CML

The Food and Drug Administration has cleared Bio-Rad’s digital polymerase chain reaction (PCR) testing solution to monitor patients’ molecular response to treatment for chronic myeloid leukemia.

The QXDx AutoDG ddPCR System combines Bio-Rad’s Droplet Digital PCR technology and the QXDx BCR-ABL %IS Kit, according to the company.

This so-called liquid biopsy test can “precisely and reproducibly” monitor the molecular response to tyrosine kinase inhibitor therapy. The current standard – reverse transcription quantitative PCR – can have variable results, especially at low levels of disease, according to Bio-Rad.

FDA clearance means that the product is “substantially equivalent” to an already-approved product and can be sold in the United States, according to the agency.

[email protected]

The Food and Drug Administration has cleared Bio-Rad’s digital polymerase chain reaction (PCR) testing solution to monitor patients’ molecular response to treatment for chronic myeloid leukemia.

The QXDx AutoDG ddPCR System combines Bio-Rad’s Droplet Digital PCR technology and the QXDx BCR-ABL %IS Kit, according to the company.

This so-called liquid biopsy test can “precisely and reproducibly” monitor the molecular response to tyrosine kinase inhibitor therapy. The current standard – reverse transcription quantitative PCR – can have variable results, especially at low levels of disease, according to Bio-Rad.

FDA clearance means that the product is “substantially equivalent” to an already-approved product and can be sold in the United States, according to the agency.

[email protected]

The Food and Drug Administration has cleared Bio-Rad’s digital polymerase chain reaction (PCR) testing solution to monitor patients’ molecular response to treatment for chronic myeloid leukemia.

The QXDx AutoDG ddPCR System combines Bio-Rad’s Droplet Digital PCR technology and the QXDx BCR-ABL %IS Kit, according to the company.

This so-called liquid biopsy test can “precisely and reproducibly” monitor the molecular response to tyrosine kinase inhibitor therapy. The current standard – reverse transcription quantitative PCR – can have variable results, especially at low levels of disease, according to Bio-Rad.

FDA clearance means that the product is “substantially equivalent” to an already-approved product and can be sold in the United States, according to the agency.

[email protected]

The University of Texas MD Anderson Cancer Center, Houston, and Ascentage Pharma of Suzhou, China, recently formed a 5-year strategic alliance to advance the development of novel cancer therapeutics, primarily for leukemia.

The collaboration, led by Hagop Kantarjian, MD, chair of leukemia at MD Anderson, will use Ascentage’s proprietary Protein-Protein Interaction drug discovery technology platform to develop the company’s apoptosis-targeted and tyrosine kinase inhibitor drug candidates.

The drug candidates will be studied as single-agent therapies and in combinations with other approved or investigational therapeutics. The candidates, chosen for their potential to treat acute myeloid leukemia (AML), chronic myeloid leukemia (CML), acute lymphoblastic leukemia (ALL), myeloproliferative neoplasms, and myelofibrosis, include:

• HQP1351, a third-generation BCR-ABL inhibitor that has been shown to be safe and “highly active” in treating patients with chronic- or accelerated-phase CML, with or without the T3151 mutation. Preliminary results of the phase 1 study were presented at the 2018 annual meeting of the American Society of Hematology (Abstract 791).
• APG-1252, a highly potent Bcl-2 family inhibitor, has high binding affinities to Bcl-2, Bcl-xL and Bcl-w. It has achieved tumor regression in small cell lung cancer, colon, breast, and ALL xenografts. A phase 1, dose-escalating study is currently being conducted (NCT03387332).
• APG-2575, a selective Bcl-2 inhibitor, is being studied in a phase 1, multicenter, single-agent trial in patients with B-cell hematologic malignancies, including multiple myeloma, chronic lymphocytic leukemia, lymphoplasmacytic lymphoma, non-Hodgkin lymphomas, and AML (NCT03537482).
• APG-1387, an inhibitor of apoptosis protein, is being studied in solid tumors and hematologic malignancies (NCT03386526). Investigators asserted that combining it with an anti–programmed death 1 antibody would be “a very attractive approach” for cancer therapy. In advanced solid tumors it has been well tolerated with manageable adverse events, according to a study presented at the 2018 annual meeting of the American Society of Clinical Oncology (Abstract 2593).
• APG-115 is an MDM2-p53 inhibitor that, when combined with radiotherapy, has been shown to enhance the antitumor effect in gastric adenocarcinoma, according to a paper published in the Journal of Experimental & Clinical Cancer Research.

“We will be investigating this pipeline of candidate therapies, and we are interested in the novel mechanism of their actions,” Dr. Kantarjian said in a statement.

[email protected]

The University of Texas MD Anderson Cancer Center, Houston, and Ascentage Pharma of Suzhou, China, recently formed a 5-year strategic alliance to advance the development of novel cancer therapeutics, primarily for leukemia.

The collaboration, led by Hagop Kantarjian, MD, chair of leukemia at MD Anderson, will use Ascentage’s proprietary Protein-Protein Interaction drug discovery technology platform to develop the company’s apoptosis-targeted and tyrosine kinase inhibitor drug candidates.

The drug candidates will be studied as single-agent therapies and in combinations with other approved or investigational therapeutics. The candidates, chosen for their potential to treat acute myeloid leukemia (AML), chronic myeloid leukemia (CML), acute lymphoblastic leukemia (ALL), myeloproliferative neoplasms, and myelofibrosis, include:

• HQP1351, a third-generation BCR-ABL inhibitor that has been shown to be safe and “highly active” in treating patients with chronic- or accelerated-phase CML, with or without the T3151 mutation. Preliminary results of the phase 1 study were presented at the 2018 annual meeting of the American Society of Hematology (Abstract 791).
• APG-1252, a highly potent Bcl-2 family inhibitor, has high binding affinities to Bcl-2, Bcl-xL and Bcl-w. It has achieved tumor regression in small cell lung cancer, colon, breast, and ALL xenografts. A phase 1, dose-escalating study is currently being conducted (NCT03387332).
• APG-2575, a selective Bcl-2 inhibitor, is being studied in a phase 1, multicenter, single-agent trial in patients with B-cell hematologic malignancies, including multiple myeloma, chronic lymphocytic leukemia, lymphoplasmacytic lymphoma, non-Hodgkin lymphomas, and AML (NCT03537482).
• APG-1387, an inhibitor of apoptosis protein, is being studied in solid tumors and hematologic malignancies (NCT03386526). Investigators asserted that combining it with an anti–programmed death 1 antibody would be “a very attractive approach” for cancer therapy. In advanced solid tumors it has been well tolerated with manageable adverse events, according to a study presented at the 2018 annual meeting of the American Society of Clinical Oncology (Abstract 2593).
• APG-115 is an MDM2-p53 inhibitor that, when combined with radiotherapy, has been shown to enhance the antitumor effect in gastric adenocarcinoma, according to a paper published in the Journal of Experimental & Clinical Cancer Research.

“We will be investigating this pipeline of candidate therapies, and we are interested in the novel mechanism of their actions,” Dr. Kantarjian said in a statement.

[email protected]

The University of Texas MD Anderson Cancer Center, Houston, and Ascentage Pharma of Suzhou, China, recently formed a 5-year strategic alliance to advance the development of novel cancer therapeutics, primarily for leukemia.

The collaboration, led by Hagop Kantarjian, MD, chair of leukemia at MD Anderson, will use Ascentage’s proprietary Protein-Protein Interaction drug discovery technology platform to develop the company’s apoptosis-targeted and tyrosine kinase inhibitor drug candidates.

The drug candidates will be studied as single-agent therapies and in combinations with other approved or investigational therapeutics. The candidates, chosen for their potential to treat acute myeloid leukemia (AML), chronic myeloid leukemia (CML), acute lymphoblastic leukemia (ALL), myeloproliferative neoplasms, and myelofibrosis, include:

• HQP1351, a third-generation BCR-ABL inhibitor that has been shown to be safe and “highly active” in treating patients with chronic- or accelerated-phase CML, with or without the T3151 mutation. Preliminary results of the phase 1 study were presented at the 2018 annual meeting of the American Society of Hematology (Abstract 791).
• APG-1252, a highly potent Bcl-2 family inhibitor, has high binding affinities to Bcl-2, Bcl-xL and Bcl-w. It has achieved tumor regression in small cell lung cancer, colon, breast, and ALL xenografts. A phase 1, dose-escalating study is currently being conducted (NCT03387332).
• APG-2575, a selective Bcl-2 inhibitor, is being studied in a phase 1, multicenter, single-agent trial in patients with B-cell hematologic malignancies, including multiple myeloma, chronic lymphocytic leukemia, lymphoplasmacytic lymphoma, non-Hodgkin lymphomas, and AML (NCT03537482).
• APG-1387, an inhibitor of apoptosis protein, is being studied in solid tumors and hematologic malignancies (NCT03386526). Investigators asserted that combining it with an anti–programmed death 1 antibody would be “a very attractive approach” for cancer therapy. In advanced solid tumors it has been well tolerated with manageable adverse events, according to a study presented at the 2018 annual meeting of the American Society of Clinical Oncology (Abstract 2593).
• APG-115 is an MDM2-p53 inhibitor that, when combined with radiotherapy, has been shown to enhance the antitumor effect in gastric adenocarcinoma, according to a paper published in the Journal of Experimental & Clinical Cancer Research.

“We will be investigating this pipeline of candidate therapies, and we are interested in the novel mechanism of their actions,” Dr. Kantarjian said in a statement.

[email protected]

Photo by Jen Smith

SAN DIEGO—Early results of the DASCERN trial indicate that patients with chronic myeloid leukemia (CML) in chronic phase who have a suboptimal response to imatinib as a first-line treatment benefit from switching to dasatinib at 3 months.

Twenty-nine percent of dasatinib-treated patients achieved a major molecular response (MMR) at 12 months, compared to 13% of patients who remained on imatinib (P=0.005).

Dasatinib-treated patients also attained MMR much faster than those on imatinib, at a median of 14 months, compared to 20 months for those treated with imatinib.

DASCERN is the first study, according to investigators, to explore the significance of an early switch for patients who have not achieved an early molecular response (EMR) with imatinib.

“[EMRs] are important because they correlate with the outcome of patients, certainly with progression-free survival and overall survival,” explained Jorge E. Cortes, MD, of The University of Texas MD Anderson Cancer Center in Houston.

“[T]he possibility of changing to dasatinib appears, with these early results, to suggest that there may be a benefit to switching these patients to achieve better long-term outcomes. But also, those patients that have these early molecular responses have a better probability of achieving deep molecular responses that we desire for treatment-free remission.”

Dr. Cortes elaborated on the DASCERN data at the 2018 ASH Annual Meeting (abstract 788*).

Study design

DASCERN (NCT01593254) is a randomized, open-label, international, phase 2b trial in adult patients with chronic-phase CML who had achieved a complete hematologic response but still had more than 10% BCR-ABL1 transcripts at 3 months.

Patients were initially treated with imatinib at 400 mg daily, and 1,126 patients had a molecular assessment at 3 months.

Those who did not achieve an MMR (n=260) were randomized in a 2:1 fashion to 100 mg daily of dasatinib (n=174) or 400 mg daily or twice daily of imatinib (n=86).

If patients subsequently failed imatinib treatment by European LeukemiaNet standards, they could cross over to dasatinib.

“Importantly, there was a window of enrollment up to 8 weeks after the 3-month assessment, allowing for time to get response results and screen and enroll patients onto the study,” Dr. Cortes clarified.

Patients were also stratified according to Sokal risk score and time from molecular assessment to randomization.

Dr. Cortes noted that about 40% of patients were started on treatment within 4 weeks of the 3-month assessment. And another 58% were enrolled between 4 and 8 weeks from the 3-month assessment.

The primary endpoint is the achievement of MMR at 12 months from the first day of imatinib treatment; that is, at about 9 months from the start of the protocol treatment, in both trial arms.

Patient characteristics

Seventy-eight percent of patients were male, and 95% were younger than 65.

“This is a relatively younger patient population,” Dr. Cortes noted. “This has to do with the fact that this was an international study with a significant representation of patients that were from Asia (73%).”

The Asian patients were primarily from China, Dr. Cortes said, “and we know that, in some parts of the world, including Asia, patients seem to be younger.”

“This is also associated with a higher percentage of patients with high-risk Sokal scores, more than 20%,” he added. “That is different than what’s seen, for example, in the U.S. or in Europe.”

The prevalence of male patients, he said, broadly represents the distribution of patients in other parts of the world.

Patient disposition

Patients were followed for a median of 30 months.

Of the randomized patients—the intent-to-treat (ITT) population—143 (84%) in the dasatinib arm and 72 (84%) in the imatinib arm continued on treatment.

Study drug toxicity was the most common reason for discontinuing treatment and occurred in 9 patients (5%) in the dasatinib arm and 3 (4%) in the imatinib arm.

Nearly half the imatinib patients (n=42, 49%) crossed over to dasatinib at a median of 9 months.

The median duration of treatment was 22 months (range, 1 – 44) for patients on imatinib who did not cross over and 15 months (range, <1 – 38) for patients on dasatinib after crossing over from imatinib.

Response

In the ITT population, the rate of MMR at 12 months was 29% in the dasatinib arm and 13% in the imatinib arm (P=0.005).

The median time to MMR was significantly shorter for patients who received dasatinib compared with imatinib—14 months and 20 months, respectively (P=0.053).

“Over 60% of patients on the dasatinib arm achieved a major molecular response,” Dr. Cortes said. “This compares to about 55% of patients on the imatinib arm, even when you consider the crossover of a significant number of these patients.”

A few patients achieved a molecular response of a 4.5-log reduction in BCR-ABL1 transcripts (MR4.5).

“Of course, the follow-up is short, but we had twice as many patients [on dasatinib] at 12 months with MR4.5— 5% with dasatinib versus 2% with imatinib,” Dr. Cortes said.

Survival outcomes

Both overall and progression-free survival “look very good with both treatment approaches,” Dr. Cortes pointed out.

At a median follow-up of 30 months, the overall survival in the ITT population was 98.8% in each treatment arm.

Progression-free survival was 96.9% in the dasatinib arm and 97.6% in the imatinib arm.

“It is important to note that no patient in either treatment arm has transformed to accelerated or blast phase,” Dr. Cortes said.

Safety

Treatment was well tolerated with both agents, Dr. Cortes observed, with very few grade 3 adverse events (AEs) noted to date.

“The one that stands out here, and it’s only 2% of patients, is headache with dasatinib,” he said.

The headache did not lead to treatment discontinuation, and the patients were managed with dose adjustments.

The investigators observed no new safety signals with either drug.

Treatment-emergent AEs of any grade occurring in 15% or fewer dasatinib- or imatinib-treated patients, respectively, in the ITT population included headache (15%, 9%), diarrhea (9%, 8%), nausea (9%, 8%), eyelid edema (1%, 9%), hypocalcemia (1%, 7%), and muscle spasms (1%, 8%).

Patients who crossed over to dasatinib had similar rates of AEs to those documented for imatinib.

“They are typical for what we know of both of these tyrosine kinase inhibitors,” Dr. Cortes stated.

Investigators observed pleural effusion in 9 (5%) patients on dasatinib, and only one grade 3. That patient discontinued therapy due to the AE.

Of the patients who were on imatinib and crossed over to dasatinib, 3 (7%) experienced pleural effusion, most of them grade 1 or 2. One patient with grade 4 discontinued therapy with dasatinib due to the AE.

“Hematologic toxicity has been mild,” Dr. Cortes said, and in keeping with the known toxicities of dasatinib and imatinib.

Grade 3/4 treatment-emergent AEs in the dasatinib and imatinib arms, respectively, in the ITT population included anemia (5%, 4%), neutropenia (11%, 16%), thrombocytopenia (11%, 11%), and leukopenia (1%, 1%).

Patients who crossed over to dasatinib experienced more of these AEs than patients who did not cross over, Dr. Cortes clarified, but they are still within the expected range with these agents.

“We acknowledge the results are early and we need to continue following for both safety and efficacy, as it will be important to see if those rates of MR4.5 continue to increase with the same difference in favor of dasatinib that we are starting to see very early on,” Dr. Cortes said.

He disclosed serving as a consultant for Pfizer, Daiichi Sankyo, Astellas Pharma, Novartis, and Bristol-Myers Squibb, and he received research funding from Pfizer, Daiichi Sankyo, Arog Pharmaceuticals, Astellas Pharma, Novartis, and Bristol-Myers Squibb.

The study was supported by Bristol-Myers Squibb. 

*Data in the abstract differ from the presentation.

Photo by Jen Smith

SAN DIEGO—Early results of the DASCERN trial indicate that patients with chronic myeloid leukemia (CML) in chronic phase who have a suboptimal response to imatinib as a first-line treatment benefit from switching to dasatinib at 3 months.

Twenty-nine percent of dasatinib-treated patients achieved a major molecular response (MMR) at 12 months, compared to 13% of patients who remained on imatinib (P=0.005).

Dasatinib-treated patients also attained MMR much faster than those on imatinib, at a median of 14 months, compared to 20 months for those treated with imatinib.

DASCERN is the first study, according to investigators, to explore the significance of an early switch for patients who have not achieved an early molecular response (EMR) with imatinib.

“[EMRs] are important because they correlate with the outcome of patients, certainly with progression-free survival and overall survival,” explained Jorge E. Cortes, MD, of The University of Texas MD Anderson Cancer Center in Houston.

“[T]he possibility of changing to dasatinib appears, with these early results, to suggest that there may be a benefit to switching these patients to achieve better long-term outcomes. But also, those patients that have these early molecular responses have a better probability of achieving deep molecular responses that we desire for treatment-free remission.”

Dr. Cortes elaborated on the DASCERN data at the 2018 ASH Annual Meeting (abstract 788*).

Study design

DASCERN (NCT01593254) is a randomized, open-label, international, phase 2b trial in adult patients with chronic-phase CML who had achieved a complete hematologic response but still had more than 10% BCR-ABL1 transcripts at 3 months.

Patients were initially treated with imatinib at 400 mg daily, and 1,126 patients had a molecular assessment at 3 months.

Those who did not achieve an MMR (n=260) were randomized in a 2:1 fashion to 100 mg daily of dasatinib (n=174) or 400 mg daily or twice daily of imatinib (n=86).

If patients subsequently failed imatinib treatment by European LeukemiaNet standards, they could cross over to dasatinib.

“Importantly, there was a window of enrollment up to 8 weeks after the 3-month assessment, allowing for time to get response results and screen and enroll patients onto the study,” Dr. Cortes clarified.

Patients were also stratified according to Sokal risk score and time from molecular assessment to randomization.

Dr. Cortes noted that about 40% of patients were started on treatment within 4 weeks of the 3-month assessment. And another 58% were enrolled between 4 and 8 weeks from the 3-month assessment.

The primary endpoint is the achievement of MMR at 12 months from the first day of imatinib treatment; that is, at about 9 months from the start of the protocol treatment, in both trial arms.

Patient characteristics

Seventy-eight percent of patients were male, and 95% were younger than 65.

“This is a relatively younger patient population,” Dr. Cortes noted. “This has to do with the fact that this was an international study with a significant representation of patients that were from Asia (73%).”

The Asian patients were primarily from China, Dr. Cortes said, “and we know that, in some parts of the world, including Asia, patients seem to be younger.”

“This is also associated with a higher percentage of patients with high-risk Sokal scores, more than 20%,” he added. “That is different than what’s seen, for example, in the U.S. or in Europe.”

The prevalence of male patients, he said, broadly represents the distribution of patients in other parts of the world.

Patient disposition

Patients were followed for a median of 30 months.

Of the randomized patients—the intent-to-treat (ITT) population—143 (84%) in the dasatinib arm and 72 (84%) in the imatinib arm continued on treatment.

Study drug toxicity was the most common reason for discontinuing treatment and occurred in 9 patients (5%) in the dasatinib arm and 3 (4%) in the imatinib arm.

Nearly half the imatinib patients (n=42, 49%) crossed over to dasatinib at a median of 9 months.

The median duration of treatment was 22 months (range, 1 – 44) for patients on imatinib who did not cross over and 15 months (range, <1 – 38) for patients on dasatinib after crossing over from imatinib.

Response

In the ITT population, the rate of MMR at 12 months was 29% in the dasatinib arm and 13% in the imatinib arm (P=0.005).

The median time to MMR was significantly shorter for patients who received dasatinib compared with imatinib—14 months and 20 months, respectively (P=0.053).

“Over 60% of patients on the dasatinib arm achieved a major molecular response,” Dr. Cortes said. “This compares to about 55% of patients on the imatinib arm, even when you consider the crossover of a significant number of these patients.”

A few patients achieved a molecular response of a 4.5-log reduction in BCR-ABL1 transcripts (MR4.5).

“Of course, the follow-up is short, but we had twice as many patients [on dasatinib] at 12 months with MR4.5— 5% with dasatinib versus 2% with imatinib,” Dr. Cortes said.

Survival outcomes

Both overall and progression-free survival “look very good with both treatment approaches,” Dr. Cortes pointed out.

At a median follow-up of 30 months, the overall survival in the ITT population was 98.8% in each treatment arm.

Progression-free survival was 96.9% in the dasatinib arm and 97.6% in the imatinib arm.

“It is important to note that no patient in either treatment arm has transformed to accelerated or blast phase,” Dr. Cortes said.

Safety

Treatment was well tolerated with both agents, Dr. Cortes observed, with very few grade 3 adverse events (AEs) noted to date.

“The one that stands out here, and it’s only 2% of patients, is headache with dasatinib,” he said.

The headache did not lead to treatment discontinuation, and the patients were managed with dose adjustments.

The investigators observed no new safety signals with either drug.

Treatment-emergent AEs of any grade occurring in 15% or fewer dasatinib- or imatinib-treated patients, respectively, in the ITT population included headache (15%, 9%), diarrhea (9%, 8%), nausea (9%, 8%), eyelid edema (1%, 9%), hypocalcemia (1%, 7%), and muscle spasms (1%, 8%).

Patients who crossed over to dasatinib had similar rates of AEs to those documented for imatinib.

“They are typical for what we know of both of these tyrosine kinase inhibitors,” Dr. Cortes stated.

Investigators observed pleural effusion in 9 (5%) patients on dasatinib, and only one grade 3. That patient discontinued therapy due to the AE.

Of the patients who were on imatinib and crossed over to dasatinib, 3 (7%) experienced pleural effusion, most of them grade 1 or 2. One patient with grade 4 discontinued therapy with dasatinib due to the AE.

“Hematologic toxicity has been mild,” Dr. Cortes said, and in keeping with the known toxicities of dasatinib and imatinib.

Grade 3/4 treatment-emergent AEs in the dasatinib and imatinib arms, respectively, in the ITT population included anemia (5%, 4%), neutropenia (11%, 16%), thrombocytopenia (11%, 11%), and leukopenia (1%, 1%).

Patients who crossed over to dasatinib experienced more of these AEs than patients who did not cross over, Dr. Cortes clarified, but they are still within the expected range with these agents.

“We acknowledge the results are early and we need to continue following for both safety and efficacy, as it will be important to see if those rates of MR4.5 continue to increase with the same difference in favor of dasatinib that we are starting to see very early on,” Dr. Cortes said.

He disclosed serving as a consultant for Pfizer, Daiichi Sankyo, Astellas Pharma, Novartis, and Bristol-Myers Squibb, and he received research funding from Pfizer, Daiichi Sankyo, Arog Pharmaceuticals, Astellas Pharma, Novartis, and Bristol-Myers Squibb.

The study was supported by Bristol-Myers Squibb. 

*Data in the abstract differ from the presentation.

Photo by Jen Smith

SAN DIEGO—Early results of the DASCERN trial indicate that patients with chronic myeloid leukemia (CML) in chronic phase who have a suboptimal response to imatinib as a first-line treatment benefit from switching to dasatinib at 3 months.

Twenty-nine percent of dasatinib-treated patients achieved a major molecular response (MMR) at 12 months, compared to 13% of patients who remained on imatinib (P=0.005).

Dasatinib-treated patients also attained MMR much faster than those on imatinib, at a median of 14 months, compared to 20 months for those treated with imatinib.

DASCERN is the first study, according to investigators, to explore the significance of an early switch for patients who have not achieved an early molecular response (EMR) with imatinib.

“[EMRs] are important because they correlate with the outcome of patients, certainly with progression-free survival and overall survival,” explained Jorge E. Cortes, MD, of The University of Texas MD Anderson Cancer Center in Houston.

“[T]he possibility of changing to dasatinib appears, with these early results, to suggest that there may be a benefit to switching these patients to achieve better long-term outcomes. But also, those patients that have these early molecular responses have a better probability of achieving deep molecular responses that we desire for treatment-free remission.”

Dr. Cortes elaborated on the DASCERN data at the 2018 ASH Annual Meeting (abstract 788*).

Study design

DASCERN (NCT01593254) is a randomized, open-label, international, phase 2b trial in adult patients with chronic-phase CML who had achieved a complete hematologic response but still had more than 10% BCR-ABL1 transcripts at 3 months.

Patients were initially treated with imatinib at 400 mg daily, and 1,126 patients had a molecular assessment at 3 months.

Those who did not achieve an MMR (n=260) were randomized in a 2:1 fashion to 100 mg daily of dasatinib (n=174) or 400 mg daily or twice daily of imatinib (n=86).

If patients subsequently failed imatinib treatment by European LeukemiaNet standards, they could cross over to dasatinib.

“Importantly, there was a window of enrollment up to 8 weeks after the 3-month assessment, allowing for time to get response results and screen and enroll patients onto the study,” Dr. Cortes clarified.

Patients were also stratified according to Sokal risk score and time from molecular assessment to randomization.

Dr. Cortes noted that about 40% of patients were started on treatment within 4 weeks of the 3-month assessment. And another 58% were enrolled between 4 and 8 weeks from the 3-month assessment.

The primary endpoint is the achievement of MMR at 12 months from the first day of imatinib treatment; that is, at about 9 months from the start of the protocol treatment, in both trial arms.

Patient characteristics

Seventy-eight percent of patients were male, and 95% were younger than 65.

“This is a relatively younger patient population,” Dr. Cortes noted. “This has to do with the fact that this was an international study with a significant representation of patients that were from Asia (73%).”

The Asian patients were primarily from China, Dr. Cortes said, “and we know that, in some parts of the world, including Asia, patients seem to be younger.”

“This is also associated with a higher percentage of patients with high-risk Sokal scores, more than 20%,” he added. “That is different than what’s seen, for example, in the U.S. or in Europe.”

The prevalence of male patients, he said, broadly represents the distribution of patients in other parts of the world.

Patient disposition

Patients were followed for a median of 30 months.

Of the randomized patients—the intent-to-treat (ITT) population—143 (84%) in the dasatinib arm and 72 (84%) in the imatinib arm continued on treatment.

Study drug toxicity was the most common reason for discontinuing treatment and occurred in 9 patients (5%) in the dasatinib arm and 3 (4%) in the imatinib arm.

Nearly half the imatinib patients (n=42, 49%) crossed over to dasatinib at a median of 9 months.

The median duration of treatment was 22 months (range, 1 – 44) for patients on imatinib who did not cross over and 15 months (range, <1 – 38) for patients on dasatinib after crossing over from imatinib.

Response

In the ITT population, the rate of MMR at 12 months was 29% in the dasatinib arm and 13% in the imatinib arm (P=0.005).

The median time to MMR was significantly shorter for patients who received dasatinib compared with imatinib—14 months and 20 months, respectively (P=0.053).

“Over 60% of patients on the dasatinib arm achieved a major molecular response,” Dr. Cortes said. “This compares to about 55% of patients on the imatinib arm, even when you consider the crossover of a significant number of these patients.”

A few patients achieved a molecular response of a 4.5-log reduction in BCR-ABL1 transcripts (MR4.5).

“Of course, the follow-up is short, but we had twice as many patients [on dasatinib] at 12 months with MR4.5— 5% with dasatinib versus 2% with imatinib,” Dr. Cortes said.

Survival outcomes

Both overall and progression-free survival “look very good with both treatment approaches,” Dr. Cortes pointed out.

At a median follow-up of 30 months, the overall survival in the ITT population was 98.8% in each treatment arm.

Progression-free survival was 96.9% in the dasatinib arm and 97.6% in the imatinib arm.

“It is important to note that no patient in either treatment arm has transformed to accelerated or blast phase,” Dr. Cortes said.

Safety

Treatment was well tolerated with both agents, Dr. Cortes observed, with very few grade 3 adverse events (AEs) noted to date.

“The one that stands out here, and it’s only 2% of patients, is headache with dasatinib,” he said.

The headache did not lead to treatment discontinuation, and the patients were managed with dose adjustments.

The investigators observed no new safety signals with either drug.

Treatment-emergent AEs of any grade occurring in 15% or fewer dasatinib- or imatinib-treated patients, respectively, in the ITT population included headache (15%, 9%), diarrhea (9%, 8%), nausea (9%, 8%), eyelid edema (1%, 9%), hypocalcemia (1%, 7%), and muscle spasms (1%, 8%).

Patients who crossed over to dasatinib had similar rates of AEs to those documented for imatinib.

“They are typical for what we know of both of these tyrosine kinase inhibitors,” Dr. Cortes stated.

Investigators observed pleural effusion in 9 (5%) patients on dasatinib, and only one grade 3. That patient discontinued therapy due to the AE.

Of the patients who were on imatinib and crossed over to dasatinib, 3 (7%) experienced pleural effusion, most of them grade 1 or 2. One patient with grade 4 discontinued therapy with dasatinib due to the AE.

“Hematologic toxicity has been mild,” Dr. Cortes said, and in keeping with the known toxicities of dasatinib and imatinib.

Grade 3/4 treatment-emergent AEs in the dasatinib and imatinib arms, respectively, in the ITT population included anemia (5%, 4%), neutropenia (11%, 16%), thrombocytopenia (11%, 11%), and leukopenia (1%, 1%).

Patients who crossed over to dasatinib experienced more of these AEs than patients who did not cross over, Dr. Cortes clarified, but they are still within the expected range with these agents.

“We acknowledge the results are early and we need to continue following for both safety and efficacy, as it will be important to see if those rates of MR4.5 continue to increase with the same difference in favor of dasatinib that we are starting to see very early on,” Dr. Cortes said.

He disclosed serving as a consultant for Pfizer, Daiichi Sankyo, Astellas Pharma, Novartis, and Bristol-Myers Squibb, and he received research funding from Pfizer, Daiichi Sankyo, Arog Pharmaceuticals, Astellas Pharma, Novartis, and Bristol-Myers Squibb.

The study was supported by Bristol-Myers Squibb. 

*Data in the abstract differ from the presentation.

Photo by Jen Smith

SAN DIEGO—Preliminary trial results suggest re-treatment with dasatinib is feasible and safe for a second attempt at tyrosine kinase inhibitor (TKI) discontinuation in chronic myeloid leukemia (CML) patients who fail to achieve treatment-free remission (TFR) after discontinuing imatinib.

However, investigators reported the rate of second TFR (TFR2) was 21% at 6 months, which was not enough to confirm, at this time, that dasatinib could improve the TFR2 rate after imatinib discontinuation failure.

Dennis Kim, MD, of the University of Toronto in Ontario, Canada, presented these results at the 2018 ASH Annual Meeting (abstract 787).

The design of this trial (NCT02268370) includes three phases: the imatinib discontinuation phase, the dasatinib re-challenge phase to achieve a molecular response of ≥ 4.5-log reduction in BCR-ABL1 transcripts (MR4.5), and the dasatinib discontinuation phase.

The primary objective of the trial is to determine the proportion of patients who remain in deep molecular remission (> MR4.5) after discontinuing dasatinib following a failed attempt at discontinuation of imatinib.

If patients had a confirmed molecular relapse after discontinuing imatinib, they were started on 100 mg of dasatinib daily, and, after achieving MR4.5 or greater for 12 months, they discontinued dasatinib for a try at the second TFR.

Investigators defined loss of molecular response, or relapse, as a loss of a major molecular response (MMR) once or loss of MR4.0 on two consecutive occasions.

Patient characteristics

The 131 enrolled CML patients were a median age of 61 (range, 21 to 84), and 62% were male.

Patients had a median 9.36 years of disease duration, 9.18 years of imatinib treatment, 6.82 years of MR4 duration, and 5.08 years of MR4.5 duration.

“The cohort has a very long history of imatinib treatment as well as MR4 duration,” Dr. Kim pointed out, “which also can affect our TFR1 rate, and I think, also, it can affect our TFR2 rate.”

TFR1 and TFR2 rates

As of October 25, the TFR1 rate using loss of MMR as the measure was 69.9% at 12 months from imatinib discontinuation. Relapse-free survival was 57.2% at that time.

Of the 53 patients who lost response, 51 patients received dasatinib. At 3 months of treatment, 97.7% achieved an MMR, 89.9% achieved MR4, and 84.6% achieved MR4.5.

Twenty-five of 51 patients treated with dasatinib attained MR4.5 for 12 months or longer and discontinued treatment for a second attempt at TFR.

Twenty-one patients are still receiving dasatinib and have attained MR4.5, but not for the 12-month duration yet.

Dr. Kim noted that the median time to achievement of molecular response after dasatinib re-challenge ranged from 2.76 months for MR4.5 to 1.71 months for MMR.

Twenty-one of 25 patients (84.0%) who discontinued dasatinib lost their molecular response at a median of 3.7 months.

The estimated TFR2 rate after dasatinib discontinuation is 21.0% to 24.4% at 6 months, which means the investigators cannot reject the null hypothesis of 28% or more patients remaining in remission.

Patients who lost response rapidly after dasatinib discontinuation also tended to lose response rapidly after imatinib discontinuation, Dr. Kim pointed out.

“However, you see some patients who do not lose their response after dasatinib discontinuation or who lose the response but later after the dasatinib discontinuation, they tend to lose their imatinib response also in a later time point,” he said. “So we started to look at the risk factors.”

Risk factor analysis

Out of seven potential risk factors, the investigators were able to demonstrate that time to molecular relapse after imatinib discontinuation, molecular relapse pattern after imatinib discontinuation, and BCR-ABL1 quantitative polymerase chain reaction (qPCR) value prior to dasatinib discontinuation “seemed to be very significant,” Dr. Kim said.

Time to molecular relapse after discontinuation of imatinib correlates with TFR2. The group of patients who relapsed in 3 to 6 months of stopping imatinib had a significantly longer TFR2 than patients who relapsed within 3 months of stopping imatinib (P=0.018).

The molecular relapse pattern also correlates with TFR2. The group with a single loss of MMR after imatinib discontinuation had a significantly shorter TFR2 than those who lost MR4 twice after imatinib discontinuation (P=0.043).

And 0% of the patients who had qPCR transcript levels between a 4.5 and 5.4 log reduction maintained TFR2 at 6 months. However, 28.7% who had qPCR deeper than 5.5 logs prior to dasatinib discontinuation had TFR2 at 6 months (P=0.017).

The risk factor analysis shed light, in part, on the reason the trial thus far failed to satisfy the null hypothesis.

“In other words, because we have selected a really good-risk group for TFR1, the remaining patients are actually a high-risk group for TFR2,” Dr. Kim said. “Because of that, the TFR2 rate might be somewhat lower than we had expected.”

“Or is it related to our conservative treatment with dasatinib, which is 12 months after achieving MR4.5 or deeper response? That may affect our TFR2 rate. We still have to think about that.”

Dr. Kim suggested stricter criteria be considered for attempting TFR2, such as achieving a 5.5 log reduction or deeper in BCR-ABL1 qPCR levels prior to the second TKI discontinuation attempt, and/or an MR4 duration of more than 12 months.

Dr. Kim disclosed receiving honoraria and research funding from Novartis and Bristol-Myers Squibb and serving as a consultant for Pfizer, Paladin, Novartis, and Bristol-Myers Squibb. 

Photo by Jen Smith

SAN DIEGO—Preliminary trial results suggest re-treatment with dasatinib is feasible and safe for a second attempt at tyrosine kinase inhibitor (TKI) discontinuation in chronic myeloid leukemia (CML) patients who fail to achieve treatment-free remission (TFR) after discontinuing imatinib.

However, investigators reported the rate of second TFR (TFR2) was 21% at 6 months, which was not enough to confirm, at this time, that dasatinib could improve the TFR2 rate after imatinib discontinuation failure.

Dennis Kim, MD, of the University of Toronto in Ontario, Canada, presented these results at the 2018 ASH Annual Meeting (abstract 787).

The design of this trial (NCT02268370) includes three phases: the imatinib discontinuation phase, the dasatinib re-challenge phase to achieve a molecular response of ≥ 4.5-log reduction in BCR-ABL1 transcripts (MR4.5), and the dasatinib discontinuation phase.

The primary objective of the trial is to determine the proportion of patients who remain in deep molecular remission (> MR4.5) after discontinuing dasatinib following a failed attempt at discontinuation of imatinib.

If patients had a confirmed molecular relapse after discontinuing imatinib, they were started on 100 mg of dasatinib daily, and, after achieving MR4.5 or greater for 12 months, they discontinued dasatinib for a try at the second TFR.

Investigators defined loss of molecular response, or relapse, as a loss of a major molecular response (MMR) once or loss of MR4.0 on two consecutive occasions.

Patient characteristics

The 131 enrolled CML patients were a median age of 61 (range, 21 to 84), and 62% were male.

Patients had a median 9.36 years of disease duration, 9.18 years of imatinib treatment, 6.82 years of MR4 duration, and 5.08 years of MR4.5 duration.

“The cohort has a very long history of imatinib treatment as well as MR4 duration,” Dr. Kim pointed out, “which also can affect our TFR1 rate, and I think, also, it can affect our TFR2 rate.”

TFR1 and TFR2 rates

As of October 25, the TFR1 rate using loss of MMR as the measure was 69.9% at 12 months from imatinib discontinuation. Relapse-free survival was 57.2% at that time.

Of the 53 patients who lost response, 51 patients received dasatinib. At 3 months of treatment, 97.7% achieved an MMR, 89.9% achieved MR4, and 84.6% achieved MR4.5.

Twenty-five of 51 patients treated with dasatinib attained MR4.5 for 12 months or longer and discontinued treatment for a second attempt at TFR.

Twenty-one patients are still receiving dasatinib and have attained MR4.5, but not for the 12-month duration yet.

Dr. Kim noted that the median time to achievement of molecular response after dasatinib re-challenge ranged from 2.76 months for MR4.5 to 1.71 months for MMR.

Twenty-one of 25 patients (84.0%) who discontinued dasatinib lost their molecular response at a median of 3.7 months.

The estimated TFR2 rate after dasatinib discontinuation is 21.0% to 24.4% at 6 months, which means the investigators cannot reject the null hypothesis of 28% or more patients remaining in remission.

Patients who lost response rapidly after dasatinib discontinuation also tended to lose response rapidly after imatinib discontinuation, Dr. Kim pointed out.

“However, you see some patients who do not lose their response after dasatinib discontinuation or who lose the response but later after the dasatinib discontinuation, they tend to lose their imatinib response also in a later time point,” he said. “So we started to look at the risk factors.”

Risk factor analysis

Out of seven potential risk factors, the investigators were able to demonstrate that time to molecular relapse after imatinib discontinuation, molecular relapse pattern after imatinib discontinuation, and BCR-ABL1 quantitative polymerase chain reaction (qPCR) value prior to dasatinib discontinuation “seemed to be very significant,” Dr. Kim said.

Time to molecular relapse after discontinuation of imatinib correlates with TFR2. The group of patients who relapsed in 3 to 6 months of stopping imatinib had a significantly longer TFR2 than patients who relapsed within 3 months of stopping imatinib (P=0.018).

The molecular relapse pattern also correlates with TFR2. The group with a single loss of MMR after imatinib discontinuation had a significantly shorter TFR2 than those who lost MR4 twice after imatinib discontinuation (P=0.043).

And 0% of the patients who had qPCR transcript levels between a 4.5 and 5.4 log reduction maintained TFR2 at 6 months. However, 28.7% who had qPCR deeper than 5.5 logs prior to dasatinib discontinuation had TFR2 at 6 months (P=0.017).

The risk factor analysis shed light, in part, on the reason the trial thus far failed to satisfy the null hypothesis.

“In other words, because we have selected a really good-risk group for TFR1, the remaining patients are actually a high-risk group for TFR2,” Dr. Kim said. “Because of that, the TFR2 rate might be somewhat lower than we had expected.”

“Or is it related to our conservative treatment with dasatinib, which is 12 months after achieving MR4.5 or deeper response? That may affect our TFR2 rate. We still have to think about that.”

Dr. Kim suggested stricter criteria be considered for attempting TFR2, such as achieving a 5.5 log reduction or deeper in BCR-ABL1 qPCR levels prior to the second TKI discontinuation attempt, and/or an MR4 duration of more than 12 months.

Dr. Kim disclosed receiving honoraria and research funding from Novartis and Bristol-Myers Squibb and serving as a consultant for Pfizer, Paladin, Novartis, and Bristol-Myers Squibb. 

Photo by Jen Smith

SAN DIEGO—Preliminary trial results suggest re-treatment with dasatinib is feasible and safe for a second attempt at tyrosine kinase inhibitor (TKI) discontinuation in chronic myeloid leukemia (CML) patients who fail to achieve treatment-free remission (TFR) after discontinuing imatinib.

However, investigators reported the rate of second TFR (TFR2) was 21% at 6 months, which was not enough to confirm, at this time, that dasatinib could improve the TFR2 rate after imatinib discontinuation failure.

Dennis Kim, MD, of the University of Toronto in Ontario, Canada, presented these results at the 2018 ASH Annual Meeting (abstract 787).

The design of this trial (NCT02268370) includes three phases: the imatinib discontinuation phase, the dasatinib re-challenge phase to achieve a molecular response of ≥ 4.5-log reduction in BCR-ABL1 transcripts (MR4.5), and the dasatinib discontinuation phase.

The primary objective of the trial is to determine the proportion of patients who remain in deep molecular remission (> MR4.5) after discontinuing dasatinib following a failed attempt at discontinuation of imatinib.

If patients had a confirmed molecular relapse after discontinuing imatinib, they were started on 100 mg of dasatinib daily, and, after achieving MR4.5 or greater for 12 months, they discontinued dasatinib for a try at the second TFR.

Investigators defined loss of molecular response, or relapse, as a loss of a major molecular response (MMR) once or loss of MR4.0 on two consecutive occasions.

Patient characteristics

The 131 enrolled CML patients were a median age of 61 (range, 21 to 84), and 62% were male.

Patients had a median 9.36 years of disease duration, 9.18 years of imatinib treatment, 6.82 years of MR4 duration, and 5.08 years of MR4.5 duration.

“The cohort has a very long history of imatinib treatment as well as MR4 duration,” Dr. Kim pointed out, “which also can affect our TFR1 rate, and I think, also, it can affect our TFR2 rate.”

TFR1 and TFR2 rates

As of October 25, the TFR1 rate using loss of MMR as the measure was 69.9% at 12 months from imatinib discontinuation. Relapse-free survival was 57.2% at that time.

Of the 53 patients who lost response, 51 patients received dasatinib. At 3 months of treatment, 97.7% achieved an MMR, 89.9% achieved MR4, and 84.6% achieved MR4.5.

Twenty-five of 51 patients treated with dasatinib attained MR4.5 for 12 months or longer and discontinued treatment for a second attempt at TFR.

Twenty-one patients are still receiving dasatinib and have attained MR4.5, but not for the 12-month duration yet.

Dr. Kim noted that the median time to achievement of molecular response after dasatinib re-challenge ranged from 2.76 months for MR4.5 to 1.71 months for MMR.

Twenty-one of 25 patients (84.0%) who discontinued dasatinib lost their molecular response at a median of 3.7 months.

The estimated TFR2 rate after dasatinib discontinuation is 21.0% to 24.4% at 6 months, which means the investigators cannot reject the null hypothesis of 28% or more patients remaining in remission.

Patients who lost response rapidly after dasatinib discontinuation also tended to lose response rapidly after imatinib discontinuation, Dr. Kim pointed out.

“However, you see some patients who do not lose their response after dasatinib discontinuation or who lose the response but later after the dasatinib discontinuation, they tend to lose their imatinib response also in a later time point,” he said. “So we started to look at the risk factors.”

Risk factor analysis

Out of seven potential risk factors, the investigators were able to demonstrate that time to molecular relapse after imatinib discontinuation, molecular relapse pattern after imatinib discontinuation, and BCR-ABL1 quantitative polymerase chain reaction (qPCR) value prior to dasatinib discontinuation “seemed to be very significant,” Dr. Kim said.

Time to molecular relapse after discontinuation of imatinib correlates with TFR2. The group of patients who relapsed in 3 to 6 months of stopping imatinib had a significantly longer TFR2 than patients who relapsed within 3 months of stopping imatinib (P=0.018).

The molecular relapse pattern also correlates with TFR2. The group with a single loss of MMR after imatinib discontinuation had a significantly shorter TFR2 than those who lost MR4 twice after imatinib discontinuation (P=0.043).

And 0% of the patients who had qPCR transcript levels between a 4.5 and 5.4 log reduction maintained TFR2 at 6 months. However, 28.7% who had qPCR deeper than 5.5 logs prior to dasatinib discontinuation had TFR2 at 6 months (P=0.017).

The risk factor analysis shed light, in part, on the reason the trial thus far failed to satisfy the null hypothesis.

“In other words, because we have selected a really good-risk group for TFR1, the remaining patients are actually a high-risk group for TFR2,” Dr. Kim said. “Because of that, the TFR2 rate might be somewhat lower than we had expected.”

“Or is it related to our conservative treatment with dasatinib, which is 12 months after achieving MR4.5 or deeper response? That may affect our TFR2 rate. We still have to think about that.”

Dr. Kim suggested stricter criteria be considered for attempting TFR2, such as achieving a 5.5 log reduction or deeper in BCR-ABL1 qPCR levels prior to the second TKI discontinuation attempt, and/or an MR4 duration of more than 12 months.

Dr. Kim disclosed receiving honoraria and research funding from Novartis and Bristol-Myers Squibb and serving as a consultant for Pfizer, Paladin, Novartis, and Bristol-Myers Squibb. 

Image by Difu Wu

Health Canada has approved the use of two tests designed to detect BCR-ABL transcripts in patients with chronic myeloid leukemia (CML)—the MRDx® BCR-ABL Test and the QuantideX qPCR BCR-ABL IS Kit.

MolecularMD’s MRDx® BCR-ABL Test is approved as an aid to monitor tyrosine kinase inhibitor (TKI) therapy in Philadelphia chromosome-positive CML patients.

This test is also approved to identify CML patients in the chronic phase being treated with nilotinib who, after sustaining a deep molecular response of MR4.5, may be eligible to stop treatment and be monitored for treatment-free remission.

Asuragen, Inc.’s QuantideX qPCR BCR-ABL IS Kit is approved for use in CML patients, regardless of whether they are taking a TKI or how their disease is being managed.

The kit is designed to detect and quantify major breakpoint (e13a2, e14a2) BCR-ABL1 fusion transcripts for use in monitoring molecular response.

Both the MRDx® BCR-ABL Test and the QuantideX qPCR BCR-ABL IS Kit are approved in the United States as well.

The QuantideX qPCR BCR-ABL IS Kit is also CE marked for clinical use in the European Union.

Image by Difu Wu

Health Canada has approved the use of two tests designed to detect BCR-ABL transcripts in patients with chronic myeloid leukemia (CML)—the MRDx® BCR-ABL Test and the QuantideX qPCR BCR-ABL IS Kit.

MolecularMD’s MRDx® BCR-ABL Test is approved as an aid to monitor tyrosine kinase inhibitor (TKI) therapy in Philadelphia chromosome-positive CML patients.

This test is also approved to identify CML patients in the chronic phase being treated with nilotinib who, after sustaining a deep molecular response of MR4.5, may be eligible to stop treatment and be monitored for treatment-free remission.

Asuragen, Inc.’s QuantideX qPCR BCR-ABL IS Kit is approved for use in CML patients, regardless of whether they are taking a TKI or how their disease is being managed.

The kit is designed to detect and quantify major breakpoint (e13a2, e14a2) BCR-ABL1 fusion transcripts for use in monitoring molecular response.

Both the MRDx® BCR-ABL Test and the QuantideX qPCR BCR-ABL IS Kit are approved in the United States as well.

The QuantideX qPCR BCR-ABL IS Kit is also CE marked for clinical use in the European Union.

Image by Difu Wu

Health Canada has approved the use of two tests designed to detect BCR-ABL transcripts in patients with chronic myeloid leukemia (CML)—the MRDx® BCR-ABL Test and the QuantideX qPCR BCR-ABL IS Kit.

MolecularMD’s MRDx® BCR-ABL Test is approved as an aid to monitor tyrosine kinase inhibitor (TKI) therapy in Philadelphia chromosome-positive CML patients.

This test is also approved to identify CML patients in the chronic phase being treated with nilotinib who, after sustaining a deep molecular response of MR4.5, may be eligible to stop treatment and be monitored for treatment-free remission.

Asuragen, Inc.’s QuantideX qPCR BCR-ABL IS Kit is approved for use in CML patients, regardless of whether they are taking a TKI or how their disease is being managed.

The kit is designed to detect and quantify major breakpoint (e13a2, e14a2) BCR-ABL1 fusion transcripts for use in monitoring molecular response.

Both the MRDx® BCR-ABL Test and the QuantideX qPCR BCR-ABL IS Kit are approved in the United States as well.

The QuantideX qPCR BCR-ABL IS Kit is also CE marked for clinical use in the European Union.

DUBROVNIK, CROATIA – Diagnosing chronic myelomonocytic leukemia (CMML) remains a challenge in 2018.

Even with updated World Health Organization (WHO) criteria, karyotyping, and genetic analyses, it can be difficult to distinguish CMML from other conditions, according to Nadira Durakovic, MD, PhD, of the University Hospital Centre Zagreb (Croatia).

However, there are characteristics that differentiate CMML from myelodysplastic syndromes (MDS), myeloproliferative neoplasms (MPNs), and atypical chronic myeloid leukemia (CML), Dr. Durakovic said at Leukemia and Lymphoma, a meeting jointly sponsored by the University of Texas MD Anderson Cancer Center and the School of Medicine at the University of Zagreb, Croatia.

Studies have suggested that monocyte subset distribution analysis can be useful for diagnosing CMML.

According to the 2016 WHO classification, patients have CMML if:

• They have persistent peripheral blood monocytosis (1×10⁹/L), with monocytes accounting for 10% of the white blood cell count.
• They do not meet WHO criteria for BCR-ABL1-positive CML, primary myelofibrosis, polycythemia vera, or essential thrombocythemia.
• There is no evidence of PCM1-JAK2 or PDGFRA, PDGFRB, or FGFR1 rearrangement.
• They have fewer than 20% blasts in the blood and bone marrow they have dysplasia in one or more myeloid lineages.

If myelodysplasia is absent or minimal, an acquired clonal cytogenetic or molecular genetic abnormality must be present. Alternatively, if patients have monocytosis that has persisted for at least 3 months, and all other causes of monocytosis have been excluded, “you can say that your patient has CMML,” Dr. Durakovic said.

Other causes of monocytosis include infections, malignancies, medications, inflammatory conditions, and other conditions, such as pregnancy.

However, Dr. Durakovic pointed out that the cause of monocytosis cannot always be determined, and, in some cases, CMML patients may not meet the WHO criteria.

“There are cases where there just aren’t enough monocytes to fulfill the WHO criteria,” Dr. Durakovic said. “You can have a patient with peripheral blood cytopenia and monocytosis who does not have 1,000 monocytes. Patients can have progressive dysplasia, can have splenomegaly, be really sick, but fail to meet WHO criteria.”
 

Differential diagnosis

“Differentiating CMML from myelodysplastic syndromes can be tough,” Dr. Durakovic said. “There are dysplastic features that are present in CMML ... but, in CMML, they are more subtle, and they are more difficult to appreciate than in myelodysplastic syndromes.”

The ratio of myeloid to erythroid cells is elevated in CMML, and patients may have atypical monocytes (paramyeloid cells) that are unique to CMML.

Dr. Durakovic noted that megakaryocyte dysplasia in CMML can be characterized by “myeloproliferative megakaryocytes,” which are large cells that cluster and have hyperlobulated nuclei, or “MDS megakaryocytes,” which are small, solitary cells with hypolobulated nuclei.

She noted that “MPN phenotype” CMML is characterized by leukocytosis, monocytosis, hepatomegaly, splenomegaly, and clinical features of myeloproliferation (fatigue, night sweats, bone pain, weight loss, etc.).

Thirty percent of cases are associated with splenomegaly, and 30% of patients can have an increase in bone marrow reticulin fibrosis.

Dr. Durakovic also noted that a prior MPN diagnosis excludes CMML. The presence of common MPN mutations, such as JAK2, CALR, or MPL, suggests a patient has an MPN with monocytosis rather than CMML.

Patients who have unclassified MPNs or MDS, rather than CMML, either do not have 1,000 monocytes or the monocytes do not represent more than 10% of the differential, Dr. Durakovic said.

It can also be difficult to differentiate CMML from atypical CML.

“Atypical CML is characterized by profound dysgranulopoiesis, absence of the BCR-ABL1 fusion gene, and neutrophilia,” Dr. Durakovic explained. “Those patients [commonly] have monocytosis, but, here, that 10% rule is valuable because their monocytes comprise less than 10% of the entire white blood cell count.”
 

Karyotyping, genotyping, and immunophenotyping

“There is no disease-defining karyotype abnormality [in CMML],” Dr. Durakovic said.

She said 30% of patients have abnormal karyotype, and the most common abnormality is trisomy 8. Unlike in patients with MDS, del(5q) and monosomal karyotypes are infrequent in patients with CMML.

Similarly, there are no “disease-defining” mutations or genetic changes in CMML, although CMML is genetically distinct from MDS, Dr. Durakovic said.

For instance, SRSF2 encodes a component of the spliceosome that is mutated in almost half of CMML patients and less than 10% of MDS patients. Likewise, ASLX1 and TET2 are “much more frequently involved” in CMML than in MDS, Dr. Durakovic said.

In a 2012 study of 275 CMML patients, researchers found that 93% of patients had at least one somatic mutation in nine recurrently mutated genes – SRFS2, ASXL1, CBL, EZH2, JAK2V617F, KRAS, NRAS, RUNX1, and TET2 (Blood. 2012;120:3080-8).

However, Dr. Durakovic noted that these mutations are found in other disorders as well, so this information may not be helpful in differentiating CMML from other disorders.

A 2015 study revealed a technique that does appear useful for identifying CMML – monocyte subset distribution analysis. For this analysis, monocytes are divided into the following categories:

• Classical/MO1 (CD14^bright/CD16⁻).
• Intermediate/MO2 (CD14^bright/CD16⁺).
• Nonclassical/MO3 (CD14^dim/CD16⁺).

The researchers found that CMML patients had an increase in the fraction of classical monocytes (with a cutoff value of 94%), as compared to healthy control subjects, patients with another hematologic disorder, and patients with reactive monocytosis (Blood. 2015 Jun 4;125[23]:3618-26).

A 2018 study confirmed that monocyte subset distribution analysis could differentiate CMML from other hematologic disorders, with the exception of atypical CML. This study also suggested that a decreased percentage of non-classical monocytes was more sensitive than an increased percentage of classical monocytes (Am J Clin Pathol. 2018 Aug 30;150[4]:293-302).

Despite the differences between these studies, “monocyte subset distribution analysis is showing promise as a method of identifying hard-to-identify CMML patients with ease and affordability,” Dr. Durakovic said.

She added that the technique can be implemented in clinical practice using the Hematoflow solution.

Dr. Durakovic did not report any conflicts of interest.

The Leukemia and Lymphoma meeting is organized by Jonathan Wood & Association, which is owned by the parent company of this news organization.
 

[email protected]
 

DUBROVNIK, CROATIA – Diagnosing chronic myelomonocytic leukemia (CMML) remains a challenge in 2018.

Even with updated World Health Organization (WHO) criteria, karyotyping, and genetic analyses, it can be difficult to distinguish CMML from other conditions, according to Nadira Durakovic, MD, PhD, of the University Hospital Centre Zagreb (Croatia).

However, there are characteristics that differentiate CMML from myelodysplastic syndromes (MDS), myeloproliferative neoplasms (MPNs), and atypical chronic myeloid leukemia (CML), Dr. Durakovic said at Leukemia and Lymphoma, a meeting jointly sponsored by the University of Texas MD Anderson Cancer Center and the School of Medicine at the University of Zagreb, Croatia.

Studies have suggested that monocyte subset distribution analysis can be useful for diagnosing CMML.

According to the 2016 WHO classification, patients have CMML if:

• They have persistent peripheral blood monocytosis (1×10⁹/L), with monocytes accounting for 10% of the white blood cell count.
• They do not meet WHO criteria for BCR-ABL1-positive CML, primary myelofibrosis, polycythemia vera, or essential thrombocythemia.
• There is no evidence of PCM1-JAK2 or PDGFRA, PDGFRB, or FGFR1 rearrangement.
• They have fewer than 20% blasts in the blood and bone marrow they have dysplasia in one or more myeloid lineages.

If myelodysplasia is absent or minimal, an acquired clonal cytogenetic or molecular genetic abnormality must be present. Alternatively, if patients have monocytosis that has persisted for at least 3 months, and all other causes of monocytosis have been excluded, “you can say that your patient has CMML,” Dr. Durakovic said.

Other causes of monocytosis include infections, malignancies, medications, inflammatory conditions, and other conditions, such as pregnancy.

However, Dr. Durakovic pointed out that the cause of monocytosis cannot always be determined, and, in some cases, CMML patients may not meet the WHO criteria.

“There are cases where there just aren’t enough monocytes to fulfill the WHO criteria,” Dr. Durakovic said. “You can have a patient with peripheral blood cytopenia and monocytosis who does not have 1,000 monocytes. Patients can have progressive dysplasia, can have splenomegaly, be really sick, but fail to meet WHO criteria.”
 

Differential diagnosis

“Differentiating CMML from myelodysplastic syndromes can be tough,” Dr. Durakovic said. “There are dysplastic features that are present in CMML ... but, in CMML, they are more subtle, and they are more difficult to appreciate than in myelodysplastic syndromes.”

The ratio of myeloid to erythroid cells is elevated in CMML, and patients may have atypical monocytes (paramyeloid cells) that are unique to CMML.

Dr. Durakovic noted that megakaryocyte dysplasia in CMML can be characterized by “myeloproliferative megakaryocytes,” which are large cells that cluster and have hyperlobulated nuclei, or “MDS megakaryocytes,” which are small, solitary cells with hypolobulated nuclei.

She noted that “MPN phenotype” CMML is characterized by leukocytosis, monocytosis, hepatomegaly, splenomegaly, and clinical features of myeloproliferation (fatigue, night sweats, bone pain, weight loss, etc.).

Thirty percent of cases are associated with splenomegaly, and 30% of patients can have an increase in bone marrow reticulin fibrosis.

Dr. Durakovic also noted that a prior MPN diagnosis excludes CMML. The presence of common MPN mutations, such as JAK2, CALR, or MPL, suggests a patient has an MPN with monocytosis rather than CMML.

Patients who have unclassified MPNs or MDS, rather than CMML, either do not have 1,000 monocytes or the monocytes do not represent more than 10% of the differential, Dr. Durakovic said.

It can also be difficult to differentiate CMML from atypical CML.

“Atypical CML is characterized by profound dysgranulopoiesis, absence of the BCR-ABL1 fusion gene, and neutrophilia,” Dr. Durakovic explained. “Those patients [commonly] have monocytosis, but, here, that 10% rule is valuable because their monocytes comprise less than 10% of the entire white blood cell count.”
 

Karyotyping, genotyping, and immunophenotyping

“There is no disease-defining karyotype abnormality [in CMML],” Dr. Durakovic said.

She said 30% of patients have abnormal karyotype, and the most common abnormality is trisomy 8. Unlike in patients with MDS, del(5q) and monosomal karyotypes are infrequent in patients with CMML.

Similarly, there are no “disease-defining” mutations or genetic changes in CMML, although CMML is genetically distinct from MDS, Dr. Durakovic said.

For instance, SRSF2 encodes a component of the spliceosome that is mutated in almost half of CMML patients and less than 10% of MDS patients. Likewise, ASLX1 and TET2 are “much more frequently involved” in CMML than in MDS, Dr. Durakovic said.

In a 2012 study of 275 CMML patients, researchers found that 93% of patients had at least one somatic mutation in nine recurrently mutated genes – SRFS2, ASXL1, CBL, EZH2, JAK2V617F, KRAS, NRAS, RUNX1, and TET2 (Blood. 2012;120:3080-8).

However, Dr. Durakovic noted that these mutations are found in other disorders as well, so this information may not be helpful in differentiating CMML from other disorders.

A 2015 study revealed a technique that does appear useful for identifying CMML – monocyte subset distribution analysis. For this analysis, monocytes are divided into the following categories:

• Classical/MO1 (CD14^bright/CD16⁻).
• Intermediate/MO2 (CD14^bright/CD16⁺).
• Nonclassical/MO3 (CD14^dim/CD16⁺).

The researchers found that CMML patients had an increase in the fraction of classical monocytes (with a cutoff value of 94%), as compared to healthy control subjects, patients with another hematologic disorder, and patients with reactive monocytosis (Blood. 2015 Jun 4;125[23]:3618-26).

A 2018 study confirmed that monocyte subset distribution analysis could differentiate CMML from other hematologic disorders, with the exception of atypical CML. This study also suggested that a decreased percentage of non-classical monocytes was more sensitive than an increased percentage of classical monocytes (Am J Clin Pathol. 2018 Aug 30;150[4]:293-302).

Despite the differences between these studies, “monocyte subset distribution analysis is showing promise as a method of identifying hard-to-identify CMML patients with ease and affordability,” Dr. Durakovic said.

She added that the technique can be implemented in clinical practice using the Hematoflow solution.

Dr. Durakovic did not report any conflicts of interest.

The Leukemia and Lymphoma meeting is organized by Jonathan Wood & Association, which is owned by the parent company of this news organization.
 

[email protected]
 

DUBROVNIK, CROATIA – Diagnosing chronic myelomonocytic leukemia (CMML) remains a challenge in 2018.

Even with updated World Health Organization (WHO) criteria, karyotyping, and genetic analyses, it can be difficult to distinguish CMML from other conditions, according to Nadira Durakovic, MD, PhD, of the University Hospital Centre Zagreb (Croatia).

However, there are characteristics that differentiate CMML from myelodysplastic syndromes (MDS), myeloproliferative neoplasms (MPNs), and atypical chronic myeloid leukemia (CML), Dr. Durakovic said at Leukemia and Lymphoma, a meeting jointly sponsored by the University of Texas MD Anderson Cancer Center and the School of Medicine at the University of Zagreb, Croatia.

Studies have suggested that monocyte subset distribution analysis can be useful for diagnosing CMML.

According to the 2016 WHO classification, patients have CMML if:

• They have persistent peripheral blood monocytosis (1×10⁹/L), with monocytes accounting for 10% of the white blood cell count.
• They do not meet WHO criteria for BCR-ABL1-positive CML, primary myelofibrosis, polycythemia vera, or essential thrombocythemia.
• There is no evidence of PCM1-JAK2 or PDGFRA, PDGFRB, or FGFR1 rearrangement.
• They have fewer than 20% blasts in the blood and bone marrow they have dysplasia in one or more myeloid lineages.

If myelodysplasia is absent or minimal, an acquired clonal cytogenetic or molecular genetic abnormality must be present. Alternatively, if patients have monocytosis that has persisted for at least 3 months, and all other causes of monocytosis have been excluded, “you can say that your patient has CMML,” Dr. Durakovic said.

Other causes of monocytosis include infections, malignancies, medications, inflammatory conditions, and other conditions, such as pregnancy.

However, Dr. Durakovic pointed out that the cause of monocytosis cannot always be determined, and, in some cases, CMML patients may not meet the WHO criteria.

“There are cases where there just aren’t enough monocytes to fulfill the WHO criteria,” Dr. Durakovic said. “You can have a patient with peripheral blood cytopenia and monocytosis who does not have 1,000 monocytes. Patients can have progressive dysplasia, can have splenomegaly, be really sick, but fail to meet WHO criteria.”
 

Differential diagnosis

“Differentiating CMML from myelodysplastic syndromes can be tough,” Dr. Durakovic said. “There are dysplastic features that are present in CMML ... but, in CMML, they are more subtle, and they are more difficult to appreciate than in myelodysplastic syndromes.”

The ratio of myeloid to erythroid cells is elevated in CMML, and patients may have atypical monocytes (paramyeloid cells) that are unique to CMML.

Dr. Durakovic noted that megakaryocyte dysplasia in CMML can be characterized by “myeloproliferative megakaryocytes,” which are large cells that cluster and have hyperlobulated nuclei, or “MDS megakaryocytes,” which are small, solitary cells with hypolobulated nuclei.

She noted that “MPN phenotype” CMML is characterized by leukocytosis, monocytosis, hepatomegaly, splenomegaly, and clinical features of myeloproliferation (fatigue, night sweats, bone pain, weight loss, etc.).

Thirty percent of cases are associated with splenomegaly, and 30% of patients can have an increase in bone marrow reticulin fibrosis.

Dr. Durakovic also noted that a prior MPN diagnosis excludes CMML. The presence of common MPN mutations, such as JAK2, CALR, or MPL, suggests a patient has an MPN with monocytosis rather than CMML.

Patients who have unclassified MPNs or MDS, rather than CMML, either do not have 1,000 monocytes or the monocytes do not represent more than 10% of the differential, Dr. Durakovic said.

It can also be difficult to differentiate CMML from atypical CML.

“Atypical CML is characterized by profound dysgranulopoiesis, absence of the BCR-ABL1 fusion gene, and neutrophilia,” Dr. Durakovic explained. “Those patients [commonly] have monocytosis, but, here, that 10% rule is valuable because their monocytes comprise less than 10% of the entire white blood cell count.”
 

Karyotyping, genotyping, and immunophenotyping

“There is no disease-defining karyotype abnormality [in CMML],” Dr. Durakovic said.

She said 30% of patients have abnormal karyotype, and the most common abnormality is trisomy 8. Unlike in patients with MDS, del(5q) and monosomal karyotypes are infrequent in patients with CMML.

Similarly, there are no “disease-defining” mutations or genetic changes in CMML, although CMML is genetically distinct from MDS, Dr. Durakovic said.

For instance, SRSF2 encodes a component of the spliceosome that is mutated in almost half of CMML patients and less than 10% of MDS patients. Likewise, ASLX1 and TET2 are “much more frequently involved” in CMML than in MDS, Dr. Durakovic said.

In a 2012 study of 275 CMML patients, researchers found that 93% of patients had at least one somatic mutation in nine recurrently mutated genes – SRFS2, ASXL1, CBL, EZH2, JAK2V617F, KRAS, NRAS, RUNX1, and TET2 (Blood. 2012;120:3080-8).

However, Dr. Durakovic noted that these mutations are found in other disorders as well, so this information may not be helpful in differentiating CMML from other disorders.

A 2015 study revealed a technique that does appear useful for identifying CMML – monocyte subset distribution analysis. For this analysis, monocytes are divided into the following categories:

• Classical/MO1 (CD14^bright/CD16⁻).
• Intermediate/MO2 (CD14^bright/CD16⁺).
• Nonclassical/MO3 (CD14^dim/CD16⁺).

The researchers found that CMML patients had an increase in the fraction of classical monocytes (with a cutoff value of 94%), as compared to healthy control subjects, patients with another hematologic disorder, and patients with reactive monocytosis (Blood. 2015 Jun 4;125[23]:3618-26).

A 2018 study confirmed that monocyte subset distribution analysis could differentiate CMML from other hematologic disorders, with the exception of atypical CML. This study also suggested that a decreased percentage of non-classical monocytes was more sensitive than an increased percentage of classical monocytes (Am J Clin Pathol. 2018 Aug 30;150[4]:293-302).

Despite the differences between these studies, “monocyte subset distribution analysis is showing promise as a method of identifying hard-to-identify CMML patients with ease and affordability,” Dr. Durakovic said.

She added that the technique can be implemented in clinical practice using the Hematoflow solution.

Dr. Durakovic did not report any conflicts of interest.

The Leukemia and Lymphoma meeting is organized by Jonathan Wood & Association, which is owned by the parent company of this news organization.
 

[email protected]
 

Photo by Darren Baker

The U.S. Food and Drug Administration (FDA) has issued a draft guidance on the use of minimal residual disease (MRD) assessment in trials of patients with hematologic malignancies.

The FDA said it developed this guidance to assist sponsors who are planning to use MRD as a biomarker in clinical trials conducted under an investigational new drug application or to support FDA approval of products intended to treat hematologic malignancies.

“As a result of important workshops where we’ve heard from stakeholders and an analysis of marketing applications showing inconsistent quality of MRD data, the FDA identified a need to provide sponsors with guidance on the use of MRD as a biomarker in regulatory submissions,” said FDA Commissioner Scott Gottlieb, MD.

The guidance explains how MRD might be used in clinical trials, highlights considerations for MRD assessment that are specific to certain hematologic malignancies, and lists requirements for regulatory submissions that utilize MRD.

The full document, “Hematologic Malignancies: Regulatory Considerations for Use of Minimal Residual Disease in Development of Drug and Biological Products for Treatment,” is available for download from the FDA website.

How MRD can be used

The guidance notes that MRD could potentially be used as a biomarker in clinical trials, specifically, as a diagnostic, prognostic, predictive, efficacy-response, or monitoring biomarker.

MRD could also be used as a surrogate endpoint, and there are two mechanisms for obtaining FDA feedback on the use of a novel surrogate endpoint to support approval of a product:

1. The drug development tool qualification process
2. Discussions with the specific Center for Drug Evaluation and Research or Center for Biologics Evaluation and Research review division.

Furthermore, a sponsor can use MRD “to select patients at high risk or to enrich the trial population,” according to the guidance.

Disease specifics

The guidance also details specific considerations for MRD assessment in individual hematologic malignancies. For example:

• In acute lymphoblastic leukemia, a patient with an MRD level of 0.1% or more in first or second complete remission has a high risk of relapse.
• In trials of acute myeloid leukemia, the sponsor should provide data showing that the marker selected to assess MRD “reflects the leukemia and not underlying clonal hematopoiesis.”
• Patients with low-risk acute promyelocytic leukemia who achieve MRD negativity after arsenic/tretinoin-based therapy are generally considered cured.
• In chronic lymphocytic leukemia, MRD can be assessed in the peripheral blood or bone marrow, but the sample source should remain the same throughout a trial.
• In chronic myeloid leukemia, MRD can be used to select and monitor patients who are eligible to discontinue treatment with tyrosine kinase inhibitors.
• In multiple myeloma, imaging techniques may be combined with MRD assessment of the bone marrow to assess patient response to treatment.

Types of technology

The guidance lists the four general technologies used for MRD assessment in hematologic malignancies:

• Multiparametric flow cytometry
• Next-generation sequencing
• Quantitative reverse transcription polymerase chain reaction of specific gene fusions
• Allele-specific oligonucleotide polymerase chain reaction.

The FDA said it does not have a preference as to which technology is used in a trial. However, the sponsor must pre-specify the technology used and should utilize the same technology throughout a trial.

The FDA also said it “does not foresee the need for co-development of an MRD assay with a drug product.” However, the assay must be analytically valid for results important to the trial, and MRD assessment must be a clinically valid biomarker in the context in which it’s used.

If the MRD assay used is not FDA-cleared or -approved, additional information about the assay must be provided to the FDA.

Photo by Darren Baker

The U.S. Food and Drug Administration (FDA) has issued a draft guidance on the use of minimal residual disease (MRD) assessment in trials of patients with hematologic malignancies.

The FDA said it developed this guidance to assist sponsors who are planning to use MRD as a biomarker in clinical trials conducted under an investigational new drug application or to support FDA approval of products intended to treat hematologic malignancies.

“As a result of important workshops where we’ve heard from stakeholders and an analysis of marketing applications showing inconsistent quality of MRD data, the FDA identified a need to provide sponsors with guidance on the use of MRD as a biomarker in regulatory submissions,” said FDA Commissioner Scott Gottlieb, MD.

The guidance explains how MRD might be used in clinical trials, highlights considerations for MRD assessment that are specific to certain hematologic malignancies, and lists requirements for regulatory submissions that utilize MRD.

The full document, “Hematologic Malignancies: Regulatory Considerations for Use of Minimal Residual Disease in Development of Drug and Biological Products for Treatment,” is available for download from the FDA website.

How MRD can be used

The guidance notes that MRD could potentially be used as a biomarker in clinical trials, specifically, as a diagnostic, prognostic, predictive, efficacy-response, or monitoring biomarker.

MRD could also be used as a surrogate endpoint, and there are two mechanisms for obtaining FDA feedback on the use of a novel surrogate endpoint to support approval of a product:

1. The drug development tool qualification process
2. Discussions with the specific Center for Drug Evaluation and Research or Center for Biologics Evaluation and Research review division.

Furthermore, a sponsor can use MRD “to select patients at high risk or to enrich the trial population,” according to the guidance.

Disease specifics

The guidance also details specific considerations for MRD assessment in individual hematologic malignancies. For example:

• In acute lymphoblastic leukemia, a patient with an MRD level of 0.1% or more in first or second complete remission has a high risk of relapse.
• In trials of acute myeloid leukemia, the sponsor should provide data showing that the marker selected to assess MRD “reflects the leukemia and not underlying clonal hematopoiesis.”
• Patients with low-risk acute promyelocytic leukemia who achieve MRD negativity after arsenic/tretinoin-based therapy are generally considered cured.
• In chronic lymphocytic leukemia, MRD can be assessed in the peripheral blood or bone marrow, but the sample source should remain the same throughout a trial.
• In chronic myeloid leukemia, MRD can be used to select and monitor patients who are eligible to discontinue treatment with tyrosine kinase inhibitors.
• In multiple myeloma, imaging techniques may be combined with MRD assessment of the bone marrow to assess patient response to treatment.

Types of technology

The guidance lists the four general technologies used for MRD assessment in hematologic malignancies:

• Multiparametric flow cytometry
• Next-generation sequencing
• Quantitative reverse transcription polymerase chain reaction of specific gene fusions
• Allele-specific oligonucleotide polymerase chain reaction.

The FDA said it does not have a preference as to which technology is used in a trial. However, the sponsor must pre-specify the technology used and should utilize the same technology throughout a trial.

The FDA also said it “does not foresee the need for co-development of an MRD assay with a drug product.” However, the assay must be analytically valid for results important to the trial, and MRD assessment must be a clinically valid biomarker in the context in which it’s used.

If the MRD assay used is not FDA-cleared or -approved, additional information about the assay must be provided to the FDA.

Photo by Darren Baker

The U.S. Food and Drug Administration (FDA) has issued a draft guidance on the use of minimal residual disease (MRD) assessment in trials of patients with hematologic malignancies.

The FDA said it developed this guidance to assist sponsors who are planning to use MRD as a biomarker in clinical trials conducted under an investigational new drug application or to support FDA approval of products intended to treat hematologic malignancies.

“As a result of important workshops where we’ve heard from stakeholders and an analysis of marketing applications showing inconsistent quality of MRD data, the FDA identified a need to provide sponsors with guidance on the use of MRD as a biomarker in regulatory submissions,” said FDA Commissioner Scott Gottlieb, MD.

The guidance explains how MRD might be used in clinical trials, highlights considerations for MRD assessment that are specific to certain hematologic malignancies, and lists requirements for regulatory submissions that utilize MRD.

The full document, “Hematologic Malignancies: Regulatory Considerations for Use of Minimal Residual Disease in Development of Drug and Biological Products for Treatment,” is available for download from the FDA website.

How MRD can be used

The guidance notes that MRD could potentially be used as a biomarker in clinical trials, specifically, as a diagnostic, prognostic, predictive, efficacy-response, or monitoring biomarker.

MRD could also be used as a surrogate endpoint, and there are two mechanisms for obtaining FDA feedback on the use of a novel surrogate endpoint to support approval of a product:

1. The drug development tool qualification process
2. Discussions with the specific Center for Drug Evaluation and Research or Center for Biologics Evaluation and Research review division.

Furthermore, a sponsor can use MRD “to select patients at high risk or to enrich the trial population,” according to the guidance.

Disease specifics

The guidance also details specific considerations for MRD assessment in individual hematologic malignancies. For example:

• In acute lymphoblastic leukemia, a patient with an MRD level of 0.1% or more in first or second complete remission has a high risk of relapse.
• In trials of acute myeloid leukemia, the sponsor should provide data showing that the marker selected to assess MRD “reflects the leukemia and not underlying clonal hematopoiesis.”
• Patients with low-risk acute promyelocytic leukemia who achieve MRD negativity after arsenic/tretinoin-based therapy are generally considered cured.
• In chronic lymphocytic leukemia, MRD can be assessed in the peripheral blood or bone marrow, but the sample source should remain the same throughout a trial.
• In chronic myeloid leukemia, MRD can be used to select and monitor patients who are eligible to discontinue treatment with tyrosine kinase inhibitors.
• In multiple myeloma, imaging techniques may be combined with MRD assessment of the bone marrow to assess patient response to treatment.

Types of technology

The guidance lists the four general technologies used for MRD assessment in hematologic malignancies:

• Multiparametric flow cytometry
• Next-generation sequencing
• Quantitative reverse transcription polymerase chain reaction of specific gene fusions
• Allele-specific oligonucleotide polymerase chain reaction.

The FDA said it does not have a preference as to which technology is used in a trial. However, the sponsor must pre-specify the technology used and should utilize the same technology throughout a trial.

The FDA also said it “does not foresee the need for co-development of an MRD assay with a drug product.” However, the assay must be analytically valid for results important to the trial, and MRD assessment must be a clinically valid biomarker in the context in which it’s used.

If the MRD assay used is not FDA-cleared or -approved, additional information about the assay must be provided to the FDA.

DUBROVNIK, CROATIA – Long-term efficacy and toxicity should inform decisions about tyrosine kinase inhibitors (TKIs) in chronic myeloid leukemia (CML), according to one expert.

Studies have indicated that long-term survival rates are similar whether CML patients receive frontline treatment with imatinib or second-generation TKIs. But the newer TKIs pose a higher risk of uncommon toxicities, Hagop M. Kantarjian, MD, said during the keynote presentation at Leukemia and Lymphoma, a meeting jointly sponsored by the University of Texas MD Anderson Cancer Center and the School of Medicine at the University of Zagreb, Croatia.

Dr. Kantarjian, a professor at MD Anderson Cancer Center in Houston, said most CML patients should receive daily treatment with TKIs – even if they are in complete cytogenetic response or 100% Philadelphia chromosome positive – because they will live longer.

Frontline treatment options for CML that are approved by the Food and Drug Administration include imatinib, dasatinib, nilotinib, and bosutinib.

Dr. Kantarjian noted that dasatinib and nilotinib bested imatinib in early analyses from clinical trials, but all three TKIs produced similar rates of overall survival (OS) and progression-free survival (PFS) at extended follow-up.

Dasatinib and imatinib produced similar rates of 5-year OS and PFS in the DASISION trial (J Clin Oncol. 2016 Jul 10;34[20]:2333-40).

In ENESTnd, 5-year OS and PFS rates were similar with nilotinib and imatinib (Leukemia. 2016 May;30[5]:1044-54).

However, the higher incidence of uncommon toxicities with the newer TKIs must be taken into account, Dr. Kantarjian said.
 

Choosing a TKI

Dr. Kantarjian recommends frontline imatinib for older patients (aged 65-70) and those who are low risk based on their Sokal score.

Second-generation TKIs should be given up front to patients who are at higher risk by Sokal and for “very young patients in whom early treatment discontinuation is important,” he said.

“In accelerated or blast phase, I always use the second-generation TKIs,” he said. “If there’s no binding mutation, I prefer dasatinib. I think it’s the most potent of them. If there are toxicities with dasatinib, bosutinib is equivalent in efficacy, so they are interchangeable.”

A TKI should not be discarded unless there is loss of complete cytogenetic response – not major molecular response – at the maximum tolerated adjusted dose that does not cause grade 3-4 toxicities or chronic grade 2 toxicities, Dr. Kantarjian added.

“We have to remember that we can go down on the dosages of, for example, imatinib, down to 200 mg a day, dasatinib as low as 20 mg a day, nilotinib as low as 150 mg twice a day or even 200 mg daily, and bosutinib down to 200 mg daily,” he said. “So if we have a patient who’s responding with side effects, we should not abandon the particular TKI, we should try to manipulate the dose schedule if they are having a good response.”

Dr. Kantarjian noted that pleural effusion is a toxicity of particular concern with dasatinib, but lowering the dose to 50 mg daily results in similar efficacy and significantly less toxicity than 100 mg daily. For patients over the age of 70, a 20-mg dose can be used.

Vaso-occlusive and vasospastic reactions are increasingly observed in patients treated with nilotinib. For that reason, Dr. Kantarjian said he prefers to forgo up-front nilotinib, particularly in patients who have cardiovascular or neurotoxic problems.

“The incidence of vaso-occlusive and vasospastic reactions is now close to 10%-15% at about 10 years with nilotinib,” Dr. Kantarjian said. “So it is not a trivial toxicity.”

For patients with vaso-occlusive/vasospastic reactions, “bosutinib is probably the safest drug,” Dr. Kantarjian said.

For second- or third-line therapy, patients can receive ponatinib or a second-generation TKI (dasatinib, nilotinib, or bosutinib), as well as omacetaxine or allogeneic stem cell transplant.

“If you disregard toxicities, I think ponatinib is the most powerful TKI, and I think that’s because we are using it at a higher dose that produces so many toxicities,” Dr. Kantarjian said.

Ponatinib is not used up front because of these toxicities, particularly pancreatitis, skin rashes, vaso-occlusive disorders, and hypertension, he added.

Dr. Kantarjian suggests giving ponatinib at 30 mg daily in patients with T315I mutation and those without guiding mutations who are resistant to second-generation TKIs.
 

Discontinuing a TKI

Dr. Kantarjian said patients can discontinue TKI therapy if they:

• Are low- or intermediate-risk by Sokal.
• Have quantifiable BCR-ABL transcripts.
• Are in chronic phase.
• Achieved an optimal response to their first TKI.
• Have been on TKI therapy for more than 8 years.
• Achieved a complete molecular response.
• Have had a molecular response for more than 2-3 years.
• Are available for monitoring every other month for the first 2 years.

Dr. Kantarjian did not report any conflicts of interest at the meeting. However, he has previously reported relationships with Novartis, Bristol-Myers Squibb, Pfizer, and Ariad Pharmaceuticals.

The Leukemia and Lymphoma meeting is organized by Jonathan Wood & Association, which is owned by the parent company of this news organization.

[email protected]

DUBROVNIK, CROATIA – Long-term efficacy and toxicity should inform decisions about tyrosine kinase inhibitors (TKIs) in chronic myeloid leukemia (CML), according to one expert.

Studies have indicated that long-term survival rates are similar whether CML patients receive frontline treatment with imatinib or second-generation TKIs. But the newer TKIs pose a higher risk of uncommon toxicities, Hagop M. Kantarjian, MD, said during the keynote presentation at Leukemia and Lymphoma, a meeting jointly sponsored by the University of Texas MD Anderson Cancer Center and the School of Medicine at the University of Zagreb, Croatia.

Dr. Kantarjian, a professor at MD Anderson Cancer Center in Houston, said most CML patients should receive daily treatment with TKIs – even if they are in complete cytogenetic response or 100% Philadelphia chromosome positive – because they will live longer.

Frontline treatment options for CML that are approved by the Food and Drug Administration include imatinib, dasatinib, nilotinib, and bosutinib.

Dr. Kantarjian noted that dasatinib and nilotinib bested imatinib in early analyses from clinical trials, but all three TKIs produced similar rates of overall survival (OS) and progression-free survival (PFS) at extended follow-up.

Dasatinib and imatinib produced similar rates of 5-year OS and PFS in the DASISION trial (J Clin Oncol. 2016 Jul 10;34[20]:2333-40).

In ENESTnd, 5-year OS and PFS rates were similar with nilotinib and imatinib (Leukemia. 2016 May;30[5]:1044-54).

However, the higher incidence of uncommon toxicities with the newer TKIs must be taken into account, Dr. Kantarjian said.
 

Choosing a TKI

Dr. Kantarjian recommends frontline imatinib for older patients (aged 65-70) and those who are low risk based on their Sokal score.

Second-generation TKIs should be given up front to patients who are at higher risk by Sokal and for “very young patients in whom early treatment discontinuation is important,” he said.

“In accelerated or blast phase, I always use the second-generation TKIs,” he said. “If there’s no binding mutation, I prefer dasatinib. I think it’s the most potent of them. If there are toxicities with dasatinib, bosutinib is equivalent in efficacy, so they are interchangeable.”

A TKI should not be discarded unless there is loss of complete cytogenetic response – not major molecular response – at the maximum tolerated adjusted dose that does not cause grade 3-4 toxicities or chronic grade 2 toxicities, Dr. Kantarjian added.

“We have to remember that we can go down on the dosages of, for example, imatinib, down to 200 mg a day, dasatinib as low as 20 mg a day, nilotinib as low as 150 mg twice a day or even 200 mg daily, and bosutinib down to 200 mg daily,” he said. “So if we have a patient who’s responding with side effects, we should not abandon the particular TKI, we should try to manipulate the dose schedule if they are having a good response.”

Dr. Kantarjian noted that pleural effusion is a toxicity of particular concern with dasatinib, but lowering the dose to 50 mg daily results in similar efficacy and significantly less toxicity than 100 mg daily. For patients over the age of 70, a 20-mg dose can be used.

Vaso-occlusive and vasospastic reactions are increasingly observed in patients treated with nilotinib. For that reason, Dr. Kantarjian said he prefers to forgo up-front nilotinib, particularly in patients who have cardiovascular or neurotoxic problems.

“The incidence of vaso-occlusive and vasospastic reactions is now close to 10%-15% at about 10 years with nilotinib,” Dr. Kantarjian said. “So it is not a trivial toxicity.”

For patients with vaso-occlusive/vasospastic reactions, “bosutinib is probably the safest drug,” Dr. Kantarjian said.

For second- or third-line therapy, patients can receive ponatinib or a second-generation TKI (dasatinib, nilotinib, or bosutinib), as well as omacetaxine or allogeneic stem cell transplant.

“If you disregard toxicities, I think ponatinib is the most powerful TKI, and I think that’s because we are using it at a higher dose that produces so many toxicities,” Dr. Kantarjian said.

Ponatinib is not used up front because of these toxicities, particularly pancreatitis, skin rashes, vaso-occlusive disorders, and hypertension, he added.

Dr. Kantarjian suggests giving ponatinib at 30 mg daily in patients with T315I mutation and those without guiding mutations who are resistant to second-generation TKIs.
 

Discontinuing a TKI

Dr. Kantarjian said patients can discontinue TKI therapy if they:

• Are low- or intermediate-risk by Sokal.
• Have quantifiable BCR-ABL transcripts.
• Are in chronic phase.
• Achieved an optimal response to their first TKI.
• Have been on TKI therapy for more than 8 years.
• Achieved a complete molecular response.
• Have had a molecular response for more than 2-3 years.
• Are available for monitoring every other month for the first 2 years.

Dr. Kantarjian did not report any conflicts of interest at the meeting. However, he has previously reported relationships with Novartis, Bristol-Myers Squibb, Pfizer, and Ariad Pharmaceuticals.

The Leukemia and Lymphoma meeting is organized by Jonathan Wood & Association, which is owned by the parent company of this news organization.

[email protected]

DUBROVNIK, CROATIA – Long-term efficacy and toxicity should inform decisions about tyrosine kinase inhibitors (TKIs) in chronic myeloid leukemia (CML), according to one expert.

Studies have indicated that long-term survival rates are similar whether CML patients receive frontline treatment with imatinib or second-generation TKIs. But the newer TKIs pose a higher risk of uncommon toxicities, Hagop M. Kantarjian, MD, said during the keynote presentation at Leukemia and Lymphoma, a meeting jointly sponsored by the University of Texas MD Anderson Cancer Center and the School of Medicine at the University of Zagreb, Croatia.

Dr. Kantarjian, a professor at MD Anderson Cancer Center in Houston, said most CML patients should receive daily treatment with TKIs – even if they are in complete cytogenetic response or 100% Philadelphia chromosome positive – because they will live longer.

Frontline treatment options for CML that are approved by the Food and Drug Administration include imatinib, dasatinib, nilotinib, and bosutinib.

Dr. Kantarjian noted that dasatinib and nilotinib bested imatinib in early analyses from clinical trials, but all three TKIs produced similar rates of overall survival (OS) and progression-free survival (PFS) at extended follow-up.

Dasatinib and imatinib produced similar rates of 5-year OS and PFS in the DASISION trial (J Clin Oncol. 2016 Jul 10;34[20]:2333-40).

In ENESTnd, 5-year OS and PFS rates were similar with nilotinib and imatinib (Leukemia. 2016 May;30[5]:1044-54).

However, the higher incidence of uncommon toxicities with the newer TKIs must be taken into account, Dr. Kantarjian said.
 

Choosing a TKI

Dr. Kantarjian recommends frontline imatinib for older patients (aged 65-70) and those who are low risk based on their Sokal score.

Second-generation TKIs should be given up front to patients who are at higher risk by Sokal and for “very young patients in whom early treatment discontinuation is important,” he said.

“In accelerated or blast phase, I always use the second-generation TKIs,” he said. “If there’s no binding mutation, I prefer dasatinib. I think it’s the most potent of them. If there are toxicities with dasatinib, bosutinib is equivalent in efficacy, so they are interchangeable.”

A TKI should not be discarded unless there is loss of complete cytogenetic response – not major molecular response – at the maximum tolerated adjusted dose that does not cause grade 3-4 toxicities or chronic grade 2 toxicities, Dr. Kantarjian added.

“We have to remember that we can go down on the dosages of, for example, imatinib, down to 200 mg a day, dasatinib as low as 20 mg a day, nilotinib as low as 150 mg twice a day or even 200 mg daily, and bosutinib down to 200 mg daily,” he said. “So if we have a patient who’s responding with side effects, we should not abandon the particular TKI, we should try to manipulate the dose schedule if they are having a good response.”

Dr. Kantarjian noted that pleural effusion is a toxicity of particular concern with dasatinib, but lowering the dose to 50 mg daily results in similar efficacy and significantly less toxicity than 100 mg daily. For patients over the age of 70, a 20-mg dose can be used.

Vaso-occlusive and vasospastic reactions are increasingly observed in patients treated with nilotinib. For that reason, Dr. Kantarjian said he prefers to forgo up-front nilotinib, particularly in patients who have cardiovascular or neurotoxic problems.

“The incidence of vaso-occlusive and vasospastic reactions is now close to 10%-15% at about 10 years with nilotinib,” Dr. Kantarjian said. “So it is not a trivial toxicity.”

For patients with vaso-occlusive/vasospastic reactions, “bosutinib is probably the safest drug,” Dr. Kantarjian said.

For second- or third-line therapy, patients can receive ponatinib or a second-generation TKI (dasatinib, nilotinib, or bosutinib), as well as omacetaxine or allogeneic stem cell transplant.

“If you disregard toxicities, I think ponatinib is the most powerful TKI, and I think that’s because we are using it at a higher dose that produces so many toxicities,” Dr. Kantarjian said.

Ponatinib is not used up front because of these toxicities, particularly pancreatitis, skin rashes, vaso-occlusive disorders, and hypertension, he added.

Dr. Kantarjian suggests giving ponatinib at 30 mg daily in patients with T315I mutation and those without guiding mutations who are resistant to second-generation TKIs.
 

Discontinuing a TKI

Dr. Kantarjian said patients can discontinue TKI therapy if they:

• Are low- or intermediate-risk by Sokal.
• Have quantifiable BCR-ABL transcripts.
• Are in chronic phase.
• Achieved an optimal response to their first TKI.
• Have been on TKI therapy for more than 8 years.
• Achieved a complete molecular response.
• Have had a molecular response for more than 2-3 years.
• Are available for monitoring every other month for the first 2 years.

Dr. Kantarjian did not report any conflicts of interest at the meeting. However, he has previously reported relationships with Novartis, Bristol-Myers Squibb, Pfizer, and Ariad Pharmaceuticals.

The Leukemia and Lymphoma meeting is organized by Jonathan Wood & Association, which is owned by the parent company of this news organization.

[email protected]

Hagop Kantarjian, MD

DUBROVNIK, CROATIA—Long-term efficacy and toxicity should inform decisions about tyrosine kinase inhibitors (TKIs) in chronic myeloid leukemia (CML), according to the keynote presenter at Leukemia and Lymphoma: Europe and the USA, Linking Knowledge and Practice.

Studies have indicated that long-term survival rates are similar whether CML patients receive frontline treatment with imatinib or second-generation TKIs.

However, the newer TKIs pose a higher risk of uncommon toxicities, said Hagop Kantarjian, MD, a professor at MD Anderson Cancer Center in Houston, Texas, who gave the meeting’s keynote speech.

Dr. Kantarjian said most CML patients should receive daily treatment with TKIs—even if they are in complete cytogenetic response or 100% Ph-positive—because they will live longer.

Frontline treatment options for CML that are approved by the U.S. Food and Drug Administration include imatinib, dasatinib, nilotinib, and bosutinib.

Dr. Kantarjian noted that dasatinib and nilotinib bested imatinib in early analyses from clinical trials, but all three TKIs produced similar rates of overall survival (OS) and progression-free survival (PFS) at extended follow-up.

Dasatinib and imatinib produced similar rates of 5-year OS and PFS in the DASISION trial.¹ In ENESTnd, 5-year OS and PFS rates were similar with nilotinib and imatinib.²

However, Dr. Kantarjian said the higher incidence of uncommon toxicities with the newer TKIs must be taken into account.

Choosing a TKI

Dr. Kantarjian recommends frontline imatinib for older patients (≥ 65 to 70) and those who are low-risk according to Sokal score.

Second-generation TKIs should be given upfront to patients who are higher-risk by Sokal and for “very young patients in whom early treatment discontinuation is important,” according to Dr. Kantarjian.

“In accelerated or blast phase, I always use the second-generation TKIs,” he said. “If there’s no binding mutation, I prefer dasatinib. I think it’s the most potent of them. If there are toxicities with dasatinib, bosutinib is equivalent in efficacy, so they are interchangeable.”

Dr. Kantarjian also said a TKI should not be discarded unless there is loss of complete cytogenetic response (not major molecular response) at the maximum tolerated adjusted dose that does not cause grade 3-4 toxicities or chronic grade 2 toxicities.

“[W]e have to remember that we can go down on the dosages of, for example, imatinib down to 200 mg a day, dasatinib as low as 20 mg a day, nilotinib as low as 150 mg twice a day or even 200 mg daily, and bosutinib down to 200 mg daily,” Dr. Kantarjian said.

“So if we have a patient who’s responding with side effects, we should not abandon the particular TKI, we should try to manipulate the dose schedule if they are having a good response.”

Dr. Kantarjian noted that pleural effusion is a toxicity of particular concern with dasatinib, but lowering the dose to 50 mg daily results in similar efficacy and significantly less toxicity than 100 mg daily. For patients over the age of 70, a 20 mg dose can be used.

Dr. Kantarjian said vaso-occlusive and vasospastic reactions are increasingly observed in patients treated with nilotinib. Therefore, he prefers to forgo upfront nilotinib, particularly in patients who have cardiovascular or neurotoxic problems.

“The incidence of vaso-occlusive and vasospastic reactions is now close to 10% to 15% at about 10 years with nilotinib,” Dr. Kantarjian said. “So it is not a trivial toxicity.”

For patients with vaso-occlusive/vasospastic reactions, “bosutinib is probably the safest drug,” Dr. Kantarjian said.

For second- or third-line therapy, patients can receive ponatinib or a second-generation TKI (dasatinib, nilotinib, or bosutinib) as well as omacetaxine or allogeneic stem cell transplant.

“If you disregard toxicities, I think ponatinib is the most powerful TKI, and I think that’s because we are using it at a higher dose that produces so many toxicities,” Dr. Kantarjian said.

He added that the reason ponatinib is not used upfront is because of these toxicities, particularly pancreatitis, skin rashes, vaso-occlusive disorders, and hypertension.

Dr. Kantarjian suggests giving ponatinib at 30 mg daily in patients with T315I mutation and those without guiding mutations who are resistant to second-generation TKIs.

When to discontinue TKIs

Dr. Kantarjian said patients can discontinue TKI therapy if they:

• Are low- or intermediate-risk by Sokal
• Have quantifiable BCR-ABL transcripts—B2A2, B3A2 (e13a2 or e14a2)
• Are in chronic phase
• Achieved an optimal response to their first TKI
• Have been on TKI therapy for more than 8 years
• Achieved a complete molecular response (MR4.5)
• Have had a molecular response for more than 2 to 3 years
• Are available for monitoring every other month for the first 2 years.

Dr. Kantarjian did not report any conflicts of interest at the meeting. However, he has previously reported relationships with Novartis (makers of imatinib and nilotinib), Bristol-Myers Squibb (makers of dasatinib), Pfizer (makers of bosutinib), and Ariad Pharmaceuticals (makers of ponatinib, now owned by Takeda Pharmaceutical Company Limited).

1. Cortes JE et al. J Clin Oncol. 2016 Jul 10; 34(20): 2333–2340. doi: 10.1200/JCO.2015.64.8899

2. Hochhaus A et al. Leukemia. 2016 May; 30(5): 1044–1054. doi: 10.1038/leu.2016.5

Hagop Kantarjian, MD

DUBROVNIK, CROATIA—Long-term efficacy and toxicity should inform decisions about tyrosine kinase inhibitors (TKIs) in chronic myeloid leukemia (CML), according to the keynote presenter at Leukemia and Lymphoma: Europe and the USA, Linking Knowledge and Practice.

Studies have indicated that long-term survival rates are similar whether CML patients receive frontline treatment with imatinib or second-generation TKIs.

However, the newer TKIs pose a higher risk of uncommon toxicities, said Hagop Kantarjian, MD, a professor at MD Anderson Cancer Center in Houston, Texas, who gave the meeting’s keynote speech.

Dr. Kantarjian said most CML patients should receive daily treatment with TKIs—even if they are in complete cytogenetic response or 100% Ph-positive—because they will live longer.

Frontline treatment options for CML that are approved by the U.S. Food and Drug Administration include imatinib, dasatinib, nilotinib, and bosutinib.

Dr. Kantarjian noted that dasatinib and nilotinib bested imatinib in early analyses from clinical trials, but all three TKIs produced similar rates of overall survival (OS) and progression-free survival (PFS) at extended follow-up.

Dasatinib and imatinib produced similar rates of 5-year OS and PFS in the DASISION trial.¹ In ENESTnd, 5-year OS and PFS rates were similar with nilotinib and imatinib.²

However, Dr. Kantarjian said the higher incidence of uncommon toxicities with the newer TKIs must be taken into account.

Choosing a TKI

Dr. Kantarjian recommends frontline imatinib for older patients (≥ 65 to 70) and those who are low-risk according to Sokal score.

Second-generation TKIs should be given upfront to patients who are higher-risk by Sokal and for “very young patients in whom early treatment discontinuation is important,” according to Dr. Kantarjian.

“In accelerated or blast phase, I always use the second-generation TKIs,” he said. “If there’s no binding mutation, I prefer dasatinib. I think it’s the most potent of them. If there are toxicities with dasatinib, bosutinib is equivalent in efficacy, so they are interchangeable.”

Dr. Kantarjian also said a TKI should not be discarded unless there is loss of complete cytogenetic response (not major molecular response) at the maximum tolerated adjusted dose that does not cause grade 3-4 toxicities or chronic grade 2 toxicities.

“[W]e have to remember that we can go down on the dosages of, for example, imatinib down to 200 mg a day, dasatinib as low as 20 mg a day, nilotinib as low as 150 mg twice a day or even 200 mg daily, and bosutinib down to 200 mg daily,” Dr. Kantarjian said.

“So if we have a patient who’s responding with side effects, we should not abandon the particular TKI, we should try to manipulate the dose schedule if they are having a good response.”

Dr. Kantarjian noted that pleural effusion is a toxicity of particular concern with dasatinib, but lowering the dose to 50 mg daily results in similar efficacy and significantly less toxicity than 100 mg daily. For patients over the age of 70, a 20 mg dose can be used.

Dr. Kantarjian said vaso-occlusive and vasospastic reactions are increasingly observed in patients treated with nilotinib. Therefore, he prefers to forgo upfront nilotinib, particularly in patients who have cardiovascular or neurotoxic problems.

“The incidence of vaso-occlusive and vasospastic reactions is now close to 10% to 15% at about 10 years with nilotinib,” Dr. Kantarjian said. “So it is not a trivial toxicity.”

For patients with vaso-occlusive/vasospastic reactions, “bosutinib is probably the safest drug,” Dr. Kantarjian said.

For second- or third-line therapy, patients can receive ponatinib or a second-generation TKI (dasatinib, nilotinib, or bosutinib) as well as omacetaxine or allogeneic stem cell transplant.

“If you disregard toxicities, I think ponatinib is the most powerful TKI, and I think that’s because we are using it at a higher dose that produces so many toxicities,” Dr. Kantarjian said.

He added that the reason ponatinib is not used upfront is because of these toxicities, particularly pancreatitis, skin rashes, vaso-occlusive disorders, and hypertension.

Dr. Kantarjian suggests giving ponatinib at 30 mg daily in patients with T315I mutation and those without guiding mutations who are resistant to second-generation TKIs.

When to discontinue TKIs

Dr. Kantarjian said patients can discontinue TKI therapy if they:

• Are low- or intermediate-risk by Sokal
• Have quantifiable BCR-ABL transcripts—B2A2, B3A2 (e13a2 or e14a2)
• Are in chronic phase
• Achieved an optimal response to their first TKI
• Have been on TKI therapy for more than 8 years
• Achieved a complete molecular response (MR4.5)
• Have had a molecular response for more than 2 to 3 years
• Are available for monitoring every other month for the first 2 years.

Dr. Kantarjian did not report any conflicts of interest at the meeting. However, he has previously reported relationships with Novartis (makers of imatinib and nilotinib), Bristol-Myers Squibb (makers of dasatinib), Pfizer (makers of bosutinib), and Ariad Pharmaceuticals (makers of ponatinib, now owned by Takeda Pharmaceutical Company Limited).

1. Cortes JE et al. J Clin Oncol. 2016 Jul 10; 34(20): 2333–2340. doi: 10.1200/JCO.2015.64.8899

2. Hochhaus A et al. Leukemia. 2016 May; 30(5): 1044–1054. doi: 10.1038/leu.2016.5

Hagop Kantarjian, MD

DUBROVNIK, CROATIA—Long-term efficacy and toxicity should inform decisions about tyrosine kinase inhibitors (TKIs) in chronic myeloid leukemia (CML), according to the keynote presenter at Leukemia and Lymphoma: Europe and the USA, Linking Knowledge and Practice.

Studies have indicated that long-term survival rates are similar whether CML patients receive frontline treatment with imatinib or second-generation TKIs.

However, the newer TKIs pose a higher risk of uncommon toxicities, said Hagop Kantarjian, MD, a professor at MD Anderson Cancer Center in Houston, Texas, who gave the meeting’s keynote speech.

Dr. Kantarjian said most CML patients should receive daily treatment with TKIs—even if they are in complete cytogenetic response or 100% Ph-positive—because they will live longer.

Frontline treatment options for CML that are approved by the U.S. Food and Drug Administration include imatinib, dasatinib, nilotinib, and bosutinib.

Dr. Kantarjian noted that dasatinib and nilotinib bested imatinib in early analyses from clinical trials, but all three TKIs produced similar rates of overall survival (OS) and progression-free survival (PFS) at extended follow-up.

Dasatinib and imatinib produced similar rates of 5-year OS and PFS in the DASISION trial.¹ In ENESTnd, 5-year OS and PFS rates were similar with nilotinib and imatinib.²

However, Dr. Kantarjian said the higher incidence of uncommon toxicities with the newer TKIs must be taken into account.

Choosing a TKI

Dr. Kantarjian recommends frontline imatinib for older patients (≥ 65 to 70) and those who are low-risk according to Sokal score.

Second-generation TKIs should be given upfront to patients who are higher-risk by Sokal and for “very young patients in whom early treatment discontinuation is important,” according to Dr. Kantarjian.

“In accelerated or blast phase, I always use the second-generation TKIs,” he said. “If there’s no binding mutation, I prefer dasatinib. I think it’s the most potent of them. If there are toxicities with dasatinib, bosutinib is equivalent in efficacy, so they are interchangeable.”

Dr. Kantarjian also said a TKI should not be discarded unless there is loss of complete cytogenetic response (not major molecular response) at the maximum tolerated adjusted dose that does not cause grade 3-4 toxicities or chronic grade 2 toxicities.

“[W]e have to remember that we can go down on the dosages of, for example, imatinib down to 200 mg a day, dasatinib as low as 20 mg a day, nilotinib as low as 150 mg twice a day or even 200 mg daily, and bosutinib down to 200 mg daily,” Dr. Kantarjian said.

“So if we have a patient who’s responding with side effects, we should not abandon the particular TKI, we should try to manipulate the dose schedule if they are having a good response.”

Dr. Kantarjian noted that pleural effusion is a toxicity of particular concern with dasatinib, but lowering the dose to 50 mg daily results in similar efficacy and significantly less toxicity than 100 mg daily. For patients over the age of 70, a 20 mg dose can be used.

Dr. Kantarjian said vaso-occlusive and vasospastic reactions are increasingly observed in patients treated with nilotinib. Therefore, he prefers to forgo upfront nilotinib, particularly in patients who have cardiovascular or neurotoxic problems.

“The incidence of vaso-occlusive and vasospastic reactions is now close to 10% to 15% at about 10 years with nilotinib,” Dr. Kantarjian said. “So it is not a trivial toxicity.”

For patients with vaso-occlusive/vasospastic reactions, “bosutinib is probably the safest drug,” Dr. Kantarjian said.

For second- or third-line therapy, patients can receive ponatinib or a second-generation TKI (dasatinib, nilotinib, or bosutinib) as well as omacetaxine or allogeneic stem cell transplant.

“If you disregard toxicities, I think ponatinib is the most powerful TKI, and I think that’s because we are using it at a higher dose that produces so many toxicities,” Dr. Kantarjian said.

He added that the reason ponatinib is not used upfront is because of these toxicities, particularly pancreatitis, skin rashes, vaso-occlusive disorders, and hypertension.

Dr. Kantarjian suggests giving ponatinib at 30 mg daily in patients with T315I mutation and those without guiding mutations who are resistant to second-generation TKIs.

When to discontinue TKIs

Dr. Kantarjian said patients can discontinue TKI therapy if they:

• Are low- or intermediate-risk by Sokal
• Have quantifiable BCR-ABL transcripts—B2A2, B3A2 (e13a2 or e14a2)
• Are in chronic phase
• Achieved an optimal response to their first TKI
• Have been on TKI therapy for more than 8 years
• Achieved a complete molecular response (MR4.5)
• Have had a molecular response for more than 2 to 3 years
• Are available for monitoring every other month for the first 2 years.

Dr. Kantarjian did not report any conflicts of interest at the meeting. However, he has previously reported relationships with Novartis (makers of imatinib and nilotinib), Bristol-Myers Squibb (makers of dasatinib), Pfizer (makers of bosutinib), and Ariad Pharmaceuticals (makers of ponatinib, now owned by Takeda Pharmaceutical Company Limited).

1. Cortes JE et al. J Clin Oncol. 2016 Jul 10; 34(20): 2333–2340. doi: 10.1200/JCO.2015.64.8899

2. Hochhaus A et al. Leukemia. 2016 May; 30(5): 1044–1054. doi: 10.1038/leu.2016.5

NEW YORK – Despite initial concerns that stopping tyrosine kinase inhibitor treatment would be ill-advised in patients with chronic myeloid leukemia (CML), clinical trial data suggest it is a safe and reasonable strategy, according to a leading expert.

“About 95% of people in all of these trials will regain their original response when they start off on therapy again,” said Jerald P. Radich, MD, of Fred Hutchinson Cancer Research Center/Seattle Cancer Care Alliance.

“There’s been a few that don’t, but blast crisis has been very, very rare, thank goodness, so it looks to be fairly safe for now,” Dr. Radich said at the National Comprehensive Cancer Network Hematologic Malignancies Annual Congress.

That being said, careful follow up is still required, Dr. Radich cautioned, noting that there was still an excess of CML in Hiroshima and Nagasaki atomic bomb survivors evident decades after radiation exposure.

“CML is a very strange disease,” he said. “You can’t eliminate the possibility of some slow-growing clone that, once you take [a patient] off tyrosine kinase therapy, is going into an accelerated phase and might take years to manifest itself.”

In one of the latest reports to shed light on what happens after discontinuation, investigators for the ENESTop study reported that treatment-free remission “seems achievable” in patients who have sustained, deep remissions after discontinuing nilotinib second-line therapy (Ann Intern Med. 2018 Apr 3;168[7]:461-70).

In ENESTop, chronic phase CML patients on tyrosine kinase inhibitors for at least 3 years were eligible to discontinue therapy if they achieved MR^4.5 (BCR-ABL1IS of 0.0032% or less) and maintained that response level during a 1-year consolidation phase.

Out of 163 patients in the study, 126 met the criteria to enter the treatment-free remission phase; of that subset, 58% maintained treatment-free remission at 48 weeks, while 53% maintained it at 96 weeks, investigators said.

For 56 patients who restarted nilotinib, 55 regained at least major molecular response (MMR), and 52 regained MR^4.5, while none had progression to accelerated phase or blast crisis, according to the report.

Similarly, earlier reported results from the ENESTfreedom trial showed that, of 190 patients entering the treatment-free remission phase after a median duration of 43.5 months on nilotinib, more than half remained in MMR or better at 48 weeks (Leukemia. 2017 Jul;31[7]:1525-31).

Of 86 patients who started nilotinib again after losing MMR, 98.8% regained MMR and 88.4% regained MR^4.5 by the data cutoff date for the trial.

Duration and depth of response may make a “little bit of difference” in likelihood of relapse, Dr. Radich added.

In an interim analysis of a prospective multicenter, nonrandomized European discontinuation trial (EURO-SKI), investigators found that patients achieving deep molecular responses had good molecular relapse-free survival (Lancet Oncol. 2018 Jun;19[6]:747-57).

Based on that, investigators suggested that patients with deep molecular responses should be considered for discontinuation to spare them from side effects and to reduce health expenditures.

Results of these and other trials are “pretty much unbelievable,” Dr. Radich said. That’s in part because mathematical modeling – extrapolated from early trials – had suggested it could take nearly 50 years to completely eradicate minimal residual disease with tyrosine kinase inhibitors, and that the cumulative cure rate after 30 years of treatment could be as low as 31%.

Dr. Radich reported financial disclosures related to Amgen, Novartis, and Seattle Genetics.

NEW YORK – Despite initial concerns that stopping tyrosine kinase inhibitor treatment would be ill-advised in patients with chronic myeloid leukemia (CML), clinical trial data suggest it is a safe and reasonable strategy, according to a leading expert.

“About 95% of people in all of these trials will regain their original response when they start off on therapy again,” said Jerald P. Radich, MD, of Fred Hutchinson Cancer Research Center/Seattle Cancer Care Alliance.

“There’s been a few that don’t, but blast crisis has been very, very rare, thank goodness, so it looks to be fairly safe for now,” Dr. Radich said at the National Comprehensive Cancer Network Hematologic Malignancies Annual Congress.

That being said, careful follow up is still required, Dr. Radich cautioned, noting that there was still an excess of CML in Hiroshima and Nagasaki atomic bomb survivors evident decades after radiation exposure.

“CML is a very strange disease,” he said. “You can’t eliminate the possibility of some slow-growing clone that, once you take [a patient] off tyrosine kinase therapy, is going into an accelerated phase and might take years to manifest itself.”

In one of the latest reports to shed light on what happens after discontinuation, investigators for the ENESTop study reported that treatment-free remission “seems achievable” in patients who have sustained, deep remissions after discontinuing nilotinib second-line therapy (Ann Intern Med. 2018 Apr 3;168[7]:461-70).

In ENESTop, chronic phase CML patients on tyrosine kinase inhibitors for at least 3 years were eligible to discontinue therapy if they achieved MR^4.5 (BCR-ABL1IS of 0.0032% or less) and maintained that response level during a 1-year consolidation phase.

Out of 163 patients in the study, 126 met the criteria to enter the treatment-free remission phase; of that subset, 58% maintained treatment-free remission at 48 weeks, while 53% maintained it at 96 weeks, investigators said.

For 56 patients who restarted nilotinib, 55 regained at least major molecular response (MMR), and 52 regained MR^4.5, while none had progression to accelerated phase or blast crisis, according to the report.

Similarly, earlier reported results from the ENESTfreedom trial showed that, of 190 patients entering the treatment-free remission phase after a median duration of 43.5 months on nilotinib, more than half remained in MMR or better at 48 weeks (Leukemia. 2017 Jul;31[7]:1525-31).

Of 86 patients who started nilotinib again after losing MMR, 98.8% regained MMR and 88.4% regained MR^4.5 by the data cutoff date for the trial.

Duration and depth of response may make a “little bit of difference” in likelihood of relapse, Dr. Radich added.

In an interim analysis of a prospective multicenter, nonrandomized European discontinuation trial (EURO-SKI), investigators found that patients achieving deep molecular responses had good molecular relapse-free survival (Lancet Oncol. 2018 Jun;19[6]:747-57).

Based on that, investigators suggested that patients with deep molecular responses should be considered for discontinuation to spare them from side effects and to reduce health expenditures.

Results of these and other trials are “pretty much unbelievable,” Dr. Radich said. That’s in part because mathematical modeling – extrapolated from early trials – had suggested it could take nearly 50 years to completely eradicate minimal residual disease with tyrosine kinase inhibitors, and that the cumulative cure rate after 30 years of treatment could be as low as 31%.

Dr. Radich reported financial disclosures related to Amgen, Novartis, and Seattle Genetics.

NEW YORK – Despite initial concerns that stopping tyrosine kinase inhibitor treatment would be ill-advised in patients with chronic myeloid leukemia (CML), clinical trial data suggest it is a safe and reasonable strategy, according to a leading expert.

“About 95% of people in all of these trials will regain their original response when they start off on therapy again,” said Jerald P. Radich, MD, of Fred Hutchinson Cancer Research Center/Seattle Cancer Care Alliance.

“There’s been a few that don’t, but blast crisis has been very, very rare, thank goodness, so it looks to be fairly safe for now,” Dr. Radich said at the National Comprehensive Cancer Network Hematologic Malignancies Annual Congress.

That being said, careful follow up is still required, Dr. Radich cautioned, noting that there was still an excess of CML in Hiroshima and Nagasaki atomic bomb survivors evident decades after radiation exposure.

“CML is a very strange disease,” he said. “You can’t eliminate the possibility of some slow-growing clone that, once you take [a patient] off tyrosine kinase therapy, is going into an accelerated phase and might take years to manifest itself.”

In one of the latest reports to shed light on what happens after discontinuation, investigators for the ENESTop study reported that treatment-free remission “seems achievable” in patients who have sustained, deep remissions after discontinuing nilotinib second-line therapy (Ann Intern Med. 2018 Apr 3;168[7]:461-70).

In ENESTop, chronic phase CML patients on tyrosine kinase inhibitors for at least 3 years were eligible to discontinue therapy if they achieved MR^4.5 (BCR-ABL1IS of 0.0032% or less) and maintained that response level during a 1-year consolidation phase.

Out of 163 patients in the study, 126 met the criteria to enter the treatment-free remission phase; of that subset, 58% maintained treatment-free remission at 48 weeks, while 53% maintained it at 96 weeks, investigators said.

For 56 patients who restarted nilotinib, 55 regained at least major molecular response (MMR), and 52 regained MR^4.5, while none had progression to accelerated phase or blast crisis, according to the report.

Similarly, earlier reported results from the ENESTfreedom trial showed that, of 190 patients entering the treatment-free remission phase after a median duration of 43.5 months on nilotinib, more than half remained in MMR or better at 48 weeks (Leukemia. 2017 Jul;31[7]:1525-31).

Of 86 patients who started nilotinib again after losing MMR, 98.8% regained MMR and 88.4% regained MR^4.5 by the data cutoff date for the trial.

Duration and depth of response may make a “little bit of difference” in likelihood of relapse, Dr. Radich added.

In an interim analysis of a prospective multicenter, nonrandomized European discontinuation trial (EURO-SKI), investigators found that patients achieving deep molecular responses had good molecular relapse-free survival (Lancet Oncol. 2018 Jun;19[6]:747-57).

Based on that, investigators suggested that patients with deep molecular responses should be considered for discontinuation to spare them from side effects and to reduce health expenditures.

Results of these and other trials are “pretty much unbelievable,” Dr. Radich said. That’s in part because mathematical modeling – extrapolated from early trials – had suggested it could take nearly 50 years to completely eradicate minimal residual disease with tyrosine kinase inhibitors, and that the cumulative cure rate after 30 years of treatment could be as low as 31%.

Dr. Radich reported financial disclosures related to Amgen, Novartis, and Seattle Genetics.