ASH 2016

Micrograph showing

acute myeloid leukemia

SAN DIEGO—A next-generation DNA hypomethylating agent has demonstrated clinical activity and an acceptable safety profile in relapsed/refractory acute myeloid leukemia (AML), according to researchers.

The agent, guadecitabine, produced a composite complete response (CRc) rate of 23% in a phase 2 study.

CRc was observed in all patient subgroups and was associated with longer survival, regardless of whether patients went on to receive a transplant.

Based on these results, researchers are initiating a phase 3 trial of the drug in relapsed/refractory AML.

Naval Daver, MD, of the University of Texas MD Anderson Cancer Center in Houston, presented the phase 2 results at the 2016 ASH Annual Meeting (abstract 904). The study was sponsored by Astex Pharmaceuticals.

Guadecitabine (formerly SGI-110) is a hypomethylating dinucleotide of decitabine and deoxyguanosine that is resistant to cytidine deaminase degradation. It is administered as a small volume subcutaneous injection, which results in extended decitabine exposure.

“Rapid metabolization, elimination shortens the in vivo exposure and may limit the efficacy of decitabine,” Dr Daver noted. “Guadecitabine was engineered to improve the in vivo levels . . . and the efficacy of decitabine by blocking the rapid elimination.”

In the phase 2 trial, Dr Daver and his colleagues investigated guadecitabine in 103 patients with relapsed/refractory AML. The patients’ median age was 60 (range, 22-82), and 60% were male. Eighty-six percent of patients had an ECOG performance status of 0-1, and 41% had poor-risk cytogenetics.

The median number of prior therapies was 2 (range, 1-7). All patients had received prior chemotherapy, 85% had received prior induction with 7+3 (a continuous infusion of cytarabine for 7 days plus daunorubicin for 3 days), and 18% had a prior hematopoietic stem cell transplant (HSCT).

Fifty-three percent of patients had a CR to first induction, and 47% were primary refractory.

Treatment

The researchers tested 2 different doses and schedules of guadecitabine. In the first cohort (5-day regimen), 50 patients were randomized (1:1) to either 60 mg/m²/day (n=24) or 90 mg/m²/day (n=26) on days 1-5.

In the second cohort (10-day regimen), 53 patients were assigned to treatment with 60 mg/m²/day on days 1-5 and days 8-12 for up to 4 cycles, followed by 60 mg/m²/day on days 1-5 in subsequent cycles.

Cycles were scheduled every 28 days for both regimens. Dose reductions and delays were allowed based on response and tolerability. And patients remained on treatment as long as they continued to benefit without unacceptable toxicity.

Response

The study’s primary endpoint was the CRc rate, which consisted of CR plus CR with incomplete platelet recovery (CRp) plus CR with incomplete neutrophil recovery (CRi).

The CRc rate was 16% in the 5-day cohort and 30% in the 10-day cohort. The CR rate was 6% and 19%, respectively. The CRp rate was 2% and 7%, respectively. And the CRi rate was 8% and 4%, respectively.

There was a trend toward a higher CR/CRc rate with the 10-day regimen (P=0.074 and 0.106, respectively).

There was no significant difference in CRc according to patient age (65 and older vs younger than 65), cytogenetics, prior HSCT, response to induction, or time from last therapy (less than 6 months vs 6 months or more).

However, the CRc rate was significantly lower for patients with an ECOG performance status of 2 than for those with a status of 0-1 (P<0.001).

Survival

For the entire study cohort, the median overall survival (OS) was 6.6 months, the 1-year OS was 28%, and the 2-year OS was 19%.

The median OS was 7.1 months with the 10-day regimen and 5.7 months with the 5-day regimen. This difference was not significant (P=0.51).

The median OS was not reached for patients who achieved a CR or for those who achieved a CRp plus a CRi. For patients who did not achieve a CRc, the median OS was 5.6 months (P<0.01).

The median OS was not reached for patients who had a CRc, whether or not they received a subsequent HSCT. There was no significant difference between patients who received an HSCT post-guadecitabine and those who did not (P=0.87).

Likewise, there was no significant difference in OS according to patient age, prior HSCT, or response to induction.

However, OS was significantly worse for patients with an ECOG performance status of 2 (P<0.001), those with poor-risk cytogenetics (P<0.001), and those for whom 6 months or more had elapsed since their last therapy (P=0.015).

Safety

Common grade 3 or higher adverse events (regardless of the relationship to therapy) were febrile neutropenia (60%), pneumonia (36%), thrombocytopenia (36%), anemia (31%), neutropenia (19%), and sepsis (16%).

The 30-day mortality rate was 3.9%, and the 60-day mortality rate was 11.7%.

Micrograph showing

acute myeloid leukemia

SAN DIEGO—A next-generation DNA hypomethylating agent has demonstrated clinical activity and an acceptable safety profile in relapsed/refractory acute myeloid leukemia (AML), according to researchers.

The agent, guadecitabine, produced a composite complete response (CRc) rate of 23% in a phase 2 study.

CRc was observed in all patient subgroups and was associated with longer survival, regardless of whether patients went on to receive a transplant.

Based on these results, researchers are initiating a phase 3 trial of the drug in relapsed/refractory AML.

Naval Daver, MD, of the University of Texas MD Anderson Cancer Center in Houston, presented the phase 2 results at the 2016 ASH Annual Meeting (abstract 904). The study was sponsored by Astex Pharmaceuticals.

Guadecitabine (formerly SGI-110) is a hypomethylating dinucleotide of decitabine and deoxyguanosine that is resistant to cytidine deaminase degradation. It is administered as a small volume subcutaneous injection, which results in extended decitabine exposure.

“Rapid metabolization, elimination shortens the in vivo exposure and may limit the efficacy of decitabine,” Dr Daver noted. “Guadecitabine was engineered to improve the in vivo levels . . . and the efficacy of decitabine by blocking the rapid elimination.”

In the phase 2 trial, Dr Daver and his colleagues investigated guadecitabine in 103 patients with relapsed/refractory AML. The patients’ median age was 60 (range, 22-82), and 60% were male. Eighty-six percent of patients had an ECOG performance status of 0-1, and 41% had poor-risk cytogenetics.

The median number of prior therapies was 2 (range, 1-7). All patients had received prior chemotherapy, 85% had received prior induction with 7+3 (a continuous infusion of cytarabine for 7 days plus daunorubicin for 3 days), and 18% had a prior hematopoietic stem cell transplant (HSCT).

Fifty-three percent of patients had a CR to first induction, and 47% were primary refractory.

Treatment

The researchers tested 2 different doses and schedules of guadecitabine. In the first cohort (5-day regimen), 50 patients were randomized (1:1) to either 60 mg/m²/day (n=24) or 90 mg/m²/day (n=26) on days 1-5.

In the second cohort (10-day regimen), 53 patients were assigned to treatment with 60 mg/m²/day on days 1-5 and days 8-12 for up to 4 cycles, followed by 60 mg/m²/day on days 1-5 in subsequent cycles.

Cycles were scheduled every 28 days for both regimens. Dose reductions and delays were allowed based on response and tolerability. And patients remained on treatment as long as they continued to benefit without unacceptable toxicity.

Response

The study’s primary endpoint was the CRc rate, which consisted of CR plus CR with incomplete platelet recovery (CRp) plus CR with incomplete neutrophil recovery (CRi).

The CRc rate was 16% in the 5-day cohort and 30% in the 10-day cohort. The CR rate was 6% and 19%, respectively. The CRp rate was 2% and 7%, respectively. And the CRi rate was 8% and 4%, respectively.

There was a trend toward a higher CR/CRc rate with the 10-day regimen (P=0.074 and 0.106, respectively).

There was no significant difference in CRc according to patient age (65 and older vs younger than 65), cytogenetics, prior HSCT, response to induction, or time from last therapy (less than 6 months vs 6 months or more).

However, the CRc rate was significantly lower for patients with an ECOG performance status of 2 than for those with a status of 0-1 (P<0.001).

Survival

For the entire study cohort, the median overall survival (OS) was 6.6 months, the 1-year OS was 28%, and the 2-year OS was 19%.

The median OS was 7.1 months with the 10-day regimen and 5.7 months with the 5-day regimen. This difference was not significant (P=0.51).

The median OS was not reached for patients who achieved a CR or for those who achieved a CRp plus a CRi. For patients who did not achieve a CRc, the median OS was 5.6 months (P<0.01).

The median OS was not reached for patients who had a CRc, whether or not they received a subsequent HSCT. There was no significant difference between patients who received an HSCT post-guadecitabine and those who did not (P=0.87).

Likewise, there was no significant difference in OS according to patient age, prior HSCT, or response to induction.

However, OS was significantly worse for patients with an ECOG performance status of 2 (P<0.001), those with poor-risk cytogenetics (P<0.001), and those for whom 6 months or more had elapsed since their last therapy (P=0.015).

Safety

Common grade 3 or higher adverse events (regardless of the relationship to therapy) were febrile neutropenia (60%), pneumonia (36%), thrombocytopenia (36%), anemia (31%), neutropenia (19%), and sepsis (16%).

The 30-day mortality rate was 3.9%, and the 60-day mortality rate was 11.7%.

Micrograph showing

acute myeloid leukemia

SAN DIEGO—A next-generation DNA hypomethylating agent has demonstrated clinical activity and an acceptable safety profile in relapsed/refractory acute myeloid leukemia (AML), according to researchers.

The agent, guadecitabine, produced a composite complete response (CRc) rate of 23% in a phase 2 study.

CRc was observed in all patient subgroups and was associated with longer survival, regardless of whether patients went on to receive a transplant.

Based on these results, researchers are initiating a phase 3 trial of the drug in relapsed/refractory AML.

Naval Daver, MD, of the University of Texas MD Anderson Cancer Center in Houston, presented the phase 2 results at the 2016 ASH Annual Meeting (abstract 904). The study was sponsored by Astex Pharmaceuticals.

Guadecitabine (formerly SGI-110) is a hypomethylating dinucleotide of decitabine and deoxyguanosine that is resistant to cytidine deaminase degradation. It is administered as a small volume subcutaneous injection, which results in extended decitabine exposure.

“Rapid metabolization, elimination shortens the in vivo exposure and may limit the efficacy of decitabine,” Dr Daver noted. “Guadecitabine was engineered to improve the in vivo levels . . . and the efficacy of decitabine by blocking the rapid elimination.”

In the phase 2 trial, Dr Daver and his colleagues investigated guadecitabine in 103 patients with relapsed/refractory AML. The patients’ median age was 60 (range, 22-82), and 60% were male. Eighty-six percent of patients had an ECOG performance status of 0-1, and 41% had poor-risk cytogenetics.

The median number of prior therapies was 2 (range, 1-7). All patients had received prior chemotherapy, 85% had received prior induction with 7+3 (a continuous infusion of cytarabine for 7 days plus daunorubicin for 3 days), and 18% had a prior hematopoietic stem cell transplant (HSCT).

Fifty-three percent of patients had a CR to first induction, and 47% were primary refractory.

Treatment

The researchers tested 2 different doses and schedules of guadecitabine. In the first cohort (5-day regimen), 50 patients were randomized (1:1) to either 60 mg/m²/day (n=24) or 90 mg/m²/day (n=26) on days 1-5.

In the second cohort (10-day regimen), 53 patients were assigned to treatment with 60 mg/m²/day on days 1-5 and days 8-12 for up to 4 cycles, followed by 60 mg/m²/day on days 1-5 in subsequent cycles.

Cycles were scheduled every 28 days for both regimens. Dose reductions and delays were allowed based on response and tolerability. And patients remained on treatment as long as they continued to benefit without unacceptable toxicity.

Response

The study’s primary endpoint was the CRc rate, which consisted of CR plus CR with incomplete platelet recovery (CRp) plus CR with incomplete neutrophil recovery (CRi).

The CRc rate was 16% in the 5-day cohort and 30% in the 10-day cohort. The CR rate was 6% and 19%, respectively. The CRp rate was 2% and 7%, respectively. And the CRi rate was 8% and 4%, respectively.

There was a trend toward a higher CR/CRc rate with the 10-day regimen (P=0.074 and 0.106, respectively).

There was no significant difference in CRc according to patient age (65 and older vs younger than 65), cytogenetics, prior HSCT, response to induction, or time from last therapy (less than 6 months vs 6 months or more).

However, the CRc rate was significantly lower for patients with an ECOG performance status of 2 than for those with a status of 0-1 (P<0.001).

Survival

For the entire study cohort, the median overall survival (OS) was 6.6 months, the 1-year OS was 28%, and the 2-year OS was 19%.

The median OS was 7.1 months with the 10-day regimen and 5.7 months with the 5-day regimen. This difference was not significant (P=0.51).

The median OS was not reached for patients who achieved a CR or for those who achieved a CRp plus a CRi. For patients who did not achieve a CRc, the median OS was 5.6 months (P<0.01).

The median OS was not reached for patients who had a CRc, whether or not they received a subsequent HSCT. There was no significant difference between patients who received an HSCT post-guadecitabine and those who did not (P=0.87).

Likewise, there was no significant difference in OS according to patient age, prior HSCT, or response to induction.

However, OS was significantly worse for patients with an ECOG performance status of 2 (P<0.001), those with poor-risk cytogenetics (P<0.001), and those for whom 6 months or more had elapsed since their last therapy (P=0.015).

Safety

Common grade 3 or higher adverse events (regardless of the relationship to therapy) were febrile neutropenia (60%), pneumonia (36%), thrombocytopenia (36%), anemia (31%), neutropenia (19%), and sepsis (16%).

The 30-day mortality rate was 3.9%, and the 60-day mortality rate was 11.7%.

John Mascarenhas, MD

SAN DIEGO—The JAK2/FLT3 inhibitor pacritinib significantly reduces spleen volume and symptoms in patients with myelofibrosis and low platelet counts,

compared to best available therapy (BAT), according to results of the PERSIST-2 trial.

In this phase 3 trial, BAT included the JAK1/2 inhibitor ruxolitinib. And pacritinib demonstrated benefits over BAT despite a truncated trial.

The US Food and Drug Administration (FDA) placed PERSIST-2 on clinical hold in February 2016 due to concerns over interim survival results, bleeding, and cardiovascular events.

Patients randomized at least 22 weeks prior to the clinical hold contributed data to the week 24 endpoint, the results of which were presented at the 2016 ASH Annual Meeting.

John Mascarenhas, MD, of Icahn School of Medicine at Mount Sinai in New York, New York, delivered the results as a late-breaking abstract (LBA-5).

Ruxolitinib is FDA-approved to treat myelofibrosis, but it is associated with dose-limiting cytopenias and is not indicated for patients with platelet counts less than 50,000/μL.

The earlier PERSIST-1 trial demonstrated sustained spleen volume reduction (SVR) and symptom control with pacritinib therapy regardless of baseline platelet count, but it did not include ruxolitinib in the BAT arm.

PERSIST-2 study design

Patients were randomized on a 1:1:1 basis to pacritinib at 400 mg once daily (PAC QD), pacritinib at 200 mg twice daily (PAC BID), or BAT, including ruxolitinib.

Patients had to have primary or secondary myelofibrosis and platelet counts of 100,000/μL or less. Patients were allowed to have had prior JAK2 inhibitors.

Crossover from BAT was allowed after progression at any time or at week 24.

The study had 2 primary endpoints: percent of patients achieving a 35% or greater SVR and the percent of patients achieving a 50% or more reduction in total symptom score (TSS) by MPN-SAF TSS 2.0.

The primary study objective was the efficacy of pooled QD and BID pacritinib compared to BAT. The secondary objective was the efficacy of QD or BD separately compared to BAT.

Patient demographics

The study randomized 311 patients, and 221 were included in the intent-to-treat efficacy population.

The efficacy population consisted of all patients randomized prior to September 7, 2015, which allowed their data to be included in the week 24 endpoint analysis prior to the clinical hold.

The PAC QD arm consisted of 75 patients with a median age of 69 (range, 39-85). Seventy-one percent were 65 or older, and about half were male.

About three-quarters had an ECOG performance status of 0-1, 61% had primary myelofibrosis, 21% had primary polycythemia vera (PPV), and 17% had primary essential thrombocythemia (PET). About half were DIPSS Intermediate-2 risk, 80% were JAK2^V617F positive, and 51% had a platelet count less than 50,000/μL.

The PAC BID arm consisted of 74 patients with a median age of 67 (range, 39-85). Sixty-two percent were 65 or older, and 65% were male.

Eighty-eight percent had an ECOG performance status of 0-1, 74% had primary myelofibrosis, 19% had PPV, and 7% had PET. About half were DIPSS Intermediate-2 risk, 80% were JAK2^V617F positive, and 42% had a platelet count less than 50,000/μL.

The BAT arm consisted of 72 patients with a median age of 69 (range, 32-83). Seventy-one percent were 65 or older, and about half were male.

Three-quarters had an ECOG performance status of 0-1, 60% had primary myelofibrosis, 22% had PPV, and 18% had PET. About half were DIPSS Intermediate-2 risk, 71% were JAK2^V617F positive, and 44% had a platelet count less than 50,000/µL.

Prior ruxolitinib therapy was consistent across the arms—41.3% (PAC QD), 42% (PAC BID), and 46% (BAT).

“Now, it’s important to note,” Dr Mascarenhas said, “that the most common BAT was ruxolitinib, 45%, and hydroxyurea, 19%. And 19% of BAT patients actually had no treatment, watch and wait. This highlights the fact that this is an area where there is really no other viable therapeutic option for these patients.”

Efficacy

Pacritinib-treated patients had significantly greater spleen reduction from baseline to week 24 than BAT-treated patients, with 18% (QD+BID), 15% (QD), and 22% (BID) achieving 35% or more SVR compared to 3% in the BAT arm.

Pacritinib-treated patients also experienced greater TSS reduction, with 25% (QD+BID), 17% (QD), and 32% (BID) reporting 50% or more reduction in TSS compared to 14% in the BAT arm. However, only the PAC BID arm was significantly different from BAT.

SVR in all subgroups—age, gender, JAK2 mutation status, prior treatment, platelet count, hemoglobin, peripheral blasts, and white blood cell count—demonstrated superiority for pacritinib.

Median changes in individual symptom scores were also better in the pacritinib arms than in the BAT arm in almost every category—tiredness, early satiety, abdominal discomfort, inactivity, night sweats, bone pain, and pain under ribs on the left side.

Pruritus was the only category in which BAT was superior, and that was compared to the QD arm and not the BID arm.

The majority of patients who stopped pacritinib therapy were taken off due to the clinical hold.

There were no significant differences between the groups in overall survival. Hazard ratios for overall survival (95% confidence intervals) were 0.68 (0.30, 1.53) for PAC BID vs BAT, 1.18 (0.57, 2.44) for PAC QD vs BAT, and 0.61 (0.27, 1.35) for PAC BID vs QD.

PAC BID maintained this survival advantage compared with BAT across nearly all demographic and myelofibrosis-associated risk factors.

Patients who were red blood cell transfusion-dependent at baseline experienced a statistically significant decrease in transfusion frequency from baseline to week 24 in both the QD and BID pacritinib arms compared with BAT.

And thrombocytopenia was not a significant factor for patients who were receiving pacritinib and had platelet counts less than 50,000/μL.

Toxicity

The most common treatment-emergent adverse events (AEs) associated with pacritinib were diarrhea, nausea, vomiting, anemia, and thrombocytopenia. They were generally less frequent for BID compared with QD administration.

The most common serious adverse events (SAEs)—occurring in 5% of patients or more in any arms—were anemia (5%, 8%, and 3%), thrombocytopenia (2%, 6%, and 2%), pneumonia (5%, 6%, and 4%), and acute renal failure (5%, 2%, and 2%) in the QD, BID, and BAT arms, respectively.

SAEs of interest included congestive heart failure, atrial fibrillation, cardiac arrest, epistaxis, and subdural hematoma, which occurred in 3% or fewer patients in any arm.

“They [the SAEs] were relatively infrequent, and there was not a clear signal of toxicity,” Dr Mascarenhas said.

Deaths

Deaths in the intent-to-treat evaluable population were censored at the time of full clinical hold.

For the entire enrolled population, 15/104 deaths occurred in the QD arm, 10/107 in the BID arm, and 14/100 in the BAT arm.

After the full clinical hold, 7, 10, and 6 deaths occurred in the QD, BID, and BAT arms, respectively.

Seven of 20 patients died after crossover to pacritinib. Five were due to AEs—3 cardiac, 1 bleeding, and 1 other.

“It’s important to note that progression of disease was the leading cause of death in the PAC BID arm,” Dr Mascarenhas noted. “This is after the patients stopped the drug [when the trial was on clinical hold].”

Conclusions

Despite study truncation, pacritinib (QD+BID) was significantly more effective than BAT for SVR (P=0.001) and trended toward improved TSS (P=0.079).

Pacritinib BID appeared more effective than QD versus BAT for SVR and TSS, and pacritinib BID appeared to have a better benefit/risk profile than BAT.

“This is a well-tolerated drug in many respects,” Dr Mascarenhas said. “This is a patient population that is quite ill, low platelets, poor outcome, and they did pretty well.”

When asked about the future of pacritinib, Dr Mascarenhas said he believes the benefit-to-risk ratio is in favor of the drug.

“Pacritinib offers patients in this vulnerable situation an opportunity for symptom relief, basically spleen and symptoms,” he said. “So I think this is a drug that will hopefully move forward.”

Dr Mascarenhas disclosed research funding from CTI Biopharma, the sponsor of the trial.

John Mascarenhas, MD

SAN DIEGO—The JAK2/FLT3 inhibitor pacritinib significantly reduces spleen volume and symptoms in patients with myelofibrosis and low platelet counts,

compared to best available therapy (BAT), according to results of the PERSIST-2 trial.

In this phase 3 trial, BAT included the JAK1/2 inhibitor ruxolitinib. And pacritinib demonstrated benefits over BAT despite a truncated trial.

The US Food and Drug Administration (FDA) placed PERSIST-2 on clinical hold in February 2016 due to concerns over interim survival results, bleeding, and cardiovascular events.

Patients randomized at least 22 weeks prior to the clinical hold contributed data to the week 24 endpoint, the results of which were presented at the 2016 ASH Annual Meeting.

John Mascarenhas, MD, of Icahn School of Medicine at Mount Sinai in New York, New York, delivered the results as a late-breaking abstract (LBA-5).

Ruxolitinib is FDA-approved to treat myelofibrosis, but it is associated with dose-limiting cytopenias and is not indicated for patients with platelet counts less than 50,000/μL.

The earlier PERSIST-1 trial demonstrated sustained spleen volume reduction (SVR) and symptom control with pacritinib therapy regardless of baseline platelet count, but it did not include ruxolitinib in the BAT arm.

PERSIST-2 study design

Patients were randomized on a 1:1:1 basis to pacritinib at 400 mg once daily (PAC QD), pacritinib at 200 mg twice daily (PAC BID), or BAT, including ruxolitinib.

Patients had to have primary or secondary myelofibrosis and platelet counts of 100,000/μL or less. Patients were allowed to have had prior JAK2 inhibitors.

Crossover from BAT was allowed after progression at any time or at week 24.

The study had 2 primary endpoints: percent of patients achieving a 35% or greater SVR and the percent of patients achieving a 50% or more reduction in total symptom score (TSS) by MPN-SAF TSS 2.0.

The primary study objective was the efficacy of pooled QD and BID pacritinib compared to BAT. The secondary objective was the efficacy of QD or BD separately compared to BAT.

Patient demographics

The study randomized 311 patients, and 221 were included in the intent-to-treat efficacy population.

The efficacy population consisted of all patients randomized prior to September 7, 2015, which allowed their data to be included in the week 24 endpoint analysis prior to the clinical hold.

The PAC QD arm consisted of 75 patients with a median age of 69 (range, 39-85). Seventy-one percent were 65 or older, and about half were male.

About three-quarters had an ECOG performance status of 0-1, 61% had primary myelofibrosis, 21% had primary polycythemia vera (PPV), and 17% had primary essential thrombocythemia (PET). About half were DIPSS Intermediate-2 risk, 80% were JAK2^V617F positive, and 51% had a platelet count less than 50,000/μL.

The PAC BID arm consisted of 74 patients with a median age of 67 (range, 39-85). Sixty-two percent were 65 or older, and 65% were male.

Eighty-eight percent had an ECOG performance status of 0-1, 74% had primary myelofibrosis, 19% had PPV, and 7% had PET. About half were DIPSS Intermediate-2 risk, 80% were JAK2^V617F positive, and 42% had a platelet count less than 50,000/μL.

The BAT arm consisted of 72 patients with a median age of 69 (range, 32-83). Seventy-one percent were 65 or older, and about half were male.

Three-quarters had an ECOG performance status of 0-1, 60% had primary myelofibrosis, 22% had PPV, and 18% had PET. About half were DIPSS Intermediate-2 risk, 71% were JAK2^V617F positive, and 44% had a platelet count less than 50,000/µL.

Prior ruxolitinib therapy was consistent across the arms—41.3% (PAC QD), 42% (PAC BID), and 46% (BAT).

“Now, it’s important to note,” Dr Mascarenhas said, “that the most common BAT was ruxolitinib, 45%, and hydroxyurea, 19%. And 19% of BAT patients actually had no treatment, watch and wait. This highlights the fact that this is an area where there is really no other viable therapeutic option for these patients.”

Efficacy

Pacritinib-treated patients had significantly greater spleen reduction from baseline to week 24 than BAT-treated patients, with 18% (QD+BID), 15% (QD), and 22% (BID) achieving 35% or more SVR compared to 3% in the BAT arm.

Pacritinib-treated patients also experienced greater TSS reduction, with 25% (QD+BID), 17% (QD), and 32% (BID) reporting 50% or more reduction in TSS compared to 14% in the BAT arm. However, only the PAC BID arm was significantly different from BAT.

SVR in all subgroups—age, gender, JAK2 mutation status, prior treatment, platelet count, hemoglobin, peripheral blasts, and white blood cell count—demonstrated superiority for pacritinib.

Median changes in individual symptom scores were also better in the pacritinib arms than in the BAT arm in almost every category—tiredness, early satiety, abdominal discomfort, inactivity, night sweats, bone pain, and pain under ribs on the left side.

Pruritus was the only category in which BAT was superior, and that was compared to the QD arm and not the BID arm.

The majority of patients who stopped pacritinib therapy were taken off due to the clinical hold.

There were no significant differences between the groups in overall survival. Hazard ratios for overall survival (95% confidence intervals) were 0.68 (0.30, 1.53) for PAC BID vs BAT, 1.18 (0.57, 2.44) for PAC QD vs BAT, and 0.61 (0.27, 1.35) for PAC BID vs QD.

PAC BID maintained this survival advantage compared with BAT across nearly all demographic and myelofibrosis-associated risk factors.

Patients who were red blood cell transfusion-dependent at baseline experienced a statistically significant decrease in transfusion frequency from baseline to week 24 in both the QD and BID pacritinib arms compared with BAT.

And thrombocytopenia was not a significant factor for patients who were receiving pacritinib and had platelet counts less than 50,000/μL.

Toxicity

The most common treatment-emergent adverse events (AEs) associated with pacritinib were diarrhea, nausea, vomiting, anemia, and thrombocytopenia. They were generally less frequent for BID compared with QD administration.

The most common serious adverse events (SAEs)—occurring in 5% of patients or more in any arms—were anemia (5%, 8%, and 3%), thrombocytopenia (2%, 6%, and 2%), pneumonia (5%, 6%, and 4%), and acute renal failure (5%, 2%, and 2%) in the QD, BID, and BAT arms, respectively.

SAEs of interest included congestive heart failure, atrial fibrillation, cardiac arrest, epistaxis, and subdural hematoma, which occurred in 3% or fewer patients in any arm.

“They [the SAEs] were relatively infrequent, and there was not a clear signal of toxicity,” Dr Mascarenhas said.

Deaths

Deaths in the intent-to-treat evaluable population were censored at the time of full clinical hold.

For the entire enrolled population, 15/104 deaths occurred in the QD arm, 10/107 in the BID arm, and 14/100 in the BAT arm.

After the full clinical hold, 7, 10, and 6 deaths occurred in the QD, BID, and BAT arms, respectively.

Seven of 20 patients died after crossover to pacritinib. Five were due to AEs—3 cardiac, 1 bleeding, and 1 other.

“It’s important to note that progression of disease was the leading cause of death in the PAC BID arm,” Dr Mascarenhas noted. “This is after the patients stopped the drug [when the trial was on clinical hold].”

Conclusions

Despite study truncation, pacritinib (QD+BID) was significantly more effective than BAT for SVR (P=0.001) and trended toward improved TSS (P=0.079).

Pacritinib BID appeared more effective than QD versus BAT for SVR and TSS, and pacritinib BID appeared to have a better benefit/risk profile than BAT.

“This is a well-tolerated drug in many respects,” Dr Mascarenhas said. “This is a patient population that is quite ill, low platelets, poor outcome, and they did pretty well.”

When asked about the future of pacritinib, Dr Mascarenhas said he believes the benefit-to-risk ratio is in favor of the drug.

“Pacritinib offers patients in this vulnerable situation an opportunity for symptom relief, basically spleen and symptoms,” he said. “So I think this is a drug that will hopefully move forward.”

Dr Mascarenhas disclosed research funding from CTI Biopharma, the sponsor of the trial.

John Mascarenhas, MD

SAN DIEGO—The JAK2/FLT3 inhibitor pacritinib significantly reduces spleen volume and symptoms in patients with myelofibrosis and low platelet counts,

compared to best available therapy (BAT), according to results of the PERSIST-2 trial.

In this phase 3 trial, BAT included the JAK1/2 inhibitor ruxolitinib. And pacritinib demonstrated benefits over BAT despite a truncated trial.

The US Food and Drug Administration (FDA) placed PERSIST-2 on clinical hold in February 2016 due to concerns over interim survival results, bleeding, and cardiovascular events.

Patients randomized at least 22 weeks prior to the clinical hold contributed data to the week 24 endpoint, the results of which were presented at the 2016 ASH Annual Meeting.

John Mascarenhas, MD, of Icahn School of Medicine at Mount Sinai in New York, New York, delivered the results as a late-breaking abstract (LBA-5).

Ruxolitinib is FDA-approved to treat myelofibrosis, but it is associated with dose-limiting cytopenias and is not indicated for patients with platelet counts less than 50,000/μL.

The earlier PERSIST-1 trial demonstrated sustained spleen volume reduction (SVR) and symptom control with pacritinib therapy regardless of baseline platelet count, but it did not include ruxolitinib in the BAT arm.

PERSIST-2 study design

Patients were randomized on a 1:1:1 basis to pacritinib at 400 mg once daily (PAC QD), pacritinib at 200 mg twice daily (PAC BID), or BAT, including ruxolitinib.

Patients had to have primary or secondary myelofibrosis and platelet counts of 100,000/μL or less. Patients were allowed to have had prior JAK2 inhibitors.

Crossover from BAT was allowed after progression at any time or at week 24.

The study had 2 primary endpoints: percent of patients achieving a 35% or greater SVR and the percent of patients achieving a 50% or more reduction in total symptom score (TSS) by MPN-SAF TSS 2.0.

The primary study objective was the efficacy of pooled QD and BID pacritinib compared to BAT. The secondary objective was the efficacy of QD or BD separately compared to BAT.

Patient demographics

The study randomized 311 patients, and 221 were included in the intent-to-treat efficacy population.

The efficacy population consisted of all patients randomized prior to September 7, 2015, which allowed their data to be included in the week 24 endpoint analysis prior to the clinical hold.

The PAC QD arm consisted of 75 patients with a median age of 69 (range, 39-85). Seventy-one percent were 65 or older, and about half were male.

About three-quarters had an ECOG performance status of 0-1, 61% had primary myelofibrosis, 21% had primary polycythemia vera (PPV), and 17% had primary essential thrombocythemia (PET). About half were DIPSS Intermediate-2 risk, 80% were JAK2^V617F positive, and 51% had a platelet count less than 50,000/μL.

The PAC BID arm consisted of 74 patients with a median age of 67 (range, 39-85). Sixty-two percent were 65 or older, and 65% were male.

Eighty-eight percent had an ECOG performance status of 0-1, 74% had primary myelofibrosis, 19% had PPV, and 7% had PET. About half were DIPSS Intermediate-2 risk, 80% were JAK2^V617F positive, and 42% had a platelet count less than 50,000/μL.

The BAT arm consisted of 72 patients with a median age of 69 (range, 32-83). Seventy-one percent were 65 or older, and about half were male.

Three-quarters had an ECOG performance status of 0-1, 60% had primary myelofibrosis, 22% had PPV, and 18% had PET. About half were DIPSS Intermediate-2 risk, 71% were JAK2^V617F positive, and 44% had a platelet count less than 50,000/µL.

Prior ruxolitinib therapy was consistent across the arms—41.3% (PAC QD), 42% (PAC BID), and 46% (BAT).

“Now, it’s important to note,” Dr Mascarenhas said, “that the most common BAT was ruxolitinib, 45%, and hydroxyurea, 19%. And 19% of BAT patients actually had no treatment, watch and wait. This highlights the fact that this is an area where there is really no other viable therapeutic option for these patients.”

Efficacy

Pacritinib-treated patients had significantly greater spleen reduction from baseline to week 24 than BAT-treated patients, with 18% (QD+BID), 15% (QD), and 22% (BID) achieving 35% or more SVR compared to 3% in the BAT arm.

Pacritinib-treated patients also experienced greater TSS reduction, with 25% (QD+BID), 17% (QD), and 32% (BID) reporting 50% or more reduction in TSS compared to 14% in the BAT arm. However, only the PAC BID arm was significantly different from BAT.

SVR in all subgroups—age, gender, JAK2 mutation status, prior treatment, platelet count, hemoglobin, peripheral blasts, and white blood cell count—demonstrated superiority for pacritinib.

Median changes in individual symptom scores were also better in the pacritinib arms than in the BAT arm in almost every category—tiredness, early satiety, abdominal discomfort, inactivity, night sweats, bone pain, and pain under ribs on the left side.

Pruritus was the only category in which BAT was superior, and that was compared to the QD arm and not the BID arm.

The majority of patients who stopped pacritinib therapy were taken off due to the clinical hold.

There were no significant differences between the groups in overall survival. Hazard ratios for overall survival (95% confidence intervals) were 0.68 (0.30, 1.53) for PAC BID vs BAT, 1.18 (0.57, 2.44) for PAC QD vs BAT, and 0.61 (0.27, 1.35) for PAC BID vs QD.

PAC BID maintained this survival advantage compared with BAT across nearly all demographic and myelofibrosis-associated risk factors.

Patients who were red blood cell transfusion-dependent at baseline experienced a statistically significant decrease in transfusion frequency from baseline to week 24 in both the QD and BID pacritinib arms compared with BAT.

And thrombocytopenia was not a significant factor for patients who were receiving pacritinib and had platelet counts less than 50,000/μL.

Toxicity

The most common treatment-emergent adverse events (AEs) associated with pacritinib were diarrhea, nausea, vomiting, anemia, and thrombocytopenia. They were generally less frequent for BID compared with QD administration.

The most common serious adverse events (SAEs)—occurring in 5% of patients or more in any arms—were anemia (5%, 8%, and 3%), thrombocytopenia (2%, 6%, and 2%), pneumonia (5%, 6%, and 4%), and acute renal failure (5%, 2%, and 2%) in the QD, BID, and BAT arms, respectively.

SAEs of interest included congestive heart failure, atrial fibrillation, cardiac arrest, epistaxis, and subdural hematoma, which occurred in 3% or fewer patients in any arm.

“They [the SAEs] were relatively infrequent, and there was not a clear signal of toxicity,” Dr Mascarenhas said.

Deaths

Deaths in the intent-to-treat evaluable population were censored at the time of full clinical hold.

For the entire enrolled population, 15/104 deaths occurred in the QD arm, 10/107 in the BID arm, and 14/100 in the BAT arm.

After the full clinical hold, 7, 10, and 6 deaths occurred in the QD, BID, and BAT arms, respectively.

Seven of 20 patients died after crossover to pacritinib. Five were due to AEs—3 cardiac, 1 bleeding, and 1 other.

“It’s important to note that progression of disease was the leading cause of death in the PAC BID arm,” Dr Mascarenhas noted. “This is after the patients stopped the drug [when the trial was on clinical hold].”

Conclusions

Despite study truncation, pacritinib (QD+BID) was significantly more effective than BAT for SVR (P=0.001) and trended toward improved TSS (P=0.079).

Pacritinib BID appeared more effective than QD versus BAT for SVR and TSS, and pacritinib BID appeared to have a better benefit/risk profile than BAT.

“This is a well-tolerated drug in many respects,” Dr Mascarenhas said. “This is a patient population that is quite ill, low platelets, poor outcome, and they did pretty well.”

When asked about the future of pacritinib, Dr Mascarenhas said he believes the benefit-to-risk ratio is in favor of the drug.

“Pacritinib offers patients in this vulnerable situation an opportunity for symptom relief, basically spleen and symptoms,” he said. “So I think this is a drug that will hopefully move forward.”

Dr Mascarenhas disclosed research funding from CTI Biopharma, the sponsor of the trial.

2016 ASH Annual Meeting

© Todd Buchanan 2016

SAN DIEGO—The oral BCL-2 inhibitor venetoclax can produce high objective response rates (ORRs) in chronic lymphocytic leukemia (CLL) patients who have failed treatment with at least one B-cell receptor inhibitor, according to investigators.

In a phase 2 study, venetoclax produced an ORR of 67% among all patients enrolled.

The drug produced a 70% ORR among patients who had failed treatment with ibrutinib and a 62% ORR among patients who had failed idelalisib.

“This represents the first prospective study in this patient population and does demonstrate high rates of durable responses, certainly making [venetoclax] a very viable option for a challenging group of patients to treat,” said study investigator Jeffrey Jones, MD, of The Ohio State University in Columbus.

Dr Jones presented results from this trial at the 2016 ASH Annual Meeting (abstract 637*). This study is sponsored by AbbVie in collaboration with Genentech/Roche.

The trial enrolled patients with CLL who relapsed after or were refractory to ibrutinib (arm A) or idelalisib (arm B). At the time of the data cut-off, 64 patients had been enrolled and treated with venetoclax, including 43 patients in arm A and 21 in arm B.

Patients received venetoclax via a recommended dose-titration schedule—20 mg once daily in week 1, 50 mg daily in week 2, 100 mg daily in week 3, 200 mg daily in week 4, and 400 mg daily from week 5 onward. Patients continued to receive the drug until disease progression or unacceptable toxicity.

To mitigate the risk of tumor lysis syndrome (TLS), patients received prophylaxis with uric acid lowering agents and hydration starting at least 72 hours before the first dose of venetoclax.

Patients with a high tumor burden were hospitalized for the first 20 mg dose and the first 50 mg dose, and they received intravenous hydration and rasburicase. Laboratory values were monitored at the first dose and all dose increases.

Patient characteristics: Arm A

Among patients who had failed ibrutinib, the median age was 66 (range, 48-80). Forty-nine percent of the patients had del(17p), and 35% had bulky nodal disease (5 cm or greater).

The median number of prior treatments was 4 (range, 1-12). All patients had received ibrutinib, but 9% had also received idelalisib. Ninety-one percent of patients were refractory to ibrutinib, and 5% were refractory to idelalisib.

The median time on ibrutinib was 17 months (range, 1-56), and the median time on idelalisib was 10 months (range, 2-31).

Patient characteristics: Arm B

Among patients who had failed idelalisib, the median age was 68 (range, 56-85). Ten percent of patients had del(17p), and 52% had bulky nodal disease (5 cm or greater).

The median number of prior treatments was 3 (range, 1-11). All patients had received idelalisib, but 24% had also received ibrutinib. Sixty-seven percent of patients were refractory to idelalisib, and 10% were refractory to ibrutinib.

The median time on idelalisib was 8 months (range, 1-27), and the median time on ibrutinib was 6 months (range, 2-11).

Results: Arm A

The median time on study in arm A was 13 months (range, 0.1-18). Eighteen patients in this arm discontinued the study—12 due to disease progression, 3 due to adverse events (AEs), 2 due to stem cell transplant, and 1 patient withdrew consent.

The ORR was 70% according to an independent review committee (IRC) and 67% according to investigators.

The rate of complete response (CR) was 0%, and the rate of CR with incomplete bone marrow recovery (CRi) was 2% according to the IRC. According to investigators, the CR rate was 5%, and the CRi rate was 2%.

Sixty-seven percent of patients had a partial response (PR) according to the IRC, and 56% had a PR according to investigators.

Results: Arm B

The median time on study in arm B was 9 months (range, 1.3-16). Four patients in this arm discontinued the study—3 related to disease progression and 1 for an “other” reason.

The ORR was 62% according to the IRC and 57% according to investigators.

The rate of CR/CRi was 0% according to the IRC. According to investigators, the CR rate was 10%, and the CRi rate was 5%.

Sixty-two percent of patients had a PR according to the IRC, and 43% had a PR according to investigators.

Results: Overall

The ORR was 67% according to the IRC and 64% according to investigators.

Forty-five percent of patient samples analyzed (14/31) demonstrated minimal residual disease (MRD) negativity in the peripheral blood between weeks 24 and 48. Five patients with sustained MRD negativity had bone marrow evaluations, and 1 was MRD negative.

At 11.8 months of follow-up, the median duration of response, progression-free survival, and overall survival had not been reached. The estimated 12-month progression-free survival for all patients was 80%.

“Venetoclax has been well-tolerated,” Dr Jones noted. “The toxicity profile in this study is consistent with previous reports. Most of the toxicity has been cytopenias, which can be managed with dose adjustments or supportive care interventions, such as G-CSF.”

All 64 patients experienced an AE. Common AEs were neutropenia (58%), thrombocytopenia (44%), diarrhea (42%), nausea (41%), anemia (36%), fatigue (31%), decreased white blood cell count (22%), and hyperphosphatemia (22%).

Eighty-three percent of patients had grade 3/4 AEs, including neutropenia (45%), thrombocytopenia (28%), anemia (22%), decreased white blood cell count (13%), febrile neutropenia (11%), and pneumonia (11%).

Fifty-three percent of patients had serious AEs, including febrile neutropenia (9%), pneumonia (8%), multi-organ failure (3%), septic shock (3%), and increased potassium (3%).

There were no cases of clinical TLS. However, 1 patient with high tumor burden met Howard criteria for laboratory TLS.

*Information presented at the meeting differs from the abstract.

2016 ASH Annual Meeting

© Todd Buchanan 2016

SAN DIEGO—The oral BCL-2 inhibitor venetoclax can produce high objective response rates (ORRs) in chronic lymphocytic leukemia (CLL) patients who have failed treatment with at least one B-cell receptor inhibitor, according to investigators.

In a phase 2 study, venetoclax produced an ORR of 67% among all patients enrolled.

The drug produced a 70% ORR among patients who had failed treatment with ibrutinib and a 62% ORR among patients who had failed idelalisib.

“This represents the first prospective study in this patient population and does demonstrate high rates of durable responses, certainly making [venetoclax] a very viable option for a challenging group of patients to treat,” said study investigator Jeffrey Jones, MD, of The Ohio State University in Columbus.

Dr Jones presented results from this trial at the 2016 ASH Annual Meeting (abstract 637*). This study is sponsored by AbbVie in collaboration with Genentech/Roche.

The trial enrolled patients with CLL who relapsed after or were refractory to ibrutinib (arm A) or idelalisib (arm B). At the time of the data cut-off, 64 patients had been enrolled and treated with venetoclax, including 43 patients in arm A and 21 in arm B.

Patients received venetoclax via a recommended dose-titration schedule—20 mg once daily in week 1, 50 mg daily in week 2, 100 mg daily in week 3, 200 mg daily in week 4, and 400 mg daily from week 5 onward. Patients continued to receive the drug until disease progression or unacceptable toxicity.

To mitigate the risk of tumor lysis syndrome (TLS), patients received prophylaxis with uric acid lowering agents and hydration starting at least 72 hours before the first dose of venetoclax.

Patients with a high tumor burden were hospitalized for the first 20 mg dose and the first 50 mg dose, and they received intravenous hydration and rasburicase. Laboratory values were monitored at the first dose and all dose increases.

Patient characteristics: Arm A

Among patients who had failed ibrutinib, the median age was 66 (range, 48-80). Forty-nine percent of the patients had del(17p), and 35% had bulky nodal disease (5 cm or greater).

The median number of prior treatments was 4 (range, 1-12). All patients had received ibrutinib, but 9% had also received idelalisib. Ninety-one percent of patients were refractory to ibrutinib, and 5% were refractory to idelalisib.

The median time on ibrutinib was 17 months (range, 1-56), and the median time on idelalisib was 10 months (range, 2-31).

Patient characteristics: Arm B

Among patients who had failed idelalisib, the median age was 68 (range, 56-85). Ten percent of patients had del(17p), and 52% had bulky nodal disease (5 cm or greater).

The median number of prior treatments was 3 (range, 1-11). All patients had received idelalisib, but 24% had also received ibrutinib. Sixty-seven percent of patients were refractory to idelalisib, and 10% were refractory to ibrutinib.

The median time on idelalisib was 8 months (range, 1-27), and the median time on ibrutinib was 6 months (range, 2-11).

Results: Arm A

The median time on study in arm A was 13 months (range, 0.1-18). Eighteen patients in this arm discontinued the study—12 due to disease progression, 3 due to adverse events (AEs), 2 due to stem cell transplant, and 1 patient withdrew consent.

The ORR was 70% according to an independent review committee (IRC) and 67% according to investigators.

The rate of complete response (CR) was 0%, and the rate of CR with incomplete bone marrow recovery (CRi) was 2% according to the IRC. According to investigators, the CR rate was 5%, and the CRi rate was 2%.

Sixty-seven percent of patients had a partial response (PR) according to the IRC, and 56% had a PR according to investigators.

Results: Arm B

The median time on study in arm B was 9 months (range, 1.3-16). Four patients in this arm discontinued the study—3 related to disease progression and 1 for an “other” reason.

The ORR was 62% according to the IRC and 57% according to investigators.

The rate of CR/CRi was 0% according to the IRC. According to investigators, the CR rate was 10%, and the CRi rate was 5%.

Sixty-two percent of patients had a PR according to the IRC, and 43% had a PR according to investigators.

Results: Overall

The ORR was 67% according to the IRC and 64% according to investigators.

Forty-five percent of patient samples analyzed (14/31) demonstrated minimal residual disease (MRD) negativity in the peripheral blood between weeks 24 and 48. Five patients with sustained MRD negativity had bone marrow evaluations, and 1 was MRD negative.

At 11.8 months of follow-up, the median duration of response, progression-free survival, and overall survival had not been reached. The estimated 12-month progression-free survival for all patients was 80%.

“Venetoclax has been well-tolerated,” Dr Jones noted. “The toxicity profile in this study is consistent with previous reports. Most of the toxicity has been cytopenias, which can be managed with dose adjustments or supportive care interventions, such as G-CSF.”

All 64 patients experienced an AE. Common AEs were neutropenia (58%), thrombocytopenia (44%), diarrhea (42%), nausea (41%), anemia (36%), fatigue (31%), decreased white blood cell count (22%), and hyperphosphatemia (22%).

Eighty-three percent of patients had grade 3/4 AEs, including neutropenia (45%), thrombocytopenia (28%), anemia (22%), decreased white blood cell count (13%), febrile neutropenia (11%), and pneumonia (11%).

Fifty-three percent of patients had serious AEs, including febrile neutropenia (9%), pneumonia (8%), multi-organ failure (3%), septic shock (3%), and increased potassium (3%).

There were no cases of clinical TLS. However, 1 patient with high tumor burden met Howard criteria for laboratory TLS.

*Information presented at the meeting differs from the abstract.

2016 ASH Annual Meeting

© Todd Buchanan 2016

SAN DIEGO—The oral BCL-2 inhibitor venetoclax can produce high objective response rates (ORRs) in chronic lymphocytic leukemia (CLL) patients who have failed treatment with at least one B-cell receptor inhibitor, according to investigators.

In a phase 2 study, venetoclax produced an ORR of 67% among all patients enrolled.

The drug produced a 70% ORR among patients who had failed treatment with ibrutinib and a 62% ORR among patients who had failed idelalisib.

“This represents the first prospective study in this patient population and does demonstrate high rates of durable responses, certainly making [venetoclax] a very viable option for a challenging group of patients to treat,” said study investigator Jeffrey Jones, MD, of The Ohio State University in Columbus.

Dr Jones presented results from this trial at the 2016 ASH Annual Meeting (abstract 637*). This study is sponsored by AbbVie in collaboration with Genentech/Roche.

The trial enrolled patients with CLL who relapsed after or were refractory to ibrutinib (arm A) or idelalisib (arm B). At the time of the data cut-off, 64 patients had been enrolled and treated with venetoclax, including 43 patients in arm A and 21 in arm B.

Patients received venetoclax via a recommended dose-titration schedule—20 mg once daily in week 1, 50 mg daily in week 2, 100 mg daily in week 3, 200 mg daily in week 4, and 400 mg daily from week 5 onward. Patients continued to receive the drug until disease progression or unacceptable toxicity.

To mitigate the risk of tumor lysis syndrome (TLS), patients received prophylaxis with uric acid lowering agents and hydration starting at least 72 hours before the first dose of venetoclax.

Patients with a high tumor burden were hospitalized for the first 20 mg dose and the first 50 mg dose, and they received intravenous hydration and rasburicase. Laboratory values were monitored at the first dose and all dose increases.

Patient characteristics: Arm A

Among patients who had failed ibrutinib, the median age was 66 (range, 48-80). Forty-nine percent of the patients had del(17p), and 35% had bulky nodal disease (5 cm or greater).

The median number of prior treatments was 4 (range, 1-12). All patients had received ibrutinib, but 9% had also received idelalisib. Ninety-one percent of patients were refractory to ibrutinib, and 5% were refractory to idelalisib.

The median time on ibrutinib was 17 months (range, 1-56), and the median time on idelalisib was 10 months (range, 2-31).

Patient characteristics: Arm B

Among patients who had failed idelalisib, the median age was 68 (range, 56-85). Ten percent of patients had del(17p), and 52% had bulky nodal disease (5 cm or greater).

The median number of prior treatments was 3 (range, 1-11). All patients had received idelalisib, but 24% had also received ibrutinib. Sixty-seven percent of patients were refractory to idelalisib, and 10% were refractory to ibrutinib.

The median time on idelalisib was 8 months (range, 1-27), and the median time on ibrutinib was 6 months (range, 2-11).

Results: Arm A

The median time on study in arm A was 13 months (range, 0.1-18). Eighteen patients in this arm discontinued the study—12 due to disease progression, 3 due to adverse events (AEs), 2 due to stem cell transplant, and 1 patient withdrew consent.

The ORR was 70% according to an independent review committee (IRC) and 67% according to investigators.

The rate of complete response (CR) was 0%, and the rate of CR with incomplete bone marrow recovery (CRi) was 2% according to the IRC. According to investigators, the CR rate was 5%, and the CRi rate was 2%.

Sixty-seven percent of patients had a partial response (PR) according to the IRC, and 56% had a PR according to investigators.

Results: Arm B

The median time on study in arm B was 9 months (range, 1.3-16). Four patients in this arm discontinued the study—3 related to disease progression and 1 for an “other” reason.

The ORR was 62% according to the IRC and 57% according to investigators.

The rate of CR/CRi was 0% according to the IRC. According to investigators, the CR rate was 10%, and the CRi rate was 5%.

Sixty-two percent of patients had a PR according to the IRC, and 43% had a PR according to investigators.

Results: Overall

The ORR was 67% according to the IRC and 64% according to investigators.

Forty-five percent of patient samples analyzed (14/31) demonstrated minimal residual disease (MRD) negativity in the peripheral blood between weeks 24 and 48. Five patients with sustained MRD negativity had bone marrow evaluations, and 1 was MRD negative.

At 11.8 months of follow-up, the median duration of response, progression-free survival, and overall survival had not been reached. The estimated 12-month progression-free survival for all patients was 80%.

“Venetoclax has been well-tolerated,” Dr Jones noted. “The toxicity profile in this study is consistent with previous reports. Most of the toxicity has been cytopenias, which can be managed with dose adjustments or supportive care interventions, such as G-CSF.”

All 64 patients experienced an AE. Common AEs were neutropenia (58%), thrombocytopenia (44%), diarrhea (42%), nausea (41%), anemia (36%), fatigue (31%), decreased white blood cell count (22%), and hyperphosphatemia (22%).

Eighty-three percent of patients had grade 3/4 AEs, including neutropenia (45%), thrombocytopenia (28%), anemia (22%), decreased white blood cell count (13%), febrile neutropenia (11%), and pneumonia (11%).

Fifty-three percent of patients had serious AEs, including febrile neutropenia (9%), pneumonia (8%), multi-organ failure (3%), septic shock (3%), and increased potassium (3%).

There were no cases of clinical TLS. However, 1 patient with high tumor burden met Howard criteria for laboratory TLS.

*Information presented at the meeting differs from the abstract.

Jacqueline Mays, DDS, PhD

Photo courtesy of NIH

SAN DIEGO—Results of a phase 2 study suggest an oral mouth rinse formulation of the steroid clobetasol could provide short-term treatment of oral chronic graft-vs-host disease (cGVHD).

A majority of patients had a greater than 25% improvement in their cGVHD after using the clobetasol rinse, and patients reported improvements in oral health-related quality of life.

The rinse even proved effective in patients who had failed prior treatment with clobetasol ointment.

However, researchers found evidence to suggest the clobetasol rinse is not suitable for unmonitored, long-term use, as some patients experienced adrenal suppression.

Jacqueline W. Mays, DDS, PhD, of the National Institutes of Health (NIH) in Bethesda, Maryland, presented these findings at the 2016 ASH Annual Meeting (abstract 826).

Dr Mays noted that topical therapy for oral cGVHD is intended to spare patients from exposure to systemic immunosuppressive agents.

According to NIH consensus criteria, dexamethasone is recommended as the first-line topical therapy for these patients. However, clinical trial data suggest only 29% to 58% of patients respond to this therapy.

Second-line treatment is not well-established, but it typically consists of topical steroids in a gel or ointment formulation. Unfortunately, patient compliance is an issue with this type of treatment.

“If you can imagine trying to apply something in a petrolatum base to the inside of your very wet wall cavity, you can imagine that’s a challenge for a healthy individual, much less for a chronic graft-vs-host disease patient who often will have joint mobility and fine motor issues,” Dr Mays said.

“So this leads to frequent treatment failures of topical regimens, not only due to the drug agents but also due to patient compliance.”

Dr Mays noted that clobetasol is a superpotent synthetic glucocorticoid that has been used off-label in ointment form to treat refractory oral GVHD.

In an attempt to overcome the application challenges with this ointment and improve patient adherence to oral cGVHD treatment, Dr Mays and her colleagues decided to investigate a clobetasol 0.05% solution formulated as an oral rinse in an aqueous base.

The team tested the rinse in a phase 2 trial with an initial 2-week randomized, double-blind, placebo-controlled period.

Patient population

The trial enrolled and randomized 36 patients with oral cGVHD. The patients had an Oral Mucositis Rating Scale (OMRS) score of ≥20 with moderate erythema and/or ulceration. They also had stable or tapering systemic therapy during the 2 weeks prior to starting the study and for the duration of the blinded period.

The patients’ median age was 42 (range, 18-68), and 20 were male. Thirty-five patients received ablative conditioning, 18 received a related-donor transplant, 34 received a matched-donor transplant, and 30 received a peripheral blood stem cell graft.

The median time from cGVHD diagnosis to trial enrollment was 257 days (range, 15-3013). Thirty-six patients had mouth cGVHD, 21 had skin cGVHD, 26 had eye cGVHD, 14 had gastrointestinal cGVHD, 16 had liver cGVHD, 11 had lung cGVHD, and 10 had cGVHD of the joints and fascia.

Six patients had not received any prior oral topical therapy. The other 30 patients had a median of 2 prior oral topical therapies. Eleven patients had received prior clobetasol ointment.

Treatment

The patients were randomized to receive clobetasol or placebo rinse for 2 weeks (blinded period). After that, all patients received clobetasol rinse until they completed 28 days of treatment.

The patients were required to perform a 2-minute swish with 10 ml of clobetasol rinse 3 times daily and a once-daily swish with nystatin (100,000 u/ml) rinse for antifungal prophylaxis. The patients continued on systemic pneumocystis, antiviral, and antifungal prophylaxis, per NIH cGVHD guidelines.

Thirty-two of the patients completed treatment, using the clobetasol rinse for the full 28 days.

Four patients went off study before completing 28 days of treatment. One of these patients could not tolerate the rinse. This patient had gastrointestinal issues that were attributed (by the patient and the physician) to use of the study drug.

Two patients went off study because they could not make it to the NIH for follow-up visits, and 1 patient died. The death was unrelated to the study drug.

Safety

Dr Mays noted that small amounts of clobetasol were detectable in the bloodstream, but she and her colleagues found this was not directly correlated to patient serum cortisol levels.

However, the researchers did observe a significant drop in serum cortisol levels from baseline to day 28, suggesting the rinse has an adrenal impact.

On the other hand, the peripheral lymphocyte profile was unchanged by the use of clobetasol rinse, which suggests there were no significant systemic immunosuppressive effects.

Adverse events considered possibly or probably related to clobetasol rinse included herpes simplex virus reactivation (n=3, grade 2-3), oral candidiasis (n=3, grade 2), other oral viral infection (n=1, grade 2), facial edema (n=3, grade 1), and adrenal suppression (6 grade 1 and 1 grade 2).

Dr Mays noted that many of the patients came on the study with adrenal suppression, but the clobetasol rinse had an additional impact.

Efficacy

The study’s primary endpoint was change in oral cGVHD severity scale at day 28 compared to baseline. Complete response was defined as a score of 0 on the erythema and ulceration components. Partial response was defined as a 25% decrease in score.

Progression was defined as a 25% increase in initial score. Stable disease was defined as a status that does not meet the criteria for progression or response.

Ninety-one percent of patients had a greater than 25% improvement in oral cGVHD severity scale. Nineteen percent of patients had a complete response, 72% of patients had a partial response, and 9% had stable disease. None of the patients progressed.

Dr Mays noted that patients who failed treatment with prior clobetasol ointment responded similarly to the clobetasol rinse when compared with the full study cohort.

Among the 11 patients with prior clobetasol ointment, 18% had a complete response, 73% had a partial response, 9% had stable disease, and none progressed.

Clobetasol rinse significantly decreased the clinical OMRS score (P<0.0001) and improved cGVHD pathology diagnosis (P=0.0001).

Patients reported a significant improvement in oral health-based quality of life (P=0.0008) after completing treatment, as well as significant improvements in oral pain (P=0.017) and oral sensitivity (P=0.0081).

Though saliva production did not change significantly from baseline to day 28, patients reported a significant improvement in oral dryness (P=0.014).

The blinded period of the study showed that placebo treatment was not effective. There was a significant difference between the placebo and clobetasol groups with regard to improvement in OMRS score from baseline to day 14 (P=0.0031).

“We found clobetasol oral rinse to be both effective and safe for short-term treatment of oral mucosal cGVHD and hope that it will improve sparing of systemic immunosuppressants in this patient population,” Dr Mays said. “Its risk profile is generally not suitable for unmonitored, long-term use.”

Jacqueline Mays, DDS, PhD

Photo courtesy of NIH

SAN DIEGO—Results of a phase 2 study suggest an oral mouth rinse formulation of the steroid clobetasol could provide short-term treatment of oral chronic graft-vs-host disease (cGVHD).

A majority of patients had a greater than 25% improvement in their cGVHD after using the clobetasol rinse, and patients reported improvements in oral health-related quality of life.

The rinse even proved effective in patients who had failed prior treatment with clobetasol ointment.

However, researchers found evidence to suggest the clobetasol rinse is not suitable for unmonitored, long-term use, as some patients experienced adrenal suppression.

Jacqueline W. Mays, DDS, PhD, of the National Institutes of Health (NIH) in Bethesda, Maryland, presented these findings at the 2016 ASH Annual Meeting (abstract 826).

Dr Mays noted that topical therapy for oral cGVHD is intended to spare patients from exposure to systemic immunosuppressive agents.

According to NIH consensus criteria, dexamethasone is recommended as the first-line topical therapy for these patients. However, clinical trial data suggest only 29% to 58% of patients respond to this therapy.

Second-line treatment is not well-established, but it typically consists of topical steroids in a gel or ointment formulation. Unfortunately, patient compliance is an issue with this type of treatment.

“If you can imagine trying to apply something in a petrolatum base to the inside of your very wet wall cavity, you can imagine that’s a challenge for a healthy individual, much less for a chronic graft-vs-host disease patient who often will have joint mobility and fine motor issues,” Dr Mays said.

“So this leads to frequent treatment failures of topical regimens, not only due to the drug agents but also due to patient compliance.”

Dr Mays noted that clobetasol is a superpotent synthetic glucocorticoid that has been used off-label in ointment form to treat refractory oral GVHD.

In an attempt to overcome the application challenges with this ointment and improve patient adherence to oral cGVHD treatment, Dr Mays and her colleagues decided to investigate a clobetasol 0.05% solution formulated as an oral rinse in an aqueous base.

The team tested the rinse in a phase 2 trial with an initial 2-week randomized, double-blind, placebo-controlled period.

Patient population

The trial enrolled and randomized 36 patients with oral cGVHD. The patients had an Oral Mucositis Rating Scale (OMRS) score of ≥20 with moderate erythema and/or ulceration. They also had stable or tapering systemic therapy during the 2 weeks prior to starting the study and for the duration of the blinded period.

The patients’ median age was 42 (range, 18-68), and 20 were male. Thirty-five patients received ablative conditioning, 18 received a related-donor transplant, 34 received a matched-donor transplant, and 30 received a peripheral blood stem cell graft.

The median time from cGVHD diagnosis to trial enrollment was 257 days (range, 15-3013). Thirty-six patients had mouth cGVHD, 21 had skin cGVHD, 26 had eye cGVHD, 14 had gastrointestinal cGVHD, 16 had liver cGVHD, 11 had lung cGVHD, and 10 had cGVHD of the joints and fascia.

Six patients had not received any prior oral topical therapy. The other 30 patients had a median of 2 prior oral topical therapies. Eleven patients had received prior clobetasol ointment.

Treatment

The patients were randomized to receive clobetasol or placebo rinse for 2 weeks (blinded period). After that, all patients received clobetasol rinse until they completed 28 days of treatment.

The patients were required to perform a 2-minute swish with 10 ml of clobetasol rinse 3 times daily and a once-daily swish with nystatin (100,000 u/ml) rinse for antifungal prophylaxis. The patients continued on systemic pneumocystis, antiviral, and antifungal prophylaxis, per NIH cGVHD guidelines.

Thirty-two of the patients completed treatment, using the clobetasol rinse for the full 28 days.

Four patients went off study before completing 28 days of treatment. One of these patients could not tolerate the rinse. This patient had gastrointestinal issues that were attributed (by the patient and the physician) to use of the study drug.

Two patients went off study because they could not make it to the NIH for follow-up visits, and 1 patient died. The death was unrelated to the study drug.

Safety

Dr Mays noted that small amounts of clobetasol were detectable in the bloodstream, but she and her colleagues found this was not directly correlated to patient serum cortisol levels.

However, the researchers did observe a significant drop in serum cortisol levels from baseline to day 28, suggesting the rinse has an adrenal impact.

On the other hand, the peripheral lymphocyte profile was unchanged by the use of clobetasol rinse, which suggests there were no significant systemic immunosuppressive effects.

Adverse events considered possibly or probably related to clobetasol rinse included herpes simplex virus reactivation (n=3, grade 2-3), oral candidiasis (n=3, grade 2), other oral viral infection (n=1, grade 2), facial edema (n=3, grade 1), and adrenal suppression (6 grade 1 and 1 grade 2).

Dr Mays noted that many of the patients came on the study with adrenal suppression, but the clobetasol rinse had an additional impact.

Efficacy

The study’s primary endpoint was change in oral cGVHD severity scale at day 28 compared to baseline. Complete response was defined as a score of 0 on the erythema and ulceration components. Partial response was defined as a 25% decrease in score.

Progression was defined as a 25% increase in initial score. Stable disease was defined as a status that does not meet the criteria for progression or response.

Ninety-one percent of patients had a greater than 25% improvement in oral cGVHD severity scale. Nineteen percent of patients had a complete response, 72% of patients had a partial response, and 9% had stable disease. None of the patients progressed.

Dr Mays noted that patients who failed treatment with prior clobetasol ointment responded similarly to the clobetasol rinse when compared with the full study cohort.

Among the 11 patients with prior clobetasol ointment, 18% had a complete response, 73% had a partial response, 9% had stable disease, and none progressed.

Clobetasol rinse significantly decreased the clinical OMRS score (P<0.0001) and improved cGVHD pathology diagnosis (P=0.0001).

Patients reported a significant improvement in oral health-based quality of life (P=0.0008) after completing treatment, as well as significant improvements in oral pain (P=0.017) and oral sensitivity (P=0.0081).

Though saliva production did not change significantly from baseline to day 28, patients reported a significant improvement in oral dryness (P=0.014).

The blinded period of the study showed that placebo treatment was not effective. There was a significant difference between the placebo and clobetasol groups with regard to improvement in OMRS score from baseline to day 14 (P=0.0031).

“We found clobetasol oral rinse to be both effective and safe for short-term treatment of oral mucosal cGVHD and hope that it will improve sparing of systemic immunosuppressants in this patient population,” Dr Mays said. “Its risk profile is generally not suitable for unmonitored, long-term use.”

Jacqueline Mays, DDS, PhD

Photo courtesy of NIH

SAN DIEGO—Results of a phase 2 study suggest an oral mouth rinse formulation of the steroid clobetasol could provide short-term treatment of oral chronic graft-vs-host disease (cGVHD).

A majority of patients had a greater than 25% improvement in their cGVHD after using the clobetasol rinse, and patients reported improvements in oral health-related quality of life.

The rinse even proved effective in patients who had failed prior treatment with clobetasol ointment.

However, researchers found evidence to suggest the clobetasol rinse is not suitable for unmonitored, long-term use, as some patients experienced adrenal suppression.

Jacqueline W. Mays, DDS, PhD, of the National Institutes of Health (NIH) in Bethesda, Maryland, presented these findings at the 2016 ASH Annual Meeting (abstract 826).

Dr Mays noted that topical therapy for oral cGVHD is intended to spare patients from exposure to systemic immunosuppressive agents.

According to NIH consensus criteria, dexamethasone is recommended as the first-line topical therapy for these patients. However, clinical trial data suggest only 29% to 58% of patients respond to this therapy.

Second-line treatment is not well-established, but it typically consists of topical steroids in a gel or ointment formulation. Unfortunately, patient compliance is an issue with this type of treatment.

“If you can imagine trying to apply something in a petrolatum base to the inside of your very wet wall cavity, you can imagine that’s a challenge for a healthy individual, much less for a chronic graft-vs-host disease patient who often will have joint mobility and fine motor issues,” Dr Mays said.

“So this leads to frequent treatment failures of topical regimens, not only due to the drug agents but also due to patient compliance.”

Dr Mays noted that clobetasol is a superpotent synthetic glucocorticoid that has been used off-label in ointment form to treat refractory oral GVHD.

In an attempt to overcome the application challenges with this ointment and improve patient adherence to oral cGVHD treatment, Dr Mays and her colleagues decided to investigate a clobetasol 0.05% solution formulated as an oral rinse in an aqueous base.

The team tested the rinse in a phase 2 trial with an initial 2-week randomized, double-blind, placebo-controlled period.

Patient population

The trial enrolled and randomized 36 patients with oral cGVHD. The patients had an Oral Mucositis Rating Scale (OMRS) score of ≥20 with moderate erythema and/or ulceration. They also had stable or tapering systemic therapy during the 2 weeks prior to starting the study and for the duration of the blinded period.

The patients’ median age was 42 (range, 18-68), and 20 were male. Thirty-five patients received ablative conditioning, 18 received a related-donor transplant, 34 received a matched-donor transplant, and 30 received a peripheral blood stem cell graft.

The median time from cGVHD diagnosis to trial enrollment was 257 days (range, 15-3013). Thirty-six patients had mouth cGVHD, 21 had skin cGVHD, 26 had eye cGVHD, 14 had gastrointestinal cGVHD, 16 had liver cGVHD, 11 had lung cGVHD, and 10 had cGVHD of the joints and fascia.

Six patients had not received any prior oral topical therapy. The other 30 patients had a median of 2 prior oral topical therapies. Eleven patients had received prior clobetasol ointment.

Treatment

The patients were randomized to receive clobetasol or placebo rinse for 2 weeks (blinded period). After that, all patients received clobetasol rinse until they completed 28 days of treatment.

The patients were required to perform a 2-minute swish with 10 ml of clobetasol rinse 3 times daily and a once-daily swish with nystatin (100,000 u/ml) rinse for antifungal prophylaxis. The patients continued on systemic pneumocystis, antiviral, and antifungal prophylaxis, per NIH cGVHD guidelines.

Thirty-two of the patients completed treatment, using the clobetasol rinse for the full 28 days.

Four patients went off study before completing 28 days of treatment. One of these patients could not tolerate the rinse. This patient had gastrointestinal issues that were attributed (by the patient and the physician) to use of the study drug.

Two patients went off study because they could not make it to the NIH for follow-up visits, and 1 patient died. The death was unrelated to the study drug.

Safety

Dr Mays noted that small amounts of clobetasol were detectable in the bloodstream, but she and her colleagues found this was not directly correlated to patient serum cortisol levels.

However, the researchers did observe a significant drop in serum cortisol levels from baseline to day 28, suggesting the rinse has an adrenal impact.

On the other hand, the peripheral lymphocyte profile was unchanged by the use of clobetasol rinse, which suggests there were no significant systemic immunosuppressive effects.

Adverse events considered possibly or probably related to clobetasol rinse included herpes simplex virus reactivation (n=3, grade 2-3), oral candidiasis (n=3, grade 2), other oral viral infection (n=1, grade 2), facial edema (n=3, grade 1), and adrenal suppression (6 grade 1 and 1 grade 2).

Dr Mays noted that many of the patients came on the study with adrenal suppression, but the clobetasol rinse had an additional impact.

Efficacy

The study’s primary endpoint was change in oral cGVHD severity scale at day 28 compared to baseline. Complete response was defined as a score of 0 on the erythema and ulceration components. Partial response was defined as a 25% decrease in score.

Progression was defined as a 25% increase in initial score. Stable disease was defined as a status that does not meet the criteria for progression or response.

Ninety-one percent of patients had a greater than 25% improvement in oral cGVHD severity scale. Nineteen percent of patients had a complete response, 72% of patients had a partial response, and 9% had stable disease. None of the patients progressed.

Dr Mays noted that patients who failed treatment with prior clobetasol ointment responded similarly to the clobetasol rinse when compared with the full study cohort.

Among the 11 patients with prior clobetasol ointment, 18% had a complete response, 73% had a partial response, 9% had stable disease, and none progressed.

Clobetasol rinse significantly decreased the clinical OMRS score (P<0.0001) and improved cGVHD pathology diagnosis (P=0.0001).

Patients reported a significant improvement in oral health-based quality of life (P=0.0008) after completing treatment, as well as significant improvements in oral pain (P=0.017) and oral sensitivity (P=0.0081).

Though saliva production did not change significantly from baseline to day 28, patients reported a significant improvement in oral dryness (P=0.014).

The blinded period of the study showed that placebo treatment was not effective. There was a significant difference between the placebo and clobetasol groups with regard to improvement in OMRS score from baseline to day 14 (P=0.0031).

“We found clobetasol oral rinse to be both effective and safe for short-term treatment of oral mucosal cGVHD and hope that it will improve sparing of systemic immunosuppressants in this patient population,” Dr Mays said. “Its risk profile is generally not suitable for unmonitored, long-term use.”

 

 

Attendees at the 2016

ASH Annual Meeting

 

SAN DIEGO—When patients with chronic lymphocytic leukemia (CLL) cannot tolerate one Bruton’s tyrosine kinase (BTK) inhibitor, they may do well on another, according to a presentation at the 2016 ASH Annual Meeting.

Researchers conducting a phase 1/2 study found that acalabrutinib was “well-tolerated” and demonstrated “promising activity” in patients intolerant to ibrutinib.

Seventy-nine percent of patients responded to acalabrutinib.

And although 36% of patients had a recurrence of an adverse event (AE) they experienced while on ibrutinib, none of the patients discontinued acalabrutinib due to AE recurrence.

Farrukh T. Awan, MD, of The Ohio State University in Columbus, Ohio, presented these results at the meeting as abstract 638.*

Dr Awan noted that integrating ibrutinib into standard CLL therapy has improved patient outcomes, but a lack of tolerability observed in some patients suggests that more selective BTK inhibition may be desirable.

“We know that around 10% to 20% of patients who are treated with ibrutinib would have to stop therapy because of an adverse event,” Dr Awan said. “Acalabrutinib is a highly selective, potent BTK inhibitor that has shown promising efficacy, and that [research] was published last year.”

In this ongoing, phase 1/2 study, Dr Awan and his colleagues are testing acalabrutinib in patients with CLL/small lymphocytic leukemia. The study has enrolled multiple cohorts of patients—relapsed/refractory, treatment-naïve, Richter’s transformation/prolymphocytic leukemia, and ibrutinib intolerant.

At this year’s ASH meeting, Dr Awan presented data on the 33 CLL patients who were ibrutinib intolerant. The patients’ median age was 64 (range, 50-82), 61% were male, 97% had an ECOG performance status of 0-1, 52% had Rai stage III-IV, and 31% had bulky disease.

The median number of prior therapies was 4 (range, 2-13), and 91% of patients had ibrutinib as their last therapy. The median duration of prior ibrutinib treatment was 11.5 months (range, 1-62), and the median time from ending ibrutinib to starting acalabrutinib was 47 days (range, 3-331 days).

Treatment and safety

Patients received acalabrutinib at 100 mg twice daily (n=30) or 200 mg daily (n=3) until disease progression or discontinuation for another reason. The patients’ median time on therapy was 12.2 months (range, 0.2-23.6 months).

Nine patients discontinued treatment—3 due to disease progression, 3 due to AEs, 2 due to an increase in BTK C481S mutation frequency in the peripheral blood and central nervous system involvement, and 1 due to physician decision (because the patient had concurrent hemophilia).

The 3 AEs that led to treatment discontinuation were fatal hemorrhagic stroke, fatal fungal infection, and metastatic endometrial cancer. All 3 events were considered unrelated to acalabrutinib.

Serious AEs occurred in 11 patients (33%). A serious AE that occurred in more than 1 patient was pneumonia (n=2).

The most common AEs were diarrhea (52%, grade 1-2), headache (39%, grade 1-2), cough (24%, grade 1-2), increased weight (24%, grade 1-2), nausea (21%, grade 1-2), contusion (18%, grade 1-2), ecchymosis (18%, grade 1-2), fatigue (18%, grade 1-2), hypertension (18% overall, 6% ≥ grade 3), pyrexia (18% overall, 3% ≥ grade 3), vomiting (18%, grade 1-2), myalgia (15% overall, 3% ≥ grade 3), rash (15%, grade 1-2), stomatitis (15%, grade 1-2), upper respiratory tract infection (15%, grade 1-2), and urinary tract infection (15%, grade 1-2).

AE recurrence

Twelve patients (36%) had a recurrence of ibrutinib-related AEs—a total of 16 events. Fourteen of these events either decreased in severity or were unchanged with acalabrutinib treatment.

The events without a change in severity were atrial fibrillation (n=1), fatigue (n=1), muscle spasms (n=1), myalgia (n=1), peripheral edema (n=1), panniculitis (n=1), and rash (n=1).

The events that decreased in severity were diarrhea (n=2), arthralgia (n=1), ecchymosis (n=1), fatigue (n=1), panniculitis (n=1), and rash (n=1).

The events that increased in severity were contusion (n=1, grade 1 to 2) and fatigue (n=1, grade 1 to 2).

None of the patients discontinued acalabrutinib due to AE recurrence.

Efficacy

Twenty-nine patients were evaluable for efficacy.

The overall response rate was 79% (n=23). One patient had a complete response (3%), 15 had a partial response (52%), and 7 had a partial response with lymphocytosis (24%). Six patients had stable disease (21%).

The median time to response was 1.9 months. Eighty-one percent of responding patients have a response duration of 12 months or longer.

The median progression-free survival has not been reached.

The research is sponsored by Acerta Pharma.

*Information presented at the meeting differs from the abstract.

 

 

Attendees at the 2016

ASH Annual Meeting

 

SAN DIEGO—When patients with chronic lymphocytic leukemia (CLL) cannot tolerate one Bruton’s tyrosine kinase (BTK) inhibitor, they may do well on another, according to a presentation at the 2016 ASH Annual Meeting.

Researchers conducting a phase 1/2 study found that acalabrutinib was “well-tolerated” and demonstrated “promising activity” in patients intolerant to ibrutinib.

Seventy-nine percent of patients responded to acalabrutinib.

And although 36% of patients had a recurrence of an adverse event (AE) they experienced while on ibrutinib, none of the patients discontinued acalabrutinib due to AE recurrence.

Farrukh T. Awan, MD, of The Ohio State University in Columbus, Ohio, presented these results at the meeting as abstract 638.*

Dr Awan noted that integrating ibrutinib into standard CLL therapy has improved patient outcomes, but a lack of tolerability observed in some patients suggests that more selective BTK inhibition may be desirable.

“We know that around 10% to 20% of patients who are treated with ibrutinib would have to stop therapy because of an adverse event,” Dr Awan said. “Acalabrutinib is a highly selective, potent BTK inhibitor that has shown promising efficacy, and that [research] was published last year.”

In this ongoing, phase 1/2 study, Dr Awan and his colleagues are testing acalabrutinib in patients with CLL/small lymphocytic leukemia. The study has enrolled multiple cohorts of patients—relapsed/refractory, treatment-naïve, Richter’s transformation/prolymphocytic leukemia, and ibrutinib intolerant.

At this year’s ASH meeting, Dr Awan presented data on the 33 CLL patients who were ibrutinib intolerant. The patients’ median age was 64 (range, 50-82), 61% were male, 97% had an ECOG performance status of 0-1, 52% had Rai stage III-IV, and 31% had bulky disease.

The median number of prior therapies was 4 (range, 2-13), and 91% of patients had ibrutinib as their last therapy. The median duration of prior ibrutinib treatment was 11.5 months (range, 1-62), and the median time from ending ibrutinib to starting acalabrutinib was 47 days (range, 3-331 days).

Treatment and safety

Patients received acalabrutinib at 100 mg twice daily (n=30) or 200 mg daily (n=3) until disease progression or discontinuation for another reason. The patients’ median time on therapy was 12.2 months (range, 0.2-23.6 months).

Nine patients discontinued treatment—3 due to disease progression, 3 due to AEs, 2 due to an increase in BTK C481S mutation frequency in the peripheral blood and central nervous system involvement, and 1 due to physician decision (because the patient had concurrent hemophilia).

The 3 AEs that led to treatment discontinuation were fatal hemorrhagic stroke, fatal fungal infection, and metastatic endometrial cancer. All 3 events were considered unrelated to acalabrutinib.

Serious AEs occurred in 11 patients (33%). A serious AE that occurred in more than 1 patient was pneumonia (n=2).

The most common AEs were diarrhea (52%, grade 1-2), headache (39%, grade 1-2), cough (24%, grade 1-2), increased weight (24%, grade 1-2), nausea (21%, grade 1-2), contusion (18%, grade 1-2), ecchymosis (18%, grade 1-2), fatigue (18%, grade 1-2), hypertension (18% overall, 6% ≥ grade 3), pyrexia (18% overall, 3% ≥ grade 3), vomiting (18%, grade 1-2), myalgia (15% overall, 3% ≥ grade 3), rash (15%, grade 1-2), stomatitis (15%, grade 1-2), upper respiratory tract infection (15%, grade 1-2), and urinary tract infection (15%, grade 1-2).

AE recurrence

Twelve patients (36%) had a recurrence of ibrutinib-related AEs—a total of 16 events. Fourteen of these events either decreased in severity or were unchanged with acalabrutinib treatment.

The events without a change in severity were atrial fibrillation (n=1), fatigue (n=1), muscle spasms (n=1), myalgia (n=1), peripheral edema (n=1), panniculitis (n=1), and rash (n=1).

The events that decreased in severity were diarrhea (n=2), arthralgia (n=1), ecchymosis (n=1), fatigue (n=1), panniculitis (n=1), and rash (n=1).

The events that increased in severity were contusion (n=1, grade 1 to 2) and fatigue (n=1, grade 1 to 2).

None of the patients discontinued acalabrutinib due to AE recurrence.

Efficacy

Twenty-nine patients were evaluable for efficacy.

The overall response rate was 79% (n=23). One patient had a complete response (3%), 15 had a partial response (52%), and 7 had a partial response with lymphocytosis (24%). Six patients had stable disease (21%).

The median time to response was 1.9 months. Eighty-one percent of responding patients have a response duration of 12 months or longer.

The median progression-free survival has not been reached.

The research is sponsored by Acerta Pharma.

*Information presented at the meeting differs from the abstract.

 

 

Attendees at the 2016

ASH Annual Meeting

 

SAN DIEGO—When patients with chronic lymphocytic leukemia (CLL) cannot tolerate one Bruton’s tyrosine kinase (BTK) inhibitor, they may do well on another, according to a presentation at the 2016 ASH Annual Meeting.

Researchers conducting a phase 1/2 study found that acalabrutinib was “well-tolerated” and demonstrated “promising activity” in patients intolerant to ibrutinib.

Seventy-nine percent of patients responded to acalabrutinib.

And although 36% of patients had a recurrence of an adverse event (AE) they experienced while on ibrutinib, none of the patients discontinued acalabrutinib due to AE recurrence.

Farrukh T. Awan, MD, of The Ohio State University in Columbus, Ohio, presented these results at the meeting as abstract 638.*

Dr Awan noted that integrating ibrutinib into standard CLL therapy has improved patient outcomes, but a lack of tolerability observed in some patients suggests that more selective BTK inhibition may be desirable.

“We know that around 10% to 20% of patients who are treated with ibrutinib would have to stop therapy because of an adverse event,” Dr Awan said. “Acalabrutinib is a highly selective, potent BTK inhibitor that has shown promising efficacy, and that [research] was published last year.”

In this ongoing, phase 1/2 study, Dr Awan and his colleagues are testing acalabrutinib in patients with CLL/small lymphocytic leukemia. The study has enrolled multiple cohorts of patients—relapsed/refractory, treatment-naïve, Richter’s transformation/prolymphocytic leukemia, and ibrutinib intolerant.

At this year’s ASH meeting, Dr Awan presented data on the 33 CLL patients who were ibrutinib intolerant. The patients’ median age was 64 (range, 50-82), 61% were male, 97% had an ECOG performance status of 0-1, 52% had Rai stage III-IV, and 31% had bulky disease.

The median number of prior therapies was 4 (range, 2-13), and 91% of patients had ibrutinib as their last therapy. The median duration of prior ibrutinib treatment was 11.5 months (range, 1-62), and the median time from ending ibrutinib to starting acalabrutinib was 47 days (range, 3-331 days).

Treatment and safety

Patients received acalabrutinib at 100 mg twice daily (n=30) or 200 mg daily (n=3) until disease progression or discontinuation for another reason. The patients’ median time on therapy was 12.2 months (range, 0.2-23.6 months).

Nine patients discontinued treatment—3 due to disease progression, 3 due to AEs, 2 due to an increase in BTK C481S mutation frequency in the peripheral blood and central nervous system involvement, and 1 due to physician decision (because the patient had concurrent hemophilia).

The 3 AEs that led to treatment discontinuation were fatal hemorrhagic stroke, fatal fungal infection, and metastatic endometrial cancer. All 3 events were considered unrelated to acalabrutinib.

Serious AEs occurred in 11 patients (33%). A serious AE that occurred in more than 1 patient was pneumonia (n=2).

The most common AEs were diarrhea (52%, grade 1-2), headache (39%, grade 1-2), cough (24%, grade 1-2), increased weight (24%, grade 1-2), nausea (21%, grade 1-2), contusion (18%, grade 1-2), ecchymosis (18%, grade 1-2), fatigue (18%, grade 1-2), hypertension (18% overall, 6% ≥ grade 3), pyrexia (18% overall, 3% ≥ grade 3), vomiting (18%, grade 1-2), myalgia (15% overall, 3% ≥ grade 3), rash (15%, grade 1-2), stomatitis (15%, grade 1-2), upper respiratory tract infection (15%, grade 1-2), and urinary tract infection (15%, grade 1-2).

AE recurrence

Twelve patients (36%) had a recurrence of ibrutinib-related AEs—a total of 16 events. Fourteen of these events either decreased in severity or were unchanged with acalabrutinib treatment.

The events without a change in severity were atrial fibrillation (n=1), fatigue (n=1), muscle spasms (n=1), myalgia (n=1), peripheral edema (n=1), panniculitis (n=1), and rash (n=1).

The events that decreased in severity were diarrhea (n=2), arthralgia (n=1), ecchymosis (n=1), fatigue (n=1), panniculitis (n=1), and rash (n=1).

The events that increased in severity were contusion (n=1, grade 1 to 2) and fatigue (n=1, grade 1 to 2).

None of the patients discontinued acalabrutinib due to AE recurrence.

Efficacy

Twenty-nine patients were evaluable for efficacy.

The overall response rate was 79% (n=23). One patient had a complete response (3%), 15 had a partial response (52%), and 7 had a partial response with lymphocytosis (24%). Six patients had stable disease (21%).

The median time to response was 1.9 months. Eighty-one percent of responding patients have a response duration of 12 months or longer.

The median progression-free survival has not been reached.

The research is sponsored by Acerta Pharma.

*Information presented at the meeting differs from the abstract.

Lindsey George, MD

SAN DIEGO—Researchers say they have optimized the SPK-9001 adeno-associated viral (AAV) vector

so that a “simple infusion” has significantly reduced bleeding events and the need for regular factor IX (FIX) infusions in 9 hemophilia B patients.

Eight of the patients were able to stop receiving FIX infusions and achieved an annualized bleeding rate (ABR) of 0. One patient had an ABR of 2 and required on-demand FIX therapy.

Lindsey George, MD, of the University of Pennsylvania in Philadelphia, presented these data, updating the interim results from the phase 1/2 trial of SPK-9001, during the plenary session of the 2016 ASH Annual Meeting (abstract 3*).

The trial is sponsored by Spark Therapeutics in collaboration with Pfizer.

Dr George explained that the bulk of hemophilia gene transfer efforts have coalesced around the use of in vitro, liver-directed, recombinant AAV vectors.

Earlier data showed sustained FIX activity at approximately 5% with AAV-serotype 8 (AAV8) vectors at 2 x 10¹² vg/kg. However, levels of FIX:C at 12% are necessary to avoid bleeding into the joints, and higher doses elicit a capsid immune response.

Therefore, the team hypothesized that a highly efficient vector capsid and expression cassette, administered at low doses, would increase FIX expression to therapeutic levels and minimize the risk of a capsid immune response.

They developed an AAV capsid (Spark100) with a liver promoter and an expression cassette consisting of a codon-optimized, single-strand transgene encoding FIX-Padua.

In a prior AAV liver-directed gene transfer clinical trial, no patient developed inhibitors.

So the team conducted a phase 1/2 trial in males age 18 and older who had FIX:C levels of 2% or less.

The patients had to have less than 1:5 neutralizing antibodies to Spark100, more than 50 factor exposure days, no prior history of FIX inhibitors, no active hepatitis B or C virus, and liver fibrosis of stage 2 or less. They had to have a negative HIV viral load with CD4 levels of 200/mm³ or more.

At baseline, patients had to be on prophylaxis or be receiving on-demand therapy and have 4 or more bleeding events the year prior to infusion or a history of hemophilic arthropathy.

Results

The researchers enrolled 9 participants, ages 18 to 52. Six patients were on prophylaxis, and 3 had on-demand therapy at baseline.

They received a 1-hour, outpatient, intravenous infusion of SPK-9001 at 5 x 10¹¹ vg/kg and were followed up for 52 weeks, with a long-term follow-up of 14 years.

Five patients had a history of HCV, and 1 had a history of HIV and was maintained on antiretroviral therapy.

One patient had neutralizing antibody titers to Spark100 capsid at a 1:1 ratio.

Prior to receiving SPK-9001, the patients required an annual number of infusions ranging from 0 to 159. Three patients had ABRs of 0, but the remaining patients had ABRs of 1, 2, 4, 10, 12, and 49.

After receiving SPK-9001, 8 of the patients were able to stop receiving FIX infusions and

achieved an ABR of 0. One patient had an ABR of 2 and required on-demand FIX therapy.

Dr George described one patient, a 23-year-old male who had severe hemophilia B and was maintained on weekly rFIX-Fc prophylaxis. He had no history of HCV or HIV.

Prior to receiving SPK-9001, he had 98 infusions and 4 breakthrough bleeds. After SPK-9001, he had a FIX activity level of 33% of normal at 52 weeks, no bleeding episodes, and required no rescue factor.

He had no vector-related adverse events, required no immunosuppression, and was safely off prophylaxis.

“Clinically, what this has meant for this man is he is now off his prophylaxis, he has no longer had breakthrough bleeding events, and he has not required factor for any reason,” Dr George said.

Capsid immune responses

Seven patients had less than 1:1 Spark100 neutralizing antibody at baseline and did not require steroids.

Their mean steady-state FIX activity was 31.9 + 7.4% at a follow-up of 12 to 52 weeks. Their liver function tests remained less than 1.5 times the upper limit of normal.

Two patients had capsid immune responses requiring steroid treatment.

One patient, a 45-year-old male, had a FIX:C of 1.9%, experienced 49 bleeding events prior to receiving SPK-9001, and was treated on-demand.

After SPK-9001, he had no vector-related adverse events, received a course of prednisone, and, at 20 weeks follow-up, had experienced no bleeding events and did not require factor use.

The second patient who had a capsid immune response was 36 years of age and on FIX prophylaxis. He had a history of HCV and no history of HIV.

After SPK-9001, he experienced no bleeding and required no factor use. He had grade 1 transaminase toxicity, which returned to within normal limits.

He is taking 40 mg prednisone daily and has stable FIX:C activity at 49 days after vector infusion.

Overall transgene-derived FIX activity

At a follow-up of 7 to 52 weeks, for a cumulative 238 weeks for all patients, their mean steady-state FIX activity was 28.3 + 10.0% of normal.

They had no vector or procedure-related unexpected adverse events, although 1 patient had transient grade 1 transaminase toxicity.

No patient developed FIX alloinhibitory antibodies.

One patient had FIX:C activity of 68% of normal at 7 weeks, and the first patient infused had 33% FIX:C activity at 52 weeks.

The transgene-derived FIX activity resulted in a significant reduction in bleeding events (P<0.05) and factor use (P<0.05). All patients stopped their prophylaxis.

The researchers recommend a larger cohort and continued observation to confirm these results.

Dr George noted that SPK-9001 has received breakthrough therapy designation from the US Food and Drug Administration.

*Information presented at the meeting differs from the abstract.

Lindsey George, MD

SAN DIEGO—Researchers say they have optimized the SPK-9001 adeno-associated viral (AAV) vector

so that a “simple infusion” has significantly reduced bleeding events and the need for regular factor IX (FIX) infusions in 9 hemophilia B patients.

Eight of the patients were able to stop receiving FIX infusions and achieved an annualized bleeding rate (ABR) of 0. One patient had an ABR of 2 and required on-demand FIX therapy.

Lindsey George, MD, of the University of Pennsylvania in Philadelphia, presented these data, updating the interim results from the phase 1/2 trial of SPK-9001, during the plenary session of the 2016 ASH Annual Meeting (abstract 3*).

The trial is sponsored by Spark Therapeutics in collaboration with Pfizer.

Dr George explained that the bulk of hemophilia gene transfer efforts have coalesced around the use of in vitro, liver-directed, recombinant AAV vectors.

Earlier data showed sustained FIX activity at approximately 5% with AAV-serotype 8 (AAV8) vectors at 2 x 10¹² vg/kg. However, levels of FIX:C at 12% are necessary to avoid bleeding into the joints, and higher doses elicit a capsid immune response.

Therefore, the team hypothesized that a highly efficient vector capsid and expression cassette, administered at low doses, would increase FIX expression to therapeutic levels and minimize the risk of a capsid immune response.

They developed an AAV capsid (Spark100) with a liver promoter and an expression cassette consisting of a codon-optimized, single-strand transgene encoding FIX-Padua.

In a prior AAV liver-directed gene transfer clinical trial, no patient developed inhibitors.

So the team conducted a phase 1/2 trial in males age 18 and older who had FIX:C levels of 2% or less.

The patients had to have less than 1:5 neutralizing antibodies to Spark100, more than 50 factor exposure days, no prior history of FIX inhibitors, no active hepatitis B or C virus, and liver fibrosis of stage 2 or less. They had to have a negative HIV viral load with CD4 levels of 200/mm³ or more.

At baseline, patients had to be on prophylaxis or be receiving on-demand therapy and have 4 or more bleeding events the year prior to infusion or a history of hemophilic arthropathy.

Results

The researchers enrolled 9 participants, ages 18 to 52. Six patients were on prophylaxis, and 3 had on-demand therapy at baseline.

They received a 1-hour, outpatient, intravenous infusion of SPK-9001 at 5 x 10¹¹ vg/kg and were followed up for 52 weeks, with a long-term follow-up of 14 years.

Five patients had a history of HCV, and 1 had a history of HIV and was maintained on antiretroviral therapy.

One patient had neutralizing antibody titers to Spark100 capsid at a 1:1 ratio.

Prior to receiving SPK-9001, the patients required an annual number of infusions ranging from 0 to 159. Three patients had ABRs of 0, but the remaining patients had ABRs of 1, 2, 4, 10, 12, and 49.

After receiving SPK-9001, 8 of the patients were able to stop receiving FIX infusions and

achieved an ABR of 0. One patient had an ABR of 2 and required on-demand FIX therapy.

Dr George described one patient, a 23-year-old male who had severe hemophilia B and was maintained on weekly rFIX-Fc prophylaxis. He had no history of HCV or HIV.

Prior to receiving SPK-9001, he had 98 infusions and 4 breakthrough bleeds. After SPK-9001, he had a FIX activity level of 33% of normal at 52 weeks, no bleeding episodes, and required no rescue factor.

He had no vector-related adverse events, required no immunosuppression, and was safely off prophylaxis.

“Clinically, what this has meant for this man is he is now off his prophylaxis, he has no longer had breakthrough bleeding events, and he has not required factor for any reason,” Dr George said.

Capsid immune responses

Seven patients had less than 1:1 Spark100 neutralizing antibody at baseline and did not require steroids.

Their mean steady-state FIX activity was 31.9 + 7.4% at a follow-up of 12 to 52 weeks. Their liver function tests remained less than 1.5 times the upper limit of normal.

Two patients had capsid immune responses requiring steroid treatment.

One patient, a 45-year-old male, had a FIX:C of 1.9%, experienced 49 bleeding events prior to receiving SPK-9001, and was treated on-demand.

After SPK-9001, he had no vector-related adverse events, received a course of prednisone, and, at 20 weeks follow-up, had experienced no bleeding events and did not require factor use.

The second patient who had a capsid immune response was 36 years of age and on FIX prophylaxis. He had a history of HCV and no history of HIV.

After SPK-9001, he experienced no bleeding and required no factor use. He had grade 1 transaminase toxicity, which returned to within normal limits.

He is taking 40 mg prednisone daily and has stable FIX:C activity at 49 days after vector infusion.

Overall transgene-derived FIX activity

At a follow-up of 7 to 52 weeks, for a cumulative 238 weeks for all patients, their mean steady-state FIX activity was 28.3 + 10.0% of normal.

They had no vector or procedure-related unexpected adverse events, although 1 patient had transient grade 1 transaminase toxicity.

No patient developed FIX alloinhibitory antibodies.

One patient had FIX:C activity of 68% of normal at 7 weeks, and the first patient infused had 33% FIX:C activity at 52 weeks.

The transgene-derived FIX activity resulted in a significant reduction in bleeding events (P<0.05) and factor use (P<0.05). All patients stopped their prophylaxis.

The researchers recommend a larger cohort and continued observation to confirm these results.

Dr George noted that SPK-9001 has received breakthrough therapy designation from the US Food and Drug Administration.

*Information presented at the meeting differs from the abstract.

Lindsey George, MD

SAN DIEGO—Researchers say they have optimized the SPK-9001 adeno-associated viral (AAV) vector

so that a “simple infusion” has significantly reduced bleeding events and the need for regular factor IX (FIX) infusions in 9 hemophilia B patients.

Eight of the patients were able to stop receiving FIX infusions and achieved an annualized bleeding rate (ABR) of 0. One patient had an ABR of 2 and required on-demand FIX therapy.

Lindsey George, MD, of the University of Pennsylvania in Philadelphia, presented these data, updating the interim results from the phase 1/2 trial of SPK-9001, during the plenary session of the 2016 ASH Annual Meeting (abstract 3*).

The trial is sponsored by Spark Therapeutics in collaboration with Pfizer.

Dr George explained that the bulk of hemophilia gene transfer efforts have coalesced around the use of in vitro, liver-directed, recombinant AAV vectors.

Earlier data showed sustained FIX activity at approximately 5% with AAV-serotype 8 (AAV8) vectors at 2 x 10¹² vg/kg. However, levels of FIX:C at 12% are necessary to avoid bleeding into the joints, and higher doses elicit a capsid immune response.

Therefore, the team hypothesized that a highly efficient vector capsid and expression cassette, administered at low doses, would increase FIX expression to therapeutic levels and minimize the risk of a capsid immune response.

They developed an AAV capsid (Spark100) with a liver promoter and an expression cassette consisting of a codon-optimized, single-strand transgene encoding FIX-Padua.

In a prior AAV liver-directed gene transfer clinical trial, no patient developed inhibitors.

So the team conducted a phase 1/2 trial in males age 18 and older who had FIX:C levels of 2% or less.

The patients had to have less than 1:5 neutralizing antibodies to Spark100, more than 50 factor exposure days, no prior history of FIX inhibitors, no active hepatitis B or C virus, and liver fibrosis of stage 2 or less. They had to have a negative HIV viral load with CD4 levels of 200/mm³ or more.

At baseline, patients had to be on prophylaxis or be receiving on-demand therapy and have 4 or more bleeding events the year prior to infusion or a history of hemophilic arthropathy.

Results

The researchers enrolled 9 participants, ages 18 to 52. Six patients were on prophylaxis, and 3 had on-demand therapy at baseline.

They received a 1-hour, outpatient, intravenous infusion of SPK-9001 at 5 x 10¹¹ vg/kg and were followed up for 52 weeks, with a long-term follow-up of 14 years.

Five patients had a history of HCV, and 1 had a history of HIV and was maintained on antiretroviral therapy.

One patient had neutralizing antibody titers to Spark100 capsid at a 1:1 ratio.

Prior to receiving SPK-9001, the patients required an annual number of infusions ranging from 0 to 159. Three patients had ABRs of 0, but the remaining patients had ABRs of 1, 2, 4, 10, 12, and 49.

After receiving SPK-9001, 8 of the patients were able to stop receiving FIX infusions and

achieved an ABR of 0. One patient had an ABR of 2 and required on-demand FIX therapy.

Dr George described one patient, a 23-year-old male who had severe hemophilia B and was maintained on weekly rFIX-Fc prophylaxis. He had no history of HCV or HIV.

Prior to receiving SPK-9001, he had 98 infusions and 4 breakthrough bleeds. After SPK-9001, he had a FIX activity level of 33% of normal at 52 weeks, no bleeding episodes, and required no rescue factor.

He had no vector-related adverse events, required no immunosuppression, and was safely off prophylaxis.

“Clinically, what this has meant for this man is he is now off his prophylaxis, he has no longer had breakthrough bleeding events, and he has not required factor for any reason,” Dr George said.

Capsid immune responses

Seven patients had less than 1:1 Spark100 neutralizing antibody at baseline and did not require steroids.

Their mean steady-state FIX activity was 31.9 + 7.4% at a follow-up of 12 to 52 weeks. Their liver function tests remained less than 1.5 times the upper limit of normal.

Two patients had capsid immune responses requiring steroid treatment.

One patient, a 45-year-old male, had a FIX:C of 1.9%, experienced 49 bleeding events prior to receiving SPK-9001, and was treated on-demand.

After SPK-9001, he had no vector-related adverse events, received a course of prednisone, and, at 20 weeks follow-up, had experienced no bleeding events and did not require factor use.

The second patient who had a capsid immune response was 36 years of age and on FIX prophylaxis. He had a history of HCV and no history of HIV.

After SPK-9001, he experienced no bleeding and required no factor use. He had grade 1 transaminase toxicity, which returned to within normal limits.

He is taking 40 mg prednisone daily and has stable FIX:C activity at 49 days after vector infusion.

Overall transgene-derived FIX activity

At a follow-up of 7 to 52 weeks, for a cumulative 238 weeks for all patients, their mean steady-state FIX activity was 28.3 + 10.0% of normal.

They had no vector or procedure-related unexpected adverse events, although 1 patient had transient grade 1 transaminase toxicity.

No patient developed FIX alloinhibitory antibodies.

One patient had FIX:C activity of 68% of normal at 7 weeks, and the first patient infused had 33% FIX:C activity at 52 weeks.

The transgene-derived FIX activity resulted in a significant reduction in bleeding events (P<0.05) and factor use (P<0.05). All patients stopped their prophylaxis.

The researchers recommend a larger cohort and continued observation to confirm these results.

Dr George noted that SPK-9001 has received breakthrough therapy designation from the US Food and Drug Administration.

*Information presented at the meeting differs from the abstract.

Poster session at the

2016 ASH Annual Meeting

SAN DIEGO—Many patients living with myeloproliferative neoplasms (MPNs) have a high burden of disease that affects their quality of life and limits their ability to work, according to research presented at the 2016 ASH Annual Meeting.

Researchers conducted the first-ever international survey of MPN patients, including those with myelofibrosis (MF), polycythemia vera (PV), and essential thrombocythemia (ET).

Patients reported a high prevalence of symptoms, an increase in the number of symptoms from diagnosis, and reductions in emotional well-being, quality of life, and ability to work.

“The survey results help paint the full picture of the impact of these diseases,” said Claire Harrison, DM, of Guy’s and St. Thomas’ NHS Foundation Trust in London, UK.

“The dominating symptom is fatigue, which validates what we are seeing in the clinic. The novel findings regarding the impact on patient’s work life show the consequences of MPNs.”

Dr Harrison and her colleagues reported these findings at the meeting as (abstract 4267*).

The international MPN LANDMARK survey included 699 patients with MPNs (174 with MF, 223 with PV, and 302 with ET), and physicians who treated these conditions across Germany, Italy, UK, Japan, Canada, and Australia.

Patients completed an online questionnaire to measure MPN-related symptoms experienced over the past year and the impact of their condition on quality of life and ability to work.

Patients reported that their disease negatively impacted their ability to complete daily activities by 40%. Patients also noted 35% impairment in their capacity to work. Patients who missed work over the last 7 days due to illness reported missing an average of 3.1 hours due to their disease and/or symptom burden.

“For one quarter of PV patients, the disease stopped them from working, and another one quarter voluntarily reduced their work time,” Dr Harrison said. “This was surprising. Even though their disease was managed, it impacted their work life.”

She noted that many of her PV patients are young, working professionals.

Results also showed that about three-quarters of patients who experienced symptoms suffered a significant reduction in quality of life due to symptoms (83% of MF patients, 72% of PV patients, and 74% of ET patients).

These results are consistent with those from a previous US LANDMARK survey of MPN patients.

The most commonly reported symptom in the last 12 months was fatigue (54% of MF patients, 45% of PV patients, and 64% of ET patients). This was also the symptom patients stated they most wanted to resolve.

“Patients stated doctors often don’t ask enough about the details of symptoms,” Dr Harrison said.

In addition to physical symptoms, about one-third of patients felt anxious or worried about their disease (34% of MF patients, 29% of PV patients, and 26% of ET patients).

“We found a mismatch in aspirations of MPN patients and their physicians,” Dr Harrison said. “For example, physicians said it was important to teach PV patients to prevent blood clots. PV patients were more concerned with having a better quality of life and slowing disease progression.”

A comprehensive symptom assessment is important to help physicians understand other hardships of these diseases, she said, noting “in our service, we enlist nutritionists and psychologists and also use physiotherapists and occupational therapists.”

*Information presented at the meeting differs from the abstract.

Poster session at the

2016 ASH Annual Meeting

SAN DIEGO—Many patients living with myeloproliferative neoplasms (MPNs) have a high burden of disease that affects their quality of life and limits their ability to work, according to research presented at the 2016 ASH Annual Meeting.

Researchers conducted the first-ever international survey of MPN patients, including those with myelofibrosis (MF), polycythemia vera (PV), and essential thrombocythemia (ET).

Patients reported a high prevalence of symptoms, an increase in the number of symptoms from diagnosis, and reductions in emotional well-being, quality of life, and ability to work.

“The survey results help paint the full picture of the impact of these diseases,” said Claire Harrison, DM, of Guy’s and St. Thomas’ NHS Foundation Trust in London, UK.

“The dominating symptom is fatigue, which validates what we are seeing in the clinic. The novel findings regarding the impact on patient’s work life show the consequences of MPNs.”

Dr Harrison and her colleagues reported these findings at the meeting as (abstract 4267*).

The international MPN LANDMARK survey included 699 patients with MPNs (174 with MF, 223 with PV, and 302 with ET), and physicians who treated these conditions across Germany, Italy, UK, Japan, Canada, and Australia.

Patients completed an online questionnaire to measure MPN-related symptoms experienced over the past year and the impact of their condition on quality of life and ability to work.

Patients reported that their disease negatively impacted their ability to complete daily activities by 40%. Patients also noted 35% impairment in their capacity to work. Patients who missed work over the last 7 days due to illness reported missing an average of 3.1 hours due to their disease and/or symptom burden.

“For one quarter of PV patients, the disease stopped them from working, and another one quarter voluntarily reduced their work time,” Dr Harrison said. “This was surprising. Even though their disease was managed, it impacted their work life.”

She noted that many of her PV patients are young, working professionals.

Results also showed that about three-quarters of patients who experienced symptoms suffered a significant reduction in quality of life due to symptoms (83% of MF patients, 72% of PV patients, and 74% of ET patients).

These results are consistent with those from a previous US LANDMARK survey of MPN patients.

The most commonly reported symptom in the last 12 months was fatigue (54% of MF patients, 45% of PV patients, and 64% of ET patients). This was also the symptom patients stated they most wanted to resolve.

“Patients stated doctors often don’t ask enough about the details of symptoms,” Dr Harrison said.

In addition to physical symptoms, about one-third of patients felt anxious or worried about their disease (34% of MF patients, 29% of PV patients, and 26% of ET patients).

“We found a mismatch in aspirations of MPN patients and their physicians,” Dr Harrison said. “For example, physicians said it was important to teach PV patients to prevent blood clots. PV patients were more concerned with having a better quality of life and slowing disease progression.”

A comprehensive symptom assessment is important to help physicians understand other hardships of these diseases, she said, noting “in our service, we enlist nutritionists and psychologists and also use physiotherapists and occupational therapists.”

*Information presented at the meeting differs from the abstract.

Poster session at the

2016 ASH Annual Meeting

SAN DIEGO—Many patients living with myeloproliferative neoplasms (MPNs) have a high burden of disease that affects their quality of life and limits their ability to work, according to research presented at the 2016 ASH Annual Meeting.

Researchers conducted the first-ever international survey of MPN patients, including those with myelofibrosis (MF), polycythemia vera (PV), and essential thrombocythemia (ET).

Patients reported a high prevalence of symptoms, an increase in the number of symptoms from diagnosis, and reductions in emotional well-being, quality of life, and ability to work.

“The survey results help paint the full picture of the impact of these diseases,” said Claire Harrison, DM, of Guy’s and St. Thomas’ NHS Foundation Trust in London, UK.

“The dominating symptom is fatigue, which validates what we are seeing in the clinic. The novel findings regarding the impact on patient’s work life show the consequences of MPNs.”

Dr Harrison and her colleagues reported these findings at the meeting as (abstract 4267*).

The international MPN LANDMARK survey included 699 patients with MPNs (174 with MF, 223 with PV, and 302 with ET), and physicians who treated these conditions across Germany, Italy, UK, Japan, Canada, and Australia.

Patients completed an online questionnaire to measure MPN-related symptoms experienced over the past year and the impact of their condition on quality of life and ability to work.

Patients reported that their disease negatively impacted their ability to complete daily activities by 40%. Patients also noted 35% impairment in their capacity to work. Patients who missed work over the last 7 days due to illness reported missing an average of 3.1 hours due to their disease and/or symptom burden.

“For one quarter of PV patients, the disease stopped them from working, and another one quarter voluntarily reduced their work time,” Dr Harrison said. “This was surprising. Even though their disease was managed, it impacted their work life.”

She noted that many of her PV patients are young, working professionals.

Results also showed that about three-quarters of patients who experienced symptoms suffered a significant reduction in quality of life due to symptoms (83% of MF patients, 72% of PV patients, and 74% of ET patients).

These results are consistent with those from a previous US LANDMARK survey of MPN patients.

The most commonly reported symptom in the last 12 months was fatigue (54% of MF patients, 45% of PV patients, and 64% of ET patients). This was also the symptom patients stated they most wanted to resolve.

“Patients stated doctors often don’t ask enough about the details of symptoms,” Dr Harrison said.

In addition to physical symptoms, about one-third of patients felt anxious or worried about their disease (34% of MF patients, 29% of PV patients, and 26% of ET patients).

“We found a mismatch in aspirations of MPN patients and their physicians,” Dr Harrison said. “For example, physicians said it was important to teach PV patients to prevent blood clots. PV patients were more concerned with having a better quality of life and slowing disease progression.”

A comprehensive symptom assessment is important to help physicians understand other hardships of these diseases, she said, noting “in our service, we enlist nutritionists and psychologists and also use physiotherapists and occupational therapists.”

*Information presented at the meeting differs from the abstract.

Francois-Xavier Mahon, MD, PhD

© Todd Buchanan 2016

SAN DIEGO—Updated results of the EURO-SKI trial support the idea that certain chronic myeloid leukemia (CML) patients can safely stop tyrosine kinase inhibitor (TKI) therapy.

About half of the patients studied, who had been in deep molecular remission for at least 1 year, had no evidence of relapse for at least 1 year after stopping TKI therapy.

Francis-Xavier Mahon, MD, PhD, of the Bergonie Cancer Center at the University of Bordeaux in France, presented this finding at the 2016 ASH Annual Meeting (abstract 787*).

Stopping treatment is an emerging goal of CML management. Several studies have demonstrated the feasibility of stopping treatment, and consistent results over time have validated the concept of treatment-free remission (TFR), Dr Mahon said.

“A sustained deep molecular response on long-term TKI therapy seems to be necessary prior to attempting TFR,” he noted. “However, the exact preconditions for stopping CML treatments are not yet defined.”

Dr Mahon and his colleagues studied 821 chronic phase CML patients treated with TKIs (imatinib, dasatinib, or nilotinib) for at least 3 years. The patients were in deep molecular remission (MR4) for at least a year.

Dr Mahon reported on an intention-to-stop-treatment analysis of 755 patients. Their median age at diagnosis was 52 years, median time from diagnosis to stopping TKI therapy was 7.7 years, median duration of TKI therapy was 7.4 years, and median duration of deep molecular remission before stopping TKI therapy was 4.7 years.

At a median follow-up of 14.9 months, about half of patients (378/755) were still alive and in major molecular response. Molecular recurrence-free survival was 61% at 6 months, 55% at 12 months, 52% at 18 months, 50% at 24 months, and 47% at 36 months.

Most loss of molecular response came within the first 6 months after stopping treatment. Most patients regained their previous remission level after resuming TKI therapy, and no study participants progressed to a dangerous state of advanced disease.

Dr Mahon noted that longer duration of imatinib therapy prior to stopping TKIs, optimally 5.8 years or longer, correlates to a higher probability of relapse-free survival. Gender, age, and other variables, such as Sokal scores, do not predict the probability of successful stopping.

“With inclusion and relapse criteria less strict than in many previous trials, and with decentralized but standardized PCR monitoring, stopping of TKI therapy in a large cohort of CML patients appears feasible and safe,” Dr Mahon said. “This trial demonstrates that half of patients are still off treatment without molecular recurrence after a median 15 months.”

Current guidelines recommend that most patients who achieve remission with TKI therapy continue taking the drugs indefinitely, yet it is unclear whether continued therapy is necessary for all patients.

The European Leukemia Net are expected to propose new guidelines in the next 6 months, which Dr Mahon hopes will define a consensus regarding durability of TKI therapy and provide recommendations on whether stopping TKIs can be moved into the clinic for appropriate patients.

*Information presented at the meeting differs from the abstract.

Francois-Xavier Mahon, MD, PhD

© Todd Buchanan 2016

SAN DIEGO—Updated results of the EURO-SKI trial support the idea that certain chronic myeloid leukemia (CML) patients can safely stop tyrosine kinase inhibitor (TKI) therapy.

About half of the patients studied, who had been in deep molecular remission for at least 1 year, had no evidence of relapse for at least 1 year after stopping TKI therapy.

Francis-Xavier Mahon, MD, PhD, of the Bergonie Cancer Center at the University of Bordeaux in France, presented this finding at the 2016 ASH Annual Meeting (abstract 787*).

Stopping treatment is an emerging goal of CML management. Several studies have demonstrated the feasibility of stopping treatment, and consistent results over time have validated the concept of treatment-free remission (TFR), Dr Mahon said.

“A sustained deep molecular response on long-term TKI therapy seems to be necessary prior to attempting TFR,” he noted. “However, the exact preconditions for stopping CML treatments are not yet defined.”

Dr Mahon and his colleagues studied 821 chronic phase CML patients treated with TKIs (imatinib, dasatinib, or nilotinib) for at least 3 years. The patients were in deep molecular remission (MR4) for at least a year.

Dr Mahon reported on an intention-to-stop-treatment analysis of 755 patients. Their median age at diagnosis was 52 years, median time from diagnosis to stopping TKI therapy was 7.7 years, median duration of TKI therapy was 7.4 years, and median duration of deep molecular remission before stopping TKI therapy was 4.7 years.

At a median follow-up of 14.9 months, about half of patients (378/755) were still alive and in major molecular response. Molecular recurrence-free survival was 61% at 6 months, 55% at 12 months, 52% at 18 months, 50% at 24 months, and 47% at 36 months.

Most loss of molecular response came within the first 6 months after stopping treatment. Most patients regained their previous remission level after resuming TKI therapy, and no study participants progressed to a dangerous state of advanced disease.

Dr Mahon noted that longer duration of imatinib therapy prior to stopping TKIs, optimally 5.8 years or longer, correlates to a higher probability of relapse-free survival. Gender, age, and other variables, such as Sokal scores, do not predict the probability of successful stopping.

“With inclusion and relapse criteria less strict than in many previous trials, and with decentralized but standardized PCR monitoring, stopping of TKI therapy in a large cohort of CML patients appears feasible and safe,” Dr Mahon said. “This trial demonstrates that half of patients are still off treatment without molecular recurrence after a median 15 months.”

Current guidelines recommend that most patients who achieve remission with TKI therapy continue taking the drugs indefinitely, yet it is unclear whether continued therapy is necessary for all patients.

The European Leukemia Net are expected to propose new guidelines in the next 6 months, which Dr Mahon hopes will define a consensus regarding durability of TKI therapy and provide recommendations on whether stopping TKIs can be moved into the clinic for appropriate patients.

*Information presented at the meeting differs from the abstract.

Francois-Xavier Mahon, MD, PhD

© Todd Buchanan 2016

SAN DIEGO—Updated results of the EURO-SKI trial support the idea that certain chronic myeloid leukemia (CML) patients can safely stop tyrosine kinase inhibitor (TKI) therapy.

About half of the patients studied, who had been in deep molecular remission for at least 1 year, had no evidence of relapse for at least 1 year after stopping TKI therapy.

Francis-Xavier Mahon, MD, PhD, of the Bergonie Cancer Center at the University of Bordeaux in France, presented this finding at the 2016 ASH Annual Meeting (abstract 787*).

Stopping treatment is an emerging goal of CML management. Several studies have demonstrated the feasibility of stopping treatment, and consistent results over time have validated the concept of treatment-free remission (TFR), Dr Mahon said.

“A sustained deep molecular response on long-term TKI therapy seems to be necessary prior to attempting TFR,” he noted. “However, the exact preconditions for stopping CML treatments are not yet defined.”

Dr Mahon and his colleagues studied 821 chronic phase CML patients treated with TKIs (imatinib, dasatinib, or nilotinib) for at least 3 years. The patients were in deep molecular remission (MR4) for at least a year.

Dr Mahon reported on an intention-to-stop-treatment analysis of 755 patients. Their median age at diagnosis was 52 years, median time from diagnosis to stopping TKI therapy was 7.7 years, median duration of TKI therapy was 7.4 years, and median duration of deep molecular remission before stopping TKI therapy was 4.7 years.

At a median follow-up of 14.9 months, about half of patients (378/755) were still alive and in major molecular response. Molecular recurrence-free survival was 61% at 6 months, 55% at 12 months, 52% at 18 months, 50% at 24 months, and 47% at 36 months.

Most loss of molecular response came within the first 6 months after stopping treatment. Most patients regained their previous remission level after resuming TKI therapy, and no study participants progressed to a dangerous state of advanced disease.

Dr Mahon noted that longer duration of imatinib therapy prior to stopping TKIs, optimally 5.8 years or longer, correlates to a higher probability of relapse-free survival. Gender, age, and other variables, such as Sokal scores, do not predict the probability of successful stopping.

“With inclusion and relapse criteria less strict than in many previous trials, and with decentralized but standardized PCR monitoring, stopping of TKI therapy in a large cohort of CML patients appears feasible and safe,” Dr Mahon said. “This trial demonstrates that half of patients are still off treatment without molecular recurrence after a median 15 months.”

Current guidelines recommend that most patients who achieve remission with TKI therapy continue taking the drugs indefinitely, yet it is unclear whether continued therapy is necessary for all patients.

The European Leukemia Net are expected to propose new guidelines in the next 6 months, which Dr Mahon hopes will define a consensus regarding durability of TKI therapy and provide recommendations on whether stopping TKIs can be moved into the clinic for appropriate patients.

*Information presented at the meeting differs from the abstract.

SAN DIEGO – It took a clinical trial with a byzantine design to prove it, but neither posttransplant consolidation therapy nor second transplant offered any additional survival benefits to patients with multiple myeloma, including patients with high-risk disease who were treated with an upfront thalidomide analogue and a proteasome inhibitor, followed by stem cell transplant and lenalidomide maintenance.

Among 758 patients with multiple myeloma who underwent standard induction therapy, followed by melphalan conditioning and autologous stem cell transplant (ASCT), there were no differences in either progression-free survival (PFS) or overall survival (OS) among patients assigned to follow-on therapy with either lenalidomide (Revlimid) maintenance alone; consolidation therapy with four cycles of lenalidomide (Revlimid), bortezomib (Velcade), and dexamethasone (RVD), followed by lenalidomide maintenance; or second transplant, followed by lenalidomide maintenance, reported  Edward A. Stadtmauer, MD, coleader of the hematologic malignancies program at the Abramson Cancer Center, and chief of the section of hematologic malignancies, University of Pennsylvania, Philadelphia.

Neil Osterweil/Frontline Medical News

SAN DIEGO – It took a clinical trial with a byzantine design to prove it, but neither posttransplant consolidation therapy nor second transplant offered any additional survival benefits to patients with multiple myeloma, including patients with high-risk disease who were treated with an upfront thalidomide analogue and a proteasome inhibitor, followed by stem cell transplant and lenalidomide maintenance.

Among 758 patients with multiple myeloma who underwent standard induction therapy, followed by melphalan conditioning and autologous stem cell transplant (ASCT), there were no differences in either progression-free survival (PFS) or overall survival (OS) among patients assigned to follow-on therapy with either lenalidomide (Revlimid) maintenance alone; consolidation therapy with four cycles of lenalidomide (Revlimid), bortezomib (Velcade), and dexamethasone (RVD), followed by lenalidomide maintenance; or second transplant, followed by lenalidomide maintenance, reported  Edward A. Stadtmauer, MD, coleader of the hematologic malignancies program at the Abramson Cancer Center, and chief of the section of hematologic malignancies, University of Pennsylvania, Philadelphia.

Neil Osterweil/Frontline Medical News

SAN DIEGO – It took a clinical trial with a byzantine design to prove it, but neither posttransplant consolidation therapy nor second transplant offered any additional survival benefits to patients with multiple myeloma, including patients with high-risk disease who were treated with an upfront thalidomide analogue and a proteasome inhibitor, followed by stem cell transplant and lenalidomide maintenance.

Among 758 patients with multiple myeloma who underwent standard induction therapy, followed by melphalan conditioning and autologous stem cell transplant (ASCT), there were no differences in either progression-free survival (PFS) or overall survival (OS) among patients assigned to follow-on therapy with either lenalidomide (Revlimid) maintenance alone; consolidation therapy with four cycles of lenalidomide (Revlimid), bortezomib (Velcade), and dexamethasone (RVD), followed by lenalidomide maintenance; or second transplant, followed by lenalidomide maintenance, reported  Edward A. Stadtmauer, MD, coleader of the hematologic malignancies program at the Abramson Cancer Center, and chief of the section of hematologic malignancies, University of Pennsylvania, Philadelphia.

Neil Osterweil/Frontline Medical News

SAN DIEGO – Using less than a drop of blood, a portable microsensor provided a comprehensive coagulation profile in minutes and perfectly distinguished various coagulopathies from normal blood samples – handily beating both activated partial thromboplastin time (aPTT) and prothrombin time (PT).

Dubbed ClotChip, the disposable device detects coagulation factors and platelet activity by using a technique called dielectric spectroscopy, Evi X. Stavrou, MD, of Case Western Reserve University, Cleveland, said in a video interview at the annual meeting of the American Society of Hematology. It points the way for comprehensive, rapid, point-of-care assessment of critically ill or severely injured patients and those who need ongoing monitoring to evaluate response to anticoagulant therapy, she added.

By plotting rates of true positives (patients with coagulopathies) against rates of true negatives (controls), the researchers obtained areas under the receiver operating curves of 100% for ClotChip, 78% for aPTT, and 57% for PT. In other words, ClotChip correctly identified all cases and controls in this small patient cohort, which neither aPTT or PT did.

Dr. Stavrou and her coinvestigators had no relevant financial disclosures.

SAN DIEGO – Using less than a drop of blood, a portable microsensor provided a comprehensive coagulation profile in minutes and perfectly distinguished various coagulopathies from normal blood samples – handily beating both activated partial thromboplastin time (aPTT) and prothrombin time (PT).

Dubbed ClotChip, the disposable device detects coagulation factors and platelet activity by using a technique called dielectric spectroscopy, Evi X. Stavrou, MD, of Case Western Reserve University, Cleveland, said in a video interview at the annual meeting of the American Society of Hematology. It points the way for comprehensive, rapid, point-of-care assessment of critically ill or severely injured patients and those who need ongoing monitoring to evaluate response to anticoagulant therapy, she added.

By plotting rates of true positives (patients with coagulopathies) against rates of true negatives (controls), the researchers obtained areas under the receiver operating curves of 100% for ClotChip, 78% for aPTT, and 57% for PT. In other words, ClotChip correctly identified all cases and controls in this small patient cohort, which neither aPTT or PT did.

Dr. Stavrou and her coinvestigators had no relevant financial disclosures.

SAN DIEGO – Using less than a drop of blood, a portable microsensor provided a comprehensive coagulation profile in minutes and perfectly distinguished various coagulopathies from normal blood samples – handily beating both activated partial thromboplastin time (aPTT) and prothrombin time (PT).

Dubbed ClotChip, the disposable device detects coagulation factors and platelet activity by using a technique called dielectric spectroscopy, Evi X. Stavrou, MD, of Case Western Reserve University, Cleveland, said in a video interview at the annual meeting of the American Society of Hematology. It points the way for comprehensive, rapid, point-of-care assessment of critically ill or severely injured patients and those who need ongoing monitoring to evaluate response to anticoagulant therapy, she added.

By plotting rates of true positives (patients with coagulopathies) against rates of true negatives (controls), the researchers obtained areas under the receiver operating curves of 100% for ClotChip, 78% for aPTT, and 57% for PT. In other words, ClotChip correctly identified all cases and controls in this small patient cohort, which neither aPTT or PT did.

Dr. Stavrou and her coinvestigators had no relevant financial disclosures.