abstracts are now available online.

Saturday, Dec. 5

Clinical applications of newly approved drugs

The popular special education session on clinical applications of newly approved drugs returns on Saturday, Dec. 5 at 9:30 a.m., with didactic presentations that address issues clinicians may face such as drug-drug interactions, side effects, and adverse events. The three drugs to be discussed this year are: idarucizumab (Praxbind), the first specific reversal agent approved for dabigatran reversal; blinatumomab (Blincyto), approved for second-line treatment of Philadelphia chromosomenegative acute lymphoblastic leukemia; and the histone deacetylase (HDAC) inhibitor panobinostat (Farydak), approved for the treatment of multiple myeloma.

Adoptive immunotherapy

One presentation to look out for next month is abstract 99at 12:30 p.m. on Saturday, Dec. 5 in the adoptive immunotherapy session, Dr. Williams told reporters. The chimeric antigen receptor (CAR)-T-cell approach has relied on genetically engineering the patient’s own T cells to rev up the immune system. This group’s approach is to treat B-cell malignancies after allogeneic hematopoietic stem cell transplantation using a single infusion of anti-CD19 CAR-T cells from the patient’s transplant donor.

Eight of 20 patients treated with this strategy achieved remission, including six complete remissions and two partial remissions. Importantly, none of these patients developed acute graft-versus-host disease, a potential consequence of using allogeneic rather than autologous T cells, he said. The authors also noted that patients who responded and went into remission were marked by higher numbers of these infused CAR-T cells in their circulation, suggesting a biomarker of response.

Checkpoint, please?

Immunotherapy is a “very hot area,” so ASH has put together a special session at 4 p.m. Saturday called “Checkpoint, Please?” Dr. Williams said. Topics include the role of programmed death (PD)-1 and PD-ligand 1 in acute and chronic graft-versus-host disease, checkpoint blockade with neoantigen cancer vaccines, and insights into the mechanisms of action of anti-CTLA-4 (cytotoxic T-lymphocyte–associated protein 4) antibody therapy.

Sunday, Dec. 6

Precision medicine

Sunday’s plenary scientific session will include several noteworthy personalized medicine abstracts featuring emerging therapies targeted to specific genetic subtypes, Dr. Lee, from the University of Washington, Seattle, said.

Plenary abstract 6 is a large, multinational study looking at whether adding the multikinase inhibitor midostaurin to standard induction therapy and carried through 1 year of maintenance would improve outcomes in newly diagnosed acute myeloid leukemia with FLT3 mutations. Patients with these deleterious mutations do enter remission with chemotherapy, but often relapse.

Overall and event-free survival were better at 5 years by about 7% to 8% in the experimental arm using midostaurin, she said. Caveats are that complete response rates were similar in both arms and lower than reported in other trials.

“Because we know that patients with this FLT3 mutation have a very poor prognosis with standard chemotherapy, more than half of the patients in this trial received an allogeneic transplant,” Dr. Lee noted. “But the abstract does say that the results are similar if you censor at the time of the transplant.”

In this same vein of precision medicine is plenary abstract 1, testing whether adding rituximab to standard chemotherapy improves outcomes in adults with CD-20–positive, Philadelphia chromosome–negative, B-cell precursor acute lymphoblastic leukemia (ALL). Rituximab (Rituxan) binds to CD-20, which is found in about 30% to 50% of adult B-cell ALL, she said.

At 2 years, patients treated with rituximab had longer event-free survival than controls (65% vs. 52%; P = .038), but similar overall survival (71% vs. 64%; P = .09), according to the abstract. The rituximab arm also received more allogeneic transplants, but again, after censoring the data, the abstract states that both event-free and overall survival were longer with rituximab, Dr. Lee said.

Sickle cell anemia

Sunday’s plenary session will also feature the very important TWiTCH (TCD with Transfusions Changing to Hydroxyurea) study evaluating hydroxyurea therapy as an alternative to chronic blood transfusions to prevent stroke. Stroke is one of the most dreaded complications of sickle cell disease, occurring in up to 10% of children, Dr. Williams said. Though transfusions are effective, they have to be continued indefinitely and lead to iron overload. Hydroxyurea increases the amount of fetal hemoglobin and fetal red blood cells and has become a standard therapy to attenuate the complications of sickle cell.

The phase III noninferiority study, which used Transcranial Doppler (TCD) screening to identify children at elevated risk for stroke, showed that hydroxyurea “was as good as current therapy with red cell transfusions and there was some indication, although not significant, that it might even be superior in lowering the TCD levels,” Dr. Williams said. An added benefit of the hydroxyurea was that it improved the patients’ iron overload status. There were no strokes in either group.

Sunday’s abstract 202 is another presentation “that I’m sure will get a lot of attention,” Dr. Williams said. It offers updated details on outcomes from patients with sickle cell disease (SCD) treated with a novel gene therapy transduced with the LentiGlobin BB305 (Bluebird Bio) lentiviral vector. Patients with beta thalassemia major have remained transfusion-independent for more than a year after this treatment, with results now available from four patients with SCD. One patient with a severe phenotype has had no sickle cell complications and has been able to stop his transfusion therapy, while two of the other four patients are also transfusion-independent.

“This is an early study showing what appears to be efficacy of the gene therapy approach not in thalassemia, but in sickle cell disease,” Dr. Williams said, noting that abstract 3233 will also feature results using LentiGlobin gene therapy in severe SCD.

ASH/EHA joint symposium

Also noteworthy is a special joint ASH/European Hematology Association symposium looking at how well genomic data are being incorporated into practice in the U.S. and Europe.

Monday, Dec. 7

ASH/FDA joint symposium

A joint ASH/FDA symposium on late-breaking drug approvals is new this year and features drugs that gained approval in November 2015. FDA product-reviewers will discuss safety and efficacy issues in the clinical approval trials and toxicity studies, while clinicians will share their experiences in the real-world use of these drugs.

“This is information that is really going to be very hot off the press and presented in conjunction with the FDA,” Dr. Lee said.

Dr. Williams reported research funding from Bluebird Bio. Dr. Lee reported having no conflicts of interest.

[email protected]

SAN FRANCISCO – The National Comprehensive Cancer Network (NCCN) has introduced an easy-to-use visual tool called Evidence Blocks to help physicians and patients compare various treatment options and individualize the selection among them.

“This information can serve as a starting point for shared decision making between the patient and health care team based on individual patients’ value systems,” chief executive officer Dr. Robert W. Carlson said at the NCCN Annual Congress: Hematologic Malignancies, where the tool was unveiled in a session and related press conference.

The first two NCCN guidelines to incorporate the Evidence Blocks – those for multiple myeloma and chronic myelogenous leukemia – were released at the same time. The organization hopes to incorporate them into all of its guidelines by early 2017, he said.

Development of the Evidence Blocks

The NCCN developed the Evidence Blocks to address requests from various stakeholders, according to Dr. Carlson. Guideline users wanted to know more about the rationale behind recommended therapies, asked for inclusion of information on costs, and sought an aid that would allow patients to make decisions based on their individual values.

“The patient perception of value is what should be most important to us,” he commented. “But even among patients, the concept of value differs greatly from patient to patient,” based on factors such as age, comorbidities, treatment goals, and health insurance coverage.

Each Evidence Block graphically displays five measures of information on a recommended therapy: efficacy, safety, quality of the evidence supporting the recommendation, consistency of the evidence supporting the recommendation, and affordability. Each column in the block represents one measure.

Blue shading indicates panelists’ average numeric score for the therapy on that measure rounded to the nearest integer, ranging from 1 (least favorable) to 5 (most favorable). Therefore, the more shading a therapy has, the more favorable its score.

The Evidence Blocks are added to the guidelines and aligned vertically on pages. “This display of the information graphically allows for very efficient scanning of multiple options for therapy. Comparisons across several regimens can be done very quickly and intuitively,” Dr. Carlson noted.

“We believe that the presentation of this type of information allows the health care provider and patient to make their own judgments of the value of specific interventions,” he added.

The affordability measure has generated the most discussion among panelists and stakeholders, according to Dr. Carlson. For this measure, panelists estimated the total cost of care for a therapy, including the costs of drugs, administration, required supportive care, toxicity monitoring, and care associated with management of toxicity. Scores range from very expensive to very inexpensive.

“We don’t use a dollar amount. Rather, it’s sort of what’s the total cost to society, if you will, of the medical intervention part of this,” he explained. “It’s important to understand that these estimates are not necessarily what a patient would pay because many patients have insurance programs that cover all of this cost.… However, we felt it was important to give patients as well as providers an estimate of what the overall magnitude of expense is because there are patients who have huge deductibles, there’s the doughnut hole within Medicare, and there are patients who have no insurance.”

The Evidence Blocks may help address a “conspiracy of silence” between physicians and patients when it comes to discussing treatment costs, whereby neither party wants to bring up this thorny issue, according to Dr. Carlson. “The Evidence Blocks demystify the discussion of cost because the affordability issue is there in front of you. So it gives people permission to talk about cost and affordability.”

It should be relatively easy to teach patients to use the Evidence Blocks. “I think you’ll find your patients will actually be interested in this and that they will not have as much difficulty interpreting this as you think they will, because the patient advocacy groups and the patient advocates that we have spoken with about this, they get this almost instantly,” he said.

Oncologist perspective

There is a critical need for tools such as the Evidence Blocks in making treatment decisions today, according to Dr. George Somlo, professor in the department of medical oncology and therapeutics research at the City of Hope Comprehensive Cancer Center in Duarte, Calif., and also a member of the NCCN multiple myeloma and breast cancer guideline panels.

Treatment options for multiple myeloma, as for many cancers, have exploded in the past few decades, he noted. “How do you go from making sense of having two drugs with a very poor outcome predicted to having literally dozens of agents approved and used in combination, and in essence being at the verge of curing patients with multiple myeloma?”

Dr. Somlo agreed that inclusion of costs in the Evidence Blocks would likely be beneficial as a conversation starter, recalling, “I’ve had patients who did not fill their prescription for a potentially curative medication because they were worried about the $2,500 or $3,500 copay.”

Patient-physician discussion will be important when it comes to using information from the new tool, he said. For example, in the NCCN guideline for multiple myeloma, some of the first-line regimens have identical Evidence Blocks; thus, consideration of factors such as comorbidities will become important.

“This kind of evidence-based scoring system can guide that kind of discussion with the patient and can tailor the individual therapeutic regimens,” he concluded.

Patient perspective

Breast cancer survivor Marta Nichols, who is vice president of investor relations at GoDaddy and a member of the California Breast Cancer Research Council based in San Francisco, welcomed the Evidence Blocks as a tool that will allow patients to make more informed decisions according to what matters most to them.

Only 33 years old at diagnosis, she and her husband had just begun to think about starting a family. “So my primary concern coming into my physician’s office was my fertility and what impact the treatment would have on my fertility. Certainly most physicians are concerned with efficacy – they want to see you survive. My concern was not just surviving, but also thriving and being able to give birth to children down the line,” she explained.

Patients today are overwhelmed not only by their cancer diagnosis, but also by the many treatment options and the new emphasis on shared decision making, Ms. Nichols noted. And that’s where the Evidence Blocks can make a difference.

“When I was diagnosed, it would have been hugely helpful for me to have information laid out in this very clear and systematic way… It would have given us the ability to make a much more informed decision,” she commented.

Multiple myeloma survivor Donald B. Orosco, who is president and chief financial officer of Orosco & Associates and owner of Monterey (Calif.) Speed and Sport, agreed, noting that his priorities when given the diagnosis more than two decades ago at age 47 differed somewhat.

“I adopted the feeling early on that I probably wasn’t going to see a cure for the disease in my lifetime, but I could accept that,” he elaborated. “I just said ‘Really, I’m interested in quality-of-life issues. I’d like to see my kids go into high school or possibly college.’ So I adopted [an approach of] trying to find something for me that would keep me alive and give me a relatively comfortable quality of life, that would allow me to continue to race cars or do whatever I had to do.”

Dr. Carlson, Dr. Somlo, Ms. Nichols, and Mr. Orosco disclosed no relevant conflicts of interest.

SAN FRANCISCO – The National Comprehensive Cancer Network (NCCN) has introduced an easy-to-use visual tool called Evidence Blocks to help physicians and patients compare various treatment options and individualize the selection among them.

“This information can serve as a starting point for shared decision making between the patient and health care team based on individual patients’ value systems,” chief executive officer Dr. Robert W. Carlson said at the NCCN Annual Congress: Hematologic Malignancies, where the tool was unveiled in a session and related press conference.

The first two NCCN guidelines to incorporate the Evidence Blocks – those for multiple myeloma and chronic myelogenous leukemia – were released at the same time. The organization hopes to incorporate them into all of its guidelines by early 2017, he said.

Development of the Evidence Blocks

The NCCN developed the Evidence Blocks to address requests from various stakeholders, according to Dr. Carlson. Guideline users wanted to know more about the rationale behind recommended therapies, asked for inclusion of information on costs, and sought an aid that would allow patients to make decisions based on their individual values.

“The patient perception of value is what should be most important to us,” he commented. “But even among patients, the concept of value differs greatly from patient to patient,” based on factors such as age, comorbidities, treatment goals, and health insurance coverage.

Each Evidence Block graphically displays five measures of information on a recommended therapy: efficacy, safety, quality of the evidence supporting the recommendation, consistency of the evidence supporting the recommendation, and affordability. Each column in the block represents one measure.

Blue shading indicates panelists’ average numeric score for the therapy on that measure rounded to the nearest integer, ranging from 1 (least favorable) to 5 (most favorable). Therefore, the more shading a therapy has, the more favorable its score.

The Evidence Blocks are added to the guidelines and aligned vertically on pages. “This display of the information graphically allows for very efficient scanning of multiple options for therapy. Comparisons across several regimens can be done very quickly and intuitively,” Dr. Carlson noted.

“We believe that the presentation of this type of information allows the health care provider and patient to make their own judgments of the value of specific interventions,” he added.

The affordability measure has generated the most discussion among panelists and stakeholders, according to Dr. Carlson. For this measure, panelists estimated the total cost of care for a therapy, including the costs of drugs, administration, required supportive care, toxicity monitoring, and care associated with management of toxicity. Scores range from very expensive to very inexpensive.

“We don’t use a dollar amount. Rather, it’s sort of what’s the total cost to society, if you will, of the medical intervention part of this,” he explained. “It’s important to understand that these estimates are not necessarily what a patient would pay because many patients have insurance programs that cover all of this cost.… However, we felt it was important to give patients as well as providers an estimate of what the overall magnitude of expense is because there are patients who have huge deductibles, there’s the doughnut hole within Medicare, and there are patients who have no insurance.”

The Evidence Blocks may help address a “conspiracy of silence” between physicians and patients when it comes to discussing treatment costs, whereby neither party wants to bring up this thorny issue, according to Dr. Carlson. “The Evidence Blocks demystify the discussion of cost because the affordability issue is there in front of you. So it gives people permission to talk about cost and affordability.”

It should be relatively easy to teach patients to use the Evidence Blocks. “I think you’ll find your patients will actually be interested in this and that they will not have as much difficulty interpreting this as you think they will, because the patient advocacy groups and the patient advocates that we have spoken with about this, they get this almost instantly,” he said.

Oncologist perspective

There is a critical need for tools such as the Evidence Blocks in making treatment decisions today, according to Dr. George Somlo, professor in the department of medical oncology and therapeutics research at the City of Hope Comprehensive Cancer Center in Duarte, Calif., and also a member of the NCCN multiple myeloma and breast cancer guideline panels.

Treatment options for multiple myeloma, as for many cancers, have exploded in the past few decades, he noted. “How do you go from making sense of having two drugs with a very poor outcome predicted to having literally dozens of agents approved and used in combination, and in essence being at the verge of curing patients with multiple myeloma?”

Dr. Somlo agreed that inclusion of costs in the Evidence Blocks would likely be beneficial as a conversation starter, recalling, “I’ve had patients who did not fill their prescription for a potentially curative medication because they were worried about the $2,500 or $3,500 copay.”

Patient-physician discussion will be important when it comes to using information from the new tool, he said. For example, in the NCCN guideline for multiple myeloma, some of the first-line regimens have identical Evidence Blocks; thus, consideration of factors such as comorbidities will become important.

“This kind of evidence-based scoring system can guide that kind of discussion with the patient and can tailor the individual therapeutic regimens,” he concluded.

Patient perspective

Breast cancer survivor Marta Nichols, who is vice president of investor relations at GoDaddy and a member of the California Breast Cancer Research Council based in San Francisco, welcomed the Evidence Blocks as a tool that will allow patients to make more informed decisions according to what matters most to them.

Only 33 years old at diagnosis, she and her husband had just begun to think about starting a family. “So my primary concern coming into my physician’s office was my fertility and what impact the treatment would have on my fertility. Certainly most physicians are concerned with efficacy – they want to see you survive. My concern was not just surviving, but also thriving and being able to give birth to children down the line,” she explained.

Patients today are overwhelmed not only by their cancer diagnosis, but also by the many treatment options and the new emphasis on shared decision making, Ms. Nichols noted. And that’s where the Evidence Blocks can make a difference.

“When I was diagnosed, it would have been hugely helpful for me to have information laid out in this very clear and systematic way… It would have given us the ability to make a much more informed decision,” she commented.

Multiple myeloma survivor Donald B. Orosco, who is president and chief financial officer of Orosco & Associates and owner of Monterey (Calif.) Speed and Sport, agreed, noting that his priorities when given the diagnosis more than two decades ago at age 47 differed somewhat.

“I adopted the feeling early on that I probably wasn’t going to see a cure for the disease in my lifetime, but I could accept that,” he elaborated. “I just said ‘Really, I’m interested in quality-of-life issues. I’d like to see my kids go into high school or possibly college.’ So I adopted [an approach of] trying to find something for me that would keep me alive and give me a relatively comfortable quality of life, that would allow me to continue to race cars or do whatever I had to do.”

Dr. Carlson, Dr. Somlo, Ms. Nichols, and Mr. Orosco disclosed no relevant conflicts of interest.

SAN FRANCISCO – The National Comprehensive Cancer Network (NCCN) has introduced an easy-to-use visual tool called Evidence Blocks to help physicians and patients compare various treatment options and individualize the selection among them.

“This information can serve as a starting point for shared decision making between the patient and health care team based on individual patients’ value systems,” chief executive officer Dr. Robert W. Carlson said at the NCCN Annual Congress: Hematologic Malignancies, where the tool was unveiled in a session and related press conference.

The first two NCCN guidelines to incorporate the Evidence Blocks – those for multiple myeloma and chronic myelogenous leukemia – were released at the same time. The organization hopes to incorporate them into all of its guidelines by early 2017, he said.

Development of the Evidence Blocks

The NCCN developed the Evidence Blocks to address requests from various stakeholders, according to Dr. Carlson. Guideline users wanted to know more about the rationale behind recommended therapies, asked for inclusion of information on costs, and sought an aid that would allow patients to make decisions based on their individual values.

“The patient perception of value is what should be most important to us,” he commented. “But even among patients, the concept of value differs greatly from patient to patient,” based on factors such as age, comorbidities, treatment goals, and health insurance coverage.

Each Evidence Block graphically displays five measures of information on a recommended therapy: efficacy, safety, quality of the evidence supporting the recommendation, consistency of the evidence supporting the recommendation, and affordability. Each column in the block represents one measure.

Blue shading indicates panelists’ average numeric score for the therapy on that measure rounded to the nearest integer, ranging from 1 (least favorable) to 5 (most favorable). Therefore, the more shading a therapy has, the more favorable its score.

The Evidence Blocks are added to the guidelines and aligned vertically on pages. “This display of the information graphically allows for very efficient scanning of multiple options for therapy. Comparisons across several regimens can be done very quickly and intuitively,” Dr. Carlson noted.

“We believe that the presentation of this type of information allows the health care provider and patient to make their own judgments of the value of specific interventions,” he added.

The affordability measure has generated the most discussion among panelists and stakeholders, according to Dr. Carlson. For this measure, panelists estimated the total cost of care for a therapy, including the costs of drugs, administration, required supportive care, toxicity monitoring, and care associated with management of toxicity. Scores range from very expensive to very inexpensive.

“We don’t use a dollar amount. Rather, it’s sort of what’s the total cost to society, if you will, of the medical intervention part of this,” he explained. “It’s important to understand that these estimates are not necessarily what a patient would pay because many patients have insurance programs that cover all of this cost.… However, we felt it was important to give patients as well as providers an estimate of what the overall magnitude of expense is because there are patients who have huge deductibles, there’s the doughnut hole within Medicare, and there are patients who have no insurance.”

The Evidence Blocks may help address a “conspiracy of silence” between physicians and patients when it comes to discussing treatment costs, whereby neither party wants to bring up this thorny issue, according to Dr. Carlson. “The Evidence Blocks demystify the discussion of cost because the affordability issue is there in front of you. So it gives people permission to talk about cost and affordability.”

It should be relatively easy to teach patients to use the Evidence Blocks. “I think you’ll find your patients will actually be interested in this and that they will not have as much difficulty interpreting this as you think they will, because the patient advocacy groups and the patient advocates that we have spoken with about this, they get this almost instantly,” he said.

Oncologist perspective

There is a critical need for tools such as the Evidence Blocks in making treatment decisions today, according to Dr. George Somlo, professor in the department of medical oncology and therapeutics research at the City of Hope Comprehensive Cancer Center in Duarte, Calif., and also a member of the NCCN multiple myeloma and breast cancer guideline panels.

Treatment options for multiple myeloma, as for many cancers, have exploded in the past few decades, he noted. “How do you go from making sense of having two drugs with a very poor outcome predicted to having literally dozens of agents approved and used in combination, and in essence being at the verge of curing patients with multiple myeloma?”

Dr. Somlo agreed that inclusion of costs in the Evidence Blocks would likely be beneficial as a conversation starter, recalling, “I’ve had patients who did not fill their prescription for a potentially curative medication because they were worried about the $2,500 or $3,500 copay.”

Patient-physician discussion will be important when it comes to using information from the new tool, he said. For example, in the NCCN guideline for multiple myeloma, some of the first-line regimens have identical Evidence Blocks; thus, consideration of factors such as comorbidities will become important.

“This kind of evidence-based scoring system can guide that kind of discussion with the patient and can tailor the individual therapeutic regimens,” he concluded.

Patient perspective

Breast cancer survivor Marta Nichols, who is vice president of investor relations at GoDaddy and a member of the California Breast Cancer Research Council based in San Francisco, welcomed the Evidence Blocks as a tool that will allow patients to make more informed decisions according to what matters most to them.

Only 33 years old at diagnosis, she and her husband had just begun to think about starting a family. “So my primary concern coming into my physician’s office was my fertility and what impact the treatment would have on my fertility. Certainly most physicians are concerned with efficacy – they want to see you survive. My concern was not just surviving, but also thriving and being able to give birth to children down the line,” she explained.

Patients today are overwhelmed not only by their cancer diagnosis, but also by the many treatment options and the new emphasis on shared decision making, Ms. Nichols noted. And that’s where the Evidence Blocks can make a difference.

“When I was diagnosed, it would have been hugely helpful for me to have information laid out in this very clear and systematic way… It would have given us the ability to make a much more informed decision,” she commented.

Multiple myeloma survivor Donald B. Orosco, who is president and chief financial officer of Orosco & Associates and owner of Monterey (Calif.) Speed and Sport, agreed, noting that his priorities when given the diagnosis more than two decades ago at age 47 differed somewhat.

“I adopted the feeling early on that I probably wasn’t going to see a cure for the disease in my lifetime, but I could accept that,” he elaborated. “I just said ‘Really, I’m interested in quality-of-life issues. I’d like to see my kids go into high school or possibly college.’ So I adopted [an approach of] trying to find something for me that would keep me alive and give me a relatively comfortable quality of life, that would allow me to continue to race cars or do whatever I had to do.”

Dr. Carlson, Dr. Somlo, Ms. Nichols, and Mr. Orosco disclosed no relevant conflicts of interest.

SAN FRANCISCO – “We really have an embarrassment of riches in chronic myelogenous leukemia, and the question is, which patients get which drugs? That’s really the major question that drives clinical care right now,” Dr. Jerald P. Radich, chair of the NCCN guidelines panel for chronic myelogenous leukemia (CML), told attendees of the National Comprehensive Cancer Network 10th Annual Congress: Hematologic Malignancies.

He discussed a variety of setting-specific quandaries in disease management and recent evidence from trials that is helping to provide some answers. He also reviewed some of the finer points of the NCCN’s CML guidelines, a new version of which was released at the congress.

How do you choose front-line therapy?

Tyrosine kinase inhibitors (TKIs) have dramatically improved the prognosis of CML, according to Dr. Radich, who is a member of the clinical research division, Fred Hutchinson Cancer Research Center, and an associate professor in the medical oncology division, University of Washington, both in Seattle.

Today, three TKIs—imatinib (Gleevec) and the second-generation agents nilotinib (Tasigna) and dasatinib (Sprycel)—are approved by the Food and Drug Administration as front-line therapy.

The 8-year data from the IRIS trial (International Randomized Study of Interferon Vs STI571), which tested imatinib in patients with newly diagnosed chronic-phase CML, showed that event-free survival was 81% and overall survival was 85% (Blood. 2009;114:462. Abstract 1126). “No matter how you slice it, these patients have done fantastically well,” Dr. Radich said.

The two other, newer therapies, nilotinib and dasatinib, have yielded significantly better short-term cytogenetic response and major molecular response rates in numerous trials. “But curiously enough, if you look at overall survival, there is no difference,” he commented. “We don’t know why the short-term efficacy of the second generations hasn’t translated into long-term efficacy yet.”

In the guidelines, the three front-line TKIs are nearly identical with respect to their Evidence Blocks, a new tool added to facilitate treatment comparisons and decision making.

But specific toxicities differ across the agents, which may tilt the decision one way or another. “If somebody has a history of really bad atherosclerotic events previously, then imatinib is probably not the best drug for them. If somebody has a history of pulmonary issues, then dasatinib may not be the best drug for them. And if somebody has diabetes, nilotinib probably isn’t the best drug for them,” Dr. Radich elaborated.

Costs for the three drugs are the same at present, he said. But imatinib will likely become available as a generic next year, which may make that drug the most attractive from the financial perspective.

When do you switch therapies?

There is some debate about how long to persevere with a front-line therapy when monitoring suggests the response is suboptimal, according to Dr. Radich.

Data have identified the BCR-ABL1 transcript level at 3 months to be a good predictor of long-term survival (J Clin Oncol. 2012;30:232-8). “We in the NCCN have said at 3 months or 6 months, you should consider changing [if the response is suboptimal]. You don’t have to, but you should consider changing because there are some other [therapies] that get rid of that,” he said.

However, he cautioned, a true assessment of response hinges critically on patients’ compliance with therapy. Studies using electronic monitors hidden in the caps of pill bottles suggest that even though the majority of patients say they take their TKI daily, only about 15% actually do.

Studies out of Europe and Australia have shown that some patients with a suboptimal response will have progression to accelerated phase/blast crisis in the interim between 3 months and 6 months, Dr. Radich noted. “So if you think that your patient is really, really religiously taking their drug, and if they still have not responded very well at 3 months, that might be an indication that you can consider changing therapy.”

Which second-line TKI should patients get?

The options for second-line TKI therapy include nilotinib and dasatinib, as well as bosutinib (Bosulif) and ponatinib (Iclusig).

About half of patients who experience progression on or become resistant to their first-line TKI have mutations, according to Dr. Radich. Here, a mutational analysis is warranted as the second-line agents differ somewhat with respect to the mutations they act against, which may guide the choice of agent. And toxicity profile may again dictate drugs that can and can’t be used for a specific patient.

Patients who have genuine resistance are unlikely to achieve a cure although they may have a cytogenetic response. “Most of us think that resistance might be forever and if we have a patient who has genuinely become resistant, you don’t need to transplant them necessarily [right away]. But that’s the time you have to have a conversation about doing transplantation and start doing HLA typing and the like,” he said.

Data suggest that the cytogenetic response to second-line therapy at 3 months predicts how patients will fare longer term (ASH 2008. Abstract 332).

“That ends up being a pretty good time point because if you have a patient who’s resistant and you start the search for a donor, for an HLA match, the median time to finding a donor is about 4 months,” Dr. Radich commented. “So a practical point is if you have to switch to a second-generation drug, you start a search. You find a donor, you evaluate again. If the patient had a great response, you say fine, we’re going to follow you; if they don’t, that’s a good time to move to transplant.”

In the guidelines, the Evidence Blocks for second-line (and later-line) therapies generally show what one might expect from clinical practice, Dr. Radich said. “As you march from primary therapy to secondary therapy to tertiary therapy, what happens? You all know, toxicity increases in those settings, efficacy goes down. And that’s exactly what happens here. And if you match up all these drugs, we say there is no difference in which one you pick.”

Can you discontinue therapy?

“The other issue that is really driving a lot of CML strategy these days is the issue of discontinuation,” Dr. Radich commented. Conventional belief has been that TKIs do not eliminate CML stem cells; therefore, patients will need to be on therapy lifelong.

“Turns out, like many things, we were wrong,” he said. “There have been a number of studies now showing that if you are PCR negative for a number of years and get off therapy, about 60% of patients will relapse usually within the first 3 months, but about 40% of patients will actually remain negative for BCR-ABL up to 2-3 years.”

“Now the good part is that all the patients pretty much who have relapse and get put back on drug go back to getting a response; they don’t go into complete molecular remission, however. And the reason that we worry that all these patients should still be [discontinued] on a clinical trial as opposed to doing it at home is we don’t know the long-term consequences of this,” Dr. Radich said.

A period of unopposed BCR-ABL activity may allow emergence of resistant clones that take years to become clinically evident, he noted. In fact, data from Hiroshima survivors show that CML can have “an amazing dormancy,” possibly 70 years.

“So I think you have to approach any discontinuation with some caution. The risk is probably very low, but it’s actually probably a number,” he said. The guidelines therefore recommend that in patients whose disease is responding to TKIs, discontinuation should be undertaken only in a clinical trial.

“How this weighs in, I think, is if you look at CMR [complete molecular response] rates, they are higher with second-generations than with imatinib. So if you have a patient who you some day want to get to a discontinuation trial, a younger person who wants to have children and the like, then second-generations might be your best option for getting them there,” Dr. Radich proposed.

Take-home message

The guidelines, with all of their algorithms and the new Evidence Blocks, are helpful but do not replace clinical wisdom and experience, Dr. Radich asserted in closing.

“You have to kind of use your clinical judgment, and that trumps everything else,” he said. “The other thing that’s important is all of you have different experiences with using these drugs, and nothing replaces that. If you are someone who uses drug A all the time, you know how to anticipate the complications, you know what to look for. It’s a lot better [to use that drug] than just jumping to drug C when you have never used it or have little experience, because really experience is the main thing.”

Dr. Radich disclosed that he has consulting and/or research funding relationships with Ariad Pharmaceuticals, Gilead Sciences, and Novartis.

SAN FRANCISCO – “We really have an embarrassment of riches in chronic myelogenous leukemia, and the question is, which patients get which drugs? That’s really the major question that drives clinical care right now,” Dr. Jerald P. Radich, chair of the NCCN guidelines panel for chronic myelogenous leukemia (CML), told attendees of the National Comprehensive Cancer Network 10th Annual Congress: Hematologic Malignancies.

He discussed a variety of setting-specific quandaries in disease management and recent evidence from trials that is helping to provide some answers. He also reviewed some of the finer points of the NCCN’s CML guidelines, a new version of which was released at the congress.

How do you choose front-line therapy?

Tyrosine kinase inhibitors (TKIs) have dramatically improved the prognosis of CML, according to Dr. Radich, who is a member of the clinical research division, Fred Hutchinson Cancer Research Center, and an associate professor in the medical oncology division, University of Washington, both in Seattle.

Today, three TKIs—imatinib (Gleevec) and the second-generation agents nilotinib (Tasigna) and dasatinib (Sprycel)—are approved by the Food and Drug Administration as front-line therapy.

The 8-year data from the IRIS trial (International Randomized Study of Interferon Vs STI571), which tested imatinib in patients with newly diagnosed chronic-phase CML, showed that event-free survival was 81% and overall survival was 85% (Blood. 2009;114:462. Abstract 1126). “No matter how you slice it, these patients have done fantastically well,” Dr. Radich said.

The two other, newer therapies, nilotinib and dasatinib, have yielded significantly better short-term cytogenetic response and major molecular response rates in numerous trials. “But curiously enough, if you look at overall survival, there is no difference,” he commented. “We don’t know why the short-term efficacy of the second generations hasn’t translated into long-term efficacy yet.”

In the guidelines, the three front-line TKIs are nearly identical with respect to their Evidence Blocks, a new tool added to facilitate treatment comparisons and decision making.

But specific toxicities differ across the agents, which may tilt the decision one way or another. “If somebody has a history of really bad atherosclerotic events previously, then imatinib is probably not the best drug for them. If somebody has a history of pulmonary issues, then dasatinib may not be the best drug for them. And if somebody has diabetes, nilotinib probably isn’t the best drug for them,” Dr. Radich elaborated.

Costs for the three drugs are the same at present, he said. But imatinib will likely become available as a generic next year, which may make that drug the most attractive from the financial perspective.

When do you switch therapies?

There is some debate about how long to persevere with a front-line therapy when monitoring suggests the response is suboptimal, according to Dr. Radich.

Data have identified the BCR-ABL1 transcript level at 3 months to be a good predictor of long-term survival (J Clin Oncol. 2012;30:232-8). “We in the NCCN have said at 3 months or 6 months, you should consider changing [if the response is suboptimal]. You don’t have to, but you should consider changing because there are some other [therapies] that get rid of that,” he said.

However, he cautioned, a true assessment of response hinges critically on patients’ compliance with therapy. Studies using electronic monitors hidden in the caps of pill bottles suggest that even though the majority of patients say they take their TKI daily, only about 15% actually do.

Studies out of Europe and Australia have shown that some patients with a suboptimal response will have progression to accelerated phase/blast crisis in the interim between 3 months and 6 months, Dr. Radich noted. “So if you think that your patient is really, really religiously taking their drug, and if they still have not responded very well at 3 months, that might be an indication that you can consider changing therapy.”

Which second-line TKI should patients get?

The options for second-line TKI therapy include nilotinib and dasatinib, as well as bosutinib (Bosulif) and ponatinib (Iclusig).

About half of patients who experience progression on or become resistant to their first-line TKI have mutations, according to Dr. Radich. Here, a mutational analysis is warranted as the second-line agents differ somewhat with respect to the mutations they act against, which may guide the choice of agent. And toxicity profile may again dictate drugs that can and can’t be used for a specific patient.

Patients who have genuine resistance are unlikely to achieve a cure although they may have a cytogenetic response. “Most of us think that resistance might be forever and if we have a patient who has genuinely become resistant, you don’t need to transplant them necessarily [right away]. But that’s the time you have to have a conversation about doing transplantation and start doing HLA typing and the like,” he said.

Data suggest that the cytogenetic response to second-line therapy at 3 months predicts how patients will fare longer term (ASH 2008. Abstract 332).

“That ends up being a pretty good time point because if you have a patient who’s resistant and you start the search for a donor, for an HLA match, the median time to finding a donor is about 4 months,” Dr. Radich commented. “So a practical point is if you have to switch to a second-generation drug, you start a search. You find a donor, you evaluate again. If the patient had a great response, you say fine, we’re going to follow you; if they don’t, that’s a good time to move to transplant.”

In the guidelines, the Evidence Blocks for second-line (and later-line) therapies generally show what one might expect from clinical practice, Dr. Radich said. “As you march from primary therapy to secondary therapy to tertiary therapy, what happens? You all know, toxicity increases in those settings, efficacy goes down. And that’s exactly what happens here. And if you match up all these drugs, we say there is no difference in which one you pick.”

Can you discontinue therapy?

“The other issue that is really driving a lot of CML strategy these days is the issue of discontinuation,” Dr. Radich commented. Conventional belief has been that TKIs do not eliminate CML stem cells; therefore, patients will need to be on therapy lifelong.

“Turns out, like many things, we were wrong,” he said. “There have been a number of studies now showing that if you are PCR negative for a number of years and get off therapy, about 60% of patients will relapse usually within the first 3 months, but about 40% of patients will actually remain negative for BCR-ABL up to 2-3 years.”

“Now the good part is that all the patients pretty much who have relapse and get put back on drug go back to getting a response; they don’t go into complete molecular remission, however. And the reason that we worry that all these patients should still be [discontinued] on a clinical trial as opposed to doing it at home is we don’t know the long-term consequences of this,” Dr. Radich said.

A period of unopposed BCR-ABL activity may allow emergence of resistant clones that take years to become clinically evident, he noted. In fact, data from Hiroshima survivors show that CML can have “an amazing dormancy,” possibly 70 years.

“So I think you have to approach any discontinuation with some caution. The risk is probably very low, but it’s actually probably a number,” he said. The guidelines therefore recommend that in patients whose disease is responding to TKIs, discontinuation should be undertaken only in a clinical trial.

“How this weighs in, I think, is if you look at CMR [complete molecular response] rates, they are higher with second-generations than with imatinib. So if you have a patient who you some day want to get to a discontinuation trial, a younger person who wants to have children and the like, then second-generations might be your best option for getting them there,” Dr. Radich proposed.

Take-home message

The guidelines, with all of their algorithms and the new Evidence Blocks, are helpful but do not replace clinical wisdom and experience, Dr. Radich asserted in closing.

“You have to kind of use your clinical judgment, and that trumps everything else,” he said. “The other thing that’s important is all of you have different experiences with using these drugs, and nothing replaces that. If you are someone who uses drug A all the time, you know how to anticipate the complications, you know what to look for. It’s a lot better [to use that drug] than just jumping to drug C when you have never used it or have little experience, because really experience is the main thing.”

Dr. Radich disclosed that he has consulting and/or research funding relationships with Ariad Pharmaceuticals, Gilead Sciences, and Novartis.

SAN FRANCISCO – “We really have an embarrassment of riches in chronic myelogenous leukemia, and the question is, which patients get which drugs? That’s really the major question that drives clinical care right now,” Dr. Jerald P. Radich, chair of the NCCN guidelines panel for chronic myelogenous leukemia (CML), told attendees of the National Comprehensive Cancer Network 10th Annual Congress: Hematologic Malignancies.

He discussed a variety of setting-specific quandaries in disease management and recent evidence from trials that is helping to provide some answers. He also reviewed some of the finer points of the NCCN’s CML guidelines, a new version of which was released at the congress.

How do you choose front-line therapy?

Tyrosine kinase inhibitors (TKIs) have dramatically improved the prognosis of CML, according to Dr. Radich, who is a member of the clinical research division, Fred Hutchinson Cancer Research Center, and an associate professor in the medical oncology division, University of Washington, both in Seattle.

Today, three TKIs—imatinib (Gleevec) and the second-generation agents nilotinib (Tasigna) and dasatinib (Sprycel)—are approved by the Food and Drug Administration as front-line therapy.

The 8-year data from the IRIS trial (International Randomized Study of Interferon Vs STI571), which tested imatinib in patients with newly diagnosed chronic-phase CML, showed that event-free survival was 81% and overall survival was 85% (Blood. 2009;114:462. Abstract 1126). “No matter how you slice it, these patients have done fantastically well,” Dr. Radich said.

The two other, newer therapies, nilotinib and dasatinib, have yielded significantly better short-term cytogenetic response and major molecular response rates in numerous trials. “But curiously enough, if you look at overall survival, there is no difference,” he commented. “We don’t know why the short-term efficacy of the second generations hasn’t translated into long-term efficacy yet.”

In the guidelines, the three front-line TKIs are nearly identical with respect to their Evidence Blocks, a new tool added to facilitate treatment comparisons and decision making.

But specific toxicities differ across the agents, which may tilt the decision one way or another. “If somebody has a history of really bad atherosclerotic events previously, then imatinib is probably not the best drug for them. If somebody has a history of pulmonary issues, then dasatinib may not be the best drug for them. And if somebody has diabetes, nilotinib probably isn’t the best drug for them,” Dr. Radich elaborated.

Costs for the three drugs are the same at present, he said. But imatinib will likely become available as a generic next year, which may make that drug the most attractive from the financial perspective.

When do you switch therapies?

There is some debate about how long to persevere with a front-line therapy when monitoring suggests the response is suboptimal, according to Dr. Radich.

Data have identified the BCR-ABL1 transcript level at 3 months to be a good predictor of long-term survival (J Clin Oncol. 2012;30:232-8). “We in the NCCN have said at 3 months or 6 months, you should consider changing [if the response is suboptimal]. You don’t have to, but you should consider changing because there are some other [therapies] that get rid of that,” he said.

However, he cautioned, a true assessment of response hinges critically on patients’ compliance with therapy. Studies using electronic monitors hidden in the caps of pill bottles suggest that even though the majority of patients say they take their TKI daily, only about 15% actually do.

Studies out of Europe and Australia have shown that some patients with a suboptimal response will have progression to accelerated phase/blast crisis in the interim between 3 months and 6 months, Dr. Radich noted. “So if you think that your patient is really, really religiously taking their drug, and if they still have not responded very well at 3 months, that might be an indication that you can consider changing therapy.”

Which second-line TKI should patients get?

The options for second-line TKI therapy include nilotinib and dasatinib, as well as bosutinib (Bosulif) and ponatinib (Iclusig).

About half of patients who experience progression on or become resistant to their first-line TKI have mutations, according to Dr. Radich. Here, a mutational analysis is warranted as the second-line agents differ somewhat with respect to the mutations they act against, which may guide the choice of agent. And toxicity profile may again dictate drugs that can and can’t be used for a specific patient.

Patients who have genuine resistance are unlikely to achieve a cure although they may have a cytogenetic response. “Most of us think that resistance might be forever and if we have a patient who has genuinely become resistant, you don’t need to transplant them necessarily [right away]. But that’s the time you have to have a conversation about doing transplantation and start doing HLA typing and the like,” he said.

Data suggest that the cytogenetic response to second-line therapy at 3 months predicts how patients will fare longer term (ASH 2008. Abstract 332).

“That ends up being a pretty good time point because if you have a patient who’s resistant and you start the search for a donor, for an HLA match, the median time to finding a donor is about 4 months,” Dr. Radich commented. “So a practical point is if you have to switch to a second-generation drug, you start a search. You find a donor, you evaluate again. If the patient had a great response, you say fine, we’re going to follow you; if they don’t, that’s a good time to move to transplant.”

In the guidelines, the Evidence Blocks for second-line (and later-line) therapies generally show what one might expect from clinical practice, Dr. Radich said. “As you march from primary therapy to secondary therapy to tertiary therapy, what happens? You all know, toxicity increases in those settings, efficacy goes down. And that’s exactly what happens here. And if you match up all these drugs, we say there is no difference in which one you pick.”

Can you discontinue therapy?

“The other issue that is really driving a lot of CML strategy these days is the issue of discontinuation,” Dr. Radich commented. Conventional belief has been that TKIs do not eliminate CML stem cells; therefore, patients will need to be on therapy lifelong.

“Turns out, like many things, we were wrong,” he said. “There have been a number of studies now showing that if you are PCR negative for a number of years and get off therapy, about 60% of patients will relapse usually within the first 3 months, but about 40% of patients will actually remain negative for BCR-ABL up to 2-3 years.”

“Now the good part is that all the patients pretty much who have relapse and get put back on drug go back to getting a response; they don’t go into complete molecular remission, however. And the reason that we worry that all these patients should still be [discontinued] on a clinical trial as opposed to doing it at home is we don’t know the long-term consequences of this,” Dr. Radich said.

A period of unopposed BCR-ABL activity may allow emergence of resistant clones that take years to become clinically evident, he noted. In fact, data from Hiroshima survivors show that CML can have “an amazing dormancy,” possibly 70 years.

“So I think you have to approach any discontinuation with some caution. The risk is probably very low, but it’s actually probably a number,” he said. The guidelines therefore recommend that in patients whose disease is responding to TKIs, discontinuation should be undertaken only in a clinical trial.

“How this weighs in, I think, is if you look at CMR [complete molecular response] rates, they are higher with second-generations than with imatinib. So if you have a patient who you some day want to get to a discontinuation trial, a younger person who wants to have children and the like, then second-generations might be your best option for getting them there,” Dr. Radich proposed.

Take-home message

The guidelines, with all of their algorithms and the new Evidence Blocks, are helpful but do not replace clinical wisdom and experience, Dr. Radich asserted in closing.

“You have to kind of use your clinical judgment, and that trumps everything else,” he said. “The other thing that’s important is all of you have different experiences with using these drugs, and nothing replaces that. If you are someone who uses drug A all the time, you know how to anticipate the complications, you know what to look for. It’s a lot better [to use that drug] than just jumping to drug C when you have never used it or have little experience, because really experience is the main thing.”

Dr. Radich disclosed that he has consulting and/or research funding relationships with Ariad Pharmaceuticals, Gilead Sciences, and Novartis.

CHICAGO – Major molecular response rates at 12 months were better among chronic myeloid leukemia patients treated with dasatinib/nilotinib vs. imatinib for first-line therapy, and among patients enrolled vs. not enrolled in clinical trials, in a retrospective review of patients treated with first-line tyrosine kinase inhibitors between 2002 and 2014.

The overall rates of major molecular response (MMR) at 12 and 24 months in the 51 patients in the study were 23.5% (12 patients) and 44.9% (22 patients), which was comparable to historical data, Dr. Isabelle Phuong Le reported in a poster at the American Society of Hematology Meeting on Hematologic Malignancies.

The MMR rate among those treated with dasatinib/nilotinib first line was 53%, compared with 10% for those treated with imatinib, said Dr. Le of the University of Texas Health Science Center, San Antonio.

Further the MMR rates at 12 and 24 months among those enrolled vs. not enrolled in clinical trials were 83% vs 15% and 100% vs. 45%, respectively, she noted.

Patients in the analysis were adults with a mean age of 44.6 years who had chronic phase chronic myeloid leukemia (CML). Almost half (49%) were Hispanic, and 56.9% were women. Two-thirds (66.7%) received imatinib first line, and 33.3% received dasatinib/nilotinib first line. More than a third (37.2%) were younger than age 40 years, 15% had a language barrier, and 11.7% were enrolled in clinical trials.

No differences in the MMR rates at 12 and 24 months were seen between Hispanics and non-Hispanics, those with and without language barrier, or men and women, nor were any differences seen between those with more than three lines of therapy and those with three or fewer lines of therapy, or between patients older vs. younger than 40 years, although there was a trend toward improved response rates in older patients, she noted.

“Our patients have similar MMR rates at 12 months and 24 months compared to historical data,” Dr. Le wrote, noting that the findings regarding improved MMR rates with dasatinib/nilotinib were expected.

The findings regarding improved MMR rates among those enrolled in clinical trials could be due to “selective patients as clinical trial patients, more controlled and monitored treatment, frequent follow-ups, and better education regarding disease and treatment,” she said, concluding that “ we can improve treatment response rates in our patients with better disease education.”

Dr. Le reported having no disclosures.

[email protected]

CHICAGO – Major molecular response rates at 12 months were better among chronic myeloid leukemia patients treated with dasatinib/nilotinib vs. imatinib for first-line therapy, and among patients enrolled vs. not enrolled in clinical trials, in a retrospective review of patients treated with first-line tyrosine kinase inhibitors between 2002 and 2014.

The overall rates of major molecular response (MMR) at 12 and 24 months in the 51 patients in the study were 23.5% (12 patients) and 44.9% (22 patients), which was comparable to historical data, Dr. Isabelle Phuong Le reported in a poster at the American Society of Hematology Meeting on Hematologic Malignancies.

The MMR rate among those treated with dasatinib/nilotinib first line was 53%, compared with 10% for those treated with imatinib, said Dr. Le of the University of Texas Health Science Center, San Antonio.

Further the MMR rates at 12 and 24 months among those enrolled vs. not enrolled in clinical trials were 83% vs 15% and 100% vs. 45%, respectively, she noted.

Patients in the analysis were adults with a mean age of 44.6 years who had chronic phase chronic myeloid leukemia (CML). Almost half (49%) were Hispanic, and 56.9% were women. Two-thirds (66.7%) received imatinib first line, and 33.3% received dasatinib/nilotinib first line. More than a third (37.2%) were younger than age 40 years, 15% had a language barrier, and 11.7% were enrolled in clinical trials.

No differences in the MMR rates at 12 and 24 months were seen between Hispanics and non-Hispanics, those with and without language barrier, or men and women, nor were any differences seen between those with more than three lines of therapy and those with three or fewer lines of therapy, or between patients older vs. younger than 40 years, although there was a trend toward improved response rates in older patients, she noted.

“Our patients have similar MMR rates at 12 months and 24 months compared to historical data,” Dr. Le wrote, noting that the findings regarding improved MMR rates with dasatinib/nilotinib were expected.

The findings regarding improved MMR rates among those enrolled in clinical trials could be due to “selective patients as clinical trial patients, more controlled and monitored treatment, frequent follow-ups, and better education regarding disease and treatment,” she said, concluding that “ we can improve treatment response rates in our patients with better disease education.”

Dr. Le reported having no disclosures.

[email protected]

CHICAGO – Major molecular response rates at 12 months were better among chronic myeloid leukemia patients treated with dasatinib/nilotinib vs. imatinib for first-line therapy, and among patients enrolled vs. not enrolled in clinical trials, in a retrospective review of patients treated with first-line tyrosine kinase inhibitors between 2002 and 2014.

The overall rates of major molecular response (MMR) at 12 and 24 months in the 51 patients in the study were 23.5% (12 patients) and 44.9% (22 patients), which was comparable to historical data, Dr. Isabelle Phuong Le reported in a poster at the American Society of Hematology Meeting on Hematologic Malignancies.

The MMR rate among those treated with dasatinib/nilotinib first line was 53%, compared with 10% for those treated with imatinib, said Dr. Le of the University of Texas Health Science Center, San Antonio.

Further the MMR rates at 12 and 24 months among those enrolled vs. not enrolled in clinical trials were 83% vs 15% and 100% vs. 45%, respectively, she noted.

Patients in the analysis were adults with a mean age of 44.6 years who had chronic phase chronic myeloid leukemia (CML). Almost half (49%) were Hispanic, and 56.9% were women. Two-thirds (66.7%) received imatinib first line, and 33.3% received dasatinib/nilotinib first line. More than a third (37.2%) were younger than age 40 years, 15% had a language barrier, and 11.7% were enrolled in clinical trials.

No differences in the MMR rates at 12 and 24 months were seen between Hispanics and non-Hispanics, those with and without language barrier, or men and women, nor were any differences seen between those with more than three lines of therapy and those with three or fewer lines of therapy, or between patients older vs. younger than 40 years, although there was a trend toward improved response rates in older patients, she noted.

“Our patients have similar MMR rates at 12 months and 24 months compared to historical data,” Dr. Le wrote, noting that the findings regarding improved MMR rates with dasatinib/nilotinib were expected.

The findings regarding improved MMR rates among those enrolled in clinical trials could be due to “selective patients as clinical trial patients, more controlled and monitored treatment, frequent follow-ups, and better education regarding disease and treatment,” she said, concluding that “ we can improve treatment response rates in our patients with better disease education.”

Dr. Le reported having no disclosures.

[email protected]

CHICAGO – Chronic myeloid leukemia is highly treatable, and a “functional cure” appears to be within reach, according to Dr. Michael J. Mauro.

In fact, an “embarrassment of riches” exists when it comes to initial therapy for CML: In the United States there are five approved tyrosine kinase inhibitors (TKIs), and three are approved for front-line therapy, Dr. Mauro of Memorial Sloan Kettering Cancer Center, New York, said at the American Society of Hematology Meeting on Hematologic Malignancies.

Success, however, is contingent on managing reversible early toxicity, adherence to therapy, achieving landmarks of response, and remaining vigilant for late effects of therapy, he said.

Given the multitude of treatment options and the breadth of available data, Dr. Mauro said he counsels newly diagnosed patients that various treatment options are valid, and that “there may not be a right or wrong answer” for initial therapy. He also counsels patients that tolerability is manageable – and finding the right fit is an important process, and that response milestones are crucial and should be optimized.

It is important, he said, to discuss late toxicity concerns, to review comorbid conditions to help predict potential problems and identify risk, to consider the ramifications of potential toxicity, and to consider adherence.

“We need to portray therapy as really being medium- to long-term,” he said, noting that the urgency to think about treatment-free remission should be tempered by the reality that years of treatment are required first.

Risks and benefits of treatment should be discussed, and the acceptable balance determined in conjunction with the patient, he said, explaining that toxicities vary for the different TKIs.

Imatinib, for example, can be associated with edema/fluid retention, myalgias, hypophosphatemia, and gastrointestinal effects. Dasatinib can be associated with pleural/pericardial effusion, pulmonary arterial hypertension, and bleeding risk. Other toxicities associated with certain TKIs include pancreatic enzyme elevation, rash, and vascular adverse events.

Whether newly diagnosed patients should be directed away from certain agents remains unclear, as available data are open to interpretation, and the mechanism of action for some crucial late effects is unknown. Vascular disease should, however, be considered when making the decision, he said.

Given the available data on late toxicity with various therapies, a cardiovascular evaluation is advisable when initiating TKI therapy, he added.

Consider partnering with primary care, cardiology, or cardio-oncology specialists, and manage risk factors and findings of the evaluation as appropriate, irrespective of the CML, he said. Monitor for progression of cardiovascular risks or adverse events carefully, he added.

His approach for following recently diagnosed CML patients involves:

• A cardiovascular evaluation, at least including age- and comorbidity-appropriate studies, and an up-to-date cardiovascular risk profile. If nilotinib is used, he screens for peripheral, cerebral, and cardiovascular disease – an approach increasingly supported by data. If dasatinib is used, echocardiography is warranted to look for changes that suggest pulmonary hypertension. “And of course we should monitor blood pressure, lipid, and glycemic control,” he added.

• Initial studies, including bone marrow and quantitative polymerase chain reaction – international scale (qPCR IS).

• Lab studies every 1-2 weeks for at least 6 weeks, with titration thereafter as indicated, including for change in therapy.

• A 3-month assessment using qPCR IS. This is very important for following patient response, he said, noting that if the response surpasses compete cytogenetic remission and blood count is acceptable and stable, a repeat bone marrow study may be unnecessary.

• Sequential molecular analyses at least every 3 months.

• Repeat cardiovascular evaluation if/when indicated.

The 3-month response is an opportunity to critically appraise therapy choice and response trajectory; a therapy change is possible based on this assessment, he said. Responses at 6 and 12 months are also important, and changes in therapy for missed milestones at these time points are warranted as deeper remissions are sought.

At 18 months, the focus is on major molecular response, he added, noting that as patients get into deeper molecular remissions, plateaus and fluctuations are common; the nuances of determining who is well enough to consider for treatment-free remission remain to be sorted out in clinical trials.

In general, it appears that 3 years of therapy with about 2 years of optimal minimal residual disease is required prior to consideration for treatment-free remission, he said.

Dr. Mauro has consulted for and/or received research funding from Ariad, Bristol-Myers Squibb, Novartis, and Oregon Health & Science University.

[email protected]

CHICAGO – Chronic myeloid leukemia is highly treatable, and a “functional cure” appears to be within reach, according to Dr. Michael J. Mauro.

In fact, an “embarrassment of riches” exists when it comes to initial therapy for CML: In the United States there are five approved tyrosine kinase inhibitors (TKIs), and three are approved for front-line therapy, Dr. Mauro of Memorial Sloan Kettering Cancer Center, New York, said at the American Society of Hematology Meeting on Hematologic Malignancies.

Success, however, is contingent on managing reversible early toxicity, adherence to therapy, achieving landmarks of response, and remaining vigilant for late effects of therapy, he said.

Given the multitude of treatment options and the breadth of available data, Dr. Mauro said he counsels newly diagnosed patients that various treatment options are valid, and that “there may not be a right or wrong answer” for initial therapy. He also counsels patients that tolerability is manageable – and finding the right fit is an important process, and that response milestones are crucial and should be optimized.

It is important, he said, to discuss late toxicity concerns, to review comorbid conditions to help predict potential problems and identify risk, to consider the ramifications of potential toxicity, and to consider adherence.

“We need to portray therapy as really being medium- to long-term,” he said, noting that the urgency to think about treatment-free remission should be tempered by the reality that years of treatment are required first.

Risks and benefits of treatment should be discussed, and the acceptable balance determined in conjunction with the patient, he said, explaining that toxicities vary for the different TKIs.

Imatinib, for example, can be associated with edema/fluid retention, myalgias, hypophosphatemia, and gastrointestinal effects. Dasatinib can be associated with pleural/pericardial effusion, pulmonary arterial hypertension, and bleeding risk. Other toxicities associated with certain TKIs include pancreatic enzyme elevation, rash, and vascular adverse events.

Whether newly diagnosed patients should be directed away from certain agents remains unclear, as available data are open to interpretation, and the mechanism of action for some crucial late effects is unknown. Vascular disease should, however, be considered when making the decision, he said.

Given the available data on late toxicity with various therapies, a cardiovascular evaluation is advisable when initiating TKI therapy, he added.

Consider partnering with primary care, cardiology, or cardio-oncology specialists, and manage risk factors and findings of the evaluation as appropriate, irrespective of the CML, he said. Monitor for progression of cardiovascular risks or adverse events carefully, he added.

His approach for following recently diagnosed CML patients involves:

• A cardiovascular evaluation, at least including age- and comorbidity-appropriate studies, and an up-to-date cardiovascular risk profile. If nilotinib is used, he screens for peripheral, cerebral, and cardiovascular disease – an approach increasingly supported by data. If dasatinib is used, echocardiography is warranted to look for changes that suggest pulmonary hypertension. “And of course we should monitor blood pressure, lipid, and glycemic control,” he added.

• Initial studies, including bone marrow and quantitative polymerase chain reaction – international scale (qPCR IS).

• Lab studies every 1-2 weeks for at least 6 weeks, with titration thereafter as indicated, including for change in therapy.

• A 3-month assessment using qPCR IS. This is very important for following patient response, he said, noting that if the response surpasses compete cytogenetic remission and blood count is acceptable and stable, a repeat bone marrow study may be unnecessary.

• Sequential molecular analyses at least every 3 months.

• Repeat cardiovascular evaluation if/when indicated.

The 3-month response is an opportunity to critically appraise therapy choice and response trajectory; a therapy change is possible based on this assessment, he said. Responses at 6 and 12 months are also important, and changes in therapy for missed milestones at these time points are warranted as deeper remissions are sought.

At 18 months, the focus is on major molecular response, he added, noting that as patients get into deeper molecular remissions, plateaus and fluctuations are common; the nuances of determining who is well enough to consider for treatment-free remission remain to be sorted out in clinical trials.

In general, it appears that 3 years of therapy with about 2 years of optimal minimal residual disease is required prior to consideration for treatment-free remission, he said.

Dr. Mauro has consulted for and/or received research funding from Ariad, Bristol-Myers Squibb, Novartis, and Oregon Health & Science University.

[email protected]

CHICAGO – Chronic myeloid leukemia is highly treatable, and a “functional cure” appears to be within reach, according to Dr. Michael J. Mauro.

In fact, an “embarrassment of riches” exists when it comes to initial therapy for CML: In the United States there are five approved tyrosine kinase inhibitors (TKIs), and three are approved for front-line therapy, Dr. Mauro of Memorial Sloan Kettering Cancer Center, New York, said at the American Society of Hematology Meeting on Hematologic Malignancies.

Success, however, is contingent on managing reversible early toxicity, adherence to therapy, achieving landmarks of response, and remaining vigilant for late effects of therapy, he said.

Given the multitude of treatment options and the breadth of available data, Dr. Mauro said he counsels newly diagnosed patients that various treatment options are valid, and that “there may not be a right or wrong answer” for initial therapy. He also counsels patients that tolerability is manageable – and finding the right fit is an important process, and that response milestones are crucial and should be optimized.

It is important, he said, to discuss late toxicity concerns, to review comorbid conditions to help predict potential problems and identify risk, to consider the ramifications of potential toxicity, and to consider adherence.

“We need to portray therapy as really being medium- to long-term,” he said, noting that the urgency to think about treatment-free remission should be tempered by the reality that years of treatment are required first.

Risks and benefits of treatment should be discussed, and the acceptable balance determined in conjunction with the patient, he said, explaining that toxicities vary for the different TKIs.

Imatinib, for example, can be associated with edema/fluid retention, myalgias, hypophosphatemia, and gastrointestinal effects. Dasatinib can be associated with pleural/pericardial effusion, pulmonary arterial hypertension, and bleeding risk. Other toxicities associated with certain TKIs include pancreatic enzyme elevation, rash, and vascular adverse events.

Whether newly diagnosed patients should be directed away from certain agents remains unclear, as available data are open to interpretation, and the mechanism of action for some crucial late effects is unknown. Vascular disease should, however, be considered when making the decision, he said.

Given the available data on late toxicity with various therapies, a cardiovascular evaluation is advisable when initiating TKI therapy, he added.

Consider partnering with primary care, cardiology, or cardio-oncology specialists, and manage risk factors and findings of the evaluation as appropriate, irrespective of the CML, he said. Monitor for progression of cardiovascular risks or adverse events carefully, he added.

His approach for following recently diagnosed CML patients involves:

• A cardiovascular evaluation, at least including age- and comorbidity-appropriate studies, and an up-to-date cardiovascular risk profile. If nilotinib is used, he screens for peripheral, cerebral, and cardiovascular disease – an approach increasingly supported by data. If dasatinib is used, echocardiography is warranted to look for changes that suggest pulmonary hypertension. “And of course we should monitor blood pressure, lipid, and glycemic control,” he added.

• Initial studies, including bone marrow and quantitative polymerase chain reaction – international scale (qPCR IS).

• Lab studies every 1-2 weeks for at least 6 weeks, with titration thereafter as indicated, including for change in therapy.

• A 3-month assessment using qPCR IS. This is very important for following patient response, he said, noting that if the response surpasses compete cytogenetic remission and blood count is acceptable and stable, a repeat bone marrow study may be unnecessary.

• Sequential molecular analyses at least every 3 months.

• Repeat cardiovascular evaluation if/when indicated.

The 3-month response is an opportunity to critically appraise therapy choice and response trajectory; a therapy change is possible based on this assessment, he said. Responses at 6 and 12 months are also important, and changes in therapy for missed milestones at these time points are warranted as deeper remissions are sought.

At 18 months, the focus is on major molecular response, he added, noting that as patients get into deeper molecular remissions, plateaus and fluctuations are common; the nuances of determining who is well enough to consider for treatment-free remission remain to be sorted out in clinical trials.

In general, it appears that 3 years of therapy with about 2 years of optimal minimal residual disease is required prior to consideration for treatment-free remission, he said.

Dr. Mauro has consulted for and/or received research funding from Ariad, Bristol-Myers Squibb, Novartis, and Oregon Health & Science University.

[email protected]

The tyrosine kinase inhibitor ponatinib produced a high degree of complete cytogenetic responses when used in first-line treatment of patients with chronic myeloid leukemia in chronic phase. But the drug’s toxicities, especially its propensity for causing thromboembolic events, mitigate against its upfront use, investigators say.

In a small phase II study, 90% of evaluable patients with chronic-phase chronic myeloid leukemia (CML) treated with the tyrosine kinase inhibitor (TKI) had a complete cytogenetic response (CCyR) after 3 months, and 94% had a CCyR after 6 months, but that efficacy came at the cost of significant adverse events requiring dose reductions, treatment interruptions, and early termination of the trial for safety reasons at the recommendation of the Food and Drug Administration, reported Dr. Preetesh Jain of MD Anderson Cancer Center in Houston, Tex., and colleagues.

“[O]ur study shows that ponatinib is a very potent TKI with high clinical activity in the first-line treatment of patients with chronic-phase CML. However, at the doses currently used in other settings, the safety profile might not be appropriate for treatment of this patient population who have other treatment options with high efficacy,” the investigators wrote (Lancet Haematol. 2015;2[9]:e376-e383).

Ponatinib (Iclusig) is a third-generation TKI with action against malignancies with mutations in the ABL kinase domain that make the cancers resistant to first- and second-generation TKIs such as imatinib (Gleevec), dasatinib (Sprycel), and nilotinib (Tasigna).

Ponatinib is approved in the United States for treatment of adult patients with CML positive for the T3151 mutation in chronic phase, accelerated phase, or blast phase, or T3151-positive Philadelphia chromosome positive acute lymphoblastic leukemia (Ph+ALL). It is also approved for treatment of adults with chronic phase, accelerated phase, or blast phase CML or Ph+ALL for whom no other TKI is indicated.

The drug labeling carries a boxed warning about increased risk for vascular occlusion, heart failure, and hepatotoxicity. The warning notes that “[a]rterial and venous thrombosis and occlusions have occurred in at least 27% of Iclusig-treated patients, including fatal myocardial infarction, stroke, stenosis of large arterial vessels of the brain, severe peripheral vascular disease, and the need for urgent revascularization procedures.”

In a single-arm, open label trial, the investigators enrolled 51 patients with recently diagnosed CML in chronic phase, starting them on doses of oral ponatinib 45 mg daily. The protocol was later amended to a starting dose of 30 mg daily because of the high frequency of dose reductions required among patients started at 45 mg. Following a warning from the FDA about vascular complications with the drug, patients were started on daily low-dose aspirin (81 mg), and all drug doses were reduced to either 30 mg or 15 mg daily.

One of the patients discontinued therapy prior to assessment because of the FDA warning, leaving 50 for assessment at 6 months.

Of 46 patients evaluable for the primary outcome of CCyR by 6 months, 43 (94%) achieved it. Major molecular responses, defined as a BCR-ABL to ABL transcript ratio of 0.1% or lower, occurred in 40 of 50 patients (80%) evaluable for this secondary endpoint, and deep molecular response (MR4.5), defined as a ratio less than 0.0032% or lower, occurred in 28 of 50 (55%).

Cardiovascular events, primarily hypertension, occurred in 25 patients (49%), 15 (29%) had grade 3-4 myelosuppression, and 5 patients (10%) developed cerebrovascular or vaso-occlusive disease.

In all, 43 patients (85%) needed treatment interruptions at some time and 45 (88%) needed dose reductions. The study was terminated in June 2014, a little more than a year after recruitment began.

The study was sponsored by MD Anderson Cancer Center with partial support from Ariad Pharmaceuticals. Coauthors Hagop Kantarjian, Elias Jabbour, and Jorge Cortes report receiving grants, research support, or serving as consultants to Ariad.

The tyrosine kinase inhibitor ponatinib produced a high degree of complete cytogenetic responses when used in first-line treatment of patients with chronic myeloid leukemia in chronic phase. But the drug’s toxicities, especially its propensity for causing thromboembolic events, mitigate against its upfront use, investigators say.

In a small phase II study, 90% of evaluable patients with chronic-phase chronic myeloid leukemia (CML) treated with the tyrosine kinase inhibitor (TKI) had a complete cytogenetic response (CCyR) after 3 months, and 94% had a CCyR after 6 months, but that efficacy came at the cost of significant adverse events requiring dose reductions, treatment interruptions, and early termination of the trial for safety reasons at the recommendation of the Food and Drug Administration, reported Dr. Preetesh Jain of MD Anderson Cancer Center in Houston, Tex., and colleagues.

“[O]ur study shows that ponatinib is a very potent TKI with high clinical activity in the first-line treatment of patients with chronic-phase CML. However, at the doses currently used in other settings, the safety profile might not be appropriate for treatment of this patient population who have other treatment options with high efficacy,” the investigators wrote (Lancet Haematol. 2015;2[9]:e376-e383).

Ponatinib (Iclusig) is a third-generation TKI with action against malignancies with mutations in the ABL kinase domain that make the cancers resistant to first- and second-generation TKIs such as imatinib (Gleevec), dasatinib (Sprycel), and nilotinib (Tasigna).

Ponatinib is approved in the United States for treatment of adult patients with CML positive for the T3151 mutation in chronic phase, accelerated phase, or blast phase, or T3151-positive Philadelphia chromosome positive acute lymphoblastic leukemia (Ph+ALL). It is also approved for treatment of adults with chronic phase, accelerated phase, or blast phase CML or Ph+ALL for whom no other TKI is indicated.

The drug labeling carries a boxed warning about increased risk for vascular occlusion, heart failure, and hepatotoxicity. The warning notes that “[a]rterial and venous thrombosis and occlusions have occurred in at least 27% of Iclusig-treated patients, including fatal myocardial infarction, stroke, stenosis of large arterial vessels of the brain, severe peripheral vascular disease, and the need for urgent revascularization procedures.”

In a single-arm, open label trial, the investigators enrolled 51 patients with recently diagnosed CML in chronic phase, starting them on doses of oral ponatinib 45 mg daily. The protocol was later amended to a starting dose of 30 mg daily because of the high frequency of dose reductions required among patients started at 45 mg. Following a warning from the FDA about vascular complications with the drug, patients were started on daily low-dose aspirin (81 mg), and all drug doses were reduced to either 30 mg or 15 mg daily.

One of the patients discontinued therapy prior to assessment because of the FDA warning, leaving 50 for assessment at 6 months.

Of 46 patients evaluable for the primary outcome of CCyR by 6 months, 43 (94%) achieved it. Major molecular responses, defined as a BCR-ABL to ABL transcript ratio of 0.1% or lower, occurred in 40 of 50 patients (80%) evaluable for this secondary endpoint, and deep molecular response (MR4.5), defined as a ratio less than 0.0032% or lower, occurred in 28 of 50 (55%).

Cardiovascular events, primarily hypertension, occurred in 25 patients (49%), 15 (29%) had grade 3-4 myelosuppression, and 5 patients (10%) developed cerebrovascular or vaso-occlusive disease.

In all, 43 patients (85%) needed treatment interruptions at some time and 45 (88%) needed dose reductions. The study was terminated in June 2014, a little more than a year after recruitment began.

The study was sponsored by MD Anderson Cancer Center with partial support from Ariad Pharmaceuticals. Coauthors Hagop Kantarjian, Elias Jabbour, and Jorge Cortes report receiving grants, research support, or serving as consultants to Ariad.

The tyrosine kinase inhibitor ponatinib produced a high degree of complete cytogenetic responses when used in first-line treatment of patients with chronic myeloid leukemia in chronic phase. But the drug’s toxicities, especially its propensity for causing thromboembolic events, mitigate against its upfront use, investigators say.

In a small phase II study, 90% of evaluable patients with chronic-phase chronic myeloid leukemia (CML) treated with the tyrosine kinase inhibitor (TKI) had a complete cytogenetic response (CCyR) after 3 months, and 94% had a CCyR after 6 months, but that efficacy came at the cost of significant adverse events requiring dose reductions, treatment interruptions, and early termination of the trial for safety reasons at the recommendation of the Food and Drug Administration, reported Dr. Preetesh Jain of MD Anderson Cancer Center in Houston, Tex., and colleagues.

“[O]ur study shows that ponatinib is a very potent TKI with high clinical activity in the first-line treatment of patients with chronic-phase CML. However, at the doses currently used in other settings, the safety profile might not be appropriate for treatment of this patient population who have other treatment options with high efficacy,” the investigators wrote (Lancet Haematol. 2015;2[9]:e376-e383).

Ponatinib (Iclusig) is a third-generation TKI with action against malignancies with mutations in the ABL kinase domain that make the cancers resistant to first- and second-generation TKIs such as imatinib (Gleevec), dasatinib (Sprycel), and nilotinib (Tasigna).

Ponatinib is approved in the United States for treatment of adult patients with CML positive for the T3151 mutation in chronic phase, accelerated phase, or blast phase, or T3151-positive Philadelphia chromosome positive acute lymphoblastic leukemia (Ph+ALL). It is also approved for treatment of adults with chronic phase, accelerated phase, or blast phase CML or Ph+ALL for whom no other TKI is indicated.

The drug labeling carries a boxed warning about increased risk for vascular occlusion, heart failure, and hepatotoxicity. The warning notes that “[a]rterial and venous thrombosis and occlusions have occurred in at least 27% of Iclusig-treated patients, including fatal myocardial infarction, stroke, stenosis of large arterial vessels of the brain, severe peripheral vascular disease, and the need for urgent revascularization procedures.”

In a single-arm, open label trial, the investigators enrolled 51 patients with recently diagnosed CML in chronic phase, starting them on doses of oral ponatinib 45 mg daily. The protocol was later amended to a starting dose of 30 mg daily because of the high frequency of dose reductions required among patients started at 45 mg. Following a warning from the FDA about vascular complications with the drug, patients were started on daily low-dose aspirin (81 mg), and all drug doses were reduced to either 30 mg or 15 mg daily.

One of the patients discontinued therapy prior to assessment because of the FDA warning, leaving 50 for assessment at 6 months.

Of 46 patients evaluable for the primary outcome of CCyR by 6 months, 43 (94%) achieved it. Major molecular responses, defined as a BCR-ABL to ABL transcript ratio of 0.1% or lower, occurred in 40 of 50 patients (80%) evaluable for this secondary endpoint, and deep molecular response (MR4.5), defined as a ratio less than 0.0032% or lower, occurred in 28 of 50 (55%).

Cardiovascular events, primarily hypertension, occurred in 25 patients (49%), 15 (29%) had grade 3-4 myelosuppression, and 5 patients (10%) developed cerebrovascular or vaso-occlusive disease.

In all, 43 patients (85%) needed treatment interruptions at some time and 45 (88%) needed dose reductions. The study was terminated in June 2014, a little more than a year after recruitment began.

The study was sponsored by MD Anderson Cancer Center with partial support from Ariad Pharmaceuticals. Coauthors Hagop Kantarjian, Elias Jabbour, and Jorge Cortes report receiving grants, research support, or serving as consultants to Ariad.

Chromosome 3 abnormalities, specifically 3q26.2 rearrangements, were associated with treatment resistance and poor prognosis in patients with chronic myelogenous leukemia (CML), report Dr. Wei Wang and coauthors of the department of hematopathology at the University of Texas MD Anderson Cancer Center in Houston.

National Human Genome Research Institute/Wikimedia Commons/Public Domain

A study of 2,013 CML patients found that just 6% of those with 3q26.2 abnormalities achieved complete cytogenetic response during the course of tyrosine kinase inhibitor (TKI) treatment. Patients with other chromosome 3 abnormalities had a significantly better response rate of 42% the investigators found.

Additionally, patients with 3q26.2 chromosome rearrangements had significantly worse survival rates than those with abnormalities involving other chromosomes, with 2-year overall survival rates of 22% and 60%, respectively.

The lack of response to TKI treatment “raises the issue of how to manage these patients,” Dr. Wang and associates said in the report.

“TKIs themselves are not sufficient to control the disease with 3q26.2 abnormalities,” they added. “Intensive therapy, stem cell transplantation, or investigational therapy targeted to EVI1 should be considered,” concluded the authors, who declared that they had no competing financial interests.

Read the full article in Blood.

Chromosome 3 abnormalities, specifically 3q26.2 rearrangements, were associated with treatment resistance and poor prognosis in patients with chronic myelogenous leukemia (CML), report Dr. Wei Wang and coauthors of the department of hematopathology at the University of Texas MD Anderson Cancer Center in Houston.

National Human Genome Research Institute/Wikimedia Commons/Public Domain

A study of 2,013 CML patients found that just 6% of those with 3q26.2 abnormalities achieved complete cytogenetic response during the course of tyrosine kinase inhibitor (TKI) treatment. Patients with other chromosome 3 abnormalities had a significantly better response rate of 42% the investigators found.

Additionally, patients with 3q26.2 chromosome rearrangements had significantly worse survival rates than those with abnormalities involving other chromosomes, with 2-year overall survival rates of 22% and 60%, respectively.

The lack of response to TKI treatment “raises the issue of how to manage these patients,” Dr. Wang and associates said in the report.

“TKIs themselves are not sufficient to control the disease with 3q26.2 abnormalities,” they added. “Intensive therapy, stem cell transplantation, or investigational therapy targeted to EVI1 should be considered,” concluded the authors, who declared that they had no competing financial interests.

Read the full article in Blood.

Chromosome 3 abnormalities, specifically 3q26.2 rearrangements, were associated with treatment resistance and poor prognosis in patients with chronic myelogenous leukemia (CML), report Dr. Wei Wang and coauthors of the department of hematopathology at the University of Texas MD Anderson Cancer Center in Houston.

National Human Genome Research Institute/Wikimedia Commons/Public Domain

A study of 2,013 CML patients found that just 6% of those with 3q26.2 abnormalities achieved complete cytogenetic response during the course of tyrosine kinase inhibitor (TKI) treatment. Patients with other chromosome 3 abnormalities had a significantly better response rate of 42% the investigators found.

Additionally, patients with 3q26.2 chromosome rearrangements had significantly worse survival rates than those with abnormalities involving other chromosomes, with 2-year overall survival rates of 22% and 60%, respectively.

The lack of response to TKI treatment “raises the issue of how to manage these patients,” Dr. Wang and associates said in the report.

“TKIs themselves are not sufficient to control the disease with 3q26.2 abnormalities,” they added. “Intensive therapy, stem cell transplantation, or investigational therapy targeted to EVI1 should be considered,” concluded the authors, who declared that they had no competing financial interests.

Read the full article in Blood.