Leukemia, Myelodysplasia, Transplantation

Lugano, Switzerland– It’s in the BAG: For patients with treatment-naive or relapsed/refractory chronic lymphocytic leukemia, a regimen consisting of debulking with bendamustine (Treanda) followed sequentially by obinutuzumab (Gazyva) and venetoclax (Venclexta) was associated with a high overall response rate and a large majority of patients being negative for minimal residual disease (MRD) in peripheral blood.

In the open-label, phase II CLL2-BAG study in 66 patients, the overall response rate at the end of induction was 95%, and 87% of patients were negative for MRD, reported Paula Cramer, MD, of the University of Cologne (Germany).

“This sequential treatment of bendamustine followed by obinutuzumab and venetoclax does not lead to any cumulative or unexpected toxicity. As compared to other trials, it’s important to point out that only one laboratory TLS [tumor lysis syndrome] occurred with venetoclax. Maybe that’s explained by the sequential start of all three drugs,” she said at the International Conference on Malignant Lymphoma.

The trial is based on a concept the investigators call “sequential triple-T” (tailored and targeted treatment) aimed at complete eradication of MRD.

The 66 patients (median age, 59 years) had either previously untreated or relapsed/refractory CLL; 34 of the treatment-naive and 29 of the relapsed/refractory patients were evaluable for response.

At enrollment, patients who had an absolute lymphocyte count of 25,000/mcL or greater and/or lymph nodes 5 cm or larger received two cycles of debulking with bendamustine 70 mg/m² on days 1 and 2 every 28 days, unless this was contraindicated.

The induction phase consisted of obinutuzumab 1,000 mg administered three times in cycle 1, then every 4 weeks for cycles 2 through 6. Venetoclax was started during cycle 2 with a dose escalation to 400 mg daily over a period of 5 weeks.

Maintenance therapy consisted of daily venetoclax and obinutuzumab every 3 months until MRD negativity or up to 24 months.

A total of 45 patients (31 who were treatment naive and 14 with relapsed/refractory disease) underwent debulking. Of this group 36 patients received both cycles, and 9 discontinued early because of either adverse events (5 patients), disease progression (1), or unknown reasons (3).

Sixty of the 66 patients received the full six induction cycles. Three patients who had fewer than two cycles were excluded according to protocol. Of these three, two heavily pretreated patients died of sepsis and one of myocardial infarction in cycle 1.

Responses

In all, 24 patients (53%) who had debulking had a response during that phase based on International Workshop on CLL (IWCLL) criteria, for an overall response rate (ORR) of 53%. Thirteen patients had stable disease after debulking, and four had disease progression.

Responses after induction according to IWCLL criteria, the primary endpoint, included five patients with a complete response (three treatment-naive and two relapsed/refractory patients), and 20 patients (14 treatment-naive and six relapsed/refractory patients) with an unconfirmed or clinical complete response or a complete response with incomplete recovery of counts.

In addition, 35 patients (17 who were treatment naive and 18 with relapsed/refractory disease) had a partial response. No patients had stable disease, and three patients, all with relapsed/refractory disease, had disease progression.

Of the 63 patients who had at least two cycles of therapy, 87% were MRD negative. Eight patients had MRD assessments by bone marrow, and all eight were MRD negative.

The maintenance phase of the trial is ongoing and the data are not mature, but 56 patients (30 who were treatment naive and 26 with relapsed/refractory disease) have started on maintenance therapy. Of this group, 28 have stopped maintenance, including 21 patients who stopped because they achieved MRD negativity, 5 who discontinued because of adverse events, and 2 with disease progression or Richter’s transformation.

At 15 months of follow-up, progression-free survival was 100% in patients who received the combination as the frontline therapy, and 83% in the patients with relapsed/refractory disease.

Adverse events

In the debulking phase, 34 patients (72%) experienced adverse events of any grade, including 16 patients with grade 3 or 4 events

Adverse events associated with debulking included neutropenia and anemia, each seen in five patients, thrombocytopenia and infection each seen in three patients, and coronary artery disorders, rash, tumor lysis syndrome, vomiting, and pyrexia in one patient each.

Sixty of the 66 patients received the full six induction cycles. Three patients who had fewer than two cycles were excluded according to protocol. Of these three, two heavily pretreated patients died of sepsis and one of myocardial infarction in cycle 1.

All but 3 of the 63 patients had an adverse event, and 44 patients had at least one grade 3 or 4 adverse event.

Cytopenias, infections, infusion-related reactions, and neoplasms were the most common adverse events.

There were three grade 3 laboratory-confirmed cases of tumor lysis syndrome, one each occurring during bendamustine debulking, obinutuzumab administration, and venetoclax administration.

Something other than venetoclax?

Davide Rossi, MD, PhD, of the Oncology Institute of Southern Switzerland in Bellinzona, the invited discussant, questioned whether venetoclax is the best agent to use in sequential triple-T therapy.

“We know that venetoclax is more active in blood and bone marrow than in lymph nodes and, indeed, a proportion of cases achieving all the criteria for a CR [complete response] in the bone marrow and the peripheral blood, including MRD negativity, may still have some residual [disease in] lymph nodes,” he said.

Drugs that inhibit the B-cell receptor pathway may be more effective at eradicating MRD in the lymph node compartment, Dr. Cramer said.

The study was sponsored by the German CLL study group. Dr. Cramer disclosed financial ties to multiple entities. Dr. Rossi did not report disclosures.
 

Lugano, Switzerland– It’s in the BAG: For patients with treatment-naive or relapsed/refractory chronic lymphocytic leukemia, a regimen consisting of debulking with bendamustine (Treanda) followed sequentially by obinutuzumab (Gazyva) and venetoclax (Venclexta) was associated with a high overall response rate and a large majority of patients being negative for minimal residual disease (MRD) in peripheral blood.

In the open-label, phase II CLL2-BAG study in 66 patients, the overall response rate at the end of induction was 95%, and 87% of patients were negative for MRD, reported Paula Cramer, MD, of the University of Cologne (Germany).

“This sequential treatment of bendamustine followed by obinutuzumab and venetoclax does not lead to any cumulative or unexpected toxicity. As compared to other trials, it’s important to point out that only one laboratory TLS [tumor lysis syndrome] occurred with venetoclax. Maybe that’s explained by the sequential start of all three drugs,” she said at the International Conference on Malignant Lymphoma.

The trial is based on a concept the investigators call “sequential triple-T” (tailored and targeted treatment) aimed at complete eradication of MRD.

The 66 patients (median age, 59 years) had either previously untreated or relapsed/refractory CLL; 34 of the treatment-naive and 29 of the relapsed/refractory patients were evaluable for response.

At enrollment, patients who had an absolute lymphocyte count of 25,000/mcL or greater and/or lymph nodes 5 cm or larger received two cycles of debulking with bendamustine 70 mg/m² on days 1 and 2 every 28 days, unless this was contraindicated.

The induction phase consisted of obinutuzumab 1,000 mg administered three times in cycle 1, then every 4 weeks for cycles 2 through 6. Venetoclax was started during cycle 2 with a dose escalation to 400 mg daily over a period of 5 weeks.

Maintenance therapy consisted of daily venetoclax and obinutuzumab every 3 months until MRD negativity or up to 24 months.

A total of 45 patients (31 who were treatment naive and 14 with relapsed/refractory disease) underwent debulking. Of this group 36 patients received both cycles, and 9 discontinued early because of either adverse events (5 patients), disease progression (1), or unknown reasons (3).

Sixty of the 66 patients received the full six induction cycles. Three patients who had fewer than two cycles were excluded according to protocol. Of these three, two heavily pretreated patients died of sepsis and one of myocardial infarction in cycle 1.

Responses

In all, 24 patients (53%) who had debulking had a response during that phase based on International Workshop on CLL (IWCLL) criteria, for an overall response rate (ORR) of 53%. Thirteen patients had stable disease after debulking, and four had disease progression.

Responses after induction according to IWCLL criteria, the primary endpoint, included five patients with a complete response (three treatment-naive and two relapsed/refractory patients), and 20 patients (14 treatment-naive and six relapsed/refractory patients) with an unconfirmed or clinical complete response or a complete response with incomplete recovery of counts.

In addition, 35 patients (17 who were treatment naive and 18 with relapsed/refractory disease) had a partial response. No patients had stable disease, and three patients, all with relapsed/refractory disease, had disease progression.

Of the 63 patients who had at least two cycles of therapy, 87% were MRD negative. Eight patients had MRD assessments by bone marrow, and all eight were MRD negative.

The maintenance phase of the trial is ongoing and the data are not mature, but 56 patients (30 who were treatment naive and 26 with relapsed/refractory disease) have started on maintenance therapy. Of this group, 28 have stopped maintenance, including 21 patients who stopped because they achieved MRD negativity, 5 who discontinued because of adverse events, and 2 with disease progression or Richter’s transformation.

At 15 months of follow-up, progression-free survival was 100% in patients who received the combination as the frontline therapy, and 83% in the patients with relapsed/refractory disease.

Adverse events

In the debulking phase, 34 patients (72%) experienced adverse events of any grade, including 16 patients with grade 3 or 4 events

Adverse events associated with debulking included neutropenia and anemia, each seen in five patients, thrombocytopenia and infection each seen in three patients, and coronary artery disorders, rash, tumor lysis syndrome, vomiting, and pyrexia in one patient each.

Sixty of the 66 patients received the full six induction cycles. Three patients who had fewer than two cycles were excluded according to protocol. Of these three, two heavily pretreated patients died of sepsis and one of myocardial infarction in cycle 1.

All but 3 of the 63 patients had an adverse event, and 44 patients had at least one grade 3 or 4 adverse event.

Cytopenias, infections, infusion-related reactions, and neoplasms were the most common adverse events.

There were three grade 3 laboratory-confirmed cases of tumor lysis syndrome, one each occurring during bendamustine debulking, obinutuzumab administration, and venetoclax administration.

Something other than venetoclax?

Davide Rossi, MD, PhD, of the Oncology Institute of Southern Switzerland in Bellinzona, the invited discussant, questioned whether venetoclax is the best agent to use in sequential triple-T therapy.

“We know that venetoclax is more active in blood and bone marrow than in lymph nodes and, indeed, a proportion of cases achieving all the criteria for a CR [complete response] in the bone marrow and the peripheral blood, including MRD negativity, may still have some residual [disease in] lymph nodes,” he said.

Drugs that inhibit the B-cell receptor pathway may be more effective at eradicating MRD in the lymph node compartment, Dr. Cramer said.

The study was sponsored by the German CLL study group. Dr. Cramer disclosed financial ties to multiple entities. Dr. Rossi did not report disclosures.
 

Lugano, Switzerland– It’s in the BAG: For patients with treatment-naive or relapsed/refractory chronic lymphocytic leukemia, a regimen consisting of debulking with bendamustine (Treanda) followed sequentially by obinutuzumab (Gazyva) and venetoclax (Venclexta) was associated with a high overall response rate and a large majority of patients being negative for minimal residual disease (MRD) in peripheral blood.

In the open-label, phase II CLL2-BAG study in 66 patients, the overall response rate at the end of induction was 95%, and 87% of patients were negative for MRD, reported Paula Cramer, MD, of the University of Cologne (Germany).

“This sequential treatment of bendamustine followed by obinutuzumab and venetoclax does not lead to any cumulative or unexpected toxicity. As compared to other trials, it’s important to point out that only one laboratory TLS [tumor lysis syndrome] occurred with venetoclax. Maybe that’s explained by the sequential start of all three drugs,” she said at the International Conference on Malignant Lymphoma.

The trial is based on a concept the investigators call “sequential triple-T” (tailored and targeted treatment) aimed at complete eradication of MRD.

The 66 patients (median age, 59 years) had either previously untreated or relapsed/refractory CLL; 34 of the treatment-naive and 29 of the relapsed/refractory patients were evaluable for response.

At enrollment, patients who had an absolute lymphocyte count of 25,000/mcL or greater and/or lymph nodes 5 cm or larger received two cycles of debulking with bendamustine 70 mg/m² on days 1 and 2 every 28 days, unless this was contraindicated.

The induction phase consisted of obinutuzumab 1,000 mg administered three times in cycle 1, then every 4 weeks for cycles 2 through 6. Venetoclax was started during cycle 2 with a dose escalation to 400 mg daily over a period of 5 weeks.

Maintenance therapy consisted of daily venetoclax and obinutuzumab every 3 months until MRD negativity or up to 24 months.

A total of 45 patients (31 who were treatment naive and 14 with relapsed/refractory disease) underwent debulking. Of this group 36 patients received both cycles, and 9 discontinued early because of either adverse events (5 patients), disease progression (1), or unknown reasons (3).

Sixty of the 66 patients received the full six induction cycles. Three patients who had fewer than two cycles were excluded according to protocol. Of these three, two heavily pretreated patients died of sepsis and one of myocardial infarction in cycle 1.

Responses

In all, 24 patients (53%) who had debulking had a response during that phase based on International Workshop on CLL (IWCLL) criteria, for an overall response rate (ORR) of 53%. Thirteen patients had stable disease after debulking, and four had disease progression.

Responses after induction according to IWCLL criteria, the primary endpoint, included five patients with a complete response (three treatment-naive and two relapsed/refractory patients), and 20 patients (14 treatment-naive and six relapsed/refractory patients) with an unconfirmed or clinical complete response or a complete response with incomplete recovery of counts.

In addition, 35 patients (17 who were treatment naive and 18 with relapsed/refractory disease) had a partial response. No patients had stable disease, and three patients, all with relapsed/refractory disease, had disease progression.

Of the 63 patients who had at least two cycles of therapy, 87% were MRD negative. Eight patients had MRD assessments by bone marrow, and all eight were MRD negative.

The maintenance phase of the trial is ongoing and the data are not mature, but 56 patients (30 who were treatment naive and 26 with relapsed/refractory disease) have started on maintenance therapy. Of this group, 28 have stopped maintenance, including 21 patients who stopped because they achieved MRD negativity, 5 who discontinued because of adverse events, and 2 with disease progression or Richter’s transformation.

At 15 months of follow-up, progression-free survival was 100% in patients who received the combination as the frontline therapy, and 83% in the patients with relapsed/refractory disease.

Adverse events

In the debulking phase, 34 patients (72%) experienced adverse events of any grade, including 16 patients with grade 3 or 4 events

Adverse events associated with debulking included neutropenia and anemia, each seen in five patients, thrombocytopenia and infection each seen in three patients, and coronary artery disorders, rash, tumor lysis syndrome, vomiting, and pyrexia in one patient each.

Sixty of the 66 patients received the full six induction cycles. Three patients who had fewer than two cycles were excluded according to protocol. Of these three, two heavily pretreated patients died of sepsis and one of myocardial infarction in cycle 1.

All but 3 of the 63 patients had an adverse event, and 44 patients had at least one grade 3 or 4 adverse event.

Cytopenias, infections, infusion-related reactions, and neoplasms were the most common adverse events.

There were three grade 3 laboratory-confirmed cases of tumor lysis syndrome, one each occurring during bendamustine debulking, obinutuzumab administration, and venetoclax administration.

Something other than venetoclax?

Davide Rossi, MD, PhD, of the Oncology Institute of Southern Switzerland in Bellinzona, the invited discussant, questioned whether venetoclax is the best agent to use in sequential triple-T therapy.

“We know that venetoclax is more active in blood and bone marrow than in lymph nodes and, indeed, a proportion of cases achieving all the criteria for a CR [complete response] in the bone marrow and the peripheral blood, including MRD negativity, may still have some residual [disease in] lymph nodes,” he said.

Drugs that inhibit the B-cell receptor pathway may be more effective at eradicating MRD in the lymph node compartment, Dr. Cramer said.

The study was sponsored by the German CLL study group. Dr. Cramer disclosed financial ties to multiple entities. Dr. Rossi did not report disclosures.
 

AML cells

Update as of June 21:  The US Food and Drug Administration (FDA) has placed the Investigational New Drug (IND) application for vadastuximab talirine on hold. No clinical trial may resume under the IND until the FDA lifts the clinical hold.

On the advice of the Independent Data Monitoring Committee, Seattle Genetics is discontinuing the phase 3 CASCADE clinical trial of vadastuximab talirine as frontline treatment in older patients with acute myeloid leukemia (AML).

The company is also suspending patient enrollment and treatment in all its vadastuximab trials, including the ongoing phase 1/2 trial in frontline high-risk myelodysplastic syndromes (MDS).

In December last year, the US Food and Drug Administration (FDA) had placed the trials of vadastuximab on full and partial clinical holds due to the potential risk of hepatotoxicity.

The FDA lifted the hold in March of this year. However, concerns regarding a higher rate of deaths, including fatal infections but not liver toxicity, in the vadastuximab arm compared to control prompted the company to discontinue the phase 3 trial.

Vadastuximab talirene is an antibody-drug conjugate (ADC) targeted to CD33, which is expressed on most AML and MDS blasts. The ADC technology links anti-cancer compounds with targeting antibodies to precisely kill cancer cells and spare healthy ones.

Seattle Genetics’ ADC for Hodgkin lymphoma, brentuximab vedotin, was granted accelerated approval by the FDA in 2011.

The CASCADE trial was evaluating vadastuximab in combination with the hypomethylating agents (HMAs) azacytidine or decitabine compared to an HMA alone in older patients with newly diagnosed AML.

In addition to the MDS trial, the company is stopping enrollment onto the trial of vadastuximab in combination with 7+3 chemotherapy in newly diagnosed, younger AML patients and vadastuximab given prior to or after allogeneic hematopoietic stem cell transplant in AML patients.

Calling the decision “disappointing and unexpected,” Clay Siegall, PhD, president and CEO of Seattle Genetics, said, “Patient safety is our highest priority, and we will closely review the data and evaluate next steps.” 

AML cells

Update as of June 21:  The US Food and Drug Administration (FDA) has placed the Investigational New Drug (IND) application for vadastuximab talirine on hold. No clinical trial may resume under the IND until the FDA lifts the clinical hold.

On the advice of the Independent Data Monitoring Committee, Seattle Genetics is discontinuing the phase 3 CASCADE clinical trial of vadastuximab talirine as frontline treatment in older patients with acute myeloid leukemia (AML).

The company is also suspending patient enrollment and treatment in all its vadastuximab trials, including the ongoing phase 1/2 trial in frontline high-risk myelodysplastic syndromes (MDS).

In December last year, the US Food and Drug Administration (FDA) had placed the trials of vadastuximab on full and partial clinical holds due to the potential risk of hepatotoxicity.

The FDA lifted the hold in March of this year. However, concerns regarding a higher rate of deaths, including fatal infections but not liver toxicity, in the vadastuximab arm compared to control prompted the company to discontinue the phase 3 trial.

Vadastuximab talirene is an antibody-drug conjugate (ADC) targeted to CD33, which is expressed on most AML and MDS blasts. The ADC technology links anti-cancer compounds with targeting antibodies to precisely kill cancer cells and spare healthy ones.

Seattle Genetics’ ADC for Hodgkin lymphoma, brentuximab vedotin, was granted accelerated approval by the FDA in 2011.

The CASCADE trial was evaluating vadastuximab in combination with the hypomethylating agents (HMAs) azacytidine or decitabine compared to an HMA alone in older patients with newly diagnosed AML.

In addition to the MDS trial, the company is stopping enrollment onto the trial of vadastuximab in combination with 7+3 chemotherapy in newly diagnosed, younger AML patients and vadastuximab given prior to or after allogeneic hematopoietic stem cell transplant in AML patients.

Calling the decision “disappointing and unexpected,” Clay Siegall, PhD, president and CEO of Seattle Genetics, said, “Patient safety is our highest priority, and we will closely review the data and evaluate next steps.” 

AML cells

Update as of June 21:  The US Food and Drug Administration (FDA) has placed the Investigational New Drug (IND) application for vadastuximab talirine on hold. No clinical trial may resume under the IND until the FDA lifts the clinical hold.

On the advice of the Independent Data Monitoring Committee, Seattle Genetics is discontinuing the phase 3 CASCADE clinical trial of vadastuximab talirine as frontline treatment in older patients with acute myeloid leukemia (AML).

The company is also suspending patient enrollment and treatment in all its vadastuximab trials, including the ongoing phase 1/2 trial in frontline high-risk myelodysplastic syndromes (MDS).

In December last year, the US Food and Drug Administration (FDA) had placed the trials of vadastuximab on full and partial clinical holds due to the potential risk of hepatotoxicity.

The FDA lifted the hold in March of this year. However, concerns regarding a higher rate of deaths, including fatal infections but not liver toxicity, in the vadastuximab arm compared to control prompted the company to discontinue the phase 3 trial.

Vadastuximab talirene is an antibody-drug conjugate (ADC) targeted to CD33, which is expressed on most AML and MDS blasts. The ADC technology links anti-cancer compounds with targeting antibodies to precisely kill cancer cells and spare healthy ones.

Seattle Genetics’ ADC for Hodgkin lymphoma, brentuximab vedotin, was granted accelerated approval by the FDA in 2011.

The CASCADE trial was evaluating vadastuximab in combination with the hypomethylating agents (HMAs) azacytidine or decitabine compared to an HMA alone in older patients with newly diagnosed AML.

In addition to the MDS trial, the company is stopping enrollment onto the trial of vadastuximab in combination with 7+3 chemotherapy in newly diagnosed, younger AML patients and vadastuximab given prior to or after allogeneic hematopoietic stem cell transplant in AML patients.

Calling the decision “disappointing and unexpected,” Clay Siegall, PhD, president and CEO of Seattle Genetics, said, “Patient safety is our highest priority, and we will closely review the data and evaluate next steps.” 

Photo © ASCO/Todd Buchanan 2017

CHICAGO – The neurotoxicity in adult patients with relapsed or refractory B-cell acute lymphocytic leukemia (B-ALL) treated with CD19 CAR T cells is a separate process from cytokine release syndrome (CRS) and needs to be treated separately, according to a new study presented at the American Society of Clinical Oncology annual meeting (abstract 3019).

CD19-specific CAR-modified T cells produce high, durable anti-tumor activity, but can be associated with treatment-related toxicities, including CRS and neurotoxicity.

Neurotoxicity is poorly understood and it hasn't been clear where to focus further research, said Bianca Santomasso, MD, of Memorial Sloan Kettering Cancer Center in New York, New York.

Dr Santomasso and colleagues had conducted a phase 1 study using autologous 19-CAR T cells in adult patients with relapsing/refractory B-ALL, with high response rates.

To gain a better understanding of CD19 CAR T-cell-associated neurotoxicity, they analyzed clinical and research parameters after stratifying patients by neurotoxicity grade.

At ASCO, she reported neurologic symptom presentation in 51 adult patients with relapsed/refractory B-ALL who were treated with CAR T cells following conditioning chemotherapy, along with cerebrospinal fluid (CSF) data and neuroimaging findings associated with neurotoxicity.

Of the 51 patients treated, 10 patients (20%) developed mild neurologic symptoms (grade 1 or 2) and 21 patients (41%) developed severe neurotoxicity (grade 3 or 4).

No grade 5 neurotoxicity or diffuse cerebral edema occurred and, in all but one case, neurologic symptoms fully resolved.

Fourteen patients (27.4%) developed severe CRS; 6 patients received tocilizumab alone, 13 patients tocilizumab plus steroids, 4 patients steroids alone, and 29 patients supportive care.

The cytokines IL-6, IL-8, IL-10, interferon gamma, and granulocyte-colony stimulating factor were elevated in CSF over serum at the time of neurotoxicity and correlated with CSF protein levels.

“We found no significant correlation between neurotoxicity grade and the CAR T-cell concentration in the CSF during neurotoxicity,” Dr Santomasso said. “Instead, CSF protein level was correlated with neurotoxicity grade.”

Neurotoxicity was associated with peak CAR T-cell expansion in the blood and peak serum levels of several cytokines associated with T-cell activation or proliferation, she said.

“CAR T cells traffic to the CSF of patients with all grades of neurotoxicity, including grade 0, and there is no significant correlation between CAR T cells in CSF at the time of acute neurotoxicity and grade of neurotoxicity,” Dr Santomasso reported. “This suggests that neurotoxicity is not directly mediated by CAR T cells, which cross into the spinal fluid.”

Some chemokines/cytokines are elevated in CSF relative to serum, suggesting CNS-specific production of these factors, she said.

“Clinicians treating these patients tend to lump CRS and neurotoxicity together. Now we have an increasing understanding that these adverse events are separated in time and possibly in underlying pathology,” said Dr Santomasso.

“Even when patients recover from CRS, they could still be at risk for neurotoxicity.”

She noted that the neurotoxicity symptoms that B-ALL patients develop in the setting of CAR T cells are manageable.

In a subset of patients with severe neurotoxicity, T2/FLAIR changes were observed, which resolved with steroids and neurologic symptom resolution. 

Photo © ASCO/Todd Buchanan 2017

CHICAGO – The neurotoxicity in adult patients with relapsed or refractory B-cell acute lymphocytic leukemia (B-ALL) treated with CD19 CAR T cells is a separate process from cytokine release syndrome (CRS) and needs to be treated separately, according to a new study presented at the American Society of Clinical Oncology annual meeting (abstract 3019).

CD19-specific CAR-modified T cells produce high, durable anti-tumor activity, but can be associated with treatment-related toxicities, including CRS and neurotoxicity.

Neurotoxicity is poorly understood and it hasn't been clear where to focus further research, said Bianca Santomasso, MD, of Memorial Sloan Kettering Cancer Center in New York, New York.

Dr Santomasso and colleagues had conducted a phase 1 study using autologous 19-CAR T cells in adult patients with relapsing/refractory B-ALL, with high response rates.

To gain a better understanding of CD19 CAR T-cell-associated neurotoxicity, they analyzed clinical and research parameters after stratifying patients by neurotoxicity grade.

At ASCO, she reported neurologic symptom presentation in 51 adult patients with relapsed/refractory B-ALL who were treated with CAR T cells following conditioning chemotherapy, along with cerebrospinal fluid (CSF) data and neuroimaging findings associated with neurotoxicity.

Of the 51 patients treated, 10 patients (20%) developed mild neurologic symptoms (grade 1 or 2) and 21 patients (41%) developed severe neurotoxicity (grade 3 or 4).

No grade 5 neurotoxicity or diffuse cerebral edema occurred and, in all but one case, neurologic symptoms fully resolved.

Fourteen patients (27.4%) developed severe CRS; 6 patients received tocilizumab alone, 13 patients tocilizumab plus steroids, 4 patients steroids alone, and 29 patients supportive care.

The cytokines IL-6, IL-8, IL-10, interferon gamma, and granulocyte-colony stimulating factor were elevated in CSF over serum at the time of neurotoxicity and correlated with CSF protein levels.

“We found no significant correlation between neurotoxicity grade and the CAR T-cell concentration in the CSF during neurotoxicity,” Dr Santomasso said. “Instead, CSF protein level was correlated with neurotoxicity grade.”

Neurotoxicity was associated with peak CAR T-cell expansion in the blood and peak serum levels of several cytokines associated with T-cell activation or proliferation, she said.

“CAR T cells traffic to the CSF of patients with all grades of neurotoxicity, including grade 0, and there is no significant correlation between CAR T cells in CSF at the time of acute neurotoxicity and grade of neurotoxicity,” Dr Santomasso reported. “This suggests that neurotoxicity is not directly mediated by CAR T cells, which cross into the spinal fluid.”

Some chemokines/cytokines are elevated in CSF relative to serum, suggesting CNS-specific production of these factors, she said.

“Clinicians treating these patients tend to lump CRS and neurotoxicity together. Now we have an increasing understanding that these adverse events are separated in time and possibly in underlying pathology,” said Dr Santomasso.

“Even when patients recover from CRS, they could still be at risk for neurotoxicity.”

She noted that the neurotoxicity symptoms that B-ALL patients develop in the setting of CAR T cells are manageable.

In a subset of patients with severe neurotoxicity, T2/FLAIR changes were observed, which resolved with steroids and neurologic symptom resolution. 

Photo © ASCO/Todd Buchanan 2017

CHICAGO – The neurotoxicity in adult patients with relapsed or refractory B-cell acute lymphocytic leukemia (B-ALL) treated with CD19 CAR T cells is a separate process from cytokine release syndrome (CRS) and needs to be treated separately, according to a new study presented at the American Society of Clinical Oncology annual meeting (abstract 3019).

CD19-specific CAR-modified T cells produce high, durable anti-tumor activity, but can be associated with treatment-related toxicities, including CRS and neurotoxicity.

Neurotoxicity is poorly understood and it hasn't been clear where to focus further research, said Bianca Santomasso, MD, of Memorial Sloan Kettering Cancer Center in New York, New York.

Dr Santomasso and colleagues had conducted a phase 1 study using autologous 19-CAR T cells in adult patients with relapsing/refractory B-ALL, with high response rates.

To gain a better understanding of CD19 CAR T-cell-associated neurotoxicity, they analyzed clinical and research parameters after stratifying patients by neurotoxicity grade.

At ASCO, she reported neurologic symptom presentation in 51 adult patients with relapsed/refractory B-ALL who were treated with CAR T cells following conditioning chemotherapy, along with cerebrospinal fluid (CSF) data and neuroimaging findings associated with neurotoxicity.

Of the 51 patients treated, 10 patients (20%) developed mild neurologic symptoms (grade 1 or 2) and 21 patients (41%) developed severe neurotoxicity (grade 3 or 4).

No grade 5 neurotoxicity or diffuse cerebral edema occurred and, in all but one case, neurologic symptoms fully resolved.

Fourteen patients (27.4%) developed severe CRS; 6 patients received tocilizumab alone, 13 patients tocilizumab plus steroids, 4 patients steroids alone, and 29 patients supportive care.

The cytokines IL-6, IL-8, IL-10, interferon gamma, and granulocyte-colony stimulating factor were elevated in CSF over serum at the time of neurotoxicity and correlated with CSF protein levels.

“We found no significant correlation between neurotoxicity grade and the CAR T-cell concentration in the CSF during neurotoxicity,” Dr Santomasso said. “Instead, CSF protein level was correlated with neurotoxicity grade.”

Neurotoxicity was associated with peak CAR T-cell expansion in the blood and peak serum levels of several cytokines associated with T-cell activation or proliferation, she said.

“CAR T cells traffic to the CSF of patients with all grades of neurotoxicity, including grade 0, and there is no significant correlation between CAR T cells in CSF at the time of acute neurotoxicity and grade of neurotoxicity,” Dr Santomasso reported. “This suggests that neurotoxicity is not directly mediated by CAR T cells, which cross into the spinal fluid.”

Some chemokines/cytokines are elevated in CSF relative to serum, suggesting CNS-specific production of these factors, she said.

“Clinicians treating these patients tend to lump CRS and neurotoxicity together. Now we have an increasing understanding that these adverse events are separated in time and possibly in underlying pathology,” said Dr Santomasso.

“Even when patients recover from CRS, they could still be at risk for neurotoxicity.”

She noted that the neurotoxicity symptoms that B-ALL patients develop in the setting of CAR T cells are manageable.

In a subset of patients with severe neurotoxicity, T2/FLAIR changes were observed, which resolved with steroids and neurologic symptom resolution. 

Photo © ASCO/David Eulitt 2017

CHICAGO—Chimeric antigen receptor (CAR) T cells combined with ibrutinib enhance T-cell function and can induce complete remission (CR) in patients with chronic lymphocytic leukemia (CLL), researchers report.

Many CLL patients receive ibrutinib treatment, which is well tolerated, but few patients achieve CR.

Immunotherapy with anti-CD19 CAR T cells has induced CR in 25% - 45% of patients with CLL, Saar Gill, MD, of the University of Pennsylvania in Philadelphia, told Hematology Times, and these CRs tend to be durable.

So investigators conducted a pilot trial in 10 patients to test whether combining anti-CD19 CAR T cells with ibrutinib would enhance the CR rate.

Dr Gill reported the findings of the pilot trial at the ASCO 2017 Annual Meeting (abstract 7509).

The patients must have failed at least 1 regimen before ibrutinib, unless they had del(17)(p13.1) or a TP53 mutation.

T cells were lentivirally transduced to express a CAR that included humanized anti-CD19.

Patients were lymphodepleted 1 week before infusion, and ibrutinib was continued throughout the trial.

After a median follow-up of 6 months, 8 of the 9 evaluable patients show absence of CLL in the bone marrow by flow cytometry or minimal residual disease (MRD) negative, and all remain in marrow CR at last follow-up, Dr Gill said.

Radiologic responses are less clear-cut and may require longer follow-up.

“All but 1 patient achieved MRD with deep sequencing. We have deep response in the bone marrow,” Dr Gill said. He also noted that the treatment was well tolerated.

Cytokine release syndrome (CRS) developed in 9 patients: grade 1 in 2 patients, grade 2 in 6 patients, and grade 3 in 1 patient. One patient developed grade 4 tumor lysis syndrome. Treatment of CRS with the IL-6 receptor antagonist tocilizumab was not required.

There was modest residual splenomegaly in 3 of 5 patients, and adenopathy resolved in 4 of 6 patients, with progression in 1 patient.

Ibrutinib reduced CRS apparently by blocking cytokine production by T cells, said Dr Gill, adding, “The combination led to improved efficacy without increased toxicity.”

Ibrutinib may make CAR T-cell therapy more feasible.

Patients who receive ibrutinib for 6 months have a better T-cell response.

“This opens up future discussions of bringing CAR T-cell therapy earlier into CLL treatment,” said Dr Gill.

He envisions patients receiving ibrutinib for 6 months, which would allow time to manufacture T cells, and then have a T-cell infusion.

“Once patients achieve MRD, then we can discuss the possibility of stopping ibrutinib therapy,” he said.

“Most patients remain on ibrutinib, but longer follow-up may show whether remissions are sustained off ibrutinib.”

The researchers have ongoing plans to treat 25 patients with CTL19 plus ibrutinib in a continuation of this trial.

Dr Gill said longer follow-up will reveal the durability of these results “and could support evaluation of a first-line combination approach in an attempt to obviate the need for chronic therapy.” 

Photo © ASCO/David Eulitt 2017

CHICAGO—Chimeric antigen receptor (CAR) T cells combined with ibrutinib enhance T-cell function and can induce complete remission (CR) in patients with chronic lymphocytic leukemia (CLL), researchers report.

Many CLL patients receive ibrutinib treatment, which is well tolerated, but few patients achieve CR.

Immunotherapy with anti-CD19 CAR T cells has induced CR in 25% - 45% of patients with CLL, Saar Gill, MD, of the University of Pennsylvania in Philadelphia, told Hematology Times, and these CRs tend to be durable.

So investigators conducted a pilot trial in 10 patients to test whether combining anti-CD19 CAR T cells with ibrutinib would enhance the CR rate.

Dr Gill reported the findings of the pilot trial at the ASCO 2017 Annual Meeting (abstract 7509).

The patients must have failed at least 1 regimen before ibrutinib, unless they had del(17)(p13.1) or a TP53 mutation.

T cells were lentivirally transduced to express a CAR that included humanized anti-CD19.

Patients were lymphodepleted 1 week before infusion, and ibrutinib was continued throughout the trial.

After a median follow-up of 6 months, 8 of the 9 evaluable patients show absence of CLL in the bone marrow by flow cytometry or minimal residual disease (MRD) negative, and all remain in marrow CR at last follow-up, Dr Gill said.

Radiologic responses are less clear-cut and may require longer follow-up.

“All but 1 patient achieved MRD with deep sequencing. We have deep response in the bone marrow,” Dr Gill said. He also noted that the treatment was well tolerated.

Cytokine release syndrome (CRS) developed in 9 patients: grade 1 in 2 patients, grade 2 in 6 patients, and grade 3 in 1 patient. One patient developed grade 4 tumor lysis syndrome. Treatment of CRS with the IL-6 receptor antagonist tocilizumab was not required.

There was modest residual splenomegaly in 3 of 5 patients, and adenopathy resolved in 4 of 6 patients, with progression in 1 patient.

Ibrutinib reduced CRS apparently by blocking cytokine production by T cells, said Dr Gill, adding, “The combination led to improved efficacy without increased toxicity.”

Ibrutinib may make CAR T-cell therapy more feasible.

Patients who receive ibrutinib for 6 months have a better T-cell response.

“This opens up future discussions of bringing CAR T-cell therapy earlier into CLL treatment,” said Dr Gill.

He envisions patients receiving ibrutinib for 6 months, which would allow time to manufacture T cells, and then have a T-cell infusion.

“Once patients achieve MRD, then we can discuss the possibility of stopping ibrutinib therapy,” he said.

“Most patients remain on ibrutinib, but longer follow-up may show whether remissions are sustained off ibrutinib.”

The researchers have ongoing plans to treat 25 patients with CTL19 plus ibrutinib in a continuation of this trial.

Dr Gill said longer follow-up will reveal the durability of these results “and could support evaluation of a first-line combination approach in an attempt to obviate the need for chronic therapy.” 

Photo © ASCO/David Eulitt 2017

CHICAGO—Chimeric antigen receptor (CAR) T cells combined with ibrutinib enhance T-cell function and can induce complete remission (CR) in patients with chronic lymphocytic leukemia (CLL), researchers report.

Many CLL patients receive ibrutinib treatment, which is well tolerated, but few patients achieve CR.

Immunotherapy with anti-CD19 CAR T cells has induced CR in 25% - 45% of patients with CLL, Saar Gill, MD, of the University of Pennsylvania in Philadelphia, told Hematology Times, and these CRs tend to be durable.

So investigators conducted a pilot trial in 10 patients to test whether combining anti-CD19 CAR T cells with ibrutinib would enhance the CR rate.

Dr Gill reported the findings of the pilot trial at the ASCO 2017 Annual Meeting (abstract 7509).

The patients must have failed at least 1 regimen before ibrutinib, unless they had del(17)(p13.1) or a TP53 mutation.

T cells were lentivirally transduced to express a CAR that included humanized anti-CD19.

Patients were lymphodepleted 1 week before infusion, and ibrutinib was continued throughout the trial.

After a median follow-up of 6 months, 8 of the 9 evaluable patients show absence of CLL in the bone marrow by flow cytometry or minimal residual disease (MRD) negative, and all remain in marrow CR at last follow-up, Dr Gill said.

Radiologic responses are less clear-cut and may require longer follow-up.

“All but 1 patient achieved MRD with deep sequencing. We have deep response in the bone marrow,” Dr Gill said. He also noted that the treatment was well tolerated.

Cytokine release syndrome (CRS) developed in 9 patients: grade 1 in 2 patients, grade 2 in 6 patients, and grade 3 in 1 patient. One patient developed grade 4 tumor lysis syndrome. Treatment of CRS with the IL-6 receptor antagonist tocilizumab was not required.

There was modest residual splenomegaly in 3 of 5 patients, and adenopathy resolved in 4 of 6 patients, with progression in 1 patient.

Ibrutinib reduced CRS apparently by blocking cytokine production by T cells, said Dr Gill, adding, “The combination led to improved efficacy without increased toxicity.”

Ibrutinib may make CAR T-cell therapy more feasible.

Patients who receive ibrutinib for 6 months have a better T-cell response.

“This opens up future discussions of bringing CAR T-cell therapy earlier into CLL treatment,” said Dr Gill.

He envisions patients receiving ibrutinib for 6 months, which would allow time to manufacture T cells, and then have a T-cell infusion.

“Once patients achieve MRD, then we can discuss the possibility of stopping ibrutinib therapy,” he said.

“Most patients remain on ibrutinib, but longer follow-up may show whether remissions are sustained off ibrutinib.”

The researchers have ongoing plans to treat 25 patients with CTL19 plus ibrutinib in a continuation of this trial.

Dr Gill said longer follow-up will reveal the durability of these results “and could support evaluation of a first-line combination approach in an attempt to obviate the need for chronic therapy.” 

Photo © ASCO/Danny Morton 2017

CHICAGO—The experimental mutant IDH2 (mIDH2) inhibitor enasidenib has produced “admirable” overall survival in patients with mIDH2 relapsed or refractory acute myeloid leukemia (AML), according to Eytan M. Stein, MD, an investigator on the phase 1 dose escalation and expansion study.

Patients who achieved a complete remission (CR) had a median overall survival (OS) of 19.7 months and non-CR responders, 13.8 months.

“I really want to make the point,” Dr Stein said, “this is a group of patients that are highly refractory, either refractory to induction chemotherapy, refractory to standard of care approaches for patients who are unable to get induction chemotherapy, so refractory to hypomethylating agents or low-dose cytarabine.”

Mutations in IDH2 occur in approximately 12% of AML patients.

Dr Stein explained that the mutant protein converts alpha ketoglutarate to beta hydroxyglutarate (2-HG). And increased levels of intracellular 2-HG lead to methylation changes in the cell that cause a block in myeloid differentiation.

Enasidenib, also known as AG-221, is a selective, oral, potent inhibitor of the mIDH2 enzyyme.

Dr Stein, of Memorial Sloan Kettering Cancer Center in New York, New York, presented the results during the ASCO 2017 Annual Meeting (abstract 7004).

The clinical and translational papers were published simultaneously in Blood.

Study design

The phase 1/2 study had a large dose-escalation component, with 113 patients enrolled. Patients had to have an advanced hematologic malignancy with an IDH2 mutation.

Patients received cumulative daily doses of 50 mg – 650 mg of enasidenib in continuous 28-day cycles.

Four expansion arms were added, with 126 patients.

Two expansion arms were in relapsed/refractory AML patients: one in patients 60 years or older or any age if they had relapsed after bone marrow transplant (BMT), and the other in patients younger than 60 excluding those relapsed after BMT.

The other 2 expansion arms were in untreated AML patients and in patients with any hematologic malignancy ineligible for the other arms.

Dr Stein presented results for the relapsed/refractory AML patients in the dose escalation and expansion phases of the study.

The key endpoints were safety, tolerability, maximum tolerated dose (MTD), and dose-limiting toxicities; response rates as assessed by the local investigator according to IWG criteria; and assessment of clinical activity.

Dr Stein noted the phase 2 study is now completely accrued (n=91) and the recommended enasidenib dose is 100 mg/day in relapsed/refractory AML.

The MTD was not reached at doses up to 650 mg/day.

Baseline characteristics

Median age of all 239 phase 1 patients was 70 years (range, 19-100), 57% were male, and almost all patients had intermediate- or poor-risk disease.

The investigators were also interested in the co-occurring mutations in patients on screening and whether there were differences between patients with mIDH2 at R172 and R140.

Seventy-five percent of the patients (n=179) had R140 and 24% had R172 (n=57).

There was a statistically significant difference in the number of co-occurring mutations in the R140 and R172 patients, with the R140 patients having a higher co-mutation burden compared with the R172 patients, (P=0.020).

The most frequent mutations co-occurring in R140 patients were SRSF2, followed by, in descending order of frequency, DNMT3A, RUNX1, ASXL1, and 24 others.

SFSR2 does not occur in R172 patients. DNMT3A was the most frequently co-occurring mutation in R172, followed by ASXL1, BCOR, NRAS, RUNX1, KMT2A, KRAS, and STAG2.

Safety

The most common treatment-emergent adverse events (TEAE) that occurred in 20% or more of all patients of any grade included nausea (46%), hyperbilirubinemia (45%), diarrhea and fatigue (40% each), decreased appetite (38%), vomiting (32%), dyspnea (31%), cough (29%), pyrexia and febrile neutropenia (28% each), thrombocytopenia, anemia, constipation, hypokalemia, and peripheral edema (27% each), pneumonia (21%), and hyperuricemia (20%).

The only 2 grade 3/4 TEAEs that rose above the level of 5% were hyperbilirubinemia (12%) and thrombocytopenia (6%).

“The hyperbilirubinemia, as I’ve mentioned in a number of meetings before this,” Dr Stein clarified, “is one that occurs because the enzyme is an off-target effect of inhibiting the UGT1A1 enzyme, which conjugates bilirubin.”

“So a patient who goes on this study who has a defect in bilirubin conjugation because they have Gilbert’s disease, they will have a higher level of bilirubin compared to a patient who doesn’t have Gilbert’s disease. This does not appear to have any clinical sequelae. You’ll also notice AST, ALT, alkaline phosphatase or any liver failure is not on this [TEAE] list.”

Response

The overall response rate for the patients who received enasidenib 100 mg/day was 38.5% (42/109) and for all doses 40.3% (71/176).

The true CR rate was 20.2% (100 mg/day) and 19.3% for all doses.

An additional 20% achieved a CR with incomplete hematologic recovery, CR with incomplete platelet recovery, partial response (PR), and morphologic leukemia-free state  with either 100 mg enasidenib daily or all doses.

“Time to first response is not immediate,” Dr Stein pointed out. “It takes a median of 1.9 months to get there, and the time to complete remission takes even longer, a median of 3.7 months in the 100-mg experience, 3.8 months in all doses, to get to that best response.”

“I think the clinical importance of this is,” he added, “for a patient that one might have who is on this drug, it is important to keep them on the drug for a prolonged period of time so that they have the opportunity to have that response.”

Hematologic parameters also improved gradually.

Increases in platelet count, absolute neutrophil count, and hemoglobin level did not rise exponentially upon administration of study drug, but rather they slowly rose, “again getting to this point, that the drug takes time to work,” Dr Stein emphasized.

Patients in CR had very high transfusion independence rates, “which is what I would expect,” Dr Stein said. “If you are in complete remission, you should be transfusion independent.”

“What’s a little bit more interesting, though,” Dr Stein added, “is those patients who are non-CR responders. [I]n those patients who have responded but have less than a complete remission, 50% of them are independent of red cell transfusions and 50% of them are independent of platelet transfusions.”

Survival

The CR data and transfusion independence data translated into a median OS in these relapsed and refractory AML patients of 9.3 months.

And about 10% - 15% of the patients had prolonged survival up to 2 years and longer on the single agent.

Analysis of OS by best response revealed that for patients with a CR, “they really have an admirable overall survival of 19.7 months, almost 20 months,” Dr Stein said.

Patients who had a non-CR response had a median OS of 13.8 months, and non-responders had a median OS of 7.0 months.

And there was a qualitative improvement in response over time: the number of patients with CRs and PRs increased, while the number with stable disease decreased.

“Again, I think getting at the point it takes time for these responses to occur,” Dr Stein iterated.

Over the course of therapy, some responders had a differentiation of myeloblasts, so that by cycle 3, the marrow looked largely normal.

The investigators did not observe any morphological evidence of cytotoxicity or cellular aplasia.

But they did observe myeloid differentiation using FISH.

Trisomy 8 that was evident at the time of screening in responders’ myeloblasts, persisted in the promyelocytes and mature granulocyte population, and was no longer evident in the lymphoid compartment.

Baseline 2-HG levels and mIDH2 variant allele frequency were similar for responding and non-responding patients.

The investigators believe that differentiation of myeloblsts, not cytotoxicity, may drive the clinical efficacy of enasidenib.

A phase 3 trial of enasidenib monotherapy versus conventional care regimens is underway in older patients with late-stage AML, and phase 1/2 studies of enasidenib combinations are ongoing in newly diagnosed AML patients.

Enasidenib, which also has efficacy in myelodysplastic syndromes, has been granted priority review for relapsed/refractory AML by the US Food and Drug Administration. 

Photo © ASCO/Danny Morton 2017

CHICAGO—The experimental mutant IDH2 (mIDH2) inhibitor enasidenib has produced “admirable” overall survival in patients with mIDH2 relapsed or refractory acute myeloid leukemia (AML), according to Eytan M. Stein, MD, an investigator on the phase 1 dose escalation and expansion study.

Patients who achieved a complete remission (CR) had a median overall survival (OS) of 19.7 months and non-CR responders, 13.8 months.

“I really want to make the point,” Dr Stein said, “this is a group of patients that are highly refractory, either refractory to induction chemotherapy, refractory to standard of care approaches for patients who are unable to get induction chemotherapy, so refractory to hypomethylating agents or low-dose cytarabine.”

Mutations in IDH2 occur in approximately 12% of AML patients.

Dr Stein explained that the mutant protein converts alpha ketoglutarate to beta hydroxyglutarate (2-HG). And increased levels of intracellular 2-HG lead to methylation changes in the cell that cause a block in myeloid differentiation.

Enasidenib, also known as AG-221, is a selective, oral, potent inhibitor of the mIDH2 enzyyme.

Dr Stein, of Memorial Sloan Kettering Cancer Center in New York, New York, presented the results during the ASCO 2017 Annual Meeting (abstract 7004).

The clinical and translational papers were published simultaneously in Blood.

Study design

The phase 1/2 study had a large dose-escalation component, with 113 patients enrolled. Patients had to have an advanced hematologic malignancy with an IDH2 mutation.

Patients received cumulative daily doses of 50 mg – 650 mg of enasidenib in continuous 28-day cycles.

Four expansion arms were added, with 126 patients.

Two expansion arms were in relapsed/refractory AML patients: one in patients 60 years or older or any age if they had relapsed after bone marrow transplant (BMT), and the other in patients younger than 60 excluding those relapsed after BMT.

The other 2 expansion arms were in untreated AML patients and in patients with any hematologic malignancy ineligible for the other arms.

Dr Stein presented results for the relapsed/refractory AML patients in the dose escalation and expansion phases of the study.

The key endpoints were safety, tolerability, maximum tolerated dose (MTD), and dose-limiting toxicities; response rates as assessed by the local investigator according to IWG criteria; and assessment of clinical activity.

Dr Stein noted the phase 2 study is now completely accrued (n=91) and the recommended enasidenib dose is 100 mg/day in relapsed/refractory AML.

The MTD was not reached at doses up to 650 mg/day.

Baseline characteristics

Median age of all 239 phase 1 patients was 70 years (range, 19-100), 57% were male, and almost all patients had intermediate- or poor-risk disease.

The investigators were also interested in the co-occurring mutations in patients on screening and whether there were differences between patients with mIDH2 at R172 and R140.

Seventy-five percent of the patients (n=179) had R140 and 24% had R172 (n=57).

There was a statistically significant difference in the number of co-occurring mutations in the R140 and R172 patients, with the R140 patients having a higher co-mutation burden compared with the R172 patients, (P=0.020).

The most frequent mutations co-occurring in R140 patients were SRSF2, followed by, in descending order of frequency, DNMT3A, RUNX1, ASXL1, and 24 others.

SFSR2 does not occur in R172 patients. DNMT3A was the most frequently co-occurring mutation in R172, followed by ASXL1, BCOR, NRAS, RUNX1, KMT2A, KRAS, and STAG2.

Safety

The most common treatment-emergent adverse events (TEAE) that occurred in 20% or more of all patients of any grade included nausea (46%), hyperbilirubinemia (45%), diarrhea and fatigue (40% each), decreased appetite (38%), vomiting (32%), dyspnea (31%), cough (29%), pyrexia and febrile neutropenia (28% each), thrombocytopenia, anemia, constipation, hypokalemia, and peripheral edema (27% each), pneumonia (21%), and hyperuricemia (20%).

The only 2 grade 3/4 TEAEs that rose above the level of 5% were hyperbilirubinemia (12%) and thrombocytopenia (6%).

“The hyperbilirubinemia, as I’ve mentioned in a number of meetings before this,” Dr Stein clarified, “is one that occurs because the enzyme is an off-target effect of inhibiting the UGT1A1 enzyme, which conjugates bilirubin.”

“So a patient who goes on this study who has a defect in bilirubin conjugation because they have Gilbert’s disease, they will have a higher level of bilirubin compared to a patient who doesn’t have Gilbert’s disease. This does not appear to have any clinical sequelae. You’ll also notice AST, ALT, alkaline phosphatase or any liver failure is not on this [TEAE] list.”

Response

The overall response rate for the patients who received enasidenib 100 mg/day was 38.5% (42/109) and for all doses 40.3% (71/176).

The true CR rate was 20.2% (100 mg/day) and 19.3% for all doses.

An additional 20% achieved a CR with incomplete hematologic recovery, CR with incomplete platelet recovery, partial response (PR), and morphologic leukemia-free state  with either 100 mg enasidenib daily or all doses.

“Time to first response is not immediate,” Dr Stein pointed out. “It takes a median of 1.9 months to get there, and the time to complete remission takes even longer, a median of 3.7 months in the 100-mg experience, 3.8 months in all doses, to get to that best response.”

“I think the clinical importance of this is,” he added, “for a patient that one might have who is on this drug, it is important to keep them on the drug for a prolonged period of time so that they have the opportunity to have that response.”

Hematologic parameters also improved gradually.

Increases in platelet count, absolute neutrophil count, and hemoglobin level did not rise exponentially upon administration of study drug, but rather they slowly rose, “again getting to this point, that the drug takes time to work,” Dr Stein emphasized.

Patients in CR had very high transfusion independence rates, “which is what I would expect,” Dr Stein said. “If you are in complete remission, you should be transfusion independent.”

“What’s a little bit more interesting, though,” Dr Stein added, “is those patients who are non-CR responders. [I]n those patients who have responded but have less than a complete remission, 50% of them are independent of red cell transfusions and 50% of them are independent of platelet transfusions.”

Survival

The CR data and transfusion independence data translated into a median OS in these relapsed and refractory AML patients of 9.3 months.

And about 10% - 15% of the patients had prolonged survival up to 2 years and longer on the single agent.

Analysis of OS by best response revealed that for patients with a CR, “they really have an admirable overall survival of 19.7 months, almost 20 months,” Dr Stein said.

Patients who had a non-CR response had a median OS of 13.8 months, and non-responders had a median OS of 7.0 months.

And there was a qualitative improvement in response over time: the number of patients with CRs and PRs increased, while the number with stable disease decreased.

“Again, I think getting at the point it takes time for these responses to occur,” Dr Stein iterated.

Over the course of therapy, some responders had a differentiation of myeloblasts, so that by cycle 3, the marrow looked largely normal.

The investigators did not observe any morphological evidence of cytotoxicity or cellular aplasia.

But they did observe myeloid differentiation using FISH.

Trisomy 8 that was evident at the time of screening in responders’ myeloblasts, persisted in the promyelocytes and mature granulocyte population, and was no longer evident in the lymphoid compartment.

Baseline 2-HG levels and mIDH2 variant allele frequency were similar for responding and non-responding patients.

The investigators believe that differentiation of myeloblsts, not cytotoxicity, may drive the clinical efficacy of enasidenib.

A phase 3 trial of enasidenib monotherapy versus conventional care regimens is underway in older patients with late-stage AML, and phase 1/2 studies of enasidenib combinations are ongoing in newly diagnosed AML patients.

Enasidenib, which also has efficacy in myelodysplastic syndromes, has been granted priority review for relapsed/refractory AML by the US Food and Drug Administration. 

Photo © ASCO/Danny Morton 2017

CHICAGO—The experimental mutant IDH2 (mIDH2) inhibitor enasidenib has produced “admirable” overall survival in patients with mIDH2 relapsed or refractory acute myeloid leukemia (AML), according to Eytan M. Stein, MD, an investigator on the phase 1 dose escalation and expansion study.

Patients who achieved a complete remission (CR) had a median overall survival (OS) of 19.7 months and non-CR responders, 13.8 months.

“I really want to make the point,” Dr Stein said, “this is a group of patients that are highly refractory, either refractory to induction chemotherapy, refractory to standard of care approaches for patients who are unable to get induction chemotherapy, so refractory to hypomethylating agents or low-dose cytarabine.”

Mutations in IDH2 occur in approximately 12% of AML patients.

Dr Stein explained that the mutant protein converts alpha ketoglutarate to beta hydroxyglutarate (2-HG). And increased levels of intracellular 2-HG lead to methylation changes in the cell that cause a block in myeloid differentiation.

Enasidenib, also known as AG-221, is a selective, oral, potent inhibitor of the mIDH2 enzyyme.

Dr Stein, of Memorial Sloan Kettering Cancer Center in New York, New York, presented the results during the ASCO 2017 Annual Meeting (abstract 7004).

The clinical and translational papers were published simultaneously in Blood.

Study design

The phase 1/2 study had a large dose-escalation component, with 113 patients enrolled. Patients had to have an advanced hematologic malignancy with an IDH2 mutation.

Patients received cumulative daily doses of 50 mg – 650 mg of enasidenib in continuous 28-day cycles.

Four expansion arms were added, with 126 patients.

Two expansion arms were in relapsed/refractory AML patients: one in patients 60 years or older or any age if they had relapsed after bone marrow transplant (BMT), and the other in patients younger than 60 excluding those relapsed after BMT.

The other 2 expansion arms were in untreated AML patients and in patients with any hematologic malignancy ineligible for the other arms.

Dr Stein presented results for the relapsed/refractory AML patients in the dose escalation and expansion phases of the study.

The key endpoints were safety, tolerability, maximum tolerated dose (MTD), and dose-limiting toxicities; response rates as assessed by the local investigator according to IWG criteria; and assessment of clinical activity.

Dr Stein noted the phase 2 study is now completely accrued (n=91) and the recommended enasidenib dose is 100 mg/day in relapsed/refractory AML.

The MTD was not reached at doses up to 650 mg/day.

Baseline characteristics

Median age of all 239 phase 1 patients was 70 years (range, 19-100), 57% were male, and almost all patients had intermediate- or poor-risk disease.

The investigators were also interested in the co-occurring mutations in patients on screening and whether there were differences between patients with mIDH2 at R172 and R140.

Seventy-five percent of the patients (n=179) had R140 and 24% had R172 (n=57).

There was a statistically significant difference in the number of co-occurring mutations in the R140 and R172 patients, with the R140 patients having a higher co-mutation burden compared with the R172 patients, (P=0.020).

The most frequent mutations co-occurring in R140 patients were SRSF2, followed by, in descending order of frequency, DNMT3A, RUNX1, ASXL1, and 24 others.

SFSR2 does not occur in R172 patients. DNMT3A was the most frequently co-occurring mutation in R172, followed by ASXL1, BCOR, NRAS, RUNX1, KMT2A, KRAS, and STAG2.

Safety

The most common treatment-emergent adverse events (TEAE) that occurred in 20% or more of all patients of any grade included nausea (46%), hyperbilirubinemia (45%), diarrhea and fatigue (40% each), decreased appetite (38%), vomiting (32%), dyspnea (31%), cough (29%), pyrexia and febrile neutropenia (28% each), thrombocytopenia, anemia, constipation, hypokalemia, and peripheral edema (27% each), pneumonia (21%), and hyperuricemia (20%).

The only 2 grade 3/4 TEAEs that rose above the level of 5% were hyperbilirubinemia (12%) and thrombocytopenia (6%).

“The hyperbilirubinemia, as I’ve mentioned in a number of meetings before this,” Dr Stein clarified, “is one that occurs because the enzyme is an off-target effect of inhibiting the UGT1A1 enzyme, which conjugates bilirubin.”

“So a patient who goes on this study who has a defect in bilirubin conjugation because they have Gilbert’s disease, they will have a higher level of bilirubin compared to a patient who doesn’t have Gilbert’s disease. This does not appear to have any clinical sequelae. You’ll also notice AST, ALT, alkaline phosphatase or any liver failure is not on this [TEAE] list.”

Response

The overall response rate for the patients who received enasidenib 100 mg/day was 38.5% (42/109) and for all doses 40.3% (71/176).

The true CR rate was 20.2% (100 mg/day) and 19.3% for all doses.

An additional 20% achieved a CR with incomplete hematologic recovery, CR with incomplete platelet recovery, partial response (PR), and morphologic leukemia-free state  with either 100 mg enasidenib daily or all doses.

“Time to first response is not immediate,” Dr Stein pointed out. “It takes a median of 1.9 months to get there, and the time to complete remission takes even longer, a median of 3.7 months in the 100-mg experience, 3.8 months in all doses, to get to that best response.”

“I think the clinical importance of this is,” he added, “for a patient that one might have who is on this drug, it is important to keep them on the drug for a prolonged period of time so that they have the opportunity to have that response.”

Hematologic parameters also improved gradually.

Increases in platelet count, absolute neutrophil count, and hemoglobin level did not rise exponentially upon administration of study drug, but rather they slowly rose, “again getting to this point, that the drug takes time to work,” Dr Stein emphasized.

Patients in CR had very high transfusion independence rates, “which is what I would expect,” Dr Stein said. “If you are in complete remission, you should be transfusion independent.”

“What’s a little bit more interesting, though,” Dr Stein added, “is those patients who are non-CR responders. [I]n those patients who have responded but have less than a complete remission, 50% of them are independent of red cell transfusions and 50% of them are independent of platelet transfusions.”

Survival

The CR data and transfusion independence data translated into a median OS in these relapsed and refractory AML patients of 9.3 months.

And about 10% - 15% of the patients had prolonged survival up to 2 years and longer on the single agent.

Analysis of OS by best response revealed that for patients with a CR, “they really have an admirable overall survival of 19.7 months, almost 20 months,” Dr Stein said.

Patients who had a non-CR response had a median OS of 13.8 months, and non-responders had a median OS of 7.0 months.

And there was a qualitative improvement in response over time: the number of patients with CRs and PRs increased, while the number with stable disease decreased.

“Again, I think getting at the point it takes time for these responses to occur,” Dr Stein iterated.

Over the course of therapy, some responders had a differentiation of myeloblasts, so that by cycle 3, the marrow looked largely normal.

The investigators did not observe any morphological evidence of cytotoxicity or cellular aplasia.

But they did observe myeloid differentiation using FISH.

Trisomy 8 that was evident at the time of screening in responders’ myeloblasts, persisted in the promyelocytes and mature granulocyte population, and was no longer evident in the lymphoid compartment.

Baseline 2-HG levels and mIDH2 variant allele frequency were similar for responding and non-responding patients.

The investigators believe that differentiation of myeloblsts, not cytotoxicity, may drive the clinical efficacy of enasidenib.

A phase 3 trial of enasidenib monotherapy versus conventional care regimens is underway in older patients with late-stage AML, and phase 1/2 studies of enasidenib combinations are ongoing in newly diagnosed AML patients.

Enasidenib, which also has efficacy in myelodysplastic syndromes, has been granted priority review for relapsed/refractory AML by the US Food and Drug Administration. 

Photo © ASCO/Danny Morton 2017

CHICAGO—Next generation sequencing (NGS) has shown that the FLT3 inhibitor gilteritinib can produce deep molecular responses in a subset of patients with acute myeloid leukemia (AML), according to new research.

Gilteritinib is a highly selective FLT3/AXL inhibitor that is active against FLT3-ITD and FLT3-D835 mutations, but minimal residual disease (MRD) had not systematically been assessed previously in AML patients treated with potent FLT3 inhibitors.

Investigators believed that MRD evaluation in these patients could serve as a useful marker of FLT3 inhibitor efficacy. They therefore conducted an exploratory analysis of a subset of AML patients treated with gilteritinib on the Chrysalis study.

Jessica K. Altman, MD, of the Robert H. Lurie Cancer Center of Northwestern University in Chicago, Illinois, presented the findings at the ASCO 2017 Annual Meeting (abstract 7003).

Chrysalis study: Efficacy and survival

The phase 1/2 Chrysalis study examined the tolerability and antileukemic activity of once daily gilteritinib in a FLT3-ITD-enriched relapsed/refractory AML population of approximately 250 patients.

Overall, gilteritinib was well tolerated and had consistency and potent FLT3 inhibition at doses of >80 mg/day.

The maximum tolerated dose was 300 mg/day. Dose-limiting toxicities were diarrhea and liver function abnormalities.

The greatest overall response rate was 52% and the longest median overall survival (OS) duration was 31 weeks, observed in patients at doses >80 mg/day.

The composite complete remission (CR) rate, comprised of CR, CR with incomplete count recovery (Cri), and CR with incomplete platelet recovery (CRp), was 41%.

The median OS was 31 weeks, and median duration of response 20 weeks.

“Survival probabilities demonstrated that the overall survival for patients who received 80 mg of gilteritinib was higher than those who received less than 80 mg,” Dr Altman said.

Molecular response assessment

Dr Altman then presented the molecular response assessment.

The investigators included all FLT3-ITD mutated patients enrolled in the gilteritinib 120 and 200 mg/day dose cohorts and had bone marrow aspirates available at baseline and at 1 or more additional time points.

“The group I’m reporting on,” Dr Altman explained, “comprises 51% of all FLT3-ITD mutated patients treated at these 2 dose levels.”

FLT3-ITD and total FLT3 alleles were quantified by a novel NGS assay using an Illumina® sequencing platform. Read depth of at least 100,000 reads per sample were implemented.

“Evaluation of MRD was exploratory and it was not prespecified in the study,” Dr Altman noted.

Hence, the investigators defined a molecular response as an ITD signal ratio—FLT3-ITD : FLT3 total—of <10^-2.

They defined major molecular response (MMR) as an ITD signal ratio of <10^-3, and negative MRD status as <10^-4.

Patient characteristics

Baseline characteristics of the 80 patients in the MRD analysis group were similar to those of the entire Chrysalis study population.

Median age was 61 years (range, 23 – 86) and the patients were heavily pretreated: 35% had 3 or more prior lines of AML therapy, and 28% had received a prior FLT3 inhibitor. About a third had prior allogeneic hematopoietic stem cell transplant.

Molecular response

Median OS in this cohort was 32.6 weeks, very similar to the entire study population.

Twenty patients (25%) achieved a molecular response, 18 (23%) an MMR, and 13 (16%) were MRD negative.

The median time to achieve a minimum ITD signal ratio was 8.2 weeks (range, 3.7 – 64).

And molecular response correlated with improved OS.

“The 20 patients who achieved a molecular response had a median overall survival of 59.6 weeks,” Dr Altman said, “which is statistically significantly different and I think clinically different than those who did not attain a molecular response.”

Patients who did not achieve a molecular response had a median overall survival of 28.4 weeks.

“As you could predict,” she added, “the molecular response was greater in those who attained a complete remission than those who had a CRp or Cri.”

Investigators observed similar results in patients who achieved an MMR, using the the cutoff point of 10^-3.

“When we stratified by MRD negative status,” she said, “which was an ITD signal ratio of 10^-4 or better, there’s clear separation of the Kaplan Meier curves for OS in this cohort again.”

Dr Altman pointed out that this was the first clinical trial to demonstrate that patients with AML treated with a FLT3 inhibitor can attain a molecular response.

“Also, and importantly, there is now a sensitive and specific assay for the detection of minimal residual disease in FLT3-ITD mutated patients and it has the potential to be widely adopted across trials and in clinical practice.”

MRD is prospectively being evaluated in 2 gilteritinib phase 3 maintenance studies.

The trial was sponsored by Astellas Pharma Global Development, Inc. 

Photo © ASCO/Danny Morton 2017

CHICAGO—Next generation sequencing (NGS) has shown that the FLT3 inhibitor gilteritinib can produce deep molecular responses in a subset of patients with acute myeloid leukemia (AML), according to new research.

Gilteritinib is a highly selective FLT3/AXL inhibitor that is active against FLT3-ITD and FLT3-D835 mutations, but minimal residual disease (MRD) had not systematically been assessed previously in AML patients treated with potent FLT3 inhibitors.

Investigators believed that MRD evaluation in these patients could serve as a useful marker of FLT3 inhibitor efficacy. They therefore conducted an exploratory analysis of a subset of AML patients treated with gilteritinib on the Chrysalis study.

Jessica K. Altman, MD, of the Robert H. Lurie Cancer Center of Northwestern University in Chicago, Illinois, presented the findings at the ASCO 2017 Annual Meeting (abstract 7003).

Chrysalis study: Efficacy and survival

The phase 1/2 Chrysalis study examined the tolerability and antileukemic activity of once daily gilteritinib in a FLT3-ITD-enriched relapsed/refractory AML population of approximately 250 patients.

Overall, gilteritinib was well tolerated and had consistency and potent FLT3 inhibition at doses of >80 mg/day.

The maximum tolerated dose was 300 mg/day. Dose-limiting toxicities were diarrhea and liver function abnormalities.

The greatest overall response rate was 52% and the longest median overall survival (OS) duration was 31 weeks, observed in patients at doses >80 mg/day.

The composite complete remission (CR) rate, comprised of CR, CR with incomplete count recovery (Cri), and CR with incomplete platelet recovery (CRp), was 41%.

The median OS was 31 weeks, and median duration of response 20 weeks.

“Survival probabilities demonstrated that the overall survival for patients who received 80 mg of gilteritinib was higher than those who received less than 80 mg,” Dr Altman said.

Molecular response assessment

Dr Altman then presented the molecular response assessment.

The investigators included all FLT3-ITD mutated patients enrolled in the gilteritinib 120 and 200 mg/day dose cohorts and had bone marrow aspirates available at baseline and at 1 or more additional time points.

“The group I’m reporting on,” Dr Altman explained, “comprises 51% of all FLT3-ITD mutated patients treated at these 2 dose levels.”

FLT3-ITD and total FLT3 alleles were quantified by a novel NGS assay using an Illumina® sequencing platform. Read depth of at least 100,000 reads per sample were implemented.

“Evaluation of MRD was exploratory and it was not prespecified in the study,” Dr Altman noted.

Hence, the investigators defined a molecular response as an ITD signal ratio—FLT3-ITD : FLT3 total—of <10^-2.

They defined major molecular response (MMR) as an ITD signal ratio of <10^-3, and negative MRD status as <10^-4.

Patient characteristics

Baseline characteristics of the 80 patients in the MRD analysis group were similar to those of the entire Chrysalis study population.

Median age was 61 years (range, 23 – 86) and the patients were heavily pretreated: 35% had 3 or more prior lines of AML therapy, and 28% had received a prior FLT3 inhibitor. About a third had prior allogeneic hematopoietic stem cell transplant.

Molecular response

Median OS in this cohort was 32.6 weeks, very similar to the entire study population.

Twenty patients (25%) achieved a molecular response, 18 (23%) an MMR, and 13 (16%) were MRD negative.

The median time to achieve a minimum ITD signal ratio was 8.2 weeks (range, 3.7 – 64).

And molecular response correlated with improved OS.

“The 20 patients who achieved a molecular response had a median overall survival of 59.6 weeks,” Dr Altman said, “which is statistically significantly different and I think clinically different than those who did not attain a molecular response.”

Patients who did not achieve a molecular response had a median overall survival of 28.4 weeks.

“As you could predict,” she added, “the molecular response was greater in those who attained a complete remission than those who had a CRp or Cri.”

Investigators observed similar results in patients who achieved an MMR, using the the cutoff point of 10^-3.

“When we stratified by MRD negative status,” she said, “which was an ITD signal ratio of 10^-4 or better, there’s clear separation of the Kaplan Meier curves for OS in this cohort again.”

Dr Altman pointed out that this was the first clinical trial to demonstrate that patients with AML treated with a FLT3 inhibitor can attain a molecular response.

“Also, and importantly, there is now a sensitive and specific assay for the detection of minimal residual disease in FLT3-ITD mutated patients and it has the potential to be widely adopted across trials and in clinical practice.”

MRD is prospectively being evaluated in 2 gilteritinib phase 3 maintenance studies.

The trial was sponsored by Astellas Pharma Global Development, Inc. 

Photo © ASCO/Danny Morton 2017

CHICAGO—Next generation sequencing (NGS) has shown that the FLT3 inhibitor gilteritinib can produce deep molecular responses in a subset of patients with acute myeloid leukemia (AML), according to new research.

Gilteritinib is a highly selective FLT3/AXL inhibitor that is active against FLT3-ITD and FLT3-D835 mutations, but minimal residual disease (MRD) had not systematically been assessed previously in AML patients treated with potent FLT3 inhibitors.

Investigators believed that MRD evaluation in these patients could serve as a useful marker of FLT3 inhibitor efficacy. They therefore conducted an exploratory analysis of a subset of AML patients treated with gilteritinib on the Chrysalis study.

Jessica K. Altman, MD, of the Robert H. Lurie Cancer Center of Northwestern University in Chicago, Illinois, presented the findings at the ASCO 2017 Annual Meeting (abstract 7003).

Chrysalis study: Efficacy and survival

The phase 1/2 Chrysalis study examined the tolerability and antileukemic activity of once daily gilteritinib in a FLT3-ITD-enriched relapsed/refractory AML population of approximately 250 patients.

Overall, gilteritinib was well tolerated and had consistency and potent FLT3 inhibition at doses of >80 mg/day.

The maximum tolerated dose was 300 mg/day. Dose-limiting toxicities were diarrhea and liver function abnormalities.

The greatest overall response rate was 52% and the longest median overall survival (OS) duration was 31 weeks, observed in patients at doses >80 mg/day.

The composite complete remission (CR) rate, comprised of CR, CR with incomplete count recovery (Cri), and CR with incomplete platelet recovery (CRp), was 41%.

The median OS was 31 weeks, and median duration of response 20 weeks.

“Survival probabilities demonstrated that the overall survival for patients who received 80 mg of gilteritinib was higher than those who received less than 80 mg,” Dr Altman said.

Molecular response assessment

Dr Altman then presented the molecular response assessment.

The investigators included all FLT3-ITD mutated patients enrolled in the gilteritinib 120 and 200 mg/day dose cohorts and had bone marrow aspirates available at baseline and at 1 or more additional time points.

“The group I’m reporting on,” Dr Altman explained, “comprises 51% of all FLT3-ITD mutated patients treated at these 2 dose levels.”

FLT3-ITD and total FLT3 alleles were quantified by a novel NGS assay using an Illumina® sequencing platform. Read depth of at least 100,000 reads per sample were implemented.

“Evaluation of MRD was exploratory and it was not prespecified in the study,” Dr Altman noted.

Hence, the investigators defined a molecular response as an ITD signal ratio—FLT3-ITD : FLT3 total—of <10^-2.

They defined major molecular response (MMR) as an ITD signal ratio of <10^-3, and negative MRD status as <10^-4.

Patient characteristics

Baseline characteristics of the 80 patients in the MRD analysis group were similar to those of the entire Chrysalis study population.

Median age was 61 years (range, 23 – 86) and the patients were heavily pretreated: 35% had 3 or more prior lines of AML therapy, and 28% had received a prior FLT3 inhibitor. About a third had prior allogeneic hematopoietic stem cell transplant.

Molecular response

Median OS in this cohort was 32.6 weeks, very similar to the entire study population.

Twenty patients (25%) achieved a molecular response, 18 (23%) an MMR, and 13 (16%) were MRD negative.

The median time to achieve a minimum ITD signal ratio was 8.2 weeks (range, 3.7 – 64).

And molecular response correlated with improved OS.

“The 20 patients who achieved a molecular response had a median overall survival of 59.6 weeks,” Dr Altman said, “which is statistically significantly different and I think clinically different than those who did not attain a molecular response.”

Patients who did not achieve a molecular response had a median overall survival of 28.4 weeks.

“As you could predict,” she added, “the molecular response was greater in those who attained a complete remission than those who had a CRp or Cri.”

Investigators observed similar results in patients who achieved an MMR, using the the cutoff point of 10^-3.

“When we stratified by MRD negative status,” she said, “which was an ITD signal ratio of 10^-4 or better, there’s clear separation of the Kaplan Meier curves for OS in this cohort again.”

Dr Altman pointed out that this was the first clinical trial to demonstrate that patients with AML treated with a FLT3 inhibitor can attain a molecular response.

“Also, and importantly, there is now a sensitive and specific assay for the detection of minimal residual disease in FLT3-ITD mutated patients and it has the potential to be widely adopted across trials and in clinical practice.”

MRD is prospectively being evaluated in 2 gilteritinib phase 3 maintenance studies.

The trial was sponsored by Astellas Pharma Global Development, Inc. 

General Medical Sciences

CHICAGO—While 67% of newly diagnosed patients with acute myeloid leukemia (AML) receive some genetic testing, only 9% receive all 7 of the genetic tests recommended by the National Comprehensive Cancer Network (NCCN), according to new research.

The data comes from the CONNECT MDS/AML Disease Registry, which collects treatment and outcome statistics from 86 sites across the United States, both academic medical centers and community settings. The findings reflect data gathered from 2013 to 2016.

Previously, data on genetic testing in AML patients came primarily from clinical trials, where adherence to guidelines is very high. The current analysis evaluated adherence to genetic testing guidelines in AML treated outside the clinic trial setting.

Daniel A. Pollyea, MD, of the University of Colorado Comprehensive Cancer Center in Aurora, presented the findings on behalf of the CONNECT MDS/AML Disease Registry Scientific Steering Committee (abstract 7022).

The CONNECT registry is a US prospective, observational cohort study of patients with newly diagnosed AML or myelodysplastic syndromes (MDS) aged 55 years or older. Enrollment is ongoing and study clinicians make all clinical decisions.

NCCN guidelines recommend testing AML patients for NPM1, FLT3-ITD, CEBPA, IDH1, IDH2, DNMT3A, and KIT mutations.

“We now know a tremendous amount about the genetic underpinnings of the disease,” Dr Pollyea said.

“We can test for these genetic changes in the clinic to see what’s making a patient’s disease tick. And often there are targeted therapies that can be matched with these genetic changes," he added. "But there’s a disconnect between what can be done, what should be done, and what is being done.”

The current analysis evaluated genetic testing in 259 AML patients, 173 (67%) of whom had some genetic testing.

The likelihood of patients getting tested varied by type of treatment center, age, karyotype, and insurance.

Patients treated at academic medical centers had higher rates of testing than those treated at community clinics (76% and 62%, respectively), P= 0.018

Patients younger than 65 years more often were tested than older patients (83% and 60%, respectively), P= 0.0003.

Patients with non-Medicare insurance were more often tested than those with Medicare (74% and 61%, respectively), P= .025.

And patients with normal karyotype were more often tested than those with abnormal karyotype (77% and 59%, respectively), P= 0.006.

Of the 173 patients who had some genetic testing, only 15 (9%) had all the molecular tests recommended by NCCN.

Of the 7 recommended tests, NPM1 (77%) and FLT3-ITD (76%) were most often reported and DNMT3A least often (16%).

Dr Pollyea attributed the lack of adherence to the guidelines in part to willingness of insurance companies to pay for testing.

He also suggested the guidelines themselves might need adjustment, given the low adherence rate.

Nevertheless, he affirmed the guidelines are well founded. “I think the guidelines are pretty solid and, in my opinion, I would say they don’t go far enough in recommending genetic testing.”

“We’re in our infancy with this testing, and even earlier than infancy in seeing how we’re doing on testing. But now with this registry we at least have the infrastructure available to ask these kinds of questions,” Dr Pollyea added. 

General Medical Sciences

CHICAGO—While 67% of newly diagnosed patients with acute myeloid leukemia (AML) receive some genetic testing, only 9% receive all 7 of the genetic tests recommended by the National Comprehensive Cancer Network (NCCN), according to new research.

The data comes from the CONNECT MDS/AML Disease Registry, which collects treatment and outcome statistics from 86 sites across the United States, both academic medical centers and community settings. The findings reflect data gathered from 2013 to 2016.

Previously, data on genetic testing in AML patients came primarily from clinical trials, where adherence to guidelines is very high. The current analysis evaluated adherence to genetic testing guidelines in AML treated outside the clinic trial setting.

Daniel A. Pollyea, MD, of the University of Colorado Comprehensive Cancer Center in Aurora, presented the findings on behalf of the CONNECT MDS/AML Disease Registry Scientific Steering Committee (abstract 7022).

The CONNECT registry is a US prospective, observational cohort study of patients with newly diagnosed AML or myelodysplastic syndromes (MDS) aged 55 years or older. Enrollment is ongoing and study clinicians make all clinical decisions.

NCCN guidelines recommend testing AML patients for NPM1, FLT3-ITD, CEBPA, IDH1, IDH2, DNMT3A, and KIT mutations.

“We now know a tremendous amount about the genetic underpinnings of the disease,” Dr Pollyea said.

“We can test for these genetic changes in the clinic to see what’s making a patient’s disease tick. And often there are targeted therapies that can be matched with these genetic changes," he added. "But there’s a disconnect between what can be done, what should be done, and what is being done.”

The current analysis evaluated genetic testing in 259 AML patients, 173 (67%) of whom had some genetic testing.

The likelihood of patients getting tested varied by type of treatment center, age, karyotype, and insurance.

Patients treated at academic medical centers had higher rates of testing than those treated at community clinics (76% and 62%, respectively), P= 0.018

Patients younger than 65 years more often were tested than older patients (83% and 60%, respectively), P= 0.0003.

Patients with non-Medicare insurance were more often tested than those with Medicare (74% and 61%, respectively), P= .025.

And patients with normal karyotype were more often tested than those with abnormal karyotype (77% and 59%, respectively), P= 0.006.

Of the 173 patients who had some genetic testing, only 15 (9%) had all the molecular tests recommended by NCCN.

Of the 7 recommended tests, NPM1 (77%) and FLT3-ITD (76%) were most often reported and DNMT3A least often (16%).

Dr Pollyea attributed the lack of adherence to the guidelines in part to willingness of insurance companies to pay for testing.

He also suggested the guidelines themselves might need adjustment, given the low adherence rate.

Nevertheless, he affirmed the guidelines are well founded. “I think the guidelines are pretty solid and, in my opinion, I would say they don’t go far enough in recommending genetic testing.”

“We’re in our infancy with this testing, and even earlier than infancy in seeing how we’re doing on testing. But now with this registry we at least have the infrastructure available to ask these kinds of questions,” Dr Pollyea added. 

General Medical Sciences

CHICAGO—While 67% of newly diagnosed patients with acute myeloid leukemia (AML) receive some genetic testing, only 9% receive all 7 of the genetic tests recommended by the National Comprehensive Cancer Network (NCCN), according to new research.

The data comes from the CONNECT MDS/AML Disease Registry, which collects treatment and outcome statistics from 86 sites across the United States, both academic medical centers and community settings. The findings reflect data gathered from 2013 to 2016.

Previously, data on genetic testing in AML patients came primarily from clinical trials, where adherence to guidelines is very high. The current analysis evaluated adherence to genetic testing guidelines in AML treated outside the clinic trial setting.

Daniel A. Pollyea, MD, of the University of Colorado Comprehensive Cancer Center in Aurora, presented the findings on behalf of the CONNECT MDS/AML Disease Registry Scientific Steering Committee (abstract 7022).

The CONNECT registry is a US prospective, observational cohort study of patients with newly diagnosed AML or myelodysplastic syndromes (MDS) aged 55 years or older. Enrollment is ongoing and study clinicians make all clinical decisions.

NCCN guidelines recommend testing AML patients for NPM1, FLT3-ITD, CEBPA, IDH1, IDH2, DNMT3A, and KIT mutations.

“We now know a tremendous amount about the genetic underpinnings of the disease,” Dr Pollyea said.

“We can test for these genetic changes in the clinic to see what’s making a patient’s disease tick. And often there are targeted therapies that can be matched with these genetic changes," he added. "But there’s a disconnect between what can be done, what should be done, and what is being done.”

The current analysis evaluated genetic testing in 259 AML patients, 173 (67%) of whom had some genetic testing.

The likelihood of patients getting tested varied by type of treatment center, age, karyotype, and insurance.

Patients treated at academic medical centers had higher rates of testing than those treated at community clinics (76% and 62%, respectively), P= 0.018

Patients younger than 65 years more often were tested than older patients (83% and 60%, respectively), P= 0.0003.

Patients with non-Medicare insurance were more often tested than those with Medicare (74% and 61%, respectively), P= .025.

And patients with normal karyotype were more often tested than those with abnormal karyotype (77% and 59%, respectively), P= 0.006.

Of the 173 patients who had some genetic testing, only 15 (9%) had all the molecular tests recommended by NCCN.

Of the 7 recommended tests, NPM1 (77%) and FLT3-ITD (76%) were most often reported and DNMT3A least often (16%).

Dr Pollyea attributed the lack of adherence to the guidelines in part to willingness of insurance companies to pay for testing.

He also suggested the guidelines themselves might need adjustment, given the low adherence rate.

Nevertheless, he affirmed the guidelines are well founded. “I think the guidelines are pretty solid and, in my opinion, I would say they don’t go far enough in recommending genetic testing.”

“We’re in our infancy with this testing, and even earlier than infancy in seeing how we’re doing on testing. But now with this registry we at least have the infrastructure available to ask these kinds of questions,” Dr Pollyea added. 

Image by Difu Wu

The European Commission has approved the inclusion of treatment-free remission (TFR) data in the European Union (EU) product information for nilotinib (Tasigna®).

TFR is the ability to maintain molecular response after stopping tyrosine kinase inhibitor (TKI) therapy in patients with Ph+ chronic myeloid leukemia in chronic phase (CML-CP).

Nilotinib is approved for the treatment of CML-CP in adults resistant or intolerant to at least one prior therapy, including imatinib, and for the treatment of adults with newly diagnosed Ph+ CML.

Nilotinib is the first and only TKI to include TFR data in its product information in the EU, according to Novartis, developer of the drug.

Two large international Ph+ CML trials assessing nilotinib discontinuation—ENESTfreedom and ENESTop—formed the basis of the decision.

The two open-label trials showed that half of Ph+ CML-CP patients who met rigorous predefined response criteria maintained TFR after stopping nilotinib, both in the frontline setting and after switching from imatinib.

Both trials included regular and frequent molecular monitoring of BCR-ABL levels with an assay that could measure transcript levels down to a molecular response (MR) of 4.5. Frequent monitoring after discontinuation helped determine loss of MR 4.0 and major molecular response, indicating the need to re-initiate treatment.

ENESTfreedom

This phase 2 trial (Evaluating Nilotinib Efficacy and Safety in Clinical Trials - Following REsponsE in De nOvo CML-CP Patients) involved 215 patients with Ph+ CML-CP treated at 132 sites across 19 countries.

The trial evaluated whether treatment could be stopped in 190 of the patients after they had achieved a response of MR 4.5 and a sustained deep molecular response for 1 year as first-line treatment.

The results showed that 51.6% of the patients in the trial could discontinue therapy and remain in TFR at the 48-week analysis.

However, ENESTfreedom did not meet its primary endpoint of 50% or more of patients in MMR at 48 weeks in the TFR phase. The median treatment duration was 3.6 years.

Adverse events in the trial included musculoskeletal pain (24.7%) during the first years of the TFR phase compared with 16.3% in those still on nilotinib.

No patient progressed to advanced phase/blast crisis.

ENESTop

This phase 2 trial (Evaluating Nilotinib Efficacy and Safety Trial) involved 163 patients with Ph+ CML-CP treated at 63 sites across 18 countries. Investigators evaluated 126 patients who had been treated with imatinib and then switched to nilotinib and had achieved a sustained deep molecular response for 1 year while on nilotinib.

The trial demonstrated that 57.9% of patients maintained a molecular resonse at 48 weeks after stopping treatment. The trial met its primary endpoint—the proportion of patients who did not lose MR 4.0 or MMR within 48 weeks of discontinuing nilotinib in the TFR phase.

Again, the rates of musuloskeletal pain were higher in the first year of TFR than in patients still on nilotinib in the consolidation phase, 42.1% and 14.3%, respectively.

Results of the EURO-SKI trial also support the idea that certain CML patients can safely stop TKI therapy.

For full prescribing information, see the product insert.

Image by Difu Wu

The European Commission has approved the inclusion of treatment-free remission (TFR) data in the European Union (EU) product information for nilotinib (Tasigna®).

TFR is the ability to maintain molecular response after stopping tyrosine kinase inhibitor (TKI) therapy in patients with Ph+ chronic myeloid leukemia in chronic phase (CML-CP).

Nilotinib is approved for the treatment of CML-CP in adults resistant or intolerant to at least one prior therapy, including imatinib, and for the treatment of adults with newly diagnosed Ph+ CML.

Nilotinib is the first and only TKI to include TFR data in its product information in the EU, according to Novartis, developer of the drug.

Two large international Ph+ CML trials assessing nilotinib discontinuation—ENESTfreedom and ENESTop—formed the basis of the decision.

The two open-label trials showed that half of Ph+ CML-CP patients who met rigorous predefined response criteria maintained TFR after stopping nilotinib, both in the frontline setting and after switching from imatinib.

Both trials included regular and frequent molecular monitoring of BCR-ABL levels with an assay that could measure transcript levels down to a molecular response (MR) of 4.5. Frequent monitoring after discontinuation helped determine loss of MR 4.0 and major molecular response, indicating the need to re-initiate treatment.

ENESTfreedom

This phase 2 trial (Evaluating Nilotinib Efficacy and Safety in Clinical Trials - Following REsponsE in De nOvo CML-CP Patients) involved 215 patients with Ph+ CML-CP treated at 132 sites across 19 countries.

The trial evaluated whether treatment could be stopped in 190 of the patients after they had achieved a response of MR 4.5 and a sustained deep molecular response for 1 year as first-line treatment.

The results showed that 51.6% of the patients in the trial could discontinue therapy and remain in TFR at the 48-week analysis.

However, ENESTfreedom did not meet its primary endpoint of 50% or more of patients in MMR at 48 weeks in the TFR phase. The median treatment duration was 3.6 years.

Adverse events in the trial included musculoskeletal pain (24.7%) during the first years of the TFR phase compared with 16.3% in those still on nilotinib.

No patient progressed to advanced phase/blast crisis.

ENESTop

This phase 2 trial (Evaluating Nilotinib Efficacy and Safety Trial) involved 163 patients with Ph+ CML-CP treated at 63 sites across 18 countries. Investigators evaluated 126 patients who had been treated with imatinib and then switched to nilotinib and had achieved a sustained deep molecular response for 1 year while on nilotinib.

The trial demonstrated that 57.9% of patients maintained a molecular resonse at 48 weeks after stopping treatment. The trial met its primary endpoint—the proportion of patients who did not lose MR 4.0 or MMR within 48 weeks of discontinuing nilotinib in the TFR phase.

Again, the rates of musuloskeletal pain were higher in the first year of TFR than in patients still on nilotinib in the consolidation phase, 42.1% and 14.3%, respectively.

Results of the EURO-SKI trial also support the idea that certain CML patients can safely stop TKI therapy.

For full prescribing information, see the product insert.

Image by Difu Wu

The European Commission has approved the inclusion of treatment-free remission (TFR) data in the European Union (EU) product information for nilotinib (Tasigna®).

TFR is the ability to maintain molecular response after stopping tyrosine kinase inhibitor (TKI) therapy in patients with Ph+ chronic myeloid leukemia in chronic phase (CML-CP).

Nilotinib is approved for the treatment of CML-CP in adults resistant or intolerant to at least one prior therapy, including imatinib, and for the treatment of adults with newly diagnosed Ph+ CML.

Nilotinib is the first and only TKI to include TFR data in its product information in the EU, according to Novartis, developer of the drug.

Two large international Ph+ CML trials assessing nilotinib discontinuation—ENESTfreedom and ENESTop—formed the basis of the decision.

The two open-label trials showed that half of Ph+ CML-CP patients who met rigorous predefined response criteria maintained TFR after stopping nilotinib, both in the frontline setting and after switching from imatinib.

Both trials included regular and frequent molecular monitoring of BCR-ABL levels with an assay that could measure transcript levels down to a molecular response (MR) of 4.5. Frequent monitoring after discontinuation helped determine loss of MR 4.0 and major molecular response, indicating the need to re-initiate treatment.

ENESTfreedom

This phase 2 trial (Evaluating Nilotinib Efficacy and Safety in Clinical Trials - Following REsponsE in De nOvo CML-CP Patients) involved 215 patients with Ph+ CML-CP treated at 132 sites across 19 countries.

The trial evaluated whether treatment could be stopped in 190 of the patients after they had achieved a response of MR 4.5 and a sustained deep molecular response for 1 year as first-line treatment.

The results showed that 51.6% of the patients in the trial could discontinue therapy and remain in TFR at the 48-week analysis.

However, ENESTfreedom did not meet its primary endpoint of 50% or more of patients in MMR at 48 weeks in the TFR phase. The median treatment duration was 3.6 years.

Adverse events in the trial included musculoskeletal pain (24.7%) during the first years of the TFR phase compared with 16.3% in those still on nilotinib.

No patient progressed to advanced phase/blast crisis.

ENESTop

This phase 2 trial (Evaluating Nilotinib Efficacy and Safety Trial) involved 163 patients with Ph+ CML-CP treated at 63 sites across 18 countries. Investigators evaluated 126 patients who had been treated with imatinib and then switched to nilotinib and had achieved a sustained deep molecular response for 1 year while on nilotinib.

The trial demonstrated that 57.9% of patients maintained a molecular resonse at 48 weeks after stopping treatment. The trial met its primary endpoint—the proportion of patients who did not lose MR 4.0 or MMR within 48 weeks of discontinuing nilotinib in the TFR phase.

Again, the rates of musuloskeletal pain were higher in the first year of TFR than in patients still on nilotinib in the consolidation phase, 42.1% and 14.3%, respectively.

Results of the EURO-SKI trial also support the idea that certain CML patients can safely stop TKI therapy.

For full prescribing information, see the product insert.

Photo by Bill Branson

CHICAGO—The largest ongoing and prospective trial of pediatric patients with chronic myeloid leukemia in chronic phase (CML-CP), according to the best knowledge of the investigators, has found dasatinib to be safe and effective as first- or second-line therapy for these children.

Patients refractory to or intolerant of imatinib had a major cytogenetic response (MCyR) by 3 months and responses at 12 and 24 months exceeded 90%.

Newly diagnosed patients had a complete cytogenetic response (CCyR) by 6 months.

“We believe our data suggests that dasatinib could be considered as a new standard of care (SOC) for children with CML in chronic phase,” said study author Lia Gore, MD, of the University of Colorado School of Medicine/Children’s Hospital Colorado in Aurora.

She presented the findings of the study at the ASCO 2017 Annual Meeting (abstract 10511).

Study design

CA 180-226 is a phase 2, open-label, nonrandomized, prospective study conducted in 18 countries. Patients younger than 18 years with newly diagnosed CML-CP, or imatinib-resistant/intolerant (R/I) CML-CP, or CML in accelerated phase, or Ph+ acute lymphoblastic leukemia (ALL) were enrolled on the study between March 2009 and September 2014.

Dr Gore’s presentation focused on the CML-CP patients in the study, both the newly diagnosed and the imatinib-R/I patients.

The imatinib-R/I patients received dasatinib 60 mg/m² tablets once daily, and the newly diagnosed patients received the same tablet dosage daily or a powdered formulation for oral suspension (PFOS) of dasatinib at 72 mg/m² daily.

Dr Gore noted the different dosage in the oral suspension formulation is based on bioavailability studies performed in adults, which was determined to be equivalent to the 60 mg/m² tablet formulation.

Once accrual was reached in the tablet cohort, newly diagnosed patients were accrued to the PFOS cohort. The patients on PFOS could switch to tablets after a year or more on the oral suspension.

Patients remained on treatment until disease progression, unacceptable toxicity occurred, or the patient/physician preference.

All patients had a minimum follow-up of 2 years. The longest follow-up was more than 90 months.

Primary objectives of the study were MCyR greater than 30% for imatinib-R/I patients and complete CCyR greater than 55% for newly diagnosed patients.

Secondary objectives included time to and duration of response, major molecular response (MMR), progression-free survival (PFS), overall survival (OS), and safety.

Baseline patient characteristics

One hundred thirteen patients were treated across the 3 cohorts—29 in the imatinib-R/I receiving tablets, 51 newly diagnosed patients receiving tablets, and 33 newly diagnosed patients in the PFOS arm. A total of 84 patients had newly diagnosed disease.

Of the 29 imatinib-R/I patients, 25 were resistant, 2 intolerant, and 2 undetermined. And 6 of the 25 resistant patients had defined imatinib-resistance mutations.

Median age was 13.8 years in the imatinib-R/I cohort, 12.9 years in the newly diagnosed on tablets, and 11.7 years in the PFOS group. Other baseline characteristics were similar among the cohorts.

“Importantly, there were 3 patients less than 2 years of age, and a substantial proportion of patients were actually less than 12 years of age,” Dr Gore pointed out.

Dasatinib exposure

The median duration of therapy was 50 months and 42 months in the R/I and newly diagnosed cohorts, respectively.

Forty-eight percent of the imatinib-R/I patients and 73% of the newly diagnosed patients are still on treatment. A relatively small number of patients discontinued therapy.

The median duration of therapy was shorter in the PFOS cohort because they were enrolled only after accrual to the tablet cohort. However, they were also followed up for more than 2 years.

Of the 33 patients on PFOS, 22 eventually switched to tablet formulation.

Results

The primary endpoint for imatinib-R/I patients—MCyR greater than 30%—was reached by 3 months, and MCyR at 12 and 24 months exceeded 90%. The median time to response was 3.1 months (range, 2.8 – 4.1), and median duration of response was not yet reached (range, 54.9 – not estimable).

For newly diagnosed patients, the preset defined rate of interest of 55% for CCyR was reached as early as 6 months, and exceeded 90% by 12 and 24 months.

Dr Gore pointed out that intolerant patients also reached CCyR relatively quickly, although it was not a specified endpoint.

Data indicate that responses occurred relatively quickly and continued to increase over time of follow-up.

MMR also continued to increase over time and showed no difference between formulation and response rate.

Median PFS has not been reached, as only 7 patients in each cohort had disease progression.

One imatinib-R/I patient died 1 year after stopping treatment. The patient, who had a GI bleed unrelated to dasatinib, had discontinued therapy for progressive disease with loss of MCyR.

Safety

Overall safety was very similar to the dasatinib exposure and experience in adults, Dr Gore said, and there were no differences in events between PFOS and tablets.

One patient in the PFOS cohort had a dasatinib-related grade 3 hypersensitivity reaction, which resolved after discontinuation of dasatinib.

“What’s important here,” she said, “is that there were almost no adverse events of severity in either cohort, only 1 in the imatinib refractory and intolerant and 1 in the newly diagnosed cohorts.”

“Most importantly for those of us with a lot of experience in this field,” she added, “there were no occurrences of pleural effusion, pericardial effusion, pulmonary edema, pulmonary hypertension, or any vascular occlusive events in patients noted on this trial.”

“Additionally, for pediatricians, we care a lot about what happens to growth in these patients and prospectively we collected a lot of data related to growth parameters in bone growth and development."

Of the dasatinib-related adverse events occurring in 10% or more of patients, there were only 5 growth and development events noted out of the 113 patients treated and all were grade 1 or 2 events, Dr Gore pointed out.

In the R/I cohort, one patient had osteopenia and gynecomastia. At the time of data analysis, this event had resolved even though the patient continued on dasatinib.

“We believe our data suggests that dasatinib could be considered as a new standard of care for children with CML in chronic phase,” she said.

“It includes the advantage of a liquid formulation as well as the advantages of once daily dosing and administration without regard to fed or fasting state,” she added, “which for all of us who treat children know could be quite important.”

The study was funded by Bristol-Myers Squibb.

Photo by Bill Branson

CHICAGO—The largest ongoing and prospective trial of pediatric patients with chronic myeloid leukemia in chronic phase (CML-CP), according to the best knowledge of the investigators, has found dasatinib to be safe and effective as first- or second-line therapy for these children.

Patients refractory to or intolerant of imatinib had a major cytogenetic response (MCyR) by 3 months and responses at 12 and 24 months exceeded 90%.

Newly diagnosed patients had a complete cytogenetic response (CCyR) by 6 months.

“We believe our data suggests that dasatinib could be considered as a new standard of care (SOC) for children with CML in chronic phase,” said study author Lia Gore, MD, of the University of Colorado School of Medicine/Children’s Hospital Colorado in Aurora.

She presented the findings of the study at the ASCO 2017 Annual Meeting (abstract 10511).

Study design

CA 180-226 is a phase 2, open-label, nonrandomized, prospective study conducted in 18 countries. Patients younger than 18 years with newly diagnosed CML-CP, or imatinib-resistant/intolerant (R/I) CML-CP, or CML in accelerated phase, or Ph+ acute lymphoblastic leukemia (ALL) were enrolled on the study between March 2009 and September 2014.

Dr Gore’s presentation focused on the CML-CP patients in the study, both the newly diagnosed and the imatinib-R/I patients.

The imatinib-R/I patients received dasatinib 60 mg/m² tablets once daily, and the newly diagnosed patients received the same tablet dosage daily or a powdered formulation for oral suspension (PFOS) of dasatinib at 72 mg/m² daily.

Dr Gore noted the different dosage in the oral suspension formulation is based on bioavailability studies performed in adults, which was determined to be equivalent to the 60 mg/m² tablet formulation.

Once accrual was reached in the tablet cohort, newly diagnosed patients were accrued to the PFOS cohort. The patients on PFOS could switch to tablets after a year or more on the oral suspension.

Patients remained on treatment until disease progression, unacceptable toxicity occurred, or the patient/physician preference.

All patients had a minimum follow-up of 2 years. The longest follow-up was more than 90 months.

Primary objectives of the study were MCyR greater than 30% for imatinib-R/I patients and complete CCyR greater than 55% for newly diagnosed patients.

Secondary objectives included time to and duration of response, major molecular response (MMR), progression-free survival (PFS), overall survival (OS), and safety.

Baseline patient characteristics

One hundred thirteen patients were treated across the 3 cohorts—29 in the imatinib-R/I receiving tablets, 51 newly diagnosed patients receiving tablets, and 33 newly diagnosed patients in the PFOS arm. A total of 84 patients had newly diagnosed disease.

Of the 29 imatinib-R/I patients, 25 were resistant, 2 intolerant, and 2 undetermined. And 6 of the 25 resistant patients had defined imatinib-resistance mutations.

Median age was 13.8 years in the imatinib-R/I cohort, 12.9 years in the newly diagnosed on tablets, and 11.7 years in the PFOS group. Other baseline characteristics were similar among the cohorts.

“Importantly, there were 3 patients less than 2 years of age, and a substantial proportion of patients were actually less than 12 years of age,” Dr Gore pointed out.

Dasatinib exposure

The median duration of therapy was 50 months and 42 months in the R/I and newly diagnosed cohorts, respectively.

Forty-eight percent of the imatinib-R/I patients and 73% of the newly diagnosed patients are still on treatment. A relatively small number of patients discontinued therapy.

The median duration of therapy was shorter in the PFOS cohort because they were enrolled only after accrual to the tablet cohort. However, they were also followed up for more than 2 years.

Of the 33 patients on PFOS, 22 eventually switched to tablet formulation.

Results

The primary endpoint for imatinib-R/I patients—MCyR greater than 30%—was reached by 3 months, and MCyR at 12 and 24 months exceeded 90%. The median time to response was 3.1 months (range, 2.8 – 4.1), and median duration of response was not yet reached (range, 54.9 – not estimable).

For newly diagnosed patients, the preset defined rate of interest of 55% for CCyR was reached as early as 6 months, and exceeded 90% by 12 and 24 months.

Dr Gore pointed out that intolerant patients also reached CCyR relatively quickly, although it was not a specified endpoint.

Data indicate that responses occurred relatively quickly and continued to increase over time of follow-up.

MMR also continued to increase over time and showed no difference between formulation and response rate.

Median PFS has not been reached, as only 7 patients in each cohort had disease progression.

One imatinib-R/I patient died 1 year after stopping treatment. The patient, who had a GI bleed unrelated to dasatinib, had discontinued therapy for progressive disease with loss of MCyR.

Safety

Overall safety was very similar to the dasatinib exposure and experience in adults, Dr Gore said, and there were no differences in events between PFOS and tablets.

One patient in the PFOS cohort had a dasatinib-related grade 3 hypersensitivity reaction, which resolved after discontinuation of dasatinib.

“What’s important here,” she said, “is that there were almost no adverse events of severity in either cohort, only 1 in the imatinib refractory and intolerant and 1 in the newly diagnosed cohorts.”

“Most importantly for those of us with a lot of experience in this field,” she added, “there were no occurrences of pleural effusion, pericardial effusion, pulmonary edema, pulmonary hypertension, or any vascular occlusive events in patients noted on this trial.”

“Additionally, for pediatricians, we care a lot about what happens to growth in these patients and prospectively we collected a lot of data related to growth parameters in bone growth and development."

Of the dasatinib-related adverse events occurring in 10% or more of patients, there were only 5 growth and development events noted out of the 113 patients treated and all were grade 1 or 2 events, Dr Gore pointed out.

In the R/I cohort, one patient had osteopenia and gynecomastia. At the time of data analysis, this event had resolved even though the patient continued on dasatinib.

“We believe our data suggests that dasatinib could be considered as a new standard of care for children with CML in chronic phase,” she said.

“It includes the advantage of a liquid formulation as well as the advantages of once daily dosing and administration without regard to fed or fasting state,” she added, “which for all of us who treat children know could be quite important.”

The study was funded by Bristol-Myers Squibb.

Photo by Bill Branson

CHICAGO—The largest ongoing and prospective trial of pediatric patients with chronic myeloid leukemia in chronic phase (CML-CP), according to the best knowledge of the investigators, has found dasatinib to be safe and effective as first- or second-line therapy for these children.

Patients refractory to or intolerant of imatinib had a major cytogenetic response (MCyR) by 3 months and responses at 12 and 24 months exceeded 90%.

Newly diagnosed patients had a complete cytogenetic response (CCyR) by 6 months.

“We believe our data suggests that dasatinib could be considered as a new standard of care (SOC) for children with CML in chronic phase,” said study author Lia Gore, MD, of the University of Colorado School of Medicine/Children’s Hospital Colorado in Aurora.

She presented the findings of the study at the ASCO 2017 Annual Meeting (abstract 10511).

Study design

CA 180-226 is a phase 2, open-label, nonrandomized, prospective study conducted in 18 countries. Patients younger than 18 years with newly diagnosed CML-CP, or imatinib-resistant/intolerant (R/I) CML-CP, or CML in accelerated phase, or Ph+ acute lymphoblastic leukemia (ALL) were enrolled on the study between March 2009 and September 2014.

Dr Gore’s presentation focused on the CML-CP patients in the study, both the newly diagnosed and the imatinib-R/I patients.

The imatinib-R/I patients received dasatinib 60 mg/m² tablets once daily, and the newly diagnosed patients received the same tablet dosage daily or a powdered formulation for oral suspension (PFOS) of dasatinib at 72 mg/m² daily.

Dr Gore noted the different dosage in the oral suspension formulation is based on bioavailability studies performed in adults, which was determined to be equivalent to the 60 mg/m² tablet formulation.

Once accrual was reached in the tablet cohort, newly diagnosed patients were accrued to the PFOS cohort. The patients on PFOS could switch to tablets after a year or more on the oral suspension.

Patients remained on treatment until disease progression, unacceptable toxicity occurred, or the patient/physician preference.

All patients had a minimum follow-up of 2 years. The longest follow-up was more than 90 months.

Primary objectives of the study were MCyR greater than 30% for imatinib-R/I patients and complete CCyR greater than 55% for newly diagnosed patients.

Secondary objectives included time to and duration of response, major molecular response (MMR), progression-free survival (PFS), overall survival (OS), and safety.

Baseline patient characteristics

One hundred thirteen patients were treated across the 3 cohorts—29 in the imatinib-R/I receiving tablets, 51 newly diagnosed patients receiving tablets, and 33 newly diagnosed patients in the PFOS arm. A total of 84 patients had newly diagnosed disease.

Of the 29 imatinib-R/I patients, 25 were resistant, 2 intolerant, and 2 undetermined. And 6 of the 25 resistant patients had defined imatinib-resistance mutations.

Median age was 13.8 years in the imatinib-R/I cohort, 12.9 years in the newly diagnosed on tablets, and 11.7 years in the PFOS group. Other baseline characteristics were similar among the cohorts.

“Importantly, there were 3 patients less than 2 years of age, and a substantial proportion of patients were actually less than 12 years of age,” Dr Gore pointed out.

Dasatinib exposure

The median duration of therapy was 50 months and 42 months in the R/I and newly diagnosed cohorts, respectively.

Forty-eight percent of the imatinib-R/I patients and 73% of the newly diagnosed patients are still on treatment. A relatively small number of patients discontinued therapy.

The median duration of therapy was shorter in the PFOS cohort because they were enrolled only after accrual to the tablet cohort. However, they were also followed up for more than 2 years.

Of the 33 patients on PFOS, 22 eventually switched to tablet formulation.

Results

The primary endpoint for imatinib-R/I patients—MCyR greater than 30%—was reached by 3 months, and MCyR at 12 and 24 months exceeded 90%. The median time to response was 3.1 months (range, 2.8 – 4.1), and median duration of response was not yet reached (range, 54.9 – not estimable).

For newly diagnosed patients, the preset defined rate of interest of 55% for CCyR was reached as early as 6 months, and exceeded 90% by 12 and 24 months.

Dr Gore pointed out that intolerant patients also reached CCyR relatively quickly, although it was not a specified endpoint.

Data indicate that responses occurred relatively quickly and continued to increase over time of follow-up.

MMR also continued to increase over time and showed no difference between formulation and response rate.

Median PFS has not been reached, as only 7 patients in each cohort had disease progression.

One imatinib-R/I patient died 1 year after stopping treatment. The patient, who had a GI bleed unrelated to dasatinib, had discontinued therapy for progressive disease with loss of MCyR.

Safety

Overall safety was very similar to the dasatinib exposure and experience in adults, Dr Gore said, and there were no differences in events between PFOS and tablets.

One patient in the PFOS cohort had a dasatinib-related grade 3 hypersensitivity reaction, which resolved after discontinuation of dasatinib.

“What’s important here,” she said, “is that there were almost no adverse events of severity in either cohort, only 1 in the imatinib refractory and intolerant and 1 in the newly diagnosed cohorts.”

“Most importantly for those of us with a lot of experience in this field,” she added, “there were no occurrences of pleural effusion, pericardial effusion, pulmonary edema, pulmonary hypertension, or any vascular occlusive events in patients noted on this trial.”

“Additionally, for pediatricians, we care a lot about what happens to growth in these patients and prospectively we collected a lot of data related to growth parameters in bone growth and development."

Of the dasatinib-related adverse events occurring in 10% or more of patients, there were only 5 growth and development events noted out of the 113 patients treated and all were grade 1 or 2 events, Dr Gore pointed out.

In the R/I cohort, one patient had osteopenia and gynecomastia. At the time of data analysis, this event had resolved even though the patient continued on dasatinib.

“We believe our data suggests that dasatinib could be considered as a new standard of care for children with CML in chronic phase,” she said.

“It includes the advantage of a liquid formulation as well as the advantages of once daily dosing and administration without regard to fed or fasting state,” she added, “which for all of us who treat children know could be quite important.”

The study was funded by Bristol-Myers Squibb.

Photo © ASCO/Danny Morton 2017

CHICAGO—Three of 6 pediatric patients with relapsed or refractory acute lymphoblastic leukemia (ALL) whose CD19 chimeric antigen receptor (CAR) T cells did not persist even after reinfusion demonstrated persistence when the PD-1 checkpoint inhibitor pembrolizumab was added to the regimen.

CAR T cells can persist for months or even years and have the potential to mediate long-term disease control.

But some patients recover their normal B cells, which is a marker of loss of functional CAR T cells. These patients are at a higher risk of disease relapse.

Investigators, therefore, undertook a pilot study to determine whether PD-1 checkpoint pathway inhibition can improve CAR T persistence in these patients.

Shannon L. Maude, MD, of the Children’s Hospital of Philadelphia and the University of Pennsylvania Perelman School of Medicine, shared some of the patient cases in this pilot study at the ASCO 2017 Annual Meeting (Abstract 103*).

The investigators hypothesized that possible anti-murine immunogenicity could be causing poor CAR T-cell persistence, since the first CAR T developed used scFv domains of murine origin.

If T-cell exhaustion caused poor CAR T-cell persistence, immune checkpoints might play a role. In this case, combination with PD-1 checkpoint blockade could improve persistence, they hypothesized.

The investigators proposed to administer a repeat CAR T-cell infusion for relapsed or refractory ALL patients with poor persistence and add pembrolizumab after retreatment if the patients still had poor persistence. Patients were offered the option of another reinfusion prior to treatment with pembrolizumab if their CAR T-cell persistence continued to be poor.

Investigators added pembrolizumab no earlier than 14 days after infusion and only after patients recovered from cytokine release syndrome (CRS).

The infusions in the pilot study were humanized CART19 (huCART19, CTL119), unless otherwise specified.

Patient 1 – Pembrolizumab for partial response

This patient had no response to the prior murine CD19 CAR infusion, but responded well to infusion with huCART19 with good CAR T-cell proliferation.

By day 28, the patient had achieved a complete response (CR) in bone marrow but had a minimal residual disease (MRD) level of 1.2%.

At 7 weeks, the patient had a CD19+ relapse with low levels of huCART19.

Investigators added pembrolizumb on day 52 after infusion, and the patient had a modest increase in huCART19.

The patient had a temporary clearance of peripheral blasts followed by disease progression.

Patient 2 – Pembrolizumab for no response

This patient had a CD19+ relapse at 12 months after prior murine CD19 CAR infusion.

The patient was treated with huCART19, had good proliferation, but a rapid drop of CART19, and no response of the disease with a CD19+ relapse.

The patient had a reinfusion of huCART19 at 6 weeks and investigators added pembrolizumab on day 14 after reinfusion.

The patient experienced good huCART19 proliferation and prolonged persistence, but by day 28 had persistent disease, this time with decreased expression of CD19+ cells.

Patient 3 – Pembrolizumab for poor persistence

 This patient had a CR with a prior murine CD19 CAR, but had poor persistence and early B cell recovery at 2 months.

The patient had a CD19+ relapse, was treated with huCART19, and had good proliferation again.

The patient achieved an MRD-negative CR, but because of short persistence and early B-cell recovery at 2 months, relapsed at 15 months.

The patient was reinfused at 17 months and pembrolizumab was added on day 14. The patient entered CR with prolonged persistence, but ultimately B-cell recovery occurred.

The patient was reinfused a third time, and pembrolizumab was added to the regimen every 3 weeks. The patient is experiencing prolonged persistence and continued B-cell aplasia.

Patient 4 – Pembrolizumab for poor persistence

This patient had achieved a CR with murine CAR19, but had a CD19+ relapse at 9 months. The patient then received huCART19, had good proliferation and achieved a CR, but had short persistence and B-cell recovery at 2 months.

The patient relapsed at 12 months and was reinfused with huCART19 at 14 months.

Pembrolizumab was added on day 14 after reinfusion, but the patient had no huCART19 proliferation, no response, and CD19+ MRD.

Patient 5 – Pembrolizumab for poor persistence

The patient responded to a prior murine CART19, but had a CD19+ relapse at 12 months.

The patient was infused with huCART19 and had good proliferation but short persistence. The patient was reinfused at 6 months, but again had short persistence.

The patient was reinfused again at 8 months because of B-cell recovery, and pembrolizumab was added on day 14 and administered every 3 weeks thereafter.

The patient is experiencing prolonged persistence and continued B-cell aplasia.

Patient 6 – Pembrolizumab for lymphomatous disease

This patient, who had widespread lymphadenopathy and M3 bone marrow, had not received prior CAR T cells and was treated for the first time with a murine CART19 for r/r ALL.

The patient had good expansion of CART19, but by day 28, PET scan showed widespread lymph node disease despite CR in the bone marrow.

The patient was given pembrolizumab on day 32 after infusion and every 2-3 weeks thereafter. After the addition of pembrolizumab, the patient had increased CART19 cells in blood and a significant decrease in PET-avid disease.

Summary

Three of six patients achieved objective clinical responses with pembrolizumab: 2 had prolonged B-cell aplasia, and another had a decrease in PET-avid lymphomatous disease.

The addition of pembrolizumab was also well tolerated by the patients, with minimal side effects of fever in 2 patients, cytopenias in 2 patients, and no instances of severe CRS.

The investigators believe the addition of checkpoint pathway inhibitors has the potential to prolong CAR T-cell persistence and warrants further investigation.

Photo © ASCO/Danny Morton 2017

CHICAGO—Three of 6 pediatric patients with relapsed or refractory acute lymphoblastic leukemia (ALL) whose CD19 chimeric antigen receptor (CAR) T cells did not persist even after reinfusion demonstrated persistence when the PD-1 checkpoint inhibitor pembrolizumab was added to the regimen.

CAR T cells can persist for months or even years and have the potential to mediate long-term disease control.

But some patients recover their normal B cells, which is a marker of loss of functional CAR T cells. These patients are at a higher risk of disease relapse.

Investigators, therefore, undertook a pilot study to determine whether PD-1 checkpoint pathway inhibition can improve CAR T persistence in these patients.

Shannon L. Maude, MD, of the Children’s Hospital of Philadelphia and the University of Pennsylvania Perelman School of Medicine, shared some of the patient cases in this pilot study at the ASCO 2017 Annual Meeting (Abstract 103*).

The investigators hypothesized that possible anti-murine immunogenicity could be causing poor CAR T-cell persistence, since the first CAR T developed used scFv domains of murine origin.

If T-cell exhaustion caused poor CAR T-cell persistence, immune checkpoints might play a role. In this case, combination with PD-1 checkpoint blockade could improve persistence, they hypothesized.

The investigators proposed to administer a repeat CAR T-cell infusion for relapsed or refractory ALL patients with poor persistence and add pembrolizumab after retreatment if the patients still had poor persistence. Patients were offered the option of another reinfusion prior to treatment with pembrolizumab if their CAR T-cell persistence continued to be poor.

Investigators added pembrolizumab no earlier than 14 days after infusion and only after patients recovered from cytokine release syndrome (CRS).

The infusions in the pilot study were humanized CART19 (huCART19, CTL119), unless otherwise specified.

Patient 1 – Pembrolizumab for partial response

This patient had no response to the prior murine CD19 CAR infusion, but responded well to infusion with huCART19 with good CAR T-cell proliferation.

By day 28, the patient had achieved a complete response (CR) in bone marrow but had a minimal residual disease (MRD) level of 1.2%.

At 7 weeks, the patient had a CD19+ relapse with low levels of huCART19.

Investigators added pembrolizumb on day 52 after infusion, and the patient had a modest increase in huCART19.

The patient had a temporary clearance of peripheral blasts followed by disease progression.

Patient 2 – Pembrolizumab for no response

This patient had a CD19+ relapse at 12 months after prior murine CD19 CAR infusion.

The patient was treated with huCART19, had good proliferation, but a rapid drop of CART19, and no response of the disease with a CD19+ relapse.

The patient had a reinfusion of huCART19 at 6 weeks and investigators added pembrolizumab on day 14 after reinfusion.

The patient experienced good huCART19 proliferation and prolonged persistence, but by day 28 had persistent disease, this time with decreased expression of CD19+ cells.

Patient 3 – Pembrolizumab for poor persistence

 This patient had a CR with a prior murine CD19 CAR, but had poor persistence and early B cell recovery at 2 months.

The patient had a CD19+ relapse, was treated with huCART19, and had good proliferation again.

The patient achieved an MRD-negative CR, but because of short persistence and early B-cell recovery at 2 months, relapsed at 15 months.

The patient was reinfused at 17 months and pembrolizumab was added on day 14. The patient entered CR with prolonged persistence, but ultimately B-cell recovery occurred.

The patient was reinfused a third time, and pembrolizumab was added to the regimen every 3 weeks. The patient is experiencing prolonged persistence and continued B-cell aplasia.

Patient 4 – Pembrolizumab for poor persistence

This patient had achieved a CR with murine CAR19, but had a CD19+ relapse at 9 months. The patient then received huCART19, had good proliferation and achieved a CR, but had short persistence and B-cell recovery at 2 months.

The patient relapsed at 12 months and was reinfused with huCART19 at 14 months.

Pembrolizumab was added on day 14 after reinfusion, but the patient had no huCART19 proliferation, no response, and CD19+ MRD.

Patient 5 – Pembrolizumab for poor persistence

The patient responded to a prior murine CART19, but had a CD19+ relapse at 12 months.

The patient was infused with huCART19 and had good proliferation but short persistence. The patient was reinfused at 6 months, but again had short persistence.

The patient was reinfused again at 8 months because of B-cell recovery, and pembrolizumab was added on day 14 and administered every 3 weeks thereafter.

The patient is experiencing prolonged persistence and continued B-cell aplasia.

Patient 6 – Pembrolizumab for lymphomatous disease

This patient, who had widespread lymphadenopathy and M3 bone marrow, had not received prior CAR T cells and was treated for the first time with a murine CART19 for r/r ALL.

The patient had good expansion of CART19, but by day 28, PET scan showed widespread lymph node disease despite CR in the bone marrow.

The patient was given pembrolizumab on day 32 after infusion and every 2-3 weeks thereafter. After the addition of pembrolizumab, the patient had increased CART19 cells in blood and a significant decrease in PET-avid disease.

Summary

Three of six patients achieved objective clinical responses with pembrolizumab: 2 had prolonged B-cell aplasia, and another had a decrease in PET-avid lymphomatous disease.

The addition of pembrolizumab was also well tolerated by the patients, with minimal side effects of fever in 2 patients, cytopenias in 2 patients, and no instances of severe CRS.

The investigators believe the addition of checkpoint pathway inhibitors has the potential to prolong CAR T-cell persistence and warrants further investigation.

Photo © ASCO/Danny Morton 2017

CHICAGO—Three of 6 pediatric patients with relapsed or refractory acute lymphoblastic leukemia (ALL) whose CD19 chimeric antigen receptor (CAR) T cells did not persist even after reinfusion demonstrated persistence when the PD-1 checkpoint inhibitor pembrolizumab was added to the regimen.

CAR T cells can persist for months or even years and have the potential to mediate long-term disease control.

But some patients recover their normal B cells, which is a marker of loss of functional CAR T cells. These patients are at a higher risk of disease relapse.

Investigators, therefore, undertook a pilot study to determine whether PD-1 checkpoint pathway inhibition can improve CAR T persistence in these patients.

Shannon L. Maude, MD, of the Children’s Hospital of Philadelphia and the University of Pennsylvania Perelman School of Medicine, shared some of the patient cases in this pilot study at the ASCO 2017 Annual Meeting (Abstract 103*).

The investigators hypothesized that possible anti-murine immunogenicity could be causing poor CAR T-cell persistence, since the first CAR T developed used scFv domains of murine origin.

If T-cell exhaustion caused poor CAR T-cell persistence, immune checkpoints might play a role. In this case, combination with PD-1 checkpoint blockade could improve persistence, they hypothesized.

The investigators proposed to administer a repeat CAR T-cell infusion for relapsed or refractory ALL patients with poor persistence and add pembrolizumab after retreatment if the patients still had poor persistence. Patients were offered the option of another reinfusion prior to treatment with pembrolizumab if their CAR T-cell persistence continued to be poor.

Investigators added pembrolizumab no earlier than 14 days after infusion and only after patients recovered from cytokine release syndrome (CRS).

The infusions in the pilot study were humanized CART19 (huCART19, CTL119), unless otherwise specified.

Patient 1 – Pembrolizumab for partial response

This patient had no response to the prior murine CD19 CAR infusion, but responded well to infusion with huCART19 with good CAR T-cell proliferation.

By day 28, the patient had achieved a complete response (CR) in bone marrow but had a minimal residual disease (MRD) level of 1.2%.

At 7 weeks, the patient had a CD19+ relapse with low levels of huCART19.

Investigators added pembrolizumb on day 52 after infusion, and the patient had a modest increase in huCART19.

The patient had a temporary clearance of peripheral blasts followed by disease progression.

Patient 2 – Pembrolizumab for no response

This patient had a CD19+ relapse at 12 months after prior murine CD19 CAR infusion.

The patient was treated with huCART19, had good proliferation, but a rapid drop of CART19, and no response of the disease with a CD19+ relapse.

The patient had a reinfusion of huCART19 at 6 weeks and investigators added pembrolizumab on day 14 after reinfusion.

The patient experienced good huCART19 proliferation and prolonged persistence, but by day 28 had persistent disease, this time with decreased expression of CD19+ cells.

Patient 3 – Pembrolizumab for poor persistence

 This patient had a CR with a prior murine CD19 CAR, but had poor persistence and early B cell recovery at 2 months.

The patient had a CD19+ relapse, was treated with huCART19, and had good proliferation again.

The patient achieved an MRD-negative CR, but because of short persistence and early B-cell recovery at 2 months, relapsed at 15 months.

The patient was reinfused at 17 months and pembrolizumab was added on day 14. The patient entered CR with prolonged persistence, but ultimately B-cell recovery occurred.

The patient was reinfused a third time, and pembrolizumab was added to the regimen every 3 weeks. The patient is experiencing prolonged persistence and continued B-cell aplasia.

Patient 4 – Pembrolizumab for poor persistence

This patient had achieved a CR with murine CAR19, but had a CD19+ relapse at 9 months. The patient then received huCART19, had good proliferation and achieved a CR, but had short persistence and B-cell recovery at 2 months.

The patient relapsed at 12 months and was reinfused with huCART19 at 14 months.

Pembrolizumab was added on day 14 after reinfusion, but the patient had no huCART19 proliferation, no response, and CD19+ MRD.

Patient 5 – Pembrolizumab for poor persistence

The patient responded to a prior murine CART19, but had a CD19+ relapse at 12 months.

The patient was infused with huCART19 and had good proliferation but short persistence. The patient was reinfused at 6 months, but again had short persistence.

The patient was reinfused again at 8 months because of B-cell recovery, and pembrolizumab was added on day 14 and administered every 3 weeks thereafter.

The patient is experiencing prolonged persistence and continued B-cell aplasia.

Patient 6 – Pembrolizumab for lymphomatous disease

This patient, who had widespread lymphadenopathy and M3 bone marrow, had not received prior CAR T cells and was treated for the first time with a murine CART19 for r/r ALL.

The patient had good expansion of CART19, but by day 28, PET scan showed widespread lymph node disease despite CR in the bone marrow.

The patient was given pembrolizumab on day 32 after infusion and every 2-3 weeks thereafter. After the addition of pembrolizumab, the patient had increased CART19 cells in blood and a significant decrease in PET-avid disease.

Summary

Three of six patients achieved objective clinical responses with pembrolizumab: 2 had prolonged B-cell aplasia, and another had a decrease in PET-avid lymphomatous disease.

The addition of pembrolizumab was also well tolerated by the patients, with minimal side effects of fever in 2 patients, cytopenias in 2 patients, and no instances of severe CRS.

The investigators believe the addition of checkpoint pathway inhibitors has the potential to prolong CAR T-cell persistence and warrants further investigation.