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Venetoclax promising in unfit elderly AML patients
New York – For unfit elderly patients with acute myeloid leukemia (AML), venetoclax may be one of the most promising potential options that is emerging, according to an expert in the field.
The oral B-cell lymphoma 2 (BCL-2) inhibitor is the treatment that some in the AML community are “most excited about” for this population, Eunice S. Wang, MD, of Roswell Park Comprehensive Cancer Center in Buffalo, N.Y., said at the National Comprehensive Cancer Network (NCCN) Annual Congress: Hematologic Malignancies.
Venetoclax is currently approved by the Food and Drug Administration for previously treated chronic lymphocytic leukemia (CLL), alone or in combination with rituximab. It has been granted four Breakthrough Therapy designations from the FDA in AML. In July 2018, AbbVie submitted a Supplemental New Drug Application to the FDA for its use in combination with a hypomethylating agent (HMA) or in combination with low-dose cytarabine (LDAC) for the treatment of newly diagnosed AML patients who are ineligible for intensive chemotherapy.
“This agent doesn’t work on its own but had worked in the refractory setting and can be a great option upfront,” Dr. Wang said.
About half the patients were alive at 1 year following treatment with venetoclax plus low-dose chemotherapy, whether that was LDAC or an HMA, she said, commenting on recently reported results.
In a phase 1b trial, venetoclax was evaluated in combination with either azacitidine or decitabine. In recently reported preliminary results that included 57 patients aged 65 years or older who were ineligible for standard induction therapy, the combination was well tolerated and had promising activity (Lancet Oncol. 2018 Feb;19[2]:216-28).
Overall, 35 patients (61%) had complete remission (CR) or complete remission with incomplete marrow recovery (CRi).
In another report on this same trial, which included 33 patients from a single participating center who received venetoclax and azacytidine, the overall response rate was 91%, including 19 (58%) with CR and 9 (27%) with CRi (Blood. 2017 Dec;130 [Suppl 1]:181).
A separate phase 1/2 trial examined venetoclax plus LDAC in treatment-naive elderly patients unfit for intensive chemotherapy. In the 1-year outcomes that have been reported, the observed CR/CRi rate was 62%, median overall survival was an “encouraging” 11.4 months, and the observed 12-month overall survival was 46% in 61 patients treated at a venetoclax dose of 600 mg (Blood. 2017 Dec;130 [Suppl 1]:890).
In those 61 patients, treatment-related grade 3/4 adverse events included thrombocytopenia in 59%, neutropenia in 46%, febrile neutropenia in 36%, anemia in 28%, decreased white blood cell count in 26%, and one case of tumor lysis syndrome, according to the report.
Based on those findings in a cohort of patients with poor risk features, venetoclax 600 mg plus LDAC was carried forward to be evaluated in an ongoing phase 3 study, investigators noted at the time.
Dr. Wang reported financial relationships with AbbVie, Amgen, ImmunoGen, Incyte, Novartis, and Otsuka.
New York – For unfit elderly patients with acute myeloid leukemia (AML), venetoclax may be one of the most promising potential options that is emerging, according to an expert in the field.
The oral B-cell lymphoma 2 (BCL-2) inhibitor is the treatment that some in the AML community are “most excited about” for this population, Eunice S. Wang, MD, of Roswell Park Comprehensive Cancer Center in Buffalo, N.Y., said at the National Comprehensive Cancer Network (NCCN) Annual Congress: Hematologic Malignancies.
Venetoclax is currently approved by the Food and Drug Administration for previously treated chronic lymphocytic leukemia (CLL), alone or in combination with rituximab. It has been granted four Breakthrough Therapy designations from the FDA in AML. In July 2018, AbbVie submitted a Supplemental New Drug Application to the FDA for its use in combination with a hypomethylating agent (HMA) or in combination with low-dose cytarabine (LDAC) for the treatment of newly diagnosed AML patients who are ineligible for intensive chemotherapy.
“This agent doesn’t work on its own but had worked in the refractory setting and can be a great option upfront,” Dr. Wang said.
About half the patients were alive at 1 year following treatment with venetoclax plus low-dose chemotherapy, whether that was LDAC or an HMA, she said, commenting on recently reported results.
In a phase 1b trial, venetoclax was evaluated in combination with either azacitidine or decitabine. In recently reported preliminary results that included 57 patients aged 65 years or older who were ineligible for standard induction therapy, the combination was well tolerated and had promising activity (Lancet Oncol. 2018 Feb;19[2]:216-28).
Overall, 35 patients (61%) had complete remission (CR) or complete remission with incomplete marrow recovery (CRi).
In another report on this same trial, which included 33 patients from a single participating center who received venetoclax and azacytidine, the overall response rate was 91%, including 19 (58%) with CR and 9 (27%) with CRi (Blood. 2017 Dec;130 [Suppl 1]:181).
A separate phase 1/2 trial examined venetoclax plus LDAC in treatment-naive elderly patients unfit for intensive chemotherapy. In the 1-year outcomes that have been reported, the observed CR/CRi rate was 62%, median overall survival was an “encouraging” 11.4 months, and the observed 12-month overall survival was 46% in 61 patients treated at a venetoclax dose of 600 mg (Blood. 2017 Dec;130 [Suppl 1]:890).
In those 61 patients, treatment-related grade 3/4 adverse events included thrombocytopenia in 59%, neutropenia in 46%, febrile neutropenia in 36%, anemia in 28%, decreased white blood cell count in 26%, and one case of tumor lysis syndrome, according to the report.
Based on those findings in a cohort of patients with poor risk features, venetoclax 600 mg plus LDAC was carried forward to be evaluated in an ongoing phase 3 study, investigators noted at the time.
Dr. Wang reported financial relationships with AbbVie, Amgen, ImmunoGen, Incyte, Novartis, and Otsuka.
New York – For unfit elderly patients with acute myeloid leukemia (AML), venetoclax may be one of the most promising potential options that is emerging, according to an expert in the field.
The oral B-cell lymphoma 2 (BCL-2) inhibitor is the treatment that some in the AML community are “most excited about” for this population, Eunice S. Wang, MD, of Roswell Park Comprehensive Cancer Center in Buffalo, N.Y., said at the National Comprehensive Cancer Network (NCCN) Annual Congress: Hematologic Malignancies.
Venetoclax is currently approved by the Food and Drug Administration for previously treated chronic lymphocytic leukemia (CLL), alone or in combination with rituximab. It has been granted four Breakthrough Therapy designations from the FDA in AML. In July 2018, AbbVie submitted a Supplemental New Drug Application to the FDA for its use in combination with a hypomethylating agent (HMA) or in combination with low-dose cytarabine (LDAC) for the treatment of newly diagnosed AML patients who are ineligible for intensive chemotherapy.
“This agent doesn’t work on its own but had worked in the refractory setting and can be a great option upfront,” Dr. Wang said.
About half the patients were alive at 1 year following treatment with venetoclax plus low-dose chemotherapy, whether that was LDAC or an HMA, she said, commenting on recently reported results.
In a phase 1b trial, venetoclax was evaluated in combination with either azacitidine or decitabine. In recently reported preliminary results that included 57 patients aged 65 years or older who were ineligible for standard induction therapy, the combination was well tolerated and had promising activity (Lancet Oncol. 2018 Feb;19[2]:216-28).
Overall, 35 patients (61%) had complete remission (CR) or complete remission with incomplete marrow recovery (CRi).
In another report on this same trial, which included 33 patients from a single participating center who received venetoclax and azacytidine, the overall response rate was 91%, including 19 (58%) with CR and 9 (27%) with CRi (Blood. 2017 Dec;130 [Suppl 1]:181).
A separate phase 1/2 trial examined venetoclax plus LDAC in treatment-naive elderly patients unfit for intensive chemotherapy. In the 1-year outcomes that have been reported, the observed CR/CRi rate was 62%, median overall survival was an “encouraging” 11.4 months, and the observed 12-month overall survival was 46% in 61 patients treated at a venetoclax dose of 600 mg (Blood. 2017 Dec;130 [Suppl 1]:890).
In those 61 patients, treatment-related grade 3/4 adverse events included thrombocytopenia in 59%, neutropenia in 46%, febrile neutropenia in 36%, anemia in 28%, decreased white blood cell count in 26%, and one case of tumor lysis syndrome, according to the report.
Based on those findings in a cohort of patients with poor risk features, venetoclax 600 mg plus LDAC was carried forward to be evaluated in an ongoing phase 3 study, investigators noted at the time.
Dr. Wang reported financial relationships with AbbVie, Amgen, ImmunoGen, Incyte, Novartis, and Otsuka.
EXPERT ANALYSIS FROM THE NCCN ANNUAL CONGRESS: HEMATOLOGIC MALIGNANCIES
Novel agents changing treatment algorithm in AML
NEW YORK—Recent drug approvals for acute myeloid leukemia (AML) have greatly expanded options for treating patients, according to a presentation at the NCCN 13th Annual Congress: Hematologic Malignancies.
Richard M. Stone, MD, of the Dana-Farber Cancer Institute in Boston, M.A., gave this presentation, providing some guidance for how to incorporate newly approved AML drugs into practice.
Dr. Stone also discussed therapies and treatment strategies that are under investigation.
Midostaurin
Midostaurin was approved by the U.S. Food and Drug Administration (FDA) in 2017. It is approved for use in combination with standard cytarabine and daunorubicin induction, followed by cytarabine consolidation, in adults with newly diagnosed AML who are FLT3-mutation-positive, as detected by an FDA-approved test.
Even though FLT3-ITD mutation confers a bad prognosis in AML, midostaurin capitalizes on the activated enzyme by inhibiting it.
The RATIFY trial (CALGB 10603) enrolled only FLT3-mutated AML patients younger than 60 and randomized them to induction and consolidation with or without midostaurin.
“Bottom line, being on midostaurin was a good thing,” Dr. Stone said.
Midostaurin led to a 23% reduction in the risk of death, and the 4-year survival rate was improved by about 7%.
“What is meaningful, if you happen to get a transplant in CR1 [first complete remission], you may be going to transplant with lower disease burden,” Dr. Stone explained. “Adding midostaurin is probably a good thing for mutated FLT3.”
The addition of midostaurin to induction may also be appropriate for fit older adults with FLT3 mutations, Dr. Stone said.
Gemtuzumab ozogamicin
The antibody-drug conjugate gemtuzumab ozogamicin has been around for almost 20 years and has an “interesting” history, according to Dr. Stone.
Gemtuzumab ozogamicin was first approved by the FDA in 2000, based on a 30% remission rate in relapsed AML.
However, the agent was voluntarily withdrawn from the market in 2010 because it was used in the upfront setting with chemotherapy and didn’t show a benefit.
Recent studies of the agent suggested use of the agent should be revisited but with lower doses.
Data from the ALFA 0701 study was key for the FDA’s re-approval of gemtuzumab in 2017.
According to Dr. Stone, the most important finding of this trial was the major event-free survival benefit for those on gemtuzumab, which was 41% at 2 years, compared to 17% for the control group.
Overall survival, however, was not significantly superior with gemtuzumab.
A meta-analysis of 5 trials showed that adding gemtuzumab to treatment of patients with favorable and intermediate risk conferred a survival advantage, but this was not the case in patients with adverse-risk cytogenetics.
Fit older adults with CBF mutation may benefit from the addition of gemtuzumab, Dr. Stone said.
He also pointed out that gemtuzumab has a big “booby prize,” which is veno-occlusive disease, shown to be a problem with high doses of gemtuzumab and transplant.
CPX-351
CPX-351 is a liposomal co-formulation of cytarabine and daunorubicin, the two drugs delivered separately in the standard induction chemotherapy referred to as 7+3.
Last year, the FDA approved CPX-351 to treat adults who have AML with myelodysplasia-related changes or newly diagnosed, therapy-related AML.
In a phase 3 trial, CPX-351 conferred a survival advantage over standard 7+3. There was a 31% reduction in the risk of death with CPX-351.
Patients who went on to transplant after CPX-351 did much better than patients who received 7+3 and transplant, with a hazard ratio of 0.51.
Dr. Stone noted that minimal residual disease was not measured, “but it’s quite possible that patients who had CPX went into transplant with a lower level of disease burden.”
Dr. Stone also said CPX-351 may be added to induction for fit older patients with secondary AML.
Enasidenib and ivosidenib
In relapsed AML, the treatment approach is to induce a second complete remission and then proceed to allogeneic stem cell transplant.
Traditionally, FLAG-IDA (fludarabine, cytarabine, idarubicin, and G-CSF) and MEC (mitoxantrone, etoposide, and cytarabine) have been used as salvage, and another course of 7+3 is an option if the patient has been disease-free for over a year.
Now, however, enasidenib and ivosidenib may be an option for IDH2- and IDH1-mutated patients, respectively.
The FDA approved enasidenib in 2017 to treat adults with relapsed or refractory AML and an IDH2 mutation, as detected by an FDA-approved test.
Ivosidenib was approved by the FDA this year to treat adults with relapsed or refractory AML who have an IDH1 mutation, as detected by an FDA-approved test.
New approaches on the horizon
Dr. Stone noted that gilteritinib and quizartinib are currently in development for FLT3-mutated patients, and he anticipates these therapies will be approved by the FDA in 2019.
Dr. Stone also touched on other new approaches under investigation, such as hedgehog pathway inhibition, dysregulation of the spliceosome complex, inhibiting MDM2, and strengthening the immune system.
However, he believes the most important is BCL-2 inhibition with venetoclax.
Venetoclax combined with a hypomethylator (azacitidine or decitabine) produced a response rate of 75% with azacitidine, double what one would expect with azacitidine or decitabine alone, Dr. Stone noted.
And venetoclax with low-dose cytarabine may enable elderly good-risk patients to avoid 7+3.
Dr. Stone’s presentation also covered genes commonly mutated in AML, the increasing scrutiny of complete remission, and minimal residual disease assessment. An account of this part of the presentation can be found here: “Current management of AML patients.”
NEW YORK—Recent drug approvals for acute myeloid leukemia (AML) have greatly expanded options for treating patients, according to a presentation at the NCCN 13th Annual Congress: Hematologic Malignancies.
Richard M. Stone, MD, of the Dana-Farber Cancer Institute in Boston, M.A., gave this presentation, providing some guidance for how to incorporate newly approved AML drugs into practice.
Dr. Stone also discussed therapies and treatment strategies that are under investigation.
Midostaurin
Midostaurin was approved by the U.S. Food and Drug Administration (FDA) in 2017. It is approved for use in combination with standard cytarabine and daunorubicin induction, followed by cytarabine consolidation, in adults with newly diagnosed AML who are FLT3-mutation-positive, as detected by an FDA-approved test.
Even though FLT3-ITD mutation confers a bad prognosis in AML, midostaurin capitalizes on the activated enzyme by inhibiting it.
The RATIFY trial (CALGB 10603) enrolled only FLT3-mutated AML patients younger than 60 and randomized them to induction and consolidation with or without midostaurin.
“Bottom line, being on midostaurin was a good thing,” Dr. Stone said.
Midostaurin led to a 23% reduction in the risk of death, and the 4-year survival rate was improved by about 7%.
“What is meaningful, if you happen to get a transplant in CR1 [first complete remission], you may be going to transplant with lower disease burden,” Dr. Stone explained. “Adding midostaurin is probably a good thing for mutated FLT3.”
The addition of midostaurin to induction may also be appropriate for fit older adults with FLT3 mutations, Dr. Stone said.
Gemtuzumab ozogamicin
The antibody-drug conjugate gemtuzumab ozogamicin has been around for almost 20 years and has an “interesting” history, according to Dr. Stone.
Gemtuzumab ozogamicin was first approved by the FDA in 2000, based on a 30% remission rate in relapsed AML.
However, the agent was voluntarily withdrawn from the market in 2010 because it was used in the upfront setting with chemotherapy and didn’t show a benefit.
Recent studies of the agent suggested use of the agent should be revisited but with lower doses.
Data from the ALFA 0701 study was key for the FDA’s re-approval of gemtuzumab in 2017.
According to Dr. Stone, the most important finding of this trial was the major event-free survival benefit for those on gemtuzumab, which was 41% at 2 years, compared to 17% for the control group.
Overall survival, however, was not significantly superior with gemtuzumab.
A meta-analysis of 5 trials showed that adding gemtuzumab to treatment of patients with favorable and intermediate risk conferred a survival advantage, but this was not the case in patients with adverse-risk cytogenetics.
Fit older adults with CBF mutation may benefit from the addition of gemtuzumab, Dr. Stone said.
He also pointed out that gemtuzumab has a big “booby prize,” which is veno-occlusive disease, shown to be a problem with high doses of gemtuzumab and transplant.
CPX-351
CPX-351 is a liposomal co-formulation of cytarabine and daunorubicin, the two drugs delivered separately in the standard induction chemotherapy referred to as 7+3.
Last year, the FDA approved CPX-351 to treat adults who have AML with myelodysplasia-related changes or newly diagnosed, therapy-related AML.
In a phase 3 trial, CPX-351 conferred a survival advantage over standard 7+3. There was a 31% reduction in the risk of death with CPX-351.
Patients who went on to transplant after CPX-351 did much better than patients who received 7+3 and transplant, with a hazard ratio of 0.51.
Dr. Stone noted that minimal residual disease was not measured, “but it’s quite possible that patients who had CPX went into transplant with a lower level of disease burden.”
Dr. Stone also said CPX-351 may be added to induction for fit older patients with secondary AML.
Enasidenib and ivosidenib
In relapsed AML, the treatment approach is to induce a second complete remission and then proceed to allogeneic stem cell transplant.
Traditionally, FLAG-IDA (fludarabine, cytarabine, idarubicin, and G-CSF) and MEC (mitoxantrone, etoposide, and cytarabine) have been used as salvage, and another course of 7+3 is an option if the patient has been disease-free for over a year.
Now, however, enasidenib and ivosidenib may be an option for IDH2- and IDH1-mutated patients, respectively.
The FDA approved enasidenib in 2017 to treat adults with relapsed or refractory AML and an IDH2 mutation, as detected by an FDA-approved test.
Ivosidenib was approved by the FDA this year to treat adults with relapsed or refractory AML who have an IDH1 mutation, as detected by an FDA-approved test.
New approaches on the horizon
Dr. Stone noted that gilteritinib and quizartinib are currently in development for FLT3-mutated patients, and he anticipates these therapies will be approved by the FDA in 2019.
Dr. Stone also touched on other new approaches under investigation, such as hedgehog pathway inhibition, dysregulation of the spliceosome complex, inhibiting MDM2, and strengthening the immune system.
However, he believes the most important is BCL-2 inhibition with venetoclax.
Venetoclax combined with a hypomethylator (azacitidine or decitabine) produced a response rate of 75% with azacitidine, double what one would expect with azacitidine or decitabine alone, Dr. Stone noted.
And venetoclax with low-dose cytarabine may enable elderly good-risk patients to avoid 7+3.
Dr. Stone’s presentation also covered genes commonly mutated in AML, the increasing scrutiny of complete remission, and minimal residual disease assessment. An account of this part of the presentation can be found here: “Current management of AML patients.”
NEW YORK—Recent drug approvals for acute myeloid leukemia (AML) have greatly expanded options for treating patients, according to a presentation at the NCCN 13th Annual Congress: Hematologic Malignancies.
Richard M. Stone, MD, of the Dana-Farber Cancer Institute in Boston, M.A., gave this presentation, providing some guidance for how to incorporate newly approved AML drugs into practice.
Dr. Stone also discussed therapies and treatment strategies that are under investigation.
Midostaurin
Midostaurin was approved by the U.S. Food and Drug Administration (FDA) in 2017. It is approved for use in combination with standard cytarabine and daunorubicin induction, followed by cytarabine consolidation, in adults with newly diagnosed AML who are FLT3-mutation-positive, as detected by an FDA-approved test.
Even though FLT3-ITD mutation confers a bad prognosis in AML, midostaurin capitalizes on the activated enzyme by inhibiting it.
The RATIFY trial (CALGB 10603) enrolled only FLT3-mutated AML patients younger than 60 and randomized them to induction and consolidation with or without midostaurin.
“Bottom line, being on midostaurin was a good thing,” Dr. Stone said.
Midostaurin led to a 23% reduction in the risk of death, and the 4-year survival rate was improved by about 7%.
“What is meaningful, if you happen to get a transplant in CR1 [first complete remission], you may be going to transplant with lower disease burden,” Dr. Stone explained. “Adding midostaurin is probably a good thing for mutated FLT3.”
The addition of midostaurin to induction may also be appropriate for fit older adults with FLT3 mutations, Dr. Stone said.
Gemtuzumab ozogamicin
The antibody-drug conjugate gemtuzumab ozogamicin has been around for almost 20 years and has an “interesting” history, according to Dr. Stone.
Gemtuzumab ozogamicin was first approved by the FDA in 2000, based on a 30% remission rate in relapsed AML.
However, the agent was voluntarily withdrawn from the market in 2010 because it was used in the upfront setting with chemotherapy and didn’t show a benefit.
Recent studies of the agent suggested use of the agent should be revisited but with lower doses.
Data from the ALFA 0701 study was key for the FDA’s re-approval of gemtuzumab in 2017.
According to Dr. Stone, the most important finding of this trial was the major event-free survival benefit for those on gemtuzumab, which was 41% at 2 years, compared to 17% for the control group.
Overall survival, however, was not significantly superior with gemtuzumab.
A meta-analysis of 5 trials showed that adding gemtuzumab to treatment of patients with favorable and intermediate risk conferred a survival advantage, but this was not the case in patients with adverse-risk cytogenetics.
Fit older adults with CBF mutation may benefit from the addition of gemtuzumab, Dr. Stone said.
He also pointed out that gemtuzumab has a big “booby prize,” which is veno-occlusive disease, shown to be a problem with high doses of gemtuzumab and transplant.
CPX-351
CPX-351 is a liposomal co-formulation of cytarabine and daunorubicin, the two drugs delivered separately in the standard induction chemotherapy referred to as 7+3.
Last year, the FDA approved CPX-351 to treat adults who have AML with myelodysplasia-related changes or newly diagnosed, therapy-related AML.
In a phase 3 trial, CPX-351 conferred a survival advantage over standard 7+3. There was a 31% reduction in the risk of death with CPX-351.
Patients who went on to transplant after CPX-351 did much better than patients who received 7+3 and transplant, with a hazard ratio of 0.51.
Dr. Stone noted that minimal residual disease was not measured, “but it’s quite possible that patients who had CPX went into transplant with a lower level of disease burden.”
Dr. Stone also said CPX-351 may be added to induction for fit older patients with secondary AML.
Enasidenib and ivosidenib
In relapsed AML, the treatment approach is to induce a second complete remission and then proceed to allogeneic stem cell transplant.
Traditionally, FLAG-IDA (fludarabine, cytarabine, idarubicin, and G-CSF) and MEC (mitoxantrone, etoposide, and cytarabine) have been used as salvage, and another course of 7+3 is an option if the patient has been disease-free for over a year.
Now, however, enasidenib and ivosidenib may be an option for IDH2- and IDH1-mutated patients, respectively.
The FDA approved enasidenib in 2017 to treat adults with relapsed or refractory AML and an IDH2 mutation, as detected by an FDA-approved test.
Ivosidenib was approved by the FDA this year to treat adults with relapsed or refractory AML who have an IDH1 mutation, as detected by an FDA-approved test.
New approaches on the horizon
Dr. Stone noted that gilteritinib and quizartinib are currently in development for FLT3-mutated patients, and he anticipates these therapies will be approved by the FDA in 2019.
Dr. Stone also touched on other new approaches under investigation, such as hedgehog pathway inhibition, dysregulation of the spliceosome complex, inhibiting MDM2, and strengthening the immune system.
However, he believes the most important is BCL-2 inhibition with venetoclax.
Venetoclax combined with a hypomethylator (azacitidine or decitabine) produced a response rate of 75% with azacitidine, double what one would expect with azacitidine or decitabine alone, Dr. Stone noted.
And venetoclax with low-dose cytarabine may enable elderly good-risk patients to avoid 7+3.
Dr. Stone’s presentation also covered genes commonly mutated in AML, the increasing scrutiny of complete remission, and minimal residual disease assessment. An account of this part of the presentation can be found here: “Current management of AML patients.”
Current management of AML patients
NEW YORK—A presentation at the NCCN 13th Annual Congress: Hematologic Malignancies outlined current practices for managing patients with acute myeloid leukemia (AML).
Richard M. Stone, MD, of the Dana-Farber Cancer Institute in Boston, M.A., noted that management of AML now includes increased screening of commonly mutated genes, greater scrutiny of complete remission (CR), and a focus on minimal residual disease (MRD).
Genetics and cytogenetics
Genome sequencing projects in AML have revealed about 30 genes commonly mutated in AML patients, which can be further divided into 9 subcategories, Dr. Stone said.
He noted that the list of genes to screen for is getting longer every year, from FLT3-ITD, NPM1, and CEBPA last year, to RUNX1, TP53, ASXL1, KIT, and CBF mutations this year.
“Just looking at genetics, you can tell if you have CEBPA mutation, you are most likely going to be free of AML, and if you have TP53, you are in big trouble,” Dr. Stone said.
He added that the mutation status of IDH1/2, DNMT3A, and TET2 will be important in the future.
“So, basically, I like to have an NGS [next-generation sequencing] panel on all of our patients with AML today,” Dr. Stone said. “It’s probably going to be cheaper than trying to do the shotgun approach we were recently used to.”
Achieving CR
Dr. Stone noted that the first goal of AML treatment is to reduce the gross leukemia to undetectable levels with induction therapy and to achieve a CR.
“But there are real good remissions and not so good remissions,” he said. “But once we get into remission, that’s just the beginning of the curative approach.”
The second goal is to reduce patients’ leukemic cells still present at CR to a level low enough to achieve prolonged disease-free survival.
“CR is coming under more scrutiny,” according to Dr. Stone, because some patients with CR have low blasts, but the blood counts aren’t returning to normal.
“[T]here’s CRc, CRi, CRp, you name it, all the little subscripts, which mean the remission really isn’t as strong as it should be,” Dr. Stone said.
“But if you do have a complete remission with low blast counts in the marrow and blood and normal blood counts, you might have an MRD-negative remission, which is the goal.”
Quantitation techniques and MRD
The European LeukemiaNet recommends all AML patients have an MRD assessment at the time of remission by either multiparameter flow cytometry (MFC) or molecular means.
The most sensitive techniques to determine disease burden are MFC and polymerase chain reaction (PCR)-based methods, both of which are sensitive enough to find one leukemic cell in 10,000 cells (10-4).
NGS techniques are becoming more sensitive, Dr. Stone added, but probably not down to the level of 10-4.
In a study by Ivey et al, MRD levels based on PCR of NPM1-mutated patients after two rounds of chemotherapy could independently predict clinical outcome. Overall survival was 73% for MRD-negative patients and 24% for MRD-positive patients.
MFC and NGS data have been shown in a study by Jongen-Lavrencic et al to be mutually helpful. If a patient is positive by neither method, the relapse rate is low. If the patient is positive by both, the relapse rate is high. And if the patient is positive by one and negative by the other, the relapse rate is intermediate.
“So what do we do with this?” Dr. Stone asked. “The problem is, I don’t know what to do with that data except get worried.”
The dilemma is that if patients are MRD-positive in remission, they are probably not going to respond well to a transplant. And if they are MRD-negative, they don’t need a transplant.
A retrospective study by Milano et al indicated that MRD-positive patients seem to fare better than expected with a double umbilical cord blood transplant. However, Dr. Stone noted that this finding has not been confirmed prospectively.
The most exciting aspect of MRD in AML, Dr. Stone said, is it may allow us to get to new drugs quicker by revealing whether a drug is actually lowering MRD burden.
Dr. Stone also discussed newly approved drugs for AML and new treatment approaches under investigation. Details on that portion of his presentation are available here: “Novel agents changing treatment algorithm in AML.”
NEW YORK—A presentation at the NCCN 13th Annual Congress: Hematologic Malignancies outlined current practices for managing patients with acute myeloid leukemia (AML).
Richard M. Stone, MD, of the Dana-Farber Cancer Institute in Boston, M.A., noted that management of AML now includes increased screening of commonly mutated genes, greater scrutiny of complete remission (CR), and a focus on minimal residual disease (MRD).
Genetics and cytogenetics
Genome sequencing projects in AML have revealed about 30 genes commonly mutated in AML patients, which can be further divided into 9 subcategories, Dr. Stone said.
He noted that the list of genes to screen for is getting longer every year, from FLT3-ITD, NPM1, and CEBPA last year, to RUNX1, TP53, ASXL1, KIT, and CBF mutations this year.
“Just looking at genetics, you can tell if you have CEBPA mutation, you are most likely going to be free of AML, and if you have TP53, you are in big trouble,” Dr. Stone said.
He added that the mutation status of IDH1/2, DNMT3A, and TET2 will be important in the future.
“So, basically, I like to have an NGS [next-generation sequencing] panel on all of our patients with AML today,” Dr. Stone said. “It’s probably going to be cheaper than trying to do the shotgun approach we were recently used to.”
Achieving CR
Dr. Stone noted that the first goal of AML treatment is to reduce the gross leukemia to undetectable levels with induction therapy and to achieve a CR.
“But there are real good remissions and not so good remissions,” he said. “But once we get into remission, that’s just the beginning of the curative approach.”
The second goal is to reduce patients’ leukemic cells still present at CR to a level low enough to achieve prolonged disease-free survival.
“CR is coming under more scrutiny,” according to Dr. Stone, because some patients with CR have low blasts, but the blood counts aren’t returning to normal.
“[T]here’s CRc, CRi, CRp, you name it, all the little subscripts, which mean the remission really isn’t as strong as it should be,” Dr. Stone said.
“But if you do have a complete remission with low blast counts in the marrow and blood and normal blood counts, you might have an MRD-negative remission, which is the goal.”
Quantitation techniques and MRD
The European LeukemiaNet recommends all AML patients have an MRD assessment at the time of remission by either multiparameter flow cytometry (MFC) or molecular means.
The most sensitive techniques to determine disease burden are MFC and polymerase chain reaction (PCR)-based methods, both of which are sensitive enough to find one leukemic cell in 10,000 cells (10-4).
NGS techniques are becoming more sensitive, Dr. Stone added, but probably not down to the level of 10-4.
In a study by Ivey et al, MRD levels based on PCR of NPM1-mutated patients after two rounds of chemotherapy could independently predict clinical outcome. Overall survival was 73% for MRD-negative patients and 24% for MRD-positive patients.
MFC and NGS data have been shown in a study by Jongen-Lavrencic et al to be mutually helpful. If a patient is positive by neither method, the relapse rate is low. If the patient is positive by both, the relapse rate is high. And if the patient is positive by one and negative by the other, the relapse rate is intermediate.
“So what do we do with this?” Dr. Stone asked. “The problem is, I don’t know what to do with that data except get worried.”
The dilemma is that if patients are MRD-positive in remission, they are probably not going to respond well to a transplant. And if they are MRD-negative, they don’t need a transplant.
A retrospective study by Milano et al indicated that MRD-positive patients seem to fare better than expected with a double umbilical cord blood transplant. However, Dr. Stone noted that this finding has not been confirmed prospectively.
The most exciting aspect of MRD in AML, Dr. Stone said, is it may allow us to get to new drugs quicker by revealing whether a drug is actually lowering MRD burden.
Dr. Stone also discussed newly approved drugs for AML and new treatment approaches under investigation. Details on that portion of his presentation are available here: “Novel agents changing treatment algorithm in AML.”
NEW YORK—A presentation at the NCCN 13th Annual Congress: Hematologic Malignancies outlined current practices for managing patients with acute myeloid leukemia (AML).
Richard M. Stone, MD, of the Dana-Farber Cancer Institute in Boston, M.A., noted that management of AML now includes increased screening of commonly mutated genes, greater scrutiny of complete remission (CR), and a focus on minimal residual disease (MRD).
Genetics and cytogenetics
Genome sequencing projects in AML have revealed about 30 genes commonly mutated in AML patients, which can be further divided into 9 subcategories, Dr. Stone said.
He noted that the list of genes to screen for is getting longer every year, from FLT3-ITD, NPM1, and CEBPA last year, to RUNX1, TP53, ASXL1, KIT, and CBF mutations this year.
“Just looking at genetics, you can tell if you have CEBPA mutation, you are most likely going to be free of AML, and if you have TP53, you are in big trouble,” Dr. Stone said.
He added that the mutation status of IDH1/2, DNMT3A, and TET2 will be important in the future.
“So, basically, I like to have an NGS [next-generation sequencing] panel on all of our patients with AML today,” Dr. Stone said. “It’s probably going to be cheaper than trying to do the shotgun approach we were recently used to.”
Achieving CR
Dr. Stone noted that the first goal of AML treatment is to reduce the gross leukemia to undetectable levels with induction therapy and to achieve a CR.
“But there are real good remissions and not so good remissions,” he said. “But once we get into remission, that’s just the beginning of the curative approach.”
The second goal is to reduce patients’ leukemic cells still present at CR to a level low enough to achieve prolonged disease-free survival.
“CR is coming under more scrutiny,” according to Dr. Stone, because some patients with CR have low blasts, but the blood counts aren’t returning to normal.
“[T]here’s CRc, CRi, CRp, you name it, all the little subscripts, which mean the remission really isn’t as strong as it should be,” Dr. Stone said.
“But if you do have a complete remission with low blast counts in the marrow and blood and normal blood counts, you might have an MRD-negative remission, which is the goal.”
Quantitation techniques and MRD
The European LeukemiaNet recommends all AML patients have an MRD assessment at the time of remission by either multiparameter flow cytometry (MFC) or molecular means.
The most sensitive techniques to determine disease burden are MFC and polymerase chain reaction (PCR)-based methods, both of which are sensitive enough to find one leukemic cell in 10,000 cells (10-4).
NGS techniques are becoming more sensitive, Dr. Stone added, but probably not down to the level of 10-4.
In a study by Ivey et al, MRD levels based on PCR of NPM1-mutated patients after two rounds of chemotherapy could independently predict clinical outcome. Overall survival was 73% for MRD-negative patients and 24% for MRD-positive patients.
MFC and NGS data have been shown in a study by Jongen-Lavrencic et al to be mutually helpful. If a patient is positive by neither method, the relapse rate is low. If the patient is positive by both, the relapse rate is high. And if the patient is positive by one and negative by the other, the relapse rate is intermediate.
“So what do we do with this?” Dr. Stone asked. “The problem is, I don’t know what to do with that data except get worried.”
The dilemma is that if patients are MRD-positive in remission, they are probably not going to respond well to a transplant. And if they are MRD-negative, they don’t need a transplant.
A retrospective study by Milano et al indicated that MRD-positive patients seem to fare better than expected with a double umbilical cord blood transplant. However, Dr. Stone noted that this finding has not been confirmed prospectively.
The most exciting aspect of MRD in AML, Dr. Stone said, is it may allow us to get to new drugs quicker by revealing whether a drug is actually lowering MRD burden.
Dr. Stone also discussed newly approved drugs for AML and new treatment approaches under investigation. Details on that portion of his presentation are available here: “Novel agents changing treatment algorithm in AML.”
FLT3 inhibitor approved for rel/ref AML in Japan
The Japanese Ministry of Health, Labour and Welfare (MHLW) has approved the FLT3 inhibitor gilteritinib (Xospata®) to treat patients with FLT3-positive relapsed or refractory acute myeloid leukemia (AML).
Gilteritinib is available in 40 mg tablets. The usual recommended starting dose of gilteritinib for an adult is 120 mg once daily.
The dosage may be adjusted depending on the patient’s condition. However, the daily maximum dose should be 200 mg.
Gilteritinib has demonstrated inhibitory activity against FLT3 internal tandem duplication and FLT tyrosine kinase domain mutation. These two mutations are present in approximately one-third of AML patients.
The MHLW approval of gilteritinib is based on interim results from the phase 3 ADMIRAL study (NCT02421939).
ADIMRAL is designed to compare gilteritinib to salvage chemotherapy in adults who have AML with FLT3 mutations and have relapsed after or are refractory to frontline therapy.
Patients are randomized in a 2:1 ratio to receive gilteritinib (120 mg) or salvage chemotherapy, which may consist of low-dose cytarabine, azacitidine, MEC (mitoxantrone, etoposide, and cytarabine), or FLAG-IDA (fludarabine, cytarabine, and granulocyte colony-stimulating factor [G-CSF] with idarubicin).
Results from this trial have not yet been presented or published. However, a description of the trial was presented at the 2018 ASCO Annual Meeting (abstract TPS7075).
Results from a phase 1/2 study of gilteritinib in AML were published in The Lancet Oncology in 2017.
Orphan and SAKIGAKE designations
The MHLW previously granted SAKIGAKE designation and orphan drug designation to gilteritinib.
To receive orphan designation, a product (drug or medical device) must be intended for use in less than 50,000 patients in Japan. Furthermore, orphan products must be indicated for the treatment of serious diseases for which there are high medical needs.
Companies granted orphan designation can receive preferential tax treatment as well as subsidies through the National Institute of Biomedical Innovation (NIBIO) to reduce the financial burden of product development.
Companies with orphan designation can also receive guidance and consultation from the MHLW, the Pharmaceuticals and Medical Devices Agency (PMDA), and NIBIO on research and development activities.
Orphan designation also allows for priority review and an extension of the re-examination period—up to 10 years for drugs and up to 7 years for medical devices.
SAKIGAKE designation can shorten the review period for a product via prioritized consultation, substantial pre-application consultation, and prioritized review.
SAKIGAKE designation also helps promote development with the review partner system (to be conducted by the PMDA) and “substantial” post-marketing safety measures.
The Japanese Ministry of Health, Labour and Welfare (MHLW) has approved the FLT3 inhibitor gilteritinib (Xospata®) to treat patients with FLT3-positive relapsed or refractory acute myeloid leukemia (AML).
Gilteritinib is available in 40 mg tablets. The usual recommended starting dose of gilteritinib for an adult is 120 mg once daily.
The dosage may be adjusted depending on the patient’s condition. However, the daily maximum dose should be 200 mg.
Gilteritinib has demonstrated inhibitory activity against FLT3 internal tandem duplication and FLT tyrosine kinase domain mutation. These two mutations are present in approximately one-third of AML patients.
The MHLW approval of gilteritinib is based on interim results from the phase 3 ADMIRAL study (NCT02421939).
ADIMRAL is designed to compare gilteritinib to salvage chemotherapy in adults who have AML with FLT3 mutations and have relapsed after or are refractory to frontline therapy.
Patients are randomized in a 2:1 ratio to receive gilteritinib (120 mg) or salvage chemotherapy, which may consist of low-dose cytarabine, azacitidine, MEC (mitoxantrone, etoposide, and cytarabine), or FLAG-IDA (fludarabine, cytarabine, and granulocyte colony-stimulating factor [G-CSF] with idarubicin).
Results from this trial have not yet been presented or published. However, a description of the trial was presented at the 2018 ASCO Annual Meeting (abstract TPS7075).
Results from a phase 1/2 study of gilteritinib in AML were published in The Lancet Oncology in 2017.
Orphan and SAKIGAKE designations
The MHLW previously granted SAKIGAKE designation and orphan drug designation to gilteritinib.
To receive orphan designation, a product (drug or medical device) must be intended for use in less than 50,000 patients in Japan. Furthermore, orphan products must be indicated for the treatment of serious diseases for which there are high medical needs.
Companies granted orphan designation can receive preferential tax treatment as well as subsidies through the National Institute of Biomedical Innovation (NIBIO) to reduce the financial burden of product development.
Companies with orphan designation can also receive guidance and consultation from the MHLW, the Pharmaceuticals and Medical Devices Agency (PMDA), and NIBIO on research and development activities.
Orphan designation also allows for priority review and an extension of the re-examination period—up to 10 years for drugs and up to 7 years for medical devices.
SAKIGAKE designation can shorten the review period for a product via prioritized consultation, substantial pre-application consultation, and prioritized review.
SAKIGAKE designation also helps promote development with the review partner system (to be conducted by the PMDA) and “substantial” post-marketing safety measures.
The Japanese Ministry of Health, Labour and Welfare (MHLW) has approved the FLT3 inhibitor gilteritinib (Xospata®) to treat patients with FLT3-positive relapsed or refractory acute myeloid leukemia (AML).
Gilteritinib is available in 40 mg tablets. The usual recommended starting dose of gilteritinib for an adult is 120 mg once daily.
The dosage may be adjusted depending on the patient’s condition. However, the daily maximum dose should be 200 mg.
Gilteritinib has demonstrated inhibitory activity against FLT3 internal tandem duplication and FLT tyrosine kinase domain mutation. These two mutations are present in approximately one-third of AML patients.
The MHLW approval of gilteritinib is based on interim results from the phase 3 ADMIRAL study (NCT02421939).
ADIMRAL is designed to compare gilteritinib to salvage chemotherapy in adults who have AML with FLT3 mutations and have relapsed after or are refractory to frontline therapy.
Patients are randomized in a 2:1 ratio to receive gilteritinib (120 mg) or salvage chemotherapy, which may consist of low-dose cytarabine, azacitidine, MEC (mitoxantrone, etoposide, and cytarabine), or FLAG-IDA (fludarabine, cytarabine, and granulocyte colony-stimulating factor [G-CSF] with idarubicin).
Results from this trial have not yet been presented or published. However, a description of the trial was presented at the 2018 ASCO Annual Meeting (abstract TPS7075).
Results from a phase 1/2 study of gilteritinib in AML were published in The Lancet Oncology in 2017.
Orphan and SAKIGAKE designations
The MHLW previously granted SAKIGAKE designation and orphan drug designation to gilteritinib.
To receive orphan designation, a product (drug or medical device) must be intended for use in less than 50,000 patients in Japan. Furthermore, orphan products must be indicated for the treatment of serious diseases for which there are high medical needs.
Companies granted orphan designation can receive preferential tax treatment as well as subsidies through the National Institute of Biomedical Innovation (NIBIO) to reduce the financial burden of product development.
Companies with orphan designation can also receive guidance and consultation from the MHLW, the Pharmaceuticals and Medical Devices Agency (PMDA), and NIBIO on research and development activities.
Orphan designation also allows for priority review and an extension of the re-examination period—up to 10 years for drugs and up to 7 years for medical devices.
SAKIGAKE designation can shorten the review period for a product via prioritized consultation, substantial pre-application consultation, and prioritized review.
SAKIGAKE designation also helps promote development with the review partner system (to be conducted by the PMDA) and “substantial” post-marketing safety measures.
NGS can predict AML relapse after HSCT
Next-generation sequencing (NGS) can be used to predict relapse in acute myeloid leukemia (AML) patients undergoing hematopoietic stem cell transplant (HSCT), according to research published in Blood.
Researchers found that patients with a higher variant allele frequency (VAF) 21 days after HSCT had a higher risk of relapse and death.
“We can detect mutations in patients’ bone marrow cells 3 weeks after the transplant and, based on that, predict the likelihood of their relapse,” explained study author Zhaolei Zhang, PhD, of the University of Toronto in Ontario, Canada.
Dr. Zhang and his colleagues performed NGS on 529 bone marrow samples from 104 AML patients who underwent chemotherapy and HSCT.
The samples were collected at the time of diagnosis, during the chemotherapy-induced remission, and 3 weeks after HSCT. A subset of patients also gave samples at 3 months, 6 months, and 12 months after HSCT.
The researchers identified 256 mutations that were present in 90 patients at diagnosis and looked for those same mutations at each sampling point.
Chemotherapy and HSCT eliminated most AML cells, leading to a reduction in mutation frequency. However, in some patients, mutations observed at diagnosis could still be detected after chemotherapy and at day 21 after HSCT, indicating the presence of treatment-resistant AML cells.
Allelic burdens at day 21 post-HSCT were higher in patients who ultimately relapsed, and the mutations observed at day 21 expanded at relapse.
The 3-year relapse rate was 56.2% in patients with a VAF greater than 0.2% at day 21 post-HSCT, compared to 16.0% in patients with a lower or no mutational burden (P<0.001).
The 3-year overall survival rates were 36.5% in patients with a VAF greater than 0.2% and 67.0% for patients with a lower or no mutational burden (P=0.006).
In multivariate analyses, VAF0.2% at day 21 was an independent adverse prognostic factor for relapse—hazard ratio, 4.75 (P<0.001)—and overall survival—hazard ratio, 3.07 (P=0.003).
Dr. Zhang and his colleagues said these results suggest NGS-based monitoring after HSCT “provides valuable information” that, together with a patient’s baseline mutational profile and clinical evaluation, can be used to predict outcomes of transplant.
This study was supported by research grants from the Natural Science and Engineering Council of Canada, Leukemia and Lymphoma Society of Canada, Princess Margaret Foundation, National Research Foundation of Korea, and National Natural Science Foundation of China.
Next-generation sequencing (NGS) can be used to predict relapse in acute myeloid leukemia (AML) patients undergoing hematopoietic stem cell transplant (HSCT), according to research published in Blood.
Researchers found that patients with a higher variant allele frequency (VAF) 21 days after HSCT had a higher risk of relapse and death.
“We can detect mutations in patients’ bone marrow cells 3 weeks after the transplant and, based on that, predict the likelihood of their relapse,” explained study author Zhaolei Zhang, PhD, of the University of Toronto in Ontario, Canada.
Dr. Zhang and his colleagues performed NGS on 529 bone marrow samples from 104 AML patients who underwent chemotherapy and HSCT.
The samples were collected at the time of diagnosis, during the chemotherapy-induced remission, and 3 weeks after HSCT. A subset of patients also gave samples at 3 months, 6 months, and 12 months after HSCT.
The researchers identified 256 mutations that were present in 90 patients at diagnosis and looked for those same mutations at each sampling point.
Chemotherapy and HSCT eliminated most AML cells, leading to a reduction in mutation frequency. However, in some patients, mutations observed at diagnosis could still be detected after chemotherapy and at day 21 after HSCT, indicating the presence of treatment-resistant AML cells.
Allelic burdens at day 21 post-HSCT were higher in patients who ultimately relapsed, and the mutations observed at day 21 expanded at relapse.
The 3-year relapse rate was 56.2% in patients with a VAF greater than 0.2% at day 21 post-HSCT, compared to 16.0% in patients with a lower or no mutational burden (P<0.001).
The 3-year overall survival rates were 36.5% in patients with a VAF greater than 0.2% and 67.0% for patients with a lower or no mutational burden (P=0.006).
In multivariate analyses, VAF0.2% at day 21 was an independent adverse prognostic factor for relapse—hazard ratio, 4.75 (P<0.001)—and overall survival—hazard ratio, 3.07 (P=0.003).
Dr. Zhang and his colleagues said these results suggest NGS-based monitoring after HSCT “provides valuable information” that, together with a patient’s baseline mutational profile and clinical evaluation, can be used to predict outcomes of transplant.
This study was supported by research grants from the Natural Science and Engineering Council of Canada, Leukemia and Lymphoma Society of Canada, Princess Margaret Foundation, National Research Foundation of Korea, and National Natural Science Foundation of China.
Next-generation sequencing (NGS) can be used to predict relapse in acute myeloid leukemia (AML) patients undergoing hematopoietic stem cell transplant (HSCT), according to research published in Blood.
Researchers found that patients with a higher variant allele frequency (VAF) 21 days after HSCT had a higher risk of relapse and death.
“We can detect mutations in patients’ bone marrow cells 3 weeks after the transplant and, based on that, predict the likelihood of their relapse,” explained study author Zhaolei Zhang, PhD, of the University of Toronto in Ontario, Canada.
Dr. Zhang and his colleagues performed NGS on 529 bone marrow samples from 104 AML patients who underwent chemotherapy and HSCT.
The samples were collected at the time of diagnosis, during the chemotherapy-induced remission, and 3 weeks after HSCT. A subset of patients also gave samples at 3 months, 6 months, and 12 months after HSCT.
The researchers identified 256 mutations that were present in 90 patients at diagnosis and looked for those same mutations at each sampling point.
Chemotherapy and HSCT eliminated most AML cells, leading to a reduction in mutation frequency. However, in some patients, mutations observed at diagnosis could still be detected after chemotherapy and at day 21 after HSCT, indicating the presence of treatment-resistant AML cells.
Allelic burdens at day 21 post-HSCT were higher in patients who ultimately relapsed, and the mutations observed at day 21 expanded at relapse.
The 3-year relapse rate was 56.2% in patients with a VAF greater than 0.2% at day 21 post-HSCT, compared to 16.0% in patients with a lower or no mutational burden (P<0.001).
The 3-year overall survival rates were 36.5% in patients with a VAF greater than 0.2% and 67.0% for patients with a lower or no mutational burden (P=0.006).
In multivariate analyses, VAF0.2% at day 21 was an independent adverse prognostic factor for relapse—hazard ratio, 4.75 (P<0.001)—and overall survival—hazard ratio, 3.07 (P=0.003).
Dr. Zhang and his colleagues said these results suggest NGS-based monitoring after HSCT “provides valuable information” that, together with a patient’s baseline mutational profile and clinical evaluation, can be used to predict outcomes of transplant.
This study was supported by research grants from the Natural Science and Engineering Council of Canada, Leukemia and Lymphoma Society of Canada, Princess Margaret Foundation, National Research Foundation of Korea, and National Natural Science Foundation of China.
Researchers propose new acute leukemia subtypes
An extensive analysis of mixed phenotype acute leukemia (MPAL) has led to new insights that may have implications for disease classification and treatment.
Researchers believe they have identified new subtypes of MPAL that should be included in the World Health Organization classification for acute leukemia.
Each of these subtypes share genomic characteristics with other acute leukemias, which suggests they might respond to treatments that are already in use.
This research also has shed light on how MPAL evolves and appears to provide an explanation for why MPAL displays characteristics of both acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL).
“ALL and AML have very different treatments, but MPAL has features of both, so the question of how best to treat patients with MPAL has been challenging the leukemia community worldwide, and long-term survival of patients has been poor,” said study author Charles G. Mullighan, MD, of St. Jude Children’s Research Hospital in Memphis, Tenn.
In the current study, published in Nature, Dr. Mullighan and his colleagues used whole-genome, whole-exome, and RNA sequencing to analyze 115 samples from pediatric patients with MPAL.
The analysis revealed mutations that define the two most common subtypes of MPAL – B/myeloid and T/myeloid – and suggested these subtypes share similarities with other leukemia subtypes.
The researchers found that 48% of B/myeloid MPAL cases carried rearrangements in ZNF384, a characteristic that is also found in cases of B-cell ALL. In fact, the team said the gene expression profiles of ZNF384r B-ALL and ZNF384r MPAL were indistinguishable.
“That is biologically and clinically important,” Dr. Mullighan said. “The findings suggest the ZNF384 rearrangement defines a distinct leukemia subtype, and the alteration should be used to guide treatment.”
The researchers noted that patients with ZNF384r exhibited higher FLT3 expression than that of patients with other types of B/myeloid or T/myeloid MPAL, so patients with ZNF384r MPAL might respond well to treatment with a FLT3 inhibitor.
This study also showed that cases of B/myeloid MPAL without ZNF384r shared genomic features with other B-ALL subtypes, such as Ph-like B-ALL.
In addition, the analysis showed that T/myeloid MPAL and early T-cell precursor ALL have similar gene expression profiles.
The team identified several genes that were mutated at similar frequencies in T/myeloid MPAL and early T-cell precursor ALL, including WT1, ETV6, EZH2, and FLT3.
WT1 was the most frequently mutated transcription factor gene in T/myeloid MPAL.
Based on these findings, the researchers said the WHO classification of acute leukemia should be updated to include: ZNF384r acute leukemia (either B-ALL or MPAL), WT1-mutant T/myeloid MPAL, and Ph-like B/myeloid MPAL.
This research was supported by the National Cancer Institute, the National Institutes of Health, Cookies for Kids’ Cancer, and other organizations. The researchers reported having no competing interests.
SOURCE: Alexander TB et al. Nature. 2018 Sep 12. doi: 10.1038/s41586-018-0436-0.
An extensive analysis of mixed phenotype acute leukemia (MPAL) has led to new insights that may have implications for disease classification and treatment.
Researchers believe they have identified new subtypes of MPAL that should be included in the World Health Organization classification for acute leukemia.
Each of these subtypes share genomic characteristics with other acute leukemias, which suggests they might respond to treatments that are already in use.
This research also has shed light on how MPAL evolves and appears to provide an explanation for why MPAL displays characteristics of both acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL).
“ALL and AML have very different treatments, but MPAL has features of both, so the question of how best to treat patients with MPAL has been challenging the leukemia community worldwide, and long-term survival of patients has been poor,” said study author Charles G. Mullighan, MD, of St. Jude Children’s Research Hospital in Memphis, Tenn.
In the current study, published in Nature, Dr. Mullighan and his colleagues used whole-genome, whole-exome, and RNA sequencing to analyze 115 samples from pediatric patients with MPAL.
The analysis revealed mutations that define the two most common subtypes of MPAL – B/myeloid and T/myeloid – and suggested these subtypes share similarities with other leukemia subtypes.
The researchers found that 48% of B/myeloid MPAL cases carried rearrangements in ZNF384, a characteristic that is also found in cases of B-cell ALL. In fact, the team said the gene expression profiles of ZNF384r B-ALL and ZNF384r MPAL were indistinguishable.
“That is biologically and clinically important,” Dr. Mullighan said. “The findings suggest the ZNF384 rearrangement defines a distinct leukemia subtype, and the alteration should be used to guide treatment.”
The researchers noted that patients with ZNF384r exhibited higher FLT3 expression than that of patients with other types of B/myeloid or T/myeloid MPAL, so patients with ZNF384r MPAL might respond well to treatment with a FLT3 inhibitor.
This study also showed that cases of B/myeloid MPAL without ZNF384r shared genomic features with other B-ALL subtypes, such as Ph-like B-ALL.
In addition, the analysis showed that T/myeloid MPAL and early T-cell precursor ALL have similar gene expression profiles.
The team identified several genes that were mutated at similar frequencies in T/myeloid MPAL and early T-cell precursor ALL, including WT1, ETV6, EZH2, and FLT3.
WT1 was the most frequently mutated transcription factor gene in T/myeloid MPAL.
Based on these findings, the researchers said the WHO classification of acute leukemia should be updated to include: ZNF384r acute leukemia (either B-ALL or MPAL), WT1-mutant T/myeloid MPAL, and Ph-like B/myeloid MPAL.
This research was supported by the National Cancer Institute, the National Institutes of Health, Cookies for Kids’ Cancer, and other organizations. The researchers reported having no competing interests.
SOURCE: Alexander TB et al. Nature. 2018 Sep 12. doi: 10.1038/s41586-018-0436-0.
An extensive analysis of mixed phenotype acute leukemia (MPAL) has led to new insights that may have implications for disease classification and treatment.
Researchers believe they have identified new subtypes of MPAL that should be included in the World Health Organization classification for acute leukemia.
Each of these subtypes share genomic characteristics with other acute leukemias, which suggests they might respond to treatments that are already in use.
This research also has shed light on how MPAL evolves and appears to provide an explanation for why MPAL displays characteristics of both acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL).
“ALL and AML have very different treatments, but MPAL has features of both, so the question of how best to treat patients with MPAL has been challenging the leukemia community worldwide, and long-term survival of patients has been poor,” said study author Charles G. Mullighan, MD, of St. Jude Children’s Research Hospital in Memphis, Tenn.
In the current study, published in Nature, Dr. Mullighan and his colleagues used whole-genome, whole-exome, and RNA sequencing to analyze 115 samples from pediatric patients with MPAL.
The analysis revealed mutations that define the two most common subtypes of MPAL – B/myeloid and T/myeloid – and suggested these subtypes share similarities with other leukemia subtypes.
The researchers found that 48% of B/myeloid MPAL cases carried rearrangements in ZNF384, a characteristic that is also found in cases of B-cell ALL. In fact, the team said the gene expression profiles of ZNF384r B-ALL and ZNF384r MPAL were indistinguishable.
“That is biologically and clinically important,” Dr. Mullighan said. “The findings suggest the ZNF384 rearrangement defines a distinct leukemia subtype, and the alteration should be used to guide treatment.”
The researchers noted that patients with ZNF384r exhibited higher FLT3 expression than that of patients with other types of B/myeloid or T/myeloid MPAL, so patients with ZNF384r MPAL might respond well to treatment with a FLT3 inhibitor.
This study also showed that cases of B/myeloid MPAL without ZNF384r shared genomic features with other B-ALL subtypes, such as Ph-like B-ALL.
In addition, the analysis showed that T/myeloid MPAL and early T-cell precursor ALL have similar gene expression profiles.
The team identified several genes that were mutated at similar frequencies in T/myeloid MPAL and early T-cell precursor ALL, including WT1, ETV6, EZH2, and FLT3.
WT1 was the most frequently mutated transcription factor gene in T/myeloid MPAL.
Based on these findings, the researchers said the WHO classification of acute leukemia should be updated to include: ZNF384r acute leukemia (either B-ALL or MPAL), WT1-mutant T/myeloid MPAL, and Ph-like B/myeloid MPAL.
This research was supported by the National Cancer Institute, the National Institutes of Health, Cookies for Kids’ Cancer, and other organizations. The researchers reported having no competing interests.
SOURCE: Alexander TB et al. Nature. 2018 Sep 12. doi: 10.1038/s41586-018-0436-0.
FROM NATURE
Key clinical point:
Major finding: In total, 48% of B/myeloid MPAL cases carried rearrangements in ZNF384, a characteristic that is also found in cases of B-cell ALL.
Study details: Whole-genome, -exome, and RNA sequencing of 115 samples from pediatric patients with MPAL.
Disclosures: This research was supported by the National Cancer Institute and other organizations. The researchers reported having no competing interests.
Source: Alexander TB et al. Nature. 2018 Sep 12. doi: 10.1038/s41586-018-0436-0.
Pruritus linked to wide variety of cancers
A wide variety of hematologic, dermatologic, and solid organ malignancies are associated with pruritus, a large, single-center, retrospective study suggests.
Blacks with pruritus had a higher odds ratio of hematologic malignancies, among others, while whites had higher likelihood of liver, gastrointestinal, respiratory and gynecologic cancers, results of the study show.
The results by race help address a gap in the literature, according to Shawn G. Kwatra, MD, of Johns Hopkins University, Baltimore, and his coinvestigators.
“Little is known about the association between pruritus and malignancy among different ethnic groups,” Dr. Kwatra and his coauthors wrote in the Journal of the American Academy of Dermatology.
The study shows a stronger association with more types of malignancies than has been reported previously, according to the investigators.
“The main difference is that prior studies focused on diagnosis of malignancy after the onset of pruritus, while our study includes malignancies diagnosed on or after pruritus onset,” they wrote.
Retrospective data for the study, which came from the Johns Hopkins Health System, included 16,925 patients aged 18 years or older who presented with itching or pruritus between April 4, 2013 and Dec. 31, 2017.
Of those 16,925 patients, 2,903 were also diagnosed with a concomitant malignancy during that time period. Compared with patients with no itching diagnosis during that time period, the pruritus patients more likely to have a concomitant malignancy, with an OR of 5.76 (95% confidence interval, 5.53-6.00), Dr. Kwatra and his colleagues found.
Malignancies most strongly associated with pruritus included those of the skin, liver, gallbladder and biliary tract, and hematopoietic system.
Among hematologic malignancies, pruritus was most strongly linked to myeloid leukemia and primary cutaneous lymphoma, while among skin cancers, squamous cell carcinoma was most strongly linked.
Whites had higher odds of any malignancy versus blacks, according to investigators, with ORs of 6.12 (95% CI, 5.81-6.46) and 5.61 (95% CI, 5.21-6.04), respectively.
Blacks with pruritus had higher ORs for hematologic and soft tissue malignancies including those of the muscle, fat, and peripheral nerve, investigators said, while whites had higher ORs for skin and liver malignancies.
The investigators also looked at the prevalence of skin eruptions in patients with pruritus and malignancy. “Eruption is variable by malignancy type and points to differing underlying mechanisms of pruritus,” they reported.
The highest rates of skin eruption were in patients with myeloid leukemia at 66%, followed by bone cancers at 58%, lymphocytic leukemia at 57%, multiple myeloma at 53%, and bronchus at 53%. The lowest rates of skin eruption were in patients with gallbladder and biliary tract, colon, pancreas, and liver malignancies.
Dr. Kwatra reported that he is an advisory board member for Menlo Therapeutics and Trevi Therapeutics.
SOURCE: Kwatra SG et al. J Am Acad Dermatol. 2018 Sep 11. doi: 10.1016/j.jaad.2018.08.044.
A wide variety of hematologic, dermatologic, and solid organ malignancies are associated with pruritus, a large, single-center, retrospective study suggests.
Blacks with pruritus had a higher odds ratio of hematologic malignancies, among others, while whites had higher likelihood of liver, gastrointestinal, respiratory and gynecologic cancers, results of the study show.
The results by race help address a gap in the literature, according to Shawn G. Kwatra, MD, of Johns Hopkins University, Baltimore, and his coinvestigators.
“Little is known about the association between pruritus and malignancy among different ethnic groups,” Dr. Kwatra and his coauthors wrote in the Journal of the American Academy of Dermatology.
The study shows a stronger association with more types of malignancies than has been reported previously, according to the investigators.
“The main difference is that prior studies focused on diagnosis of malignancy after the onset of pruritus, while our study includes malignancies diagnosed on or after pruritus onset,” they wrote.
Retrospective data for the study, which came from the Johns Hopkins Health System, included 16,925 patients aged 18 years or older who presented with itching or pruritus between April 4, 2013 and Dec. 31, 2017.
Of those 16,925 patients, 2,903 were also diagnosed with a concomitant malignancy during that time period. Compared with patients with no itching diagnosis during that time period, the pruritus patients more likely to have a concomitant malignancy, with an OR of 5.76 (95% confidence interval, 5.53-6.00), Dr. Kwatra and his colleagues found.
Malignancies most strongly associated with pruritus included those of the skin, liver, gallbladder and biliary tract, and hematopoietic system.
Among hematologic malignancies, pruritus was most strongly linked to myeloid leukemia and primary cutaneous lymphoma, while among skin cancers, squamous cell carcinoma was most strongly linked.
Whites had higher odds of any malignancy versus blacks, according to investigators, with ORs of 6.12 (95% CI, 5.81-6.46) and 5.61 (95% CI, 5.21-6.04), respectively.
Blacks with pruritus had higher ORs for hematologic and soft tissue malignancies including those of the muscle, fat, and peripheral nerve, investigators said, while whites had higher ORs for skin and liver malignancies.
The investigators also looked at the prevalence of skin eruptions in patients with pruritus and malignancy. “Eruption is variable by malignancy type and points to differing underlying mechanisms of pruritus,” they reported.
The highest rates of skin eruption were in patients with myeloid leukemia at 66%, followed by bone cancers at 58%, lymphocytic leukemia at 57%, multiple myeloma at 53%, and bronchus at 53%. The lowest rates of skin eruption were in patients with gallbladder and biliary tract, colon, pancreas, and liver malignancies.
Dr. Kwatra reported that he is an advisory board member for Menlo Therapeutics and Trevi Therapeutics.
SOURCE: Kwatra SG et al. J Am Acad Dermatol. 2018 Sep 11. doi: 10.1016/j.jaad.2018.08.044.
A wide variety of hematologic, dermatologic, and solid organ malignancies are associated with pruritus, a large, single-center, retrospective study suggests.
Blacks with pruritus had a higher odds ratio of hematologic malignancies, among others, while whites had higher likelihood of liver, gastrointestinal, respiratory and gynecologic cancers, results of the study show.
The results by race help address a gap in the literature, according to Shawn G. Kwatra, MD, of Johns Hopkins University, Baltimore, and his coinvestigators.
“Little is known about the association between pruritus and malignancy among different ethnic groups,” Dr. Kwatra and his coauthors wrote in the Journal of the American Academy of Dermatology.
The study shows a stronger association with more types of malignancies than has been reported previously, according to the investigators.
“The main difference is that prior studies focused on diagnosis of malignancy after the onset of pruritus, while our study includes malignancies diagnosed on or after pruritus onset,” they wrote.
Retrospective data for the study, which came from the Johns Hopkins Health System, included 16,925 patients aged 18 years or older who presented with itching or pruritus between April 4, 2013 and Dec. 31, 2017.
Of those 16,925 patients, 2,903 were also diagnosed with a concomitant malignancy during that time period. Compared with patients with no itching diagnosis during that time period, the pruritus patients more likely to have a concomitant malignancy, with an OR of 5.76 (95% confidence interval, 5.53-6.00), Dr. Kwatra and his colleagues found.
Malignancies most strongly associated with pruritus included those of the skin, liver, gallbladder and biliary tract, and hematopoietic system.
Among hematologic malignancies, pruritus was most strongly linked to myeloid leukemia and primary cutaneous lymphoma, while among skin cancers, squamous cell carcinoma was most strongly linked.
Whites had higher odds of any malignancy versus blacks, according to investigators, with ORs of 6.12 (95% CI, 5.81-6.46) and 5.61 (95% CI, 5.21-6.04), respectively.
Blacks with pruritus had higher ORs for hematologic and soft tissue malignancies including those of the muscle, fat, and peripheral nerve, investigators said, while whites had higher ORs for skin and liver malignancies.
The investigators also looked at the prevalence of skin eruptions in patients with pruritus and malignancy. “Eruption is variable by malignancy type and points to differing underlying mechanisms of pruritus,” they reported.
The highest rates of skin eruption were in patients with myeloid leukemia at 66%, followed by bone cancers at 58%, lymphocytic leukemia at 57%, multiple myeloma at 53%, and bronchus at 53%. The lowest rates of skin eruption were in patients with gallbladder and biliary tract, colon, pancreas, and liver malignancies.
Dr. Kwatra reported that he is an advisory board member for Menlo Therapeutics and Trevi Therapeutics.
SOURCE: Kwatra SG et al. J Am Acad Dermatol. 2018 Sep 11. doi: 10.1016/j.jaad.2018.08.044.
FROM THE JOURNAL OF THE AMERICAN ACADEMY OF DERMATOLOGY
Key clinical point:
Major finding: Blacks with pruritus had higher odds ratios for hematologic and soft tissue malignancies, while whites had higher ORs for skin and liver malignancies.
Study details: A retrospective study of 16,925 adults with itching or pruritus seen at a tertiary care center.
Disclosures: Dr. Kwatra reported serving as an advisory board member for Menlo Therapeutics and Trevi Therapeutics.
Source: Kwatra SG et al. J Am Acad Dermatol. 2018 Sep 11. doi: 10.1016/j.jaad.2018.08.044.
Insights could change treatment, classification of MPAL
An extensive analysis of mixed phenotype acute leukemia (MPAL) has led to new insights that may have implications for disease classification and treatment.
Researchers believe they have identified new subtypes of MPAL that should be included in the World Health Organization (WHO) classification for acute leukemia.
Each of these subtypes shares genomic characteristics with other acute leukemias, which suggests the new subtypes might respond to treatments that are already in use.
This research has also shed light on how MPAL evolves and appears to provide an explanation for why MPAL displays characteristics of both acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL).
“ALL and AML have very different treatments, but MPAL has features of both, so the question of how best to treat patients with MPAL has been challenging the leukemia community worldwide, and long-term survival of patients has been poor,” said Charles Mullighan, MBBS, MD, of St. Jude Children’s Research Hospital in Memphis, Tennessee.
With these issues in mind, Dr. Mullighan and his colleagues conducted their study of MPAL and described their findings in Nature.
New classifications
The researchers used whole-genome, whole-exome, and RNA sequencing to analyze 115 samples from pediatric patients with MPAL.
The analysis revealed mutations that define the two most common subtypes of MPAL—B/myeloid and T/myeloid—and suggested these subtypes share similarities with other leukemia subtypes.
The researchers found that 48% of B/myeloid MPAL cases carried rearrangements in ZNF384, a characteristic that is also found in cases of B-cell ALL. In fact, the team said the gene expression profiles of ZNF384r B-ALL and ZNF384r MPAL were indistinguishable.
“That is biologically and clinically important,” Dr. Mullighan said. “The findings suggest the ZNF384 rearrangement defines a distinct leukemia subtype, and the alteration should be used to guide treatment.”
The researchers noted that patients with ZNF384r exhibited higher FLT3 expression than patients with other types of B/myeloid or T/myeloid MPAL, so patients with ZNF384r MPAL might respond well to treatment with a FLT3 inhibitor.
This study also showed that cases of B/myeloid MPAL without ZNF384r shared genomic features with other B-ALL subtypes, such as Ph-like B-ALL, which may have implications for treatment.
Another of the researchers’ discoveries was that T/myeloid MPAL and early T-cell precursor ALL have similar gene expression profiles.
The team identified several genes that were mutated at similar frequencies in T/myeloid MPAL and early T-cell precursor ALL, including WT1, ETV6, EZH2, and FLT3. WT1 was the most frequently mutated transcription factor gene in T/myeloid MPAL.
Based on these findings, the researchers said the WHO classification of acute leukemia should be updated to include:
- ZNF384r acute leukemia (either B-ALL or MPAL)
- WT1-mutant T/myeloid MPAL
- Ph-like B/myeloid MPAL.
Evolution of MPAL
The researchers’ analyses also revealed leukemia-initiating genetic alterations in early hematopoietic progenitors.
The team said this and other findings—including the common genomic features of ZNF384r MPAL and B-ALL—suggest the ambiguous phenotype of MPAL results from alterations in immature hematopoietic progenitors.
“These findings suggest that the founding mutation occurs early in blood cell development, in some cases in hematopoietic stem cells, and results in an acute leukemia with features of both myeloid and lymphoid cells,” said study author Thomas Alexander, MD, of the University of North Carolina at Chapel Hill.
“One previous theory was that the reason you have two different cancer types within the same patient is that they acquire different mutations that drive them to become AML or ALL, with genomically distinct tumors within the same patient. That doesn’t seem to be the case from our data. Our proposed model is that the mutations occur earlier in development in cells that retain the potential to acquire myeloid or lymphoid features.”
This research was supported by the National Cancer Institute, the National Institutes of Health, Cookies for Kids’ Cancer, and other organizations.
An extensive analysis of mixed phenotype acute leukemia (MPAL) has led to new insights that may have implications for disease classification and treatment.
Researchers believe they have identified new subtypes of MPAL that should be included in the World Health Organization (WHO) classification for acute leukemia.
Each of these subtypes shares genomic characteristics with other acute leukemias, which suggests the new subtypes might respond to treatments that are already in use.
This research has also shed light on how MPAL evolves and appears to provide an explanation for why MPAL displays characteristics of both acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL).
“ALL and AML have very different treatments, but MPAL has features of both, so the question of how best to treat patients with MPAL has been challenging the leukemia community worldwide, and long-term survival of patients has been poor,” said Charles Mullighan, MBBS, MD, of St. Jude Children’s Research Hospital in Memphis, Tennessee.
With these issues in mind, Dr. Mullighan and his colleagues conducted their study of MPAL and described their findings in Nature.
New classifications
The researchers used whole-genome, whole-exome, and RNA sequencing to analyze 115 samples from pediatric patients with MPAL.
The analysis revealed mutations that define the two most common subtypes of MPAL—B/myeloid and T/myeloid—and suggested these subtypes share similarities with other leukemia subtypes.
The researchers found that 48% of B/myeloid MPAL cases carried rearrangements in ZNF384, a characteristic that is also found in cases of B-cell ALL. In fact, the team said the gene expression profiles of ZNF384r B-ALL and ZNF384r MPAL were indistinguishable.
“That is biologically and clinically important,” Dr. Mullighan said. “The findings suggest the ZNF384 rearrangement defines a distinct leukemia subtype, and the alteration should be used to guide treatment.”
The researchers noted that patients with ZNF384r exhibited higher FLT3 expression than patients with other types of B/myeloid or T/myeloid MPAL, so patients with ZNF384r MPAL might respond well to treatment with a FLT3 inhibitor.
This study also showed that cases of B/myeloid MPAL without ZNF384r shared genomic features with other B-ALL subtypes, such as Ph-like B-ALL, which may have implications for treatment.
Another of the researchers’ discoveries was that T/myeloid MPAL and early T-cell precursor ALL have similar gene expression profiles.
The team identified several genes that were mutated at similar frequencies in T/myeloid MPAL and early T-cell precursor ALL, including WT1, ETV6, EZH2, and FLT3. WT1 was the most frequently mutated transcription factor gene in T/myeloid MPAL.
Based on these findings, the researchers said the WHO classification of acute leukemia should be updated to include:
- ZNF384r acute leukemia (either B-ALL or MPAL)
- WT1-mutant T/myeloid MPAL
- Ph-like B/myeloid MPAL.
Evolution of MPAL
The researchers’ analyses also revealed leukemia-initiating genetic alterations in early hematopoietic progenitors.
The team said this and other findings—including the common genomic features of ZNF384r MPAL and B-ALL—suggest the ambiguous phenotype of MPAL results from alterations in immature hematopoietic progenitors.
“These findings suggest that the founding mutation occurs early in blood cell development, in some cases in hematopoietic stem cells, and results in an acute leukemia with features of both myeloid and lymphoid cells,” said study author Thomas Alexander, MD, of the University of North Carolina at Chapel Hill.
“One previous theory was that the reason you have two different cancer types within the same patient is that they acquire different mutations that drive them to become AML or ALL, with genomically distinct tumors within the same patient. That doesn’t seem to be the case from our data. Our proposed model is that the mutations occur earlier in development in cells that retain the potential to acquire myeloid or lymphoid features.”
This research was supported by the National Cancer Institute, the National Institutes of Health, Cookies for Kids’ Cancer, and other organizations.
An extensive analysis of mixed phenotype acute leukemia (MPAL) has led to new insights that may have implications for disease classification and treatment.
Researchers believe they have identified new subtypes of MPAL that should be included in the World Health Organization (WHO) classification for acute leukemia.
Each of these subtypes shares genomic characteristics with other acute leukemias, which suggests the new subtypes might respond to treatments that are already in use.
This research has also shed light on how MPAL evolves and appears to provide an explanation for why MPAL displays characteristics of both acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL).
“ALL and AML have very different treatments, but MPAL has features of both, so the question of how best to treat patients with MPAL has been challenging the leukemia community worldwide, and long-term survival of patients has been poor,” said Charles Mullighan, MBBS, MD, of St. Jude Children’s Research Hospital in Memphis, Tennessee.
With these issues in mind, Dr. Mullighan and his colleagues conducted their study of MPAL and described their findings in Nature.
New classifications
The researchers used whole-genome, whole-exome, and RNA sequencing to analyze 115 samples from pediatric patients with MPAL.
The analysis revealed mutations that define the two most common subtypes of MPAL—B/myeloid and T/myeloid—and suggested these subtypes share similarities with other leukemia subtypes.
The researchers found that 48% of B/myeloid MPAL cases carried rearrangements in ZNF384, a characteristic that is also found in cases of B-cell ALL. In fact, the team said the gene expression profiles of ZNF384r B-ALL and ZNF384r MPAL were indistinguishable.
“That is biologically and clinically important,” Dr. Mullighan said. “The findings suggest the ZNF384 rearrangement defines a distinct leukemia subtype, and the alteration should be used to guide treatment.”
The researchers noted that patients with ZNF384r exhibited higher FLT3 expression than patients with other types of B/myeloid or T/myeloid MPAL, so patients with ZNF384r MPAL might respond well to treatment with a FLT3 inhibitor.
This study also showed that cases of B/myeloid MPAL without ZNF384r shared genomic features with other B-ALL subtypes, such as Ph-like B-ALL, which may have implications for treatment.
Another of the researchers’ discoveries was that T/myeloid MPAL and early T-cell precursor ALL have similar gene expression profiles.
The team identified several genes that were mutated at similar frequencies in T/myeloid MPAL and early T-cell precursor ALL, including WT1, ETV6, EZH2, and FLT3. WT1 was the most frequently mutated transcription factor gene in T/myeloid MPAL.
Based on these findings, the researchers said the WHO classification of acute leukemia should be updated to include:
- ZNF384r acute leukemia (either B-ALL or MPAL)
- WT1-mutant T/myeloid MPAL
- Ph-like B/myeloid MPAL.
Evolution of MPAL
The researchers’ analyses also revealed leukemia-initiating genetic alterations in early hematopoietic progenitors.
The team said this and other findings—including the common genomic features of ZNF384r MPAL and B-ALL—suggest the ambiguous phenotype of MPAL results from alterations in immature hematopoietic progenitors.
“These findings suggest that the founding mutation occurs early in blood cell development, in some cases in hematopoietic stem cells, and results in an acute leukemia with features of both myeloid and lymphoid cells,” said study author Thomas Alexander, MD, of the University of North Carolina at Chapel Hill.
“One previous theory was that the reason you have two different cancer types within the same patient is that they acquire different mutations that drive them to become AML or ALL, with genomically distinct tumors within the same patient. That doesn’t seem to be the case from our data. Our proposed model is that the mutations occur earlier in development in cells that retain the potential to acquire myeloid or lymphoid features.”
This research was supported by the National Cancer Institute, the National Institutes of Health, Cookies for Kids’ Cancer, and other organizations.
Prophylaxis reduces bacteremia in some kids
In a phase 3 study, levofloxacin prophylaxis significantly reduced bacteremia in children with acute leukemias who received intensive chemotherapy.
However, the risk of bacteremia was not significantly reduced with levofloxacin in another cohort of children who underwent hematopoietic stem cell transplant (HSCT).
Sarah Alexander, MD, of the Hospital for Sick Children in Toronto, Ontario, Canada, and her colleagues reported these findings in JAMA.
This multicenter, randomized trial (ACCL0934) enrolled patients aged 6 months to 21 years.
There were 200 patients with acute leukemias (acute myeloid leukemia or relapsed acute lymphoblastic leukemia) who were set to receive chemotherapy and 424 patients who were to receive a myeloablative autologous or allogeneic HSCT.
The acute leukemia patients were randomized to receive no prophylaxis (n=100) or levofloxacin prophylaxis (n=100) for two consecutive cycles of chemotherapy.
The HSCT recipients were randomized to receive no prophylaxis (n=214) or levofloxacin prophylaxis (n=210) during one HSCT procedure.
Results
In the primary analysis of the acute leukemia group (n=195), the incidence of bacteremia was 21.9% for those randomized to levofloxacin and 43.4% for those who did not receive prophylaxis (P=0.001).
In the primary analysis of the HSCT group (n=418), the incidence of bacteremia was 11.0% in the levofloxacin arm and 17.3% in the control arm (P=0.06).
However, a post hoc analysis accounting for time at risk showed a significant difference in favor of prophylaxis in both the acute leukemia and HSCT groups and a similar effect size between groups.
For the acute leukemia group, the rate of bacteremic episodes in the post hoc analysis was 4.9 versus 9.4 per 1,000 patient-days in the prophylaxis and control arms, respectively (P=0.008).
In the HSCT group, the rate of bacteremic episodes was 5.3 versus 10.0 per 1,000 patient-days in the prophylaxis and control arms, respectively (P=0.02).
The researchers said it is possible that the effect of prophylaxis was similar between the HSCT and acute leukemia groups, but there was reduced power to detect a significant difference because of fewer events among HSCT recipients.
However, the differences between the HSCT and acute leukemia groups in the primary analysis might also be explained by differences in supportive care measures or infections with pathogens that had differential sensitivity to levofloxacin.
The researchers noted that levofloxacin-resistant pathogens, such as viridans group streptococcal isolates and several gram-negative isolates, often were detected in patients who had bacteremia events despite prophylaxis. This suggests other interventions in combination with levofloxacin prophylaxis are probably needed to further decrease risk.
Dr. Alexander and her colleagues also said further randomized studies are needed to better understand the risks of levofloxacin in relation to its benefits.
In the current study, there were 23 serious adverse events reported in 8 patients. Twelve of these events, occurring in two patients, may have been related to levofloxacin.
This research was supported by grants from the Community Clinical Oncology Program and National Cancer Institute. Dr. Alexander reported no disclosures. Coauthors reported disclosures related to Bristol-Myers Squibb, Chimerix, Jazz Pharmaceuticals, and the Children’s Oncology Group.
In a phase 3 study, levofloxacin prophylaxis significantly reduced bacteremia in children with acute leukemias who received intensive chemotherapy.
However, the risk of bacteremia was not significantly reduced with levofloxacin in another cohort of children who underwent hematopoietic stem cell transplant (HSCT).
Sarah Alexander, MD, of the Hospital for Sick Children in Toronto, Ontario, Canada, and her colleagues reported these findings in JAMA.
This multicenter, randomized trial (ACCL0934) enrolled patients aged 6 months to 21 years.
There were 200 patients with acute leukemias (acute myeloid leukemia or relapsed acute lymphoblastic leukemia) who were set to receive chemotherapy and 424 patients who were to receive a myeloablative autologous or allogeneic HSCT.
The acute leukemia patients were randomized to receive no prophylaxis (n=100) or levofloxacin prophylaxis (n=100) for two consecutive cycles of chemotherapy.
The HSCT recipients were randomized to receive no prophylaxis (n=214) or levofloxacin prophylaxis (n=210) during one HSCT procedure.
Results
In the primary analysis of the acute leukemia group (n=195), the incidence of bacteremia was 21.9% for those randomized to levofloxacin and 43.4% for those who did not receive prophylaxis (P=0.001).
In the primary analysis of the HSCT group (n=418), the incidence of bacteremia was 11.0% in the levofloxacin arm and 17.3% in the control arm (P=0.06).
However, a post hoc analysis accounting for time at risk showed a significant difference in favor of prophylaxis in both the acute leukemia and HSCT groups and a similar effect size between groups.
For the acute leukemia group, the rate of bacteremic episodes in the post hoc analysis was 4.9 versus 9.4 per 1,000 patient-days in the prophylaxis and control arms, respectively (P=0.008).
In the HSCT group, the rate of bacteremic episodes was 5.3 versus 10.0 per 1,000 patient-days in the prophylaxis and control arms, respectively (P=0.02).
The researchers said it is possible that the effect of prophylaxis was similar between the HSCT and acute leukemia groups, but there was reduced power to detect a significant difference because of fewer events among HSCT recipients.
However, the differences between the HSCT and acute leukemia groups in the primary analysis might also be explained by differences in supportive care measures or infections with pathogens that had differential sensitivity to levofloxacin.
The researchers noted that levofloxacin-resistant pathogens, such as viridans group streptococcal isolates and several gram-negative isolates, often were detected in patients who had bacteremia events despite prophylaxis. This suggests other interventions in combination with levofloxacin prophylaxis are probably needed to further decrease risk.
Dr. Alexander and her colleagues also said further randomized studies are needed to better understand the risks of levofloxacin in relation to its benefits.
In the current study, there were 23 serious adverse events reported in 8 patients. Twelve of these events, occurring in two patients, may have been related to levofloxacin.
This research was supported by grants from the Community Clinical Oncology Program and National Cancer Institute. Dr. Alexander reported no disclosures. Coauthors reported disclosures related to Bristol-Myers Squibb, Chimerix, Jazz Pharmaceuticals, and the Children’s Oncology Group.
In a phase 3 study, levofloxacin prophylaxis significantly reduced bacteremia in children with acute leukemias who received intensive chemotherapy.
However, the risk of bacteremia was not significantly reduced with levofloxacin in another cohort of children who underwent hematopoietic stem cell transplant (HSCT).
Sarah Alexander, MD, of the Hospital for Sick Children in Toronto, Ontario, Canada, and her colleagues reported these findings in JAMA.
This multicenter, randomized trial (ACCL0934) enrolled patients aged 6 months to 21 years.
There were 200 patients with acute leukemias (acute myeloid leukemia or relapsed acute lymphoblastic leukemia) who were set to receive chemotherapy and 424 patients who were to receive a myeloablative autologous or allogeneic HSCT.
The acute leukemia patients were randomized to receive no prophylaxis (n=100) or levofloxacin prophylaxis (n=100) for two consecutive cycles of chemotherapy.
The HSCT recipients were randomized to receive no prophylaxis (n=214) or levofloxacin prophylaxis (n=210) during one HSCT procedure.
Results
In the primary analysis of the acute leukemia group (n=195), the incidence of bacteremia was 21.9% for those randomized to levofloxacin and 43.4% for those who did not receive prophylaxis (P=0.001).
In the primary analysis of the HSCT group (n=418), the incidence of bacteremia was 11.0% in the levofloxacin arm and 17.3% in the control arm (P=0.06).
However, a post hoc analysis accounting for time at risk showed a significant difference in favor of prophylaxis in both the acute leukemia and HSCT groups and a similar effect size between groups.
For the acute leukemia group, the rate of bacteremic episodes in the post hoc analysis was 4.9 versus 9.4 per 1,000 patient-days in the prophylaxis and control arms, respectively (P=0.008).
In the HSCT group, the rate of bacteremic episodes was 5.3 versus 10.0 per 1,000 patient-days in the prophylaxis and control arms, respectively (P=0.02).
The researchers said it is possible that the effect of prophylaxis was similar between the HSCT and acute leukemia groups, but there was reduced power to detect a significant difference because of fewer events among HSCT recipients.
However, the differences between the HSCT and acute leukemia groups in the primary analysis might also be explained by differences in supportive care measures or infections with pathogens that had differential sensitivity to levofloxacin.
The researchers noted that levofloxacin-resistant pathogens, such as viridans group streptococcal isolates and several gram-negative isolates, often were detected in patients who had bacteremia events despite prophylaxis. This suggests other interventions in combination with levofloxacin prophylaxis are probably needed to further decrease risk.
Dr. Alexander and her colleagues also said further randomized studies are needed to better understand the risks of levofloxacin in relation to its benefits.
In the current study, there were 23 serious adverse events reported in 8 patients. Twelve of these events, occurring in two patients, may have been related to levofloxacin.
This research was supported by grants from the Community Clinical Oncology Program and National Cancer Institute. Dr. Alexander reported no disclosures. Coauthors reported disclosures related to Bristol-Myers Squibb, Chimerix, Jazz Pharmaceuticals, and the Children’s Oncology Group.
Cell population appears to drive relapse in AML
Researchers believe they have identified cells that are responsible for relapse of acute myeloid leukemia (AML).
These “leukemic-regenerating cells” (LRCs), which are distinct from leukemic stem cells (LSCs), seem to arise in response to chemotherapy.
Experiments in mouse models of AML suggested that targeting LRCs could reduce the risk of relapse, and analyses of AML patient samples suggested LRCs might be used to predict relapse.
Allison Boyd, PhD, of McMaster University in Hamilton, Ont., and her colleagues reported these findings in Cancer Cell.
The researchers evaluated the leukemic populations that persist after chemotherapy by analyzing AML patient samples and xenograft AML models. The team found that LSCs were depleted by chemotherapy, and a different cell population, LRCs, appeared to arise in response to treatment.
LRCs are “molecularly distinct from therapy-naive LSCs,” the researchers said. In fact, the team identified 19 genes that are preferentially expressed by LRCs and could be treated with drugs.
One of these genes is DRD2, and the researchers found they could target LRCs using a small-molecule antagonist of DRD2.
Targeting LRCs
Dr. Boyd and her colleagues compared the effects of treatment with a DRD2 antagonist in AML xenografts populated with therapy-naive LSCs and AML xenografts that harbored LRCs following exposure to cytarabine.
The researchers said DRD2 antagonist therapy “moderately” affected AML progenitors in the LSC model but “had profound effects on regenerating LRCs.”
Treatment with the DRD2 antagonist also improved the efficacy of chemotherapy.
In xenografts derived from one AML patient, treatment with cytarabine alone left 50% of mice with residual disease. However, the addition of the DRD2 antagonist enabled 100% of the mice to achieve disease-free status.
In xenografts derived from a patient with more aggressive AML, all recipient mice had residual disease after receiving cytarabine. Treatment with the DRD2 antagonist slowed leukemic regrowth and nearly doubled the time to relapse.
Targeting LRCs also reduced disease regeneration potential in samples from other AML patients.
“This is a major clinical opportunity because this type of leukemia is very diverse and responds differently across patients,” Dr. Boyd said. “It has been a challenge in a clinical setting to find a commonality for therapeutic targeting across the wide array of patients, and these regenerative cells provide that similarity.”
Predicting relapse
Dr. Boyd and her colleagues also analyzed bone marrow samples collected from AML patients approximately 3 weeks after they completed standard induction chemotherapy.
The team found that progenitor activity was enriched among residual leukemic cells. However, patient cells lacked gene expression signatures related to therapy-naive LSCs.
“Instead, these highly regenerative AML cells preferentially expressed our LRC signature,” the researchers said.
The team also found evidence to suggest that LRC molecular profiles arise temporarily after chemotherapy. The LRC signature was not observed at diagnosis or once AML was reestablished at relapse.
“We think there are opportunities here because now we have a window where we can kick the cancer while it’s down,” Dr. Boyd said.
She and her colleagues also found the LRC signature might be useful for predicting relapse in AML patients.
The team assessed expression of SLC2A2, an LRC marker that has overlapping expression with DRD2, in seven patients who were in remission after induction.
Chemotherapy increased expression of SLC2A2 only in the four patients who had residual disease – not in the three patients who remained in disease-free remission for at least 5 years. “These results suggest that LRC populations represent reservoirs of residual disease, and LRC marker expression levels can be linked to clinical outcomes of AML relapse,” the researchers said.
This study was supported by the Canadian Cancer Society, the Canadian Institutes of Health Research, the Ontario Institute for Cancer Research, and other organizations.
SOURCE: Boyd AL et al. Cancer Cell. 2018 Sep 10. doi: 10.1016/j.ccell.2018.08.007.
Researchers believe they have identified cells that are responsible for relapse of acute myeloid leukemia (AML).
These “leukemic-regenerating cells” (LRCs), which are distinct from leukemic stem cells (LSCs), seem to arise in response to chemotherapy.
Experiments in mouse models of AML suggested that targeting LRCs could reduce the risk of relapse, and analyses of AML patient samples suggested LRCs might be used to predict relapse.
Allison Boyd, PhD, of McMaster University in Hamilton, Ont., and her colleagues reported these findings in Cancer Cell.
The researchers evaluated the leukemic populations that persist after chemotherapy by analyzing AML patient samples and xenograft AML models. The team found that LSCs were depleted by chemotherapy, and a different cell population, LRCs, appeared to arise in response to treatment.
LRCs are “molecularly distinct from therapy-naive LSCs,” the researchers said. In fact, the team identified 19 genes that are preferentially expressed by LRCs and could be treated with drugs.
One of these genes is DRD2, and the researchers found they could target LRCs using a small-molecule antagonist of DRD2.
Targeting LRCs
Dr. Boyd and her colleagues compared the effects of treatment with a DRD2 antagonist in AML xenografts populated with therapy-naive LSCs and AML xenografts that harbored LRCs following exposure to cytarabine.
The researchers said DRD2 antagonist therapy “moderately” affected AML progenitors in the LSC model but “had profound effects on regenerating LRCs.”
Treatment with the DRD2 antagonist also improved the efficacy of chemotherapy.
In xenografts derived from one AML patient, treatment with cytarabine alone left 50% of mice with residual disease. However, the addition of the DRD2 antagonist enabled 100% of the mice to achieve disease-free status.
In xenografts derived from a patient with more aggressive AML, all recipient mice had residual disease after receiving cytarabine. Treatment with the DRD2 antagonist slowed leukemic regrowth and nearly doubled the time to relapse.
Targeting LRCs also reduced disease regeneration potential in samples from other AML patients.
“This is a major clinical opportunity because this type of leukemia is very diverse and responds differently across patients,” Dr. Boyd said. “It has been a challenge in a clinical setting to find a commonality for therapeutic targeting across the wide array of patients, and these regenerative cells provide that similarity.”
Predicting relapse
Dr. Boyd and her colleagues also analyzed bone marrow samples collected from AML patients approximately 3 weeks after they completed standard induction chemotherapy.
The team found that progenitor activity was enriched among residual leukemic cells. However, patient cells lacked gene expression signatures related to therapy-naive LSCs.
“Instead, these highly regenerative AML cells preferentially expressed our LRC signature,” the researchers said.
The team also found evidence to suggest that LRC molecular profiles arise temporarily after chemotherapy. The LRC signature was not observed at diagnosis or once AML was reestablished at relapse.
“We think there are opportunities here because now we have a window where we can kick the cancer while it’s down,” Dr. Boyd said.
She and her colleagues also found the LRC signature might be useful for predicting relapse in AML patients.
The team assessed expression of SLC2A2, an LRC marker that has overlapping expression with DRD2, in seven patients who were in remission after induction.
Chemotherapy increased expression of SLC2A2 only in the four patients who had residual disease – not in the three patients who remained in disease-free remission for at least 5 years. “These results suggest that LRC populations represent reservoirs of residual disease, and LRC marker expression levels can be linked to clinical outcomes of AML relapse,” the researchers said.
This study was supported by the Canadian Cancer Society, the Canadian Institutes of Health Research, the Ontario Institute for Cancer Research, and other organizations.
SOURCE: Boyd AL et al. Cancer Cell. 2018 Sep 10. doi: 10.1016/j.ccell.2018.08.007.
Researchers believe they have identified cells that are responsible for relapse of acute myeloid leukemia (AML).
These “leukemic-regenerating cells” (LRCs), which are distinct from leukemic stem cells (LSCs), seem to arise in response to chemotherapy.
Experiments in mouse models of AML suggested that targeting LRCs could reduce the risk of relapse, and analyses of AML patient samples suggested LRCs might be used to predict relapse.
Allison Boyd, PhD, of McMaster University in Hamilton, Ont., and her colleagues reported these findings in Cancer Cell.
The researchers evaluated the leukemic populations that persist after chemotherapy by analyzing AML patient samples and xenograft AML models. The team found that LSCs were depleted by chemotherapy, and a different cell population, LRCs, appeared to arise in response to treatment.
LRCs are “molecularly distinct from therapy-naive LSCs,” the researchers said. In fact, the team identified 19 genes that are preferentially expressed by LRCs and could be treated with drugs.
One of these genes is DRD2, and the researchers found they could target LRCs using a small-molecule antagonist of DRD2.
Targeting LRCs
Dr. Boyd and her colleagues compared the effects of treatment with a DRD2 antagonist in AML xenografts populated with therapy-naive LSCs and AML xenografts that harbored LRCs following exposure to cytarabine.
The researchers said DRD2 antagonist therapy “moderately” affected AML progenitors in the LSC model but “had profound effects on regenerating LRCs.”
Treatment with the DRD2 antagonist also improved the efficacy of chemotherapy.
In xenografts derived from one AML patient, treatment with cytarabine alone left 50% of mice with residual disease. However, the addition of the DRD2 antagonist enabled 100% of the mice to achieve disease-free status.
In xenografts derived from a patient with more aggressive AML, all recipient mice had residual disease after receiving cytarabine. Treatment with the DRD2 antagonist slowed leukemic regrowth and nearly doubled the time to relapse.
Targeting LRCs also reduced disease regeneration potential in samples from other AML patients.
“This is a major clinical opportunity because this type of leukemia is very diverse and responds differently across patients,” Dr. Boyd said. “It has been a challenge in a clinical setting to find a commonality for therapeutic targeting across the wide array of patients, and these regenerative cells provide that similarity.”
Predicting relapse
Dr. Boyd and her colleagues also analyzed bone marrow samples collected from AML patients approximately 3 weeks after they completed standard induction chemotherapy.
The team found that progenitor activity was enriched among residual leukemic cells. However, patient cells lacked gene expression signatures related to therapy-naive LSCs.
“Instead, these highly regenerative AML cells preferentially expressed our LRC signature,” the researchers said.
The team also found evidence to suggest that LRC molecular profiles arise temporarily after chemotherapy. The LRC signature was not observed at diagnosis or once AML was reestablished at relapse.
“We think there are opportunities here because now we have a window where we can kick the cancer while it’s down,” Dr. Boyd said.
She and her colleagues also found the LRC signature might be useful for predicting relapse in AML patients.
The team assessed expression of SLC2A2, an LRC marker that has overlapping expression with DRD2, in seven patients who were in remission after induction.
Chemotherapy increased expression of SLC2A2 only in the four patients who had residual disease – not in the three patients who remained in disease-free remission for at least 5 years. “These results suggest that LRC populations represent reservoirs of residual disease, and LRC marker expression levels can be linked to clinical outcomes of AML relapse,” the researchers said.
This study was supported by the Canadian Cancer Society, the Canadian Institutes of Health Research, the Ontario Institute for Cancer Research, and other organizations.
SOURCE: Boyd AL et al. Cancer Cell. 2018 Sep 10. doi: 10.1016/j.ccell.2018.08.007.
FROM CANCER CELL
Key clinical point: “Leukemic-regenerating cells” (LRCs) may drive relapse in acute myeloid leukemia (AML).
Major finding: LRCs could be useful for predicting relapse, and targeting LRCs might reduce relapse risk.
Study details: Research in AML patient samples and xenograft AML models.
Disclosures: This study was supported by the Canadian Cancer Society and other organizations.
Source: Boyd AL et al. Cancer Cell. 2018 Sep 10. doi: 10.1016/j.ccell.2018.08.007.