Leukemia, Myelodysplasia, Transplantation

Richard Stone, MD

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However, the agent was voluntarily withdrawn from the market in 2010 because it was used in the upfront setting with chemotherapy and didn’t show a benefit.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.”

Richard Stone, MD

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.”

Richard Stone, MD

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.”

Hematologic Malignancies

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.”

Hematologic Malignancies

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.”

Hematologic Malignancies

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.”

Image by Lance Liotta

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.

Image by Lance Liotta

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.

Image by Lance Liotta

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.

Bacteremic sepsis during acute lymphoblastic leukemia (ALL) treatment may contribute to neurocognitive dysfunction later in life, results of a cohort study suggest.

Xavier_S/Thinkstock

Pediatric ALL survivors who had sepsis while on treatment performed worse on measures of intelligence, attention, executive function, and processing speed than survivors with no sepsis history, according to study results.

Links between sepsis and impaired neurocognitive function found in this study have “practice-changing implications” for cancer survivors, investigators reported in JAMA Pediatrics.

“Prevention of infection, early recognition and appropriate management of sepsis, and preemptive neurocognitive interventions should be prioritized, because these might prevent or ameliorate neurologic damage,” said Joshua Wolf, MBBS, of St. Jude Children’s Research Hospital, Memphis, and the coauthors of the report.

The study included 212 children who, at a median age of 5 years, had received risk-adapted chemotherapy for ALL with no hematopoietic cell transplant or cranial irradiation.

Sixteen of the patients (7.5%) had a history of bacteremic sepsis during ALL therapy, according to retrospectively obtained data.

As a part of the study, all participants participated in neurocognitive testing, which was done at a median of 7.7 years after diagnosis.

Patients with a history of bacteremic sepsis performed poorly on multiple measures of neurocognitive function, as compared with all other participants, according to results of analyses that were adjusted for multiple potentially confounding factors, such as age, race, and leukemia risk category.

Although not all neurocognitive measures were significantly different between groups, survivors with a sepsis history performed worse on evaluations of spatial planning (difference, 0.78; 95% confidence interval, 0.57-1.00), verbal fluency (0.38; 95% CI, 0.14-0.62), and attention (0.63; 95% CI, 0.30-0.95), among other measures, investigators said.

This is believed to be the first published study looking at potential links between sepsis during ALL treatment and long-term neurocognitive dysfunction, investigators said. However, similar observations have been made in other patient populations, they added.

Exactly how sepsis might lead to neurocognitive deficits remains unclear. “In the population of children with cancer, these mechanisms might be augmented by increased blood-brain barrier permeability to neurotoxic chemotherapy drugs,” they said in their report.

Further study is needed to look at potential brain injury mechanisms, and to validate the current findings in other ALL patient cohorts, they concluded.

The study was supported by the National Institute of Mental Health, the National Cancer Institute, and the American Lebanese Syrian Associated Charities. The researchers reported having no conflicts of interest.

SOURCE: Cheung YT et al. JAMA Pediatr. 2018 Sep 24. doi:10.1001/jamapediatrics.2018.2500.

Bacteremic sepsis during acute lymphoblastic leukemia (ALL) treatment may contribute to neurocognitive dysfunction later in life, results of a cohort study suggest.

Xavier_S/Thinkstock

Pediatric ALL survivors who had sepsis while on treatment performed worse on measures of intelligence, attention, executive function, and processing speed than survivors with no sepsis history, according to study results.

Links between sepsis and impaired neurocognitive function found in this study have “practice-changing implications” for cancer survivors, investigators reported in JAMA Pediatrics.

“Prevention of infection, early recognition and appropriate management of sepsis, and preemptive neurocognitive interventions should be prioritized, because these might prevent or ameliorate neurologic damage,” said Joshua Wolf, MBBS, of St. Jude Children’s Research Hospital, Memphis, and the coauthors of the report.

The study included 212 children who, at a median age of 5 years, had received risk-adapted chemotherapy for ALL with no hematopoietic cell transplant or cranial irradiation.

Sixteen of the patients (7.5%) had a history of bacteremic sepsis during ALL therapy, according to retrospectively obtained data.

As a part of the study, all participants participated in neurocognitive testing, which was done at a median of 7.7 years after diagnosis.

Patients with a history of bacteremic sepsis performed poorly on multiple measures of neurocognitive function, as compared with all other participants, according to results of analyses that were adjusted for multiple potentially confounding factors, such as age, race, and leukemia risk category.

Although not all neurocognitive measures were significantly different between groups, survivors with a sepsis history performed worse on evaluations of spatial planning (difference, 0.78; 95% confidence interval, 0.57-1.00), verbal fluency (0.38; 95% CI, 0.14-0.62), and attention (0.63; 95% CI, 0.30-0.95), among other measures, investigators said.

This is believed to be the first published study looking at potential links between sepsis during ALL treatment and long-term neurocognitive dysfunction, investigators said. However, similar observations have been made in other patient populations, they added.

Exactly how sepsis might lead to neurocognitive deficits remains unclear. “In the population of children with cancer, these mechanisms might be augmented by increased blood-brain barrier permeability to neurotoxic chemotherapy drugs,” they said in their report.

Further study is needed to look at potential brain injury mechanisms, and to validate the current findings in other ALL patient cohorts, they concluded.

The study was supported by the National Institute of Mental Health, the National Cancer Institute, and the American Lebanese Syrian Associated Charities. The researchers reported having no conflicts of interest.

SOURCE: Cheung YT et al. JAMA Pediatr. 2018 Sep 24. doi:10.1001/jamapediatrics.2018.2500.

Bacteremic sepsis during acute lymphoblastic leukemia (ALL) treatment may contribute to neurocognitive dysfunction later in life, results of a cohort study suggest.

Xavier_S/Thinkstock

Pediatric ALL survivors who had sepsis while on treatment performed worse on measures of intelligence, attention, executive function, and processing speed than survivors with no sepsis history, according to study results.

Links between sepsis and impaired neurocognitive function found in this study have “practice-changing implications” for cancer survivors, investigators reported in JAMA Pediatrics.

“Prevention of infection, early recognition and appropriate management of sepsis, and preemptive neurocognitive interventions should be prioritized, because these might prevent or ameliorate neurologic damage,” said Joshua Wolf, MBBS, of St. Jude Children’s Research Hospital, Memphis, and the coauthors of the report.

The study included 212 children who, at a median age of 5 years, had received risk-adapted chemotherapy for ALL with no hematopoietic cell transplant or cranial irradiation.

Sixteen of the patients (7.5%) had a history of bacteremic sepsis during ALL therapy, according to retrospectively obtained data.

As a part of the study, all participants participated in neurocognitive testing, which was done at a median of 7.7 years after diagnosis.

Patients with a history of bacteremic sepsis performed poorly on multiple measures of neurocognitive function, as compared with all other participants, according to results of analyses that were adjusted for multiple potentially confounding factors, such as age, race, and leukemia risk category.

Although not all neurocognitive measures were significantly different between groups, survivors with a sepsis history performed worse on evaluations of spatial planning (difference, 0.78; 95% confidence interval, 0.57-1.00), verbal fluency (0.38; 95% CI, 0.14-0.62), and attention (0.63; 95% CI, 0.30-0.95), among other measures, investigators said.

This is believed to be the first published study looking at potential links between sepsis during ALL treatment and long-term neurocognitive dysfunction, investigators said. However, similar observations have been made in other patient populations, they added.

Exactly how sepsis might lead to neurocognitive deficits remains unclear. “In the population of children with cancer, these mechanisms might be augmented by increased blood-brain barrier permeability to neurotoxic chemotherapy drugs,” they said in their report.

Further study is needed to look at potential brain injury mechanisms, and to validate the current findings in other ALL patient cohorts, they concluded.

The study was supported by the National Institute of Mental Health, the National Cancer Institute, and the American Lebanese Syrian Associated Charities. The researchers reported having no conflicts of interest.

SOURCE: Cheung YT et al. JAMA Pediatr. 2018 Sep 24. doi:10.1001/jamapediatrics.2018.2500.

Photo courtesy of Amgen

The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) said it will re-examine a recent opinion on blinatumomab (Blincyto).

In July, the CHMP recommended against approving blinatumomab to treat patients with B-cell precursor acute lymphoblastic leukemia (BCP-ALL) who have minimal residual disease (MRD).

However, the CHMP has agreed to re-examine its position and issue a final recommendation.

Blinatumomab is currently approved by the European Commission (EC) as monotherapy for adults with Philadelphia chromosome-negative, CD19-positive, relapsed or refractory BCP-ALL.

Blinatumomab is also approved as monotherapy for pediatric patients age 1 year or older who have relapsed/refractory, Philadelphia chromosome-negative, CD19-positive BCP-ALL and have received at least two prior therapies or relapsed after allogeneic hematopoietic stem cell transplant.

Amgen is seeking an extension of the marketing authorization for blinatumomab to include BCP-ALL patients with MRD.

The CHMP previously recommended against approving blinatumomab for these patients based on data from the BLAST study. Results from this phase 2 trial were published in Blood in April.

The CHMP noted that, although blinatumomab helped clear away residual cells in many patients in the BLAST trial, there is no strong evidence that this leads to improved survival.

Given the uncertainty, the CHMP was of the opinion that the benefits of blinatumomab do not outweigh its risks in MRD-positive BCP-ALL patients.

However, Amgen request a re-examination of the CHMP’s opinion, and the CHMP has complied.

The CHMP’s recommendations are reviewed by the EC, which has the authority to approve medicines for use in the European Union, Norway, Iceland, and Liechtenstein. The EC usually makes a decision within 67 days of CHMP recommendations.

Photo courtesy of Amgen

The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) said it will re-examine a recent opinion on blinatumomab (Blincyto).

In July, the CHMP recommended against approving blinatumomab to treat patients with B-cell precursor acute lymphoblastic leukemia (BCP-ALL) who have minimal residual disease (MRD).

However, the CHMP has agreed to re-examine its position and issue a final recommendation.

Blinatumomab is currently approved by the European Commission (EC) as monotherapy for adults with Philadelphia chromosome-negative, CD19-positive, relapsed or refractory BCP-ALL.

Blinatumomab is also approved as monotherapy for pediatric patients age 1 year or older who have relapsed/refractory, Philadelphia chromosome-negative, CD19-positive BCP-ALL and have received at least two prior therapies or relapsed after allogeneic hematopoietic stem cell transplant.

Amgen is seeking an extension of the marketing authorization for blinatumomab to include BCP-ALL patients with MRD.

The CHMP previously recommended against approving blinatumomab for these patients based on data from the BLAST study. Results from this phase 2 trial were published in Blood in April.

The CHMP noted that, although blinatumomab helped clear away residual cells in many patients in the BLAST trial, there is no strong evidence that this leads to improved survival.

Given the uncertainty, the CHMP was of the opinion that the benefits of blinatumomab do not outweigh its risks in MRD-positive BCP-ALL patients.

However, Amgen request a re-examination of the CHMP’s opinion, and the CHMP has complied.

The CHMP’s recommendations are reviewed by the EC, which has the authority to approve medicines for use in the European Union, Norway, Iceland, and Liechtenstein. The EC usually makes a decision within 67 days of CHMP recommendations.

Photo courtesy of Amgen

The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) said it will re-examine a recent opinion on blinatumomab (Blincyto).

In July, the CHMP recommended against approving blinatumomab to treat patients with B-cell precursor acute lymphoblastic leukemia (BCP-ALL) who have minimal residual disease (MRD).

However, the CHMP has agreed to re-examine its position and issue a final recommendation.

Blinatumomab is currently approved by the European Commission (EC) as monotherapy for adults with Philadelphia chromosome-negative, CD19-positive, relapsed or refractory BCP-ALL.

Blinatumomab is also approved as monotherapy for pediatric patients age 1 year or older who have relapsed/refractory, Philadelphia chromosome-negative, CD19-positive BCP-ALL and have received at least two prior therapies or relapsed after allogeneic hematopoietic stem cell transplant.

Amgen is seeking an extension of the marketing authorization for blinatumomab to include BCP-ALL patients with MRD.

The CHMP previously recommended against approving blinatumomab for these patients based on data from the BLAST study. Results from this phase 2 trial were published in Blood in April.

The CHMP noted that, although blinatumomab helped clear away residual cells in many patients in the BLAST trial, there is no strong evidence that this leads to improved survival.

Given the uncertainty, the CHMP was of the opinion that the benefits of blinatumomab do not outweigh its risks in MRD-positive BCP-ALL patients.

However, Amgen request a re-examination of the CHMP’s opinion, and the CHMP has complied.

The CHMP’s recommendations are reviewed by the EC, which has the authority to approve medicines for use in the European Union, Norway, Iceland, and Liechtenstein. The EC usually makes a decision within 67 days of CHMP recommendations.

Photo from Amgen

The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended approval for three proposed biosimilars of pegfilgrastim—Ziextenzo, Pelmeg, and Fulphila.

If approved by the European Commission (EC), these products would be used for the same indication as the reference medicine, Neulasta (pegfilgrastim).

Neulasta has been EC-approved since 2002 to reduce the duration of neutropenia and the incidence of febrile neutropenia in adults who receive cytotoxic chemotherapy to treat malignancies except chronic myeloid leukemia and myelodysplastic syndromes.

According to the CHMP, data suggest that Ziextenzo, Pelmeg, and Fulphila all have quality, efficacy, and safety profiles comparable to Neulasta.

The EC is expected to make a decision on the approval of Ziextenzo, Pelmeg, and Fulphila within 67 days of the CHMP’s opinion.

The EC’s decision will apply to the European Union. Norway, Iceland, and Liechtenstein will make corresponding decisions based on the EC’s judgement.

Ziextenzo is being developed by Sandoz GmbH, Pelmeg is being developed by Cinfa Biotech S.L., and Fulphila is being developed by MYLAN S.A.S.

Photo from Amgen

The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended approval for three proposed biosimilars of pegfilgrastim—Ziextenzo, Pelmeg, and Fulphila.

If approved by the European Commission (EC), these products would be used for the same indication as the reference medicine, Neulasta (pegfilgrastim).

Neulasta has been EC-approved since 2002 to reduce the duration of neutropenia and the incidence of febrile neutropenia in adults who receive cytotoxic chemotherapy to treat malignancies except chronic myeloid leukemia and myelodysplastic syndromes.

According to the CHMP, data suggest that Ziextenzo, Pelmeg, and Fulphila all have quality, efficacy, and safety profiles comparable to Neulasta.

The EC is expected to make a decision on the approval of Ziextenzo, Pelmeg, and Fulphila within 67 days of the CHMP’s opinion.

The EC’s decision will apply to the European Union. Norway, Iceland, and Liechtenstein will make corresponding decisions based on the EC’s judgement.

Ziextenzo is being developed by Sandoz GmbH, Pelmeg is being developed by Cinfa Biotech S.L., and Fulphila is being developed by MYLAN S.A.S.

Photo from Amgen

The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended approval for three proposed biosimilars of pegfilgrastim—Ziextenzo, Pelmeg, and Fulphila.

If approved by the European Commission (EC), these products would be used for the same indication as the reference medicine, Neulasta (pegfilgrastim).

Neulasta has been EC-approved since 2002 to reduce the duration of neutropenia and the incidence of febrile neutropenia in adults who receive cytotoxic chemotherapy to treat malignancies except chronic myeloid leukemia and myelodysplastic syndromes.

According to the CHMP, data suggest that Ziextenzo, Pelmeg, and Fulphila all have quality, efficacy, and safety profiles comparable to Neulasta.

The EC is expected to make a decision on the approval of Ziextenzo, Pelmeg, and Fulphila within 67 days of the CHMP’s opinion.

The EC’s decision will apply to the European Union. Norway, Iceland, and Liechtenstein will make corresponding decisions based on the EC’s judgement.

Ziextenzo is being developed by Sandoz GmbH, Pelmeg is being developed by Cinfa Biotech S.L., and Fulphila is being developed by MYLAN S.A.S.

Photo courtesy of Abbvie

The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended that the European Commission (EC) approve a new indication for venetoclax (Venclyxto®).

AbbVie is seeking EC approval for venetoclax in combination with rituximab for the treatment of patients with relapsed/refractory chronic lymphocytic leukemia (CLL) who have received at least one prior therapy.

The EC typically makes an approval decision within 67 days of the CHMP’s opinion.

The EC’s decision will apply to the European Union, Norway, Iceland, and Liechtenstein.

Venetoclax is already EC-approved as monotherapy for:

• Adults with CLL who have 17p deletion or TP53 mutation and are unsuitable for or have failed treatment with a B-cell receptor pathway inhibitor
• Adults with CLL who do not have 17p deletion or TP53 mutation but have failed both chemoimmunotherapy and a B-cell receptor pathway inhibitor.

The CHMP’s recommendation to approve venetoclax in combination with rituximab is supported by the phase 3 MURANO trial. Results from MURANO were published in The New England Journal of Medicine in March.

The trial included 389 CLL patients who were randomized to receive venetoclax plus rituximab (VEN+R) or bendamustine plus rituximab (B+R). The median follow-up was 23.8 months.

According to investigators, the median progression-free survival was not reached in the VEN+R arm and was 17.0 months in the B+R arm (hazard ratio, 0.17; P<0.0001).

According to an independent review committee, the median progression-free survival was not reached in the VEN+R arm and was 18.1 months in the B+R arm (hazard ratio, 0.20; P<0.0001).

Grade 3/4 adverse events (AEs) with at least a 2% difference in incidence between the treatment groups (in the VEN+R and B+R arms, respectively) included:

• Neutropenia (57.7% and 38.8%)
• Infections and infestations (17.5% and 21.8%)
• Anemia (10.8% and 13.8%)
• Thrombocytopenia (5.7% and 10.1%)
• Febrile neutropenia (3.6% and 9.6%)
• Pneumonia (5.2% and 8.0%)
• Infusion-related reaction (1.5% and 5.3%)
• Tumor lysis syndrome (3.1% and 1.1%)
• Hypotension (0% and 2.7%)
• Hyperglycemia (2.1% and 0%)
• Hypogammaglobulinemia (2.1% and 0%).

Serious AEs with at least a 2% difference in incidence between the treatment groups (in the VEN+R and B+R arms, respectively) were:

• Pneumonia (8.2% and 8.0%)
• Febrile neutropenia (3.6% and 8.5%)
• Pyrexia (2.6% and 6.9%)
• Anemia (1.5% and 2.7%)
• Infusion-related reaction (0.5% and 3.2%)
• Sepsis (0.5% and 2.1%)
• Tumor lysis syndrome (2.1% and 0.5%)
• Hypotension (0% and 2.7%).

Fatal AEs occurred in 5.2% of patients in the VEN+R arm and 5.9% in the B+R arm.

Fatal AEs in the VEN+R arm included pneumonia (n=3), sepsis (n=1), thrombocytopenia (n=1), cardiac failure (n=1), myocardial infarction (n=1), sudden cardiac death (n=1), colorectal cancer (n=1), status epilepticus (n=1), and acute respiratory failure (n=1). Two cases of pneumonia occurred in the setting of progression/Richter transformation.

Photo courtesy of Abbvie

The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended that the European Commission (EC) approve a new indication for venetoclax (Venclyxto®).

AbbVie is seeking EC approval for venetoclax in combination with rituximab for the treatment of patients with relapsed/refractory chronic lymphocytic leukemia (CLL) who have received at least one prior therapy.

The EC typically makes an approval decision within 67 days of the CHMP’s opinion.

The EC’s decision will apply to the European Union, Norway, Iceland, and Liechtenstein.

Venetoclax is already EC-approved as monotherapy for:

• Adults with CLL who have 17p deletion or TP53 mutation and are unsuitable for or have failed treatment with a B-cell receptor pathway inhibitor
• Adults with CLL who do not have 17p deletion or TP53 mutation but have failed both chemoimmunotherapy and a B-cell receptor pathway inhibitor.

The CHMP’s recommendation to approve venetoclax in combination with rituximab is supported by the phase 3 MURANO trial. Results from MURANO were published in The New England Journal of Medicine in March.

The trial included 389 CLL patients who were randomized to receive venetoclax plus rituximab (VEN+R) or bendamustine plus rituximab (B+R). The median follow-up was 23.8 months.

According to investigators, the median progression-free survival was not reached in the VEN+R arm and was 17.0 months in the B+R arm (hazard ratio, 0.17; P<0.0001).

According to an independent review committee, the median progression-free survival was not reached in the VEN+R arm and was 18.1 months in the B+R arm (hazard ratio, 0.20; P<0.0001).

Grade 3/4 adverse events (AEs) with at least a 2% difference in incidence between the treatment groups (in the VEN+R and B+R arms, respectively) included:

• Neutropenia (57.7% and 38.8%)
• Infections and infestations (17.5% and 21.8%)
• Anemia (10.8% and 13.8%)
• Thrombocytopenia (5.7% and 10.1%)
• Febrile neutropenia (3.6% and 9.6%)
• Pneumonia (5.2% and 8.0%)
• Infusion-related reaction (1.5% and 5.3%)
• Tumor lysis syndrome (3.1% and 1.1%)
• Hypotension (0% and 2.7%)
• Hyperglycemia (2.1% and 0%)
• Hypogammaglobulinemia (2.1% and 0%).

Serious AEs with at least a 2% difference in incidence between the treatment groups (in the VEN+R and B+R arms, respectively) were:

• Pneumonia (8.2% and 8.0%)
• Febrile neutropenia (3.6% and 8.5%)
• Pyrexia (2.6% and 6.9%)
• Anemia (1.5% and 2.7%)
• Infusion-related reaction (0.5% and 3.2%)
• Sepsis (0.5% and 2.1%)
• Tumor lysis syndrome (2.1% and 0.5%)
• Hypotension (0% and 2.7%).

Fatal AEs occurred in 5.2% of patients in the VEN+R arm and 5.9% in the B+R arm.

Fatal AEs in the VEN+R arm included pneumonia (n=3), sepsis (n=1), thrombocytopenia (n=1), cardiac failure (n=1), myocardial infarction (n=1), sudden cardiac death (n=1), colorectal cancer (n=1), status epilepticus (n=1), and acute respiratory failure (n=1). Two cases of pneumonia occurred in the setting of progression/Richter transformation.

Photo courtesy of Abbvie

The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended that the European Commission (EC) approve a new indication for venetoclax (Venclyxto®).

AbbVie is seeking EC approval for venetoclax in combination with rituximab for the treatment of patients with relapsed/refractory chronic lymphocytic leukemia (CLL) who have received at least one prior therapy.

The EC typically makes an approval decision within 67 days of the CHMP’s opinion.

The EC’s decision will apply to the European Union, Norway, Iceland, and Liechtenstein.

Venetoclax is already EC-approved as monotherapy for:

• Adults with CLL who have 17p deletion or TP53 mutation and are unsuitable for or have failed treatment with a B-cell receptor pathway inhibitor
• Adults with CLL who do not have 17p deletion or TP53 mutation but have failed both chemoimmunotherapy and a B-cell receptor pathway inhibitor.

The CHMP’s recommendation to approve venetoclax in combination with rituximab is supported by the phase 3 MURANO trial. Results from MURANO were published in The New England Journal of Medicine in March.

The trial included 389 CLL patients who were randomized to receive venetoclax plus rituximab (VEN+R) or bendamustine plus rituximab (B+R). The median follow-up was 23.8 months.

According to investigators, the median progression-free survival was not reached in the VEN+R arm and was 17.0 months in the B+R arm (hazard ratio, 0.17; P<0.0001).

According to an independent review committee, the median progression-free survival was not reached in the VEN+R arm and was 18.1 months in the B+R arm (hazard ratio, 0.20; P<0.0001).

Grade 3/4 adverse events (AEs) with at least a 2% difference in incidence between the treatment groups (in the VEN+R and B+R arms, respectively) included:

• Neutropenia (57.7% and 38.8%)
• Infections and infestations (17.5% and 21.8%)
• Anemia (10.8% and 13.8%)
• Thrombocytopenia (5.7% and 10.1%)
• Febrile neutropenia (3.6% and 9.6%)
• Pneumonia (5.2% and 8.0%)
• Infusion-related reaction (1.5% and 5.3%)
• Tumor lysis syndrome (3.1% and 1.1%)
• Hypotension (0% and 2.7%)
• Hyperglycemia (2.1% and 0%)
• Hypogammaglobulinemia (2.1% and 0%).

Serious AEs with at least a 2% difference in incidence between the treatment groups (in the VEN+R and B+R arms, respectively) were:

• Pneumonia (8.2% and 8.0%)
• Febrile neutropenia (3.6% and 8.5%)
• Pyrexia (2.6% and 6.9%)
• Anemia (1.5% and 2.7%)
• Infusion-related reaction (0.5% and 3.2%)
• Sepsis (0.5% and 2.1%)
• Tumor lysis syndrome (2.1% and 0.5%)
• Hypotension (0% and 2.7%).

Fatal AEs occurred in 5.2% of patients in the VEN+R arm and 5.9% in the B+R arm.

Fatal AEs in the VEN+R arm included pneumonia (n=3), sepsis (n=1), thrombocytopenia (n=1), cardiac failure (n=1), myocardial infarction (n=1), sudden cardiac death (n=1), colorectal cancer (n=1), status epilepticus (n=1), and acute respiratory failure (n=1). Two cases of pneumonia occurred in the setting of progression/Richter transformation.

Institute of Pathology

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, VAF^0.2% 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.

Institute of Pathology

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, VAF^0.2% 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.

Institute of Pathology

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, VAF^0.2% 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.

Micrograph showing CLL

New research has linked stress levels to markers of progressive disease in patients with chronic lymphocytic leukemia (CLL).

Researchers found that CLL patients who reported more stress also had higher absolute lymphocyte counts and elevated levels of three other markers of more advanced disease—tumor necrosis factor-α (TNFα), interleukin 16 (IL-16), and chemokine ligand 3 (CCL3).

“All four variables we measured are related to prognosis in CLL patients, so they have a lot of relevance,” said study author Barbara L. Andersen, PhD, of The Ohio State University in Columbus.

She and her colleagues described this research in Cancer.

The study involved 96 patients with relapsed/refractory CLL who were entering a phase 2 trial of ibrutinib (NCT01589302). Data collection for this study was done before patients received their first dose of ibrutinib.

All patients completed a survey that measured CLL-related stress. They were asked questions like how often they had intrusive thoughts about their disease, how often they tried to avoid thinking about it, and how often they felt jumpy and easily startled.

The researchers used blood samples to determine patients’ absolute lymphocyte counts and to measure levels of eight cytokines known to promote unhealthy levels of inflammation—IL-6, IL-10, IL-16, TNFα, a proliferation‐inducing ligand (APRIL), B‐cell activating factor (BAFF), vascular endothelial growth factor (VEGF), and CCL3.

In an analysis controlling for demographic characteristics, comorbidities, the presence of 17p deletion, and correlates of inflammation, higher stress was significantly associated with higher:

• Absolute lymphocyte counts (P<0.05)
• Levels of TNFα (P<0.05)
• Levels of IL‐16 (P<0.01)
• Levels of CCL3 (P<0.05).

“The fact that stress shows an effect on CLL even after we controlled for other factors suggests it may be relevant to the course of CLL,” Dr. Andersen said.

She added that the researchers are still following these patients and will examine the relationship between stress and disease markers throughout treatment.

This study was supported by the National Cancer Institute, Pharmacylics (the company developing ibrutinib), and a Pelotonia Idea Award from The Ohio State University Comprehensive Cancer Center.

Micrograph showing CLL

New research has linked stress levels to markers of progressive disease in patients with chronic lymphocytic leukemia (CLL).

Researchers found that CLL patients who reported more stress also had higher absolute lymphocyte counts and elevated levels of three other markers of more advanced disease—tumor necrosis factor-α (TNFα), interleukin 16 (IL-16), and chemokine ligand 3 (CCL3).

“All four variables we measured are related to prognosis in CLL patients, so they have a lot of relevance,” said study author Barbara L. Andersen, PhD, of The Ohio State University in Columbus.

She and her colleagues described this research in Cancer.

The study involved 96 patients with relapsed/refractory CLL who were entering a phase 2 trial of ibrutinib (NCT01589302). Data collection for this study was done before patients received their first dose of ibrutinib.

All patients completed a survey that measured CLL-related stress. They were asked questions like how often they had intrusive thoughts about their disease, how often they tried to avoid thinking about it, and how often they felt jumpy and easily startled.

The researchers used blood samples to determine patients’ absolute lymphocyte counts and to measure levels of eight cytokines known to promote unhealthy levels of inflammation—IL-6, IL-10, IL-16, TNFα, a proliferation‐inducing ligand (APRIL), B‐cell activating factor (BAFF), vascular endothelial growth factor (VEGF), and CCL3.

In an analysis controlling for demographic characteristics, comorbidities, the presence of 17p deletion, and correlates of inflammation, higher stress was significantly associated with higher:

• Absolute lymphocyte counts (P<0.05)
• Levels of TNFα (P<0.05)
• Levels of IL‐16 (P<0.01)
• Levels of CCL3 (P<0.05).

“The fact that stress shows an effect on CLL even after we controlled for other factors suggests it may be relevant to the course of CLL,” Dr. Andersen said.

She added that the researchers are still following these patients and will examine the relationship between stress and disease markers throughout treatment.

This study was supported by the National Cancer Institute, Pharmacylics (the company developing ibrutinib), and a Pelotonia Idea Award from The Ohio State University Comprehensive Cancer Center.

Micrograph showing CLL

New research has linked stress levels to markers of progressive disease in patients with chronic lymphocytic leukemia (CLL).

Researchers found that CLL patients who reported more stress also had higher absolute lymphocyte counts and elevated levels of three other markers of more advanced disease—tumor necrosis factor-α (TNFα), interleukin 16 (IL-16), and chemokine ligand 3 (CCL3).

“All four variables we measured are related to prognosis in CLL patients, so they have a lot of relevance,” said study author Barbara L. Andersen, PhD, of The Ohio State University in Columbus.

She and her colleagues described this research in Cancer.

The study involved 96 patients with relapsed/refractory CLL who were entering a phase 2 trial of ibrutinib (NCT01589302). Data collection for this study was done before patients received their first dose of ibrutinib.

All patients completed a survey that measured CLL-related stress. They were asked questions like how often they had intrusive thoughts about their disease, how often they tried to avoid thinking about it, and how often they felt jumpy and easily startled.

The researchers used blood samples to determine patients’ absolute lymphocyte counts and to measure levels of eight cytokines known to promote unhealthy levels of inflammation—IL-6, IL-10, IL-16, TNFα, a proliferation‐inducing ligand (APRIL), B‐cell activating factor (BAFF), vascular endothelial growth factor (VEGF), and CCL3.

In an analysis controlling for demographic characteristics, comorbidities, the presence of 17p deletion, and correlates of inflammation, higher stress was significantly associated with higher:

• Absolute lymphocyte counts (P<0.05)
• Levels of TNFα (P<0.05)
• Levels of IL‐16 (P<0.01)
• Levels of CCL3 (P<0.05).

“The fact that stress shows an effect on CLL even after we controlled for other factors suggests it may be relevant to the course of CLL,” Dr. Andersen said.

She added that the researchers are still following these patients and will examine the relationship between stress and disease markers throughout treatment.

This study was supported by the National Cancer Institute, Pharmacylics (the company developing ibrutinib), and a Pelotonia Idea Award from The Ohio State University Comprehensive Cancer Center.

Cancer Research Center

The U.S. Food and Drug Administration (FDA) has granted orphan drug designation to OBI-3424 for the treatment of acute lymphoblastic leukemia (ALL).

OBI-3424 is a small-molecule prodrug that targets cancers overexpressing aldo-keto reductase 1C3 (AKR1C3) and selectively releases a DNA alkylating agent in the presence of the AKR1C3 enzyme.

AKR1C3 overexpression has been observed in ALL, particularly T-cell ALL.

OBI-3424 demonstrated activity against T-ALL in preclinical research presented as a poster at the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics in October 2017.

Researchers reported that OBI-3424 “exerted profound in vivo efficacy” against T-ALL xenografts derived mainly from patients with aggressive and fatal T-ALL.

The researchers said OBI-3424 significantly reduced leukemia bone marrow infiltration in 4 of 6 evaluable T-ALL xenografts, and OBI-3424 was considered well tolerated.

The poster presentation describing this research is available for download from the website of OBI Pharma, the company developing OBI-3424 in cooperation with Ascenta Pharma.

OBI-3424 also has orphan drug designation from the FDA as a treatment for hepatocellular carcinoma.

Enrollment has begun in a phase 1/2 trial (NCT03592264) of OBI-3424 in patients with hepatocellular carcinoma and castrate-resistant prostate cancer.

About orphan designation

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

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

Cancer Research Center

The U.S. Food and Drug Administration (FDA) has granted orphan drug designation to OBI-3424 for the treatment of acute lymphoblastic leukemia (ALL).

OBI-3424 is a small-molecule prodrug that targets cancers overexpressing aldo-keto reductase 1C3 (AKR1C3) and selectively releases a DNA alkylating agent in the presence of the AKR1C3 enzyme.

AKR1C3 overexpression has been observed in ALL, particularly T-cell ALL.

OBI-3424 demonstrated activity against T-ALL in preclinical research presented as a poster at the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics in October 2017.

Researchers reported that OBI-3424 “exerted profound in vivo efficacy” against T-ALL xenografts derived mainly from patients with aggressive and fatal T-ALL.

The researchers said OBI-3424 significantly reduced leukemia bone marrow infiltration in 4 of 6 evaluable T-ALL xenografts, and OBI-3424 was considered well tolerated.

The poster presentation describing this research is available for download from the website of OBI Pharma, the company developing OBI-3424 in cooperation with Ascenta Pharma.

OBI-3424 also has orphan drug designation from the FDA as a treatment for hepatocellular carcinoma.

Enrollment has begun in a phase 1/2 trial (NCT03592264) of OBI-3424 in patients with hepatocellular carcinoma and castrate-resistant prostate cancer.

About orphan designation

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

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

Cancer Research Center

The U.S. Food and Drug Administration (FDA) has granted orphan drug designation to OBI-3424 for the treatment of acute lymphoblastic leukemia (ALL).

OBI-3424 is a small-molecule prodrug that targets cancers overexpressing aldo-keto reductase 1C3 (AKR1C3) and selectively releases a DNA alkylating agent in the presence of the AKR1C3 enzyme.

AKR1C3 overexpression has been observed in ALL, particularly T-cell ALL.

OBI-3424 demonstrated activity against T-ALL in preclinical research presented as a poster at the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics in October 2017.

Researchers reported that OBI-3424 “exerted profound in vivo efficacy” against T-ALL xenografts derived mainly from patients with aggressive and fatal T-ALL.

The researchers said OBI-3424 significantly reduced leukemia bone marrow infiltration in 4 of 6 evaluable T-ALL xenografts, and OBI-3424 was considered well tolerated.

The poster presentation describing this research is available for download from the website of OBI Pharma, the company developing OBI-3424 in cooperation with Ascenta Pharma.

OBI-3424 also has orphan drug designation from the FDA as a treatment for hepatocellular carcinoma.

Enrollment has begun in a phase 1/2 trial (NCT03592264) of OBI-3424 in patients with hepatocellular carcinoma and castrate-resistant prostate cancer.

About orphan designation

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

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