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Ixazomib could improve treatment of AML
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.
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.
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.
Team recommends melanoma screening in CLL
Patients with chronic lymphocytic leukemia (CLL) should be routinely monitored for melanoma, according to researchers.
A study of 470 CLL patients showed they have a significantly higher risk of invasive melanoma than the general population.
Most of the melanomas reported in this study were detected via routine surveillance, and most were discovered before they reached an advanced stage.
Clive Zent, MD, of Wilmot Cancer Institute at the University of Rochester Medical Center in Rochester, New York, and his colleagues described this study in Leukemia Research.
The researchers analyzed data on 470 CLL patients followed for 2849 person-years. Eighteen of these patients developed 22 melanomas. This included 14 cases of invasive melanoma in 13 patients.
The rate of invasive melanoma was significantly higher in this CLL cohort than the rate observed in the age- and sex-matched general population. The standardized incidence ratio was 6.32.
“We do not for sure know why CLL patients are more susceptible to melanoma, but the most likely cause is a suppressed immune system,” Dr Zent noted.
“Normally, in people with healthy immune systems, malignant skin cells might be detected and destroyed before they become a problem. But in CLL patients, failure of this control system increases the rate at which cancer cells can grow into tumors and also the likelihood that they will become invasive or spread to distant sites.”
Detection and management
Fifteen of the 22 melanomas (68.2%) in the CLL cohort were detected via surveillance in a dermatology clinic, and 2 (9.1%) were detected at the CLL/lymphoma clinic.
Three cases of melanoma (14.3%) were detected within the first year of a patient’s CLL diagnosis.
Seven melanomas (33.3%) were detected at pathologic stage 0, 8 (38.1%) at stage I, 2 (9.5%) at stage II, 3 (14.3%) at stage III, and 1 (4.8%) at stage IV. Detailed data were not available for the remaining case.
Melanomas were managed with wide local excision (n=19), sentinel node biopsies (n=6), Mohs surgery (n=1), drugs (n=2), palliative care (n=1), and comfort care (n=1).
The 4 patients who received drugs, palliative care, or comfort care had advanced melanoma.
The patient who received palliative care was still alive at 2.4 years of follow-up. The patient who received comfort care died of metastatic melanoma 1.4 years after diagnosis.
The third patient with advanced melanoma received 2 cycles of dacarbazine and palliative radiation to lung and brain metastases. This patient died 3.6 years after melanoma diagnosis.
The fourth patient received ipilimumab for the melanoma while also receiving ibrutinib to treat her CLL. When the ipilimumab failed, the patient proceeded to pembrolizumab and achieved a near-complete response within 3 months. Then, an intensely hypermetabolic abdominal node was detected and successfully treated with radiation.
The patient continued on pembrolizumab, and her melanoma was in sustained remission at last follow-up, after 23 cycles of pembrolizumab. Her CLL was still responding to ibrutinib at that point as well.
Based on these data, Dr Zent and his colleagues recommend routine melanoma screening for CLL patients. The team believes such surveillance might decrease morbidity and mortality in these patients, although more research is needed to confirm this theory.
Patients with chronic lymphocytic leukemia (CLL) should be routinely monitored for melanoma, according to researchers.
A study of 470 CLL patients showed they have a significantly higher risk of invasive melanoma than the general population.
Most of the melanomas reported in this study were detected via routine surveillance, and most were discovered before they reached an advanced stage.
Clive Zent, MD, of Wilmot Cancer Institute at the University of Rochester Medical Center in Rochester, New York, and his colleagues described this study in Leukemia Research.
The researchers analyzed data on 470 CLL patients followed for 2849 person-years. Eighteen of these patients developed 22 melanomas. This included 14 cases of invasive melanoma in 13 patients.
The rate of invasive melanoma was significantly higher in this CLL cohort than the rate observed in the age- and sex-matched general population. The standardized incidence ratio was 6.32.
“We do not for sure know why CLL patients are more susceptible to melanoma, but the most likely cause is a suppressed immune system,” Dr Zent noted.
“Normally, in people with healthy immune systems, malignant skin cells might be detected and destroyed before they become a problem. But in CLL patients, failure of this control system increases the rate at which cancer cells can grow into tumors and also the likelihood that they will become invasive or spread to distant sites.”
Detection and management
Fifteen of the 22 melanomas (68.2%) in the CLL cohort were detected via surveillance in a dermatology clinic, and 2 (9.1%) were detected at the CLL/lymphoma clinic.
Three cases of melanoma (14.3%) were detected within the first year of a patient’s CLL diagnosis.
Seven melanomas (33.3%) were detected at pathologic stage 0, 8 (38.1%) at stage I, 2 (9.5%) at stage II, 3 (14.3%) at stage III, and 1 (4.8%) at stage IV. Detailed data were not available for the remaining case.
Melanomas were managed with wide local excision (n=19), sentinel node biopsies (n=6), Mohs surgery (n=1), drugs (n=2), palliative care (n=1), and comfort care (n=1).
The 4 patients who received drugs, palliative care, or comfort care had advanced melanoma.
The patient who received palliative care was still alive at 2.4 years of follow-up. The patient who received comfort care died of metastatic melanoma 1.4 years after diagnosis.
The third patient with advanced melanoma received 2 cycles of dacarbazine and palliative radiation to lung and brain metastases. This patient died 3.6 years after melanoma diagnosis.
The fourth patient received ipilimumab for the melanoma while also receiving ibrutinib to treat her CLL. When the ipilimumab failed, the patient proceeded to pembrolizumab and achieved a near-complete response within 3 months. Then, an intensely hypermetabolic abdominal node was detected and successfully treated with radiation.
The patient continued on pembrolizumab, and her melanoma was in sustained remission at last follow-up, after 23 cycles of pembrolizumab. Her CLL was still responding to ibrutinib at that point as well.
Based on these data, Dr Zent and his colleagues recommend routine melanoma screening for CLL patients. The team believes such surveillance might decrease morbidity and mortality in these patients, although more research is needed to confirm this theory.
Patients with chronic lymphocytic leukemia (CLL) should be routinely monitored for melanoma, according to researchers.
A study of 470 CLL patients showed they have a significantly higher risk of invasive melanoma than the general population.
Most of the melanomas reported in this study were detected via routine surveillance, and most were discovered before they reached an advanced stage.
Clive Zent, MD, of Wilmot Cancer Institute at the University of Rochester Medical Center in Rochester, New York, and his colleagues described this study in Leukemia Research.
The researchers analyzed data on 470 CLL patients followed for 2849 person-years. Eighteen of these patients developed 22 melanomas. This included 14 cases of invasive melanoma in 13 patients.
The rate of invasive melanoma was significantly higher in this CLL cohort than the rate observed in the age- and sex-matched general population. The standardized incidence ratio was 6.32.
“We do not for sure know why CLL patients are more susceptible to melanoma, but the most likely cause is a suppressed immune system,” Dr Zent noted.
“Normally, in people with healthy immune systems, malignant skin cells might be detected and destroyed before they become a problem. But in CLL patients, failure of this control system increases the rate at which cancer cells can grow into tumors and also the likelihood that they will become invasive or spread to distant sites.”
Detection and management
Fifteen of the 22 melanomas (68.2%) in the CLL cohort were detected via surveillance in a dermatology clinic, and 2 (9.1%) were detected at the CLL/lymphoma clinic.
Three cases of melanoma (14.3%) were detected within the first year of a patient’s CLL diagnosis.
Seven melanomas (33.3%) were detected at pathologic stage 0, 8 (38.1%) at stage I, 2 (9.5%) at stage II, 3 (14.3%) at stage III, and 1 (4.8%) at stage IV. Detailed data were not available for the remaining case.
Melanomas were managed with wide local excision (n=19), sentinel node biopsies (n=6), Mohs surgery (n=1), drugs (n=2), palliative care (n=1), and comfort care (n=1).
The 4 patients who received drugs, palliative care, or comfort care had advanced melanoma.
The patient who received palliative care was still alive at 2.4 years of follow-up. The patient who received comfort care died of metastatic melanoma 1.4 years after diagnosis.
The third patient with advanced melanoma received 2 cycles of dacarbazine and palliative radiation to lung and brain metastases. This patient died 3.6 years after melanoma diagnosis.
The fourth patient received ipilimumab for the melanoma while also receiving ibrutinib to treat her CLL. When the ipilimumab failed, the patient proceeded to pembrolizumab and achieved a near-complete response within 3 months. Then, an intensely hypermetabolic abdominal node was detected and successfully treated with radiation.
The patient continued on pembrolizumab, and her melanoma was in sustained remission at last follow-up, after 23 cycles of pembrolizumab. Her CLL was still responding to ibrutinib at that point as well.
Based on these data, Dr Zent and his colleagues recommend routine melanoma screening for CLL patients. The team believes such surveillance might decrease morbidity and mortality in these patients, although more research is needed to confirm this theory.
Frequent BCCs linked to blood cancers
New research suggests people who develop frequent cases of basal cell carcinoma (BCC) have an increased risk of leukemias, lymphomas, and other cancers.
“We discovered that people who develop 6 or more basal cell carcinomas during a 10-year period are about 3 times more likely than the general population to develop other, unrelated cancers,” said Kavita Sarin, MD, PhD, of Stanford University School of Medicine in California.
“We’re hopeful that this finding could be a way to identify people at an increased risk for a life-threatening malignancy before those cancers develop.”
Dr Sarin and her colleagues reported their findings in JCI Insight.
Stanford cohort
The researchers first studied 61 patients treated at Stanford Health Care for unusually frequent BCCs—an average of 11 per patient over a 10-year period. The team investigated whether these patients may have mutations in 29 genes that code for DNA damage repair proteins.
“We found that about 20% of the people with frequent basal cell carcinomas have a mutation in one of the genes responsible for repairing DNA damage, versus about 3% of the general population,” Dr Sarin said. “That’s shockingly high.”
Specifically, there were 12 BCC patients (19.7%) who had 13 pathogenic mutations in 12 genes—APC, BARD1, BRCA1, BRCA2, CDH1, CHEK2, MLH1, MSH2, MSH6, MUTYH, NBN, and PALB2. And 3.0% of non-Finnish European subjects in the Exome Aggregation Consortium had pathogenic mutations in these 12 genes.
Furthermore, 21 of the 61 BCC patients (64.4%) had a history of additional cancers. This included 5 hematologic malignancies (leukemia/lymphoma), 5 invasive melanomas, and 2 breast, 2 colon, and 5 prostate cancers.
When the researchers compared the cancer prevalence in these patients to the Surveillance, Epidemiology, and End Results-estimated prevalence of cancer in the 60- to 69-year-old population of European descent, the BCC cohort had an increased risk of any cancer—a relative risk (RR) of 3.5 (P<0.001).
The RR was 3.5 for leukemia and lymphoma (P=0.004), 11.9 for invasive melanoma (P<0.001), 4.5 for colon cancer (P=0.030), 5.6 for breast cancer (P=0.009), and 4.7 for prostate cancer (P<0.001).
Insurance cohort
To confirm the findings in the Stanford cohort, the researchers applied a similar analysis to a large medical insurance claims database, Truven MarketScan.
The database contained 111,562 patients with 1 case of BCC, 13,264 patients with 6 or more BCCs, and 2920 patients with 12 or more BCCs. Truven patients with no history of BCC served as controls.
The researchers adjusted for age and sex and found that patients with 1 BCC, 6 or more BCCs, and 12 or more BCCs had an increased risk of any cancer compared to controls.
The odds ratio (OR) for any cancer was 1.61 for patients with 1 BCC, 3.12 for those with 6 or more BCCs, and 4.15 for patients with 12 or more BCCs.
The OR for Hodgkin lymphoma was 2.27 for patients with 1 BCC, 8.94 for patients with 6 or more BCCs, and 15.41 for patients with 12 or more BCCs.
The OR for non-Hodgkin lymphoma was 1.40 for patients with 1 BCC, 2.59 for patients with 6 or more BCCs, and 3.10 for patients with 12 or more BCCs.
The OR for leukemia was 1.76 for patients with 1 BCC, 3.23 for patients with 6 or more BCCs, and 5.78 for patients with 12 or more BCCs.
The researchers pointed out that, the more BCCs an individual had, the more likely that person was to have had other cancers as well.
“I was surprised to see such a strong correlation, but it’s also very gratifying,” Dr Sarin said. “Now, we can ask patients with repeated basal cell carcinomas whether they have family members with other types of cancers and perhaps suggest that they consider genetic testing and increased screening.”
The researchers are continuing to enroll Stanford patients in their study to learn whether particular mutations in genes responsible for repairing DNA damage are linked to the development of specific malignancies. The team would also like to conduct a similar study in patients with frequent melanomas.
The current study was supported by the Dermatology Foundation, the Stanford Society of Physician Scholars, the American Skin Association, and Pellepharm Inc.
New research suggests people who develop frequent cases of basal cell carcinoma (BCC) have an increased risk of leukemias, lymphomas, and other cancers.
“We discovered that people who develop 6 or more basal cell carcinomas during a 10-year period are about 3 times more likely than the general population to develop other, unrelated cancers,” said Kavita Sarin, MD, PhD, of Stanford University School of Medicine in California.
“We’re hopeful that this finding could be a way to identify people at an increased risk for a life-threatening malignancy before those cancers develop.”
Dr Sarin and her colleagues reported their findings in JCI Insight.
Stanford cohort
The researchers first studied 61 patients treated at Stanford Health Care for unusually frequent BCCs—an average of 11 per patient over a 10-year period. The team investigated whether these patients may have mutations in 29 genes that code for DNA damage repair proteins.
“We found that about 20% of the people with frequent basal cell carcinomas have a mutation in one of the genes responsible for repairing DNA damage, versus about 3% of the general population,” Dr Sarin said. “That’s shockingly high.”
Specifically, there were 12 BCC patients (19.7%) who had 13 pathogenic mutations in 12 genes—APC, BARD1, BRCA1, BRCA2, CDH1, CHEK2, MLH1, MSH2, MSH6, MUTYH, NBN, and PALB2. And 3.0% of non-Finnish European subjects in the Exome Aggregation Consortium had pathogenic mutations in these 12 genes.
Furthermore, 21 of the 61 BCC patients (64.4%) had a history of additional cancers. This included 5 hematologic malignancies (leukemia/lymphoma), 5 invasive melanomas, and 2 breast, 2 colon, and 5 prostate cancers.
When the researchers compared the cancer prevalence in these patients to the Surveillance, Epidemiology, and End Results-estimated prevalence of cancer in the 60- to 69-year-old population of European descent, the BCC cohort had an increased risk of any cancer—a relative risk (RR) of 3.5 (P<0.001).
The RR was 3.5 for leukemia and lymphoma (P=0.004), 11.9 for invasive melanoma (P<0.001), 4.5 for colon cancer (P=0.030), 5.6 for breast cancer (P=0.009), and 4.7 for prostate cancer (P<0.001).
Insurance cohort
To confirm the findings in the Stanford cohort, the researchers applied a similar analysis to a large medical insurance claims database, Truven MarketScan.
The database contained 111,562 patients with 1 case of BCC, 13,264 patients with 6 or more BCCs, and 2920 patients with 12 or more BCCs. Truven patients with no history of BCC served as controls.
The researchers adjusted for age and sex and found that patients with 1 BCC, 6 or more BCCs, and 12 or more BCCs had an increased risk of any cancer compared to controls.
The odds ratio (OR) for any cancer was 1.61 for patients with 1 BCC, 3.12 for those with 6 or more BCCs, and 4.15 for patients with 12 or more BCCs.
The OR for Hodgkin lymphoma was 2.27 for patients with 1 BCC, 8.94 for patients with 6 or more BCCs, and 15.41 for patients with 12 or more BCCs.
The OR for non-Hodgkin lymphoma was 1.40 for patients with 1 BCC, 2.59 for patients with 6 or more BCCs, and 3.10 for patients with 12 or more BCCs.
The OR for leukemia was 1.76 for patients with 1 BCC, 3.23 for patients with 6 or more BCCs, and 5.78 for patients with 12 or more BCCs.
The researchers pointed out that, the more BCCs an individual had, the more likely that person was to have had other cancers as well.
“I was surprised to see such a strong correlation, but it’s also very gratifying,” Dr Sarin said. “Now, we can ask patients with repeated basal cell carcinomas whether they have family members with other types of cancers and perhaps suggest that they consider genetic testing and increased screening.”
The researchers are continuing to enroll Stanford patients in their study to learn whether particular mutations in genes responsible for repairing DNA damage are linked to the development of specific malignancies. The team would also like to conduct a similar study in patients with frequent melanomas.
The current study was supported by the Dermatology Foundation, the Stanford Society of Physician Scholars, the American Skin Association, and Pellepharm Inc.
New research suggests people who develop frequent cases of basal cell carcinoma (BCC) have an increased risk of leukemias, lymphomas, and other cancers.
“We discovered that people who develop 6 or more basal cell carcinomas during a 10-year period are about 3 times more likely than the general population to develop other, unrelated cancers,” said Kavita Sarin, MD, PhD, of Stanford University School of Medicine in California.
“We’re hopeful that this finding could be a way to identify people at an increased risk for a life-threatening malignancy before those cancers develop.”
Dr Sarin and her colleagues reported their findings in JCI Insight.
Stanford cohort
The researchers first studied 61 patients treated at Stanford Health Care for unusually frequent BCCs—an average of 11 per patient over a 10-year period. The team investigated whether these patients may have mutations in 29 genes that code for DNA damage repair proteins.
“We found that about 20% of the people with frequent basal cell carcinomas have a mutation in one of the genes responsible for repairing DNA damage, versus about 3% of the general population,” Dr Sarin said. “That’s shockingly high.”
Specifically, there were 12 BCC patients (19.7%) who had 13 pathogenic mutations in 12 genes—APC, BARD1, BRCA1, BRCA2, CDH1, CHEK2, MLH1, MSH2, MSH6, MUTYH, NBN, and PALB2. And 3.0% of non-Finnish European subjects in the Exome Aggregation Consortium had pathogenic mutations in these 12 genes.
Furthermore, 21 of the 61 BCC patients (64.4%) had a history of additional cancers. This included 5 hematologic malignancies (leukemia/lymphoma), 5 invasive melanomas, and 2 breast, 2 colon, and 5 prostate cancers.
When the researchers compared the cancer prevalence in these patients to the Surveillance, Epidemiology, and End Results-estimated prevalence of cancer in the 60- to 69-year-old population of European descent, the BCC cohort had an increased risk of any cancer—a relative risk (RR) of 3.5 (P<0.001).
The RR was 3.5 for leukemia and lymphoma (P=0.004), 11.9 for invasive melanoma (P<0.001), 4.5 for colon cancer (P=0.030), 5.6 for breast cancer (P=0.009), and 4.7 for prostate cancer (P<0.001).
Insurance cohort
To confirm the findings in the Stanford cohort, the researchers applied a similar analysis to a large medical insurance claims database, Truven MarketScan.
The database contained 111,562 patients with 1 case of BCC, 13,264 patients with 6 or more BCCs, and 2920 patients with 12 or more BCCs. Truven patients with no history of BCC served as controls.
The researchers adjusted for age and sex and found that patients with 1 BCC, 6 or more BCCs, and 12 or more BCCs had an increased risk of any cancer compared to controls.
The odds ratio (OR) for any cancer was 1.61 for patients with 1 BCC, 3.12 for those with 6 or more BCCs, and 4.15 for patients with 12 or more BCCs.
The OR for Hodgkin lymphoma was 2.27 for patients with 1 BCC, 8.94 for patients with 6 or more BCCs, and 15.41 for patients with 12 or more BCCs.
The OR for non-Hodgkin lymphoma was 1.40 for patients with 1 BCC, 2.59 for patients with 6 or more BCCs, and 3.10 for patients with 12 or more BCCs.
The OR for leukemia was 1.76 for patients with 1 BCC, 3.23 for patients with 6 or more BCCs, and 5.78 for patients with 12 or more BCCs.
The researchers pointed out that, the more BCCs an individual had, the more likely that person was to have had other cancers as well.
“I was surprised to see such a strong correlation, but it’s also very gratifying,” Dr Sarin said. “Now, we can ask patients with repeated basal cell carcinomas whether they have family members with other types of cancers and perhaps suggest that they consider genetic testing and increased screening.”
The researchers are continuing to enroll Stanford patients in their study to learn whether particular mutations in genes responsible for repairing DNA damage are linked to the development of specific malignancies. The team would also like to conduct a similar study in patients with frequent melanomas.
The current study was supported by the Dermatology Foundation, the Stanford Society of Physician Scholars, the American Skin Association, and Pellepharm Inc.
Comprehensive sequencing informs treatment for MM
A comprehensive RNA and DNA sequencing platform can guide treatment decisions for late-stage and drug-resistant multiple myeloma (MM), according to a study published in JCO Precision Oncology.
Researchers used the platform to generate treatment suggestions for 64 MM patients who had exhausted all approved treatment options.
Of the 21 evaluable patients who received the sequencing-recommended therapies, 67% achieved a response. Five patients had ongoing responses at the end of the trial.
“Our study shows how a precision medicine approach incorporating RNA sequencing may identify viable and effective therapeutic options beyond the current FDA-approved armamentarium for multiple myeloma patients,” said study author Samir Parekh, MD, of the Icahn School of Medicine at Mount Sinai in New York, New York.
“The trial has allowed us to test the accuracy of our platform, laying the foundation for our next-generation precision medicine framework.”
Dr Parekh and his colleagues used DNA and RNA sequencing data to generate personalized treatment recommendations for 64 heavily pretreated MM patients.
The patients had received a median of 7 lines of therapy. Most patients (61%) were male, their median age was 59 (range, 40-85), and 67% had high-risk cytogenetics.
The sequencing data yielded treatment recommendations for 63 patients. Twenty-six patients (42%) actually received at least 1 of the recommended treatments.
The treatments (given alone or in combination) were:
- Trametinib (n=16)—recommended because of mutations in NRAS or KRAS
- Venetoclax (n=8)—recommended because of high BCL2 expression
- Panobinostat (n=6)—recommended due to activation of the HDAC pathway and/or by RNA-based drug repurposing selecting the pan-HDAC inhibitor vorinostat
- Dabrafenib (n=1)—recommended because of concurrent BRAF and RAS mutations
- Etoposide (n=2)—selected by RNA-based drug repurposing.
Twenty-one patients were evaluable for response. The researchers noted that 11 of these patients received treatment based on RNA findings, 8 based on DNA, and 2 based on both.
One patient achieved a complete response, 3 had a very good partial response, 10 had a partial response, 2 had a minimal response (25% reduction of disease marker), 3 had stable disease, and 2 progressed.
That means the overall response rate was 66.6% (14/21), and the clinical benefit rate (minimal response or better) was 76.2% (16/21).
The median duration of response was 131 days (range, 37-372), and 5 patients were still in response at the end of the study (September, 1, 2017).
Mount Sinai researchers have received funding to develop a clinical trial that will incorporate machine learning algorithms into this precision medicine platform, which will implement interactive learning techniques to refine the predictions based on a patient’s success with the therapies and a physician’s opinion of the treatment plan.
“This research is part of an accelerating paradigm shift in cancer therapy where treatment may be given based on the specific genomic alterations observed in a patient’s tumor rather than on the tumor histology or tissue type,” said study author Joel Dudley, PhD, of the Icahn School of Medicine at Mount Sinai.
“RNA sequencing will likely complement current precision medicine strategies in the near future due to its ability to capture more dynamic aspects of unique tumor biology and provide information beyond what is capable with DNA alone.”
A comprehensive RNA and DNA sequencing platform can guide treatment decisions for late-stage and drug-resistant multiple myeloma (MM), according to a study published in JCO Precision Oncology.
Researchers used the platform to generate treatment suggestions for 64 MM patients who had exhausted all approved treatment options.
Of the 21 evaluable patients who received the sequencing-recommended therapies, 67% achieved a response. Five patients had ongoing responses at the end of the trial.
“Our study shows how a precision medicine approach incorporating RNA sequencing may identify viable and effective therapeutic options beyond the current FDA-approved armamentarium for multiple myeloma patients,” said study author Samir Parekh, MD, of the Icahn School of Medicine at Mount Sinai in New York, New York.
“The trial has allowed us to test the accuracy of our platform, laying the foundation for our next-generation precision medicine framework.”
Dr Parekh and his colleagues used DNA and RNA sequencing data to generate personalized treatment recommendations for 64 heavily pretreated MM patients.
The patients had received a median of 7 lines of therapy. Most patients (61%) were male, their median age was 59 (range, 40-85), and 67% had high-risk cytogenetics.
The sequencing data yielded treatment recommendations for 63 patients. Twenty-six patients (42%) actually received at least 1 of the recommended treatments.
The treatments (given alone or in combination) were:
- Trametinib (n=16)—recommended because of mutations in NRAS or KRAS
- Venetoclax (n=8)—recommended because of high BCL2 expression
- Panobinostat (n=6)—recommended due to activation of the HDAC pathway and/or by RNA-based drug repurposing selecting the pan-HDAC inhibitor vorinostat
- Dabrafenib (n=1)—recommended because of concurrent BRAF and RAS mutations
- Etoposide (n=2)—selected by RNA-based drug repurposing.
Twenty-one patients were evaluable for response. The researchers noted that 11 of these patients received treatment based on RNA findings, 8 based on DNA, and 2 based on both.
One patient achieved a complete response, 3 had a very good partial response, 10 had a partial response, 2 had a minimal response (25% reduction of disease marker), 3 had stable disease, and 2 progressed.
That means the overall response rate was 66.6% (14/21), and the clinical benefit rate (minimal response or better) was 76.2% (16/21).
The median duration of response was 131 days (range, 37-372), and 5 patients were still in response at the end of the study (September, 1, 2017).
Mount Sinai researchers have received funding to develop a clinical trial that will incorporate machine learning algorithms into this precision medicine platform, which will implement interactive learning techniques to refine the predictions based on a patient’s success with the therapies and a physician’s opinion of the treatment plan.
“This research is part of an accelerating paradigm shift in cancer therapy where treatment may be given based on the specific genomic alterations observed in a patient’s tumor rather than on the tumor histology or tissue type,” said study author Joel Dudley, PhD, of the Icahn School of Medicine at Mount Sinai.
“RNA sequencing will likely complement current precision medicine strategies in the near future due to its ability to capture more dynamic aspects of unique tumor biology and provide information beyond what is capable with DNA alone.”
A comprehensive RNA and DNA sequencing platform can guide treatment decisions for late-stage and drug-resistant multiple myeloma (MM), according to a study published in JCO Precision Oncology.
Researchers used the platform to generate treatment suggestions for 64 MM patients who had exhausted all approved treatment options.
Of the 21 evaluable patients who received the sequencing-recommended therapies, 67% achieved a response. Five patients had ongoing responses at the end of the trial.
“Our study shows how a precision medicine approach incorporating RNA sequencing may identify viable and effective therapeutic options beyond the current FDA-approved armamentarium for multiple myeloma patients,” said study author Samir Parekh, MD, of the Icahn School of Medicine at Mount Sinai in New York, New York.
“The trial has allowed us to test the accuracy of our platform, laying the foundation for our next-generation precision medicine framework.”
Dr Parekh and his colleagues used DNA and RNA sequencing data to generate personalized treatment recommendations for 64 heavily pretreated MM patients.
The patients had received a median of 7 lines of therapy. Most patients (61%) were male, their median age was 59 (range, 40-85), and 67% had high-risk cytogenetics.
The sequencing data yielded treatment recommendations for 63 patients. Twenty-six patients (42%) actually received at least 1 of the recommended treatments.
The treatments (given alone or in combination) were:
- Trametinib (n=16)—recommended because of mutations in NRAS or KRAS
- Venetoclax (n=8)—recommended because of high BCL2 expression
- Panobinostat (n=6)—recommended due to activation of the HDAC pathway and/or by RNA-based drug repurposing selecting the pan-HDAC inhibitor vorinostat
- Dabrafenib (n=1)—recommended because of concurrent BRAF and RAS mutations
- Etoposide (n=2)—selected by RNA-based drug repurposing.
Twenty-one patients were evaluable for response. The researchers noted that 11 of these patients received treatment based on RNA findings, 8 based on DNA, and 2 based on both.
One patient achieved a complete response, 3 had a very good partial response, 10 had a partial response, 2 had a minimal response (25% reduction of disease marker), 3 had stable disease, and 2 progressed.
That means the overall response rate was 66.6% (14/21), and the clinical benefit rate (minimal response or better) was 76.2% (16/21).
The median duration of response was 131 days (range, 37-372), and 5 patients were still in response at the end of the study (September, 1, 2017).
Mount Sinai researchers have received funding to develop a clinical trial that will incorporate machine learning algorithms into this precision medicine platform, which will implement interactive learning techniques to refine the predictions based on a patient’s success with the therapies and a physician’s opinion of the treatment plan.
“This research is part of an accelerating paradigm shift in cancer therapy where treatment may be given based on the specific genomic alterations observed in a patient’s tumor rather than on the tumor histology or tissue type,” said study author Joel Dudley, PhD, of the Icahn School of Medicine at Mount Sinai.
“RNA sequencing will likely complement current precision medicine strategies in the near future due to its ability to capture more dynamic aspects of unique tumor biology and provide information beyond what is capable with DNA alone.”
Tool identifies potential treatment for resistant MM
Researchers say they have developed a computational platform that can be used to identify optimal treatments for multiple myeloma (MM).
Using this tool, the quadratic phenotypic optimization platform (QPOP), the researchers identified a 2-drug combination that proved effective against bortezomib-resistant MM in vitro.
The combination—decitabine and mitomycin C—also decreased tumor volume and prolonged survival in a mouse model of bortezomib-resistant MM.
Masturah Bte Mohd Abdul Rashid, of the Cancer Science Institute of Singapore, and her colleagues reported these results in Science Translational Medicine.
The researchers explained that QPOP approximates biological responses to therapies using advanced mathematical equations. Unlike conventional models, QPOP doesn’t require predetermined information about the mechanisms or composition of a drug.
To test QPOP’s utility in MM, the researchers began by identifying candidate drugs that might be effective against bortezomib-resistant MM. They screened 114 approved oncology drugs on 2 MM cell lines—RPMI 8226 and bortezomib-resistant RPMI 8226 (P100v).
The drugs that proved most effective against P100v were dactinomycin, decitabine, mechlorethamine hydrochloride, and mitomycin C.
The researchers wanted to identify optimal drug combinations, so they conducted a QPOP analysis including the 4 most effective drugs and an additional 10 drugs used to treat MM. The 10 drugs were bortezomib, carfilzomib, cyclophosphamide monohydrate, dexamethasone, doxorubucin, lenalidomide, panobinostat, plerixafor, thalidomide, and zoledronic acid.
The team tested 2 dosages of the 14 drugs in 128 combinations, then narrowed the list to 9 drugs and tested them at 3 dosages in 155 combinations.
This revealed the top 3 combinations:
- Decitabine and mitomycin C
- Mechlorethamine hydrochloride, decitabine, and mitomycin C
- Bortezomib, mechlorethamine hydrochloride, and mitomycin C.
The researchers said these combinations act by reversing the DNA methylation and tumor suppressor silencing that often occurs after acquired bortezomib resistance.
The team noted that the top 3 combinations had synergistic interactions, but the QPOP analysis revealed antagonistic interactions as well. For example, bortezomib and dexamethasone proved antagonistic, as did bortezomib and panobinostat.
The researchers conducted further testing to determine the optimal dosage of decitabine and mitomycin C. Results suggested both drugs should be given at 1.5 mg/kg.
The team then treated P100v tumor-bearing mice with decitabine and mitomycin C, both at 1.5 mg/kg, either alone or in combination.
Mice that received the combination had a decrease in tumor size and prolonged survival compared to mice that received DMSO (P=0.0130), decitabine alone (P=0.0121), or mitomycin C alone (P=0.00174).
The researchers also compared decitabine and mitomycin C in combination to 2 bortezomib-based combinations used to treat MM—bortezomib/dexamethasone/melphalan and bortezomib/dexamethasone/lenalidomide—in P100v tumor-bearing mice.
There was a significant decrease in tumor volume with decitabine/mitomycin C compared to bortezomib/dexamethasone/melphalan (P=0.000376) and bortezomib/dexamethasone/lenalidomide (P=0.000691).
Mice that received decitabine/mitomycin C had significantly longer survival than mice that received bortezomib/dexamethasone/melphalan (P=0.0389) or bortezomib/dexamethasone/lenalidomide (P=0.0246).
Neither survival times nor tumor volumes were significantly different between the mice that received DMSO and those that received either of the bortezomib-based combinations.
Researchers say they have developed a computational platform that can be used to identify optimal treatments for multiple myeloma (MM).
Using this tool, the quadratic phenotypic optimization platform (QPOP), the researchers identified a 2-drug combination that proved effective against bortezomib-resistant MM in vitro.
The combination—decitabine and mitomycin C—also decreased tumor volume and prolonged survival in a mouse model of bortezomib-resistant MM.
Masturah Bte Mohd Abdul Rashid, of the Cancer Science Institute of Singapore, and her colleagues reported these results in Science Translational Medicine.
The researchers explained that QPOP approximates biological responses to therapies using advanced mathematical equations. Unlike conventional models, QPOP doesn’t require predetermined information about the mechanisms or composition of a drug.
To test QPOP’s utility in MM, the researchers began by identifying candidate drugs that might be effective against bortezomib-resistant MM. They screened 114 approved oncology drugs on 2 MM cell lines—RPMI 8226 and bortezomib-resistant RPMI 8226 (P100v).
The drugs that proved most effective against P100v were dactinomycin, decitabine, mechlorethamine hydrochloride, and mitomycin C.
The researchers wanted to identify optimal drug combinations, so they conducted a QPOP analysis including the 4 most effective drugs and an additional 10 drugs used to treat MM. The 10 drugs were bortezomib, carfilzomib, cyclophosphamide monohydrate, dexamethasone, doxorubucin, lenalidomide, panobinostat, plerixafor, thalidomide, and zoledronic acid.
The team tested 2 dosages of the 14 drugs in 128 combinations, then narrowed the list to 9 drugs and tested them at 3 dosages in 155 combinations.
This revealed the top 3 combinations:
- Decitabine and mitomycin C
- Mechlorethamine hydrochloride, decitabine, and mitomycin C
- Bortezomib, mechlorethamine hydrochloride, and mitomycin C.
The researchers said these combinations act by reversing the DNA methylation and tumor suppressor silencing that often occurs after acquired bortezomib resistance.
The team noted that the top 3 combinations had synergistic interactions, but the QPOP analysis revealed antagonistic interactions as well. For example, bortezomib and dexamethasone proved antagonistic, as did bortezomib and panobinostat.
The researchers conducted further testing to determine the optimal dosage of decitabine and mitomycin C. Results suggested both drugs should be given at 1.5 mg/kg.
The team then treated P100v tumor-bearing mice with decitabine and mitomycin C, both at 1.5 mg/kg, either alone or in combination.
Mice that received the combination had a decrease in tumor size and prolonged survival compared to mice that received DMSO (P=0.0130), decitabine alone (P=0.0121), or mitomycin C alone (P=0.00174).
The researchers also compared decitabine and mitomycin C in combination to 2 bortezomib-based combinations used to treat MM—bortezomib/dexamethasone/melphalan and bortezomib/dexamethasone/lenalidomide—in P100v tumor-bearing mice.
There was a significant decrease in tumor volume with decitabine/mitomycin C compared to bortezomib/dexamethasone/melphalan (P=0.000376) and bortezomib/dexamethasone/lenalidomide (P=0.000691).
Mice that received decitabine/mitomycin C had significantly longer survival than mice that received bortezomib/dexamethasone/melphalan (P=0.0389) or bortezomib/dexamethasone/lenalidomide (P=0.0246).
Neither survival times nor tumor volumes were significantly different between the mice that received DMSO and those that received either of the bortezomib-based combinations.
Researchers say they have developed a computational platform that can be used to identify optimal treatments for multiple myeloma (MM).
Using this tool, the quadratic phenotypic optimization platform (QPOP), the researchers identified a 2-drug combination that proved effective against bortezomib-resistant MM in vitro.
The combination—decitabine and mitomycin C—also decreased tumor volume and prolonged survival in a mouse model of bortezomib-resistant MM.
Masturah Bte Mohd Abdul Rashid, of the Cancer Science Institute of Singapore, and her colleagues reported these results in Science Translational Medicine.
The researchers explained that QPOP approximates biological responses to therapies using advanced mathematical equations. Unlike conventional models, QPOP doesn’t require predetermined information about the mechanisms or composition of a drug.
To test QPOP’s utility in MM, the researchers began by identifying candidate drugs that might be effective against bortezomib-resistant MM. They screened 114 approved oncology drugs on 2 MM cell lines—RPMI 8226 and bortezomib-resistant RPMI 8226 (P100v).
The drugs that proved most effective against P100v were dactinomycin, decitabine, mechlorethamine hydrochloride, and mitomycin C.
The researchers wanted to identify optimal drug combinations, so they conducted a QPOP analysis including the 4 most effective drugs and an additional 10 drugs used to treat MM. The 10 drugs were bortezomib, carfilzomib, cyclophosphamide monohydrate, dexamethasone, doxorubucin, lenalidomide, panobinostat, plerixafor, thalidomide, and zoledronic acid.
The team tested 2 dosages of the 14 drugs in 128 combinations, then narrowed the list to 9 drugs and tested them at 3 dosages in 155 combinations.
This revealed the top 3 combinations:
- Decitabine and mitomycin C
- Mechlorethamine hydrochloride, decitabine, and mitomycin C
- Bortezomib, mechlorethamine hydrochloride, and mitomycin C.
The researchers said these combinations act by reversing the DNA methylation and tumor suppressor silencing that often occurs after acquired bortezomib resistance.
The team noted that the top 3 combinations had synergistic interactions, but the QPOP analysis revealed antagonistic interactions as well. For example, bortezomib and dexamethasone proved antagonistic, as did bortezomib and panobinostat.
The researchers conducted further testing to determine the optimal dosage of decitabine and mitomycin C. Results suggested both drugs should be given at 1.5 mg/kg.
The team then treated P100v tumor-bearing mice with decitabine and mitomycin C, both at 1.5 mg/kg, either alone or in combination.
Mice that received the combination had a decrease in tumor size and prolonged survival compared to mice that received DMSO (P=0.0130), decitabine alone (P=0.0121), or mitomycin C alone (P=0.00174).
The researchers also compared decitabine and mitomycin C in combination to 2 bortezomib-based combinations used to treat MM—bortezomib/dexamethasone/melphalan and bortezomib/dexamethasone/lenalidomide—in P100v tumor-bearing mice.
There was a significant decrease in tumor volume with decitabine/mitomycin C compared to bortezomib/dexamethasone/melphalan (P=0.000376) and bortezomib/dexamethasone/lenalidomide (P=0.000691).
Mice that received decitabine/mitomycin C had significantly longer survival than mice that received bortezomib/dexamethasone/melphalan (P=0.0389) or bortezomib/dexamethasone/lenalidomide (P=0.0246).
Neither survival times nor tumor volumes were significantly different between the mice that received DMSO and those that received either of the bortezomib-based combinations.
FDA approves mogamulizumab for MF, SS
The US Food and Drug Administration (FDA) has approved mogamulizumab-kpkc (Poteligeo®) for the treatment of adults with relapsed or refractory mycosis fungoides (MF) or Sézary syndrome (SS) after at least 1 prior systemic therapy.
Mogamulizumab is a humanized monoclonal antibody directed against CC chemokine receptor 4 (CCR4). It is the first biologic agent targeting CCR4 to be approved for patients in the US.
Mogamulizumab is expected to be commercially available in the fourth quarter of 2018.
The FDA previously granted mogamulizumab breakthrough therapy and orphan drug designations as well as priority review.
The FDA’s approval of mogamulizumab is supported by the phase 3 MAVORIC trial. Results from this trial were presented at the 10th Annual T-cell Lymphoma Forum in February.
MAVORIC enrolled 372 adults with histologically confirmed MF or SS who had failed at least 1 systemic therapy. They were randomized to receive mogamulizumab at 1.0 mg/kg (weekly for the first 4-week cycle and then every 2 weeks) or vorinostat at 400 mg daily.
Patients were treated until disease progression or unacceptable toxicity. Those receiving vorinostat could cross over to mogamulizumab if they progressed or experienced intolerable toxicity.
Baseline characteristics were similar between the treatment arms.
The study’s primary endpoint was progression-free survival. The median progression-free survival was 7.7 months with mogamulizumab and 3.1 months with vorinostat (hazard ratio=0.53, P<0.0001).
The global overall response rate (ORR) was 28% (52/189) in the mogamulizumab arm and 5% (9/186) in the vorinostat arm (P<0.0001).
For patients with MF, the ORR was 21% with mogamulizumab and 7% with vorinostat. For SS patients, the ORR was 37% and 2%, respectively.
After crossover, the ORR in the mogamulizumab arm was 30% (41/136).
The median duration of response (DOR) was 14 months in the mogamulizumab arm and 9 months in the vorinostat arm.
For MF patients, the median DOR was 13 months with mogamulizumab and 9 months with vorinostat. For SS patients, the median DOR was 17 months and 7 months, respectively.
The most common treatment-emergent adverse events (AEs), occurring in at least 20% of patients in either arm (mogamulizumab and vorinostat, respectively), were:
- Infusion-related reactions (33.2% vs 0.5%)
- Drug eruptions (23.9% vs 0.5%)
- Diarrhea (23.4% vs 61.8%)
- Nausea (15.2% vs 42.5%)
- Thrombocytopenia (11.4% vs 30.6%)
- Dysgeusia (3.3% vs 28.0%)
- Increased blood creatinine (3.3% vs 28.0%)
- Decreased appetite (7.6% vs 24.7%).
There were no grade 4 AEs in the mogamulizumab arm. Grade 3 AEs in mogamulizumab recipients included drug eruptions (n=8), infusion-related reactions (n=3), fatigue (n=3), decreased appetite (n=2), nausea (n=1), pyrexia (n=1), and diarrhea (n=1).
The US Food and Drug Administration (FDA) has approved mogamulizumab-kpkc (Poteligeo®) for the treatment of adults with relapsed or refractory mycosis fungoides (MF) or Sézary syndrome (SS) after at least 1 prior systemic therapy.
Mogamulizumab is a humanized monoclonal antibody directed against CC chemokine receptor 4 (CCR4). It is the first biologic agent targeting CCR4 to be approved for patients in the US.
Mogamulizumab is expected to be commercially available in the fourth quarter of 2018.
The FDA previously granted mogamulizumab breakthrough therapy and orphan drug designations as well as priority review.
The FDA’s approval of mogamulizumab is supported by the phase 3 MAVORIC trial. Results from this trial were presented at the 10th Annual T-cell Lymphoma Forum in February.
MAVORIC enrolled 372 adults with histologically confirmed MF or SS who had failed at least 1 systemic therapy. They were randomized to receive mogamulizumab at 1.0 mg/kg (weekly for the first 4-week cycle and then every 2 weeks) or vorinostat at 400 mg daily.
Patients were treated until disease progression or unacceptable toxicity. Those receiving vorinostat could cross over to mogamulizumab if they progressed or experienced intolerable toxicity.
Baseline characteristics were similar between the treatment arms.
The study’s primary endpoint was progression-free survival. The median progression-free survival was 7.7 months with mogamulizumab and 3.1 months with vorinostat (hazard ratio=0.53, P<0.0001).
The global overall response rate (ORR) was 28% (52/189) in the mogamulizumab arm and 5% (9/186) in the vorinostat arm (P<0.0001).
For patients with MF, the ORR was 21% with mogamulizumab and 7% with vorinostat. For SS patients, the ORR was 37% and 2%, respectively.
After crossover, the ORR in the mogamulizumab arm was 30% (41/136).
The median duration of response (DOR) was 14 months in the mogamulizumab arm and 9 months in the vorinostat arm.
For MF patients, the median DOR was 13 months with mogamulizumab and 9 months with vorinostat. For SS patients, the median DOR was 17 months and 7 months, respectively.
The most common treatment-emergent adverse events (AEs), occurring in at least 20% of patients in either arm (mogamulizumab and vorinostat, respectively), were:
- Infusion-related reactions (33.2% vs 0.5%)
- Drug eruptions (23.9% vs 0.5%)
- Diarrhea (23.4% vs 61.8%)
- Nausea (15.2% vs 42.5%)
- Thrombocytopenia (11.4% vs 30.6%)
- Dysgeusia (3.3% vs 28.0%)
- Increased blood creatinine (3.3% vs 28.0%)
- Decreased appetite (7.6% vs 24.7%).
There were no grade 4 AEs in the mogamulizumab arm. Grade 3 AEs in mogamulizumab recipients included drug eruptions (n=8), infusion-related reactions (n=3), fatigue (n=3), decreased appetite (n=2), nausea (n=1), pyrexia (n=1), and diarrhea (n=1).
The US Food and Drug Administration (FDA) has approved mogamulizumab-kpkc (Poteligeo®) for the treatment of adults with relapsed or refractory mycosis fungoides (MF) or Sézary syndrome (SS) after at least 1 prior systemic therapy.
Mogamulizumab is a humanized monoclonal antibody directed against CC chemokine receptor 4 (CCR4). It is the first biologic agent targeting CCR4 to be approved for patients in the US.
Mogamulizumab is expected to be commercially available in the fourth quarter of 2018.
The FDA previously granted mogamulizumab breakthrough therapy and orphan drug designations as well as priority review.
The FDA’s approval of mogamulizumab is supported by the phase 3 MAVORIC trial. Results from this trial were presented at the 10th Annual T-cell Lymphoma Forum in February.
MAVORIC enrolled 372 adults with histologically confirmed MF or SS who had failed at least 1 systemic therapy. They were randomized to receive mogamulizumab at 1.0 mg/kg (weekly for the first 4-week cycle and then every 2 weeks) or vorinostat at 400 mg daily.
Patients were treated until disease progression or unacceptable toxicity. Those receiving vorinostat could cross over to mogamulizumab if they progressed or experienced intolerable toxicity.
Baseline characteristics were similar between the treatment arms.
The study’s primary endpoint was progression-free survival. The median progression-free survival was 7.7 months with mogamulizumab and 3.1 months with vorinostat (hazard ratio=0.53, P<0.0001).
The global overall response rate (ORR) was 28% (52/189) in the mogamulizumab arm and 5% (9/186) in the vorinostat arm (P<0.0001).
For patients with MF, the ORR was 21% with mogamulizumab and 7% with vorinostat. For SS patients, the ORR was 37% and 2%, respectively.
After crossover, the ORR in the mogamulizumab arm was 30% (41/136).
The median duration of response (DOR) was 14 months in the mogamulizumab arm and 9 months in the vorinostat arm.
For MF patients, the median DOR was 13 months with mogamulizumab and 9 months with vorinostat. For SS patients, the median DOR was 17 months and 7 months, respectively.
The most common treatment-emergent adverse events (AEs), occurring in at least 20% of patients in either arm (mogamulizumab and vorinostat, respectively), were:
- Infusion-related reactions (33.2% vs 0.5%)
- Drug eruptions (23.9% vs 0.5%)
- Diarrhea (23.4% vs 61.8%)
- Nausea (15.2% vs 42.5%)
- Thrombocytopenia (11.4% vs 30.6%)
- Dysgeusia (3.3% vs 28.0%)
- Increased blood creatinine (3.3% vs 28.0%)
- Decreased appetite (7.6% vs 24.7%).
There were no grade 4 AEs in the mogamulizumab arm. Grade 3 AEs in mogamulizumab recipients included drug eruptions (n=8), infusion-related reactions (n=3), fatigue (n=3), decreased appetite (n=2), nausea (n=1), pyrexia (n=1), and diarrhea (n=1).
Health Canada approves emicizumab
Health Canada has approved emicizumab (Hemlibra®) for use as routine prophylaxis to prevent or reduce bleeding episodes in hemophilia A patients with factor VIII inhibitors.
Emicizumab is a bispecific factor IXa- and factor X-directed antibody. It bridges activated factor IX and factor X to restore the natural function of missing activated factor VIII that is needed for effective blood clotting.
Emicizumab is given as a once-weekly subcutaneous injection.
“Preventing bleeds in patients with hemophilia A can be extremely challenging, usually requiring patients to self-infuse medications multiple times a week, or even daily,” said Jayson Stoffman, MD, of the University of Manitoba in Winnipeg.
“The development of inhibitors adds a significant challenge, with more demanding treatments that are often less effective. Hemlibra offers these patients the chance to effectively reduce the frequency of their bleeds with a once-weekly injection at home. This could significantly improve the quality of life for inhibitor patients, and particularly children and their families.”
Trial results
The Health Canada approval of emicizumab is based on data from a pair of phase 3 trials—HAVEN 1 and HAVEN 2.
Results from HAVEN 1 were published in NEJM and presented at the 26th ISTH Congress in July 2017. Updated results from HAVEN 2 were presented at the 2017 ASH Annual Meeting in December.
HAVEN 1
This study enrolled 109 patients (age 12 and older) with hemophilia A and factor VIII inhibitors who were previously treated with bypassing agents (BPAs) on demand or as prophylaxis.
The patients were randomized to receive emicizumab prophylaxis or no prophylaxis. On-demand treatment of breakthrough bleeds with BPAs was allowed.
There was an 87% reduction in treated bleeds with emicizumab compared to no prophylaxis (P<0.0001). And there was an 80% reduction in all bleeds with emicizumab (P<0.0001).
The proportion of patients with 0 treated bleeds was 62.9% among emicizumab recipients and 5.6% among patients who did not receive prophylaxis.
Adverse events (AEs) occurring in at least 5% of patients treated with emicizumab were local injection site reactions, headache, fatigue, upper respiratory tract infection, and arthralgia.
Two patients experienced thromboembolic events (TEs), and 3 had thrombotic microangiopathy (TMA) while receiving emicizumab prophylaxis and more than 100 µ/kg/day of activated prothrombin complex concentrate, on average, for 24 hours or more before the event. Two of these patients had also received recombinant factor VIIa.
Neither TE required anticoagulation therapy, and 1 patient restarted emicizumab. The cases of TMA observed were transient, and 1 patient restarted emicizumab.
There was 1 death, but it was considered unrelated to emicizumab. The patient had developed TMA but died of rectal hemorrhage.
HAVEN 2
In this single-arm trial, researchers evaluated emicizumab prophylaxis in 60 patients, ages 1 to 17, who had hemophilia A with factor VIII inhibitors.
The efficacy analysis included 57 patients who were younger than 12. The 3 older patients were only included in the safety analysis.
Of the 57 patients, 64.9% had 0 bleeds, 94.7% had 0 treated bleeds, and 98.2% had 0 treated spontaneous bleeds/treated joint bleeds. None of the patients had treated target joint bleeds.
A subset of 23 patients received emicizumab for at least 12 weeks (median treatment duration of 38.1 weeks; range, 12.7 to 41.6 weeks).
Of these 23 patients, 34.8% had 0 bleeds, 87.0% had 0 treated bleeds, and 95.7% had 0 treated spontaneous bleeds/treated joint bleeds.
There were 40 patients who had a total of 201 AEs. The most common of these were viral upper respiratory tract infections (16.7%) and injection site reactions (16.7%).
There were no TEs or TMA events, and none of the patients tested positive for anti-drug antibodies. None of the 7 serious AEs in this trial were considered treatment-related.
Health Canada has approved emicizumab (Hemlibra®) for use as routine prophylaxis to prevent or reduce bleeding episodes in hemophilia A patients with factor VIII inhibitors.
Emicizumab is a bispecific factor IXa- and factor X-directed antibody. It bridges activated factor IX and factor X to restore the natural function of missing activated factor VIII that is needed for effective blood clotting.
Emicizumab is given as a once-weekly subcutaneous injection.
“Preventing bleeds in patients with hemophilia A can be extremely challenging, usually requiring patients to self-infuse medications multiple times a week, or even daily,” said Jayson Stoffman, MD, of the University of Manitoba in Winnipeg.
“The development of inhibitors adds a significant challenge, with more demanding treatments that are often less effective. Hemlibra offers these patients the chance to effectively reduce the frequency of their bleeds with a once-weekly injection at home. This could significantly improve the quality of life for inhibitor patients, and particularly children and their families.”
Trial results
The Health Canada approval of emicizumab is based on data from a pair of phase 3 trials—HAVEN 1 and HAVEN 2.
Results from HAVEN 1 were published in NEJM and presented at the 26th ISTH Congress in July 2017. Updated results from HAVEN 2 were presented at the 2017 ASH Annual Meeting in December.
HAVEN 1
This study enrolled 109 patients (age 12 and older) with hemophilia A and factor VIII inhibitors who were previously treated with bypassing agents (BPAs) on demand or as prophylaxis.
The patients were randomized to receive emicizumab prophylaxis or no prophylaxis. On-demand treatment of breakthrough bleeds with BPAs was allowed.
There was an 87% reduction in treated bleeds with emicizumab compared to no prophylaxis (P<0.0001). And there was an 80% reduction in all bleeds with emicizumab (P<0.0001).
The proportion of patients with 0 treated bleeds was 62.9% among emicizumab recipients and 5.6% among patients who did not receive prophylaxis.
Adverse events (AEs) occurring in at least 5% of patients treated with emicizumab were local injection site reactions, headache, fatigue, upper respiratory tract infection, and arthralgia.
Two patients experienced thromboembolic events (TEs), and 3 had thrombotic microangiopathy (TMA) while receiving emicizumab prophylaxis and more than 100 µ/kg/day of activated prothrombin complex concentrate, on average, for 24 hours or more before the event. Two of these patients had also received recombinant factor VIIa.
Neither TE required anticoagulation therapy, and 1 patient restarted emicizumab. The cases of TMA observed were transient, and 1 patient restarted emicizumab.
There was 1 death, but it was considered unrelated to emicizumab. The patient had developed TMA but died of rectal hemorrhage.
HAVEN 2
In this single-arm trial, researchers evaluated emicizumab prophylaxis in 60 patients, ages 1 to 17, who had hemophilia A with factor VIII inhibitors.
The efficacy analysis included 57 patients who were younger than 12. The 3 older patients were only included in the safety analysis.
Of the 57 patients, 64.9% had 0 bleeds, 94.7% had 0 treated bleeds, and 98.2% had 0 treated spontaneous bleeds/treated joint bleeds. None of the patients had treated target joint bleeds.
A subset of 23 patients received emicizumab for at least 12 weeks (median treatment duration of 38.1 weeks; range, 12.7 to 41.6 weeks).
Of these 23 patients, 34.8% had 0 bleeds, 87.0% had 0 treated bleeds, and 95.7% had 0 treated spontaneous bleeds/treated joint bleeds.
There were 40 patients who had a total of 201 AEs. The most common of these were viral upper respiratory tract infections (16.7%) and injection site reactions (16.7%).
There were no TEs or TMA events, and none of the patients tested positive for anti-drug antibodies. None of the 7 serious AEs in this trial were considered treatment-related.
Health Canada has approved emicizumab (Hemlibra®) for use as routine prophylaxis to prevent or reduce bleeding episodes in hemophilia A patients with factor VIII inhibitors.
Emicizumab is a bispecific factor IXa- and factor X-directed antibody. It bridges activated factor IX and factor X to restore the natural function of missing activated factor VIII that is needed for effective blood clotting.
Emicizumab is given as a once-weekly subcutaneous injection.
“Preventing bleeds in patients with hemophilia A can be extremely challenging, usually requiring patients to self-infuse medications multiple times a week, or even daily,” said Jayson Stoffman, MD, of the University of Manitoba in Winnipeg.
“The development of inhibitors adds a significant challenge, with more demanding treatments that are often less effective. Hemlibra offers these patients the chance to effectively reduce the frequency of their bleeds with a once-weekly injection at home. This could significantly improve the quality of life for inhibitor patients, and particularly children and their families.”
Trial results
The Health Canada approval of emicizumab is based on data from a pair of phase 3 trials—HAVEN 1 and HAVEN 2.
Results from HAVEN 1 were published in NEJM and presented at the 26th ISTH Congress in July 2017. Updated results from HAVEN 2 were presented at the 2017 ASH Annual Meeting in December.
HAVEN 1
This study enrolled 109 patients (age 12 and older) with hemophilia A and factor VIII inhibitors who were previously treated with bypassing agents (BPAs) on demand or as prophylaxis.
The patients were randomized to receive emicizumab prophylaxis or no prophylaxis. On-demand treatment of breakthrough bleeds with BPAs was allowed.
There was an 87% reduction in treated bleeds with emicizumab compared to no prophylaxis (P<0.0001). And there was an 80% reduction in all bleeds with emicizumab (P<0.0001).
The proportion of patients with 0 treated bleeds was 62.9% among emicizumab recipients and 5.6% among patients who did not receive prophylaxis.
Adverse events (AEs) occurring in at least 5% of patients treated with emicizumab were local injection site reactions, headache, fatigue, upper respiratory tract infection, and arthralgia.
Two patients experienced thromboembolic events (TEs), and 3 had thrombotic microangiopathy (TMA) while receiving emicizumab prophylaxis and more than 100 µ/kg/day of activated prothrombin complex concentrate, on average, for 24 hours or more before the event. Two of these patients had also received recombinant factor VIIa.
Neither TE required anticoagulation therapy, and 1 patient restarted emicizumab. The cases of TMA observed were transient, and 1 patient restarted emicizumab.
There was 1 death, but it was considered unrelated to emicizumab. The patient had developed TMA but died of rectal hemorrhage.
HAVEN 2
In this single-arm trial, researchers evaluated emicizumab prophylaxis in 60 patients, ages 1 to 17, who had hemophilia A with factor VIII inhibitors.
The efficacy analysis included 57 patients who were younger than 12. The 3 older patients were only included in the safety analysis.
Of the 57 patients, 64.9% had 0 bleeds, 94.7% had 0 treated bleeds, and 98.2% had 0 treated spontaneous bleeds/treated joint bleeds. None of the patients had treated target joint bleeds.
A subset of 23 patients received emicizumab for at least 12 weeks (median treatment duration of 38.1 weeks; range, 12.7 to 41.6 weeks).
Of these 23 patients, 34.8% had 0 bleeds, 87.0% had 0 treated bleeds, and 95.7% had 0 treated spontaneous bleeds/treated joint bleeds.
There were 40 patients who had a total of 201 AEs. The most common of these were viral upper respiratory tract infections (16.7%) and injection site reactions (16.7%).
There were no TEs or TMA events, and none of the patients tested positive for anti-drug antibodies. None of the 7 serious AEs in this trial were considered treatment-related.
Drug could be repurposed for T-ALL
Venetoclax might improve the treatment of certain patients with T-cell acute lymphoblastic leukemia (T-ALL), according to preclinical research published in Leukemia.
Researchers found that a ribosomal defect—the R98S mutation in ribosomal protein L10 (RPL10 R98S)—causes overexpression of BCL-2 in T-ALL.
The BCL-2 inhibitor venetoclax induced apoptosis of RPL10 R98S T-ALL cells and inhibited leukemia progression in mouse models of RPL10 R98S T-ALL.
The researchers therefore believe venetoclax could be used, in combination with other drugs, to treat T-ALL patients with RPL10 R98S.
“In the past couple of years, it has become clear that ribosome defects play a role in different types of cancer,” said study author Kim De Keersmaecker, PhD, of KU Leuven in Leuven, Belgium.
“In the case of a ribosome defect, the cells still produce proteins, but the balance between their quantities is slightly off, which leads to cancer.”
Dr De Keersmaecker and her colleagues noted that RPL10 R98S affects 8% of pediatric patients with T-ALL.
With this study, the researchers found that RPL10 R98S mutant cells were more resilient than wild-type (WT) cells. In overgrowth condition, Ba/F3 RPL10 R98S mutant cells “displayed a clear survival benefit” over RPL10 WT cells.
Likewise, RPL10 R98S Jurkat cells exhibited a survival benefit over WT Jurkat cells in overgrowth condition. And RPL10 R98S Jurkat cells were more resistant to treatment with doxorubicin.
Dr De Keersmaecker and her colleagues said the increased survival they observed in RPL10 R98S mutant cells is associated with enhanced BCL-2 expression. So the team decided to test a BCL-2 inhibitor in RPL10 R98S leukemic cells.
In vitro, venetoclax induced slightly more apoptosis in Jurkat RPL10 R98S cells than WT Jurkat cells. In vivo, venetoclax induced apoptosis in RPL10 R98S T-ALL cells but not WT T-ALL cells.
The researchers also found that venetoclax could re-sensitize RPL10 R98S cells to doxorubicin.
Finally, the team injected RPL10 WT and R98S samples from pediatric T-ALL patients into mice and treated the animals with DMSO or venetoclax (50 mg/kg) once a week.
Venetoclax had very little effect on the RPL10 WT mice. Percentages of human CD45 T-ALL cells in the peripheral blood were similar whether mice received DMSO or venetoclax.
However, in the RPL10 R98S mice, those that received DMSO experienced disease progression, while there were no signs of leukemia progression in the peripheral blood of mice that received venetoclax.
The splenomegaly observed in DMSO-treated mice was “almost completely suppressed” in mice that received venetoclax, according to the researchers.
The team also said they observed a 30% to 50% suppression of human CD45 leukemia cell engraftment in the bone marrow and the presence of 30% to 40% mouse CD45 cells in mice treated with venetoclax.
On the other hand, mice treated with DMSO had more than 95% human leukemia infiltration in the bone marrow and no mouse CD45-expressing cells.
Dr De Keersmaecker and her colleagues said these results suggest RPL10 R98S pediatric T-ALL is sensitive to BCL-2 targeted therapies such as venetoclax. However, venetoclax alone would not be sufficient to treat this type of T-ALL.
“Patients with leukemia often get a drug cocktail, while our study only tested the BCL-2 inhibitor,” Dr De Keersmaecker said. “That’s why our follow-up study will focus on a cocktail of this BCL-2 inhibitor and other drugs. For patients with the ribosome defect analyzed in our study, this avenue is definitely worth examining in greater detail.”
Venetoclax might improve the treatment of certain patients with T-cell acute lymphoblastic leukemia (T-ALL), according to preclinical research published in Leukemia.
Researchers found that a ribosomal defect—the R98S mutation in ribosomal protein L10 (RPL10 R98S)—causes overexpression of BCL-2 in T-ALL.
The BCL-2 inhibitor venetoclax induced apoptosis of RPL10 R98S T-ALL cells and inhibited leukemia progression in mouse models of RPL10 R98S T-ALL.
The researchers therefore believe venetoclax could be used, in combination with other drugs, to treat T-ALL patients with RPL10 R98S.
“In the past couple of years, it has become clear that ribosome defects play a role in different types of cancer,” said study author Kim De Keersmaecker, PhD, of KU Leuven in Leuven, Belgium.
“In the case of a ribosome defect, the cells still produce proteins, but the balance between their quantities is slightly off, which leads to cancer.”
Dr De Keersmaecker and her colleagues noted that RPL10 R98S affects 8% of pediatric patients with T-ALL.
With this study, the researchers found that RPL10 R98S mutant cells were more resilient than wild-type (WT) cells. In overgrowth condition, Ba/F3 RPL10 R98S mutant cells “displayed a clear survival benefit” over RPL10 WT cells.
Likewise, RPL10 R98S Jurkat cells exhibited a survival benefit over WT Jurkat cells in overgrowth condition. And RPL10 R98S Jurkat cells were more resistant to treatment with doxorubicin.
Dr De Keersmaecker and her colleagues said the increased survival they observed in RPL10 R98S mutant cells is associated with enhanced BCL-2 expression. So the team decided to test a BCL-2 inhibitor in RPL10 R98S leukemic cells.
In vitro, venetoclax induced slightly more apoptosis in Jurkat RPL10 R98S cells than WT Jurkat cells. In vivo, venetoclax induced apoptosis in RPL10 R98S T-ALL cells but not WT T-ALL cells.
The researchers also found that venetoclax could re-sensitize RPL10 R98S cells to doxorubicin.
Finally, the team injected RPL10 WT and R98S samples from pediatric T-ALL patients into mice and treated the animals with DMSO or venetoclax (50 mg/kg) once a week.
Venetoclax had very little effect on the RPL10 WT mice. Percentages of human CD45 T-ALL cells in the peripheral blood were similar whether mice received DMSO or venetoclax.
However, in the RPL10 R98S mice, those that received DMSO experienced disease progression, while there were no signs of leukemia progression in the peripheral blood of mice that received venetoclax.
The splenomegaly observed in DMSO-treated mice was “almost completely suppressed” in mice that received venetoclax, according to the researchers.
The team also said they observed a 30% to 50% suppression of human CD45 leukemia cell engraftment in the bone marrow and the presence of 30% to 40% mouse CD45 cells in mice treated with venetoclax.
On the other hand, mice treated with DMSO had more than 95% human leukemia infiltration in the bone marrow and no mouse CD45-expressing cells.
Dr De Keersmaecker and her colleagues said these results suggest RPL10 R98S pediatric T-ALL is sensitive to BCL-2 targeted therapies such as venetoclax. However, venetoclax alone would not be sufficient to treat this type of T-ALL.
“Patients with leukemia often get a drug cocktail, while our study only tested the BCL-2 inhibitor,” Dr De Keersmaecker said. “That’s why our follow-up study will focus on a cocktail of this BCL-2 inhibitor and other drugs. For patients with the ribosome defect analyzed in our study, this avenue is definitely worth examining in greater detail.”
Venetoclax might improve the treatment of certain patients with T-cell acute lymphoblastic leukemia (T-ALL), according to preclinical research published in Leukemia.
Researchers found that a ribosomal defect—the R98S mutation in ribosomal protein L10 (RPL10 R98S)—causes overexpression of BCL-2 in T-ALL.
The BCL-2 inhibitor venetoclax induced apoptosis of RPL10 R98S T-ALL cells and inhibited leukemia progression in mouse models of RPL10 R98S T-ALL.
The researchers therefore believe venetoclax could be used, in combination with other drugs, to treat T-ALL patients with RPL10 R98S.
“In the past couple of years, it has become clear that ribosome defects play a role in different types of cancer,” said study author Kim De Keersmaecker, PhD, of KU Leuven in Leuven, Belgium.
“In the case of a ribosome defect, the cells still produce proteins, but the balance between their quantities is slightly off, which leads to cancer.”
Dr De Keersmaecker and her colleagues noted that RPL10 R98S affects 8% of pediatric patients with T-ALL.
With this study, the researchers found that RPL10 R98S mutant cells were more resilient than wild-type (WT) cells. In overgrowth condition, Ba/F3 RPL10 R98S mutant cells “displayed a clear survival benefit” over RPL10 WT cells.
Likewise, RPL10 R98S Jurkat cells exhibited a survival benefit over WT Jurkat cells in overgrowth condition. And RPL10 R98S Jurkat cells were more resistant to treatment with doxorubicin.
Dr De Keersmaecker and her colleagues said the increased survival they observed in RPL10 R98S mutant cells is associated with enhanced BCL-2 expression. So the team decided to test a BCL-2 inhibitor in RPL10 R98S leukemic cells.
In vitro, venetoclax induced slightly more apoptosis in Jurkat RPL10 R98S cells than WT Jurkat cells. In vivo, venetoclax induced apoptosis in RPL10 R98S T-ALL cells but not WT T-ALL cells.
The researchers also found that venetoclax could re-sensitize RPL10 R98S cells to doxorubicin.
Finally, the team injected RPL10 WT and R98S samples from pediatric T-ALL patients into mice and treated the animals with DMSO or venetoclax (50 mg/kg) once a week.
Venetoclax had very little effect on the RPL10 WT mice. Percentages of human CD45 T-ALL cells in the peripheral blood were similar whether mice received DMSO or venetoclax.
However, in the RPL10 R98S mice, those that received DMSO experienced disease progression, while there were no signs of leukemia progression in the peripheral blood of mice that received venetoclax.
The splenomegaly observed in DMSO-treated mice was “almost completely suppressed” in mice that received venetoclax, according to the researchers.
The team also said they observed a 30% to 50% suppression of human CD45 leukemia cell engraftment in the bone marrow and the presence of 30% to 40% mouse CD45 cells in mice treated with venetoclax.
On the other hand, mice treated with DMSO had more than 95% human leukemia infiltration in the bone marrow and no mouse CD45-expressing cells.
Dr De Keersmaecker and her colleagues said these results suggest RPL10 R98S pediatric T-ALL is sensitive to BCL-2 targeted therapies such as venetoclax. However, venetoclax alone would not be sufficient to treat this type of T-ALL.
“Patients with leukemia often get a drug cocktail, while our study only tested the BCL-2 inhibitor,” Dr De Keersmaecker said. “That’s why our follow-up study will focus on a cocktail of this BCL-2 inhibitor and other drugs. For patients with the ribosome defect analyzed in our study, this avenue is definitely worth examining in greater detail.”
FDA grants fast track designation to dilanubicel
The US Food and Drug Administration (FDA) has granted fast track designation to dilanubicel (NLA101) for use in patients with high-risk hematologic malignancies receiving an allogeneic cord blood transplant.
Dilanubicel is a universal-donor, ex-vivo-expanded hematopoietic stem and progenitor cell product.
It is intended to induce short-term hematopoiesis, which lasts until a patient’s immune system recovers.
However, dilanubicel may also produce long-term immunologic benefits and could potentially improve survival in transplant recipients, according to Nohla Therapeutics, the company developing the product.
Dilanubicel is manufactured ahead of time, cryopreserved, and intended for immediate off-the-shelf use.
Dilanubicel also has orphan drug designation from the FDA.
About fast track, orphan designations
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. The 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.
Trials of dilanubicel
The fast track and orphan designations for dilanubicel were supported by data from a phase 2, single-center study. Results from this study were presented in a poster at the 23rd Congress of European Hematology Association (EHA) in June.
The trial included 15 patients with hematologic malignancies who underwent a cord blood transplant. Conditioning consisted of fludarabine (75 mg/m2), cyclophosphamide (120 mg/kg), and total body irradiation (13.2 Gy).
Patients received unmanipulated cord blood unit(s), followed 4 hours later by dilanubicel infusion. Prophylaxis for graft-vs-host disease (GVHD) was cyclosporine/mycophenolate mofetil.
The researchers compared outcomes in the 15 dilanubicel recipients to outcomes in a concurrent control cohort of 50 patients treated with the same transplant protocol, minus dilanubicel.
The time to neutrophil and platelet recovery were both significantly better in dilanubicel recipients than controls.
At day 100, the cumulative incidence of neutrophil recovery was 100% in dilanubicel recipients and 94% in controls (P=0.005). The median time to neutrophil recovery was 19 days (range, 9-31) and 25 days (range, 14-45), respectively.
The cumulative incidence of platelet recovery was 93% in dilanubicel recipients and 74% in controls (P=0.02). The median time to platelet recovery was 35 days (range, 21-86) and 48 days (range, 24-158), respectively.
At 100 days, there were no cases of grade 3-4 acute GVHD in dilanubicel recipients, but the incidence of grade 3-4 acute GVHD was 29% in the control group.
At 5 years, 27% of dilanubicel recipients had experienced chronic GVHD, compared to 38% of the control group.
There were no cases of transplant related mortality (TRM) in dilanubicel recipients, but the rate of TRM was 16% in the control group.
Two dilanubicel recipients (13%) relapsed post-transplant and subsequently died.
The 5-year disease-free survival rate was 87% in dilanubicel recipients and 66% in the control group. Overall survival rates were the same (87% and 66%, respectively).
Dilanubicel is currently under investigation in a phase 2b trial (NCT01690520) that has enrolled 160 patients with hematologic malignancies. The goal of the trial is to determine whether adding dilanubicel to standard donor cord blood transplant decreases the time to hematopoietic recovery, thereby reducing associated morbidities and mortality.
Another phase 2 trial, called LAUNCH (NCT03301597), is currently enrolling patients who have acute myeloid leukemia and chemotherapy-induced myelosuppression. The goals of this trial are to evaluate dilanubicel’s ability to reduce the rate of grade 3 or higher infections associated with chemotherapy-induced neutropenia and to identify the lowest effective cell dose of dilanubicel.
The US Food and Drug Administration (FDA) has granted fast track designation to dilanubicel (NLA101) for use in patients with high-risk hematologic malignancies receiving an allogeneic cord blood transplant.
Dilanubicel is a universal-donor, ex-vivo-expanded hematopoietic stem and progenitor cell product.
It is intended to induce short-term hematopoiesis, which lasts until a patient’s immune system recovers.
However, dilanubicel may also produce long-term immunologic benefits and could potentially improve survival in transplant recipients, according to Nohla Therapeutics, the company developing the product.
Dilanubicel is manufactured ahead of time, cryopreserved, and intended for immediate off-the-shelf use.
Dilanubicel also has orphan drug designation from the FDA.
About fast track, orphan designations
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. The 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.
Trials of dilanubicel
The fast track and orphan designations for dilanubicel were supported by data from a phase 2, single-center study. Results from this study were presented in a poster at the 23rd Congress of European Hematology Association (EHA) in June.
The trial included 15 patients with hematologic malignancies who underwent a cord blood transplant. Conditioning consisted of fludarabine (75 mg/m2), cyclophosphamide (120 mg/kg), and total body irradiation (13.2 Gy).
Patients received unmanipulated cord blood unit(s), followed 4 hours later by dilanubicel infusion. Prophylaxis for graft-vs-host disease (GVHD) was cyclosporine/mycophenolate mofetil.
The researchers compared outcomes in the 15 dilanubicel recipients to outcomes in a concurrent control cohort of 50 patients treated with the same transplant protocol, minus dilanubicel.
The time to neutrophil and platelet recovery were both significantly better in dilanubicel recipients than controls.
At day 100, the cumulative incidence of neutrophil recovery was 100% in dilanubicel recipients and 94% in controls (P=0.005). The median time to neutrophil recovery was 19 days (range, 9-31) and 25 days (range, 14-45), respectively.
The cumulative incidence of platelet recovery was 93% in dilanubicel recipients and 74% in controls (P=0.02). The median time to platelet recovery was 35 days (range, 21-86) and 48 days (range, 24-158), respectively.
At 100 days, there were no cases of grade 3-4 acute GVHD in dilanubicel recipients, but the incidence of grade 3-4 acute GVHD was 29% in the control group.
At 5 years, 27% of dilanubicel recipients had experienced chronic GVHD, compared to 38% of the control group.
There were no cases of transplant related mortality (TRM) in dilanubicel recipients, but the rate of TRM was 16% in the control group.
Two dilanubicel recipients (13%) relapsed post-transplant and subsequently died.
The 5-year disease-free survival rate was 87% in dilanubicel recipients and 66% in the control group. Overall survival rates were the same (87% and 66%, respectively).
Dilanubicel is currently under investigation in a phase 2b trial (NCT01690520) that has enrolled 160 patients with hematologic malignancies. The goal of the trial is to determine whether adding dilanubicel to standard donor cord blood transplant decreases the time to hematopoietic recovery, thereby reducing associated morbidities and mortality.
Another phase 2 trial, called LAUNCH (NCT03301597), is currently enrolling patients who have acute myeloid leukemia and chemotherapy-induced myelosuppression. The goals of this trial are to evaluate dilanubicel’s ability to reduce the rate of grade 3 or higher infections associated with chemotherapy-induced neutropenia and to identify the lowest effective cell dose of dilanubicel.
The US Food and Drug Administration (FDA) has granted fast track designation to dilanubicel (NLA101) for use in patients with high-risk hematologic malignancies receiving an allogeneic cord blood transplant.
Dilanubicel is a universal-donor, ex-vivo-expanded hematopoietic stem and progenitor cell product.
It is intended to induce short-term hematopoiesis, which lasts until a patient’s immune system recovers.
However, dilanubicel may also produce long-term immunologic benefits and could potentially improve survival in transplant recipients, according to Nohla Therapeutics, the company developing the product.
Dilanubicel is manufactured ahead of time, cryopreserved, and intended for immediate off-the-shelf use.
Dilanubicel also has orphan drug designation from the FDA.
About fast track, orphan designations
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. The 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.
Trials of dilanubicel
The fast track and orphan designations for dilanubicel were supported by data from a phase 2, single-center study. Results from this study were presented in a poster at the 23rd Congress of European Hematology Association (EHA) in June.
The trial included 15 patients with hematologic malignancies who underwent a cord blood transplant. Conditioning consisted of fludarabine (75 mg/m2), cyclophosphamide (120 mg/kg), and total body irradiation (13.2 Gy).
Patients received unmanipulated cord blood unit(s), followed 4 hours later by dilanubicel infusion. Prophylaxis for graft-vs-host disease (GVHD) was cyclosporine/mycophenolate mofetil.
The researchers compared outcomes in the 15 dilanubicel recipients to outcomes in a concurrent control cohort of 50 patients treated with the same transplant protocol, minus dilanubicel.
The time to neutrophil and platelet recovery were both significantly better in dilanubicel recipients than controls.
At day 100, the cumulative incidence of neutrophil recovery was 100% in dilanubicel recipients and 94% in controls (P=0.005). The median time to neutrophil recovery was 19 days (range, 9-31) and 25 days (range, 14-45), respectively.
The cumulative incidence of platelet recovery was 93% in dilanubicel recipients and 74% in controls (P=0.02). The median time to platelet recovery was 35 days (range, 21-86) and 48 days (range, 24-158), respectively.
At 100 days, there were no cases of grade 3-4 acute GVHD in dilanubicel recipients, but the incidence of grade 3-4 acute GVHD was 29% in the control group.
At 5 years, 27% of dilanubicel recipients had experienced chronic GVHD, compared to 38% of the control group.
There were no cases of transplant related mortality (TRM) in dilanubicel recipients, but the rate of TRM was 16% in the control group.
Two dilanubicel recipients (13%) relapsed post-transplant and subsequently died.
The 5-year disease-free survival rate was 87% in dilanubicel recipients and 66% in the control group. Overall survival rates were the same (87% and 66%, respectively).
Dilanubicel is currently under investigation in a phase 2b trial (NCT01690520) that has enrolled 160 patients with hematologic malignancies. The goal of the trial is to determine whether adding dilanubicel to standard donor cord blood transplant decreases the time to hematopoietic recovery, thereby reducing associated morbidities and mortality.
Another phase 2 trial, called LAUNCH (NCT03301597), is currently enrolling patients who have acute myeloid leukemia and chemotherapy-induced myelosuppression. The goals of this trial are to evaluate dilanubicel’s ability to reduce the rate of grade 3 or higher infections associated with chemotherapy-induced neutropenia and to identify the lowest effective cell dose of dilanubicel.
A new way to expand HSCs for UCB transplant
Researchers say they have discovered a new approach to expand hematopoietic stem cells (HSCs) from umbilical cord blood (UCB).
The team identified a protein, YTHDF2, that affects multiple targets and pathways involved in HSC self-renewal.
Experiments showed that reducing the function of YTHDF2 allowed UCB HSCs to expand.
The researchers therefore believe this approach could be used to improve UCB transplants.
“If we can expand cord adult stem cells, that could potentially decrease the number of cords needed per treatment,” said Linheng Li, PhD, of Stowers Institute for Medical Research in Kansas City, Missouri. “That’s a huge advantage.”
Dr Li and his colleagues conducted this research and described the work in Cell Research.
Past studies suggested that N6-methyladenosine (m6A) modulates the expression of a group of mRNAs that are critical for stem cell fate determination.
As the m6A reader YTHDF2 promotes targeted mRNA decay, Dr Li and his colleagues decided to target YTHDF2.
The researchers knocked out YTHDF2 function in a mouse model and observed an increase in functional HSCs. However, impairing YTHDF2 function did not alter lineage differentiation or lead to an increase in hematologic malignancies.
The researchers also knocked down YTHDF2 function in human UCB hematopoietic stem and progenitor cells. After 7 days of ex vivo culture, there was a roughly 14-fold increase in both the frequency and absolute number of HSCs with YTHDF2 knockdown (KD) cells compared to control cells.
When human UCB cells were transplanted into mice, there was a 9-fold increase in hematopoietic cell engraftment with YTHDF2 KD cells compared to control cells. In addition, the HSC frequency was about 4-fold higher in YTHDF2 KD cells.
The researchers transplanted bone marrow from primary recipient mice into sublethally irradiated secondary mice and found that, 12 weeks after transplant, human hematopoietic cell chimerism in the bone marrow was higher in YTHDF2 KD mice than in controls.
There was an 8-fold increase in competitive repopulating units from YTHDF2 KD cells compared to control cells.
As for why targeting YTHDF2 results in HSC expansion, the researchers found that YTHDF2 regulates HSC self-renewal gene expression by m6A-mediated mRNA decay.
The team discovered that m6A was enriched in mRNAs encoding transcription factors that are critical for stem cell self-renewal (such as GATA2, ETV6, STAT5, and TAL1). YTHDF2 recognizes these mRNAs and promotes their degradation.
“This work represents a path forward by demonstrating the ability to reliably expand adult stem cells from umbilical cord blood in the laboratory without terminally differentiating the cells into more mature and relatively short-lived blood cells,” said Joseph McGuirk, MD, a professor at the University of Kansas Health System who was not directly involved with this study.
“These findings represent a major advance in the field and have significant potential to improve the outcomes of thousands of children and adults who undergo umbilical cord blood transplantation every year.”
Researchers say they have discovered a new approach to expand hematopoietic stem cells (HSCs) from umbilical cord blood (UCB).
The team identified a protein, YTHDF2, that affects multiple targets and pathways involved in HSC self-renewal.
Experiments showed that reducing the function of YTHDF2 allowed UCB HSCs to expand.
The researchers therefore believe this approach could be used to improve UCB transplants.
“If we can expand cord adult stem cells, that could potentially decrease the number of cords needed per treatment,” said Linheng Li, PhD, of Stowers Institute for Medical Research in Kansas City, Missouri. “That’s a huge advantage.”
Dr Li and his colleagues conducted this research and described the work in Cell Research.
Past studies suggested that N6-methyladenosine (m6A) modulates the expression of a group of mRNAs that are critical for stem cell fate determination.
As the m6A reader YTHDF2 promotes targeted mRNA decay, Dr Li and his colleagues decided to target YTHDF2.
The researchers knocked out YTHDF2 function in a mouse model and observed an increase in functional HSCs. However, impairing YTHDF2 function did not alter lineage differentiation or lead to an increase in hematologic malignancies.
The researchers also knocked down YTHDF2 function in human UCB hematopoietic stem and progenitor cells. After 7 days of ex vivo culture, there was a roughly 14-fold increase in both the frequency and absolute number of HSCs with YTHDF2 knockdown (KD) cells compared to control cells.
When human UCB cells were transplanted into mice, there was a 9-fold increase in hematopoietic cell engraftment with YTHDF2 KD cells compared to control cells. In addition, the HSC frequency was about 4-fold higher in YTHDF2 KD cells.
The researchers transplanted bone marrow from primary recipient mice into sublethally irradiated secondary mice and found that, 12 weeks after transplant, human hematopoietic cell chimerism in the bone marrow was higher in YTHDF2 KD mice than in controls.
There was an 8-fold increase in competitive repopulating units from YTHDF2 KD cells compared to control cells.
As for why targeting YTHDF2 results in HSC expansion, the researchers found that YTHDF2 regulates HSC self-renewal gene expression by m6A-mediated mRNA decay.
The team discovered that m6A was enriched in mRNAs encoding transcription factors that are critical for stem cell self-renewal (such as GATA2, ETV6, STAT5, and TAL1). YTHDF2 recognizes these mRNAs and promotes their degradation.
“This work represents a path forward by demonstrating the ability to reliably expand adult stem cells from umbilical cord blood in the laboratory without terminally differentiating the cells into more mature and relatively short-lived blood cells,” said Joseph McGuirk, MD, a professor at the University of Kansas Health System who was not directly involved with this study.
“These findings represent a major advance in the field and have significant potential to improve the outcomes of thousands of children and adults who undergo umbilical cord blood transplantation every year.”
Researchers say they have discovered a new approach to expand hematopoietic stem cells (HSCs) from umbilical cord blood (UCB).
The team identified a protein, YTHDF2, that affects multiple targets and pathways involved in HSC self-renewal.
Experiments showed that reducing the function of YTHDF2 allowed UCB HSCs to expand.
The researchers therefore believe this approach could be used to improve UCB transplants.
“If we can expand cord adult stem cells, that could potentially decrease the number of cords needed per treatment,” said Linheng Li, PhD, of Stowers Institute for Medical Research in Kansas City, Missouri. “That’s a huge advantage.”
Dr Li and his colleagues conducted this research and described the work in Cell Research.
Past studies suggested that N6-methyladenosine (m6A) modulates the expression of a group of mRNAs that are critical for stem cell fate determination.
As the m6A reader YTHDF2 promotes targeted mRNA decay, Dr Li and his colleagues decided to target YTHDF2.
The researchers knocked out YTHDF2 function in a mouse model and observed an increase in functional HSCs. However, impairing YTHDF2 function did not alter lineage differentiation or lead to an increase in hematologic malignancies.
The researchers also knocked down YTHDF2 function in human UCB hematopoietic stem and progenitor cells. After 7 days of ex vivo culture, there was a roughly 14-fold increase in both the frequency and absolute number of HSCs with YTHDF2 knockdown (KD) cells compared to control cells.
When human UCB cells were transplanted into mice, there was a 9-fold increase in hematopoietic cell engraftment with YTHDF2 KD cells compared to control cells. In addition, the HSC frequency was about 4-fold higher in YTHDF2 KD cells.
The researchers transplanted bone marrow from primary recipient mice into sublethally irradiated secondary mice and found that, 12 weeks after transplant, human hematopoietic cell chimerism in the bone marrow was higher in YTHDF2 KD mice than in controls.
There was an 8-fold increase in competitive repopulating units from YTHDF2 KD cells compared to control cells.
As for why targeting YTHDF2 results in HSC expansion, the researchers found that YTHDF2 regulates HSC self-renewal gene expression by m6A-mediated mRNA decay.
The team discovered that m6A was enriched in mRNAs encoding transcription factors that are critical for stem cell self-renewal (such as GATA2, ETV6, STAT5, and TAL1). YTHDF2 recognizes these mRNAs and promotes their degradation.
“This work represents a path forward by demonstrating the ability to reliably expand adult stem cells from umbilical cord blood in the laboratory without terminally differentiating the cells into more mature and relatively short-lived blood cells,” said Joseph McGuirk, MD, a professor at the University of Kansas Health System who was not directly involved with this study.
“These findings represent a major advance in the field and have significant potential to improve the outcomes of thousands of children and adults who undergo umbilical cord blood transplantation every year.”