CKT more important than del(17p) in CLL, group finds

SAN FRANCISCO—New research suggests complex metaphase karyotype (CKT) is a stronger predictor of inferior outcome than 17p deletion in patients with relapsed or refractory chronic lymphocytic leukemia (CLL) who are treated with the BTK inhibitor ibrutinib.

The study showed that CKT, defined as 3 or more distinct chromosomal abnormalities, was independently associated with inferior event-free survival (EFS) and overall survival (OS), but del(17p) was not.

According to investigators, this suggests that del(17p) patients without CKT could be managed with long-term ibrutinib and close monitoring, as these patients have similar outcomes as patients without del(17p).

However, patients with CKT will likely require treatment-intensification strategies after ibrutinib-based therapy.

“We believe that patients with a complex karyotype represent an ideal group in whom to study novel treatment approaches, including ibrutinib-based combination regimens and/or consolidated approaches after initial ibrutinib response,” said investigator Philip A. Thompson, MBBS, of the University of Texas MD Anderson Cancer Center in Houston.

Dr Thompson presented his group’s findings at the 2014 ASH Annual Meeting as abstract 22.* Investigators involved in this study received research funding or consultancy fees from Pharmacyclics, Inc., makers of ibrutinib.

Patient characteristics

Dr Thompson and his colleagues analyzed 100 patients with relapsed/refractory CLL who received treatment with ibrutinib-based regimens—50 with ibrutinib alone, 36 with ibrutinib and rituximab, and 14 with ibrutinib, rituximab, and bendamustine.

The median age was 65 (range, 35-83), patients received a median of 2 prior therapies (range, 1-12), and 19% were fludarabine-refractory. Sixty percent of patients had Rai stage III-IV disease, 52% had bulky adenopathy, 81% had unmutated IGHV, and 56% had β2-microglobulin ≥ 4.0 mg/L.

FISH was available for 94 patients, and metaphase analysis was available for 65 patients. Forty-two percent (27/65) of patients had CKT, 28% (26/94) had del(11q), and 48% (45/94) had del(17p).

Of the 45 patients who had del(17p), 23 also had CKT. And of the 49 patients who did not have del(17p), 4 had CKT.

Event-free survival

The median follow-up in surviving patients was 27 months (range, 11-48). Eight patients had planned allogeneic stem cell transplant and were censored for the EFS analysis.

“As has been shown previously, patients with 17p deletion by FISH did have inferior event-free survival,” Dr Thompson said. “And when we looked at those patients with complex metaphase karyotype, there was a highly significant inferior event-free survival in these patients, compared to those with complex karyotype.”

EFS was 78% in patients with neither del(17p) nor del(11q), 69% in patients with del(11q), and 60% in patients with del(17p) (P=0.014).

EFS was 82% in patients without CKT and 44% in those with CKT (P<0.0001). In patients with del(17p), EFS was 78% in those without CKT and 48% in those with CKT (P=0.047).

In patients without CKT, EFS was 79% in those without del(17p) or del(11q), 90% in those with del(11q), and 78% in those with del(17p) (P=0.516).

“Interestingly, when we looked at the events that occurred in those patients without complex karyotype, none were due to CLL progression or Richter’s transformation,” Dr Thompson said.

In multivariable analysis, CKT was significantly associated with EFS (P=0.011), but del(17p) was not (P=0.887).

Overall survival

There was no significant difference in OS according to the presence of del(17p) or del(11q). OS was 87% in patients with neither del(17p) nor del(11q), 81% in patients with del(11q), and 67% in patients with del(17p) (P=0.054).

However, there was a significant difference in OS for patients with and without CKT. OS was 82% in patients without CKT and 56% in patients with CKT (P=0.006).

Among patients without CKT, OS was 84% in those with neither del(17p) nor del(11q), 80% in those with del(11q), and 78% in those with del(17p) (P=0.52).

In multivariable analysis, OS was significantly associated with CKT (P=0.011) and fludarabine-refractory disease (P=0.004) but not del(17p) (P=0.981).

“So, in summary, complex karyotype appears to be a more important predictor of outcomes in patients with relapsed or refractory CLL treated with ibrutinib-based regimens than the presence of del(17p) by FISH,” Dr Thompson said.

“Patients without complex karyotype have a low rate of disease progression, including those who have del(17p). Most progressions during ibrutinib therapy occur late, beyond the 12-month time point, but survival is short after disease progression.”

*Information in the abstract differs from that presented at the meeting.

SAN FRANCISCO—New research suggests complex metaphase karyotype (CKT) is a stronger predictor of inferior outcome than 17p deletion in patients with relapsed or refractory chronic lymphocytic leukemia (CLL) who are treated with the BTK inhibitor ibrutinib.

The study showed that CKT, defined as 3 or more distinct chromosomal abnormalities, was independently associated with inferior event-free survival (EFS) and overall survival (OS), but del(17p) was not.

According to investigators, this suggests that del(17p) patients without CKT could be managed with long-term ibrutinib and close monitoring, as these patients have similar outcomes as patients without del(17p).

However, patients with CKT will likely require treatment-intensification strategies after ibrutinib-based therapy.

“We believe that patients with a complex karyotype represent an ideal group in whom to study novel treatment approaches, including ibrutinib-based combination regimens and/or consolidated approaches after initial ibrutinib response,” said investigator Philip A. Thompson, MBBS, of the University of Texas MD Anderson Cancer Center in Houston.

Dr Thompson presented his group’s findings at the 2014 ASH Annual Meeting as abstract 22.* Investigators involved in this study received research funding or consultancy fees from Pharmacyclics, Inc., makers of ibrutinib.

Patient characteristics

Dr Thompson and his colleagues analyzed 100 patients with relapsed/refractory CLL who received treatment with ibrutinib-based regimens—50 with ibrutinib alone, 36 with ibrutinib and rituximab, and 14 with ibrutinib, rituximab, and bendamustine.

The median age was 65 (range, 35-83), patients received a median of 2 prior therapies (range, 1-12), and 19% were fludarabine-refractory. Sixty percent of patients had Rai stage III-IV disease, 52% had bulky adenopathy, 81% had unmutated IGHV, and 56% had β2-microglobulin ≥ 4.0 mg/L.

FISH was available for 94 patients, and metaphase analysis was available for 65 patients. Forty-two percent (27/65) of patients had CKT, 28% (26/94) had del(11q), and 48% (45/94) had del(17p).

Of the 45 patients who had del(17p), 23 also had CKT. And of the 49 patients who did not have del(17p), 4 had CKT.

Event-free survival

The median follow-up in surviving patients was 27 months (range, 11-48). Eight patients had planned allogeneic stem cell transplant and were censored for the EFS analysis.

“As has been shown previously, patients with 17p deletion by FISH did have inferior event-free survival,” Dr Thompson said. “And when we looked at those patients with complex metaphase karyotype, there was a highly significant inferior event-free survival in these patients, compared to those with complex karyotype.”

EFS was 78% in patients with neither del(17p) nor del(11q), 69% in patients with del(11q), and 60% in patients with del(17p) (P=0.014).

EFS was 82% in patients without CKT and 44% in those with CKT (P<0.0001). In patients with del(17p), EFS was 78% in those without CKT and 48% in those with CKT (P=0.047).

In patients without CKT, EFS was 79% in those without del(17p) or del(11q), 90% in those with del(11q), and 78% in those with del(17p) (P=0.516).

“Interestingly, when we looked at the events that occurred in those patients without complex karyotype, none were due to CLL progression or Richter’s transformation,” Dr Thompson said.

In multivariable analysis, CKT was significantly associated with EFS (P=0.011), but del(17p) was not (P=0.887).

Overall survival

There was no significant difference in OS according to the presence of del(17p) or del(11q). OS was 87% in patients with neither del(17p) nor del(11q), 81% in patients with del(11q), and 67% in patients with del(17p) (P=0.054).

However, there was a significant difference in OS for patients with and without CKT. OS was 82% in patients without CKT and 56% in patients with CKT (P=0.006).

Among patients without CKT, OS was 84% in those with neither del(17p) nor del(11q), 80% in those with del(11q), and 78% in those with del(17p) (P=0.52).

In multivariable analysis, OS was significantly associated with CKT (P=0.011) and fludarabine-refractory disease (P=0.004) but not del(17p) (P=0.981).

“So, in summary, complex karyotype appears to be a more important predictor of outcomes in patients with relapsed or refractory CLL treated with ibrutinib-based regimens than the presence of del(17p) by FISH,” Dr Thompson said.

“Patients without complex karyotype have a low rate of disease progression, including those who have del(17p). Most progressions during ibrutinib therapy occur late, beyond the 12-month time point, but survival is short after disease progression.”

*Information in the abstract differs from that presented at the meeting.

SAN FRANCISCO—New research suggests complex metaphase karyotype (CKT) is a stronger predictor of inferior outcome than 17p deletion in patients with relapsed or refractory chronic lymphocytic leukemia (CLL) who are treated with the BTK inhibitor ibrutinib.

The study showed that CKT, defined as 3 or more distinct chromosomal abnormalities, was independently associated with inferior event-free survival (EFS) and overall survival (OS), but del(17p) was not.

According to investigators, this suggests that del(17p) patients without CKT could be managed with long-term ibrutinib and close monitoring, as these patients have similar outcomes as patients without del(17p).

However, patients with CKT will likely require treatment-intensification strategies after ibrutinib-based therapy.

“We believe that patients with a complex karyotype represent an ideal group in whom to study novel treatment approaches, including ibrutinib-based combination regimens and/or consolidated approaches after initial ibrutinib response,” said investigator Philip A. Thompson, MBBS, of the University of Texas MD Anderson Cancer Center in Houston.

Dr Thompson presented his group’s findings at the 2014 ASH Annual Meeting as abstract 22.* Investigators involved in this study received research funding or consultancy fees from Pharmacyclics, Inc., makers of ibrutinib.

Patient characteristics

Dr Thompson and his colleagues analyzed 100 patients with relapsed/refractory CLL who received treatment with ibrutinib-based regimens—50 with ibrutinib alone, 36 with ibrutinib and rituximab, and 14 with ibrutinib, rituximab, and bendamustine.

The median age was 65 (range, 35-83), patients received a median of 2 prior therapies (range, 1-12), and 19% were fludarabine-refractory. Sixty percent of patients had Rai stage III-IV disease, 52% had bulky adenopathy, 81% had unmutated IGHV, and 56% had β2-microglobulin ≥ 4.0 mg/L.

FISH was available for 94 patients, and metaphase analysis was available for 65 patients. Forty-two percent (27/65) of patients had CKT, 28% (26/94) had del(11q), and 48% (45/94) had del(17p).

Of the 45 patients who had del(17p), 23 also had CKT. And of the 49 patients who did not have del(17p), 4 had CKT.

Event-free survival

The median follow-up in surviving patients was 27 months (range, 11-48). Eight patients had planned allogeneic stem cell transplant and were censored for the EFS analysis.

“As has been shown previously, patients with 17p deletion by FISH did have inferior event-free survival,” Dr Thompson said. “And when we looked at those patients with complex metaphase karyotype, there was a highly significant inferior event-free survival in these patients, compared to those with complex karyotype.”

EFS was 78% in patients with neither del(17p) nor del(11q), 69% in patients with del(11q), and 60% in patients with del(17p) (P=0.014).

EFS was 82% in patients without CKT and 44% in those with CKT (P<0.0001). In patients with del(17p), EFS was 78% in those without CKT and 48% in those with CKT (P=0.047).

In patients without CKT, EFS was 79% in those without del(17p) or del(11q), 90% in those with del(11q), and 78% in those with del(17p) (P=0.516).

“Interestingly, when we looked at the events that occurred in those patients without complex karyotype, none were due to CLL progression or Richter’s transformation,” Dr Thompson said.

In multivariable analysis, CKT was significantly associated with EFS (P=0.011), but del(17p) was not (P=0.887).

Overall survival

There was no significant difference in OS according to the presence of del(17p) or del(11q). OS was 87% in patients with neither del(17p) nor del(11q), 81% in patients with del(11q), and 67% in patients with del(17p) (P=0.054).

However, there was a significant difference in OS for patients with and without CKT. OS was 82% in patients without CKT and 56% in patients with CKT (P=0.006).

Among patients without CKT, OS was 84% in those with neither del(17p) nor del(11q), 80% in those with del(11q), and 78% in those with del(17p) (P=0.52).

In multivariable analysis, OS was significantly associated with CKT (P=0.011) and fludarabine-refractory disease (P=0.004) but not del(17p) (P=0.981).

“So, in summary, complex karyotype appears to be a more important predictor of outcomes in patients with relapsed or refractory CLL treated with ibrutinib-based regimens than the presence of del(17p) by FISH,” Dr Thompson said.

“Patients without complex karyotype have a low rate of disease progression, including those who have del(17p). Most progressions during ibrutinib therapy occur late, beyond the 12-month time point, but survival is short after disease progression.”

*Information in the abstract differs from that presented at the meeting.