MD

Omacetaxine mepesuccinate has been granted accelerated approval for the treatment of adult patients with chronic phase (CP) or accelerated phase (AP) chronic myeloid leukemia (CML) with resistance or intolerance to 2 or more tyrosine kinase inhibitors (TKIs).^1,2 Approval was based on response rates observed in a combined cohort of adult CML patients from 2 clinical trials. As yet, no clinical trials have verified improved disease-related symptoms or increased survival with omacetaxine treatment.

Click on the PDF icon at the top of this introduction to read the full article.

Omacetaxine mepesuccinate has been granted accelerated approval for the treatment of adult patients with chronic phase (CP) or accelerated phase (AP) chronic myeloid leukemia (CML) with resistance or intolerance to 2 or more tyrosine kinase inhibitors (TKIs).^1,2 Approval was based on response rates observed in a combined cohort of adult CML patients from 2 clinical trials. As yet, no clinical trials have verified improved disease-related symptoms or increased survival with omacetaxine treatment.

Click on the PDF icon at the top of this introduction to read the full article.

Omacetaxine mepesuccinate has been granted accelerated approval for the treatment of adult patients with chronic phase (CP) or accelerated phase (AP) chronic myeloid leukemia (CML) with resistance or intolerance to 2 or more tyrosine kinase inhibitors (TKIs).^1,2 Approval was based on response rates observed in a combined cohort of adult CML patients from 2 clinical trials. As yet, no clinical trials have verified improved disease-related symptoms or increased survival with omacetaxine treatment.

Click on the PDF icon at the top of this introduction to read the full article.

Many oncologists remember the storied history of homoharringtonine (HHT) and wonder whatever happened to it. HHT showed initial promise for myeloid leukemias, particularly for chronic myelogenous leukemia (CML) where it seemed to induce more cytogenetic remissions than did interferon alpha.1 Unfortunately for HHT investigators, but fortunately for everybody else, these studies coincided with those being done with imatinib. The phenomenal introduction of imatinib contributed to the shelving of HHT in the mid to late 1990s.2 As is often the case, though, imatinib is not perfect. Some patients with CML develop resistance and approximately half of these do so through the acquisition of binding site mutations. One mutation in particular, T315I, rendered patients with CML resistant to all available tyrosine kinase inhibitors (TKI). In the meantime, a semisynthetic version of HHT, omacetaxine mepesuccinate, was developed. With the help of partners in industry, investigators at MD Anderson Cancer Center initiated new studies of omacetaxine in TKI resistant CML patients. Among 62 CML patients with a T315I mutation, complete hematologic response was achieved in 77% with median response duration of 9.1 months.3 Further, cytogenetic response was also achieved in a portion of patients, complete in 16%. These data prompted application for approval by the Food and Drug Administration, but were rejected for lack of a standardized test for T315I mutations. The additional data presented in the Community Translations article on page 194 formed the basis of a second application, this time for an indication in patients with CML resistant to 2 or more TKIs.

Many oncologists remember the storied history of homoharringtonine (HHT) and wonder whatever happened to it. HHT showed initial promise for myeloid leukemias, particularly for chronic myelogenous leukemia (CML) where it seemed to induce more cytogenetic remissions than did interferon alpha.1 Unfortunately for HHT investigators, but fortunately for everybody else, these studies coincided with those being done with imatinib. The phenomenal introduction of imatinib contributed to the shelving of HHT in the mid to late 1990s.2 As is often the case, though, imatinib is not perfect. Some patients with CML develop resistance and approximately half of these do so through the acquisition of binding site mutations. One mutation in particular, T315I, rendered patients with CML resistant to all available tyrosine kinase inhibitors (TKI). In the meantime, a semisynthetic version of HHT, omacetaxine mepesuccinate, was developed. With the help of partners in industry, investigators at MD Anderson Cancer Center initiated new studies of omacetaxine in TKI resistant CML patients. Among 62 CML patients with a T315I mutation, complete hematologic response was achieved in 77% with median response duration of 9.1 months.3 Further, cytogenetic response was also achieved in a portion of patients, complete in 16%. These data prompted application for approval by the Food and Drug Administration, but were rejected for lack of a standardized test for T315I mutations. The additional data presented in the Community Translations article on page 194 formed the basis of a second application, this time for an indication in patients with CML resistant to 2 or more TKIs.

Many oncologists remember the storied history of homoharringtonine (HHT) and wonder whatever happened to it. HHT showed initial promise for myeloid leukemias, particularly for chronic myelogenous leukemia (CML) where it seemed to induce more cytogenetic remissions than did interferon alpha.1 Unfortunately for HHT investigators, but fortunately for everybody else, these studies coincided with those being done with imatinib. The phenomenal introduction of imatinib contributed to the shelving of HHT in the mid to late 1990s.2 As is often the case, though, imatinib is not perfect. Some patients with CML develop resistance and approximately half of these do so through the acquisition of binding site mutations. One mutation in particular, T315I, rendered patients with CML resistant to all available tyrosine kinase inhibitors (TKI). In the meantime, a semisynthetic version of HHT, omacetaxine mepesuccinate, was developed. With the help of partners in industry, investigators at MD Anderson Cancer Center initiated new studies of omacetaxine in TKI resistant CML patients. Among 62 CML patients with a T315I mutation, complete hematologic response was achieved in 77% with median response duration of 9.1 months.3 Further, cytogenetic response was also achieved in a portion of patients, complete in 16%. These data prompted application for approval by the Food and Drug Administration, but were rejected for lack of a standardized test for T315I mutations. The additional data presented in the Community Translations article on page 194 formed the basis of a second application, this time for an indication in patients with CML resistant to 2 or more TKIs.

A57-year-old Caucasian man with a 32 pack-year history of smoking presented to the prime care clinic with a 2-week history of left index finger pain, redness, and swelling after sustaining a minor injury while closing his car door. Physical examination revealed a blackish discoloration of the skin. An X-ray of his left hand showed complete demineralization of the distal phalanx of the left index finger (Figure 1). The pain did not respond to NSAIDS, narcotics, and antibiotics. He subsequently underwent partial amputation of the finger. Pathology from the surgical specimen revealed a “poorly differentiated metastatic small-cell carcinoma” (Figure 2). He denied any dyspnea, cough, fever, night sweats, or loss of weight or appetite. The results of a computerized tomography scan of his thorax (Figure 3), abdomen, and pelvis revealed a large right lower lobe lung mass of 6.2 cm 4.2 cm adjacent to the right lower lobe bronchus that was consistent with lung cancer associated with pulmonary, hepatic, nodal, and skeletal metastasis. Magnetic resonance imaging of the brain showed multiple metastatic lesions throughout the brain, including the cerebellum. An MRI of the spine showed extensive metastatic lesions involving the thoracic vertebrae, T4 –T12, and the lumbar vertebra, L2. Given the extensive metastases and poor prognosis, the patient chose hospice care and palliative services. Discussion Digital acrometastases represent only 0.1% of all skeletal metastases.1 They have been described with various malignancies, including breast, gastrointestinal tract, head and neck, and small-cell and non–small-cell lung carcinomas.1,2 Metastases to the hand are most commonly caused by bronchogenic carcinomas,1-7 whereas foot metastases are seen with tumors originating in the gastrointestinal or genitourinary tracts.6,7 The most commonly involved bones are the phalanges in the hand and the tarsal bones in the foot.7,8 Acrometastases account for about 1 out of 500 lung cancers that present with bony metastases.2 Prognosis is grim, with a mean survival of 3– 6 months after presentation.1,2 Although acrometastasis from lung cancer itself is rare, occult lung cancer presenting as metastasis to the finger is even more unusual.

A57-year-old Caucasian man with a 32 pack-year history of smoking presented to the prime care clinic with a 2-week history of left index finger pain, redness, and swelling after sustaining a minor injury while closing his car door. Physical examination revealed a blackish discoloration of the skin. An X-ray of his left hand showed complete demineralization of the distal phalanx of the left index finger (Figure 1). The pain did not respond to NSAIDS, narcotics, and antibiotics. He subsequently underwent partial amputation of the finger. Pathology from the surgical specimen revealed a “poorly differentiated metastatic small-cell carcinoma” (Figure 2). He denied any dyspnea, cough, fever, night sweats, or loss of weight or appetite. The results of a computerized tomography scan of his thorax (Figure 3), abdomen, and pelvis revealed a large right lower lobe lung mass of 6.2 cm 4.2 cm adjacent to the right lower lobe bronchus that was consistent with lung cancer associated with pulmonary, hepatic, nodal, and skeletal metastasis. Magnetic resonance imaging of the brain showed multiple metastatic lesions throughout the brain, including the cerebellum. An MRI of the spine showed extensive metastatic lesions involving the thoracic vertebrae, T4 –T12, and the lumbar vertebra, L2. Given the extensive metastases and poor prognosis, the patient chose hospice care and palliative services. Discussion Digital acrometastases represent only 0.1% of all skeletal metastases.1 They have been described with various malignancies, including breast, gastrointestinal tract, head and neck, and small-cell and non–small-cell lung carcinomas.1,2 Metastases to the hand are most commonly caused by bronchogenic carcinomas,1-7 whereas foot metastases are seen with tumors originating in the gastrointestinal or genitourinary tracts.6,7 The most commonly involved bones are the phalanges in the hand and the tarsal bones in the foot.7,8 Acrometastases account for about 1 out of 500 lung cancers that present with bony metastases.2 Prognosis is grim, with a mean survival of 3– 6 months after presentation.1,2 Although acrometastasis from lung cancer itself is rare, occult lung cancer presenting as metastasis to the finger is even more unusual.

A57-year-old Caucasian man with a 32 pack-year history of smoking presented to the prime care clinic with a 2-week history of left index finger pain, redness, and swelling after sustaining a minor injury while closing his car door. Physical examination revealed a blackish discoloration of the skin. An X-ray of his left hand showed complete demineralization of the distal phalanx of the left index finger (Figure 1). The pain did not respond to NSAIDS, narcotics, and antibiotics. He subsequently underwent partial amputation of the finger. Pathology from the surgical specimen revealed a “poorly differentiated metastatic small-cell carcinoma” (Figure 2). He denied any dyspnea, cough, fever, night sweats, or loss of weight or appetite. The results of a computerized tomography scan of his thorax (Figure 3), abdomen, and pelvis revealed a large right lower lobe lung mass of 6.2 cm 4.2 cm adjacent to the right lower lobe bronchus that was consistent with lung cancer associated with pulmonary, hepatic, nodal, and skeletal metastasis. Magnetic resonance imaging of the brain showed multiple metastatic lesions throughout the brain, including the cerebellum. An MRI of the spine showed extensive metastatic lesions involving the thoracic vertebrae, T4 –T12, and the lumbar vertebra, L2. Given the extensive metastases and poor prognosis, the patient chose hospice care and palliative services. Discussion Digital acrometastases represent only 0.1% of all skeletal metastases.1 They have been described with various malignancies, including breast, gastrointestinal tract, head and neck, and small-cell and non–small-cell lung carcinomas.1,2 Metastases to the hand are most commonly caused by bronchogenic carcinomas,1-7 whereas foot metastases are seen with tumors originating in the gastrointestinal or genitourinary tracts.6,7 The most commonly involved bones are the phalanges in the hand and the tarsal bones in the foot.7,8 Acrometastases account for about 1 out of 500 lung cancers that present with bony metastases.2 Prognosis is grim, with a mean survival of 3– 6 months after presentation.1,2 Although acrometastasis from lung cancer itself is rare, occult lung cancer presenting as metastasis to the finger is even more unusual.

Enthusiasm continues in the medical community anxious for effective agents for men with metastatic castration-resistant prostate cancer (mCRPC). Most prostate cancer patients who develop metastatic disease are initially treated with readily available luteinizing hormone-releasing hormone (LHRH) agonists or antagonists, with or without an anti-androgen. The rationale here is to decrease androgen levels and/or block androgen receptor (AR) binding. In patients whose disease becomes refractory to this front-line hormonal deprivation, the molecular mechanisms involved in androgen independence include androgen receptor gene amplification, AR mutations that allow stimulation by a variety of weak androgens, and AR activation by autocrine production of androgens from tumor cells. Patients with metastatic castration-resistant prostate cancer (mCRPC) who biochemically recur after androgendeprivation therapy with significant prostate-specific antigen (PSA) elevations and/or who develop radiographic or symptomatic metastases are then usually considered for cytotoxic chemotherapy. The only approved initial cytotoxic chemotherapeutic agent that has demonstrated improved survival for patients with mCRPC is docetaxel. For patients who fail docetaxel, cabazitaxel with prednisone is an approved second-line treatment. Similarly, another approved second-line treatment (albeit, hormonal) for patients who have failed docetaxel therapy is abiraterone acetate, which attacks the adrenal and extragonadal synthesis of androgen. The magnitude of this effect was not appreciated until it was recognized that the androgen receptor and ligand-dependent androgen receptor signaling remain active and upregulated in men with castrate levels of testosterone ( 50 ng/dL).1 Recognition of the importance of the signaling of the androgen receptor and its seemingly independent behavior in a milieu of little or no androgen is now appreciated.

Enthusiasm continues in the medical community anxious for effective agents for men with metastatic castration-resistant prostate cancer (mCRPC). Most prostate cancer patients who develop metastatic disease are initially treated with readily available luteinizing hormone-releasing hormone (LHRH) agonists or antagonists, with or without an anti-androgen. The rationale here is to decrease androgen levels and/or block androgen receptor (AR) binding. In patients whose disease becomes refractory to this front-line hormonal deprivation, the molecular mechanisms involved in androgen independence include androgen receptor gene amplification, AR mutations that allow stimulation by a variety of weak androgens, and AR activation by autocrine production of androgens from tumor cells. Patients with metastatic castration-resistant prostate cancer (mCRPC) who biochemically recur after androgendeprivation therapy with significant prostate-specific antigen (PSA) elevations and/or who develop radiographic or symptomatic metastases are then usually considered for cytotoxic chemotherapy. The only approved initial cytotoxic chemotherapeutic agent that has demonstrated improved survival for patients with mCRPC is docetaxel. For patients who fail docetaxel, cabazitaxel with prednisone is an approved second-line treatment. Similarly, another approved second-line treatment (albeit, hormonal) for patients who have failed docetaxel therapy is abiraterone acetate, which attacks the adrenal and extragonadal synthesis of androgen. The magnitude of this effect was not appreciated until it was recognized that the androgen receptor and ligand-dependent androgen receptor signaling remain active and upregulated in men with castrate levels of testosterone ( 50 ng/dL).1 Recognition of the importance of the signaling of the androgen receptor and its seemingly independent behavior in a milieu of little or no androgen is now appreciated.

Enthusiasm continues in the medical community anxious for effective agents for men with metastatic castration-resistant prostate cancer (mCRPC). Most prostate cancer patients who develop metastatic disease are initially treated with readily available luteinizing hormone-releasing hormone (LHRH) agonists or antagonists, with or without an anti-androgen. The rationale here is to decrease androgen levels and/or block androgen receptor (AR) binding. In patients whose disease becomes refractory to this front-line hormonal deprivation, the molecular mechanisms involved in androgen independence include androgen receptor gene amplification, AR mutations that allow stimulation by a variety of weak androgens, and AR activation by autocrine production of androgens from tumor cells. Patients with metastatic castration-resistant prostate cancer (mCRPC) who biochemically recur after androgendeprivation therapy with significant prostate-specific antigen (PSA) elevations and/or who develop radiographic or symptomatic metastases are then usually considered for cytotoxic chemotherapy. The only approved initial cytotoxic chemotherapeutic agent that has demonstrated improved survival for patients with mCRPC is docetaxel. For patients who fail docetaxel, cabazitaxel with prednisone is an approved second-line treatment. Similarly, another approved second-line treatment (albeit, hormonal) for patients who have failed docetaxel therapy is abiraterone acetate, which attacks the adrenal and extragonadal synthesis of androgen. The magnitude of this effect was not appreciated until it was recognized that the androgen receptor and ligand-dependent androgen receptor signaling remain active and upregulated in men with castrate levels of testosterone ( 50 ng/dL).1 Recognition of the importance of the signaling of the androgen receptor and its seemingly independent behavior in a milieu of little or no androgen is now appreciated.

The effects of sequestration-related cuts on oncology practices have kicked in. In early April, Sarah Kliff, a blogger at The Washington Post, reported that cancer clinics had already started turning away Medicare patients because the funding cuts would make it impossible for them to continue treating their chemotherapy patients and avoid financial ruin.1 In early May, a month after the April 1 cuts took effect, we already had 2 separate survey reports, one from the American Society of Clinical Oncology (ASCO), the other from the Community Oncology Alliance (COA), that showed that the 2% cut in Medicare reimbursement had caused oncology practices “to make signifi- cant shifts in how they do business and care for patients.”2 ASCO surveyed 500 of its members (41% in suburban settings; 41%, in urban; 16%, in rural). In all, 80% of respondents said sequestration was affecting their practices, and about 75% said they were having trouble paying for chemotherapy drugs. Half of the respondents said they could care only for patients who had other sources of income independent of Medicare, 14% had stopped seeing Medicare patients, and half said they were sending their Medicare patients to outpatient infusion centers for their chemotherapy. ASCO president Sandra Swain expressed concern that some patients’ care was being disrupted and compromised, which could be detrimental to the clinical outcomes and emotional well-being of these fragile individuals, and she warned in a statement that the society’s initial findings “may just be the tip of the iceberg.”³ The fact that a quarter of respondents reported that they were planning to close satellite clinics should also raise concerns about the impact such closures might have on research and participation in clinical trials.

The effects of sequestration-related cuts on oncology practices have kicked in. In early April, Sarah Kliff, a blogger at The Washington Post, reported that cancer clinics had already started turning away Medicare patients because the funding cuts would make it impossible for them to continue treating their chemotherapy patients and avoid financial ruin.1 In early May, a month after the April 1 cuts took effect, we already had 2 separate survey reports, one from the American Society of Clinical Oncology (ASCO), the other from the Community Oncology Alliance (COA), that showed that the 2% cut in Medicare reimbursement had caused oncology practices “to make signifi- cant shifts in how they do business and care for patients.”2 ASCO surveyed 500 of its members (41% in suburban settings; 41%, in urban; 16%, in rural). In all, 80% of respondents said sequestration was affecting their practices, and about 75% said they were having trouble paying for chemotherapy drugs. Half of the respondents said they could care only for patients who had other sources of income independent of Medicare, 14% had stopped seeing Medicare patients, and half said they were sending their Medicare patients to outpatient infusion centers for their chemotherapy. ASCO president Sandra Swain expressed concern that some patients’ care was being disrupted and compromised, which could be detrimental to the clinical outcomes and emotional well-being of these fragile individuals, and she warned in a statement that the society’s initial findings “may just be the tip of the iceberg.”³ The fact that a quarter of respondents reported that they were planning to close satellite clinics should also raise concerns about the impact such closures might have on research and participation in clinical trials.

The effects of sequestration-related cuts on oncology practices have kicked in. In early April, Sarah Kliff, a blogger at The Washington Post, reported that cancer clinics had already started turning away Medicare patients because the funding cuts would make it impossible for them to continue treating their chemotherapy patients and avoid financial ruin.1 In early May, a month after the April 1 cuts took effect, we already had 2 separate survey reports, one from the American Society of Clinical Oncology (ASCO), the other from the Community Oncology Alliance (COA), that showed that the 2% cut in Medicare reimbursement had caused oncology practices “to make signifi- cant shifts in how they do business and care for patients.”2 ASCO surveyed 500 of its members (41% in suburban settings; 41%, in urban; 16%, in rural). In all, 80% of respondents said sequestration was affecting their practices, and about 75% said they were having trouble paying for chemotherapy drugs. Half of the respondents said they could care only for patients who had other sources of income independent of Medicare, 14% had stopped seeing Medicare patients, and half said they were sending their Medicare patients to outpatient infusion centers for their chemotherapy. ASCO president Sandra Swain expressed concern that some patients’ care was being disrupted and compromised, which could be detrimental to the clinical outcomes and emotional well-being of these fragile individuals, and she warned in a statement that the society’s initial findings “may just be the tip of the iceberg.”³ The fact that a quarter of respondents reported that they were planning to close satellite clinics should also raise concerns about the impact such closures might have on research and participation in clinical trials.