Researcher in the lab

Credit: Darren Baker

Researchers have identified an enzyme that appears key to prognosis and progression in multiple myeloma (MM).

The group found the enzyme, ST3GAL6, is overexpressed in MM cell lines and patients with disease.

This overexpression increases glycosylation, which escalates the interaction between MM cells and selectins.

And this encourages the circulation and spread of MM cells, as well as their retention in the bone marrow.

The researchers recounted this series of events in Blood.

“[W]e focused on alterations in [glycosylation] because of its role in cell-cell interactions and the spread of cancer cells in the blood,” said study author Michael O’Dwyer, MD, of National University of Ireland, Galway.

Using gene set enrichment analysis, he and his colleagues confirmed the overexpression of glycosylation-related signatures in MM. They also discovered the sialyltransferase ST3GAL6 was “one of the most significantly increased genes” in MM patients, when compared to healthy donors.

The team observed increased ST3GAL6 levels in both relapsed and newly diagnosed MM. And they found that higher ST3GAL6 levels were associated with decreased survival.

To expand upon these findings, the researchers went on to test 5 MM cell lines—MM1S, MM1R, U266, RPMI-8226, and H929. They found significantly higher levels of ST3GAL6 mRNA and protein in the cell lines compared to healthy CD138+ cells.

Knocking down ST3GAL6 in 2 of the cell lines—MM1S and RPMI-8226—significantly reduced the amount of alpha 2,3 sialic acid at the cell surface, which suggests that ST3GAL6 contributes to the synthesis of this glycan.

In addition, knocking down ST3GAL6 significantly reduced MM cells’ adhesion to bone marrow stem cells, human umbilical vein endothelial cells, and fibronectin. It also reduced MM cells’ transendothelial migration, attenuated Src activation in MM cells, and reduced the cells’ ability to roll on p-selectin.

Likewise, in mouse models, knockdown of ST3GAL6 reduced MM cell homing and engraftment. It also significantly decreased tumor burden and increased survival in the mice.

The researchers concluded that these findings highlight the importance of altered glycosylation, particularly sialylation, in MM cell adhesion and migration.

“Our research is crucial because it sheds new light on the biology of [MM], which could lead to new strategies to overcome resistance to treatment,” Dr O’Dwyer said. “Our aim now is to prevent these interactions that cause the spread [of MM cells] using specific enzyme and selectin inhibitors.”

Researcher in the lab

Credit: Darren Baker

Researchers have identified an enzyme that appears key to prognosis and progression in multiple myeloma (MM).

The group found the enzyme, ST3GAL6, is overexpressed in MM cell lines and patients with disease.

This overexpression increases glycosylation, which escalates the interaction between MM cells and selectins.

And this encourages the circulation and spread of MM cells, as well as their retention in the bone marrow.

The researchers recounted this series of events in Blood.

“[W]e focused on alterations in [glycosylation] because of its role in cell-cell interactions and the spread of cancer cells in the blood,” said study author Michael O’Dwyer, MD, of National University of Ireland, Galway.

Using gene set enrichment analysis, he and his colleagues confirmed the overexpression of glycosylation-related signatures in MM. They also discovered the sialyltransferase ST3GAL6 was “one of the most significantly increased genes” in MM patients, when compared to healthy donors.

The team observed increased ST3GAL6 levels in both relapsed and newly diagnosed MM. And they found that higher ST3GAL6 levels were associated with decreased survival.

To expand upon these findings, the researchers went on to test 5 MM cell lines—MM1S, MM1R, U266, RPMI-8226, and H929. They found significantly higher levels of ST3GAL6 mRNA and protein in the cell lines compared to healthy CD138+ cells.

Knocking down ST3GAL6 in 2 of the cell lines—MM1S and RPMI-8226—significantly reduced the amount of alpha 2,3 sialic acid at the cell surface, which suggests that ST3GAL6 contributes to the synthesis of this glycan.

In addition, knocking down ST3GAL6 significantly reduced MM cells’ adhesion to bone marrow stem cells, human umbilical vein endothelial cells, and fibronectin. It also reduced MM cells’ transendothelial migration, attenuated Src activation in MM cells, and reduced the cells’ ability to roll on p-selectin.

Likewise, in mouse models, knockdown of ST3GAL6 reduced MM cell homing and engraftment. It also significantly decreased tumor burden and increased survival in the mice.

The researchers concluded that these findings highlight the importance of altered glycosylation, particularly sialylation, in MM cell adhesion and migration.

“Our research is crucial because it sheds new light on the biology of [MM], which could lead to new strategies to overcome resistance to treatment,” Dr O’Dwyer said. “Our aim now is to prevent these interactions that cause the spread [of MM cells] using specific enzyme and selectin inhibitors.”

Researcher in the lab

Credit: Darren Baker

Researchers have identified an enzyme that appears key to prognosis and progression in multiple myeloma (MM).

The group found the enzyme, ST3GAL6, is overexpressed in MM cell lines and patients with disease.

This overexpression increases glycosylation, which escalates the interaction between MM cells and selectins.

And this encourages the circulation and spread of MM cells, as well as their retention in the bone marrow.

The researchers recounted this series of events in Blood.

“[W]e focused on alterations in [glycosylation] because of its role in cell-cell interactions and the spread of cancer cells in the blood,” said study author Michael O’Dwyer, MD, of National University of Ireland, Galway.

Using gene set enrichment analysis, he and his colleagues confirmed the overexpression of glycosylation-related signatures in MM. They also discovered the sialyltransferase ST3GAL6 was “one of the most significantly increased genes” in MM patients, when compared to healthy donors.

The team observed increased ST3GAL6 levels in both relapsed and newly diagnosed MM. And they found that higher ST3GAL6 levels were associated with decreased survival.

To expand upon these findings, the researchers went on to test 5 MM cell lines—MM1S, MM1R, U266, RPMI-8226, and H929. They found significantly higher levels of ST3GAL6 mRNA and protein in the cell lines compared to healthy CD138+ cells.

Knocking down ST3GAL6 in 2 of the cell lines—MM1S and RPMI-8226—significantly reduced the amount of alpha 2,3 sialic acid at the cell surface, which suggests that ST3GAL6 contributes to the synthesis of this glycan.

In addition, knocking down ST3GAL6 significantly reduced MM cells’ adhesion to bone marrow stem cells, human umbilical vein endothelial cells, and fibronectin. It also reduced MM cells’ transendothelial migration, attenuated Src activation in MM cells, and reduced the cells’ ability to roll on p-selectin.

Likewise, in mouse models, knockdown of ST3GAL6 reduced MM cell homing and engraftment. It also significantly decreased tumor burden and increased survival in the mice.

The researchers concluded that these findings highlight the importance of altered glycosylation, particularly sialylation, in MM cell adhesion and migration.

“Our research is crucial because it sheds new light on the biology of [MM], which could lead to new strategies to overcome resistance to treatment,” Dr O’Dwyer said. “Our aim now is to prevent these interactions that cause the spread [of MM cells] using specific enzyme and selectin inhibitors.”

Chronic myelogenous leukemia (CML) is caused by the constitutively active BCR-ABL fusion protein that results from t(9;22), the Philadelphia (Ph+) chromosome. Chronic myelogenous leukemia typically evolves through 3 clinical phases: an indolent chronic phase, an accelerated phase, and a terminal blast phase analogous to acute myeloid leukemia (AML) or acute lymphoblastic leukemia (ALL). Fortunately, today more than 80% of patients are diagnosed in the chronic phase of the disease.¹

Before the development of the tyrosine kinase inhibitor (TKI) imatinib, > 20% of the patients with chronic phase CML progressed to the blast phase every year.² Based on data from 8 years of follow-up with imatinib therapy, the rate of progression to the advanced phases of CML is about 1% per year, with freedom from progression at 92%.³ For the majority of patients with chronic phase CML, due to advances in treatment, the disease does not affect mortality.

For those who progress to the terminal blast phase of CML, survival is typically measured in months unless allogeneic stem cell transplant (allo-SCT) is an option. This article will review one of the major remaining problems in CML: how to manage blast phase CML. 

Definition and Diagnosis

Defining blast phase CML can be confusing, because different criteria have been proposed, none of which are biologically based. The most widely used definition is set forth by the European LeukemiaNet, recommending 30% blasts in the blood or bone marrow or the presence of extramedullary disease.¹ Clinically, blast phase CML may present with constitutional symptoms, bone pain, or symptoms related to cytopenias (fatigue, dyspnea, bleeding, infections).

Diagnostic workup should include a complete blood cell count (CBC) with differential, bone marrow analysis with conventional cytogenetics, flow cytometry to determine whether the blast phase is of myeloid or lymphoid origin, and molecular mutational analysis of the BCR-ABL tyrosine kinase domain to help guide the choice of TKI. If age and performance status are favorable, a donor search for allo-SCT should be started promptly.

Chronic myelogenous leukemia cells that contain the BCR-ABL kinase protein are genetically unstable.^4,5 Additional cytogenetic aberrations (ACAs) are seen in up to 80% of those with blast phase CML and are the most consistent predictor of blast transformation in those with chronic phase CML.⁶ Chromosomal changes are broken down into the nonrandom, “major route” ACAs (trisomy 8, additional Ph+ chromosome, isochromosome 17q, trisomy 19), considered likely to be involved in the evolution of CML, and the more random “minor route” ACAs, which may denote nothing more than the instability of the genome.^5,7 Mutations of the BCR-ABL tyrosine kinase domain are also seen in the majority of those in blast phase CML and, depending on the specific mutation, can negatively predict the response to certain TKI therapies.⁴

Prognosis

The single most important prognostic indicator for patients with CML remains the length of response to initial BCR-ABL–specific TKI therapy. Only a very small minority of patients are refractory to TKIs from the beginning; these are the patients with the worst prognosis.⁸ If the response to treatment seems inadequate, then the health care professional should first verify with the patient that he or she is taking the medicine as prescribed.¹ Lack of adherence continues to be the most common reason for less-than-ideal outcomes or fluctuations in response and plays a critical role in treatment with TKI therapy, with worse outcomes when < 90% of doses are taken.⁹

Other features associated with a poor prognosis include cytogenetic clonal evolution, > 50% blasts, and/or extramedullary disease.^7,10,11 At the time of imatinib failure, detection of mutations of the BCR-ABL tyrosine kinase domain correlates to worse 4-year event-free survival.¹² Showing the instability of the genome in CML, patients who harbor mutations of the BCR-ABL domain have a higher likelihood of relapse associated with further mutations and, therefore, potentially further TKI resistance.¹³ Once CML has progressed to the blast phase, life expectancy is, on average, less than a year.¹¹

Treatment Strategy

Currently, the most effective treatment strategy in blast phase CML is to prevent the transformation from chronic phase from ever occurring. Management of blast phase CML depends on 2 factors: (1) previous therapies; and (2) type of blast phase—myeloid or lymphoid. The goal of treatment is to knock the disease back to a clinical remission and/or a chronic phase for a long enough period to get the patient to allo-SCT if age, performance status, and suitable donor allow for it.

Using single-agent imatinib for blast phase CML has been tried in patients who have never been on TKI therapy before. Hematologic responses were seen in the majority of patients, but any form of cytogenetic response was seen in fewer than 20% of patients. Median overall survival, although better than with previous conventional chemotherapies, was still measured in months.⁶ A patient with blast phase CML who has never been on BCR-ABL–specific TKIs is very rare now; at a minimum, the patient has usually tried at least 1 TKI previously.  

If blast phase CML develops while a patient is taking imatinib, treatment with a second-generation TKIs—nilotinib or dasatinib— should be attempted if the BCR-ABL tyrosine kinase domain analysis shows no resistant mutations.¹⁴ Both nilotinib and dasatinib have been tried as single agents in patients with imatinib-refractory CML or who are unable to tolerate imatinib.^15,16 Cytogenetic response rates were 2 to 4 times higher for these agents than for imatinib when used in blast phase CML.

Table 1 reviews the common definitions of response, including cytogenetic response, to TKIs in CML. The pattern of response is usually very predictable: First, a hematologic response is seen, then a cytogenetic response, and finally, a hoped-for molecular response. Interestingly, in these studies, not all patients with blast phase CML who experienced a cytogenetic response had a hematologic response. This makes CBCs less reliable for assessing response and other peripheral blood tests, such as the interphase fluorescence in situ hybridization (I-FISH) test or the quantitative reverse transcriptase polymerase chain reaction (RT-Q-PCR) test, more important. Unfortunately, this improved cytogenetic response in blast phase CML did not translate to long-term survival advantage; median survival with these second- generation TKIs was still less than a year without transplant. If the T315I mutation is present, then clinical trials involving ponatinib or one of the newest non–FDA-approved TKIs should be considered.

Recent data involving ponatinib suggest similar response and survival rates to nilotinib and dasatinib, but this was in more heavily-pretreated CML patients who had resistance to, or unacceptable adverse effects from the second-generation TKIs or who had the BCR-ABL T315I mutation.¹⁷

In late 2013, ponatinib was voluntarily suspended from marketing and sales by its manufacturer due to a worrisome rate of serious arterial thromboembolic events reported in clinical trials and in postmarketing experience. However, the FDA reintroduced ponatinib in 2014 once additional safety measures were put in place, such as changes to the black box warning and review of the risk of arterial and venous thrombosis and occlusions.¹⁸

Table 2 compares the results between these newer TKIs in blast phase CML. If the patient can tolerate it, a combination of TKI with AML or ALL-type induction chemotherapy, preferably in a clinical trial setting, provides the best opportunity to return the patient to the chronic phase. If this is achieved, then allo-SCT represents the best chance for sustained remission or cure; allo-SCT was standard first-line therapy prior to the advent of BCR-ABL–specific TKIs. Tyrosine kinase inhibitor exposure prior to allo-SCT does not seem to affect transplantation outcomes.¹⁹ Allo-SCT while still in blast phase is discouraged because of its high risks with minimal benefit; disease-free survival rates are <10%.¹⁹ Although no scientific data support this, maintenance TKI posttransplantation seems logical, with monitoring of BCR-ABL transcript levels every 3 months.

Conclusion

With the advent of TKI therapy, the overall prognosis of CML has changed drastically. Unfortunately, the success seen with these novel agents in the chronic phase of CML has not translated into success in the blast phase of CML. Therefore, the best way to manage blast phase CML is to prevent this transformation from ever happening. The deeper and more rapid the cytogenetic and molecular response after TKI initiation, the better the long-term outcome for the patient.

If the patient progresses though TKI therapy, then combining a different TKI with a conventional induction chemotherapy regimen for acute leukemia should be tried; the goal is to achieve a remission that lasts long enough for the patient to be able to undergo allo-SCT. If the patient is not a candidate for allo-SCT, then the prognosis is extremely poor, and clinical trials with best supportive care should be considered.  

Author disclosures
The authors report no actual or potential conflicts of interest with regard to this article.

Disclaimer
The opinions expressed herein are those of the authors and do not necessarily reflect those of Federal Practitioner, Frontline Medical Communications Inc., the U.S. Government, or any of its agencies. This article may discuss unlabeled or investigational use of certain drugs. Please review complete prescribing information for specific drugs or drug combinations—including indications, contraindications, warnings, and adverse effects—before administering pharmacologic therapy to patients.

Chronic myelogenous leukemia (CML) is caused by the constitutively active BCR-ABL fusion protein that results from t(9;22), the Philadelphia (Ph+) chromosome. Chronic myelogenous leukemia typically evolves through 3 clinical phases: an indolent chronic phase, an accelerated phase, and a terminal blast phase analogous to acute myeloid leukemia (AML) or acute lymphoblastic leukemia (ALL). Fortunately, today more than 80% of patients are diagnosed in the chronic phase of the disease.¹

Before the development of the tyrosine kinase inhibitor (TKI) imatinib, > 20% of the patients with chronic phase CML progressed to the blast phase every year.² Based on data from 8 years of follow-up with imatinib therapy, the rate of progression to the advanced phases of CML is about 1% per year, with freedom from progression at 92%.³ For the majority of patients with chronic phase CML, due to advances in treatment, the disease does not affect mortality.

For those who progress to the terminal blast phase of CML, survival is typically measured in months unless allogeneic stem cell transplant (allo-SCT) is an option. This article will review one of the major remaining problems in CML: how to manage blast phase CML. 

Definition and Diagnosis

Defining blast phase CML can be confusing, because different criteria have been proposed, none of which are biologically based. The most widely used definition is set forth by the European LeukemiaNet, recommending 30% blasts in the blood or bone marrow or the presence of extramedullary disease.¹ Clinically, blast phase CML may present with constitutional symptoms, bone pain, or symptoms related to cytopenias (fatigue, dyspnea, bleeding, infections).

Diagnostic workup should include a complete blood cell count (CBC) with differential, bone marrow analysis with conventional cytogenetics, flow cytometry to determine whether the blast phase is of myeloid or lymphoid origin, and molecular mutational analysis of the BCR-ABL tyrosine kinase domain to help guide the choice of TKI. If age and performance status are favorable, a donor search for allo-SCT should be started promptly.

Chronic myelogenous leukemia cells that contain the BCR-ABL kinase protein are genetically unstable.^4,5 Additional cytogenetic aberrations (ACAs) are seen in up to 80% of those with blast phase CML and are the most consistent predictor of blast transformation in those with chronic phase CML.⁶ Chromosomal changes are broken down into the nonrandom, “major route” ACAs (trisomy 8, additional Ph+ chromosome, isochromosome 17q, trisomy 19), considered likely to be involved in the evolution of CML, and the more random “minor route” ACAs, which may denote nothing more than the instability of the genome.^5,7 Mutations of the BCR-ABL tyrosine kinase domain are also seen in the majority of those in blast phase CML and, depending on the specific mutation, can negatively predict the response to certain TKI therapies.⁴

Prognosis

The single most important prognostic indicator for patients with CML remains the length of response to initial BCR-ABL–specific TKI therapy. Only a very small minority of patients are refractory to TKIs from the beginning; these are the patients with the worst prognosis.⁸ If the response to treatment seems inadequate, then the health care professional should first verify with the patient that he or she is taking the medicine as prescribed.¹ Lack of adherence continues to be the most common reason for less-than-ideal outcomes or fluctuations in response and plays a critical role in treatment with TKI therapy, with worse outcomes when < 90% of doses are taken.⁹

Other features associated with a poor prognosis include cytogenetic clonal evolution, > 50% blasts, and/or extramedullary disease.^7,10,11 At the time of imatinib failure, detection of mutations of the BCR-ABL tyrosine kinase domain correlates to worse 4-year event-free survival.¹² Showing the instability of the genome in CML, patients who harbor mutations of the BCR-ABL domain have a higher likelihood of relapse associated with further mutations and, therefore, potentially further TKI resistance.¹³ Once CML has progressed to the blast phase, life expectancy is, on average, less than a year.¹¹

Treatment Strategy

Currently, the most effective treatment strategy in blast phase CML is to prevent the transformation from chronic phase from ever occurring. Management of blast phase CML depends on 2 factors: (1) previous therapies; and (2) type of blast phase—myeloid or lymphoid. The goal of treatment is to knock the disease back to a clinical remission and/or a chronic phase for a long enough period to get the patient to allo-SCT if age, performance status, and suitable donor allow for it.

Using single-agent imatinib for blast phase CML has been tried in patients who have never been on TKI therapy before. Hematologic responses were seen in the majority of patients, but any form of cytogenetic response was seen in fewer than 20% of patients. Median overall survival, although better than with previous conventional chemotherapies, was still measured in months.⁶ A patient with blast phase CML who has never been on BCR-ABL–specific TKIs is very rare now; at a minimum, the patient has usually tried at least 1 TKI previously.  

If blast phase CML develops while a patient is taking imatinib, treatment with a second-generation TKIs—nilotinib or dasatinib— should be attempted if the BCR-ABL tyrosine kinase domain analysis shows no resistant mutations.¹⁴ Both nilotinib and dasatinib have been tried as single agents in patients with imatinib-refractory CML or who are unable to tolerate imatinib.^15,16 Cytogenetic response rates were 2 to 4 times higher for these agents than for imatinib when used in blast phase CML.

Table 1 reviews the common definitions of response, including cytogenetic response, to TKIs in CML. The pattern of response is usually very predictable: First, a hematologic response is seen, then a cytogenetic response, and finally, a hoped-for molecular response. Interestingly, in these studies, not all patients with blast phase CML who experienced a cytogenetic response had a hematologic response. This makes CBCs less reliable for assessing response and other peripheral blood tests, such as the interphase fluorescence in situ hybridization (I-FISH) test or the quantitative reverse transcriptase polymerase chain reaction (RT-Q-PCR) test, more important. Unfortunately, this improved cytogenetic response in blast phase CML did not translate to long-term survival advantage; median survival with these second- generation TKIs was still less than a year without transplant. If the T315I mutation is present, then clinical trials involving ponatinib or one of the newest non–FDA-approved TKIs should be considered.

Recent data involving ponatinib suggest similar response and survival rates to nilotinib and dasatinib, but this was in more heavily-pretreated CML patients who had resistance to, or unacceptable adverse effects from the second-generation TKIs or who had the BCR-ABL T315I mutation.¹⁷

In late 2013, ponatinib was voluntarily suspended from marketing and sales by its manufacturer due to a worrisome rate of serious arterial thromboembolic events reported in clinical trials and in postmarketing experience. However, the FDA reintroduced ponatinib in 2014 once additional safety measures were put in place, such as changes to the black box warning and review of the risk of arterial and venous thrombosis and occlusions.¹⁸

Table 2 compares the results between these newer TKIs in blast phase CML. If the patient can tolerate it, a combination of TKI with AML or ALL-type induction chemotherapy, preferably in a clinical trial setting, provides the best opportunity to return the patient to the chronic phase. If this is achieved, then allo-SCT represents the best chance for sustained remission or cure; allo-SCT was standard first-line therapy prior to the advent of BCR-ABL–specific TKIs. Tyrosine kinase inhibitor exposure prior to allo-SCT does not seem to affect transplantation outcomes.¹⁹ Allo-SCT while still in blast phase is discouraged because of its high risks with minimal benefit; disease-free survival rates are <10%.¹⁹ Although no scientific data support this, maintenance TKI posttransplantation seems logical, with monitoring of BCR-ABL transcript levels every 3 months.

Conclusion

With the advent of TKI therapy, the overall prognosis of CML has changed drastically. Unfortunately, the success seen with these novel agents in the chronic phase of CML has not translated into success in the blast phase of CML. Therefore, the best way to manage blast phase CML is to prevent this transformation from ever happening. The deeper and more rapid the cytogenetic and molecular response after TKI initiation, the better the long-term outcome for the patient.

If the patient progresses though TKI therapy, then combining a different TKI with a conventional induction chemotherapy regimen for acute leukemia should be tried; the goal is to achieve a remission that lasts long enough for the patient to be able to undergo allo-SCT. If the patient is not a candidate for allo-SCT, then the prognosis is extremely poor, and clinical trials with best supportive care should be considered.  

Author disclosures
The authors report no actual or potential conflicts of interest with regard to this article.

Disclaimer
The opinions expressed herein are those of the authors and do not necessarily reflect those of Federal Practitioner, Frontline Medical Communications Inc., the U.S. Government, or any of its agencies. This article may discuss unlabeled or investigational use of certain drugs. Please review complete prescribing information for specific drugs or drug combinations—including indications, contraindications, warnings, and adverse effects—before administering pharmacologic therapy to patients.

Chronic myelogenous leukemia (CML) is caused by the constitutively active BCR-ABL fusion protein that results from t(9;22), the Philadelphia (Ph+) chromosome. Chronic myelogenous leukemia typically evolves through 3 clinical phases: an indolent chronic phase, an accelerated phase, and a terminal blast phase analogous to acute myeloid leukemia (AML) or acute lymphoblastic leukemia (ALL). Fortunately, today more than 80% of patients are diagnosed in the chronic phase of the disease.¹

Before the development of the tyrosine kinase inhibitor (TKI) imatinib, > 20% of the patients with chronic phase CML progressed to the blast phase every year.² Based on data from 8 years of follow-up with imatinib therapy, the rate of progression to the advanced phases of CML is about 1% per year, with freedom from progression at 92%.³ For the majority of patients with chronic phase CML, due to advances in treatment, the disease does not affect mortality.

For those who progress to the terminal blast phase of CML, survival is typically measured in months unless allogeneic stem cell transplant (allo-SCT) is an option. This article will review one of the major remaining problems in CML: how to manage blast phase CML. 

Definition and Diagnosis

Defining blast phase CML can be confusing, because different criteria have been proposed, none of which are biologically based. The most widely used definition is set forth by the European LeukemiaNet, recommending 30% blasts in the blood or bone marrow or the presence of extramedullary disease.¹ Clinically, blast phase CML may present with constitutional symptoms, bone pain, or symptoms related to cytopenias (fatigue, dyspnea, bleeding, infections).

Diagnostic workup should include a complete blood cell count (CBC) with differential, bone marrow analysis with conventional cytogenetics, flow cytometry to determine whether the blast phase is of myeloid or lymphoid origin, and molecular mutational analysis of the BCR-ABL tyrosine kinase domain to help guide the choice of TKI. If age and performance status are favorable, a donor search for allo-SCT should be started promptly.

Chronic myelogenous leukemia cells that contain the BCR-ABL kinase protein are genetically unstable.^4,5 Additional cytogenetic aberrations (ACAs) are seen in up to 80% of those with blast phase CML and are the most consistent predictor of blast transformation in those with chronic phase CML.⁶ Chromosomal changes are broken down into the nonrandom, “major route” ACAs (trisomy 8, additional Ph+ chromosome, isochromosome 17q, trisomy 19), considered likely to be involved in the evolution of CML, and the more random “minor route” ACAs, which may denote nothing more than the instability of the genome.^5,7 Mutations of the BCR-ABL tyrosine kinase domain are also seen in the majority of those in blast phase CML and, depending on the specific mutation, can negatively predict the response to certain TKI therapies.⁴

Prognosis

The single most important prognostic indicator for patients with CML remains the length of response to initial BCR-ABL–specific TKI therapy. Only a very small minority of patients are refractory to TKIs from the beginning; these are the patients with the worst prognosis.⁸ If the response to treatment seems inadequate, then the health care professional should first verify with the patient that he or she is taking the medicine as prescribed.¹ Lack of adherence continues to be the most common reason for less-than-ideal outcomes or fluctuations in response and plays a critical role in treatment with TKI therapy, with worse outcomes when < 90% of doses are taken.⁹

Other features associated with a poor prognosis include cytogenetic clonal evolution, > 50% blasts, and/or extramedullary disease.^7,10,11 At the time of imatinib failure, detection of mutations of the BCR-ABL tyrosine kinase domain correlates to worse 4-year event-free survival.¹² Showing the instability of the genome in CML, patients who harbor mutations of the BCR-ABL domain have a higher likelihood of relapse associated with further mutations and, therefore, potentially further TKI resistance.¹³ Once CML has progressed to the blast phase, life expectancy is, on average, less than a year.¹¹

Treatment Strategy

Currently, the most effective treatment strategy in blast phase CML is to prevent the transformation from chronic phase from ever occurring. Management of blast phase CML depends on 2 factors: (1) previous therapies; and (2) type of blast phase—myeloid or lymphoid. The goal of treatment is to knock the disease back to a clinical remission and/or a chronic phase for a long enough period to get the patient to allo-SCT if age, performance status, and suitable donor allow for it.

Using single-agent imatinib for blast phase CML has been tried in patients who have never been on TKI therapy before. Hematologic responses were seen in the majority of patients, but any form of cytogenetic response was seen in fewer than 20% of patients. Median overall survival, although better than with previous conventional chemotherapies, was still measured in months.⁶ A patient with blast phase CML who has never been on BCR-ABL–specific TKIs is very rare now; at a minimum, the patient has usually tried at least 1 TKI previously.  

If blast phase CML develops while a patient is taking imatinib, treatment with a second-generation TKIs—nilotinib or dasatinib— should be attempted if the BCR-ABL tyrosine kinase domain analysis shows no resistant mutations.¹⁴ Both nilotinib and dasatinib have been tried as single agents in patients with imatinib-refractory CML or who are unable to tolerate imatinib.^15,16 Cytogenetic response rates were 2 to 4 times higher for these agents than for imatinib when used in blast phase CML.

Table 1 reviews the common definitions of response, including cytogenetic response, to TKIs in CML. The pattern of response is usually very predictable: First, a hematologic response is seen, then a cytogenetic response, and finally, a hoped-for molecular response. Interestingly, in these studies, not all patients with blast phase CML who experienced a cytogenetic response had a hematologic response. This makes CBCs less reliable for assessing response and other peripheral blood tests, such as the interphase fluorescence in situ hybridization (I-FISH) test or the quantitative reverse transcriptase polymerase chain reaction (RT-Q-PCR) test, more important. Unfortunately, this improved cytogenetic response in blast phase CML did not translate to long-term survival advantage; median survival with these second- generation TKIs was still less than a year without transplant. If the T315I mutation is present, then clinical trials involving ponatinib or one of the newest non–FDA-approved TKIs should be considered.

Recent data involving ponatinib suggest similar response and survival rates to nilotinib and dasatinib, but this was in more heavily-pretreated CML patients who had resistance to, or unacceptable adverse effects from the second-generation TKIs or who had the BCR-ABL T315I mutation.¹⁷

In late 2013, ponatinib was voluntarily suspended from marketing and sales by its manufacturer due to a worrisome rate of serious arterial thromboembolic events reported in clinical trials and in postmarketing experience. However, the FDA reintroduced ponatinib in 2014 once additional safety measures were put in place, such as changes to the black box warning and review of the risk of arterial and venous thrombosis and occlusions.¹⁸

Table 2 compares the results between these newer TKIs in blast phase CML. If the patient can tolerate it, a combination of TKI with AML or ALL-type induction chemotherapy, preferably in a clinical trial setting, provides the best opportunity to return the patient to the chronic phase. If this is achieved, then allo-SCT represents the best chance for sustained remission or cure; allo-SCT was standard first-line therapy prior to the advent of BCR-ABL–specific TKIs. Tyrosine kinase inhibitor exposure prior to allo-SCT does not seem to affect transplantation outcomes.¹⁹ Allo-SCT while still in blast phase is discouraged because of its high risks with minimal benefit; disease-free survival rates are <10%.¹⁹ Although no scientific data support this, maintenance TKI posttransplantation seems logical, with monitoring of BCR-ABL transcript levels every 3 months.

Conclusion

With the advent of TKI therapy, the overall prognosis of CML has changed drastically. Unfortunately, the success seen with these novel agents in the chronic phase of CML has not translated into success in the blast phase of CML. Therefore, the best way to manage blast phase CML is to prevent this transformation from ever happening. The deeper and more rapid the cytogenetic and molecular response after TKI initiation, the better the long-term outcome for the patient.

If the patient progresses though TKI therapy, then combining a different TKI with a conventional induction chemotherapy regimen for acute leukemia should be tried; the goal is to achieve a remission that lasts long enough for the patient to be able to undergo allo-SCT. If the patient is not a candidate for allo-SCT, then the prognosis is extremely poor, and clinical trials with best supportive care should be considered.  

Author disclosures
The authors report no actual or potential conflicts of interest with regard to this article.

Disclaimer
The opinions expressed herein are those of the authors and do not necessarily reflect those of Federal Practitioner, Frontline Medical Communications Inc., the U.S. Government, or any of its agencies. This article may discuss unlabeled or investigational use of certain drugs. Please review complete prescribing information for specific drugs or drug combinations—including indications, contraindications, warnings, and adverse effects—before administering pharmacologic therapy to patients.

Cancer cells expressing MYC

Credit: Juha Klefstrom

New research suggests the MYC protein drives cell growth by inhibiting a handful of genes involved in DNA packaging and cell death.

The study showed that MYC works through a microRNA to suppress the genes’ expression.

This marks the first time that a subset of MYC-controlled genes have been identified as critical players in the protein’s cancer-causing function, and it points to new therapeutic targets for MYC-dependent cancers.

“This is a different way of thinking about the roles of microRNA and chromatin packaging in cancer,” said Dean Felsher, MD, PhD, of the Stanford University School of Medicine in California.

“We were very surprised to learn that the overexpression of one microRNA can mimic the cancerous effect of MYC.”

Dr Felsher and his colleagues reported this discovery in Cancer Cell.

The team noted that MYC overexpression has been known to prompt an increase in the levels of a microRNA family called miR-17-92.

“People have known for several years that MYC regulates the expression of microRNAs,” Dr Felsher said. “But it wasn’t clear how this was related to MYC’s oncogenic function.”

To gain some insight, Dr Felsher and his colleagues analyzed MYC-dependent cancer cells in vitro and in vivo.

The cells in which miR-17-92 expression was locked in the “on” position kept dividing even when MYC expression was blocked. This suggested that MYC works through the microRNA family to exert its cancer-causing effects.

The researchers then looked for an overlap among genes affected by MYC overexpression and those affected by miR-17-92. There were about 401 genes whose expression was either increased or suppressed by both MYC and miR-17-92.

The team chose to focus on genes that were suppressed because these genes exhibited, on average, many more binding sites for the microRNAs. They further narrowed their panel down to 15 genes regulated by more than one miR-17-92 binding site.

Of these genes, 5 stood out. Four of them—Sin3b, Hbp1, Suv420h1, and Btg1—encode proteins known to regulate chromatin packaging.

These 4 proteins affect cell proliferation and senescence by regulating gene accessibility within the chromatin. They had never before been identified as MYC or miR-17-92 targets.

The fifth gene encodes the apoptotic protein Bim. Previous research suggested that Bim expression is affected by miR-17-92.

All 5 of the proteins are known to affect either cellular proliferation, entry into senescence, or apoptosis, in part by granting or prohibiting access to genes in tightly packaged stretches of DNA in the chromatin.

“MYC is still a general amplifier of gene transcription and expression,” Dr Felsher said. “But our study shows that the maintenance of the cancerous state relies on a more focused mechanism.”

Lastly, the researchers showed that suppressing the expression of the 5 target genes, effectively mimicking MYC overexpression, partially mitigates the effect of MYC deactivation.

Up to 30% of MYC-dependent cancer cells in culture continued to grow—compared to 11% of control cells—in the absence of MYC expression. And tumors in mice either failed to regress or recurred within a few weeks.

“One of the biggest unanswered questions in oncology is how oncogenes cause cancer, and whether you can replace an oncogene with another gene product,” Dr Felsher said.

“These experiments begin to reveal how MYC affects the self-renewal decisions of cells. They may also help us target those aspects of MYC overexpression that contribute to the cancer phenotype.”

Cancer cells expressing MYC

Credit: Juha Klefstrom

New research suggests the MYC protein drives cell growth by inhibiting a handful of genes involved in DNA packaging and cell death.

The study showed that MYC works through a microRNA to suppress the genes’ expression.

This marks the first time that a subset of MYC-controlled genes have been identified as critical players in the protein’s cancer-causing function, and it points to new therapeutic targets for MYC-dependent cancers.

“This is a different way of thinking about the roles of microRNA and chromatin packaging in cancer,” said Dean Felsher, MD, PhD, of the Stanford University School of Medicine in California.

“We were very surprised to learn that the overexpression of one microRNA can mimic the cancerous effect of MYC.”

Dr Felsher and his colleagues reported this discovery in Cancer Cell.

The team noted that MYC overexpression has been known to prompt an increase in the levels of a microRNA family called miR-17-92.

“People have known for several years that MYC regulates the expression of microRNAs,” Dr Felsher said. “But it wasn’t clear how this was related to MYC’s oncogenic function.”

To gain some insight, Dr Felsher and his colleagues analyzed MYC-dependent cancer cells in vitro and in vivo.

The cells in which miR-17-92 expression was locked in the “on” position kept dividing even when MYC expression was blocked. This suggested that MYC works through the microRNA family to exert its cancer-causing effects.

The researchers then looked for an overlap among genes affected by MYC overexpression and those affected by miR-17-92. There were about 401 genes whose expression was either increased or suppressed by both MYC and miR-17-92.

The team chose to focus on genes that were suppressed because these genes exhibited, on average, many more binding sites for the microRNAs. They further narrowed their panel down to 15 genes regulated by more than one miR-17-92 binding site.

Of these genes, 5 stood out. Four of them—Sin3b, Hbp1, Suv420h1, and Btg1—encode proteins known to regulate chromatin packaging.

These 4 proteins affect cell proliferation and senescence by regulating gene accessibility within the chromatin. They had never before been identified as MYC or miR-17-92 targets.

The fifth gene encodes the apoptotic protein Bim. Previous research suggested that Bim expression is affected by miR-17-92.

All 5 of the proteins are known to affect either cellular proliferation, entry into senescence, or apoptosis, in part by granting or prohibiting access to genes in tightly packaged stretches of DNA in the chromatin.

“MYC is still a general amplifier of gene transcription and expression,” Dr Felsher said. “But our study shows that the maintenance of the cancerous state relies on a more focused mechanism.”

Lastly, the researchers showed that suppressing the expression of the 5 target genes, effectively mimicking MYC overexpression, partially mitigates the effect of MYC deactivation.

Up to 30% of MYC-dependent cancer cells in culture continued to grow—compared to 11% of control cells—in the absence of MYC expression. And tumors in mice either failed to regress or recurred within a few weeks.

“One of the biggest unanswered questions in oncology is how oncogenes cause cancer, and whether you can replace an oncogene with another gene product,” Dr Felsher said.

“These experiments begin to reveal how MYC affects the self-renewal decisions of cells. They may also help us target those aspects of MYC overexpression that contribute to the cancer phenotype.”

Cancer cells expressing MYC

Credit: Juha Klefstrom

New research suggests the MYC protein drives cell growth by inhibiting a handful of genes involved in DNA packaging and cell death.

The study showed that MYC works through a microRNA to suppress the genes’ expression.

This marks the first time that a subset of MYC-controlled genes have been identified as critical players in the protein’s cancer-causing function, and it points to new therapeutic targets for MYC-dependent cancers.

“This is a different way of thinking about the roles of microRNA and chromatin packaging in cancer,” said Dean Felsher, MD, PhD, of the Stanford University School of Medicine in California.

“We were very surprised to learn that the overexpression of one microRNA can mimic the cancerous effect of MYC.”

Dr Felsher and his colleagues reported this discovery in Cancer Cell.

The team noted that MYC overexpression has been known to prompt an increase in the levels of a microRNA family called miR-17-92.

“People have known for several years that MYC regulates the expression of microRNAs,” Dr Felsher said. “But it wasn’t clear how this was related to MYC’s oncogenic function.”

To gain some insight, Dr Felsher and his colleagues analyzed MYC-dependent cancer cells in vitro and in vivo.

The cells in which miR-17-92 expression was locked in the “on” position kept dividing even when MYC expression was blocked. This suggested that MYC works through the microRNA family to exert its cancer-causing effects.

The researchers then looked for an overlap among genes affected by MYC overexpression and those affected by miR-17-92. There were about 401 genes whose expression was either increased or suppressed by both MYC and miR-17-92.

The team chose to focus on genes that were suppressed because these genes exhibited, on average, many more binding sites for the microRNAs. They further narrowed their panel down to 15 genes regulated by more than one miR-17-92 binding site.

Of these genes, 5 stood out. Four of them—Sin3b, Hbp1, Suv420h1, and Btg1—encode proteins known to regulate chromatin packaging.

These 4 proteins affect cell proliferation and senescence by regulating gene accessibility within the chromatin. They had never before been identified as MYC or miR-17-92 targets.

The fifth gene encodes the apoptotic protein Bim. Previous research suggested that Bim expression is affected by miR-17-92.

All 5 of the proteins are known to affect either cellular proliferation, entry into senescence, or apoptosis, in part by granting or prohibiting access to genes in tightly packaged stretches of DNA in the chromatin.

“MYC is still a general amplifier of gene transcription and expression,” Dr Felsher said. “But our study shows that the maintenance of the cancerous state relies on a more focused mechanism.”

Lastly, the researchers showed that suppressing the expression of the 5 target genes, effectively mimicking MYC overexpression, partially mitigates the effect of MYC deactivation.

Up to 30% of MYC-dependent cancer cells in culture continued to grow—compared to 11% of control cells—in the absence of MYC expression. And tumors in mice either failed to regress or recurred within a few weeks.

“One of the biggest unanswered questions in oncology is how oncogenes cause cancer, and whether you can replace an oncogene with another gene product,” Dr Felsher said.

“These experiments begin to reveal how MYC affects the self-renewal decisions of cells. They may also help us target those aspects of MYC overexpression that contribute to the cancer phenotype.”

Vials of drug

Cubist Pharmaceuticals, Inc. is recalling 9 lots of the antibiotic Cubicin (daptomycin for injection), following complaints of foreign particulate matter in reconstituted vials.

Particulate matter in an intravenous drug poses a risk of thromboembolism and pulmonary embolism.

Other risks include phlebitis, the mechanical blocking of the capillaries or arterioles, the activation of platelets, the generation of microthrombi, and the formation of granulomas.

To date, there have been no adverse events associated with complaints of particulate matter from the 9 lots of Cubicin being recalled.

Cubicin is an intravenous product indicated for the treatment of skin infections and certain blood stream infections. The drug was distributed throughout the US, so the recall is nationwide.

The recall includes the following lots of Cubicin 500 mg (NDC 67919-011-01, UPC 3 67919-011-01 6):

Lot #             Expiration date           Ship dates

CDC203         DEC 2015                    9/2/13 through 9/24/13

CDC207         JAN 2016                     9/16/13 through 10/15/13

CDC213         FEB 2016                    10/1/13 through 10/7/13

CDC217         MAR 2016                   12/2/13 through 12/11/13

CDC226         APR 2016                    7/29/13 through 8/26/13

CDC234         MAY 2016                    8/26/13 through 9/19/13

CDC235         MAY 2016                    9/19/13 through 10/17/13

CDC243         JUL 2016                    10/17/13 through 11/12/13

CDC246         JUL 2016                    11/12/13 through 12/2/13

Cubist Pharmaceuticals is notifying customers of this recall by letter and phone. Customers with product from the recalled lots should quarantine the product and discontinue distribution.

To arrange for the return and replacement of product, call Cubist at (855) 534-8309 between the hours of 9 am and 7 pm EDT, Monday through Friday.

Healthcare professionals and pharmacists with medical questions regarding this recall can contact Cubist Medical Information at (877) 282-4786 between the hours of 8 am and 5:30 pm EDT, Monday through Friday.

Adverse events or quality problems associated with the use of this product can be reported to the Food and Drug Administration’s MedWatch Adverse Events Program.

Vials of drug

Cubist Pharmaceuticals, Inc. is recalling 9 lots of the antibiotic Cubicin (daptomycin for injection), following complaints of foreign particulate matter in reconstituted vials.

Particulate matter in an intravenous drug poses a risk of thromboembolism and pulmonary embolism.

Other risks include phlebitis, the mechanical blocking of the capillaries or arterioles, the activation of platelets, the generation of microthrombi, and the formation of granulomas.

To date, there have been no adverse events associated with complaints of particulate matter from the 9 lots of Cubicin being recalled.

Cubicin is an intravenous product indicated for the treatment of skin infections and certain blood stream infections. The drug was distributed throughout the US, so the recall is nationwide.

The recall includes the following lots of Cubicin 500 mg (NDC 67919-011-01, UPC 3 67919-011-01 6):

Lot #             Expiration date           Ship dates

CDC203         DEC 2015                    9/2/13 through 9/24/13

CDC207         JAN 2016                     9/16/13 through 10/15/13

CDC213         FEB 2016                    10/1/13 through 10/7/13

CDC217         MAR 2016                   12/2/13 through 12/11/13

CDC226         APR 2016                    7/29/13 through 8/26/13

CDC234         MAY 2016                    8/26/13 through 9/19/13

CDC235         MAY 2016                    9/19/13 through 10/17/13

CDC243         JUL 2016                    10/17/13 through 11/12/13

CDC246         JUL 2016                    11/12/13 through 12/2/13

Cubist Pharmaceuticals is notifying customers of this recall by letter and phone. Customers with product from the recalled lots should quarantine the product and discontinue distribution.

To arrange for the return and replacement of product, call Cubist at (855) 534-8309 between the hours of 9 am and 7 pm EDT, Monday through Friday.

Healthcare professionals and pharmacists with medical questions regarding this recall can contact Cubist Medical Information at (877) 282-4786 between the hours of 8 am and 5:30 pm EDT, Monday through Friday.

Adverse events or quality problems associated with the use of this product can be reported to the Food and Drug Administration’s MedWatch Adverse Events Program.

Vials of drug

Cubist Pharmaceuticals, Inc. is recalling 9 lots of the antibiotic Cubicin (daptomycin for injection), following complaints of foreign particulate matter in reconstituted vials.

Particulate matter in an intravenous drug poses a risk of thromboembolism and pulmonary embolism.

Other risks include phlebitis, the mechanical blocking of the capillaries or arterioles, the activation of platelets, the generation of microthrombi, and the formation of granulomas.

To date, there have been no adverse events associated with complaints of particulate matter from the 9 lots of Cubicin being recalled.

Cubicin is an intravenous product indicated for the treatment of skin infections and certain blood stream infections. The drug was distributed throughout the US, so the recall is nationwide.

The recall includes the following lots of Cubicin 500 mg (NDC 67919-011-01, UPC 3 67919-011-01 6):

Lot #             Expiration date           Ship dates

CDC203         DEC 2015                    9/2/13 through 9/24/13

CDC207         JAN 2016                     9/16/13 through 10/15/13

CDC213         FEB 2016                    10/1/13 through 10/7/13

CDC217         MAR 2016                   12/2/13 through 12/11/13

CDC226         APR 2016                    7/29/13 through 8/26/13

CDC234         MAY 2016                    8/26/13 through 9/19/13

CDC235         MAY 2016                    9/19/13 through 10/17/13

CDC243         JUL 2016                    10/17/13 through 11/12/13

CDC246         JUL 2016                    11/12/13 through 12/2/13

Cubist Pharmaceuticals is notifying customers of this recall by letter and phone. Customers with product from the recalled lots should quarantine the product and discontinue distribution.

To arrange for the return and replacement of product, call Cubist at (855) 534-8309 between the hours of 9 am and 7 pm EDT, Monday through Friday.

Healthcare professionals and pharmacists with medical questions regarding this recall can contact Cubist Medical Information at (877) 282-4786 between the hours of 8 am and 5:30 pm EDT, Monday through Friday.

Adverse events or quality problems associated with the use of this product can be reported to the Food and Drug Administration’s MedWatch Adverse Events Program.

Hematopoietic stem cells

in the bone marrow

A new epigenetic profiling technique has allowed researchers to chart histone dynamics during hematopoiesis, and it has produced some surprising results.

The researchers developed a high-sensitivity, indexing-first chromatin immunoprecipitation approach (iChIP) that requires as few as 500 cells for accurate analysis.

The techniques currently in use require millions of cells for accurate detection and analysis, but iCHIP overcomes this limitation.

David Lara-Astiaso, of the Weizmann Institute of Science in Rehovot, Israel, and his colleagues described the new method in Science.

The team used iCHIP to profile the dynamics of 4 chromatin modifications across 16 stages of hematopoietic differentiation.

“Using this powerful approach, we were able to identify the exact DNA regulatory sequences, as well as the various regulatory proteins, that are involved in controlling stem cell fate, casting light on previously unseen parts of the basic program of life,” said Nir Friedman, PhD, of the Hebrew University of Jerusalem in Israel.

The research also suggested that as many as 50% of these regulatory sequences are established and opened during intermediate stages of cell development. This means epigenetics are active at stages in which we thought cell destiny was already set.

“This changes our whole understanding of the process of blood stem cell fate decisions,” Lara-Astiaso said.

“[The discovery suggests] the process is more dynamic and flexible than previously thought, giving the cell slightly more leeway at the later stages in deciding what type of cell to turn into, in case its circumstances change.”

Although this research was conducted on mouse HSCs, the researchers believe the mechanism may hold true for other types of cells as well.

“This research creates a lot of excitement in the field, as it sets the groundwork to study these regulatory elements in humans,” said Assaf Weiner, of the Hebrew University of Jerusalem.

Discovering the exact regulatory DNA sequence controlling the fate of hematopoietic stem cells, as well as understanding the mechanism, holds promise for the development of diagnostic tools and therapeutic interventions, the researchers noted.

Hematopoietic stem cells

in the bone marrow

A new epigenetic profiling technique has allowed researchers to chart histone dynamics during hematopoiesis, and it has produced some surprising results.

The researchers developed a high-sensitivity, indexing-first chromatin immunoprecipitation approach (iChIP) that requires as few as 500 cells for accurate analysis.

The techniques currently in use require millions of cells for accurate detection and analysis, but iCHIP overcomes this limitation.

David Lara-Astiaso, of the Weizmann Institute of Science in Rehovot, Israel, and his colleagues described the new method in Science.

The team used iCHIP to profile the dynamics of 4 chromatin modifications across 16 stages of hematopoietic differentiation.

“Using this powerful approach, we were able to identify the exact DNA regulatory sequences, as well as the various regulatory proteins, that are involved in controlling stem cell fate, casting light on previously unseen parts of the basic program of life,” said Nir Friedman, PhD, of the Hebrew University of Jerusalem in Israel.

The research also suggested that as many as 50% of these regulatory sequences are established and opened during intermediate stages of cell development. This means epigenetics are active at stages in which we thought cell destiny was already set.

“This changes our whole understanding of the process of blood stem cell fate decisions,” Lara-Astiaso said.

“[The discovery suggests] the process is more dynamic and flexible than previously thought, giving the cell slightly more leeway at the later stages in deciding what type of cell to turn into, in case its circumstances change.”

Although this research was conducted on mouse HSCs, the researchers believe the mechanism may hold true for other types of cells as well.

“This research creates a lot of excitement in the field, as it sets the groundwork to study these regulatory elements in humans,” said Assaf Weiner, of the Hebrew University of Jerusalem.

Discovering the exact regulatory DNA sequence controlling the fate of hematopoietic stem cells, as well as understanding the mechanism, holds promise for the development of diagnostic tools and therapeutic interventions, the researchers noted.

Hematopoietic stem cells

in the bone marrow

A new epigenetic profiling technique has allowed researchers to chart histone dynamics during hematopoiesis, and it has produced some surprising results.

The researchers developed a high-sensitivity, indexing-first chromatin immunoprecipitation approach (iChIP) that requires as few as 500 cells for accurate analysis.

The techniques currently in use require millions of cells for accurate detection and analysis, but iCHIP overcomes this limitation.

David Lara-Astiaso, of the Weizmann Institute of Science in Rehovot, Israel, and his colleagues described the new method in Science.

The team used iCHIP to profile the dynamics of 4 chromatin modifications across 16 stages of hematopoietic differentiation.

“Using this powerful approach, we were able to identify the exact DNA regulatory sequences, as well as the various regulatory proteins, that are involved in controlling stem cell fate, casting light on previously unseen parts of the basic program of life,” said Nir Friedman, PhD, of the Hebrew University of Jerusalem in Israel.

The research also suggested that as many as 50% of these regulatory sequences are established and opened during intermediate stages of cell development. This means epigenetics are active at stages in which we thought cell destiny was already set.

“This changes our whole understanding of the process of blood stem cell fate decisions,” Lara-Astiaso said.

“[The discovery suggests] the process is more dynamic and flexible than previously thought, giving the cell slightly more leeway at the later stages in deciding what type of cell to turn into, in case its circumstances change.”

Although this research was conducted on mouse HSCs, the researchers believe the mechanism may hold true for other types of cells as well.

“This research creates a lot of excitement in the field, as it sets the groundwork to study these regulatory elements in humans,” said Assaf Weiner, of the Hebrew University of Jerusalem.

Discovering the exact regulatory DNA sequence controlling the fate of hematopoietic stem cells, as well as understanding the mechanism, holds promise for the development of diagnostic tools and therapeutic interventions, the researchers noted.

Catheter-directed thrombolysis plus anticoagulation is no more effective than anticoagulation alone in preventing in-hospital death among adults who have lower-extremity proximal deep vein thrombosis, according to a nationwide observational study reported online July 21 in JAMA Internal Medicine.

However, catheter-directed thrombolysis carries higher risks, particularly serious bleeding risks such as intracranial hemorrhage, than does anticoagulation alone, and it costs nearly three times as much money. These findings highlight the need for randomized trials "to evaluate the magnitude of the effect of catheter-directed thrombolysis on ... mortality, postthrombotic syndrome, and recurrence of DVT [deep vein thrombosis]. In the absence of such data, it may be reasonable to restrict this form of therapy to those patients who have a low bleeding risk and a high risk for postthrombotic syndrome, such as patients with iliofemoral DVT," said Dr. Riyaz Bashir of the division of cardiovascular diseases, Temple University, Philadelphia, and his associates.

© Sebastian Kaulitzki/Thinkstock

Conflicting data from several small studies as to the safety and effectiveness of catheter-directed thrombolysis have led professional societies to devise conflicting recommendations for its use: CHEST (the American College of Chest Physicians) advises against using the procedure, while the American Heart Association recommends it as a first-line therapy for certain patients. "We sought to assess real-world comparative-safety outcomes in patients with proximal and caval DVT who underwent catheter-directed thrombolysis plus anticoagulation with a group treated with anticoagulation alone using risk-adjusted propensity-score matching," the investigators said.

They analyzed data from an Agency for Healthcare Research and Quality administrative database of patient discharges from approximately 1,000 nonfederal acute-care hospitals per year for a 6-year period. They identified 90,618 patients with a discharge diagnosis of proximal DVT; propensity-score matching yielded 3,594 well-matched patients in each study group. In-hospital mortality was not significantly different between patients who had catheter-directed thrombolysis plus anticoagulation (1.2%) and those who had anticoagulation alone (0.9%), Dr. Bashir and his associates said (JAMA Intern. Med. 2014 July 21 [doi:10.1001/jamainternmed.2014.3415]).

However, rates of blood transfusion (11.1% vs. 6.5%), pulmonary embolism (17.9% vs 11.4%), and intracranial hemorrhage (0.9% vs 0.3%) were significantly higher with the invasive intervention. And patients in the catheter-directed thrombolysis group required significantly longer hospitalizations (7.2 vs. 5.0 days) and incurred significantly higher hospital expenses ($85,094 vs. $28,164). "It is imperative that the magnitude of benefit from catheter-directed therapy be substantial to justify the increased initial resource utilization and bleeding risks of this therapy," the investigators noted.

Catheter-directed thrombolysis plus anticoagulation is no more effective than anticoagulation alone in preventing in-hospital death among adults who have lower-extremity proximal deep vein thrombosis, according to a nationwide observational study reported online July 21 in JAMA Internal Medicine.

However, catheter-directed thrombolysis carries higher risks, particularly serious bleeding risks such as intracranial hemorrhage, than does anticoagulation alone, and it costs nearly three times as much money. These findings highlight the need for randomized trials "to evaluate the magnitude of the effect of catheter-directed thrombolysis on ... mortality, postthrombotic syndrome, and recurrence of DVT [deep vein thrombosis]. In the absence of such data, it may be reasonable to restrict this form of therapy to those patients who have a low bleeding risk and a high risk for postthrombotic syndrome, such as patients with iliofemoral DVT," said Dr. Riyaz Bashir of the division of cardiovascular diseases, Temple University, Philadelphia, and his associates.

© Sebastian Kaulitzki/Thinkstock

Conflicting data from several small studies as to the safety and effectiveness of catheter-directed thrombolysis have led professional societies to devise conflicting recommendations for its use: CHEST (the American College of Chest Physicians) advises against using the procedure, while the American Heart Association recommends it as a first-line therapy for certain patients. "We sought to assess real-world comparative-safety outcomes in patients with proximal and caval DVT who underwent catheter-directed thrombolysis plus anticoagulation with a group treated with anticoagulation alone using risk-adjusted propensity-score matching," the investigators said.

They analyzed data from an Agency for Healthcare Research and Quality administrative database of patient discharges from approximately 1,000 nonfederal acute-care hospitals per year for a 6-year period. They identified 90,618 patients with a discharge diagnosis of proximal DVT; propensity-score matching yielded 3,594 well-matched patients in each study group. In-hospital mortality was not significantly different between patients who had catheter-directed thrombolysis plus anticoagulation (1.2%) and those who had anticoagulation alone (0.9%), Dr. Bashir and his associates said (JAMA Intern. Med. 2014 July 21 [doi:10.1001/jamainternmed.2014.3415]).

However, rates of blood transfusion (11.1% vs. 6.5%), pulmonary embolism (17.9% vs 11.4%), and intracranial hemorrhage (0.9% vs 0.3%) were significantly higher with the invasive intervention. And patients in the catheter-directed thrombolysis group required significantly longer hospitalizations (7.2 vs. 5.0 days) and incurred significantly higher hospital expenses ($85,094 vs. $28,164). "It is imperative that the magnitude of benefit from catheter-directed therapy be substantial to justify the increased initial resource utilization and bleeding risks of this therapy," the investigators noted.

Catheter-directed thrombolysis plus anticoagulation is no more effective than anticoagulation alone in preventing in-hospital death among adults who have lower-extremity proximal deep vein thrombosis, according to a nationwide observational study reported online July 21 in JAMA Internal Medicine.

However, catheter-directed thrombolysis carries higher risks, particularly serious bleeding risks such as intracranial hemorrhage, than does anticoagulation alone, and it costs nearly three times as much money. These findings highlight the need for randomized trials "to evaluate the magnitude of the effect of catheter-directed thrombolysis on ... mortality, postthrombotic syndrome, and recurrence of DVT [deep vein thrombosis]. In the absence of such data, it may be reasonable to restrict this form of therapy to those patients who have a low bleeding risk and a high risk for postthrombotic syndrome, such as patients with iliofemoral DVT," said Dr. Riyaz Bashir of the division of cardiovascular diseases, Temple University, Philadelphia, and his associates.

© Sebastian Kaulitzki/Thinkstock

Conflicting data from several small studies as to the safety and effectiveness of catheter-directed thrombolysis have led professional societies to devise conflicting recommendations for its use: CHEST (the American College of Chest Physicians) advises against using the procedure, while the American Heart Association recommends it as a first-line therapy for certain patients. "We sought to assess real-world comparative-safety outcomes in patients with proximal and caval DVT who underwent catheter-directed thrombolysis plus anticoagulation with a group treated with anticoagulation alone using risk-adjusted propensity-score matching," the investigators said.

They analyzed data from an Agency for Healthcare Research and Quality administrative database of patient discharges from approximately 1,000 nonfederal acute-care hospitals per year for a 6-year period. They identified 90,618 patients with a discharge diagnosis of proximal DVT; propensity-score matching yielded 3,594 well-matched patients in each study group. In-hospital mortality was not significantly different between patients who had catheter-directed thrombolysis plus anticoagulation (1.2%) and those who had anticoagulation alone (0.9%), Dr. Bashir and his associates said (JAMA Intern. Med. 2014 July 21 [doi:10.1001/jamainternmed.2014.3415]).

However, rates of blood transfusion (11.1% vs. 6.5%), pulmonary embolism (17.9% vs 11.4%), and intracranial hemorrhage (0.9% vs 0.3%) were significantly higher with the invasive intervention. And patients in the catheter-directed thrombolysis group required significantly longer hospitalizations (7.2 vs. 5.0 days) and incurred significantly higher hospital expenses ($85,094 vs. $28,164). "It is imperative that the magnitude of benefit from catheter-directed therapy be substantial to justify the increased initial resource utilization and bleeding risks of this therapy," the investigators noted.

The news has been filled lately with stories of violence within correctional facilities, often involving prisoners or detainees who are alleged to have mental illness. The California prison system recently announced an initiative to reduce the use of force against mentally ill prisoners and to require correctional officers to consider an inmate’s mental health status prior to any use of force.

This is an excellent initiative, and close collaboration between security and mental health services is crucial for effective treatment of some mentally ill offenders.

However, this would be a good time to remember that not all seriously mentally ill prisoners are disruptive and that violence is a behavior rather than a diagnostic criterion. The nonsymptomatic causes of violence are important to consider as well: Is the inmate defending himself from attack by more aggressive peers? Is he taking a stand and making a display of force in order to make the point that he won’t be intimidated? Is he delirious from an unrecognized or treated medical condition? Is he having a seizure, suffering from withdrawal, or medically compromised in some other way? Or is the violence instrumental, a means to an end by a sociopathic inmate who needs to enforce his chain of command or protect his prison drug distribution channels? While for some, violence may be an outward sign of psychosis, for others it’s part of the cost of doing business.

In addition to looking at violence on an individual level, we also need to consider it from an institutional perspective. Violence may be a sign that there are serious problems not only on an individual level but possibly on an institutional one as well. Increased sensitivity to the mental status of the prisoner is only one piece of the puzzle.

Correctional officers are exposed to an environment unlike anything most civilians can imagine. They are exposed daily to threats, actual or implied assault, harassment, and sometimes even flying bodily fluids. When the prison budget doesn’t keep up with the daily institutional census, they may be required to work repeated overtime shifts or to work on tiers in which they are greatly outnumbered by the prisoners they are supposed to supervise and protect. Even when a correctional officer is not directly the subject of violence, the officer is required to respond to traumatic events like inmate-on-inmate assaults or completed suicides.

It’s not surprising, then, that many new officers leave the profession within the first 5 years, and that those who stay longer may be prone to stress-related absenteeism, substance abuse, and depression. Officers (or "guards" as the traditional media repeatedly misidentifies them) who show a change in personality or an unusually low tolerance for inmate misbehavior may be showing early signs of posttraumatic stress disorder or clinical depression. If this is being taken out on an inmate, it may also be a problem at home, leading to relationship problems or domestic violence. Officers who are cruel to a prisoner may not be particularly pleasant to civilian staff, either.

Changing a violent prison environment requires more than additional staff training and another redundant prison directive about the use of force. It requires change in a prison culture that values toughness and bravado. Access to mental health should be rapid and confidential, and not seen as an indication that an officer wants an "easy way out" through medical retirement. Security and psychiatry must work together for the care of the prisoner, but they also need to work on behalf of one another.

Dr. Hanson is a forensic psychiatrist and coauthor of "Shrink Rap: Three Psychiatrists Explain Their Work" (Baltimore: The Johns Hopkins University Press, 2011). The opinions expressed are those of the author only, and do not represent those of any of Dr. Hanson’s employers or consultees, including the Maryland Department of Health & Mental Hygiene or the Maryland State Division of Correction.

The news has been filled lately with stories of violence within correctional facilities, often involving prisoners or detainees who are alleged to have mental illness. The California prison system recently announced an initiative to reduce the use of force against mentally ill prisoners and to require correctional officers to consider an inmate’s mental health status prior to any use of force.

This is an excellent initiative, and close collaboration between security and mental health services is crucial for effective treatment of some mentally ill offenders.

However, this would be a good time to remember that not all seriously mentally ill prisoners are disruptive and that violence is a behavior rather than a diagnostic criterion. The nonsymptomatic causes of violence are important to consider as well: Is the inmate defending himself from attack by more aggressive peers? Is he taking a stand and making a display of force in order to make the point that he won’t be intimidated? Is he delirious from an unrecognized or treated medical condition? Is he having a seizure, suffering from withdrawal, or medically compromised in some other way? Or is the violence instrumental, a means to an end by a sociopathic inmate who needs to enforce his chain of command or protect his prison drug distribution channels? While for some, violence may be an outward sign of psychosis, for others it’s part of the cost of doing business.

In addition to looking at violence on an individual level, we also need to consider it from an institutional perspective. Violence may be a sign that there are serious problems not only on an individual level but possibly on an institutional one as well. Increased sensitivity to the mental status of the prisoner is only one piece of the puzzle.

Correctional officers are exposed to an environment unlike anything most civilians can imagine. They are exposed daily to threats, actual or implied assault, harassment, and sometimes even flying bodily fluids. When the prison budget doesn’t keep up with the daily institutional census, they may be required to work repeated overtime shifts or to work on tiers in which they are greatly outnumbered by the prisoners they are supposed to supervise and protect. Even when a correctional officer is not directly the subject of violence, the officer is required to respond to traumatic events like inmate-on-inmate assaults or completed suicides.

It’s not surprising, then, that many new officers leave the profession within the first 5 years, and that those who stay longer may be prone to stress-related absenteeism, substance abuse, and depression. Officers (or "guards" as the traditional media repeatedly misidentifies them) who show a change in personality or an unusually low tolerance for inmate misbehavior may be showing early signs of posttraumatic stress disorder or clinical depression. If this is being taken out on an inmate, it may also be a problem at home, leading to relationship problems or domestic violence. Officers who are cruel to a prisoner may not be particularly pleasant to civilian staff, either.

Changing a violent prison environment requires more than additional staff training and another redundant prison directive about the use of force. It requires change in a prison culture that values toughness and bravado. Access to mental health should be rapid and confidential, and not seen as an indication that an officer wants an "easy way out" through medical retirement. Security and psychiatry must work together for the care of the prisoner, but they also need to work on behalf of one another.

Dr. Hanson is a forensic psychiatrist and coauthor of "Shrink Rap: Three Psychiatrists Explain Their Work" (Baltimore: The Johns Hopkins University Press, 2011). The opinions expressed are those of the author only, and do not represent those of any of Dr. Hanson’s employers or consultees, including the Maryland Department of Health & Mental Hygiene or the Maryland State Division of Correction.

The news has been filled lately with stories of violence within correctional facilities, often involving prisoners or detainees who are alleged to have mental illness. The California prison system recently announced an initiative to reduce the use of force against mentally ill prisoners and to require correctional officers to consider an inmate’s mental health status prior to any use of force.

This is an excellent initiative, and close collaboration between security and mental health services is crucial for effective treatment of some mentally ill offenders.

However, this would be a good time to remember that not all seriously mentally ill prisoners are disruptive and that violence is a behavior rather than a diagnostic criterion. The nonsymptomatic causes of violence are important to consider as well: Is the inmate defending himself from attack by more aggressive peers? Is he taking a stand and making a display of force in order to make the point that he won’t be intimidated? Is he delirious from an unrecognized or treated medical condition? Is he having a seizure, suffering from withdrawal, or medically compromised in some other way? Or is the violence instrumental, a means to an end by a sociopathic inmate who needs to enforce his chain of command or protect his prison drug distribution channels? While for some, violence may be an outward sign of psychosis, for others it’s part of the cost of doing business.

In addition to looking at violence on an individual level, we also need to consider it from an institutional perspective. Violence may be a sign that there are serious problems not only on an individual level but possibly on an institutional one as well. Increased sensitivity to the mental status of the prisoner is only one piece of the puzzle.

Correctional officers are exposed to an environment unlike anything most civilians can imagine. They are exposed daily to threats, actual or implied assault, harassment, and sometimes even flying bodily fluids. When the prison budget doesn’t keep up with the daily institutional census, they may be required to work repeated overtime shifts or to work on tiers in which they are greatly outnumbered by the prisoners they are supposed to supervise and protect. Even when a correctional officer is not directly the subject of violence, the officer is required to respond to traumatic events like inmate-on-inmate assaults or completed suicides.

It’s not surprising, then, that many new officers leave the profession within the first 5 years, and that those who stay longer may be prone to stress-related absenteeism, substance abuse, and depression. Officers (or "guards" as the traditional media repeatedly misidentifies them) who show a change in personality or an unusually low tolerance for inmate misbehavior may be showing early signs of posttraumatic stress disorder or clinical depression. If this is being taken out on an inmate, it may also be a problem at home, leading to relationship problems or domestic violence. Officers who are cruel to a prisoner may not be particularly pleasant to civilian staff, either.

Changing a violent prison environment requires more than additional staff training and another redundant prison directive about the use of force. It requires change in a prison culture that values toughness and bravado. Access to mental health should be rapid and confidential, and not seen as an indication that an officer wants an "easy way out" through medical retirement. Security and psychiatry must work together for the care of the prisoner, but they also need to work on behalf of one another.

Dr. Hanson is a forensic psychiatrist and coauthor of "Shrink Rap: Three Psychiatrists Explain Their Work" (Baltimore: The Johns Hopkins University Press, 2011). The opinions expressed are those of the author only, and do not represent those of any of Dr. Hanson’s employers or consultees, including the Maryland Department of Health & Mental Hygiene or the Maryland State Division of Correction.

Jenny Cabas-Vargas, MD
Rheumatologist
Institute for Rheumatic and Autoimmune Diseases
Overlook Medical Center
Summit, New Jersey

Puja Chitkara, MD
Rheumatologist
Center for Arthritis and Rheumatologic Excellence (CARE)
San Diego, California

Stratos Christianakis, MD
Rheumatologist
Assistant Professor of Clinical Medicine
Keck School of Medicine of USC
Los Angeles, California

Chaim Putterman, MD
Professor of Medicine
(Rheumatology) and Microbiology & Immunology
Chief, Division of Rheumatology
Albert Einstein College of Medicine
Bronx, New York

Jenny Cabas-Vargas, MD
Rheumatologist
Institute for Rheumatic and Autoimmune Diseases
Overlook Medical Center
Summit, New Jersey

Puja Chitkara, MD
Rheumatologist
Center for Arthritis and Rheumatologic Excellence (CARE)
San Diego, California

Stratos Christianakis, MD
Rheumatologist
Assistant Professor of Clinical Medicine
Keck School of Medicine of USC
Los Angeles, California

Chaim Putterman, MD
Professor of Medicine
(Rheumatology) and Microbiology & Immunology
Chief, Division of Rheumatology
Albert Einstein College of Medicine
Bronx, New York

Jenny Cabas-Vargas, MD
Rheumatologist
Institute for Rheumatic and Autoimmune Diseases
Overlook Medical Center
Summit, New Jersey

Puja Chitkara, MD
Rheumatologist
Center for Arthritis and Rheumatologic Excellence (CARE)
San Diego, California

Stratos Christianakis, MD
Rheumatologist
Assistant Professor of Clinical Medicine
Keck School of Medicine of USC
Los Angeles, California

Chaim Putterman, MD
Professor of Medicine
(Rheumatology) and Microbiology & Immunology
Chief, Division of Rheumatology
Albert Einstein College of Medicine
Bronx, New York