Drugs don’t play well together in MF

Prescription medications

Photo courtesy of the CDC

Simultaneous administration of lenalidomide and ruxolitinib is not feasible in patients with myelofibrosis (MF), according to research published in haematologica.

Investigators said administering the drugs together proved difficult. Most patients had to stop taking lenalidomide at some point, and many did not restart the drug.

In addition, the study did not meet the predetermined efficacy criteria and was therefore terminated early.

Still, the investigators noted that 17 of 31 patients did respond to treatment, and 10 patients were still taking both drugs at the time of analysis.

The team therefore believes a sequential rather than concomitant treatment approach might work with this combination or for other agents to be combined with ruxolitinib.

Srdan Verstovsek, MD, PhD, of the MD Anderson Cancer Center in Houston, Texas, and his colleagues conducted this research. It was supported by Incyte Corporation (the company developing ruxolitinib) and MD Anderson.

The investigators initiated this study to determine if lenalidomide and ruxolitinib in combination would target distinct clinical and pathological manifestations of MF and prevent treatment-related decreases in blood counts.

They studied the combination in 31 patients with primary MF (n=15), post-polycythemia vera MF (n=12), or post-essential thrombocythemia MF (n=4). The patients’ median age was 66 (range, 37-82), and 21 had received prior treatments (range, 1-3).

The patients received ruxolitinib at 15 mg twice daily in continuous, 28-day cycles, plus 5 mg of lenalidomide once daily on days 1-21. The median follow-up was 28 months (range, 12-35+).

Dosing troubles

In all, 23 patients required dose interruptions of lenalidomide, with or without a dose decrease due to toxicity. Twenty of these interruptions occurred within the first 3 months of therapy, and 14 of the patients never restarted treatment with lenalidomide.

The reasons for dose interruption (or, ultimately, discontinuation) were low platelet count (n=8), low absolute neutrophil count (n=3), anemia (n=3), diarrhea (n=3), financial constraints (n=2), deep vein thrombosis (n=1), skin rash (n=1), transaminitis (n=1), and arthralgia/fever (n=1).

Conversely, 6 patients required an increased dose of ruxolitinib, 3 within the first 3 months. Doses were increased due to leukocytosis (n=2), suboptimal response (n=2), thrombocytosis (n=1), and progressive splenomegaly (n=1).

Discontinuation and early termination

At a median follow-up of 28 months, 25 patients (81%) were still alive, and 16 remained on study. Ten of these patients were taking both drugs, and 6 were taking ruxolitinib only.

For the 15 patients who came off the study, their reasons included concurrent disease (n=3), disease progression (n=2), myelosuppression (n=2), refractory disease (n=3), toxicities (n=2), persistent and severe lower-extremity cellulitis (n=1), non-compliance (n=1), and financial reasons (n=1).

The investigators noted that only 7 patients met the predetermined definition of efficacy—a response to combination treatment within 6 months of initiation without discontinuing either drug.

For the study to continue after the interim analysis, more than 10 patients would have to fulfill those criteria. As they did not, the study was terminated early.

Response

Seventeen patients (55%) achieved an IWG-MRT-defined response of clinical improvement in palpable spleen size. Seven patients had a 100% spleen reduction, and 10 had reduction of 50% or greater.

The median time to clinical improvement in spleen size was 1.8 months (range, 0.4-31), and the median duration of this response was 19 months (range, 3-32+). At last follow-up, 2 patients had lost their response.

One of the 17 spleen responders also achieved an IWG-MRT-defined clinical improvement in hemoglobin (increase of 2 g/dL or greater that was maintained for more than 8 weeks). The time to this response was 28 months, and the response lasted 6 months.

There were differences in response rate, response duration, time to response, and overall survival between patients who required dose interruptions and those who did not. However, none of these differences were statistically significant.

Toxicity

Grade 3/4 myelosuppression occurred in 16 patients, and there was 1 case of lower-extremity thrombosis. The most common non-hematologic adverse events (AEs) were diarrhea (n=8), nausea and vomiting (n=3), abdominal pain (n=3), and constipation (n=3).

Five patients had grade 3/4 non-hematologic AEs—diarrhea, edema, transaminitis, bilirubinemia, and acute kidney injury. Two patients discontinued treatment due to drug-related AEs—grade 2 persistent nausea and grade 3 diarrhea.

Three of the 6 deaths were documented (including 2 that occurred on-study). They were attributed to pneumonia, kidney failure, and possible stroke.

Prescription medications

Photo courtesy of the CDC

Simultaneous administration of lenalidomide and ruxolitinib is not feasible in patients with myelofibrosis (MF), according to research published in haematologica.

Investigators said administering the drugs together proved difficult. Most patients had to stop taking lenalidomide at some point, and many did not restart the drug.

In addition, the study did not meet the predetermined efficacy criteria and was therefore terminated early.

Still, the investigators noted that 17 of 31 patients did respond to treatment, and 10 patients were still taking both drugs at the time of analysis.

The team therefore believes a sequential rather than concomitant treatment approach might work with this combination or for other agents to be combined with ruxolitinib.

Srdan Verstovsek, MD, PhD, of the MD Anderson Cancer Center in Houston, Texas, and his colleagues conducted this research. It was supported by Incyte Corporation (the company developing ruxolitinib) and MD Anderson.

The investigators initiated this study to determine if lenalidomide and ruxolitinib in combination would target distinct clinical and pathological manifestations of MF and prevent treatment-related decreases in blood counts.

They studied the combination in 31 patients with primary MF (n=15), post-polycythemia vera MF (n=12), or post-essential thrombocythemia MF (n=4). The patients’ median age was 66 (range, 37-82), and 21 had received prior treatments (range, 1-3).

The patients received ruxolitinib at 15 mg twice daily in continuous, 28-day cycles, plus 5 mg of lenalidomide once daily on days 1-21. The median follow-up was 28 months (range, 12-35+).

Dosing troubles

In all, 23 patients required dose interruptions of lenalidomide, with or without a dose decrease due to toxicity. Twenty of these interruptions occurred within the first 3 months of therapy, and 14 of the patients never restarted treatment with lenalidomide.

The reasons for dose interruption (or, ultimately, discontinuation) were low platelet count (n=8), low absolute neutrophil count (n=3), anemia (n=3), diarrhea (n=3), financial constraints (n=2), deep vein thrombosis (n=1), skin rash (n=1), transaminitis (n=1), and arthralgia/fever (n=1).

Conversely, 6 patients required an increased dose of ruxolitinib, 3 within the first 3 months. Doses were increased due to leukocytosis (n=2), suboptimal response (n=2), thrombocytosis (n=1), and progressive splenomegaly (n=1).

Discontinuation and early termination

At a median follow-up of 28 months, 25 patients (81%) were still alive, and 16 remained on study. Ten of these patients were taking both drugs, and 6 were taking ruxolitinib only.

For the 15 patients who came off the study, their reasons included concurrent disease (n=3), disease progression (n=2), myelosuppression (n=2), refractory disease (n=3), toxicities (n=2), persistent and severe lower-extremity cellulitis (n=1), non-compliance (n=1), and financial reasons (n=1).

The investigators noted that only 7 patients met the predetermined definition of efficacy—a response to combination treatment within 6 months of initiation without discontinuing either drug.

For the study to continue after the interim analysis, more than 10 patients would have to fulfill those criteria. As they did not, the study was terminated early.

Response

Seventeen patients (55%) achieved an IWG-MRT-defined response of clinical improvement in palpable spleen size. Seven patients had a 100% spleen reduction, and 10 had reduction of 50% or greater.

The median time to clinical improvement in spleen size was 1.8 months (range, 0.4-31), and the median duration of this response was 19 months (range, 3-32+). At last follow-up, 2 patients had lost their response.

One of the 17 spleen responders also achieved an IWG-MRT-defined clinical improvement in hemoglobin (increase of 2 g/dL or greater that was maintained for more than 8 weeks). The time to this response was 28 months, and the response lasted 6 months.

There were differences in response rate, response duration, time to response, and overall survival between patients who required dose interruptions and those who did not. However, none of these differences were statistically significant.

Toxicity

Grade 3/4 myelosuppression occurred in 16 patients, and there was 1 case of lower-extremity thrombosis. The most common non-hematologic adverse events (AEs) were diarrhea (n=8), nausea and vomiting (n=3), abdominal pain (n=3), and constipation (n=3).

Five patients had grade 3/4 non-hematologic AEs—diarrhea, edema, transaminitis, bilirubinemia, and acute kidney injury. Two patients discontinued treatment due to drug-related AEs—grade 2 persistent nausea and grade 3 diarrhea.

Three of the 6 deaths were documented (including 2 that occurred on-study). They were attributed to pneumonia, kidney failure, and possible stroke.

Prescription medications

Photo courtesy of the CDC

Simultaneous administration of lenalidomide and ruxolitinib is not feasible in patients with myelofibrosis (MF), according to research published in haematologica.

Investigators said administering the drugs together proved difficult. Most patients had to stop taking lenalidomide at some point, and many did not restart the drug.

In addition, the study did not meet the predetermined efficacy criteria and was therefore terminated early.

Still, the investigators noted that 17 of 31 patients did respond to treatment, and 10 patients were still taking both drugs at the time of analysis.

The team therefore believes a sequential rather than concomitant treatment approach might work with this combination or for other agents to be combined with ruxolitinib.

Srdan Verstovsek, MD, PhD, of the MD Anderson Cancer Center in Houston, Texas, and his colleagues conducted this research. It was supported by Incyte Corporation (the company developing ruxolitinib) and MD Anderson.

The investigators initiated this study to determine if lenalidomide and ruxolitinib in combination would target distinct clinical and pathological manifestations of MF and prevent treatment-related decreases in blood counts.

They studied the combination in 31 patients with primary MF (n=15), post-polycythemia vera MF (n=12), or post-essential thrombocythemia MF (n=4). The patients’ median age was 66 (range, 37-82), and 21 had received prior treatments (range, 1-3).

The patients received ruxolitinib at 15 mg twice daily in continuous, 28-day cycles, plus 5 mg of lenalidomide once daily on days 1-21. The median follow-up was 28 months (range, 12-35+).

Dosing troubles

In all, 23 patients required dose interruptions of lenalidomide, with or without a dose decrease due to toxicity. Twenty of these interruptions occurred within the first 3 months of therapy, and 14 of the patients never restarted treatment with lenalidomide.

The reasons for dose interruption (or, ultimately, discontinuation) were low platelet count (n=8), low absolute neutrophil count (n=3), anemia (n=3), diarrhea (n=3), financial constraints (n=2), deep vein thrombosis (n=1), skin rash (n=1), transaminitis (n=1), and arthralgia/fever (n=1).

Conversely, 6 patients required an increased dose of ruxolitinib, 3 within the first 3 months. Doses were increased due to leukocytosis (n=2), suboptimal response (n=2), thrombocytosis (n=1), and progressive splenomegaly (n=1).

Discontinuation and early termination

At a median follow-up of 28 months, 25 patients (81%) were still alive, and 16 remained on study. Ten of these patients were taking both drugs, and 6 were taking ruxolitinib only.

For the 15 patients who came off the study, their reasons included concurrent disease (n=3), disease progression (n=2), myelosuppression (n=2), refractory disease (n=3), toxicities (n=2), persistent and severe lower-extremity cellulitis (n=1), non-compliance (n=1), and financial reasons (n=1).

The investigators noted that only 7 patients met the predetermined definition of efficacy—a response to combination treatment within 6 months of initiation without discontinuing either drug.

For the study to continue after the interim analysis, more than 10 patients would have to fulfill those criteria. As they did not, the study was terminated early.

Response

Seventeen patients (55%) achieved an IWG-MRT-defined response of clinical improvement in palpable spleen size. Seven patients had a 100% spleen reduction, and 10 had reduction of 50% or greater.

The median time to clinical improvement in spleen size was 1.8 months (range, 0.4-31), and the median duration of this response was 19 months (range, 3-32+). At last follow-up, 2 patients had lost their response.

One of the 17 spleen responders also achieved an IWG-MRT-defined clinical improvement in hemoglobin (increase of 2 g/dL or greater that was maintained for more than 8 weeks). The time to this response was 28 months, and the response lasted 6 months.

There were differences in response rate, response duration, time to response, and overall survival between patients who required dose interruptions and those who did not. However, none of these differences were statistically significant.

Toxicity

Grade 3/4 myelosuppression occurred in 16 patients, and there was 1 case of lower-extremity thrombosis. The most common non-hematologic adverse events (AEs) were diarrhea (n=8), nausea and vomiting (n=3), abdominal pain (n=3), and constipation (n=3).

Five patients had grade 3/4 non-hematologic AEs—diarrhea, edema, transaminitis, bilirubinemia, and acute kidney injury. Two patients discontinued treatment due to drug-related AEs—grade 2 persistent nausea and grade 3 diarrhea.

Three of the 6 deaths were documented (including 2 that occurred on-study). They were attributed to pneumonia, kidney failure, and possible stroke.