AML

Lab mouse

New research suggests the FOXM1 protein plays an important role in acute myeloid leukemia (AML) progression, and targeting FOXM1 could improve AML treatment.

With a retrospective study, researchers showed that overexpression of FOXM1 was associated with increased resistance to chemotherapy and inferior overall survival.

Subsequent preclinical research showed that ixazomib inhibits FOXM1, exhibits antileukemic activity, and sensitizes AML cells to chemotherapy.

Irum Khan, MD, of the University of Illinois in Chicago, and her colleagues reported these findings in JCI Insight.

Previous research showed that AML patients with NPM1 mutations have a higher rate of remission with chemotherapy, and the NPM1 protein affects the location and activity of FOXM1. NPM1 keeps FOXM1 in the nucleus where it can activate other cancer-promoting genes.

When the NPM1 gene is mutated, FOXM1 migrates out of the nucleus and into the cell’s cytoplasm, where it can’t interact with DNA. This may explain why AML patients with NPM1 mutations have a better response to chemotherapy and are less likely to relapse.

With the current research, Dr Khan and her colleagues further explored the role of FOXM1 in AML.

Retrospective analysis

The multicenter, retrospective study began with data from 111 adults with AML. They had intermediate-risk cytogenetics and a median age of 61.

Eighty-eight patients received induction with cytarabine and an anthracycline, and 80 achieved a complete remission with or without count recovery.

FOXM1 expression data were available for 74 of these patients. Fifty patients achieved remission with 1 cycle of induction, and 24 required more than 1 cycle.

“[Patients] with FOXM1 present in the nucleus of their cancer cells had worse treatment outcomes, higher rates of chemotherapy resistance, and lower survival rates compared to patients without FOXM1 present in the nucleus,” Dr Khan said.

The patients who failed their first line of induction had a more than 2-fold increase in the percentage of nuclei expressing FOXM1 in their bone marrow (P=0.004). And the average nuclear intensity of FOXM1 was significantly higher in the patients who failed their first line of induction (P=0.02).

The percentage of FOXM1-positive nuclei and the average nuclear intensity of FOXM1 both significantly predicted resistance to first-line chemotherapy. The odds ratio was 1.80 for a 10% increase in FOXM1-positive nuclei (P=0.005) and 2.5 for a 0.1 unit increase in nuclear intensity (P=0.02).

A multivariate analysis showed that the FOXM1 nuclear/cytoplasmic (N:C) ratio and nuclear FOXM1 intensity predicted inferior overall survival in a single institution. (Institutions were analyzed separately for survival). The hazard ratio was 4.7 for every 0.1 unit increase in N:C ratio (P=0.03) and 4.27 for every 0.1 unit increase in nuclear intensity (P=0.06).

Confirming the role of FOXM1

The researchers set out to confirm the role of FOXM1 via experiments in mice.

The team induced a FLT3-ITD-driven myeloproliferative neoplasm in a FOXM1-overexpressing transgenic mouse model.

These mice had more residual disease after treatment with cytarabine than control mice with normal levels of FOXM1.

“Our finding suggests that overexpression of FOXM1 directly induces chemoresistance, which matches what we saw in our analysis of patients’ FOXM1 levels and their treatment outcomes,” Dr Khan said.

Targeting FOXM1 with ixazomib

Next, the researchers showed they could produce a therapeutic response by inhibiting FOXM1 in AML. The team used ixazomib, which was shown to suppress FOXM1.

There was a 2-fold increase in apoptosis when AML patient cells were treated with ixazomib (compared to DMSO).

Ixazomib also exhibited antitumor activity in a xenograft model of AML (HL-60 cells) and reduced leukemic burden in an orthotopic model of AML (KG-1 cells).

Finally, the researchers found that ixazomib sensitized AML cells to chemotherapy. The team observed synergistic activity between ixazomib and cytarabine or 5-azacitidine.

“There is a real unmet need for new ways to get around the resistance to chemotherapy that patients who don’t have this beneficial [NPM1] mutation often face,” Dr Khan said.

“Drugs that suppress FOXM1 in combination with the standard treatment, such as ixazomib, should result in better outcomes, but clinical trials will ultimately be needed to prove this theory.”

This research was supported by grants from the National Institutes of Health and Takeda.

Lab mouse

New research suggests the FOXM1 protein plays an important role in acute myeloid leukemia (AML) progression, and targeting FOXM1 could improve AML treatment.

With a retrospective study, researchers showed that overexpression of FOXM1 was associated with increased resistance to chemotherapy and inferior overall survival.

Subsequent preclinical research showed that ixazomib inhibits FOXM1, exhibits antileukemic activity, and sensitizes AML cells to chemotherapy.

Irum Khan, MD, of the University of Illinois in Chicago, and her colleagues reported these findings in JCI Insight.

Previous research showed that AML patients with NPM1 mutations have a higher rate of remission with chemotherapy, and the NPM1 protein affects the location and activity of FOXM1. NPM1 keeps FOXM1 in the nucleus where it can activate other cancer-promoting genes.

When the NPM1 gene is mutated, FOXM1 migrates out of the nucleus and into the cell’s cytoplasm, where it can’t interact with DNA. This may explain why AML patients with NPM1 mutations have a better response to chemotherapy and are less likely to relapse.

With the current research, Dr Khan and her colleagues further explored the role of FOXM1 in AML.

Retrospective analysis

The multicenter, retrospective study began with data from 111 adults with AML. They had intermediate-risk cytogenetics and a median age of 61.

Eighty-eight patients received induction with cytarabine and an anthracycline, and 80 achieved a complete remission with or without count recovery.

FOXM1 expression data were available for 74 of these patients. Fifty patients achieved remission with 1 cycle of induction, and 24 required more than 1 cycle.

“[Patients] with FOXM1 present in the nucleus of their cancer cells had worse treatment outcomes, higher rates of chemotherapy resistance, and lower survival rates compared to patients without FOXM1 present in the nucleus,” Dr Khan said.

The patients who failed their first line of induction had a more than 2-fold increase in the percentage of nuclei expressing FOXM1 in their bone marrow (P=0.004). And the average nuclear intensity of FOXM1 was significantly higher in the patients who failed their first line of induction (P=0.02).

The percentage of FOXM1-positive nuclei and the average nuclear intensity of FOXM1 both significantly predicted resistance to first-line chemotherapy. The odds ratio was 1.80 for a 10% increase in FOXM1-positive nuclei (P=0.005) and 2.5 for a 0.1 unit increase in nuclear intensity (P=0.02).

A multivariate analysis showed that the FOXM1 nuclear/cytoplasmic (N:C) ratio and nuclear FOXM1 intensity predicted inferior overall survival in a single institution. (Institutions were analyzed separately for survival). The hazard ratio was 4.7 for every 0.1 unit increase in N:C ratio (P=0.03) and 4.27 for every 0.1 unit increase in nuclear intensity (P=0.06).

Confirming the role of FOXM1

The researchers set out to confirm the role of FOXM1 via experiments in mice.

The team induced a FLT3-ITD-driven myeloproliferative neoplasm in a FOXM1-overexpressing transgenic mouse model.

These mice had more residual disease after treatment with cytarabine than control mice with normal levels of FOXM1.

“Our finding suggests that overexpression of FOXM1 directly induces chemoresistance, which matches what we saw in our analysis of patients’ FOXM1 levels and their treatment outcomes,” Dr Khan said.

Targeting FOXM1 with ixazomib

Next, the researchers showed they could produce a therapeutic response by inhibiting FOXM1 in AML. The team used ixazomib, which was shown to suppress FOXM1.

There was a 2-fold increase in apoptosis when AML patient cells were treated with ixazomib (compared to DMSO).

Ixazomib also exhibited antitumor activity in a xenograft model of AML (HL-60 cells) and reduced leukemic burden in an orthotopic model of AML (KG-1 cells).

Finally, the researchers found that ixazomib sensitized AML cells to chemotherapy. The team observed synergistic activity between ixazomib and cytarabine or 5-azacitidine.

“There is a real unmet need for new ways to get around the resistance to chemotherapy that patients who don’t have this beneficial [NPM1] mutation often face,” Dr Khan said.

“Drugs that suppress FOXM1 in combination with the standard treatment, such as ixazomib, should result in better outcomes, but clinical trials will ultimately be needed to prove this theory.”

This research was supported by grants from the National Institutes of Health and Takeda.

Lab mouse

New research suggests the FOXM1 protein plays an important role in acute myeloid leukemia (AML) progression, and targeting FOXM1 could improve AML treatment.

With a retrospective study, researchers showed that overexpression of FOXM1 was associated with increased resistance to chemotherapy and inferior overall survival.

Subsequent preclinical research showed that ixazomib inhibits FOXM1, exhibits antileukemic activity, and sensitizes AML cells to chemotherapy.

Irum Khan, MD, of the University of Illinois in Chicago, and her colleagues reported these findings in JCI Insight.

Previous research showed that AML patients with NPM1 mutations have a higher rate of remission with chemotherapy, and the NPM1 protein affects the location and activity of FOXM1. NPM1 keeps FOXM1 in the nucleus where it can activate other cancer-promoting genes.

When the NPM1 gene is mutated, FOXM1 migrates out of the nucleus and into the cell’s cytoplasm, where it can’t interact with DNA. This may explain why AML patients with NPM1 mutations have a better response to chemotherapy and are less likely to relapse.

With the current research, Dr Khan and her colleagues further explored the role of FOXM1 in AML.

Retrospective analysis

The multicenter, retrospective study began with data from 111 adults with AML. They had intermediate-risk cytogenetics and a median age of 61.

Eighty-eight patients received induction with cytarabine and an anthracycline, and 80 achieved a complete remission with or without count recovery.

FOXM1 expression data were available for 74 of these patients. Fifty patients achieved remission with 1 cycle of induction, and 24 required more than 1 cycle.

“[Patients] with FOXM1 present in the nucleus of their cancer cells had worse treatment outcomes, higher rates of chemotherapy resistance, and lower survival rates compared to patients without FOXM1 present in the nucleus,” Dr Khan said.

The patients who failed their first line of induction had a more than 2-fold increase in the percentage of nuclei expressing FOXM1 in their bone marrow (P=0.004). And the average nuclear intensity of FOXM1 was significantly higher in the patients who failed their first line of induction (P=0.02).

The percentage of FOXM1-positive nuclei and the average nuclear intensity of FOXM1 both significantly predicted resistance to first-line chemotherapy. The odds ratio was 1.80 for a 10% increase in FOXM1-positive nuclei (P=0.005) and 2.5 for a 0.1 unit increase in nuclear intensity (P=0.02).

A multivariate analysis showed that the FOXM1 nuclear/cytoplasmic (N:C) ratio and nuclear FOXM1 intensity predicted inferior overall survival in a single institution. (Institutions were analyzed separately for survival). The hazard ratio was 4.7 for every 0.1 unit increase in N:C ratio (P=0.03) and 4.27 for every 0.1 unit increase in nuclear intensity (P=0.06).

Confirming the role of FOXM1

The researchers set out to confirm the role of FOXM1 via experiments in mice.

The team induced a FLT3-ITD-driven myeloproliferative neoplasm in a FOXM1-overexpressing transgenic mouse model.

These mice had more residual disease after treatment with cytarabine than control mice with normal levels of FOXM1.

“Our finding suggests that overexpression of FOXM1 directly induces chemoresistance, which matches what we saw in our analysis of patients’ FOXM1 levels and their treatment outcomes,” Dr Khan said.

Targeting FOXM1 with ixazomib

Next, the researchers showed they could produce a therapeutic response by inhibiting FOXM1 in AML. The team used ixazomib, which was shown to suppress FOXM1.

There was a 2-fold increase in apoptosis when AML patient cells were treated with ixazomib (compared to DMSO).

Ixazomib also exhibited antitumor activity in a xenograft model of AML (HL-60 cells) and reduced leukemic burden in an orthotopic model of AML (KG-1 cells).

Finally, the researchers found that ixazomib sensitized AML cells to chemotherapy. The team observed synergistic activity between ixazomib and cytarabine or 5-azacitidine.

“There is a real unmet need for new ways to get around the resistance to chemotherapy that patients who don’t have this beneficial [NPM1] mutation often face,” Dr Khan said.

“Drugs that suppress FOXM1 in combination with the standard treatment, such as ixazomib, should result in better outcomes, but clinical trials will ultimately be needed to prove this theory.”

This research was supported by grants from the National Institutes of Health and Takeda.

Image by Lance Liotta

The European Medicines Agency’s Committee for Orphan Medicinal Products (COMP) has recommended that PCM-075 receive orphan drug designation as a treatment for acute myeloid leukemia (AML).

PCM-075 is an oral adenosine triphosphate competitive inhibitor of the serine/threonine Polo-like kinase 1 (PLK1) enzyme, which is overexpressed in hematologic and solid tumor malignancies.

The COMP’s recommendation for PCM-075 is expected to be adopted by the European Commission at the end of this month.

Orphan drug designation in Europe is available to companies developing products intended to treat a life-threatening or chronically debilitating condition that affects fewer than 5 in 10,000 people in the European Union (EU).

The designation allows for financial and regulatory incentives that include 10 years of marketing exclusivity in the EU after product approval, eligibility for conditional marketing authorization, protocol assistance from the European Medicines Agency at reduced fees during the product development phase, and direct access to centralized marketing authorization in the EU.

PCM-075 research

PCM-075 only targets the PLK1 isoform (not PLK2 or PLK3) and has a 24-hour drug half-life with reversible, on-target hematologic toxicities, according to Trovagene, Inc., the company developing PCM-075.

Trovagene believes that PCM-075’s reversible, on-target activity, combined with an improved dose/scheduling protocol, could mean that PCM-075 will improve upon long-term outcomes observed in previous studies with a PLK inhibitor in AML.

This includes a phase 2 study in which AML patients who received a PLK inhibitor plus low-dose cytarabine (LDAC) had a higher response rate than patients who received LDAC alone—31% and 13.3%, respectively.

Trovagene said preclinical studies have shown that PCM-075 synergizes with more than 10 drugs used to treat hematologic and solid tumor malignancies. This includes FLT3 and HDAC inhibitors, taxanes, and cytotoxins.

Trovagene is now conducting a phase 1b/2 trial of PCM-075 in combination with standard care (LDAC or decitabine) in patients with AML (NCT03303339).

The company has already completed a phase 1 dose-escalation study of PCM-075 in patients with advanced metastatic solid tumor malignancies. Results from this study were published in Investigational New Drugs.

Image by Lance Liotta

The European Medicines Agency’s Committee for Orphan Medicinal Products (COMP) has recommended that PCM-075 receive orphan drug designation as a treatment for acute myeloid leukemia (AML).

PCM-075 is an oral adenosine triphosphate competitive inhibitor of the serine/threonine Polo-like kinase 1 (PLK1) enzyme, which is overexpressed in hematologic and solid tumor malignancies.

The COMP’s recommendation for PCM-075 is expected to be adopted by the European Commission at the end of this month.

Orphan drug designation in Europe is available to companies developing products intended to treat a life-threatening or chronically debilitating condition that affects fewer than 5 in 10,000 people in the European Union (EU).

The designation allows for financial and regulatory incentives that include 10 years of marketing exclusivity in the EU after product approval, eligibility for conditional marketing authorization, protocol assistance from the European Medicines Agency at reduced fees during the product development phase, and direct access to centralized marketing authorization in the EU.

PCM-075 research

PCM-075 only targets the PLK1 isoform (not PLK2 or PLK3) and has a 24-hour drug half-life with reversible, on-target hematologic toxicities, according to Trovagene, Inc., the company developing PCM-075.

Trovagene believes that PCM-075’s reversible, on-target activity, combined with an improved dose/scheduling protocol, could mean that PCM-075 will improve upon long-term outcomes observed in previous studies with a PLK inhibitor in AML.

This includes a phase 2 study in which AML patients who received a PLK inhibitor plus low-dose cytarabine (LDAC) had a higher response rate than patients who received LDAC alone—31% and 13.3%, respectively.

Trovagene said preclinical studies have shown that PCM-075 synergizes with more than 10 drugs used to treat hematologic and solid tumor malignancies. This includes FLT3 and HDAC inhibitors, taxanes, and cytotoxins.

Trovagene is now conducting a phase 1b/2 trial of PCM-075 in combination with standard care (LDAC or decitabine) in patients with AML (NCT03303339).

The company has already completed a phase 1 dose-escalation study of PCM-075 in patients with advanced metastatic solid tumor malignancies. Results from this study were published in Investigational New Drugs.

Image by Lance Liotta

The European Medicines Agency’s Committee for Orphan Medicinal Products (COMP) has recommended that PCM-075 receive orphan drug designation as a treatment for acute myeloid leukemia (AML).

PCM-075 is an oral adenosine triphosphate competitive inhibitor of the serine/threonine Polo-like kinase 1 (PLK1) enzyme, which is overexpressed in hematologic and solid tumor malignancies.

The COMP’s recommendation for PCM-075 is expected to be adopted by the European Commission at the end of this month.

Orphan drug designation in Europe is available to companies developing products intended to treat a life-threatening or chronically debilitating condition that affects fewer than 5 in 10,000 people in the European Union (EU).

The designation allows for financial and regulatory incentives that include 10 years of marketing exclusivity in the EU after product approval, eligibility for conditional marketing authorization, protocol assistance from the European Medicines Agency at reduced fees during the product development phase, and direct access to centralized marketing authorization in the EU.

PCM-075 research

PCM-075 only targets the PLK1 isoform (not PLK2 or PLK3) and has a 24-hour drug half-life with reversible, on-target hematologic toxicities, according to Trovagene, Inc., the company developing PCM-075.

Trovagene believes that PCM-075’s reversible, on-target activity, combined with an improved dose/scheduling protocol, could mean that PCM-075 will improve upon long-term outcomes observed in previous studies with a PLK inhibitor in AML.

This includes a phase 2 study in which AML patients who received a PLK inhibitor plus low-dose cytarabine (LDAC) had a higher response rate than patients who received LDAC alone—31% and 13.3%, respectively.

Trovagene said preclinical studies have shown that PCM-075 synergizes with more than 10 drugs used to treat hematologic and solid tumor malignancies. This includes FLT3 and HDAC inhibitors, taxanes, and cytotoxins.

Trovagene is now conducting a phase 1b/2 trial of PCM-075 in combination with standard care (LDAC or decitabine) in patients with AML (NCT03303339).

The company has already completed a phase 1 dose-escalation study of PCM-075 in patients with advanced metastatic solid tumor malignancies. Results from this study were published in Investigational New Drugs.

Image by Robert Paulson

Disrupting mitophagy may be a “promising strategy” for eliminating leukemia stem cells (LSCs) in acute myeloid leukemia (AML), according to researchers.

The team found that AML LSCs depend on mitophagy to maintain their “stemness,” but targeting the central metabolic stress regulator AMPK or the mitochondrial dynamics regulator FIS1 can disrupt mitophagy and impair LSC function.

Craig T. Jordan, PhD, of the University of Colorado in Aurora, and his colleagues reported these findings in Cell Stem Cell.

The researchers said in vitro experiments showed that LSCs have elevated levels of FIS1 and “distinct mitochondrial morphology.”

When the team inhibited FIS1 in the AML cell line MOLM-13 and primary AML cells, they observed disruption of mitochondrial dynamics. Experiments in mouse models indicated that FIS1 is required for LSC self-renewal.

Specifically, the researchers said they found that depletion of FIS1 hinders mitophagy and leads to inactivation of GSK3, myeloid differentiation, cell-cycle arrest, and loss of LSC function.

Dr Jordan and his colleagues also found that AMPK is an upstream regulator of FIS1, and targeting AMPK produces similar effects as targeting FIS1—namely, disrupting mitophagy and impairing LSC self-renewal.

The researchers said their findings suggest that mitochondrial stress generated from oncogenic transformation may activate AMPK signaling in LSCs. And the AMPK signaling drives FIS1-mediated mitophagy, which eliminates stressed mitochondria and allows LSCs to thrive.

However, when AMPK or FIS1 is inhibited, the damaged mitochondria are not eliminated. This leads to “GSK3 inhibition and other unknown events” that prompt differentiation and hinder LSC function.

“Leukemia stem cells require AMPK for their survival, but normal hematopoietic cells can do without it,” Dr Jordan noted. “The reason this study is so important is that, so far, nobody’s come up with a good way to kill leukemia stem cells while sparing normal blood-forming cells. If we can translate this concept to patients, the potential for improved therapy is very exciting.”

Image by Robert Paulson

Disrupting mitophagy may be a “promising strategy” for eliminating leukemia stem cells (LSCs) in acute myeloid leukemia (AML), according to researchers.

The team found that AML LSCs depend on mitophagy to maintain their “stemness,” but targeting the central metabolic stress regulator AMPK or the mitochondrial dynamics regulator FIS1 can disrupt mitophagy and impair LSC function.

Craig T. Jordan, PhD, of the University of Colorado in Aurora, and his colleagues reported these findings in Cell Stem Cell.

The researchers said in vitro experiments showed that LSCs have elevated levels of FIS1 and “distinct mitochondrial morphology.”

When the team inhibited FIS1 in the AML cell line MOLM-13 and primary AML cells, they observed disruption of mitochondrial dynamics. Experiments in mouse models indicated that FIS1 is required for LSC self-renewal.

Specifically, the researchers said they found that depletion of FIS1 hinders mitophagy and leads to inactivation of GSK3, myeloid differentiation, cell-cycle arrest, and loss of LSC function.

Dr Jordan and his colleagues also found that AMPK is an upstream regulator of FIS1, and targeting AMPK produces similar effects as targeting FIS1—namely, disrupting mitophagy and impairing LSC self-renewal.

The researchers said their findings suggest that mitochondrial stress generated from oncogenic transformation may activate AMPK signaling in LSCs. And the AMPK signaling drives FIS1-mediated mitophagy, which eliminates stressed mitochondria and allows LSCs to thrive.

However, when AMPK or FIS1 is inhibited, the damaged mitochondria are not eliminated. This leads to “GSK3 inhibition and other unknown events” that prompt differentiation and hinder LSC function.

“Leukemia stem cells require AMPK for their survival, but normal hematopoietic cells can do without it,” Dr Jordan noted. “The reason this study is so important is that, so far, nobody’s come up with a good way to kill leukemia stem cells while sparing normal blood-forming cells. If we can translate this concept to patients, the potential for improved therapy is very exciting.”

Image by Robert Paulson

Disrupting mitophagy may be a “promising strategy” for eliminating leukemia stem cells (LSCs) in acute myeloid leukemia (AML), according to researchers.

The team found that AML LSCs depend on mitophagy to maintain their “stemness,” but targeting the central metabolic stress regulator AMPK or the mitochondrial dynamics regulator FIS1 can disrupt mitophagy and impair LSC function.

Craig T. Jordan, PhD, of the University of Colorado in Aurora, and his colleagues reported these findings in Cell Stem Cell.

The researchers said in vitro experiments showed that LSCs have elevated levels of FIS1 and “distinct mitochondrial morphology.”

When the team inhibited FIS1 in the AML cell line MOLM-13 and primary AML cells, they observed disruption of mitochondrial dynamics. Experiments in mouse models indicated that FIS1 is required for LSC self-renewal.

Specifically, the researchers said they found that depletion of FIS1 hinders mitophagy and leads to inactivation of GSK3, myeloid differentiation, cell-cycle arrest, and loss of LSC function.

Dr Jordan and his colleagues also found that AMPK is an upstream regulator of FIS1, and targeting AMPK produces similar effects as targeting FIS1—namely, disrupting mitophagy and impairing LSC self-renewal.

The researchers said their findings suggest that mitochondrial stress generated from oncogenic transformation may activate AMPK signaling in LSCs. And the AMPK signaling drives FIS1-mediated mitophagy, which eliminates stressed mitochondria and allows LSCs to thrive.

However, when AMPK or FIS1 is inhibited, the damaged mitochondria are not eliminated. This leads to “GSK3 inhibition and other unknown events” that prompt differentiation and hinder LSC function.

“Leukemia stem cells require AMPK for their survival, but normal hematopoietic cells can do without it,” Dr Jordan noted. “The reason this study is so important is that, so far, nobody’s come up with a good way to kill leukemia stem cells while sparing normal blood-forming cells. If we can translate this concept to patients, the potential for improved therapy is very exciting.”

For elderly patients with CD33-positive acute myeloid leukemia (AML), vadastuximab talirine in combination with a hypomethylating agent (HMA) improves remission rates, compared with HMA therapy alone, according to a phase 1 trial.

BluePlanetEarth/thinkstockphotos.com

More than half of the patients treated with combination therapy achieved deep remission, defined as a negative-flow cytometry test for minimal residual disease. Despite these promising results, hematologic toxicity concerns may limit future trials.

“Outcomes for patients with acute myeloid leukemia (AML) remain poor, particularly in older patients,” wrote Amir T. Fathi, MD, of the division of hematology and oncology at Massachusetts General Hospital Cancer Center, Boston, and his coauthors.

Many elderly patients currently receive hypomethylating agents HMAs as a form of low-intensity therapy, but associated remission rates are low. “The development of novel, well-tolerated therapies to enhance the efficacy of HMAs could meaningfully improve the standard of care for older patients with AML,” the investigators wrote in Blood. Vadastuximab talirine is a novel antibody therapy that targets CD33; preclinical data suggested that it could be an effective combination with HMA therapy.

The phase 1 trial involved 53 patients with newly diagnosed, CD33-positive AML and a median age of 75 years. Patients were naive to HMA therapy but could have previously received other low-intensity treatments. HMA therapy was administered first; either azacitidine (75 mg/m² subcutaneous IV for 7 days) or decitabine (20 mg/m² IV for 5 days), according to institutional standards. On the last day of HMA therapy, vadastuximab talirine (10 mcg/kg IV) was given. This protocol was repeated in 28-day cycles for up to four cycles. Patients who tolerated the combination and showed a clinical response were eligible to continue therapy.

The composite remission rate (CRc: complete remission and complete remission with incomplete blood count recovery) with combination therapy was 70%. Historically, HMA monotherapies have much lower composite remission rates (decitabine, 17.8%; azacytidine, 27.8%). Of all patients achieving remission, 51% tested negative by flow cytometry for minimal residual disease. Median overall survival was 11.3 months and median relapse-free survival was 7.7 months.

“Nevertheless, the increased response rate with the addition of vadastuximab talirine to HMAs was also associated with increased toxicity when compared to single-agent HMA therapy – indicative of the greater degree of myelosuppression,” the researchers wrote. The most common grade 3 or higher adverse events were thrombocytopenia (57%), febrile neutropenia (49%), anemia (45%), neutropenia (42%), and fatigue (15%).

The investigators stated that “the overall safety profile was similar for patients treated with vadastuximab talirine in combination with azacitidine versus decitabine (with the exception of incidence of febrile neutropenia).”

Following the encouraging results of this phase 1 trial, the CASCADE phase 3 trial was launched to again compare this combination with HMA monotherapy; however, the trial was halted early because of deaths in the combination arm. The investigators cited the need for stricter protocols to ensure safety during future trials.

“With such guidance and precaution, promising combinations for AML, a disease affecting predominantly older and more frail patients, may be more effectively studied so as to enhance our current suboptimal therapeutic options,” they wrote.

Seattle Genetics provided study funding and author compensation.

SOURCE: Fathi AT et al. Blood. 2018 Jul 25. doi: 10.1182/blood-2018-03-841171.

For elderly patients with CD33-positive acute myeloid leukemia (AML), vadastuximab talirine in combination with a hypomethylating agent (HMA) improves remission rates, compared with HMA therapy alone, according to a phase 1 trial.

BluePlanetEarth/thinkstockphotos.com

More than half of the patients treated with combination therapy achieved deep remission, defined as a negative-flow cytometry test for minimal residual disease. Despite these promising results, hematologic toxicity concerns may limit future trials.

“Outcomes for patients with acute myeloid leukemia (AML) remain poor, particularly in older patients,” wrote Amir T. Fathi, MD, of the division of hematology and oncology at Massachusetts General Hospital Cancer Center, Boston, and his coauthors.

Many elderly patients currently receive hypomethylating agents HMAs as a form of low-intensity therapy, but associated remission rates are low. “The development of novel, well-tolerated therapies to enhance the efficacy of HMAs could meaningfully improve the standard of care for older patients with AML,” the investigators wrote in Blood. Vadastuximab talirine is a novel antibody therapy that targets CD33; preclinical data suggested that it could be an effective combination with HMA therapy.

The phase 1 trial involved 53 patients with newly diagnosed, CD33-positive AML and a median age of 75 years. Patients were naive to HMA therapy but could have previously received other low-intensity treatments. HMA therapy was administered first; either azacitidine (75 mg/m² subcutaneous IV for 7 days) or decitabine (20 mg/m² IV for 5 days), according to institutional standards. On the last day of HMA therapy, vadastuximab talirine (10 mcg/kg IV) was given. This protocol was repeated in 28-day cycles for up to four cycles. Patients who tolerated the combination and showed a clinical response were eligible to continue therapy.

The composite remission rate (CRc: complete remission and complete remission with incomplete blood count recovery) with combination therapy was 70%. Historically, HMA monotherapies have much lower composite remission rates (decitabine, 17.8%; azacytidine, 27.8%). Of all patients achieving remission, 51% tested negative by flow cytometry for minimal residual disease. Median overall survival was 11.3 months and median relapse-free survival was 7.7 months.

“Nevertheless, the increased response rate with the addition of vadastuximab talirine to HMAs was also associated with increased toxicity when compared to single-agent HMA therapy – indicative of the greater degree of myelosuppression,” the researchers wrote. The most common grade 3 or higher adverse events were thrombocytopenia (57%), febrile neutropenia (49%), anemia (45%), neutropenia (42%), and fatigue (15%).

The investigators stated that “the overall safety profile was similar for patients treated with vadastuximab talirine in combination with azacitidine versus decitabine (with the exception of incidence of febrile neutropenia).”

Following the encouraging results of this phase 1 trial, the CASCADE phase 3 trial was launched to again compare this combination with HMA monotherapy; however, the trial was halted early because of deaths in the combination arm. The investigators cited the need for stricter protocols to ensure safety during future trials.

“With such guidance and precaution, promising combinations for AML, a disease affecting predominantly older and more frail patients, may be more effectively studied so as to enhance our current suboptimal therapeutic options,” they wrote.

Seattle Genetics provided study funding and author compensation.

SOURCE: Fathi AT et al. Blood. 2018 Jul 25. doi: 10.1182/blood-2018-03-841171.

For elderly patients with CD33-positive acute myeloid leukemia (AML), vadastuximab talirine in combination with a hypomethylating agent (HMA) improves remission rates, compared with HMA therapy alone, according to a phase 1 trial.

BluePlanetEarth/thinkstockphotos.com

More than half of the patients treated with combination therapy achieved deep remission, defined as a negative-flow cytometry test for minimal residual disease. Despite these promising results, hematologic toxicity concerns may limit future trials.

“Outcomes for patients with acute myeloid leukemia (AML) remain poor, particularly in older patients,” wrote Amir T. Fathi, MD, of the division of hematology and oncology at Massachusetts General Hospital Cancer Center, Boston, and his coauthors.

Many elderly patients currently receive hypomethylating agents HMAs as a form of low-intensity therapy, but associated remission rates are low. “The development of novel, well-tolerated therapies to enhance the efficacy of HMAs could meaningfully improve the standard of care for older patients with AML,” the investigators wrote in Blood. Vadastuximab talirine is a novel antibody therapy that targets CD33; preclinical data suggested that it could be an effective combination with HMA therapy.

The phase 1 trial involved 53 patients with newly diagnosed, CD33-positive AML and a median age of 75 years. Patients were naive to HMA therapy but could have previously received other low-intensity treatments. HMA therapy was administered first; either azacitidine (75 mg/m² subcutaneous IV for 7 days) or decitabine (20 mg/m² IV for 5 days), according to institutional standards. On the last day of HMA therapy, vadastuximab talirine (10 mcg/kg IV) was given. This protocol was repeated in 28-day cycles for up to four cycles. Patients who tolerated the combination and showed a clinical response were eligible to continue therapy.

The composite remission rate (CRc: complete remission and complete remission with incomplete blood count recovery) with combination therapy was 70%. Historically, HMA monotherapies have much lower composite remission rates (decitabine, 17.8%; azacytidine, 27.8%). Of all patients achieving remission, 51% tested negative by flow cytometry for minimal residual disease. Median overall survival was 11.3 months and median relapse-free survival was 7.7 months.

“Nevertheless, the increased response rate with the addition of vadastuximab talirine to HMAs was also associated with increased toxicity when compared to single-agent HMA therapy – indicative of the greater degree of myelosuppression,” the researchers wrote. The most common grade 3 or higher adverse events were thrombocytopenia (57%), febrile neutropenia (49%), anemia (45%), neutropenia (42%), and fatigue (15%).

The investigators stated that “the overall safety profile was similar for patients treated with vadastuximab talirine in combination with azacitidine versus decitabine (with the exception of incidence of febrile neutropenia).”

Following the encouraging results of this phase 1 trial, the CASCADE phase 3 trial was launched to again compare this combination with HMA monotherapy; however, the trial was halted early because of deaths in the combination arm. The investigators cited the need for stricter protocols to ensure safety during future trials.

“With such guidance and precaution, promising combinations for AML, a disease affecting predominantly older and more frail patients, may be more effectively studied so as to enhance our current suboptimal therapeutic options,” they wrote.

Seattle Genetics provided study funding and author compensation.

SOURCE: Fathi AT et al. Blood. 2018 Jul 25. doi: 10.1182/blood-2018-03-841171.

AML cells

The US Food and Drug Administration (FDA) has granted breakthrough therapy designation to quizartinib, an investigational FLT3 inhibitor, for the treatment of adults with relapsed/refractory FLT3-ITD acute myeloid leukemia (AML).

The FDA granted quizartinib breakthrough designation based on results from the phase 3 QuANTUM-R study, which were presented at the 23rd Congress of the European Hematology Association in June.

QuANTUM-R enrolled adults with FLT3-ITD AML (at least 3% FLT3-ITD allelic ratio) who had refractory disease or had relapsed within 6 months of their first complete remission.

Patients were randomized to receive once-daily treatment with quizartinib (n=245) or a salvage chemotherapy regimen (n=122)—low-dose cytarabine (LoDAC, n=29); combination mitoxantrone, etoposide, and cytarabine (MEC, n=40); or combination fludarabine, cytarabine, and idarubicin (FLAG-IDA, n=53).

Responders could proceed to hematopoietic stem cell transplant (HSCT), and those in the quizartinib arm could resume quizartinib after HSCT. Thirty-two percent of quizartinib-treated patients and 12% of the chemotherapy group went on to HSCT.

The median follow-up was 23.5 months. The efficacy results include all randomized patients.

The overall response rate was 69% in the quizartinib arm and 30% in the chemotherapy arm. The complete response (CR) rate was 4% and 1%, respectively; the rate of CR with incomplete platelet recovery was 4% and 0%, respectively; and the rate of CR with incomplete hematologic recovery was 40% and 26%, respectively.

The median overall survival was 6.2 months in the quizartinib arm and 4.7 months in the chemotherapy arm (hazard ratio=0.76, P=0.0177). The 1-year overall survival rate was 27% and 20%, respectively.

The median event-free survival was 6.0 weeks in the quizartinib arm and 3.7 weeks in the chemotherapy arm (hazard ratio=0.90, P=0.1071).

The safety results include only patients who received their assigned treatment—241 patients who received quizartinib and 94 who received salvage chemotherapy (22 on LoDAC, 25 on MEC, and 47 on FLAG-IDA).

Grade 3 or higher hematologic treatment-emergent adverse events occurring in at least 5% of patients (in the quizartinib and chemotherapy groups, respectively) included thrombocytopenia (35% and 34%), anemia (30% and 29%), neutropenia (32% and 25%), febrile neutropenia (31% and 21%), and leukopenia (17% and 16%).

Grade 3 or higher nonhematologic treatment-emergent adverse events occurring in at least 5% of patients (in the quizartinib and chemotherapy groups, respectively) included fatigue (8% and 1%), hypokalemia (12% and 9%), sepsis/septic shock (16% and 18%), dyspnea (5% for both), hypophosphatemia (5% for both), and pneumonia (12% and 9%).

Three percent of patients in the quizartinib arm had grade 3 QTcF prolongation, and 2 patients discontinued quizartinib due to QTcF prolongation.

About breakthrough designation

Breakthrough designation is intended to expedite the development and review of new treatments for serious or life-threatening conditions.

The designation entitles the company developing a therapy to more intensive FDA guidance on an efficient and accelerated development program, as well as eligibility for other actions to expedite FDA review, such as rolling submission and priority review.

To earn breakthrough designation, a treatment must show encouraging early clinical results demonstrating substantial improvement over available therapies with regard to a clinically significant endpoint, or it must fulfill an unmet need.

Other designations for quizartinib

In addition to breakthrough therapy designation, quizartinib has fast track and orphan drug designations from the FDA.

The FDA’s fast track development program is designed to expedite clinical development and submission of applications for products with the potential to treat serious or life-threatening conditions and address unmet medical needs.

Fast track designation facilitates frequent interactions with the FDA review team, including meetings to discuss the product’s development plan and written communications about issues such as trial design and use of biomarkers.

Products that receive fast track designation may be eligible for accelerated approval and priority review if relevant criteria are met. Such products may also be eligible for rolling review, which allows a developer to submit individual sections of a product’s application for review as they are ready, rather than waiting until all sections are complete.

The FDA grants orphan designation to products intended to treat, diagnose, or prevent diseases/disorders that affect fewer than 200,000 people in the US.

Orphan designation provides incentives for sponsors to develop products for rare diseases. This may include tax credits toward the cost of clinical trials, prescription drug user fee waivers, and 7 years of market exclusivity if the product is approved.

AML cells

The US Food and Drug Administration (FDA) has granted breakthrough therapy designation to quizartinib, an investigational FLT3 inhibitor, for the treatment of adults with relapsed/refractory FLT3-ITD acute myeloid leukemia (AML).

The FDA granted quizartinib breakthrough designation based on results from the phase 3 QuANTUM-R study, which were presented at the 23rd Congress of the European Hematology Association in June.

QuANTUM-R enrolled adults with FLT3-ITD AML (at least 3% FLT3-ITD allelic ratio) who had refractory disease or had relapsed within 6 months of their first complete remission.

Patients were randomized to receive once-daily treatment with quizartinib (n=245) or a salvage chemotherapy regimen (n=122)—low-dose cytarabine (LoDAC, n=29); combination mitoxantrone, etoposide, and cytarabine (MEC, n=40); or combination fludarabine, cytarabine, and idarubicin (FLAG-IDA, n=53).

Responders could proceed to hematopoietic stem cell transplant (HSCT), and those in the quizartinib arm could resume quizartinib after HSCT. Thirty-two percent of quizartinib-treated patients and 12% of the chemotherapy group went on to HSCT.

The median follow-up was 23.5 months. The efficacy results include all randomized patients.

The overall response rate was 69% in the quizartinib arm and 30% in the chemotherapy arm. The complete response (CR) rate was 4% and 1%, respectively; the rate of CR with incomplete platelet recovery was 4% and 0%, respectively; and the rate of CR with incomplete hematologic recovery was 40% and 26%, respectively.

The median overall survival was 6.2 months in the quizartinib arm and 4.7 months in the chemotherapy arm (hazard ratio=0.76, P=0.0177). The 1-year overall survival rate was 27% and 20%, respectively.

The median event-free survival was 6.0 weeks in the quizartinib arm and 3.7 weeks in the chemotherapy arm (hazard ratio=0.90, P=0.1071).

The safety results include only patients who received their assigned treatment—241 patients who received quizartinib and 94 who received salvage chemotherapy (22 on LoDAC, 25 on MEC, and 47 on FLAG-IDA).

Grade 3 or higher hematologic treatment-emergent adverse events occurring in at least 5% of patients (in the quizartinib and chemotherapy groups, respectively) included thrombocytopenia (35% and 34%), anemia (30% and 29%), neutropenia (32% and 25%), febrile neutropenia (31% and 21%), and leukopenia (17% and 16%).

Grade 3 or higher nonhematologic treatment-emergent adverse events occurring in at least 5% of patients (in the quizartinib and chemotherapy groups, respectively) included fatigue (8% and 1%), hypokalemia (12% and 9%), sepsis/septic shock (16% and 18%), dyspnea (5% for both), hypophosphatemia (5% for both), and pneumonia (12% and 9%).

Three percent of patients in the quizartinib arm had grade 3 QTcF prolongation, and 2 patients discontinued quizartinib due to QTcF prolongation.

About breakthrough designation

Breakthrough designation is intended to expedite the development and review of new treatments for serious or life-threatening conditions.

The designation entitles the company developing a therapy to more intensive FDA guidance on an efficient and accelerated development program, as well as eligibility for other actions to expedite FDA review, such as rolling submission and priority review.

To earn breakthrough designation, a treatment must show encouraging early clinical results demonstrating substantial improvement over available therapies with regard to a clinically significant endpoint, or it must fulfill an unmet need.

Other designations for quizartinib

In addition to breakthrough therapy designation, quizartinib has fast track and orphan drug designations from the FDA.

The FDA’s fast track development program is designed to expedite clinical development and submission of applications for products with the potential to treat serious or life-threatening conditions and address unmet medical needs.

Fast track designation facilitates frequent interactions with the FDA review team, including meetings to discuss the product’s development plan and written communications about issues such as trial design and use of biomarkers.

Products that receive fast track designation may be eligible for accelerated approval and priority review if relevant criteria are met. Such products may also be eligible for rolling review, which allows a developer to submit individual sections of a product’s application for review as they are ready, rather than waiting until all sections are complete.

The FDA grants orphan designation to products intended to treat, diagnose, or prevent diseases/disorders that affect fewer than 200,000 people in the US.

Orphan designation provides incentives for sponsors to develop products for rare diseases. This may include tax credits toward the cost of clinical trials, prescription drug user fee waivers, and 7 years of market exclusivity if the product is approved.

AML cells

The US Food and Drug Administration (FDA) has granted breakthrough therapy designation to quizartinib, an investigational FLT3 inhibitor, for the treatment of adults with relapsed/refractory FLT3-ITD acute myeloid leukemia (AML).

The FDA granted quizartinib breakthrough designation based on results from the phase 3 QuANTUM-R study, which were presented at the 23rd Congress of the European Hematology Association in June.

QuANTUM-R enrolled adults with FLT3-ITD AML (at least 3% FLT3-ITD allelic ratio) who had refractory disease or had relapsed within 6 months of their first complete remission.

Patients were randomized to receive once-daily treatment with quizartinib (n=245) or a salvage chemotherapy regimen (n=122)—low-dose cytarabine (LoDAC, n=29); combination mitoxantrone, etoposide, and cytarabine (MEC, n=40); or combination fludarabine, cytarabine, and idarubicin (FLAG-IDA, n=53).

Responders could proceed to hematopoietic stem cell transplant (HSCT), and those in the quizartinib arm could resume quizartinib after HSCT. Thirty-two percent of quizartinib-treated patients and 12% of the chemotherapy group went on to HSCT.

The median follow-up was 23.5 months. The efficacy results include all randomized patients.

The overall response rate was 69% in the quizartinib arm and 30% in the chemotherapy arm. The complete response (CR) rate was 4% and 1%, respectively; the rate of CR with incomplete platelet recovery was 4% and 0%, respectively; and the rate of CR with incomplete hematologic recovery was 40% and 26%, respectively.

The median overall survival was 6.2 months in the quizartinib arm and 4.7 months in the chemotherapy arm (hazard ratio=0.76, P=0.0177). The 1-year overall survival rate was 27% and 20%, respectively.

The median event-free survival was 6.0 weeks in the quizartinib arm and 3.7 weeks in the chemotherapy arm (hazard ratio=0.90, P=0.1071).

The safety results include only patients who received their assigned treatment—241 patients who received quizartinib and 94 who received salvage chemotherapy (22 on LoDAC, 25 on MEC, and 47 on FLAG-IDA).

Grade 3 or higher hematologic treatment-emergent adverse events occurring in at least 5% of patients (in the quizartinib and chemotherapy groups, respectively) included thrombocytopenia (35% and 34%), anemia (30% and 29%), neutropenia (32% and 25%), febrile neutropenia (31% and 21%), and leukopenia (17% and 16%).

Grade 3 or higher nonhematologic treatment-emergent adverse events occurring in at least 5% of patients (in the quizartinib and chemotherapy groups, respectively) included fatigue (8% and 1%), hypokalemia (12% and 9%), sepsis/septic shock (16% and 18%), dyspnea (5% for both), hypophosphatemia (5% for both), and pneumonia (12% and 9%).

Three percent of patients in the quizartinib arm had grade 3 QTcF prolongation, and 2 patients discontinued quizartinib due to QTcF prolongation.

About breakthrough designation

Breakthrough designation is intended to expedite the development and review of new treatments for serious or life-threatening conditions.

The designation entitles the company developing a therapy to more intensive FDA guidance on an efficient and accelerated development program, as well as eligibility for other actions to expedite FDA review, such as rolling submission and priority review.

To earn breakthrough designation, a treatment must show encouraging early clinical results demonstrating substantial improvement over available therapies with regard to a clinically significant endpoint, or it must fulfill an unmet need.

Other designations for quizartinib

In addition to breakthrough therapy designation, quizartinib has fast track and orphan drug designations from the FDA.

The FDA’s fast track development program is designed to expedite clinical development and submission of applications for products with the potential to treat serious or life-threatening conditions and address unmet medical needs.

Fast track designation facilitates frequent interactions with the FDA review team, including meetings to discuss the product’s development plan and written communications about issues such as trial design and use of biomarkers.

Products that receive fast track designation may be eligible for accelerated approval and priority review if relevant criteria are met. Such products may also be eligible for rolling review, which allows a developer to submit individual sections of a product’s application for review as they are ready, rather than waiting until all sections are complete.

The FDA grants orphan designation to products intended to treat, diagnose, or prevent diseases/disorders that affect fewer than 200,000 people in the US.

Orphan designation provides incentives for sponsors to develop products for rare diseases. This may include tax credits toward the cost of clinical trials, prescription drug user fee waivers, and 7 years of market exclusivity if the product is approved.

Photo by Rhoda Baer

Research has shown an increase in the global incidence of leukemia and non-Hodgkin lymphoma (NHL) in recent years.

The Global Burden of Disease (GBD) study showed that, from 2006 to 2016, the incidence of NHL increased 45%, and the incidence of leukemia increased 26%.

These increases were largely due to population growth and aging.

Results from the GDB study were published in JAMA Oncology.

The study indicated that, in 2016, there were 17.2 million cases of cancer worldwide and 8.9 million cancer deaths.

One in 3 men were likely to get cancer during their lifetime, as were 1 in 5 women. Cancer was associated with 213.2 million disability-adjusted life years (DALYs).

The following table lists the 2016 global incidence and mortality figures for all cancers combined and for individual hematologic malignancies.

Leukemia

In 2016, there were 467,000 new cases of leukemia and 310,000 leukemia deaths. Leukemia was responsible for 10.2 million DALYs. Leukemia developed in 1 in 118 men and 1 in 194 women worldwide.

Between 2006 and 2016, the global leukemia incidence increased by 26%—from 370,482 to 466,802 cases.

The researchers said the factors contributing to this increase were population growth (12%), population aging (10%), and an increase in age-specific incidence rates (3%).

NHL

In 2016, there were 461,000 new cases of NHL and 240,000 NHL deaths. NHL was responsible for 6.8 million DALYs. NHL developed in 1 in 110 men and 1 in 161 women worldwide.

Between 2006 and 2016, NHL increased by 45%, from 319,078 to 461,164 cases.

The factors contributing to this increase were increasing age-specific incidence rates (17%), changing population age structure (15%), and population growth (12%).

“A large proportion of the increase in cancer incidence can be explained by improving life expectancy and population growth—a development that can at least partially be attributed to a reduced burden from other common diseases,” the study authors wrote.

The authors also pointed out that prevention efforts are less effective for hematologic malignancies than for other cancers.

Photo by Rhoda Baer

Research has shown an increase in the global incidence of leukemia and non-Hodgkin lymphoma (NHL) in recent years.

The Global Burden of Disease (GBD) study showed that, from 2006 to 2016, the incidence of NHL increased 45%, and the incidence of leukemia increased 26%.

These increases were largely due to population growth and aging.

Results from the GDB study were published in JAMA Oncology.

The study indicated that, in 2016, there were 17.2 million cases of cancer worldwide and 8.9 million cancer deaths.

One in 3 men were likely to get cancer during their lifetime, as were 1 in 5 women. Cancer was associated with 213.2 million disability-adjusted life years (DALYs).

The following table lists the 2016 global incidence and mortality figures for all cancers combined and for individual hematologic malignancies.

Leukemia

In 2016, there were 467,000 new cases of leukemia and 310,000 leukemia deaths. Leukemia was responsible for 10.2 million DALYs. Leukemia developed in 1 in 118 men and 1 in 194 women worldwide.

Between 2006 and 2016, the global leukemia incidence increased by 26%—from 370,482 to 466,802 cases.

The researchers said the factors contributing to this increase were population growth (12%), population aging (10%), and an increase in age-specific incidence rates (3%).

NHL

In 2016, there were 461,000 new cases of NHL and 240,000 NHL deaths. NHL was responsible for 6.8 million DALYs. NHL developed in 1 in 110 men and 1 in 161 women worldwide.

Between 2006 and 2016, NHL increased by 45%, from 319,078 to 461,164 cases.

The factors contributing to this increase were increasing age-specific incidence rates (17%), changing population age structure (15%), and population growth (12%).

“A large proportion of the increase in cancer incidence can be explained by improving life expectancy and population growth—a development that can at least partially be attributed to a reduced burden from other common diseases,” the study authors wrote.

The authors also pointed out that prevention efforts are less effective for hematologic malignancies than for other cancers.

Photo by Rhoda Baer

Research has shown an increase in the global incidence of leukemia and non-Hodgkin lymphoma (NHL) in recent years.

The Global Burden of Disease (GBD) study showed that, from 2006 to 2016, the incidence of NHL increased 45%, and the incidence of leukemia increased 26%.

These increases were largely due to population growth and aging.

Results from the GDB study were published in JAMA Oncology.

The study indicated that, in 2016, there were 17.2 million cases of cancer worldwide and 8.9 million cancer deaths.

One in 3 men were likely to get cancer during their lifetime, as were 1 in 5 women. Cancer was associated with 213.2 million disability-adjusted life years (DALYs).

The following table lists the 2016 global incidence and mortality figures for all cancers combined and for individual hematologic malignancies.

Leukemia

In 2016, there were 467,000 new cases of leukemia and 310,000 leukemia deaths. Leukemia was responsible for 10.2 million DALYs. Leukemia developed in 1 in 118 men and 1 in 194 women worldwide.

Between 2006 and 2016, the global leukemia incidence increased by 26%—from 370,482 to 466,802 cases.

The researchers said the factors contributing to this increase were population growth (12%), population aging (10%), and an increase in age-specific incidence rates (3%).

NHL

In 2016, there were 461,000 new cases of NHL and 240,000 NHL deaths. NHL was responsible for 6.8 million DALYs. NHL developed in 1 in 110 men and 1 in 161 women worldwide.

Between 2006 and 2016, NHL increased by 45%, from 319,078 to 461,164 cases.

The factors contributing to this increase were increasing age-specific incidence rates (17%), changing population age structure (15%), and population growth (12%).

“A large proportion of the increase in cancer incidence can be explained by improving life expectancy and population growth—a development that can at least partially be attributed to a reduced burden from other common diseases,” the study authors wrote.

The authors also pointed out that prevention efforts are less effective for hematologic malignancies than for other cancers.

Hospital/Justin Veneman

New findings could help improve treatment of an inherited bone marrow disorder known as myelodysplasia and leukemia syndrome with monosomy 7 (MLSM7), according to researchers.

While studying families affected by MLSM7, researchers identified germline mutations in SAMD9L or SAMD9 in patients who had hematologic abnormalities, myelodysplastic syndromes (MDS), or acute myeloid leukemia (AML).

However, these mutations were also present in apparently healthy family members, and the researchers found that bone marrow monosomy 7 sometimes resolved without treatment.

The team recounted these findings in JCI Insight.

The researchers analyzed blood samples from 16 siblings in 5 families affected by MLSM7 and found they all carried germline mutations in SAMD9 or SAMD9L. In 3 of the 5 families, there were apparently healthy parents who also carried the mutations.

“Surprisingly, the health consequences of these mutations varied tremendously for reasons that must still be determined, but the findings are already affecting how we may choose to manage these patients,” said study author Jeffery Klco, MD, PhD, of St. Jude Children’s Research Hospital in Memphis, Tennessee.

Three of the 16 siblings developed AML and died of the disease or related complications. Two other siblings were diagnosed with MDS.

The remaining 11 siblings with the mutations were apparently healthy, although several had been treated for anemia and other conditions associated with low blood counts.

Some of these patients had a previous history of bone marrow monosomy 7 that spontaneously corrected over time. These patients, despite no therapy, appeared to have normal bone marrow function.

“This was an even greater surprise,” Dr Klco said. “The spontaneous recovery experienced by some children with the germline mutations suggests some patients with SAMD9 and SAMD9L mutations who were previously considered candidates for bone marrow transplantation may recover hematologic function on their own.”

Dr Klco and his colleagues have a theory that could explain the spontaneous correction. The team noted that SAMD9 and SAMD9L are activated in response to viral infections. While the normal function of both proteins is poorly understood, abnormally activated SAMD9 and SAMD9L are known to inhibit cell growth.

In this study, deep sequencing showed that selective pressure on developing blood cells favors cells without the SAMD9 or SAMD9L mutations. That may increase pressure for cells to selectively jettison chromosome 7 with the gene alteration or take other molecular measures to counteract the mutant protein.

Implications for treatment

This research also showed that, in patients who developed AML, loss of chromosome 7 was associated with the development of mutations in additional genes, including ETV6, KRAS, SETBP1, and RUNX1.

These same mutations are broadly associated with monosomy 7 in AML, which suggests that understanding how SAMD9 and SAMD9L mutations contribute to leukemia has implications beyond familial cases.

The presence of secondary mutations may also help clinicians identify which patients will benefit from immediate treatment, including chemotherapy or transplant to prevent or treat AML or myelodysplasia, Dr Klco said.

For patients without the mutations or significant symptoms due to low blood cell counts, watchful waiting with careful follow-up may sometimes be an option.

“Now that we know this disease can resolve without treatment in some patients, we need to focus on developing screening and treatment guidelines,” Dr Klco said. “We want to reserve hematopoietic bone marrow transplantation for those who truly need the procedure. These findings will help to point the way.”

“So little is known about SAMD9 and SAMD9L that we need to continue working in the lab to better understand how these mutations impact blood cell development and how they are activated in response to infections and other types of stress.”

Hospital/Justin Veneman

New findings could help improve treatment of an inherited bone marrow disorder known as myelodysplasia and leukemia syndrome with monosomy 7 (MLSM7), according to researchers.

While studying families affected by MLSM7, researchers identified germline mutations in SAMD9L or SAMD9 in patients who had hematologic abnormalities, myelodysplastic syndromes (MDS), or acute myeloid leukemia (AML).

However, these mutations were also present in apparently healthy family members, and the researchers found that bone marrow monosomy 7 sometimes resolved without treatment.

The team recounted these findings in JCI Insight.

The researchers analyzed blood samples from 16 siblings in 5 families affected by MLSM7 and found they all carried germline mutations in SAMD9 or SAMD9L. In 3 of the 5 families, there were apparently healthy parents who also carried the mutations.

“Surprisingly, the health consequences of these mutations varied tremendously for reasons that must still be determined, but the findings are already affecting how we may choose to manage these patients,” said study author Jeffery Klco, MD, PhD, of St. Jude Children’s Research Hospital in Memphis, Tennessee.

Three of the 16 siblings developed AML and died of the disease or related complications. Two other siblings were diagnosed with MDS.

The remaining 11 siblings with the mutations were apparently healthy, although several had been treated for anemia and other conditions associated with low blood counts.

Some of these patients had a previous history of bone marrow monosomy 7 that spontaneously corrected over time. These patients, despite no therapy, appeared to have normal bone marrow function.

“This was an even greater surprise,” Dr Klco said. “The spontaneous recovery experienced by some children with the germline mutations suggests some patients with SAMD9 and SAMD9L mutations who were previously considered candidates for bone marrow transplantation may recover hematologic function on their own.”

Dr Klco and his colleagues have a theory that could explain the spontaneous correction. The team noted that SAMD9 and SAMD9L are activated in response to viral infections. While the normal function of both proteins is poorly understood, abnormally activated SAMD9 and SAMD9L are known to inhibit cell growth.

In this study, deep sequencing showed that selective pressure on developing blood cells favors cells without the SAMD9 or SAMD9L mutations. That may increase pressure for cells to selectively jettison chromosome 7 with the gene alteration or take other molecular measures to counteract the mutant protein.

Implications for treatment

This research also showed that, in patients who developed AML, loss of chromosome 7 was associated with the development of mutations in additional genes, including ETV6, KRAS, SETBP1, and RUNX1.

These same mutations are broadly associated with monosomy 7 in AML, which suggests that understanding how SAMD9 and SAMD9L mutations contribute to leukemia has implications beyond familial cases.

The presence of secondary mutations may also help clinicians identify which patients will benefit from immediate treatment, including chemotherapy or transplant to prevent or treat AML or myelodysplasia, Dr Klco said.

For patients without the mutations or significant symptoms due to low blood cell counts, watchful waiting with careful follow-up may sometimes be an option.

“Now that we know this disease can resolve without treatment in some patients, we need to focus on developing screening and treatment guidelines,” Dr Klco said. “We want to reserve hematopoietic bone marrow transplantation for those who truly need the procedure. These findings will help to point the way.”

“So little is known about SAMD9 and SAMD9L that we need to continue working in the lab to better understand how these mutations impact blood cell development and how they are activated in response to infections and other types of stress.”

Hospital/Justin Veneman

New findings could help improve treatment of an inherited bone marrow disorder known as myelodysplasia and leukemia syndrome with monosomy 7 (MLSM7), according to researchers.

While studying families affected by MLSM7, researchers identified germline mutations in SAMD9L or SAMD9 in patients who had hematologic abnormalities, myelodysplastic syndromes (MDS), or acute myeloid leukemia (AML).

However, these mutations were also present in apparently healthy family members, and the researchers found that bone marrow monosomy 7 sometimes resolved without treatment.

The team recounted these findings in JCI Insight.

The researchers analyzed blood samples from 16 siblings in 5 families affected by MLSM7 and found they all carried germline mutations in SAMD9 or SAMD9L. In 3 of the 5 families, there were apparently healthy parents who also carried the mutations.

“Surprisingly, the health consequences of these mutations varied tremendously for reasons that must still be determined, but the findings are already affecting how we may choose to manage these patients,” said study author Jeffery Klco, MD, PhD, of St. Jude Children’s Research Hospital in Memphis, Tennessee.

Three of the 16 siblings developed AML and died of the disease or related complications. Two other siblings were diagnosed with MDS.

The remaining 11 siblings with the mutations were apparently healthy, although several had been treated for anemia and other conditions associated with low blood counts.

Some of these patients had a previous history of bone marrow monosomy 7 that spontaneously corrected over time. These patients, despite no therapy, appeared to have normal bone marrow function.

“This was an even greater surprise,” Dr Klco said. “The spontaneous recovery experienced by some children with the germline mutations suggests some patients with SAMD9 and SAMD9L mutations who were previously considered candidates for bone marrow transplantation may recover hematologic function on their own.”

Dr Klco and his colleagues have a theory that could explain the spontaneous correction. The team noted that SAMD9 and SAMD9L are activated in response to viral infections. While the normal function of both proteins is poorly understood, abnormally activated SAMD9 and SAMD9L are known to inhibit cell growth.

In this study, deep sequencing showed that selective pressure on developing blood cells favors cells without the SAMD9 or SAMD9L mutations. That may increase pressure for cells to selectively jettison chromosome 7 with the gene alteration or take other molecular measures to counteract the mutant protein.

Implications for treatment

This research also showed that, in patients who developed AML, loss of chromosome 7 was associated with the development of mutations in additional genes, including ETV6, KRAS, SETBP1, and RUNX1.

These same mutations are broadly associated with monosomy 7 in AML, which suggests that understanding how SAMD9 and SAMD9L mutations contribute to leukemia has implications beyond familial cases.

The presence of secondary mutations may also help clinicians identify which patients will benefit from immediate treatment, including chemotherapy or transplant to prevent or treat AML or myelodysplasia, Dr Klco said.

For patients without the mutations or significant symptoms due to low blood cell counts, watchful waiting with careful follow-up may sometimes be an option.

“Now that we know this disease can resolve without treatment in some patients, we need to focus on developing screening and treatment guidelines,” Dr Klco said. “We want to reserve hematopoietic bone marrow transplantation for those who truly need the procedure. These findings will help to point the way.”

“So little is known about SAMD9 and SAMD9L that we need to continue working in the lab to better understand how these mutations impact blood cell development and how they are activated in response to infections and other types of stress.”

Image from Dreamstime

Alkylating agents, hydroxyurea (HU), and certain non-malignant diseases can significantly deplete spermatogonial cell counts in young boys, according to research published in Human Reproduction.

Boys who received alkylating agents to treat cancer had significantly lower spermatogonial cell counts than control subjects or boys with malignant/nonmalignant diseases treated with non-alkylating agents.

Five of 6 SCD patients treated with HU had a totally depleted spermatogonial pool, and the remaining patient had a low spermatogonial cell count.

Five boys with non-malignant diseases who were not exposed to chemotherapy had significantly lower spermatogonial cell counts than controls.

“Our findings of a dramatic decrease in germ cell numbers in boys treated with alkylating agents and in sickle cell disease patients treated with hydroxyurea suggest that storing frozen testicular tissue from these boys should be performed before these treatments are initiated,” said study author Cecilia Petersen, MD, PhD, of Karolinska Institutet and University Hospital in Stockholm, Sweden.

“This needs to be communicated to physicians as well as patients and their parents or carers. However, until sperm that are able to fertilize eggs are produced from stored testicular tissue, we cannot confirm that germ cell quantity might determine the success of transplantation of the tissue in adulthood. Further research on this is needed to establish a realistic fertility preservation technique.”

Dr Petersen and her colleagues also noted that preserving testicular tissue may not be a viable option for boys who have low spermatogonial cell counts prior to treatment.

Patients and controls

For this study, the researchers analyzed testicular tissue from 32 boys facing treatments that carried a high risk of infertility—testicular irradiation, chemotherapy, or radiotherapy in advance of stem cell transplant.

Twenty boys had the tissue taken after initial chemotherapy, and 12 had it taken before starting any treatment.¹

Eight patients had received chemotherapy with non-alkylating agents, 6 (all with malignancies) had received alkylating agents, and 6 (all with SCD) had received HU.

Diseases included acute lymphoblastic leukemia (n=6), SCD (n=6), acute myeloid leukemia (n=3), thalassemia major (n=3), neuroblastoma (n=2), juvenile myelomonocytic leukemia (n=2), myelodysplastic syndromes (n=2), primary immunodeficiency (n=2), Wilms tumor (n=1), adrenoleukodystrophy (n=1), hepatoblastoma (n=1), primitive neuroectodermal tumor (n=1), severe aplastic anemia (n=1), and Fanconi anemia (n=1).

The researchers compared samples from these 32 patients to 14 healthy testicular tissue samples stored in the biobank at the Karolinska University Hospital.

For both sample types, the team counted the number of spermatogonial cells found in a cross-section of seminiferous tubules.

“We could compare the number of spermatogonia with those found in the healthy boys as a way to estimate the effect of medical treatment or the disease itself on the future fertility of a patient,” explained study author Jan-Bernd Stukenborg, PhD, of Karolinska Institutet and University Hospital.

Impact of treatment

There was no significant difference in the mean quantity of spermatogonia per transverse tubular cross-section (S/T) between patients exposed to non-alkylating agents (1.7 ± 1.0, n=8) and biobank controls (4.1 ± 4.6, n=14).

However, samples from patients who received alkylating agents had a significantly lower mean S/T value (0.2 ± 0.3, n=6) than samples from patients treated with non-alkylating agents (P=0.003) and biobank controls (P<0.001).

“We found that the numbers of germ cells present in the cross-sections of the seminiferous tubules were significantly depleted and close to 0 in patients treated with alkylating agents,” Dr Stukenborg said.

Samples from the SCD patients also had a significantly lower mean S/T value (0.3 ± 0.6, n=6) than biobank controls (P=0.003).

Dr Stukenborg noted that the germ cell pool was totally depleted in 5 of the boys with SCD, and the pool was “very low” in the sixth SCD patient.

“This was not seen in patients who had not started treatment or were treated with non-alkylating agents or in the biobank tissues,” Dr Stukenborg said.²

He and his colleagues noted that it is possible for germ cells to recover to normal levels after treatment that is highly toxic to the testes, but high doses of alkylating agents and radiotherapy to the testicles are strongly associated with permanent or long-term infertility.

“The first group of boys who received bone marrow transplants are now reaching their thirties,” said study author Kirsi Jahnukainen, MD, PhD, of Helsinki University Central Hospital in Finland.

“Recent data suggest they may have a high chance of their sperm production recovering, even if they received high-dose alkylating therapies, so long as they had no testicular irradiation.”

Impact of disease

The researchers also found evidence to suggest that, for some boys, their disease may have affected spermatogonial cell counts before any treatment began.

Five patients with non-malignant disease who had not been exposed to chemotherapy (3 with thalassemia major, 1 with Fanconi anemia, and 1 with primary immunodeficiency) had a significantly lower mean S/T value (0.4 ± 0.5) than controls (P=0.006).

“Among patients who had not been treated previously with chemotherapy, there were several boys with a low number of germ cells for their age,” Dr Jahnukainen said.

“This suggests that some non-malignant diseases that require bone marrow transplants may affect the fertility of young boys even before exposure to therapy that is toxic for the testes.”

The researchers noted that a limitation of this study was that biobank samples had no detailed information regarding previous medical treatments and testicular volumes.

1. Testicular tissue is taken from patients under general anesthesia. The surgeon removes approximately 20% of the tissue from the testicular capsule in one of the testicles. For this study, a third of the tissue was taken to the Karolinska Institutet for analysis.

2. A recent meta-analysis showed that normal testicular tissue samples of newborns contain approximately 2.5 germ cells per tubular cross-section. This number decreases to approximately 1.2 within the first 3 years of age, followed by an increase up to 2.6 germ cells per tubular cross-section at 6 to 7 years, reaching a plateau until the age of 11. At the onset of puberty, an increase of up to 7 spermatogonia per tubular cross-section could be observed.

Image from Dreamstime

Alkylating agents, hydroxyurea (HU), and certain non-malignant diseases can significantly deplete spermatogonial cell counts in young boys, according to research published in Human Reproduction.

Boys who received alkylating agents to treat cancer had significantly lower spermatogonial cell counts than control subjects or boys with malignant/nonmalignant diseases treated with non-alkylating agents.

Five of 6 SCD patients treated with HU had a totally depleted spermatogonial pool, and the remaining patient had a low spermatogonial cell count.

Five boys with non-malignant diseases who were not exposed to chemotherapy had significantly lower spermatogonial cell counts than controls.

“Our findings of a dramatic decrease in germ cell numbers in boys treated with alkylating agents and in sickle cell disease patients treated with hydroxyurea suggest that storing frozen testicular tissue from these boys should be performed before these treatments are initiated,” said study author Cecilia Petersen, MD, PhD, of Karolinska Institutet and University Hospital in Stockholm, Sweden.

“This needs to be communicated to physicians as well as patients and their parents or carers. However, until sperm that are able to fertilize eggs are produced from stored testicular tissue, we cannot confirm that germ cell quantity might determine the success of transplantation of the tissue in adulthood. Further research on this is needed to establish a realistic fertility preservation technique.”

Dr Petersen and her colleagues also noted that preserving testicular tissue may not be a viable option for boys who have low spermatogonial cell counts prior to treatment.

Patients and controls

For this study, the researchers analyzed testicular tissue from 32 boys facing treatments that carried a high risk of infertility—testicular irradiation, chemotherapy, or radiotherapy in advance of stem cell transplant.

Twenty boys had the tissue taken after initial chemotherapy, and 12 had it taken before starting any treatment.¹

Eight patients had received chemotherapy with non-alkylating agents, 6 (all with malignancies) had received alkylating agents, and 6 (all with SCD) had received HU.

Diseases included acute lymphoblastic leukemia (n=6), SCD (n=6), acute myeloid leukemia (n=3), thalassemia major (n=3), neuroblastoma (n=2), juvenile myelomonocytic leukemia (n=2), myelodysplastic syndromes (n=2), primary immunodeficiency (n=2), Wilms tumor (n=1), adrenoleukodystrophy (n=1), hepatoblastoma (n=1), primitive neuroectodermal tumor (n=1), severe aplastic anemia (n=1), and Fanconi anemia (n=1).

The researchers compared samples from these 32 patients to 14 healthy testicular tissue samples stored in the biobank at the Karolinska University Hospital.

For both sample types, the team counted the number of spermatogonial cells found in a cross-section of seminiferous tubules.

“We could compare the number of spermatogonia with those found in the healthy boys as a way to estimate the effect of medical treatment or the disease itself on the future fertility of a patient,” explained study author Jan-Bernd Stukenborg, PhD, of Karolinska Institutet and University Hospital.

Impact of treatment

There was no significant difference in the mean quantity of spermatogonia per transverse tubular cross-section (S/T) between patients exposed to non-alkylating agents (1.7 ± 1.0, n=8) and biobank controls (4.1 ± 4.6, n=14).

However, samples from patients who received alkylating agents had a significantly lower mean S/T value (0.2 ± 0.3, n=6) than samples from patients treated with non-alkylating agents (P=0.003) and biobank controls (P<0.001).

“We found that the numbers of germ cells present in the cross-sections of the seminiferous tubules were significantly depleted and close to 0 in patients treated with alkylating agents,” Dr Stukenborg said.

Samples from the SCD patients also had a significantly lower mean S/T value (0.3 ± 0.6, n=6) than biobank controls (P=0.003).

Dr Stukenborg noted that the germ cell pool was totally depleted in 5 of the boys with SCD, and the pool was “very low” in the sixth SCD patient.

“This was not seen in patients who had not started treatment or were treated with non-alkylating agents or in the biobank tissues,” Dr Stukenborg said.²

He and his colleagues noted that it is possible for germ cells to recover to normal levels after treatment that is highly toxic to the testes, but high doses of alkylating agents and radiotherapy to the testicles are strongly associated with permanent or long-term infertility.

“The first group of boys who received bone marrow transplants are now reaching their thirties,” said study author Kirsi Jahnukainen, MD, PhD, of Helsinki University Central Hospital in Finland.

“Recent data suggest they may have a high chance of their sperm production recovering, even if they received high-dose alkylating therapies, so long as they had no testicular irradiation.”

Impact of disease

The researchers also found evidence to suggest that, for some boys, their disease may have affected spermatogonial cell counts before any treatment began.

Five patients with non-malignant disease who had not been exposed to chemotherapy (3 with thalassemia major, 1 with Fanconi anemia, and 1 with primary immunodeficiency) had a significantly lower mean S/T value (0.4 ± 0.5) than controls (P=0.006).

“Among patients who had not been treated previously with chemotherapy, there were several boys with a low number of germ cells for their age,” Dr Jahnukainen said.

“This suggests that some non-malignant diseases that require bone marrow transplants may affect the fertility of young boys even before exposure to therapy that is toxic for the testes.”

The researchers noted that a limitation of this study was that biobank samples had no detailed information regarding previous medical treatments and testicular volumes.

1. Testicular tissue is taken from patients under general anesthesia. The surgeon removes approximately 20% of the tissue from the testicular capsule in one of the testicles. For this study, a third of the tissue was taken to the Karolinska Institutet for analysis.

2. A recent meta-analysis showed that normal testicular tissue samples of newborns contain approximately 2.5 germ cells per tubular cross-section. This number decreases to approximately 1.2 within the first 3 years of age, followed by an increase up to 2.6 germ cells per tubular cross-section at 6 to 7 years, reaching a plateau until the age of 11. At the onset of puberty, an increase of up to 7 spermatogonia per tubular cross-section could be observed.

Image from Dreamstime

Alkylating agents, hydroxyurea (HU), and certain non-malignant diseases can significantly deplete spermatogonial cell counts in young boys, according to research published in Human Reproduction.

Boys who received alkylating agents to treat cancer had significantly lower spermatogonial cell counts than control subjects or boys with malignant/nonmalignant diseases treated with non-alkylating agents.

Five of 6 SCD patients treated with HU had a totally depleted spermatogonial pool, and the remaining patient had a low spermatogonial cell count.

Five boys with non-malignant diseases who were not exposed to chemotherapy had significantly lower spermatogonial cell counts than controls.

“Our findings of a dramatic decrease in germ cell numbers in boys treated with alkylating agents and in sickle cell disease patients treated with hydroxyurea suggest that storing frozen testicular tissue from these boys should be performed before these treatments are initiated,” said study author Cecilia Petersen, MD, PhD, of Karolinska Institutet and University Hospital in Stockholm, Sweden.

“This needs to be communicated to physicians as well as patients and their parents or carers. However, until sperm that are able to fertilize eggs are produced from stored testicular tissue, we cannot confirm that germ cell quantity might determine the success of transplantation of the tissue in adulthood. Further research on this is needed to establish a realistic fertility preservation technique.”

Dr Petersen and her colleagues also noted that preserving testicular tissue may not be a viable option for boys who have low spermatogonial cell counts prior to treatment.

Patients and controls

For this study, the researchers analyzed testicular tissue from 32 boys facing treatments that carried a high risk of infertility—testicular irradiation, chemotherapy, or radiotherapy in advance of stem cell transplant.

Twenty boys had the tissue taken after initial chemotherapy, and 12 had it taken before starting any treatment.¹

Eight patients had received chemotherapy with non-alkylating agents, 6 (all with malignancies) had received alkylating agents, and 6 (all with SCD) had received HU.

Diseases included acute lymphoblastic leukemia (n=6), SCD (n=6), acute myeloid leukemia (n=3), thalassemia major (n=3), neuroblastoma (n=2), juvenile myelomonocytic leukemia (n=2), myelodysplastic syndromes (n=2), primary immunodeficiency (n=2), Wilms tumor (n=1), adrenoleukodystrophy (n=1), hepatoblastoma (n=1), primitive neuroectodermal tumor (n=1), severe aplastic anemia (n=1), and Fanconi anemia (n=1).

The researchers compared samples from these 32 patients to 14 healthy testicular tissue samples stored in the biobank at the Karolinska University Hospital.

For both sample types, the team counted the number of spermatogonial cells found in a cross-section of seminiferous tubules.

“We could compare the number of spermatogonia with those found in the healthy boys as a way to estimate the effect of medical treatment or the disease itself on the future fertility of a patient,” explained study author Jan-Bernd Stukenborg, PhD, of Karolinska Institutet and University Hospital.

Impact of treatment

There was no significant difference in the mean quantity of spermatogonia per transverse tubular cross-section (S/T) between patients exposed to non-alkylating agents (1.7 ± 1.0, n=8) and biobank controls (4.1 ± 4.6, n=14).

However, samples from patients who received alkylating agents had a significantly lower mean S/T value (0.2 ± 0.3, n=6) than samples from patients treated with non-alkylating agents (P=0.003) and biobank controls (P<0.001).

“We found that the numbers of germ cells present in the cross-sections of the seminiferous tubules were significantly depleted and close to 0 in patients treated with alkylating agents,” Dr Stukenborg said.

Samples from the SCD patients also had a significantly lower mean S/T value (0.3 ± 0.6, n=6) than biobank controls (P=0.003).

Dr Stukenborg noted that the germ cell pool was totally depleted in 5 of the boys with SCD, and the pool was “very low” in the sixth SCD patient.

“This was not seen in patients who had not started treatment or were treated with non-alkylating agents or in the biobank tissues,” Dr Stukenborg said.²

He and his colleagues noted that it is possible for germ cells to recover to normal levels after treatment that is highly toxic to the testes, but high doses of alkylating agents and radiotherapy to the testicles are strongly associated with permanent or long-term infertility.

“The first group of boys who received bone marrow transplants are now reaching their thirties,” said study author Kirsi Jahnukainen, MD, PhD, of Helsinki University Central Hospital in Finland.

“Recent data suggest they may have a high chance of their sperm production recovering, even if they received high-dose alkylating therapies, so long as they had no testicular irradiation.”

Impact of disease

The researchers also found evidence to suggest that, for some boys, their disease may have affected spermatogonial cell counts before any treatment began.

Five patients with non-malignant disease who had not been exposed to chemotherapy (3 with thalassemia major, 1 with Fanconi anemia, and 1 with primary immunodeficiency) had a significantly lower mean S/T value (0.4 ± 0.5) than controls (P=0.006).

“Among patients who had not been treated previously with chemotherapy, there were several boys with a low number of germ cells for their age,” Dr Jahnukainen said.

“This suggests that some non-malignant diseases that require bone marrow transplants may affect the fertility of young boys even before exposure to therapy that is toxic for the testes.”

The researchers noted that a limitation of this study was that biobank samples had no detailed information regarding previous medical treatments and testicular volumes.

1. Testicular tissue is taken from patients under general anesthesia. The surgeon removes approximately 20% of the tissue from the testicular capsule in one of the testicles. For this study, a third of the tissue was taken to the Karolinska Institutet for analysis.

2. A recent meta-analysis showed that normal testicular tissue samples of newborns contain approximately 2.5 germ cells per tubular cross-section. This number decreases to approximately 1.2 within the first 3 years of age, followed by an increase up to 2.6 germ cells per tubular cross-section at 6 to 7 years, reaching a plateau until the age of 11. At the onset of puberty, an increase of up to 7 spermatogonia per tubular cross-section could be observed.

Agios Pharmaceuticals

The US Food and Drug Administration (FDA) has granted full approval for the isocitrate dehydrogenase-1 (IDH1) inhibitor ivosidenib (Tibsovo®).

The drug is approved to treat adults with relapsed or refractory acute myeloid leukemia (AML) who have an IDH1 mutation, as detected by an FDA-approved test.

Ivosidenib was approved concurrently with the RealTime IDH1 Assay, a companion diagnostic that can detect IDH1 mutation.

The FDA granted approval of ivosidenib to Agios Pharmaceuticals, Inc., and approval of the RealTime IDH1 Assay to Abbott Laboratories.

The FDA’s approval of ivosidenib was based on data from a single-arm, phase 1 study. Agios received fast track, priority review, and orphan drug designations for ivosidenib.

Safety risks

Ivosidenib must be dispensed with a patient medication guide that describes important information about the drug’s uses and risks.

The prescribing information for ivosidenib includes a Boxed Warning noting that patients treated with ivosidenib have experienced symptoms of differentiation syndrome, which can be fatal if not treated.

Signs and symptoms of differentiation syndrome may include fever, dyspnea, acute respiratory distress, radiographic pulmonary infiltrates, pleural or pericardial effusions, rapid weight gain, peripheral edema, or hepatic, renal, or multi-organ dysfunction.

At first suspicion of symptoms, doctors should treat patients with corticosteroids and monitor them closely until symptoms subside.

Ivosidenib also poses a risk of life-threatening QT prolongation and Guillain-Barré syndrome, so patients should be monitored for these adverse events (AEs) as well.

Phase 1 trial

Results from the phase 1 trial of ivosidenib were presented at the 2018 ASCO Annual Meeting and published simultaneously in NEJM. The following data were pulled from the drug’s prescribing information.

Efficacy results were available for 174 adults with relapsed/refractory AML and an IDH1 mutation identified or confirmed by the Abbott RealTime™ IDH1 assay. The patients received ivosidenib at a starting dose of 500 mg daily until disease progression, unacceptable toxicity, or hematopoietic stem cell transplant.

The patients had a median age of 67 (range, 18 to 87) and had received a median of 2 prior therapies (range, 1 to 6). Sixty-three percent were refractory to previous therapy, and 33% had secondary AML.

The study’s primary endpoint was the combined rate of complete remission (CR) rate and CR with partial hematologic improvement (CRh).

The CR+CRh rate was 32.8% (57/174), the CR rate was 24.7% (43/174), and the CRh rate was 8% (14/174).

The median duration of CR+CRh was 8.2 months (95% CI 5.6, 12). The median time to best response of CR or CRh was 2.0 months (range, 0.9 to 5.6 months).

Twelve percent of patients (21/174) went on to transplant.

The researchers evaluated the safety of ivosidenib in 179 patients treated with a dose of 500 mg daily. The median duration of exposure to ivosidenib was 3.9 months (range, 0.1 to 39.5 months).

Nineteen percent of patients (34/179) experienced differentiation syndrome. Seventy-nine percent of these patients (27/34) recovered after treatment or ivosidenib dose interruption.

The most frequent serious AEs (>5%) were differentiation syndrome (10%), leukocytosis (10%), and electrocardiogram QT prolongation (7%). There was one case of progressive multifocal leukoencephalopathy.

The most common AEs leading to dose interruption were QT prolongation (7%), differentiation syndrome (3%), leukocytosis (3%), and dyspnea (3%). AEs leading to a dose reduction included QT prolongation (1%), diarrhea (1%), nausea (1%), decreased hemoglobin (1%), and increased transaminases (1%).

AEs leading to permanent discontinuation of ivosidenib included Guillain-Barré syndrome (1%), rash (1%), stomatitis (1%), and creatinine increase (1%).

For additional data and more details on ivosidenib, see the full prescribing information or visit Tibsovo.com.

Agios Pharmaceuticals

The US Food and Drug Administration (FDA) has granted full approval for the isocitrate dehydrogenase-1 (IDH1) inhibitor ivosidenib (Tibsovo®).

The drug is approved to treat adults with relapsed or refractory acute myeloid leukemia (AML) who have an IDH1 mutation, as detected by an FDA-approved test.

Ivosidenib was approved concurrently with the RealTime IDH1 Assay, a companion diagnostic that can detect IDH1 mutation.

The FDA granted approval of ivosidenib to Agios Pharmaceuticals, Inc., and approval of the RealTime IDH1 Assay to Abbott Laboratories.

The FDA’s approval of ivosidenib was based on data from a single-arm, phase 1 study. Agios received fast track, priority review, and orphan drug designations for ivosidenib.

Safety risks

Ivosidenib must be dispensed with a patient medication guide that describes important information about the drug’s uses and risks.

The prescribing information for ivosidenib includes a Boxed Warning noting that patients treated with ivosidenib have experienced symptoms of differentiation syndrome, which can be fatal if not treated.

Signs and symptoms of differentiation syndrome may include fever, dyspnea, acute respiratory distress, radiographic pulmonary infiltrates, pleural or pericardial effusions, rapid weight gain, peripheral edema, or hepatic, renal, or multi-organ dysfunction.

At first suspicion of symptoms, doctors should treat patients with corticosteroids and monitor them closely until symptoms subside.

Ivosidenib also poses a risk of life-threatening QT prolongation and Guillain-Barré syndrome, so patients should be monitored for these adverse events (AEs) as well.

Phase 1 trial

Results from the phase 1 trial of ivosidenib were presented at the 2018 ASCO Annual Meeting and published simultaneously in NEJM. The following data were pulled from the drug’s prescribing information.

Efficacy results were available for 174 adults with relapsed/refractory AML and an IDH1 mutation identified or confirmed by the Abbott RealTime™ IDH1 assay. The patients received ivosidenib at a starting dose of 500 mg daily until disease progression, unacceptable toxicity, or hematopoietic stem cell transplant.

The patients had a median age of 67 (range, 18 to 87) and had received a median of 2 prior therapies (range, 1 to 6). Sixty-three percent were refractory to previous therapy, and 33% had secondary AML.

The study’s primary endpoint was the combined rate of complete remission (CR) rate and CR with partial hematologic improvement (CRh).

The CR+CRh rate was 32.8% (57/174), the CR rate was 24.7% (43/174), and the CRh rate was 8% (14/174).

The median duration of CR+CRh was 8.2 months (95% CI 5.6, 12). The median time to best response of CR or CRh was 2.0 months (range, 0.9 to 5.6 months).

Twelve percent of patients (21/174) went on to transplant.

The researchers evaluated the safety of ivosidenib in 179 patients treated with a dose of 500 mg daily. The median duration of exposure to ivosidenib was 3.9 months (range, 0.1 to 39.5 months).

Nineteen percent of patients (34/179) experienced differentiation syndrome. Seventy-nine percent of these patients (27/34) recovered after treatment or ivosidenib dose interruption.

The most frequent serious AEs (>5%) were differentiation syndrome (10%), leukocytosis (10%), and electrocardiogram QT prolongation (7%). There was one case of progressive multifocal leukoencephalopathy.

The most common AEs leading to dose interruption were QT prolongation (7%), differentiation syndrome (3%), leukocytosis (3%), and dyspnea (3%). AEs leading to a dose reduction included QT prolongation (1%), diarrhea (1%), nausea (1%), decreased hemoglobin (1%), and increased transaminases (1%).

AEs leading to permanent discontinuation of ivosidenib included Guillain-Barré syndrome (1%), rash (1%), stomatitis (1%), and creatinine increase (1%).

For additional data and more details on ivosidenib, see the full prescribing information or visit Tibsovo.com.

Agios Pharmaceuticals

The US Food and Drug Administration (FDA) has granted full approval for the isocitrate dehydrogenase-1 (IDH1) inhibitor ivosidenib (Tibsovo®).

The drug is approved to treat adults with relapsed or refractory acute myeloid leukemia (AML) who have an IDH1 mutation, as detected by an FDA-approved test.

Ivosidenib was approved concurrently with the RealTime IDH1 Assay, a companion diagnostic that can detect IDH1 mutation.

The FDA granted approval of ivosidenib to Agios Pharmaceuticals, Inc., and approval of the RealTime IDH1 Assay to Abbott Laboratories.

The FDA’s approval of ivosidenib was based on data from a single-arm, phase 1 study. Agios received fast track, priority review, and orphan drug designations for ivosidenib.

Safety risks

Ivosidenib must be dispensed with a patient medication guide that describes important information about the drug’s uses and risks.

The prescribing information for ivosidenib includes a Boxed Warning noting that patients treated with ivosidenib have experienced symptoms of differentiation syndrome, which can be fatal if not treated.

Signs and symptoms of differentiation syndrome may include fever, dyspnea, acute respiratory distress, radiographic pulmonary infiltrates, pleural or pericardial effusions, rapid weight gain, peripheral edema, or hepatic, renal, or multi-organ dysfunction.

At first suspicion of symptoms, doctors should treat patients with corticosteroids and monitor them closely until symptoms subside.

Ivosidenib also poses a risk of life-threatening QT prolongation and Guillain-Barré syndrome, so patients should be monitored for these adverse events (AEs) as well.

Phase 1 trial

Results from the phase 1 trial of ivosidenib were presented at the 2018 ASCO Annual Meeting and published simultaneously in NEJM. The following data were pulled from the drug’s prescribing information.

Efficacy results were available for 174 adults with relapsed/refractory AML and an IDH1 mutation identified or confirmed by the Abbott RealTime™ IDH1 assay. The patients received ivosidenib at a starting dose of 500 mg daily until disease progression, unacceptable toxicity, or hematopoietic stem cell transplant.

The patients had a median age of 67 (range, 18 to 87) and had received a median of 2 prior therapies (range, 1 to 6). Sixty-three percent were refractory to previous therapy, and 33% had secondary AML.

The study’s primary endpoint was the combined rate of complete remission (CR) rate and CR with partial hematologic improvement (CRh).

The CR+CRh rate was 32.8% (57/174), the CR rate was 24.7% (43/174), and the CRh rate was 8% (14/174).

The median duration of CR+CRh was 8.2 months (95% CI 5.6, 12). The median time to best response of CR or CRh was 2.0 months (range, 0.9 to 5.6 months).

Twelve percent of patients (21/174) went on to transplant.

The researchers evaluated the safety of ivosidenib in 179 patients treated with a dose of 500 mg daily. The median duration of exposure to ivosidenib was 3.9 months (range, 0.1 to 39.5 months).

Nineteen percent of patients (34/179) experienced differentiation syndrome. Seventy-nine percent of these patients (27/34) recovered after treatment or ivosidenib dose interruption.

The most frequent serious AEs (>5%) were differentiation syndrome (10%), leukocytosis (10%), and electrocardiogram QT prolongation (7%). There was one case of progressive multifocal leukoencephalopathy.

The most common AEs leading to dose interruption were QT prolongation (7%), differentiation syndrome (3%), leukocytosis (3%), and dyspnea (3%). AEs leading to a dose reduction included QT prolongation (1%), diarrhea (1%), nausea (1%), decreased hemoglobin (1%), and increased transaminases (1%).

AEs leading to permanent discontinuation of ivosidenib included Guillain-Barré syndrome (1%), rash (1%), stomatitis (1%), and creatinine increase (1%).

For additional data and more details on ivosidenib, see the full prescribing information or visit Tibsovo.com.

Photo by Bill Branson

The US Food and Drug Administration (FDA) has approved the leukocyte growth factor Nivestym™ (filgrastim-aafi), a biosimilar to Neupogen (filgrastim).

Nivestym is approved to treat patients with nonmyeloid malignancies who are receiving myelosuppressive chemotherapy or undergoing bone marrow transplant, acute myeloid leukemia patients receiving induction or consolidation chemotherapy, patients undergoing autologous peripheral blood progenitor cell collection, and patients with severe chronic neutropenia.

The FDA’s approval of Nivestym was based on a review of evidence suggesting the drug is highly similar to Neupogen, according to Pfizer, the company developing Nivestym.

The full approved indication for Nivestym is as follows:

• To decrease the incidence of infection, as manifested by febrile neutropenia, in patients with nonmyeloid malignancies receiving myelosuppressive anticancer drugs associated with a significant incidence of severe neutropenia with fever
• To reduce the time to neutrophil recovery and the duration of fever following induction or consolidation chemotherapy in patients with acute myeloid leukemia
• To reduce the duration of neutropenia and neutropenia-related clinical sequelae (eg, febrile neutropenia) in patients with nonmyeloid malignancies undergoing myeloablative chemotherapy followed by bone marrow transplant
• For the mobilization of autologous hematopoietic progenitor cells into the peripheral blood for collection by leukapheresis
• For chronic administration to reduce the incidence and duration of sequelae of severe neutropenia (eg, fever, infections, oropharyngeal ulcers) in symptomatic patients with congenital neutropenia, cyclic neutropenia, or idiopathic neutropenia.

For more details on Nivestym, see the full prescribing information.

Photo by Bill Branson

The US Food and Drug Administration (FDA) has approved the leukocyte growth factor Nivestym™ (filgrastim-aafi), a biosimilar to Neupogen (filgrastim).

Nivestym is approved to treat patients with nonmyeloid malignancies who are receiving myelosuppressive chemotherapy or undergoing bone marrow transplant, acute myeloid leukemia patients receiving induction or consolidation chemotherapy, patients undergoing autologous peripheral blood progenitor cell collection, and patients with severe chronic neutropenia.

The FDA’s approval of Nivestym was based on a review of evidence suggesting the drug is highly similar to Neupogen, according to Pfizer, the company developing Nivestym.

The full approved indication for Nivestym is as follows:

• To decrease the incidence of infection, as manifested by febrile neutropenia, in patients with nonmyeloid malignancies receiving myelosuppressive anticancer drugs associated with a significant incidence of severe neutropenia with fever
• To reduce the time to neutrophil recovery and the duration of fever following induction or consolidation chemotherapy in patients with acute myeloid leukemia
• To reduce the duration of neutropenia and neutropenia-related clinical sequelae (eg, febrile neutropenia) in patients with nonmyeloid malignancies undergoing myeloablative chemotherapy followed by bone marrow transplant
• For the mobilization of autologous hematopoietic progenitor cells into the peripheral blood for collection by leukapheresis
• For chronic administration to reduce the incidence and duration of sequelae of severe neutropenia (eg, fever, infections, oropharyngeal ulcers) in symptomatic patients with congenital neutropenia, cyclic neutropenia, or idiopathic neutropenia.

For more details on Nivestym, see the full prescribing information.

Photo by Bill Branson

The US Food and Drug Administration (FDA) has approved the leukocyte growth factor Nivestym™ (filgrastim-aafi), a biosimilar to Neupogen (filgrastim).

Nivestym is approved to treat patients with nonmyeloid malignancies who are receiving myelosuppressive chemotherapy or undergoing bone marrow transplant, acute myeloid leukemia patients receiving induction or consolidation chemotherapy, patients undergoing autologous peripheral blood progenitor cell collection, and patients with severe chronic neutropenia.

The FDA’s approval of Nivestym was based on a review of evidence suggesting the drug is highly similar to Neupogen, according to Pfizer, the company developing Nivestym.

The full approved indication for Nivestym is as follows:

• To decrease the incidence of infection, as manifested by febrile neutropenia, in patients with nonmyeloid malignancies receiving myelosuppressive anticancer drugs associated with a significant incidence of severe neutropenia with fever
• To reduce the time to neutrophil recovery and the duration of fever following induction or consolidation chemotherapy in patients with acute myeloid leukemia
• To reduce the duration of neutropenia and neutropenia-related clinical sequelae (eg, febrile neutropenia) in patients with nonmyeloid malignancies undergoing myeloablative chemotherapy followed by bone marrow transplant
• For the mobilization of autologous hematopoietic progenitor cells into the peripheral blood for collection by leukapheresis
• For chronic administration to reduce the incidence and duration of sequelae of severe neutropenia (eg, fever, infections, oropharyngeal ulcers) in symptomatic patients with congenital neutropenia, cyclic neutropenia, or idiopathic neutropenia.

For more details on Nivestym, see the full prescribing information.