Leukemia, Myelodysplasia, Transplantation

Photo courtesy of Janssen

The 140 mg capsules of Imbruvica® (ibrutinib) will remain on the market, according to Pharmacyclics LLC.

Pharmacyclics (an AbbVie company) and Janssen had planned to discontinue the capsules after introducing a single-tablet formulation of Imbruvica earlier this year.

However, the companies received negative feedback about the discontinuation and decided to keep the 140 mg capsules on the market.

In February, the US Food and Drug Administration (FDA) approved a single-tablet formulation of Imbruvica that is available in 4 doses—140 mg, 280 mg, 420 mg, and 560 mg.

Pharmacyclics and Janssen introduced this formulation to enable a once-a-day dosing regimen. The companies said the goal with the new formulation was to improve adherence because some patients had to take 3 or 4 pills every day to get the recommended dose of Imbruvica.

After introducing the new formulation, Pharmacyclics and Janssen planned to discontinue the 140 mg capsules.

Critics spoke out against this change in an article published in The Cancer Letter. They noted that discontinuing the old formulation would mean price increases for some patients. That’s because the single-tablet formulation of Imbruvica has the same price regardless of dose—$400 per tablet.

Patients on lower doses of Imbruvica would experience an increase in cost if they switched from the capsules to the tablet formulation. In fact, costs could triple for patients on the 140 mg dose.

Pharmacyclics argued that most patients on Imbruvica—those taking the 420 mg and 560 mg doses—would see no increase in out-of-pocket costs when transitioning to the single-tablet formulation.  And patients on the 560 mg dose would likely see a decrease in their out-of-pocket costs.

However, critics pointed to results of a recent pilot study, which indicated that the recommended dose of Imbruvica for patients with chronic lymphocytic leukemia (CLL)—420 mg—may be too high. The results suggested that CLL patients could receive lower doses of Imbruvica without a reduction in efficacy.

Therefore, keeping the 140 mg capsules on the market could mean lower costs for some CLL patients.

In addition to voicing concerns about costs, the critics pointed out that discontinuing the 140 mg capsules of Imbruvica would make it more difficult to adjust patients’ doses when needed.

Pharmacyclics said its YOU&i™ Dose Exchange Program can aid healthcare professionals in adjusting doses before patients have finished their current pack of Imbruvica. Patients would receive a “rapid shipment” of their new dose at no additional cost.

But the critics said this program “creates a barrier to optimal prescribing for some patients” and urged the FDA to review the safety of the program.

Roughly a month after the critics made this recommendation in The Cancer Letter article, Pharmacyclics announced that the 140 mg capsules of Imbruvica would remain on the market.

Photo courtesy of Janssen

The 140 mg capsules of Imbruvica® (ibrutinib) will remain on the market, according to Pharmacyclics LLC.

Pharmacyclics (an AbbVie company) and Janssen had planned to discontinue the capsules after introducing a single-tablet formulation of Imbruvica earlier this year.

However, the companies received negative feedback about the discontinuation and decided to keep the 140 mg capsules on the market.

In February, the US Food and Drug Administration (FDA) approved a single-tablet formulation of Imbruvica that is available in 4 doses—140 mg, 280 mg, 420 mg, and 560 mg.

Pharmacyclics and Janssen introduced this formulation to enable a once-a-day dosing regimen. The companies said the goal with the new formulation was to improve adherence because some patients had to take 3 or 4 pills every day to get the recommended dose of Imbruvica.

After introducing the new formulation, Pharmacyclics and Janssen planned to discontinue the 140 mg capsules.

Critics spoke out against this change in an article published in The Cancer Letter. They noted that discontinuing the old formulation would mean price increases for some patients. That’s because the single-tablet formulation of Imbruvica has the same price regardless of dose—$400 per tablet.

Patients on lower doses of Imbruvica would experience an increase in cost if they switched from the capsules to the tablet formulation. In fact, costs could triple for patients on the 140 mg dose.

Pharmacyclics argued that most patients on Imbruvica—those taking the 420 mg and 560 mg doses—would see no increase in out-of-pocket costs when transitioning to the single-tablet formulation.  And patients on the 560 mg dose would likely see a decrease in their out-of-pocket costs.

However, critics pointed to results of a recent pilot study, which indicated that the recommended dose of Imbruvica for patients with chronic lymphocytic leukemia (CLL)—420 mg—may be too high. The results suggested that CLL patients could receive lower doses of Imbruvica without a reduction in efficacy.

Therefore, keeping the 140 mg capsules on the market could mean lower costs for some CLL patients.

In addition to voicing concerns about costs, the critics pointed out that discontinuing the 140 mg capsules of Imbruvica would make it more difficult to adjust patients’ doses when needed.

Pharmacyclics said its YOU&i™ Dose Exchange Program can aid healthcare professionals in adjusting doses before patients have finished their current pack of Imbruvica. Patients would receive a “rapid shipment” of their new dose at no additional cost.

But the critics said this program “creates a barrier to optimal prescribing for some patients” and urged the FDA to review the safety of the program.

Roughly a month after the critics made this recommendation in The Cancer Letter article, Pharmacyclics announced that the 140 mg capsules of Imbruvica would remain on the market.

Photo courtesy of Janssen

The 140 mg capsules of Imbruvica® (ibrutinib) will remain on the market, according to Pharmacyclics LLC.

Pharmacyclics (an AbbVie company) and Janssen had planned to discontinue the capsules after introducing a single-tablet formulation of Imbruvica earlier this year.

However, the companies received negative feedback about the discontinuation and decided to keep the 140 mg capsules on the market.

In February, the US Food and Drug Administration (FDA) approved a single-tablet formulation of Imbruvica that is available in 4 doses—140 mg, 280 mg, 420 mg, and 560 mg.

Pharmacyclics and Janssen introduced this formulation to enable a once-a-day dosing regimen. The companies said the goal with the new formulation was to improve adherence because some patients had to take 3 or 4 pills every day to get the recommended dose of Imbruvica.

After introducing the new formulation, Pharmacyclics and Janssen planned to discontinue the 140 mg capsules.

Critics spoke out against this change in an article published in The Cancer Letter. They noted that discontinuing the old formulation would mean price increases for some patients. That’s because the single-tablet formulation of Imbruvica has the same price regardless of dose—$400 per tablet.

Patients on lower doses of Imbruvica would experience an increase in cost if they switched from the capsules to the tablet formulation. In fact, costs could triple for patients on the 140 mg dose.

Pharmacyclics argued that most patients on Imbruvica—those taking the 420 mg and 560 mg doses—would see no increase in out-of-pocket costs when transitioning to the single-tablet formulation.  And patients on the 560 mg dose would likely see a decrease in their out-of-pocket costs.

However, critics pointed to results of a recent pilot study, which indicated that the recommended dose of Imbruvica for patients with chronic lymphocytic leukemia (CLL)—420 mg—may be too high. The results suggested that CLL patients could receive lower doses of Imbruvica without a reduction in efficacy.

Therefore, keeping the 140 mg capsules on the market could mean lower costs for some CLL patients.

In addition to voicing concerns about costs, the critics pointed out that discontinuing the 140 mg capsules of Imbruvica would make it more difficult to adjust patients’ doses when needed.

Pharmacyclics said its YOU&i™ Dose Exchange Program can aid healthcare professionals in adjusting doses before patients have finished their current pack of Imbruvica. Patients would receive a “rapid shipment” of their new dose at no additional cost.

But the critics said this program “creates a barrier to optimal prescribing for some patients” and urged the FDA to review the safety of the program.

Roughly a month after the critics made this recommendation in The Cancer Letter article, Pharmacyclics announced that the 140 mg capsules of Imbruvica would remain on the market.

A set of novel chemotherapy regimens yield excellent outcomes—the best yet—among pediatric and young adult patients with T-cell malignancies, finds a phase 3 randomized controlled trial conducted by the Children’s Oncology Group (ALL0434).

“Despite very intense and complex chemotherapy, 20% of children and adolescents enrolled in Children’s Oncology Group T-cell leukemia trials between 2000 and 2005 did not survive. New drugs were needed to improve survival rates for T-cell malignancies,” lead study author Kimberly P. Dunsmore, MD, a professor at Virginia Tech, Roanoke, said in a press briefing leading up to the annual meeting of the American Society of Clinical Oncology.

The ALL0434 trial tested the addition of methotrexate (Trexall) and/or nelarabine (Arranon), a T cell–specific drug known to be efficacious in relapsed disease, to standard chemotherapy, with tailoring of the regimen to recurrence risk. Analyses were based on 1,545 patients with T-cell acute lymphoblastic leukemia (T-ALL) or T-cell lymphoblastic lymphoma (T-LL).

Results for all patients with T-ALL showed that, with addition of either or both drugs, more than 90% were alive at 4 years and more than 80% were leukemia free. Adding nelarabine to standard chemotherapy improved disease-free survival among the subset having intermediate- or high-risk disease, and the best outcomes were seen with addition of both nelarabine and an escalating dose of methotrexate.

Although patients with T-LL did not see benefit from addition of nelarabine, they still had an 85% rate of overall survival at 4 years.

“ALL0434 is the largest trial for children and young adults with T-cell malignancy ever conducted. It has the best-ever survival data,” Dr. Dunsmore commented.

“Our next steps will be to examine what implications and benefits may accrue when using nelarabine in protocols without cranial irradiation. This is to decrease long-term neurologic side effects, and we think it may be possible since nelarabine also reduces CNS relapses,” she said.

Study details

The ALL0434 trial enrolled patients aged 1-30 years with newly diagnosed T-ALL or T-LL. After induction chemotherapy, all patients received standard chemotherapy, the Children’s Oncology Group augmented Berlin-Frankfurt-Munster regimen (N Engl J Med. 1998;338:1663-71), and depending on recurrence risk, cranial irradiation.

In addition to that regimen, they were randomly assigned to four arms, according to methotrexate dosing (high dose with leucovorin rescue in the inpatient setting vs. escalating dose in the outpatient setting) and nelarabine therapy (receipt vs. nonreceipt).

Among patients with T-ALL, those with low-risk disease were ineligible for nelarabine and did not receive cranial irradiation, whereas those with intermediate- and high-risk disease were randomized to all four arms, Dr. Dunsmore explained. In addition, those who did not achieve remission on induction chemotherapy were nonrandomly assigned to the high-dose methotrexate plus nelarabine arm.

A set of novel chemotherapy regimens yield excellent outcomes—the best yet—among pediatric and young adult patients with T-cell malignancies, finds a phase 3 randomized controlled trial conducted by the Children’s Oncology Group (ALL0434).

“Despite very intense and complex chemotherapy, 20% of children and adolescents enrolled in Children’s Oncology Group T-cell leukemia trials between 2000 and 2005 did not survive. New drugs were needed to improve survival rates for T-cell malignancies,” lead study author Kimberly P. Dunsmore, MD, a professor at Virginia Tech, Roanoke, said in a press briefing leading up to the annual meeting of the American Society of Clinical Oncology.

The ALL0434 trial tested the addition of methotrexate (Trexall) and/or nelarabine (Arranon), a T cell–specific drug known to be efficacious in relapsed disease, to standard chemotherapy, with tailoring of the regimen to recurrence risk. Analyses were based on 1,545 patients with T-cell acute lymphoblastic leukemia (T-ALL) or T-cell lymphoblastic lymphoma (T-LL).

Results for all patients with T-ALL showed that, with addition of either or both drugs, more than 90% were alive at 4 years and more than 80% were leukemia free. Adding nelarabine to standard chemotherapy improved disease-free survival among the subset having intermediate- or high-risk disease, and the best outcomes were seen with addition of both nelarabine and an escalating dose of methotrexate.

Although patients with T-LL did not see benefit from addition of nelarabine, they still had an 85% rate of overall survival at 4 years.

“ALL0434 is the largest trial for children and young adults with T-cell malignancy ever conducted. It has the best-ever survival data,” Dr. Dunsmore commented.

“Our next steps will be to examine what implications and benefits may accrue when using nelarabine in protocols without cranial irradiation. This is to decrease long-term neurologic side effects, and we think it may be possible since nelarabine also reduces CNS relapses,” she said.

Study details

The ALL0434 trial enrolled patients aged 1-30 years with newly diagnosed T-ALL or T-LL. After induction chemotherapy, all patients received standard chemotherapy, the Children’s Oncology Group augmented Berlin-Frankfurt-Munster regimen (N Engl J Med. 1998;338:1663-71), and depending on recurrence risk, cranial irradiation.

In addition to that regimen, they were randomly assigned to four arms, according to methotrexate dosing (high dose with leucovorin rescue in the inpatient setting vs. escalating dose in the outpatient setting) and nelarabine therapy (receipt vs. nonreceipt).

Among patients with T-ALL, those with low-risk disease were ineligible for nelarabine and did not receive cranial irradiation, whereas those with intermediate- and high-risk disease were randomized to all four arms, Dr. Dunsmore explained. In addition, those who did not achieve remission on induction chemotherapy were nonrandomly assigned to the high-dose methotrexate plus nelarabine arm.

A set of novel chemotherapy regimens yield excellent outcomes—the best yet—among pediatric and young adult patients with T-cell malignancies, finds a phase 3 randomized controlled trial conducted by the Children’s Oncology Group (ALL0434).

“Despite very intense and complex chemotherapy, 20% of children and adolescents enrolled in Children’s Oncology Group T-cell leukemia trials between 2000 and 2005 did not survive. New drugs were needed to improve survival rates for T-cell malignancies,” lead study author Kimberly P. Dunsmore, MD, a professor at Virginia Tech, Roanoke, said in a press briefing leading up to the annual meeting of the American Society of Clinical Oncology.

The ALL0434 trial tested the addition of methotrexate (Trexall) and/or nelarabine (Arranon), a T cell–specific drug known to be efficacious in relapsed disease, to standard chemotherapy, with tailoring of the regimen to recurrence risk. Analyses were based on 1,545 patients with T-cell acute lymphoblastic leukemia (T-ALL) or T-cell lymphoblastic lymphoma (T-LL).

Results for all patients with T-ALL showed that, with addition of either or both drugs, more than 90% were alive at 4 years and more than 80% were leukemia free. Adding nelarabine to standard chemotherapy improved disease-free survival among the subset having intermediate- or high-risk disease, and the best outcomes were seen with addition of both nelarabine and an escalating dose of methotrexate.

Although patients with T-LL did not see benefit from addition of nelarabine, they still had an 85% rate of overall survival at 4 years.

“ALL0434 is the largest trial for children and young adults with T-cell malignancy ever conducted. It has the best-ever survival data,” Dr. Dunsmore commented.

“Our next steps will be to examine what implications and benefits may accrue when using nelarabine in protocols without cranial irradiation. This is to decrease long-term neurologic side effects, and we think it may be possible since nelarabine also reduces CNS relapses,” she said.

Study details

The ALL0434 trial enrolled patients aged 1-30 years with newly diagnosed T-ALL or T-LL. After induction chemotherapy, all patients received standard chemotherapy, the Children’s Oncology Group augmented Berlin-Frankfurt-Munster regimen (N Engl J Med. 1998;338:1663-71), and depending on recurrence risk, cranial irradiation.

In addition to that regimen, they were randomly assigned to four arms, according to methotrexate dosing (high dose with leucovorin rescue in the inpatient setting vs. escalating dose in the outpatient setting) and nelarabine therapy (receipt vs. nonreceipt).

Among patients with T-ALL, those with low-risk disease were ineligible for nelarabine and did not receive cranial irradiation, whereas those with intermediate- and high-risk disease were randomized to all four arms, Dr. Dunsmore explained. In addition, those who did not achieve remission on induction chemotherapy were nonrandomly assigned to the high-dose methotrexate plus nelarabine arm.

Lab mouse

Preclinical research suggests bacterial signals are crucial to the development of pre-leukemic myeloproliferation (PMP).

Researchers found that bacterial translocation leads to increased production of interleukin-6 (IL-6), which prompts PMP development in mice with Tet2 deficiency.

However, antibiotics and blockade of IL-6 were able to reverse PMP in the mice.

Bana Jabri, MD, PhD, of the University of Chicago in Illinois, and her colleagues reported these findings in Nature.

The researchers noted that, in humans and mice, TET2 deficiency leads to increased self-renewal of hematopoietic stem cells favoring the myeloid lineage, and this can lead to PMP.

However, not all humans or mice with TET2 deficiency actually develop PMP, which suggests other factors are at play.

With this in mind, the researchers studied Tet2-deficient mice. The team found that loss of Tet2 expression leads to defects in the intestinal barrier, although it isn’t clear how this occurs.

The intestinal defects allow bacteria living in the gut to spread into the blood and peripheral organs. The spread of bacteria prompts an increase in IL-6. This promotes proliferation of granulocyte–macrophage progenitors that express high levels of IL-6Rα in the absence of Tet2, and this leads to PMP.

The researchers found they could induce PMP in symptom-free Tet2^−/− mice by disrupting intestinal barrier integrity. PMP also developed in response to systemic bacterial stimuli.

However, antibiotics and blockade of IL-6 signals could reverse PMP in mice that developed symptoms. And germ-free Tet2^−/− mice did not develop symptoms, which supports the idea that bacteria must be present to drive the development of PMP.

Dr Jabri said the next step is to conduct studies in humans to see if patients with PMP also have signs of bacterial translocation. Then, clinical trials could test whether treatments that target aberrant IL-6 signals in response to bacteria can reverse the course of PMP.

Lab mouse

Preclinical research suggests bacterial signals are crucial to the development of pre-leukemic myeloproliferation (PMP).

Researchers found that bacterial translocation leads to increased production of interleukin-6 (IL-6), which prompts PMP development in mice with Tet2 deficiency.

However, antibiotics and blockade of IL-6 were able to reverse PMP in the mice.

Bana Jabri, MD, PhD, of the University of Chicago in Illinois, and her colleagues reported these findings in Nature.

The researchers noted that, in humans and mice, TET2 deficiency leads to increased self-renewal of hematopoietic stem cells favoring the myeloid lineage, and this can lead to PMP.

However, not all humans or mice with TET2 deficiency actually develop PMP, which suggests other factors are at play.

With this in mind, the researchers studied Tet2-deficient mice. The team found that loss of Tet2 expression leads to defects in the intestinal barrier, although it isn’t clear how this occurs.

The intestinal defects allow bacteria living in the gut to spread into the blood and peripheral organs. The spread of bacteria prompts an increase in IL-6. This promotes proliferation of granulocyte–macrophage progenitors that express high levels of IL-6Rα in the absence of Tet2, and this leads to PMP.

The researchers found they could induce PMP in symptom-free Tet2^−/− mice by disrupting intestinal barrier integrity. PMP also developed in response to systemic bacterial stimuli.

However, antibiotics and blockade of IL-6 signals could reverse PMP in mice that developed symptoms. And germ-free Tet2^−/− mice did not develop symptoms, which supports the idea that bacteria must be present to drive the development of PMP.

Dr Jabri said the next step is to conduct studies in humans to see if patients with PMP also have signs of bacterial translocation. Then, clinical trials could test whether treatments that target aberrant IL-6 signals in response to bacteria can reverse the course of PMP.

Lab mouse

Preclinical research suggests bacterial signals are crucial to the development of pre-leukemic myeloproliferation (PMP).

Researchers found that bacterial translocation leads to increased production of interleukin-6 (IL-6), which prompts PMP development in mice with Tet2 deficiency.

However, antibiotics and blockade of IL-6 were able to reverse PMP in the mice.

Bana Jabri, MD, PhD, of the University of Chicago in Illinois, and her colleagues reported these findings in Nature.

The researchers noted that, in humans and mice, TET2 deficiency leads to increased self-renewal of hematopoietic stem cells favoring the myeloid lineage, and this can lead to PMP.

However, not all humans or mice with TET2 deficiency actually develop PMP, which suggests other factors are at play.

With this in mind, the researchers studied Tet2-deficient mice. The team found that loss of Tet2 expression leads to defects in the intestinal barrier, although it isn’t clear how this occurs.

The intestinal defects allow bacteria living in the gut to spread into the blood and peripheral organs. The spread of bacteria prompts an increase in IL-6. This promotes proliferation of granulocyte–macrophage progenitors that express high levels of IL-6Rα in the absence of Tet2, and this leads to PMP.

The researchers found they could induce PMP in symptom-free Tet2^−/− mice by disrupting intestinal barrier integrity. PMP also developed in response to systemic bacterial stimuli.

However, antibiotics and blockade of IL-6 signals could reverse PMP in mice that developed symptoms. And germ-free Tet2^−/− mice did not develop symptoms, which supports the idea that bacteria must be present to drive the development of PMP.

Dr Jabri said the next step is to conduct studies in humans to see if patients with PMP also have signs of bacterial translocation. Then, clinical trials could test whether treatments that target aberrant IL-6 signals in response to bacteria can reverse the course of PMP.

Photo by Bill Branson

The addition of nelarabine can improve treatment outcomes for certain patients with T-cell acute lymphoblastic leukemia (T-ALL), according to a phase 3 trial.

Patients with newly diagnosed, intermediate- or high-risk T-ALL had a significant improvement in 4-year disease-free survival (DFS) if they received nelarabine in addition to chemotherapy and cranial irradiation.

The DFS benefit with nelarabine was significant for patients who received high-dose methotrexate but not for those who received escalating-dose methotrexate.

This study also included patients with T-cell lymphoblastic lymphoma (T-LL), and they did not experience an improvement in DFS with the addition of nelarabine.

Kimberly Dunsmore, MD, of Virginia Tech Carilion School of Medicine in Roanoke, presented these results in a press briefing in advance of the 2018 ASCO Annual Meeting. Additional results are scheduled to be presented at the meeting as abstract 10500.

This research was supported by the National Cancer Institute/National Institutes of Health and St. Baldrick’s Foundation. The researchers’ disclosures are listed with the abstract.

Patients and treatment

The trial enrolled 1895 patients, ages 1 to 30, who were newly diagnosed with T-ALL (94%) or T-LL (6%).

Patients received standard 4-drug induction chemotherapy, and 1307 of these patients were then randomized to 1 of 4 treatment arms.

Regardless of which arm they were randomized to, patients received an 11-drug chemotherapy regimen—the augmented Berlin-Frankfurt-Munster regimen. Intermediate- and high-risk patients in all 4 arms also received cranial irradiation.

In the first treatment arm, T-LL (n=58) and T-ALL (n=372) patients received escalating-dose methotrexate without leucovorin rescue and pegaspargase (C-MTX).

In the second treatment arm, patients with intermediate- and high-risk T-ALL (n=147) and T-LL (n=60) received C-MTX plus nelarabine (six 5-day courses at 650 mg/m²/day).

In the third arm, T-ALL patients (n=451) received high-dose methotrexate with leucovorin rescue (HD-MTX). T-LL patients were not eligible for this arm or the fourth treatment arm.

In the fourth arm, intermediate- and high-risk T-ALL patients (n=219) received HD-MTX and nelarabine (same schedule as above). This included 43 T-ALL patients who had induction failure and were assigned to this arm non-randomly.

Results

For T-ALL patients, the 4-year disease-free survival (DFS) rate was 84%, and the 4-year overall survival rate was 90%.

There was a significant improvement in DFS for T-ALL patients who received nelarabine compared to those who did not—89% and 83%, respectively (P=0.0332).

“Historically, about 80% of people [with T-ALL] live at least 4 years after being treated for their disease, but we felt we could and must do better,” Dr Dunsmore said. “Our trial shows that we could further increase survival rates by about 10%, which is very encouraging.”

Dr Dunsmore also noted that patients who received nelarabine had fewer central nervous system relapses.

Among T-ALL patients who received C-MTX, there was no significant difference in DFS for those who received nelarabine and those who did not—92% and 90%, respectively (P=0.3825).

However, for patients who received HD-MTX, the difference in DFS was significant. The DFS rate was 86% in patients who received nelarabine and 78% in those who did not (P=0.024).

For the T-ALL patients who failed induction and were assigned to HD-MTX and nelarabine, the 4-year DFS rate was 55%.

Patients with T-LL did not benefit from the addition of nelarabine. The 4-year DFS rate was 85% in the nelarabine recipients and 89% in non-recipients (P=0.2788).

There were no significant differences in overall toxicity or peripheral neurotoxicity between the treatment arms.

Dr Dunsmore said the next step with this research will be to examine the implications and potential benefits of using nelarabine in treatment protocols that do not include cranial radiation.

Photo by Bill Branson

The addition of nelarabine can improve treatment outcomes for certain patients with T-cell acute lymphoblastic leukemia (T-ALL), according to a phase 3 trial.

Patients with newly diagnosed, intermediate- or high-risk T-ALL had a significant improvement in 4-year disease-free survival (DFS) if they received nelarabine in addition to chemotherapy and cranial irradiation.

The DFS benefit with nelarabine was significant for patients who received high-dose methotrexate but not for those who received escalating-dose methotrexate.

This study also included patients with T-cell lymphoblastic lymphoma (T-LL), and they did not experience an improvement in DFS with the addition of nelarabine.

Kimberly Dunsmore, MD, of Virginia Tech Carilion School of Medicine in Roanoke, presented these results in a press briefing in advance of the 2018 ASCO Annual Meeting. Additional results are scheduled to be presented at the meeting as abstract 10500.

This research was supported by the National Cancer Institute/National Institutes of Health and St. Baldrick’s Foundation. The researchers’ disclosures are listed with the abstract.

Patients and treatment

The trial enrolled 1895 patients, ages 1 to 30, who were newly diagnosed with T-ALL (94%) or T-LL (6%).

Patients received standard 4-drug induction chemotherapy, and 1307 of these patients were then randomized to 1 of 4 treatment arms.

Regardless of which arm they were randomized to, patients received an 11-drug chemotherapy regimen—the augmented Berlin-Frankfurt-Munster regimen. Intermediate- and high-risk patients in all 4 arms also received cranial irradiation.

In the first treatment arm, T-LL (n=58) and T-ALL (n=372) patients received escalating-dose methotrexate without leucovorin rescue and pegaspargase (C-MTX).

In the second treatment arm, patients with intermediate- and high-risk T-ALL (n=147) and T-LL (n=60) received C-MTX plus nelarabine (six 5-day courses at 650 mg/m²/day).

In the third arm, T-ALL patients (n=451) received high-dose methotrexate with leucovorin rescue (HD-MTX). T-LL patients were not eligible for this arm or the fourth treatment arm.

In the fourth arm, intermediate- and high-risk T-ALL patients (n=219) received HD-MTX and nelarabine (same schedule as above). This included 43 T-ALL patients who had induction failure and were assigned to this arm non-randomly.

Results

For T-ALL patients, the 4-year disease-free survival (DFS) rate was 84%, and the 4-year overall survival rate was 90%.

There was a significant improvement in DFS for T-ALL patients who received nelarabine compared to those who did not—89% and 83%, respectively (P=0.0332).

“Historically, about 80% of people [with T-ALL] live at least 4 years after being treated for their disease, but we felt we could and must do better,” Dr Dunsmore said. “Our trial shows that we could further increase survival rates by about 10%, which is very encouraging.”

Dr Dunsmore also noted that patients who received nelarabine had fewer central nervous system relapses.

Among T-ALL patients who received C-MTX, there was no significant difference in DFS for those who received nelarabine and those who did not—92% and 90%, respectively (P=0.3825).

However, for patients who received HD-MTX, the difference in DFS was significant. The DFS rate was 86% in patients who received nelarabine and 78% in those who did not (P=0.024).

For the T-ALL patients who failed induction and were assigned to HD-MTX and nelarabine, the 4-year DFS rate was 55%.

Patients with T-LL did not benefit from the addition of nelarabine. The 4-year DFS rate was 85% in the nelarabine recipients and 89% in non-recipients (P=0.2788).

There were no significant differences in overall toxicity or peripheral neurotoxicity between the treatment arms.

Dr Dunsmore said the next step with this research will be to examine the implications and potential benefits of using nelarabine in treatment protocols that do not include cranial radiation.

Photo by Bill Branson

The addition of nelarabine can improve treatment outcomes for certain patients with T-cell acute lymphoblastic leukemia (T-ALL), according to a phase 3 trial.

Patients with newly diagnosed, intermediate- or high-risk T-ALL had a significant improvement in 4-year disease-free survival (DFS) if they received nelarabine in addition to chemotherapy and cranial irradiation.

The DFS benefit with nelarabine was significant for patients who received high-dose methotrexate but not for those who received escalating-dose methotrexate.

This study also included patients with T-cell lymphoblastic lymphoma (T-LL), and they did not experience an improvement in DFS with the addition of nelarabine.

Kimberly Dunsmore, MD, of Virginia Tech Carilion School of Medicine in Roanoke, presented these results in a press briefing in advance of the 2018 ASCO Annual Meeting. Additional results are scheduled to be presented at the meeting as abstract 10500.

This research was supported by the National Cancer Institute/National Institutes of Health and St. Baldrick’s Foundation. The researchers’ disclosures are listed with the abstract.

Patients and treatment

The trial enrolled 1895 patients, ages 1 to 30, who were newly diagnosed with T-ALL (94%) or T-LL (6%).

Patients received standard 4-drug induction chemotherapy, and 1307 of these patients were then randomized to 1 of 4 treatment arms.

Regardless of which arm they were randomized to, patients received an 11-drug chemotherapy regimen—the augmented Berlin-Frankfurt-Munster regimen. Intermediate- and high-risk patients in all 4 arms also received cranial irradiation.

In the first treatment arm, T-LL (n=58) and T-ALL (n=372) patients received escalating-dose methotrexate without leucovorin rescue and pegaspargase (C-MTX).

In the second treatment arm, patients with intermediate- and high-risk T-ALL (n=147) and T-LL (n=60) received C-MTX plus nelarabine (six 5-day courses at 650 mg/m²/day).

In the third arm, T-ALL patients (n=451) received high-dose methotrexate with leucovorin rescue (HD-MTX). T-LL patients were not eligible for this arm or the fourth treatment arm.

In the fourth arm, intermediate- and high-risk T-ALL patients (n=219) received HD-MTX and nelarabine (same schedule as above). This included 43 T-ALL patients who had induction failure and were assigned to this arm non-randomly.

Results

For T-ALL patients, the 4-year disease-free survival (DFS) rate was 84%, and the 4-year overall survival rate was 90%.

There was a significant improvement in DFS for T-ALL patients who received nelarabine compared to those who did not—89% and 83%, respectively (P=0.0332).

“Historically, about 80% of people [with T-ALL] live at least 4 years after being treated for their disease, but we felt we could and must do better,” Dr Dunsmore said. “Our trial shows that we could further increase survival rates by about 10%, which is very encouraging.”

Dr Dunsmore also noted that patients who received nelarabine had fewer central nervous system relapses.

Among T-ALL patients who received C-MTX, there was no significant difference in DFS for those who received nelarabine and those who did not—92% and 90%, respectively (P=0.3825).

However, for patients who received HD-MTX, the difference in DFS was significant. The DFS rate was 86% in patients who received nelarabine and 78% in those who did not (P=0.024).

For the T-ALL patients who failed induction and were assigned to HD-MTX and nelarabine, the 4-year DFS rate was 55%.

Patients with T-LL did not benefit from the addition of nelarabine. The 4-year DFS rate was 85% in the nelarabine recipients and 89% in non-recipients (P=0.2788).

There were no significant differences in overall toxicity or peripheral neurotoxicity between the treatment arms.

Dr Dunsmore said the next step with this research will be to examine the implications and potential benefits of using nelarabine in treatment protocols that do not include cranial radiation.

Photo by Rhoda Baer

The National Comprehensive Cancer Network (NCCN) has released guidelines for patients with acute myeloid leukemia (AML).

The guidelines are intended to help patients make better informed decision about their care.

The guidelines explain what AML is, describe testing procedures and treatment options, and provide tips to help patients choose the best treatment.

The guidelines also include a list of suggested questions for patients to bring up with their doctors, illustrations, and a glossary of key terms and acronyms.

“People with AML often aren’t aware that this isn’t a single disease but many different diseases that share fundamental characteristics,” said Martin Tallman, MD, a hematologic oncologist at Memorial Sloan Kettering Cancer Center in New York, New York, and vice-chair of the NCCN Guidelines Panel for AML.

“The good news is that the future for AML is getting a lot brighter. After 40 years without much progress, 4 new medications were just approved last year*, and more new treatment courses are in development as we speak.”

The guidelines are available for free on the NCCN website or via the NCCN Patient Guides for Cancer app. Printed versions of the guidelines can be purchased at Amazon.com.

NCCN also has guidelines for patients with acute lymphoblastic leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, Hodgkin lymphoma, multiple myeloma, myelodysplastic syndromes, myeloproliferative neoplasms, non-Hodgkin lymphomas, and Waldenström’s macroglobulinemia, as well as solid tumor malignancies.

There are patient guidelines for adolescents and young adults with cancer and guidelines on distress/supportive care, and nausea and vomiting/supportive care as well.

*(1) Midostaurin (Rydapt) was approved for adults with newly diagnosed, FLT3-positive AML

(2) Gemtuzumab ozogamicin (Mylotarg) was approved for adults with newly diagnosed AML and patients age 2 and older with relapsed/refractory AML

(3) Liposomal daunorubicin/cytarabine (Vyxeos) was approved for AML with myelodysplasia-related changes and newly diagnosed, therapy-related AML

(4) Enasidenib (Idhifa) was approved for adults with relapsed/refractory AML and an IDH2 mutation.

Photo by Rhoda Baer

The National Comprehensive Cancer Network (NCCN) has released guidelines for patients with acute myeloid leukemia (AML).

The guidelines are intended to help patients make better informed decision about their care.

The guidelines explain what AML is, describe testing procedures and treatment options, and provide tips to help patients choose the best treatment.

The guidelines also include a list of suggested questions for patients to bring up with their doctors, illustrations, and a glossary of key terms and acronyms.

“People with AML often aren’t aware that this isn’t a single disease but many different diseases that share fundamental characteristics,” said Martin Tallman, MD, a hematologic oncologist at Memorial Sloan Kettering Cancer Center in New York, New York, and vice-chair of the NCCN Guidelines Panel for AML.

“The good news is that the future for AML is getting a lot brighter. After 40 years without much progress, 4 new medications were just approved last year*, and more new treatment courses are in development as we speak.”

The guidelines are available for free on the NCCN website or via the NCCN Patient Guides for Cancer app. Printed versions of the guidelines can be purchased at Amazon.com.

NCCN also has guidelines for patients with acute lymphoblastic leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, Hodgkin lymphoma, multiple myeloma, myelodysplastic syndromes, myeloproliferative neoplasms, non-Hodgkin lymphomas, and Waldenström’s macroglobulinemia, as well as solid tumor malignancies.

There are patient guidelines for adolescents and young adults with cancer and guidelines on distress/supportive care, and nausea and vomiting/supportive care as well.

*(1) Midostaurin (Rydapt) was approved for adults with newly diagnosed, FLT3-positive AML

(2) Gemtuzumab ozogamicin (Mylotarg) was approved for adults with newly diagnosed AML and patients age 2 and older with relapsed/refractory AML

(3) Liposomal daunorubicin/cytarabine (Vyxeos) was approved for AML with myelodysplasia-related changes and newly diagnosed, therapy-related AML

(4) Enasidenib (Idhifa) was approved for adults with relapsed/refractory AML and an IDH2 mutation.

Photo by Rhoda Baer

The National Comprehensive Cancer Network (NCCN) has released guidelines for patients with acute myeloid leukemia (AML).

The guidelines are intended to help patients make better informed decision about their care.

The guidelines explain what AML is, describe testing procedures and treatment options, and provide tips to help patients choose the best treatment.

The guidelines also include a list of suggested questions for patients to bring up with their doctors, illustrations, and a glossary of key terms and acronyms.

“People with AML often aren’t aware that this isn’t a single disease but many different diseases that share fundamental characteristics,” said Martin Tallman, MD, a hematologic oncologist at Memorial Sloan Kettering Cancer Center in New York, New York, and vice-chair of the NCCN Guidelines Panel for AML.

“The good news is that the future for AML is getting a lot brighter. After 40 years without much progress, 4 new medications were just approved last year*, and more new treatment courses are in development as we speak.”

The guidelines are available for free on the NCCN website or via the NCCN Patient Guides for Cancer app. Printed versions of the guidelines can be purchased at Amazon.com.

NCCN also has guidelines for patients with acute lymphoblastic leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, Hodgkin lymphoma, multiple myeloma, myelodysplastic syndromes, myeloproliferative neoplasms, non-Hodgkin lymphomas, and Waldenström’s macroglobulinemia, as well as solid tumor malignancies.

There are patient guidelines for adolescents and young adults with cancer and guidelines on distress/supportive care, and nausea and vomiting/supportive care as well.

*(1) Midostaurin (Rydapt) was approved for adults with newly diagnosed, FLT3-positive AML

(2) Gemtuzumab ozogamicin (Mylotarg) was approved for adults with newly diagnosed AML and patients age 2 and older with relapsed/refractory AML

(3) Liposomal daunorubicin/cytarabine (Vyxeos) was approved for AML with myelodysplasia-related changes and newly diagnosed, therapy-related AML

(4) Enasidenib (Idhifa) was approved for adults with relapsed/refractory AML and an IDH2 mutation.

With advances in the understanding of cellular pathways, molecular genetics, and immunology, new drugs for cancer are being released at an increasing rate. A variety of novel agents have recently become available for use, generating excitement for patients and oncologists. Keeping track of all of these new agents is increasingly challenging. This brief review will summarize some of the newest drugs, their indications, and benefits (see related article).

Therapies by tumor

Breast cancer

CDK4/6 inhibitors. The CDK4/6 inhibitor palbociclib was approved in 2015 for the treatment of estrogen-positive, HER2-negative advanced breast cancer, and this year, two more drugs in this class – ribociclib and abemaciclib – were approved for the treatment of hormone receptor–positive breast cancer.

Ribociclib (Kisqali) 600 mg daily (3 weeks on, 1 week off) is approved for use in combination with an aromatase inhibitor. In the study on which the approval was based, there was a response rate of 53% for patients in the study group, compared with 37% for those who received aromatase inhibitor alone (progression-free survival (PFS), not reached vs 14.7 months for single-agent aromatase inhibitor).¹ The occurrence of neutropenia seemed to be similar to that in patients receiving palbociclib. However, unlike with palbociclib, ribociclib requires ECG monitoring for QTc prolongation as well as monitoring of liver function tests.

Abemaciclib (Verzenio) has been approved in combination with fulvestrant as well as a monotherapy.² PFS was 16.4 months for abemaciclib (150 mg bid in combination with fulvestrant), compared with 9.3 months for fulvestrant alone, with corresponding response rates of 48% and 21%. As monotherapy, abemaciclib 200 mg bid had a response rate of 20% with a duration of response of 8.6 months.

Tyrosine kinase inhibitors. The tyrosine kinase inhibitor neratinib (Nerlynx) was approved for extended adjuvant treatment of HER2-positive breast cancer after 1 year of adjuvant trastuzumab.³ Given at 240 mg (6 tablets) daily for a year, compared with a no-treatment control arm, it demonstrated an improvement in invasive disease-free survival (DFS) at 2 years from 91.9% to 94.2%, with no difference in overall survival yet noted. It is associated with diarrhea and also requires hepatic function monitoring.
 

Acute myelogenous leukemia

Multiple new agents were recently approved for use in acute myelogenous leukemia (AML), after decades of slow advance in new drug development.

Midostaurin (Rydapt) is an FLT3 inhibitor approved for use in combination with daunorubicin and Ara-C (cytosine arabinoside) for newly diagnosed AML with FLT3 mutations, which occur in about 30% of AML patients.⁴ It is given orally on days 8-21 at 50 mg bid with induction and consolidation.

In the study on which the approval was based, there was a 10% improvement in overall survival for this subset of AML patients who have a typically a worse prognosis. Event-free survival in patients in the study group was 8.2 months, compared with 3 months in the control arm patients, who did not receive the agent. The drug was also approved for aggressive systemic mastocytosis.

Enasidenib (Idhifa) has been approved for AML with an IDH2 mutation in the refractory/relapsed settings.⁵IDH2 mutations are present in about 20% of patients with AML. Given orally at 100 mg daily as a single agent, enasidenib was associated with a 19% complete remission rate. Patients need to be monitored for differentiation syndrome, somewhat similar to what is seen with ATRA with acute promyelocytic leukemia.

Liposomal daunorubicin and cytarabine (Vyxeos) was approved for newly diagnosed therapy- or myelodysplasia-related AML.⁶ This novel liposomal formulation combines two standard agents and is given intravenously on days 1, 3 and 5 over 90 minutes as daunorubicin 44 mg/m² and cytarabine 100 mg/ m². (For a second induction and in lower dose on consolidation cycles, it is given only on days 1 and 3). The liposomal formulation achieved a superior complete response rate compared with the standard 7+3 daunorubicin plus cytarabine regimen (38% vs 26%, respectively) and longer overall survival (9.6 versus 5.9 months) in these generally poor prognosis subsets.

Gemtuzumab ozogamicin (Mylotarg) was initially approved in 2000 but withdrawn from use in 2010 after trials failed to confirm benefit and demonstrated safety concerns. It has now been re-released in a lower dose and schedule from its original label.⁷ This immunoconjugate of an anti-CD33 bound to calicheamicin is approved for CD33-positive AML. Given at 3 mg/m² on days 1, 4, and 7 in combination with standard daunorubicin–cytarabine induction chemotherapy, it improved event-free survival from 9.5 to 17.3 months. When administered as a single agent (6 mg/m² on day 1 and 3 mg/m² on day 8) in patients who were unable or unwilling to tolerate standard chemotherapy, it improved overall survival (4.9 months versus 3.6 months for best supportive care). As a single agent in relapsed AML, given at 3 mg/m² days 1, 4, and 7 and followed by cytarabine consolidation, it was associated with a 26% complete response rate, with a median relapse-free survival of 11.6 months.
 

Ovarian/fallopian tube cancers

PARP inhibitors. For patients with ovarian/fallopian tube cancer, there are new indications and agents for PARP inhibition, including for patients with BRCA mutations (both somatic and germline) and those without BRCA mutations.

Olaparib (Lynparza) was previously approved only in a fourth-line setting for germline BRCA-mutated patients with advanced ovarian cancer, with a response rate of 34% with a median duration of 7.9 months. Given at 300 mg orally bid, it is now approved for use in maintenance in recurrence after response to platinum-based chemotherapy after 2 or more lines of therapy regardless of BRCA status. In this setting, progression-free survival increased to 8.4 months, compared with 4.8 months for placebo.⁸

Rubicarib (Rubraca) is approved for BRCA-mutated patients (either germline or somatic) with advanced ovarian cancer after two or more lines of chemotherapy.⁹ At 600 mg orally bid, results from phase 2 trials noted a 54% response rate, with a median duration of 9.2 months.

Niraparib (Zejula) is approved for use in maintenance in recurrent epithelial ovarian, fallopian tube, and primary peritoneal cancers after platinum-based chemotherapy.¹⁰ In patients with germline BRCA mutations, niraparib at 300 mg orally daily resulted in a PFS of 21 months, compared with 5.5 months with placebo; PFS in patients with nongermline BRCA mutations was 9.3 versus 3.9 months, respectively.
 

Non-small cell lung cancer with EML-4 alk translocation

Crizotinib (Xalkori) has been the mainstay for treatment of for EML4-alk translocated non-small cell lung cancer. However, alectinib (Alcensa), previously for predominantly second-line use, seems more active than crizotinib in the first-line setting, particularly in the treatment and prevention of CNS metastases.

In addition, brigantinib (Alunbrig) has been approved for patients who are intolerant/refractory to crizotinib.¹¹ At 90 mg once daily for 7 days, then escalating to 180 mg daily, it was noted to have a 50% response rate in crizotinib failures, including in the CNS.
 

Ceritinib (Zykadia) was approved at 750 mg once daily for EML4 alk positive NSCLC.¹² In first line it had a response rate of 73% (versus 27% for chemotherapy) with a remission duration of 23.9 months (versus 11.1 months for chemotherapy).
 

Therapies by drug class

PD-1/PD-L1 antibodies

Anti-PD-1 antibodies nivolumab (Opdivo) and pembrolizumab (Keytruda) are widely used for a range of tumor types. Newer approvals for pembrolizumab are for adenocarcinoma of the stomach/gastro-esophageal junction with at least 1% PD-L1 expression, and in any tumor demonstrated to be MSI-high. Newer indications for nivolumab are for bladder cancer, MSI-high colon cancer, and for hepatoma previously treated with sorafenib. The anti-PD-L1 antibody atezolizumab (Tencentriq) is now approved for platinum-resistant metastatic lung cancer, in addition to platinum-ineligible and platinum-resistant urothelial cancer.

Avelumab (Bavencio) is an anti-PD-L1 approved for both Merkel cell and previously treated urothelial cancers at a dose of 10 mg/kg every 2 weeks.¹³ It demonstrated a 33% response rate for Merkel cell and a 16% response rate for urothelial cancer.

Durvalumab (Imfinzi) is another anti PD-L1 antibody approved at 10 mg/kg every 2 weeks for previously treated urothelial cancer with a 17% response rate (RR: PD-L1 high, 26%; low, 4%).¹⁴

PI3K kinase inhibitors

Copanlisib (Aliqopa) is a PI3K inhibitor approved for relapsed follicular lymphoma in patients who have progressed after two previous lines of therapy.¹⁵ It is a 60-mg, 1-hour infusion given on days 1, 8, and 15 every 28 days. In a phase 2 trial, it had a 59% response rate (14% complete response) and a median response duration of 12.2 months.

BTK inhibitors

Acalabruitnib (Calquence) is approved for adults with previously treated mantle cell lymphoma. In a phase 2 trial at 100 mg orally bid, it achieved an 80% overall and 40% complete response rate.¹⁶ These response rates are higher than were seen for ibrutinib in its original phase 2 trial. The spectrum of toxicities seems similar to ibruitinib and includes bleeding, cytopenias, infection, and atrial fibrillation.

CD19 CAR-T cells

Perhaps the most exciting and novel new agents are genetically engineered autologous T cells. Tisagenlecleucel (Kymriah), a chimeric antigen receptor T cell (CART) that targets CD19 is approved for refractory B cell precursor acute lymphoblastic leukemia (in patients under 25 years) where the complete response rate was 83% (including patients with incomplete blood count recovery).¹⁷



Axicabtagene ciloleucel (aci-cel; Yescarta), also CD19-directed CART, is approved for adults with relapsed or refractory non-Hodgkin lymphoma after two lines of previous therapy (specifically large-cell lymphoma, primary mediastinal large B-cell lymphoma, and transformed follicular lymphoma). Response rate was 72% (complete, 51%; partial, 21%), with a median duration of response of 9.2 months.¹⁸

With advances in the understanding of cellular pathways, molecular genetics, and immunology, new drugs for cancer are being released at an increasing rate. A variety of novel agents have recently become available for use, generating excitement for patients and oncologists. Keeping track of all of these new agents is increasingly challenging. This brief review will summarize some of the newest drugs, their indications, and benefits (see related article).

Therapies by tumor

Breast cancer

CDK4/6 inhibitors. The CDK4/6 inhibitor palbociclib was approved in 2015 for the treatment of estrogen-positive, HER2-negative advanced breast cancer, and this year, two more drugs in this class – ribociclib and abemaciclib – were approved for the treatment of hormone receptor–positive breast cancer.

Ribociclib (Kisqali) 600 mg daily (3 weeks on, 1 week off) is approved for use in combination with an aromatase inhibitor. In the study on which the approval was based, there was a response rate of 53% for patients in the study group, compared with 37% for those who received aromatase inhibitor alone (progression-free survival (PFS), not reached vs 14.7 months for single-agent aromatase inhibitor).¹ The occurrence of neutropenia seemed to be similar to that in patients receiving palbociclib. However, unlike with palbociclib, ribociclib requires ECG monitoring for QTc prolongation as well as monitoring of liver function tests.

Abemaciclib (Verzenio) has been approved in combination with fulvestrant as well as a monotherapy.² PFS was 16.4 months for abemaciclib (150 mg bid in combination with fulvestrant), compared with 9.3 months for fulvestrant alone, with corresponding response rates of 48% and 21%. As monotherapy, abemaciclib 200 mg bid had a response rate of 20% with a duration of response of 8.6 months.

Tyrosine kinase inhibitors. The tyrosine kinase inhibitor neratinib (Nerlynx) was approved for extended adjuvant treatment of HER2-positive breast cancer after 1 year of adjuvant trastuzumab.³ Given at 240 mg (6 tablets) daily for a year, compared with a no-treatment control arm, it demonstrated an improvement in invasive disease-free survival (DFS) at 2 years from 91.9% to 94.2%, with no difference in overall survival yet noted. It is associated with diarrhea and also requires hepatic function monitoring.
 

Acute myelogenous leukemia

Multiple new agents were recently approved for use in acute myelogenous leukemia (AML), after decades of slow advance in new drug development.

Midostaurin (Rydapt) is an FLT3 inhibitor approved for use in combination with daunorubicin and Ara-C (cytosine arabinoside) for newly diagnosed AML with FLT3 mutations, which occur in about 30% of AML patients.⁴ It is given orally on days 8-21 at 50 mg bid with induction and consolidation.

In the study on which the approval was based, there was a 10% improvement in overall survival for this subset of AML patients who have a typically a worse prognosis. Event-free survival in patients in the study group was 8.2 months, compared with 3 months in the control arm patients, who did not receive the agent. The drug was also approved for aggressive systemic mastocytosis.

Enasidenib (Idhifa) has been approved for AML with an IDH2 mutation in the refractory/relapsed settings.⁵IDH2 mutations are present in about 20% of patients with AML. Given orally at 100 mg daily as a single agent, enasidenib was associated with a 19% complete remission rate. Patients need to be monitored for differentiation syndrome, somewhat similar to what is seen with ATRA with acute promyelocytic leukemia.

Liposomal daunorubicin and cytarabine (Vyxeos) was approved for newly diagnosed therapy- or myelodysplasia-related AML.⁶ This novel liposomal formulation combines two standard agents and is given intravenously on days 1, 3 and 5 over 90 minutes as daunorubicin 44 mg/m² and cytarabine 100 mg/ m². (For a second induction and in lower dose on consolidation cycles, it is given only on days 1 and 3). The liposomal formulation achieved a superior complete response rate compared with the standard 7+3 daunorubicin plus cytarabine regimen (38% vs 26%, respectively) and longer overall survival (9.6 versus 5.9 months) in these generally poor prognosis subsets.

Gemtuzumab ozogamicin (Mylotarg) was initially approved in 2000 but withdrawn from use in 2010 after trials failed to confirm benefit and demonstrated safety concerns. It has now been re-released in a lower dose and schedule from its original label.⁷ This immunoconjugate of an anti-CD33 bound to calicheamicin is approved for CD33-positive AML. Given at 3 mg/m² on days 1, 4, and 7 in combination with standard daunorubicin–cytarabine induction chemotherapy, it improved event-free survival from 9.5 to 17.3 months. When administered as a single agent (6 mg/m² on day 1 and 3 mg/m² on day 8) in patients who were unable or unwilling to tolerate standard chemotherapy, it improved overall survival (4.9 months versus 3.6 months for best supportive care). As a single agent in relapsed AML, given at 3 mg/m² days 1, 4, and 7 and followed by cytarabine consolidation, it was associated with a 26% complete response rate, with a median relapse-free survival of 11.6 months.
 

Ovarian/fallopian tube cancers

PARP inhibitors. For patients with ovarian/fallopian tube cancer, there are new indications and agents for PARP inhibition, including for patients with BRCA mutations (both somatic and germline) and those without BRCA mutations.

Olaparib (Lynparza) was previously approved only in a fourth-line setting for germline BRCA-mutated patients with advanced ovarian cancer, with a response rate of 34% with a median duration of 7.9 months. Given at 300 mg orally bid, it is now approved for use in maintenance in recurrence after response to platinum-based chemotherapy after 2 or more lines of therapy regardless of BRCA status. In this setting, progression-free survival increased to 8.4 months, compared with 4.8 months for placebo.⁸

Rubicarib (Rubraca) is approved for BRCA-mutated patients (either germline or somatic) with advanced ovarian cancer after two or more lines of chemotherapy.⁹ At 600 mg orally bid, results from phase 2 trials noted a 54% response rate, with a median duration of 9.2 months.

Niraparib (Zejula) is approved for use in maintenance in recurrent epithelial ovarian, fallopian tube, and primary peritoneal cancers after platinum-based chemotherapy.¹⁰ In patients with germline BRCA mutations, niraparib at 300 mg orally daily resulted in a PFS of 21 months, compared with 5.5 months with placebo; PFS in patients with nongermline BRCA mutations was 9.3 versus 3.9 months, respectively.
 

Non-small cell lung cancer with EML-4 alk translocation

Crizotinib (Xalkori) has been the mainstay for treatment of for EML4-alk translocated non-small cell lung cancer. However, alectinib (Alcensa), previously for predominantly second-line use, seems more active than crizotinib in the first-line setting, particularly in the treatment and prevention of CNS metastases.

In addition, brigantinib (Alunbrig) has been approved for patients who are intolerant/refractory to crizotinib.¹¹ At 90 mg once daily for 7 days, then escalating to 180 mg daily, it was noted to have a 50% response rate in crizotinib failures, including in the CNS.
 

Ceritinib (Zykadia) was approved at 750 mg once daily for EML4 alk positive NSCLC.¹² In first line it had a response rate of 73% (versus 27% for chemotherapy) with a remission duration of 23.9 months (versus 11.1 months for chemotherapy).
 

Therapies by drug class

PD-1/PD-L1 antibodies

Anti-PD-1 antibodies nivolumab (Opdivo) and pembrolizumab (Keytruda) are widely used for a range of tumor types. Newer approvals for pembrolizumab are for adenocarcinoma of the stomach/gastro-esophageal junction with at least 1% PD-L1 expression, and in any tumor demonstrated to be MSI-high. Newer indications for nivolumab are for bladder cancer, MSI-high colon cancer, and for hepatoma previously treated with sorafenib. The anti-PD-L1 antibody atezolizumab (Tencentriq) is now approved for platinum-resistant metastatic lung cancer, in addition to platinum-ineligible and platinum-resistant urothelial cancer.

Avelumab (Bavencio) is an anti-PD-L1 approved for both Merkel cell and previously treated urothelial cancers at a dose of 10 mg/kg every 2 weeks.¹³ It demonstrated a 33% response rate for Merkel cell and a 16% response rate for urothelial cancer.

Durvalumab (Imfinzi) is another anti PD-L1 antibody approved at 10 mg/kg every 2 weeks for previously treated urothelial cancer with a 17% response rate (RR: PD-L1 high, 26%; low, 4%).¹⁴

PI3K kinase inhibitors

Copanlisib (Aliqopa) is a PI3K inhibitor approved for relapsed follicular lymphoma in patients who have progressed after two previous lines of therapy.¹⁵ It is a 60-mg, 1-hour infusion given on days 1, 8, and 15 every 28 days. In a phase 2 trial, it had a 59% response rate (14% complete response) and a median response duration of 12.2 months.

BTK inhibitors

Acalabruitnib (Calquence) is approved for adults with previously treated mantle cell lymphoma. In a phase 2 trial at 100 mg orally bid, it achieved an 80% overall and 40% complete response rate.¹⁶ These response rates are higher than were seen for ibrutinib in its original phase 2 trial. The spectrum of toxicities seems similar to ibruitinib and includes bleeding, cytopenias, infection, and atrial fibrillation.

CD19 CAR-T cells

Perhaps the most exciting and novel new agents are genetically engineered autologous T cells. Tisagenlecleucel (Kymriah), a chimeric antigen receptor T cell (CART) that targets CD19 is approved for refractory B cell precursor acute lymphoblastic leukemia (in patients under 25 years) where the complete response rate was 83% (including patients with incomplete blood count recovery).¹⁷



Axicabtagene ciloleucel (aci-cel; Yescarta), also CD19-directed CART, is approved for adults with relapsed or refractory non-Hodgkin lymphoma after two lines of previous therapy (specifically large-cell lymphoma, primary mediastinal large B-cell lymphoma, and transformed follicular lymphoma). Response rate was 72% (complete, 51%; partial, 21%), with a median duration of response of 9.2 months.¹⁸

With advances in the understanding of cellular pathways, molecular genetics, and immunology, new drugs for cancer are being released at an increasing rate. A variety of novel agents have recently become available for use, generating excitement for patients and oncologists. Keeping track of all of these new agents is increasingly challenging. This brief review will summarize some of the newest drugs, their indications, and benefits (see related article).

Therapies by tumor

Breast cancer

CDK4/6 inhibitors. The CDK4/6 inhibitor palbociclib was approved in 2015 for the treatment of estrogen-positive, HER2-negative advanced breast cancer, and this year, two more drugs in this class – ribociclib and abemaciclib – were approved for the treatment of hormone receptor–positive breast cancer.

Ribociclib (Kisqali) 600 mg daily (3 weeks on, 1 week off) is approved for use in combination with an aromatase inhibitor. In the study on which the approval was based, there was a response rate of 53% for patients in the study group, compared with 37% for those who received aromatase inhibitor alone (progression-free survival (PFS), not reached vs 14.7 months for single-agent aromatase inhibitor).¹ The occurrence of neutropenia seemed to be similar to that in patients receiving palbociclib. However, unlike with palbociclib, ribociclib requires ECG monitoring for QTc prolongation as well as monitoring of liver function tests.

Abemaciclib (Verzenio) has been approved in combination with fulvestrant as well as a monotherapy.² PFS was 16.4 months for abemaciclib (150 mg bid in combination with fulvestrant), compared with 9.3 months for fulvestrant alone, with corresponding response rates of 48% and 21%. As monotherapy, abemaciclib 200 mg bid had a response rate of 20% with a duration of response of 8.6 months.

Tyrosine kinase inhibitors. The tyrosine kinase inhibitor neratinib (Nerlynx) was approved for extended adjuvant treatment of HER2-positive breast cancer after 1 year of adjuvant trastuzumab.³ Given at 240 mg (6 tablets) daily for a year, compared with a no-treatment control arm, it demonstrated an improvement in invasive disease-free survival (DFS) at 2 years from 91.9% to 94.2%, with no difference in overall survival yet noted. It is associated with diarrhea and also requires hepatic function monitoring.
 

Acute myelogenous leukemia

Multiple new agents were recently approved for use in acute myelogenous leukemia (AML), after decades of slow advance in new drug development.

Midostaurin (Rydapt) is an FLT3 inhibitor approved for use in combination with daunorubicin and Ara-C (cytosine arabinoside) for newly diagnosed AML with FLT3 mutations, which occur in about 30% of AML patients.⁴ It is given orally on days 8-21 at 50 mg bid with induction and consolidation.

In the study on which the approval was based, there was a 10% improvement in overall survival for this subset of AML patients who have a typically a worse prognosis. Event-free survival in patients in the study group was 8.2 months, compared with 3 months in the control arm patients, who did not receive the agent. The drug was also approved for aggressive systemic mastocytosis.

Enasidenib (Idhifa) has been approved for AML with an IDH2 mutation in the refractory/relapsed settings.⁵IDH2 mutations are present in about 20% of patients with AML. Given orally at 100 mg daily as a single agent, enasidenib was associated with a 19% complete remission rate. Patients need to be monitored for differentiation syndrome, somewhat similar to what is seen with ATRA with acute promyelocytic leukemia.

Liposomal daunorubicin and cytarabine (Vyxeos) was approved for newly diagnosed therapy- or myelodysplasia-related AML.⁶ This novel liposomal formulation combines two standard agents and is given intravenously on days 1, 3 and 5 over 90 minutes as daunorubicin 44 mg/m² and cytarabine 100 mg/ m². (For a second induction and in lower dose on consolidation cycles, it is given only on days 1 and 3). The liposomal formulation achieved a superior complete response rate compared with the standard 7+3 daunorubicin plus cytarabine regimen (38% vs 26%, respectively) and longer overall survival (9.6 versus 5.9 months) in these generally poor prognosis subsets.

Gemtuzumab ozogamicin (Mylotarg) was initially approved in 2000 but withdrawn from use in 2010 after trials failed to confirm benefit and demonstrated safety concerns. It has now been re-released in a lower dose and schedule from its original label.⁷ This immunoconjugate of an anti-CD33 bound to calicheamicin is approved for CD33-positive AML. Given at 3 mg/m² on days 1, 4, and 7 in combination with standard daunorubicin–cytarabine induction chemotherapy, it improved event-free survival from 9.5 to 17.3 months. When administered as a single agent (6 mg/m² on day 1 and 3 mg/m² on day 8) in patients who were unable or unwilling to tolerate standard chemotherapy, it improved overall survival (4.9 months versus 3.6 months for best supportive care). As a single agent in relapsed AML, given at 3 mg/m² days 1, 4, and 7 and followed by cytarabine consolidation, it was associated with a 26% complete response rate, with a median relapse-free survival of 11.6 months.
 

Ovarian/fallopian tube cancers

PARP inhibitors. For patients with ovarian/fallopian tube cancer, there are new indications and agents for PARP inhibition, including for patients with BRCA mutations (both somatic and germline) and those without BRCA mutations.

Olaparib (Lynparza) was previously approved only in a fourth-line setting for germline BRCA-mutated patients with advanced ovarian cancer, with a response rate of 34% with a median duration of 7.9 months. Given at 300 mg orally bid, it is now approved for use in maintenance in recurrence after response to platinum-based chemotherapy after 2 or more lines of therapy regardless of BRCA status. In this setting, progression-free survival increased to 8.4 months, compared with 4.8 months for placebo.⁸

Rubicarib (Rubraca) is approved for BRCA-mutated patients (either germline or somatic) with advanced ovarian cancer after two or more lines of chemotherapy.⁹ At 600 mg orally bid, results from phase 2 trials noted a 54% response rate, with a median duration of 9.2 months.

Niraparib (Zejula) is approved for use in maintenance in recurrent epithelial ovarian, fallopian tube, and primary peritoneal cancers after platinum-based chemotherapy.¹⁰ In patients with germline BRCA mutations, niraparib at 300 mg orally daily resulted in a PFS of 21 months, compared with 5.5 months with placebo; PFS in patients with nongermline BRCA mutations was 9.3 versus 3.9 months, respectively.
 

Non-small cell lung cancer with EML-4 alk translocation

Crizotinib (Xalkori) has been the mainstay for treatment of for EML4-alk translocated non-small cell lung cancer. However, alectinib (Alcensa), previously for predominantly second-line use, seems more active than crizotinib in the first-line setting, particularly in the treatment and prevention of CNS metastases.

In addition, brigantinib (Alunbrig) has been approved for patients who are intolerant/refractory to crizotinib.¹¹ At 90 mg once daily for 7 days, then escalating to 180 mg daily, it was noted to have a 50% response rate in crizotinib failures, including in the CNS.
 

Ceritinib (Zykadia) was approved at 750 mg once daily for EML4 alk positive NSCLC.¹² In first line it had a response rate of 73% (versus 27% for chemotherapy) with a remission duration of 23.9 months (versus 11.1 months for chemotherapy).
 

Therapies by drug class

PD-1/PD-L1 antibodies

Anti-PD-1 antibodies nivolumab (Opdivo) and pembrolizumab (Keytruda) are widely used for a range of tumor types. Newer approvals for pembrolizumab are for adenocarcinoma of the stomach/gastro-esophageal junction with at least 1% PD-L1 expression, and in any tumor demonstrated to be MSI-high. Newer indications for nivolumab are for bladder cancer, MSI-high colon cancer, and for hepatoma previously treated with sorafenib. The anti-PD-L1 antibody atezolizumab (Tencentriq) is now approved for platinum-resistant metastatic lung cancer, in addition to platinum-ineligible and platinum-resistant urothelial cancer.

Avelumab (Bavencio) is an anti-PD-L1 approved for both Merkel cell and previously treated urothelial cancers at a dose of 10 mg/kg every 2 weeks.¹³ It demonstrated a 33% response rate for Merkel cell and a 16% response rate for urothelial cancer.

Durvalumab (Imfinzi) is another anti PD-L1 antibody approved at 10 mg/kg every 2 weeks for previously treated urothelial cancer with a 17% response rate (RR: PD-L1 high, 26%; low, 4%).¹⁴

PI3K kinase inhibitors

Copanlisib (Aliqopa) is a PI3K inhibitor approved for relapsed follicular lymphoma in patients who have progressed after two previous lines of therapy.¹⁵ It is a 60-mg, 1-hour infusion given on days 1, 8, and 15 every 28 days. In a phase 2 trial, it had a 59% response rate (14% complete response) and a median response duration of 12.2 months.

BTK inhibitors

Acalabruitnib (Calquence) is approved for adults with previously treated mantle cell lymphoma. In a phase 2 trial at 100 mg orally bid, it achieved an 80% overall and 40% complete response rate.¹⁶ These response rates are higher than were seen for ibrutinib in its original phase 2 trial. The spectrum of toxicities seems similar to ibruitinib and includes bleeding, cytopenias, infection, and atrial fibrillation.

CD19 CAR-T cells

Perhaps the most exciting and novel new agents are genetically engineered autologous T cells. Tisagenlecleucel (Kymriah), a chimeric antigen receptor T cell (CART) that targets CD19 is approved for refractory B cell precursor acute lymphoblastic leukemia (in patients under 25 years) where the complete response rate was 83% (including patients with incomplete blood count recovery).¹⁷



Axicabtagene ciloleucel (aci-cel; Yescarta), also CD19-directed CART, is approved for adults with relapsed or refractory non-Hodgkin lymphoma after two lines of previous therapy (specifically large-cell lymphoma, primary mediastinal large B-cell lymphoma, and transformed follicular lymphoma). Response rate was 72% (complete, 51%; partial, 21%), with a median duration of response of 9.2 months.¹⁸

Photo by Daniel Gay

A group of scientists and activists are calling on the World Health Organization (WHO) to fight the spread of human T-cell leukemia virus subtype 1 (HTLV-1).

The group has written a letter to the WHO highlighting the global prevalence of HTLV-1 infection and recommending strategies to prevent the transmission of HTLV-1.

An abbreviated version of the letter was published in The Lancet. The full letter is available on the Global Virus Network (GVN)* website.

“Since my colleagues and I discovered HTLV-1 . . ., we have learned that this destructive and lethal virus is causing much devastation in communities with high prevalence,” said Robert C. Gallo, MD, co-founder and director of GVN and a professor at the University of Maryland School of Medicine in Baltimore.

“During the GVN meeting last September, I was astounded to learn of the hyper-endemic numbers in the Aboriginal population of Australia. HTLV-1 is endemic in other regions, including several islands of the Caribbean, and in countries such as Brazil, Iran, Japan, and Peru. We hope that the WHO will agree with us and begin to take action in promoting prevention strategies against HTLV-1.”

HTLV-1 prevalence

In their letter, Dr Gallo and his colleagues cite statistics of HTLV-1 prevalence around the world.

The authors note that, in a hospital-based cohort study conducted in Central Australia, 33.6% of Indigenous people tested HTLV-1 positive, with the incidence rate reaching 48.5% in older men.

Research has suggested that, in Brazil, the HTLV-1 prevalence rate is 1.8% in the general population, 1.3% in blood donors in certain regions, and 1.05% in pregnant women.

It is estimated that nearly 1 million people are HTLV-1-positive in Japan, and 850,000 to 1.7 million people in Nigeria are infected with the virus.

In Gabon, the HTLV-1 prevalence in adults is believed to be 5% to 10%. And in Central African Republic, 7% of older, female Pygmies in the southern region were found to be infected with HTLV-1.

Studies have indicated that 6.1% of the general population in Jamaica is positive for HTLV-1, and other Caribbean islands have similar prevalence rates.

The authors note that HTLV-1 and -2 have also been detected in non-endemic areas due to migration and sexual transmission.

It is estimated that 20,000 to 30,000 people are infected with HTLV-1 in the UK, and 10,000 to 25,000 people are infected in metropolitan France.

Other estimates suggest that 266,000 people are infected with HTLV-1 or -2 in the US, and 3600 people with HTLV-1 associated myelopathy/tropical spastic paraparesis (HAM/TSP) remain undiagnosed.

“The general neglect, globally, of the importance of HTLV-1 as a sexually transmitted infection that causes a range of debilitating inflammatory diseases does our patients, who request a sexual health screen, a disservice,” said Graham P. Taylor, MDMB, DSc, a professor at Imperial College London in the UK.

“It is also important to recognize the importance of mother-to-child transmission of HTLV-1 in the development of adult T-cell leukemia/lymphoma (ATLL) decades later. Despite the availability of highly sensitive and specific diagnostic tests for infection and a proven intervention, except for Japan, there are no antenatal screening programs. Evaluating the cost-effectiveness of such programs should now be a priority.”

“To prevent mother-to-child infection, the Japanese government has been offering HTLV-1 screening for all pregnant women without cost,” noted Yoshi Yamano, MD, PhD, a professor at St. Marianna University School of Medicine in Kawasaki, Japan.

“Taking a leadership role to promote research, it also provides grants for clinical trials and patient registries focused on ATLL and HAM/TSP.”

Preventing transmission

The letter outlines 5 strategies to prevent or reduce transmission of HTLV-1. The authors recommend:

1. Protecting the sexually active population with routine HTLV-1 testing in sexual health clinics and through promotion of CMPC—Counsel & Monitor HTLV-1-positive patients, notify Partners, and promote Condom usage
2. Protecting blood and organ donors and recipients by testing for HTLV, avoiding use of products that may be infected, and promoting CMPC
3. Protecting mothers, babies, and fathers via routine antenatal care testing, advising HTLV-1-positive mothers against breastfeeding (when feasible), and promoting CMPC
4. Protecting injectable drug users by promoting HTLV-1 testing, providing safe needles through needle exchange program, and promoting CMPC
5. Supporting the general population and healthcare providers by providing access to an up-to-date WHO HTLV-1 Fact Sheet that can help healthcare providers diagnose HTLV-1 and related diseases and help patients protect themselves from HTLV-1.

“This virus has been underestimated since the time of its discovery perhaps because it is restricted to certain regions or because it is not terribly infectious,” said William Hall, MD, PhD, co-founder of GVN and a professor at the University College Dublin in Ireland.

“However, for decades, it has been known that HTLV-1 is highly carcinogenic and causes severe paralytic neurologic disease and immune disorders that can lead to bacterial infections. It is time that the WHO publicize prevention strategies against this devastating virus.”

*GVN is an international coalition of medical virologists dedicated to identifying, researching, fighting, and preventing current and emerging pandemic viruses that pose a threat to public health.

Photo by Daniel Gay

A group of scientists and activists are calling on the World Health Organization (WHO) to fight the spread of human T-cell leukemia virus subtype 1 (HTLV-1).

The group has written a letter to the WHO highlighting the global prevalence of HTLV-1 infection and recommending strategies to prevent the transmission of HTLV-1.

An abbreviated version of the letter was published in The Lancet. The full letter is available on the Global Virus Network (GVN)* website.

“Since my colleagues and I discovered HTLV-1 . . ., we have learned that this destructive and lethal virus is causing much devastation in communities with high prevalence,” said Robert C. Gallo, MD, co-founder and director of GVN and a professor at the University of Maryland School of Medicine in Baltimore.

“During the GVN meeting last September, I was astounded to learn of the hyper-endemic numbers in the Aboriginal population of Australia. HTLV-1 is endemic in other regions, including several islands of the Caribbean, and in countries such as Brazil, Iran, Japan, and Peru. We hope that the WHO will agree with us and begin to take action in promoting prevention strategies against HTLV-1.”

HTLV-1 prevalence

In their letter, Dr Gallo and his colleagues cite statistics of HTLV-1 prevalence around the world.

The authors note that, in a hospital-based cohort study conducted in Central Australia, 33.6% of Indigenous people tested HTLV-1 positive, with the incidence rate reaching 48.5% in older men.

Research has suggested that, in Brazil, the HTLV-1 prevalence rate is 1.8% in the general population, 1.3% in blood donors in certain regions, and 1.05% in pregnant women.

It is estimated that nearly 1 million people are HTLV-1-positive in Japan, and 850,000 to 1.7 million people in Nigeria are infected with the virus.

In Gabon, the HTLV-1 prevalence in adults is believed to be 5% to 10%. And in Central African Republic, 7% of older, female Pygmies in the southern region were found to be infected with HTLV-1.

Studies have indicated that 6.1% of the general population in Jamaica is positive for HTLV-1, and other Caribbean islands have similar prevalence rates.

The authors note that HTLV-1 and -2 have also been detected in non-endemic areas due to migration and sexual transmission.

It is estimated that 20,000 to 30,000 people are infected with HTLV-1 in the UK, and 10,000 to 25,000 people are infected in metropolitan France.

Other estimates suggest that 266,000 people are infected with HTLV-1 or -2 in the US, and 3600 people with HTLV-1 associated myelopathy/tropical spastic paraparesis (HAM/TSP) remain undiagnosed.

“The general neglect, globally, of the importance of HTLV-1 as a sexually transmitted infection that causes a range of debilitating inflammatory diseases does our patients, who request a sexual health screen, a disservice,” said Graham P. Taylor, MDMB, DSc, a professor at Imperial College London in the UK.

“It is also important to recognize the importance of mother-to-child transmission of HTLV-1 in the development of adult T-cell leukemia/lymphoma (ATLL) decades later. Despite the availability of highly sensitive and specific diagnostic tests for infection and a proven intervention, except for Japan, there are no antenatal screening programs. Evaluating the cost-effectiveness of such programs should now be a priority.”

“To prevent mother-to-child infection, the Japanese government has been offering HTLV-1 screening for all pregnant women without cost,” noted Yoshi Yamano, MD, PhD, a professor at St. Marianna University School of Medicine in Kawasaki, Japan.

“Taking a leadership role to promote research, it also provides grants for clinical trials and patient registries focused on ATLL and HAM/TSP.”

Preventing transmission

The letter outlines 5 strategies to prevent or reduce transmission of HTLV-1. The authors recommend:

1. Protecting the sexually active population with routine HTLV-1 testing in sexual health clinics and through promotion of CMPC—Counsel & Monitor HTLV-1-positive patients, notify Partners, and promote Condom usage
2. Protecting blood and organ donors and recipients by testing for HTLV, avoiding use of products that may be infected, and promoting CMPC
3. Protecting mothers, babies, and fathers via routine antenatal care testing, advising HTLV-1-positive mothers against breastfeeding (when feasible), and promoting CMPC
4. Protecting injectable drug users by promoting HTLV-1 testing, providing safe needles through needle exchange program, and promoting CMPC
5. Supporting the general population and healthcare providers by providing access to an up-to-date WHO HTLV-1 Fact Sheet that can help healthcare providers diagnose HTLV-1 and related diseases and help patients protect themselves from HTLV-1.

“This virus has been underestimated since the time of its discovery perhaps because it is restricted to certain regions or because it is not terribly infectious,” said William Hall, MD, PhD, co-founder of GVN and a professor at the University College Dublin in Ireland.

“However, for decades, it has been known that HTLV-1 is highly carcinogenic and causes severe paralytic neurologic disease and immune disorders that can lead to bacterial infections. It is time that the WHO publicize prevention strategies against this devastating virus.”

*GVN is an international coalition of medical virologists dedicated to identifying, researching, fighting, and preventing current and emerging pandemic viruses that pose a threat to public health.

Photo by Daniel Gay

A group of scientists and activists are calling on the World Health Organization (WHO) to fight the spread of human T-cell leukemia virus subtype 1 (HTLV-1).

The group has written a letter to the WHO highlighting the global prevalence of HTLV-1 infection and recommending strategies to prevent the transmission of HTLV-1.

An abbreviated version of the letter was published in The Lancet. The full letter is available on the Global Virus Network (GVN)* website.

“Since my colleagues and I discovered HTLV-1 . . ., we have learned that this destructive and lethal virus is causing much devastation in communities with high prevalence,” said Robert C. Gallo, MD, co-founder and director of GVN and a professor at the University of Maryland School of Medicine in Baltimore.

“During the GVN meeting last September, I was astounded to learn of the hyper-endemic numbers in the Aboriginal population of Australia. HTLV-1 is endemic in other regions, including several islands of the Caribbean, and in countries such as Brazil, Iran, Japan, and Peru. We hope that the WHO will agree with us and begin to take action in promoting prevention strategies against HTLV-1.”

HTLV-1 prevalence

In their letter, Dr Gallo and his colleagues cite statistics of HTLV-1 prevalence around the world.

The authors note that, in a hospital-based cohort study conducted in Central Australia, 33.6% of Indigenous people tested HTLV-1 positive, with the incidence rate reaching 48.5% in older men.

Research has suggested that, in Brazil, the HTLV-1 prevalence rate is 1.8% in the general population, 1.3% in blood donors in certain regions, and 1.05% in pregnant women.

It is estimated that nearly 1 million people are HTLV-1-positive in Japan, and 850,000 to 1.7 million people in Nigeria are infected with the virus.

In Gabon, the HTLV-1 prevalence in adults is believed to be 5% to 10%. And in Central African Republic, 7% of older, female Pygmies in the southern region were found to be infected with HTLV-1.

Studies have indicated that 6.1% of the general population in Jamaica is positive for HTLV-1, and other Caribbean islands have similar prevalence rates.

The authors note that HTLV-1 and -2 have also been detected in non-endemic areas due to migration and sexual transmission.

It is estimated that 20,000 to 30,000 people are infected with HTLV-1 in the UK, and 10,000 to 25,000 people are infected in metropolitan France.

Other estimates suggest that 266,000 people are infected with HTLV-1 or -2 in the US, and 3600 people with HTLV-1 associated myelopathy/tropical spastic paraparesis (HAM/TSP) remain undiagnosed.

“The general neglect, globally, of the importance of HTLV-1 as a sexually transmitted infection that causes a range of debilitating inflammatory diseases does our patients, who request a sexual health screen, a disservice,” said Graham P. Taylor, MDMB, DSc, a professor at Imperial College London in the UK.

“It is also important to recognize the importance of mother-to-child transmission of HTLV-1 in the development of adult T-cell leukemia/lymphoma (ATLL) decades later. Despite the availability of highly sensitive and specific diagnostic tests for infection and a proven intervention, except for Japan, there are no antenatal screening programs. Evaluating the cost-effectiveness of such programs should now be a priority.”

“To prevent mother-to-child infection, the Japanese government has been offering HTLV-1 screening for all pregnant women without cost,” noted Yoshi Yamano, MD, PhD, a professor at St. Marianna University School of Medicine in Kawasaki, Japan.

“Taking a leadership role to promote research, it also provides grants for clinical trials and patient registries focused on ATLL and HAM/TSP.”

Preventing transmission

The letter outlines 5 strategies to prevent or reduce transmission of HTLV-1. The authors recommend:

1. Protecting the sexually active population with routine HTLV-1 testing in sexual health clinics and through promotion of CMPC—Counsel & Monitor HTLV-1-positive patients, notify Partners, and promote Condom usage
2. Protecting blood and organ donors and recipients by testing for HTLV, avoiding use of products that may be infected, and promoting CMPC
3. Protecting mothers, babies, and fathers via routine antenatal care testing, advising HTLV-1-positive mothers against breastfeeding (when feasible), and promoting CMPC
4. Protecting injectable drug users by promoting HTLV-1 testing, providing safe needles through needle exchange program, and promoting CMPC
5. Supporting the general population and healthcare providers by providing access to an up-to-date WHO HTLV-1 Fact Sheet that can help healthcare providers diagnose HTLV-1 and related diseases and help patients protect themselves from HTLV-1.

“This virus has been underestimated since the time of its discovery perhaps because it is restricted to certain regions or because it is not terribly infectious,” said William Hall, MD, PhD, co-founder of GVN and a professor at the University College Dublin in Ireland.

“However, for decades, it has been known that HTLV-1 is highly carcinogenic and causes severe paralytic neurologic disease and immune disorders that can lead to bacterial infections. It is time that the WHO publicize prevention strategies against this devastating virus.”

*GVN is an international coalition of medical virologists dedicated to identifying, researching, fighting, and preventing current and emerging pandemic viruses that pose a threat to public health.

PITTSBURGH – In the current era, children with Down syndrome who have standard risk B-cell precursor acute lymphoblastic leukemia have event-free and overall survival rates nearly as good as those of other children with standard-risk B–ALL, results of a Children’s Oncology Group study show.

Among 5,311 children enrolled in the COG AALL0331 trial, a study of combination chemotherapy for young patients with newly diagnosed ALL, the 5-year event-free survival (EFS) rate for children with Down syndrome was 86%, compared with 89% for children without Down syndrome (P = .025).

Neil Osterweil/MDedge News

At the end of induction, patients who were judged to be standard-risk average were then randomized in a 2x2 design to either standard or intensified consolidation, and to standard interim maintenance with delayed intensification, or to intensified interim maintenance with delayed intensification.

The intensified interim maintenance with delayed intensification randomization was closed in 2008 because of superior results with escalating intravenous methotrexate during interim maintenance for standard-risk ALL patients treated in the CCG 1991 trial. Subsequently, all patients enrolled in AALL0331 received escalating intravenous methotrexate during interim maintenance.

Also in AALL0331, patients with Down syndrome who had standard-high ALL were given intensified consolidation and a single vs. double intensified interim maintenance with delayed intensification; patients without Down syndrome and standard risk high received the double intensified interim maintenance regimen.

Standard-risk low Down syndrome patients and non–Down syndrome patients participated in a randomization to additional pegaspargase doses during consolidation and interim maintenance.

There were no significant differences between patients with or without Down syndrome in the proportion of either rapid or slow early responses. Significantly fewer patients with Down syndrome had standard-risk low disease, and significantly more had average or high-risk disease.

Patients with Down syndrome initially had 11.5% excess risk for death during induction, but following additional treatment modifications, the excess risk decreased to 1.7%.

Among patients with Down syndrome, one died during intensive consolidation, and two died during delayed intensification. All three deaths were due to infections. No patients with Down syndrome died during maintenance.

Patients with Down syndrome also had a significantly increased risk for infection during induction (P less than .0001).

For patients with standard-risk low disease, 5-year EFS was 100% for those with Down syndrome, compared with 95.35% for patients without. Respective rates for standard risk average and high disease were 88.07% vs. 89.63%. and 82.35% vs. 86.18%.

Down syndrome was not an independent risk factor for survival in multivariate analyses accounting for risk group, Dr. Maloney said.

COG AALL0331 was supported by the National Cancer Institute. Dr. Maloney reported having no financial disclosures.

SOURCE: Maloney K et al. ASPHO 2018, Abstract PP 2001.

PITTSBURGH – In the current era, children with Down syndrome who have standard risk B-cell precursor acute lymphoblastic leukemia have event-free and overall survival rates nearly as good as those of other children with standard-risk B–ALL, results of a Children’s Oncology Group study show.

Among 5,311 children enrolled in the COG AALL0331 trial, a study of combination chemotherapy for young patients with newly diagnosed ALL, the 5-year event-free survival (EFS) rate for children with Down syndrome was 86%, compared with 89% for children without Down syndrome (P = .025).

Neil Osterweil/MDedge News

At the end of induction, patients who were judged to be standard-risk average were then randomized in a 2x2 design to either standard or intensified consolidation, and to standard interim maintenance with delayed intensification, or to intensified interim maintenance with delayed intensification.

The intensified interim maintenance with delayed intensification randomization was closed in 2008 because of superior results with escalating intravenous methotrexate during interim maintenance for standard-risk ALL patients treated in the CCG 1991 trial. Subsequently, all patients enrolled in AALL0331 received escalating intravenous methotrexate during interim maintenance.

Also in AALL0331, patients with Down syndrome who had standard-high ALL were given intensified consolidation and a single vs. double intensified interim maintenance with delayed intensification; patients without Down syndrome and standard risk high received the double intensified interim maintenance regimen.

Standard-risk low Down syndrome patients and non–Down syndrome patients participated in a randomization to additional pegaspargase doses during consolidation and interim maintenance.

There were no significant differences between patients with or without Down syndrome in the proportion of either rapid or slow early responses. Significantly fewer patients with Down syndrome had standard-risk low disease, and significantly more had average or high-risk disease.

Patients with Down syndrome initially had 11.5% excess risk for death during induction, but following additional treatment modifications, the excess risk decreased to 1.7%.

Among patients with Down syndrome, one died during intensive consolidation, and two died during delayed intensification. All three deaths were due to infections. No patients with Down syndrome died during maintenance.

Patients with Down syndrome also had a significantly increased risk for infection during induction (P less than .0001).

For patients with standard-risk low disease, 5-year EFS was 100% for those with Down syndrome, compared with 95.35% for patients without. Respective rates for standard risk average and high disease were 88.07% vs. 89.63%. and 82.35% vs. 86.18%.

Down syndrome was not an independent risk factor for survival in multivariate analyses accounting for risk group, Dr. Maloney said.

COG AALL0331 was supported by the National Cancer Institute. Dr. Maloney reported having no financial disclosures.

SOURCE: Maloney K et al. ASPHO 2018, Abstract PP 2001.

PITTSBURGH – In the current era, children with Down syndrome who have standard risk B-cell precursor acute lymphoblastic leukemia have event-free and overall survival rates nearly as good as those of other children with standard-risk B–ALL, results of a Children’s Oncology Group study show.

Among 5,311 children enrolled in the COG AALL0331 trial, a study of combination chemotherapy for young patients with newly diagnosed ALL, the 5-year event-free survival (EFS) rate for children with Down syndrome was 86%, compared with 89% for children without Down syndrome (P = .025).

Neil Osterweil/MDedge News

At the end of induction, patients who were judged to be standard-risk average were then randomized in a 2x2 design to either standard or intensified consolidation, and to standard interim maintenance with delayed intensification, or to intensified interim maintenance with delayed intensification.

The intensified interim maintenance with delayed intensification randomization was closed in 2008 because of superior results with escalating intravenous methotrexate during interim maintenance for standard-risk ALL patients treated in the CCG 1991 trial. Subsequently, all patients enrolled in AALL0331 received escalating intravenous methotrexate during interim maintenance.

Also in AALL0331, patients with Down syndrome who had standard-high ALL were given intensified consolidation and a single vs. double intensified interim maintenance with delayed intensification; patients without Down syndrome and standard risk high received the double intensified interim maintenance regimen.

Standard-risk low Down syndrome patients and non–Down syndrome patients participated in a randomization to additional pegaspargase doses during consolidation and interim maintenance.

There were no significant differences between patients with or without Down syndrome in the proportion of either rapid or slow early responses. Significantly fewer patients with Down syndrome had standard-risk low disease, and significantly more had average or high-risk disease.

Patients with Down syndrome initially had 11.5% excess risk for death during induction, but following additional treatment modifications, the excess risk decreased to 1.7%.

Among patients with Down syndrome, one died during intensive consolidation, and two died during delayed intensification. All three deaths were due to infections. No patients with Down syndrome died during maintenance.

Patients with Down syndrome also had a significantly increased risk for infection during induction (P less than .0001).

For patients with standard-risk low disease, 5-year EFS was 100% for those with Down syndrome, compared with 95.35% for patients without. Respective rates for standard risk average and high disease were 88.07% vs. 89.63%. and 82.35% vs. 86.18%.

Down syndrome was not an independent risk factor for survival in multivariate analyses accounting for risk group, Dr. Maloney said.

COG AALL0331 was supported by the National Cancer Institute. Dr. Maloney reported having no financial disclosures.

SOURCE: Maloney K et al. ASPHO 2018, Abstract PP 2001.

Single-agent ibrutinib has had sustained efficacy and a rate of complete response that has increased over time, according to a 5-year follow-up report including 132 patients with chronic lymphocytic leukemia (CLL).

Efficacy has been maintained in both treatment-naive and relapsed/refractory CLL, despite the presence of high-risk genomic features in many patients, investigators reported in Blood.

Treatment has been well tolerated, and the occurrence of severe adverse events has diminished over time, according to Susan M. O’Brien, MD, of the Chao Family Comprehensive Cancer Center, University of California, Irvine, and her colleagues.

“The safety profile of ibrutinib over time remains acceptable and manageable, allowing almost one-half of the patients (48%) to be treated for more than 4 years and thus maximize response,” the investigators wrote.

The report was based on 5-year follow-up of patients with CLL who had been enrolled in a phase 1b/2 study (PCYC-1102) and an extension study (PCYC-1103). A total of 132 patients were evaluated, including 101 with relapsed/refractory disease and 31 who were treatment naive.

The overall response rate remained high, at 89% in this 5-year follow-up. Complete response rates increased over time, reaching 29% in treatment-naive patients and 10% in relapsed/refractory patients. In a previous report on 3-year follow-up for these patients, investigators reported complete response rates of 23% in the previously untreated group and 7% in the relapsed/refractory group. The new findings demonstrate “deepening of responses” with continued ibrutinib therapy, Dr. O’Brien and her coauthors wrote.

The 5-year rate of progression-free survival was 44% for relapsed/refractory patients and 92% for treatment-naive patients in this study. Median progression-free survival was 51 months for the relapsed/refractory cohort. “[Progression-free survival] with single-agent ibrutinib in [treatment-naive] patients appears particularly favorable, because the median has not been reached,” investigators wrote.

SOURCE: O’Brien S et al. Blood. 2018;131(17):1910-9.

Single-agent ibrutinib has had sustained efficacy and a rate of complete response that has increased over time, according to a 5-year follow-up report including 132 patients with chronic lymphocytic leukemia (CLL).

Efficacy has been maintained in both treatment-naive and relapsed/refractory CLL, despite the presence of high-risk genomic features in many patients, investigators reported in Blood.

Treatment has been well tolerated, and the occurrence of severe adverse events has diminished over time, according to Susan M. O’Brien, MD, of the Chao Family Comprehensive Cancer Center, University of California, Irvine, and her colleagues.

“The safety profile of ibrutinib over time remains acceptable and manageable, allowing almost one-half of the patients (48%) to be treated for more than 4 years and thus maximize response,” the investigators wrote.

The report was based on 5-year follow-up of patients with CLL who had been enrolled in a phase 1b/2 study (PCYC-1102) and an extension study (PCYC-1103). A total of 132 patients were evaluated, including 101 with relapsed/refractory disease and 31 who were treatment naive.

The overall response rate remained high, at 89% in this 5-year follow-up. Complete response rates increased over time, reaching 29% in treatment-naive patients and 10% in relapsed/refractory patients. In a previous report on 3-year follow-up for these patients, investigators reported complete response rates of 23% in the previously untreated group and 7% in the relapsed/refractory group. The new findings demonstrate “deepening of responses” with continued ibrutinib therapy, Dr. O’Brien and her coauthors wrote.

The 5-year rate of progression-free survival was 44% for relapsed/refractory patients and 92% for treatment-naive patients in this study. Median progression-free survival was 51 months for the relapsed/refractory cohort. “[Progression-free survival] with single-agent ibrutinib in [treatment-naive] patients appears particularly favorable, because the median has not been reached,” investigators wrote.

SOURCE: O’Brien S et al. Blood. 2018;131(17):1910-9.

Single-agent ibrutinib has had sustained efficacy and a rate of complete response that has increased over time, according to a 5-year follow-up report including 132 patients with chronic lymphocytic leukemia (CLL).

Efficacy has been maintained in both treatment-naive and relapsed/refractory CLL, despite the presence of high-risk genomic features in many patients, investigators reported in Blood.

Treatment has been well tolerated, and the occurrence of severe adverse events has diminished over time, according to Susan M. O’Brien, MD, of the Chao Family Comprehensive Cancer Center, University of California, Irvine, and her colleagues.

“The safety profile of ibrutinib over time remains acceptable and manageable, allowing almost one-half of the patients (48%) to be treated for more than 4 years and thus maximize response,” the investigators wrote.

The report was based on 5-year follow-up of patients with CLL who had been enrolled in a phase 1b/2 study (PCYC-1102) and an extension study (PCYC-1103). A total of 132 patients were evaluated, including 101 with relapsed/refractory disease and 31 who were treatment naive.

The overall response rate remained high, at 89% in this 5-year follow-up. Complete response rates increased over time, reaching 29% in treatment-naive patients and 10% in relapsed/refractory patients. In a previous report on 3-year follow-up for these patients, investigators reported complete response rates of 23% in the previously untreated group and 7% in the relapsed/refractory group. The new findings demonstrate “deepening of responses” with continued ibrutinib therapy, Dr. O’Brien and her coauthors wrote.

The 5-year rate of progression-free survival was 44% for relapsed/refractory patients and 92% for treatment-naive patients in this study. Median progression-free survival was 51 months for the relapsed/refractory cohort. “[Progression-free survival] with single-agent ibrutinib in [treatment-naive] patients appears particularly favorable, because the median has not been reached,” investigators wrote.

SOURCE: O’Brien S et al. Blood. 2018;131(17):1910-9.

Cancer Research Center

Overexpression of HOXA9 and activated JAK/STAT signaling cooperate to drive the development of T-cell acute lymphoblastic leukemia (ALL), according to researchers.

The team found that JAK3 mutations are significantly associated with elevated HOXA9 expression in T-ALL, and co-expression of HOXA9 and JAK3 mutations prompt “rapid” leukemia development in mice.

In addition, STAT5 and HOXA9 occupy similar genetic loci, which results in increased JAK-STAT signaling in leukemia cells.

These discoveries, and results of subsequent experiments, suggested that PIM1 and JAK1 are potential therapeutic targets for T-ALL.

Jan Cools, PhD, of VIB-KU Leuven Center for Cancer Biology in Leuven, Belgium, and his colleagues described this research in Cancer Discovery.

“JAK3/STAT5 mutations are important in ALL since they stimulate the growth of the cells,” Dr Cools said. “[W]e found that JAK3/STAT5 mutations frequently occur together with HOXA9 mutations.”

In analyzing data from 2 cohorts of T-ALL patients, the researchers found that IL7R/JAK/STAT5 mutations were more frequent in HOXA+ cases, and HOXA9 was “the most important upregulated gene of the HOXA cluster.” (HOXA9 expression levels were significantly higher than HOXA10 or HOXA11 levels.)

“We examined the cooperation between JAK3/STAT5 mutation and HOXA9, [and] we observed that HOXA9 boosts the effects of other genes, leading to tumor development,” said study author Charles de Bock, PhD, of VIB-KU Leuven.

“As a result, when JAK3/STAT5 mutations and HOXA9 are both present, leukemia develops more rapidly and aggressively.”

The researchers found that co-expression of HOXA9 and the JAK3 M511I mutation led to rapid leukemia development in mice. Animals with co-expression of HOXA9 and JAK3 (M511I) developed leukemia that was characterized by an increase in peripheral white blood cell counts that exceeded 10,000 cells/mm³ within 30 days.

In addition, these mice had a significant decrease in disease-free survival compared to mice with JAK3 (M511I) alone. The median disease-free survival was 25 days and 126.5 days, respectively (P<0.0001).

Further analysis revealed co-localization of HOXA9 and STAT5. The researchers also found that HOXA9 enhances transcriptional activity of STAT5 in leukemia cells.

The team said this reconfirms STAT5 as “a major central player” in T-ALL, and it suggests that STAT5 target genes such as PIM1 could be therapeutic targets for T-ALL.

To test this theory, the researchers inhibited both PIM1 and JAK1 in JAK/STAT mutant T-ALL. The PIM1 inhibitor AZD1208 and the JAK1/2 inhibitor ruxolitinib demonstrated synergy and significantly reduced leukemia burden in vivo.

Cancer Research Center

Overexpression of HOXA9 and activated JAK/STAT signaling cooperate to drive the development of T-cell acute lymphoblastic leukemia (ALL), according to researchers.

The team found that JAK3 mutations are significantly associated with elevated HOXA9 expression in T-ALL, and co-expression of HOXA9 and JAK3 mutations prompt “rapid” leukemia development in mice.

In addition, STAT5 and HOXA9 occupy similar genetic loci, which results in increased JAK-STAT signaling in leukemia cells.

These discoveries, and results of subsequent experiments, suggested that PIM1 and JAK1 are potential therapeutic targets for T-ALL.

Jan Cools, PhD, of VIB-KU Leuven Center for Cancer Biology in Leuven, Belgium, and his colleagues described this research in Cancer Discovery.

“JAK3/STAT5 mutations are important in ALL since they stimulate the growth of the cells,” Dr Cools said. “[W]e found that JAK3/STAT5 mutations frequently occur together with HOXA9 mutations.”

In analyzing data from 2 cohorts of T-ALL patients, the researchers found that IL7R/JAK/STAT5 mutations were more frequent in HOXA+ cases, and HOXA9 was “the most important upregulated gene of the HOXA cluster.” (HOXA9 expression levels were significantly higher than HOXA10 or HOXA11 levels.)

“We examined the cooperation between JAK3/STAT5 mutation and HOXA9, [and] we observed that HOXA9 boosts the effects of other genes, leading to tumor development,” said study author Charles de Bock, PhD, of VIB-KU Leuven.

“As a result, when JAK3/STAT5 mutations and HOXA9 are both present, leukemia develops more rapidly and aggressively.”

The researchers found that co-expression of HOXA9 and the JAK3 M511I mutation led to rapid leukemia development in mice. Animals with co-expression of HOXA9 and JAK3 (M511I) developed leukemia that was characterized by an increase in peripheral white blood cell counts that exceeded 10,000 cells/mm³ within 30 days.

In addition, these mice had a significant decrease in disease-free survival compared to mice with JAK3 (M511I) alone. The median disease-free survival was 25 days and 126.5 days, respectively (P<0.0001).

Further analysis revealed co-localization of HOXA9 and STAT5. The researchers also found that HOXA9 enhances transcriptional activity of STAT5 in leukemia cells.

The team said this reconfirms STAT5 as “a major central player” in T-ALL, and it suggests that STAT5 target genes such as PIM1 could be therapeutic targets for T-ALL.

To test this theory, the researchers inhibited both PIM1 and JAK1 in JAK/STAT mutant T-ALL. The PIM1 inhibitor AZD1208 and the JAK1/2 inhibitor ruxolitinib demonstrated synergy and significantly reduced leukemia burden in vivo.

Cancer Research Center

Overexpression of HOXA9 and activated JAK/STAT signaling cooperate to drive the development of T-cell acute lymphoblastic leukemia (ALL), according to researchers.

The team found that JAK3 mutations are significantly associated with elevated HOXA9 expression in T-ALL, and co-expression of HOXA9 and JAK3 mutations prompt “rapid” leukemia development in mice.

In addition, STAT5 and HOXA9 occupy similar genetic loci, which results in increased JAK-STAT signaling in leukemia cells.

These discoveries, and results of subsequent experiments, suggested that PIM1 and JAK1 are potential therapeutic targets for T-ALL.

Jan Cools, PhD, of VIB-KU Leuven Center for Cancer Biology in Leuven, Belgium, and his colleagues described this research in Cancer Discovery.

“JAK3/STAT5 mutations are important in ALL since they stimulate the growth of the cells,” Dr Cools said. “[W]e found that JAK3/STAT5 mutations frequently occur together with HOXA9 mutations.”

In analyzing data from 2 cohorts of T-ALL patients, the researchers found that IL7R/JAK/STAT5 mutations were more frequent in HOXA+ cases, and HOXA9 was “the most important upregulated gene of the HOXA cluster.” (HOXA9 expression levels were significantly higher than HOXA10 or HOXA11 levels.)

“We examined the cooperation between JAK3/STAT5 mutation and HOXA9, [and] we observed that HOXA9 boosts the effects of other genes, leading to tumor development,” said study author Charles de Bock, PhD, of VIB-KU Leuven.

“As a result, when JAK3/STAT5 mutations and HOXA9 are both present, leukemia develops more rapidly and aggressively.”

The researchers found that co-expression of HOXA9 and the JAK3 M511I mutation led to rapid leukemia development in mice. Animals with co-expression of HOXA9 and JAK3 (M511I) developed leukemia that was characterized by an increase in peripheral white blood cell counts that exceeded 10,000 cells/mm³ within 30 days.

In addition, these mice had a significant decrease in disease-free survival compared to mice with JAK3 (M511I) alone. The median disease-free survival was 25 days and 126.5 days, respectively (P<0.0001).

Further analysis revealed co-localization of HOXA9 and STAT5. The researchers also found that HOXA9 enhances transcriptional activity of STAT5 in leukemia cells.

The team said this reconfirms STAT5 as “a major central player” in T-ALL, and it suggests that STAT5 target genes such as PIM1 could be therapeutic targets for T-ALL.

To test this theory, the researchers inhibited both PIM1 and JAK1 in JAK/STAT mutant T-ALL. The PIM1 inhibitor AZD1208 and the JAK1/2 inhibitor ruxolitinib demonstrated synergy and significantly reduced leukemia burden in vivo.