CLL

Activation of hedgehog (Hh) signaling could predict early disease progression in chronic lymphocytic leukemia (CLL) and offer a new therapeutic target, according to investigators.

Approximately 11% of treatment-naive patients had mutations associated with Hh signaling, reported lead author Emanuela M. Ghia, PhD, of the University of California, San Diego, and colleagues. In addition to early progression, Hh signaling was associated with expression of GLI1, which could be a future therapeutic target. In support of this possibility, in vitro experimentation with a GLI1 inhibitor showed high cytotoxicity for GLI1-positive CLL cells.

“Targeting GLI1 could block ligand-independent and ligand-dependent Hh pathway activation and perhaps overcome the apparent resistance to SMO inhibitors,” the investigators wrote in Blood.

Using the HALT Pan-Leukemia Gene Panel, which includes 103 genes, the investigators tested for mutations in cell samples from 841 patients with treatment-naive CLL. Specifically, the investigators focused on mutations that did not map to seven well-known signaling/metabolic pathways, such as Wnt and Notch.

This strategy revealed that 89 patients (11%) had nonsynonymous mutations in genes that drive Hh signaling. These mutations were highly associated with GLI1 expression (x² test; P less than .0001), which stands to reason, as GLI1 is the main effector of the Hh signaling pathway. Of note, 62 of the 161 patients (38%) who did not test positive for an Hh pathway mutation still tested positive for GLI1, suggesting that they had Hh pathway activation, albeit without an identifiable mutational cause.

These findings are clinically significant, as GLI1 overexpression has been linked to numerous types of cancer and is an adverse prognostic indicator for acute myeloid leukemia and several carcinomas, the investigators wrote.

Considering these associations with other cancer types, the investigators looked for a relationship between GLI1 expression and outcomes in CLL. Comparing 103 patients with GLI1-positive disease with 107 GLI-negative patients revealed that GLI1 positivity was significantly associated with shorter median treatment-free survival (4.7 vs. 6.4 years; P = .002). Additional analysis showed that this prognostic relationship was present regardless of IgVH mutational status.

Based on these findings, the investigators concluded that “[a]ctivation of the Hh pathway can strongly influence disease progression in CLL.”

Two additional tests showed that GLI1-positivity was associated with cell survival. First, silencing GLI1 with a GLI1-specific small interfering RNA led to decreased cell viability. Second, GANT61, a small molecule inhibitor of GLI1, was highly cytotoxic for GLI1-positive cells. According to the investigators, these findings suggest that GLI1 could be a future therapeutic target.

“[T]his report shows that the Hh pathway frequently is activated in CLL and associated with relatively rapid disease progression, while identifying a new avenue for therapeutic intervention for patients with this disease,” they concluded.

The study was funded by the National Institutes of Health, the Cancer Stem Cell Consortium, the Canadian Institutes of Health Research, the Ontario Institute for Cancer Research, and other groups. The investigators reported having no competing financial interests.

SOURCE: Ghia EM et al. Blood. 2019 Jun 20;133(25):2651-63.

Activation of hedgehog (Hh) signaling could predict early disease progression in chronic lymphocytic leukemia (CLL) and offer a new therapeutic target, according to investigators.

Approximately 11% of treatment-naive patients had mutations associated with Hh signaling, reported lead author Emanuela M. Ghia, PhD, of the University of California, San Diego, and colleagues. In addition to early progression, Hh signaling was associated with expression of GLI1, which could be a future therapeutic target. In support of this possibility, in vitro experimentation with a GLI1 inhibitor showed high cytotoxicity for GLI1-positive CLL cells.

“Targeting GLI1 could block ligand-independent and ligand-dependent Hh pathway activation and perhaps overcome the apparent resistance to SMO inhibitors,” the investigators wrote in Blood.

Using the HALT Pan-Leukemia Gene Panel, which includes 103 genes, the investigators tested for mutations in cell samples from 841 patients with treatment-naive CLL. Specifically, the investigators focused on mutations that did not map to seven well-known signaling/metabolic pathways, such as Wnt and Notch.

This strategy revealed that 89 patients (11%) had nonsynonymous mutations in genes that drive Hh signaling. These mutations were highly associated with GLI1 expression (x² test; P less than .0001), which stands to reason, as GLI1 is the main effector of the Hh signaling pathway. Of note, 62 of the 161 patients (38%) who did not test positive for an Hh pathway mutation still tested positive for GLI1, suggesting that they had Hh pathway activation, albeit without an identifiable mutational cause.

These findings are clinically significant, as GLI1 overexpression has been linked to numerous types of cancer and is an adverse prognostic indicator for acute myeloid leukemia and several carcinomas, the investigators wrote.

Considering these associations with other cancer types, the investigators looked for a relationship between GLI1 expression and outcomes in CLL. Comparing 103 patients with GLI1-positive disease with 107 GLI-negative patients revealed that GLI1 positivity was significantly associated with shorter median treatment-free survival (4.7 vs. 6.4 years; P = .002). Additional analysis showed that this prognostic relationship was present regardless of IgVH mutational status.

Based on these findings, the investigators concluded that “[a]ctivation of the Hh pathway can strongly influence disease progression in CLL.”

Two additional tests showed that GLI1-positivity was associated with cell survival. First, silencing GLI1 with a GLI1-specific small interfering RNA led to decreased cell viability. Second, GANT61, a small molecule inhibitor of GLI1, was highly cytotoxic for GLI1-positive cells. According to the investigators, these findings suggest that GLI1 could be a future therapeutic target.

“[T]his report shows that the Hh pathway frequently is activated in CLL and associated with relatively rapid disease progression, while identifying a new avenue for therapeutic intervention for patients with this disease,” they concluded.

The study was funded by the National Institutes of Health, the Cancer Stem Cell Consortium, the Canadian Institutes of Health Research, the Ontario Institute for Cancer Research, and other groups. The investigators reported having no competing financial interests.

SOURCE: Ghia EM et al. Blood. 2019 Jun 20;133(25):2651-63.

Activation of hedgehog (Hh) signaling could predict early disease progression in chronic lymphocytic leukemia (CLL) and offer a new therapeutic target, according to investigators.

Approximately 11% of treatment-naive patients had mutations associated with Hh signaling, reported lead author Emanuela M. Ghia, PhD, of the University of California, San Diego, and colleagues. In addition to early progression, Hh signaling was associated with expression of GLI1, which could be a future therapeutic target. In support of this possibility, in vitro experimentation with a GLI1 inhibitor showed high cytotoxicity for GLI1-positive CLL cells.

“Targeting GLI1 could block ligand-independent and ligand-dependent Hh pathway activation and perhaps overcome the apparent resistance to SMO inhibitors,” the investigators wrote in Blood.

Using the HALT Pan-Leukemia Gene Panel, which includes 103 genes, the investigators tested for mutations in cell samples from 841 patients with treatment-naive CLL. Specifically, the investigators focused on mutations that did not map to seven well-known signaling/metabolic pathways, such as Wnt and Notch.

This strategy revealed that 89 patients (11%) had nonsynonymous mutations in genes that drive Hh signaling. These mutations were highly associated with GLI1 expression (x² test; P less than .0001), which stands to reason, as GLI1 is the main effector of the Hh signaling pathway. Of note, 62 of the 161 patients (38%) who did not test positive for an Hh pathway mutation still tested positive for GLI1, suggesting that they had Hh pathway activation, albeit without an identifiable mutational cause.

These findings are clinically significant, as GLI1 overexpression has been linked to numerous types of cancer and is an adverse prognostic indicator for acute myeloid leukemia and several carcinomas, the investigators wrote.

Considering these associations with other cancer types, the investigators looked for a relationship between GLI1 expression and outcomes in CLL. Comparing 103 patients with GLI1-positive disease with 107 GLI-negative patients revealed that GLI1 positivity was significantly associated with shorter median treatment-free survival (4.7 vs. 6.4 years; P = .002). Additional analysis showed that this prognostic relationship was present regardless of IgVH mutational status.

Based on these findings, the investigators concluded that “[a]ctivation of the Hh pathway can strongly influence disease progression in CLL.”

Two additional tests showed that GLI1-positivity was associated with cell survival. First, silencing GLI1 with a GLI1-specific small interfering RNA led to decreased cell viability. Second, GANT61, a small molecule inhibitor of GLI1, was highly cytotoxic for GLI1-positive cells. According to the investigators, these findings suggest that GLI1 could be a future therapeutic target.

“[T]his report shows that the Hh pathway frequently is activated in CLL and associated with relatively rapid disease progression, while identifying a new avenue for therapeutic intervention for patients with this disease,” they concluded.

The study was funded by the National Institutes of Health, the Cancer Stem Cell Consortium, the Canadian Institutes of Health Research, the Ontario Institute for Cancer Research, and other groups. The investigators reported having no competing financial interests.

SOURCE: Ghia EM et al. Blood. 2019 Jun 20;133(25):2651-63.

CHICAGO – A fixed-duration venetoclax-obinutuzumab regimen is safe and provides a superior outcome versus standard chlorambucil-obinutuzumab in elderly patients with untreated chronic lymphocytic leukemia (CLL) and comorbidities, results of a randomized phase 3 trial showed.

At 24 months, progression-free survival was 88.2% for the venetoclax-obinutuzumab regimen, versus 64.1% for chlorambucil-obinutuzumab (hazard ratio, 0.35; 95% confidence interval, 0.23-0.53; P less than .0001) in CLL-14, an open-label, multinational trial presented at the annual meeting of the American Society of Clinical Oncology.

The regimen, given for just 12 28-day cycles, also achieved the highest rate of minimal residual disease (MRD)-negative responses ever seen in a randomized prospective CLL study, according to investigator Kirsten Fischer, MD, of the University of Cologne in Germany.

“We really think that these unprecedented MRD negativity levels will eventually translate into an improved overall survival,” Dr. Fischer said during an oral abstract presentation.

Matthew Steven Davids, MD, of Dana-Farber Cancer Institute/Harvard Medical School, Boston, said venetoclax plus obinutuzumab offers the potential for 1-year, time-limited therapy, which limits concerns over long-term adherence and has the potential for cost savings, should the therapy prove to be highly durable with further follow-up.

“A limitation of the study is that the comparator arm – chlorambucil plus obinutuzumab – is directly applicable to only a relatively small subset of our older and frailer CLL patients,” Dr. Davids said during a podium discussion of the results.

“But nonetheless, venetoclax plus obinutuzumab is a promising, time-limited regimen, and CLL14 is an immediately practice-changing study for frontline CLL treatment,” he added.

The regimen stands in contrast to ibrutinib, which offers durable responses but requires continuous dosing, and FCR (fludarabine, cyclophosphamide, and rituximab), a time-limited therapy with curative potential that is restricted to younger patients with IGHV-mutated CLL, according to Dr. Davids.

In CLL-14, 432 patients were randomized 1:1 to receive venetoclax-obinutuzumab for six cycles followed by venetoclax for six cycles, or chlorambucil-obinutuzumab for six cycles followed by chlorambucil for six cycles. The median age was 72 years in the venetoclax-obinutuzumab arm and 71 years in the chlorambucil-obinutuzumab arm.

The overall response rate was 85% for venetoclax-obinutuzumab and 71% for chlorambucil-obinutuzumab (P = .0007), Dr. Fischer reported at the meeting.

The improvement in progression-free survival seen in the overall study population was also seen in patients with TP53 deletions or mutations, and in those with unmutated IGHV, Dr. Fischer reported.

Rates of MRD negativity in peripheral blood were 76% versus 35% for the venetoclax- and chlorambucil-containing combinations, respectively (P less than .001), and similarly, MRD negativity in bone marrow was 57% versus 17% (P less than .001), she said.

There were no significant differences in the rates of grade 3 or 4 neutropenia, which occurred in 52.8% of the venetoclax–obinutuzumab treated patients and 48.1% of the chlorambucil-obinutuzumab treated patients, or in grade 3 or 4 infections, which occurred in 17.5% and 15.0%, respectively, according to a report, published simultaneously in the New England Journal of Medicine (2019;380:2225-36).

Likewise, all-cause mortality was not significantly different between the arms, at 9.3% and 7.9%, respectively.

F. Hoffmann-La Roche and AbbVie supported the study. Dr. Fischer reported travel, accommodations, or expenses from Roche in her abstract disclosure.

SOURCE: Fischer K et al. ASCO 2019, Abstract 7502.

CHICAGO – A fixed-duration venetoclax-obinutuzumab regimen is safe and provides a superior outcome versus standard chlorambucil-obinutuzumab in elderly patients with untreated chronic lymphocytic leukemia (CLL) and comorbidities, results of a randomized phase 3 trial showed.

At 24 months, progression-free survival was 88.2% for the venetoclax-obinutuzumab regimen, versus 64.1% for chlorambucil-obinutuzumab (hazard ratio, 0.35; 95% confidence interval, 0.23-0.53; P less than .0001) in CLL-14, an open-label, multinational trial presented at the annual meeting of the American Society of Clinical Oncology.

The regimen, given for just 12 28-day cycles, also achieved the highest rate of minimal residual disease (MRD)-negative responses ever seen in a randomized prospective CLL study, according to investigator Kirsten Fischer, MD, of the University of Cologne in Germany.

“We really think that these unprecedented MRD negativity levels will eventually translate into an improved overall survival,” Dr. Fischer said during an oral abstract presentation.

Matthew Steven Davids, MD, of Dana-Farber Cancer Institute/Harvard Medical School, Boston, said venetoclax plus obinutuzumab offers the potential for 1-year, time-limited therapy, which limits concerns over long-term adherence and has the potential for cost savings, should the therapy prove to be highly durable with further follow-up.

“A limitation of the study is that the comparator arm – chlorambucil plus obinutuzumab – is directly applicable to only a relatively small subset of our older and frailer CLL patients,” Dr. Davids said during a podium discussion of the results.

“But nonetheless, venetoclax plus obinutuzumab is a promising, time-limited regimen, and CLL14 is an immediately practice-changing study for frontline CLL treatment,” he added.

The regimen stands in contrast to ibrutinib, which offers durable responses but requires continuous dosing, and FCR (fludarabine, cyclophosphamide, and rituximab), a time-limited therapy with curative potential that is restricted to younger patients with IGHV-mutated CLL, according to Dr. Davids.

In CLL-14, 432 patients were randomized 1:1 to receive venetoclax-obinutuzumab for six cycles followed by venetoclax for six cycles, or chlorambucil-obinutuzumab for six cycles followed by chlorambucil for six cycles. The median age was 72 years in the venetoclax-obinutuzumab arm and 71 years in the chlorambucil-obinutuzumab arm.

The overall response rate was 85% for venetoclax-obinutuzumab and 71% for chlorambucil-obinutuzumab (P = .0007), Dr. Fischer reported at the meeting.

The improvement in progression-free survival seen in the overall study population was also seen in patients with TP53 deletions or mutations, and in those with unmutated IGHV, Dr. Fischer reported.

Rates of MRD negativity in peripheral blood were 76% versus 35% for the venetoclax- and chlorambucil-containing combinations, respectively (P less than .001), and similarly, MRD negativity in bone marrow was 57% versus 17% (P less than .001), she said.

There were no significant differences in the rates of grade 3 or 4 neutropenia, which occurred in 52.8% of the venetoclax–obinutuzumab treated patients and 48.1% of the chlorambucil-obinutuzumab treated patients, or in grade 3 or 4 infections, which occurred in 17.5% and 15.0%, respectively, according to a report, published simultaneously in the New England Journal of Medicine (2019;380:2225-36).

Likewise, all-cause mortality was not significantly different between the arms, at 9.3% and 7.9%, respectively.

F. Hoffmann-La Roche and AbbVie supported the study. Dr. Fischer reported travel, accommodations, or expenses from Roche in her abstract disclosure.

SOURCE: Fischer K et al. ASCO 2019, Abstract 7502.

CHICAGO – A fixed-duration venetoclax-obinutuzumab regimen is safe and provides a superior outcome versus standard chlorambucil-obinutuzumab in elderly patients with untreated chronic lymphocytic leukemia (CLL) and comorbidities, results of a randomized phase 3 trial showed.

At 24 months, progression-free survival was 88.2% for the venetoclax-obinutuzumab regimen, versus 64.1% for chlorambucil-obinutuzumab (hazard ratio, 0.35; 95% confidence interval, 0.23-0.53; P less than .0001) in CLL-14, an open-label, multinational trial presented at the annual meeting of the American Society of Clinical Oncology.

The regimen, given for just 12 28-day cycles, also achieved the highest rate of minimal residual disease (MRD)-negative responses ever seen in a randomized prospective CLL study, according to investigator Kirsten Fischer, MD, of the University of Cologne in Germany.

“We really think that these unprecedented MRD negativity levels will eventually translate into an improved overall survival,” Dr. Fischer said during an oral abstract presentation.

Matthew Steven Davids, MD, of Dana-Farber Cancer Institute/Harvard Medical School, Boston, said venetoclax plus obinutuzumab offers the potential for 1-year, time-limited therapy, which limits concerns over long-term adherence and has the potential for cost savings, should the therapy prove to be highly durable with further follow-up.

“A limitation of the study is that the comparator arm – chlorambucil plus obinutuzumab – is directly applicable to only a relatively small subset of our older and frailer CLL patients,” Dr. Davids said during a podium discussion of the results.

“But nonetheless, venetoclax plus obinutuzumab is a promising, time-limited regimen, and CLL14 is an immediately practice-changing study for frontline CLL treatment,” he added.

The regimen stands in contrast to ibrutinib, which offers durable responses but requires continuous dosing, and FCR (fludarabine, cyclophosphamide, and rituximab), a time-limited therapy with curative potential that is restricted to younger patients with IGHV-mutated CLL, according to Dr. Davids.

In CLL-14, 432 patients were randomized 1:1 to receive venetoclax-obinutuzumab for six cycles followed by venetoclax for six cycles, or chlorambucil-obinutuzumab for six cycles followed by chlorambucil for six cycles. The median age was 72 years in the venetoclax-obinutuzumab arm and 71 years in the chlorambucil-obinutuzumab arm.

The overall response rate was 85% for venetoclax-obinutuzumab and 71% for chlorambucil-obinutuzumab (P = .0007), Dr. Fischer reported at the meeting.

The improvement in progression-free survival seen in the overall study population was also seen in patients with TP53 deletions or mutations, and in those with unmutated IGHV, Dr. Fischer reported.

Rates of MRD negativity in peripheral blood were 76% versus 35% for the venetoclax- and chlorambucil-containing combinations, respectively (P less than .001), and similarly, MRD negativity in bone marrow was 57% versus 17% (P less than .001), she said.

There were no significant differences in the rates of grade 3 or 4 neutropenia, which occurred in 52.8% of the venetoclax–obinutuzumab treated patients and 48.1% of the chlorambucil-obinutuzumab treated patients, or in grade 3 or 4 infections, which occurred in 17.5% and 15.0%, respectively, according to a report, published simultaneously in the New England Journal of Medicine (2019;380:2225-36).

Likewise, all-cause mortality was not significantly different between the arms, at 9.3% and 7.9%, respectively.

F. Hoffmann-La Roche and AbbVie supported the study. Dr. Fischer reported travel, accommodations, or expenses from Roche in her abstract disclosure.

SOURCE: Fischer K et al. ASCO 2019, Abstract 7502.

A combination of venetoclax and ibrutinib may be a safe and effective treatment option for previously untreated elderly and high-risk patients with chronic lymphocytic leukemia (CLL), according to investigators of a phase 2 trial of the combination.

VashiDonsk/Wikimedia Commons/Creative Commons BY-SA 3.0

About 88% of patients achieved complete remission or complete remission with incomplete count recovery after 12 cycles of treatment, reported lead author Nitin Jain, MD, of the University of Texas MD Anderson Cancer Center, Houston, and colleagues.

There were no new safety signals for the combination of ibrutinib, an irreversible inhibitor of Bruton’s tyrosine kinase, and venetoclax, a B-cell lymphoma 2 protein inhibitor, the investigators noted.

“This combination was reported to be safe and active in patients with mantle cell lymphoma,” they wrote in the New England Journal of Medicine. “Given the clinically complementary activity, preclinical synergism, and nonoverlapping toxic effects, we examined the safety and efficacy of combined ibrutinib and venetoclax treatment in previously untreated patients with CLL.”

In particular, the investigators recruited older patients, as this is a common population that can be challenging to treat. “Because CLL typically occurs in older adults, the majority of patients who need treatment are older than 65 years of age,” the investigators wrote. “This group of patients often has unacceptable side effects and has a lower rate of complete remission and undetectable minimal residual disease with chemoimmunotherapy than younger patients.”

The open-label, phase 2 trial enrolled 80 elderly and high-risk patients with previously untreated CLL. Eligibility required an age of at least 65 years or presence of at least one high-risk genetic feature; namely, mutated TP53, unmutated IgVH, or chromosome 11q deletion.

In order to reduce the risk of tumor lysis syndrome, ibrutinib (420 mg once daily) was given as monotherapy for three 28-day cycles. From the fourth cycle onward, venetoclax was also given, with weekly dose escalations to a target dose of 400 mg once daily. The combination was given for 24 cycles, with treatment continuation offered to patients who were still positive for minimal residual disease.

The median patient age was 65 years, with 30% of the population aged 70 years or older. A large majority (92%) had at least one high-risk genetic feature.

Following initiation with three cycles of ibrutinib, most patients had partial responses, the investigators wrote; however, with the addition of venetoclax, responses improved over time. Of all 80 patients, 59 (74%) had a best response of complete remission or complete remission with incomplete count recovery.

After six cycles, 51 out of 70 patients (73%) achieved this marker. After 12 cycles, 29 of 33 patients (88%) had this response, with 61% of the same group demonstrating undetectable minimal residual disease in bone marrow.

After 18 cycles, 25 of 26 patients (96%) had complete remission or complete remission with incomplete count recovery, 18 of which (69%) were negative for minimal residual disease. Three patients completed 24 cycles of combined therapy, all of whom achieved complete remission or complete remission with incomplete count recovery and undetectable minimal residual disease.

Focusing on patients aged 65 years or older, 74% had complete remission or complete remission with incomplete count recovery after six cycles of therapy and nearly half (44%) had undetectable minimal residual disease. After 12 cycles, these rates increased to 94% and 76%, respectively. Responses were also seen across genetically high-risk subgroups.

One patient died from a cryptococcal infection of the central nervous system; this was deemed unrelated to treatment, as symptoms began prior to initiation of treatment and only one dose of ibrutinib was given.

The estimated 1-year progression-free survival rate was 98% and the estimated overall survival rate was 99%. At the time of publication, no patients had disease progression.

Among all patients, 60% experienced grade 3 or higher adverse events, the most common being neutropenia (48%).

Almost half of the patient population (44%) required dose reductions of ibrutinib, most commonly because of atrial fibrillation, and 24% required dose reductions of venetoclax, most often because of neutropenia.

“Our data showed that combination therapy with ibrutinib and venetoclax was effective in patients with CLL, with no new toxic effects from the combination that were not reported previously for the individual agents,” the investigators wrote, adding that the efficacy findings were also “substantially better” than what has been reported with monotherapy for each of the agents in patients with CLL.

The study was funded by AbbVie, the University of Texas MD Anderson Cancer Center Chronic Lymphocytic Leukemia Moon Shot program, the Andrew Sabin Family Foundation, and the CLL Global Research Foundation. The investigators reported relationships with AbbVie, Incyte, Celgene, and other companies.

SOURCE: Jain N et al. N Engl J Med. 2019;380:2095-103.

A combination of venetoclax and ibrutinib may be a safe and effective treatment option for previously untreated elderly and high-risk patients with chronic lymphocytic leukemia (CLL), according to investigators of a phase 2 trial of the combination.

VashiDonsk/Wikimedia Commons/Creative Commons BY-SA 3.0

About 88% of patients achieved complete remission or complete remission with incomplete count recovery after 12 cycles of treatment, reported lead author Nitin Jain, MD, of the University of Texas MD Anderson Cancer Center, Houston, and colleagues.

There were no new safety signals for the combination of ibrutinib, an irreversible inhibitor of Bruton’s tyrosine kinase, and venetoclax, a B-cell lymphoma 2 protein inhibitor, the investigators noted.

“This combination was reported to be safe and active in patients with mantle cell lymphoma,” they wrote in the New England Journal of Medicine. “Given the clinically complementary activity, preclinical synergism, and nonoverlapping toxic effects, we examined the safety and efficacy of combined ibrutinib and venetoclax treatment in previously untreated patients with CLL.”

In particular, the investigators recruited older patients, as this is a common population that can be challenging to treat. “Because CLL typically occurs in older adults, the majority of patients who need treatment are older than 65 years of age,” the investigators wrote. “This group of patients often has unacceptable side effects and has a lower rate of complete remission and undetectable minimal residual disease with chemoimmunotherapy than younger patients.”

The open-label, phase 2 trial enrolled 80 elderly and high-risk patients with previously untreated CLL. Eligibility required an age of at least 65 years or presence of at least one high-risk genetic feature; namely, mutated TP53, unmutated IgVH, or chromosome 11q deletion.

In order to reduce the risk of tumor lysis syndrome, ibrutinib (420 mg once daily) was given as monotherapy for three 28-day cycles. From the fourth cycle onward, venetoclax was also given, with weekly dose escalations to a target dose of 400 mg once daily. The combination was given for 24 cycles, with treatment continuation offered to patients who were still positive for minimal residual disease.

The median patient age was 65 years, with 30% of the population aged 70 years or older. A large majority (92%) had at least one high-risk genetic feature.

Following initiation with three cycles of ibrutinib, most patients had partial responses, the investigators wrote; however, with the addition of venetoclax, responses improved over time. Of all 80 patients, 59 (74%) had a best response of complete remission or complete remission with incomplete count recovery.

After six cycles, 51 out of 70 patients (73%) achieved this marker. After 12 cycles, 29 of 33 patients (88%) had this response, with 61% of the same group demonstrating undetectable minimal residual disease in bone marrow.

After 18 cycles, 25 of 26 patients (96%) had complete remission or complete remission with incomplete count recovery, 18 of which (69%) were negative for minimal residual disease. Three patients completed 24 cycles of combined therapy, all of whom achieved complete remission or complete remission with incomplete count recovery and undetectable minimal residual disease.

Focusing on patients aged 65 years or older, 74% had complete remission or complete remission with incomplete count recovery after six cycles of therapy and nearly half (44%) had undetectable minimal residual disease. After 12 cycles, these rates increased to 94% and 76%, respectively. Responses were also seen across genetically high-risk subgroups.

One patient died from a cryptococcal infection of the central nervous system; this was deemed unrelated to treatment, as symptoms began prior to initiation of treatment and only one dose of ibrutinib was given.

The estimated 1-year progression-free survival rate was 98% and the estimated overall survival rate was 99%. At the time of publication, no patients had disease progression.

Among all patients, 60% experienced grade 3 or higher adverse events, the most common being neutropenia (48%).

Almost half of the patient population (44%) required dose reductions of ibrutinib, most commonly because of atrial fibrillation, and 24% required dose reductions of venetoclax, most often because of neutropenia.

“Our data showed that combination therapy with ibrutinib and venetoclax was effective in patients with CLL, with no new toxic effects from the combination that were not reported previously for the individual agents,” the investigators wrote, adding that the efficacy findings were also “substantially better” than what has been reported with monotherapy for each of the agents in patients with CLL.

The study was funded by AbbVie, the University of Texas MD Anderson Cancer Center Chronic Lymphocytic Leukemia Moon Shot program, the Andrew Sabin Family Foundation, and the CLL Global Research Foundation. The investigators reported relationships with AbbVie, Incyte, Celgene, and other companies.

SOURCE: Jain N et al. N Engl J Med. 2019;380:2095-103.

A combination of venetoclax and ibrutinib may be a safe and effective treatment option for previously untreated elderly and high-risk patients with chronic lymphocytic leukemia (CLL), according to investigators of a phase 2 trial of the combination.

VashiDonsk/Wikimedia Commons/Creative Commons BY-SA 3.0

About 88% of patients achieved complete remission or complete remission with incomplete count recovery after 12 cycles of treatment, reported lead author Nitin Jain, MD, of the University of Texas MD Anderson Cancer Center, Houston, and colleagues.

There were no new safety signals for the combination of ibrutinib, an irreversible inhibitor of Bruton’s tyrosine kinase, and venetoclax, a B-cell lymphoma 2 protein inhibitor, the investigators noted.

“This combination was reported to be safe and active in patients with mantle cell lymphoma,” they wrote in the New England Journal of Medicine. “Given the clinically complementary activity, preclinical synergism, and nonoverlapping toxic effects, we examined the safety and efficacy of combined ibrutinib and venetoclax treatment in previously untreated patients with CLL.”

In particular, the investigators recruited older patients, as this is a common population that can be challenging to treat. “Because CLL typically occurs in older adults, the majority of patients who need treatment are older than 65 years of age,” the investigators wrote. “This group of patients often has unacceptable side effects and has a lower rate of complete remission and undetectable minimal residual disease with chemoimmunotherapy than younger patients.”

The open-label, phase 2 trial enrolled 80 elderly and high-risk patients with previously untreated CLL. Eligibility required an age of at least 65 years or presence of at least one high-risk genetic feature; namely, mutated TP53, unmutated IgVH, or chromosome 11q deletion.

In order to reduce the risk of tumor lysis syndrome, ibrutinib (420 mg once daily) was given as monotherapy for three 28-day cycles. From the fourth cycle onward, venetoclax was also given, with weekly dose escalations to a target dose of 400 mg once daily. The combination was given for 24 cycles, with treatment continuation offered to patients who were still positive for minimal residual disease.

The median patient age was 65 years, with 30% of the population aged 70 years or older. A large majority (92%) had at least one high-risk genetic feature.

Following initiation with three cycles of ibrutinib, most patients had partial responses, the investigators wrote; however, with the addition of venetoclax, responses improved over time. Of all 80 patients, 59 (74%) had a best response of complete remission or complete remission with incomplete count recovery.

After six cycles, 51 out of 70 patients (73%) achieved this marker. After 12 cycles, 29 of 33 patients (88%) had this response, with 61% of the same group demonstrating undetectable minimal residual disease in bone marrow.

After 18 cycles, 25 of 26 patients (96%) had complete remission or complete remission with incomplete count recovery, 18 of which (69%) were negative for minimal residual disease. Three patients completed 24 cycles of combined therapy, all of whom achieved complete remission or complete remission with incomplete count recovery and undetectable minimal residual disease.

Focusing on patients aged 65 years or older, 74% had complete remission or complete remission with incomplete count recovery after six cycles of therapy and nearly half (44%) had undetectable minimal residual disease. After 12 cycles, these rates increased to 94% and 76%, respectively. Responses were also seen across genetically high-risk subgroups.

One patient died from a cryptococcal infection of the central nervous system; this was deemed unrelated to treatment, as symptoms began prior to initiation of treatment and only one dose of ibrutinib was given.

The estimated 1-year progression-free survival rate was 98% and the estimated overall survival rate was 99%. At the time of publication, no patients had disease progression.

Among all patients, 60% experienced grade 3 or higher adverse events, the most common being neutropenia (48%).

Almost half of the patient population (44%) required dose reductions of ibrutinib, most commonly because of atrial fibrillation, and 24% required dose reductions of venetoclax, most often because of neutropenia.

“Our data showed that combination therapy with ibrutinib and venetoclax was effective in patients with CLL, with no new toxic effects from the combination that were not reported previously for the individual agents,” the investigators wrote, adding that the efficacy findings were also “substantially better” than what has been reported with monotherapy for each of the agents in patients with CLL.

The study was funded by AbbVie, the University of Texas MD Anderson Cancer Center Chronic Lymphocytic Leukemia Moon Shot program, the Andrew Sabin Family Foundation, and the CLL Global Research Foundation. The investigators reported relationships with AbbVie, Incyte, Celgene, and other companies.

SOURCE: Jain N et al. N Engl J Med. 2019;380:2095-103.

A genetic analysis of patients with chronic lymphocytic leukemia treated with frontline, rituximab-based regimens found that deletion 11q22 and unmutated IgVH status may predict worse prognosis.

Michaela Spunarova, MD, of Masaryk University, Brno, Czech Republic, and colleagues conducted a genetic analysis of 177 patients with chronic lymphocytic leukemia (CLL). The results of the analysis were published in Leukemia Research.

The study focused on patients with CLL with an intact TP53 gene, looking at recurrently muted genes in CLL, genomic aberrations by fluorescence in situ hybridization, and IgVH status, according to the researchers.

The team analyzed the effects of these mutations on progression-free survival (PFS) following frontline treatment with bendamustine and rituximab (BR) or fludarabine, cyclophosphamide, and rituximab (FCR) therapeutic regimens.

Dr. Spunarova and colleagues used next-generation sequencing to analyze DNA from the patient samples. Data on 11q22, 13q14, trisomy 12, and IgVH mutation status were also considered in the analyses of PFS.

After analysis, the researchers validated that unmutated IgVH status is an indicator of poor prognosis in CLL patients with wild-type TP53 treated with frontline FCR.

When looking at both BR and FCR regimens, a single 11q22 deletion, lacking an ATM mutation on the other allele, resulted in the shortest PFS, at a median of just 16 months.

“Based on our data, special attention should be given to CLL patients harboring a sole 11q22 deletion, with no ATM mutation on the other allele, who manifest particularly short PFS,” they noted.

The researchers acknowledged a key limitation of the study was the small sample size. As a result, the results should be interpreted in a careful manner.

The study was funded by the Ministry of Health of the Czech Republic. The authors reported having no conflicts of interest.

SOURCE: Spunarova M et al. Leuk Res. 2019 Jun;81:75-81.

A genetic analysis of patients with chronic lymphocytic leukemia treated with frontline, rituximab-based regimens found that deletion 11q22 and unmutated IgVH status may predict worse prognosis.

Michaela Spunarova, MD, of Masaryk University, Brno, Czech Republic, and colleagues conducted a genetic analysis of 177 patients with chronic lymphocytic leukemia (CLL). The results of the analysis were published in Leukemia Research.

The study focused on patients with CLL with an intact TP53 gene, looking at recurrently muted genes in CLL, genomic aberrations by fluorescence in situ hybridization, and IgVH status, according to the researchers.

The team analyzed the effects of these mutations on progression-free survival (PFS) following frontline treatment with bendamustine and rituximab (BR) or fludarabine, cyclophosphamide, and rituximab (FCR) therapeutic regimens.

Dr. Spunarova and colleagues used next-generation sequencing to analyze DNA from the patient samples. Data on 11q22, 13q14, trisomy 12, and IgVH mutation status were also considered in the analyses of PFS.

After analysis, the researchers validated that unmutated IgVH status is an indicator of poor prognosis in CLL patients with wild-type TP53 treated with frontline FCR.

When looking at both BR and FCR regimens, a single 11q22 deletion, lacking an ATM mutation on the other allele, resulted in the shortest PFS, at a median of just 16 months.

“Based on our data, special attention should be given to CLL patients harboring a sole 11q22 deletion, with no ATM mutation on the other allele, who manifest particularly short PFS,” they noted.

The researchers acknowledged a key limitation of the study was the small sample size. As a result, the results should be interpreted in a careful manner.

The study was funded by the Ministry of Health of the Czech Republic. The authors reported having no conflicts of interest.

SOURCE: Spunarova M et al. Leuk Res. 2019 Jun;81:75-81.

A genetic analysis of patients with chronic lymphocytic leukemia treated with frontline, rituximab-based regimens found that deletion 11q22 and unmutated IgVH status may predict worse prognosis.

Michaela Spunarova, MD, of Masaryk University, Brno, Czech Republic, and colleagues conducted a genetic analysis of 177 patients with chronic lymphocytic leukemia (CLL). The results of the analysis were published in Leukemia Research.

The study focused on patients with CLL with an intact TP53 gene, looking at recurrently muted genes in CLL, genomic aberrations by fluorescence in situ hybridization, and IgVH status, according to the researchers.

The team analyzed the effects of these mutations on progression-free survival (PFS) following frontline treatment with bendamustine and rituximab (BR) or fludarabine, cyclophosphamide, and rituximab (FCR) therapeutic regimens.

Dr. Spunarova and colleagues used next-generation sequencing to analyze DNA from the patient samples. Data on 11q22, 13q14, trisomy 12, and IgVH mutation status were also considered in the analyses of PFS.

After analysis, the researchers validated that unmutated IgVH status is an indicator of poor prognosis in CLL patients with wild-type TP53 treated with frontline FCR.

When looking at both BR and FCR regimens, a single 11q22 deletion, lacking an ATM mutation on the other allele, resulted in the shortest PFS, at a median of just 16 months.

“Based on our data, special attention should be given to CLL patients harboring a sole 11q22 deletion, with no ATM mutation on the other allele, who manifest particularly short PFS,” they noted.

The researchers acknowledged a key limitation of the study was the small sample size. As a result, the results should be interpreted in a careful manner.

The study was funded by the Ministry of Health of the Czech Republic. The authors reported having no conflicts of interest.

SOURCE: Spunarova M et al. Leuk Res. 2019 Jun;81:75-81.

The Food and Drug Administration has approved the combination of venetoclax (Venclexta) plus obinutuzumab (Gazyva) for patients with previously untreated chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma.

The approval provides a chemotherapy-free, fixed duration treatment. The FDA based the approval on the results of the phase 3 CLL14 trial, which will be presented at the 2019 annual meeting of the American Society of Clinical Oncology.

Researchers randomized 432 patients to either a 12-month duration of venetoclax with a 6-month duration of obinutuzumab or to a 6-month duration of obinutuzumab plus chlorambucil and another 6-month duration of chlorambucil.

The newly approved combination reduced the risk of disease progression or death (progression-free survival as assessed by an independent review committee) by 67%, compared with obinutuzumab/chlorambucil (hazard ratio, 0.33; P less than .0001).

Venetoclax/obinutuzumab also had a higher rate of minimal residual disease negativity in bone marrow and peripheral blood, compared to the other combination, according to Genentech.

The most common adverse reactions of any grade reported for venetoclax/obinutuzumab were neutropenia, diarrhea, fatigue, nausea, anemia, and upper respiratory tract infection.

[email protected]

The Food and Drug Administration has approved the combination of venetoclax (Venclexta) plus obinutuzumab (Gazyva) for patients with previously untreated chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma.

The approval provides a chemotherapy-free, fixed duration treatment. The FDA based the approval on the results of the phase 3 CLL14 trial, which will be presented at the 2019 annual meeting of the American Society of Clinical Oncology.

Researchers randomized 432 patients to either a 12-month duration of venetoclax with a 6-month duration of obinutuzumab or to a 6-month duration of obinutuzumab plus chlorambucil and another 6-month duration of chlorambucil.

The newly approved combination reduced the risk of disease progression or death (progression-free survival as assessed by an independent review committee) by 67%, compared with obinutuzumab/chlorambucil (hazard ratio, 0.33; P less than .0001).

Venetoclax/obinutuzumab also had a higher rate of minimal residual disease negativity in bone marrow and peripheral blood, compared to the other combination, according to Genentech.

The most common adverse reactions of any grade reported for venetoclax/obinutuzumab were neutropenia, diarrhea, fatigue, nausea, anemia, and upper respiratory tract infection.

[email protected]

The Food and Drug Administration has approved the combination of venetoclax (Venclexta) plus obinutuzumab (Gazyva) for patients with previously untreated chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma.

The approval provides a chemotherapy-free, fixed duration treatment. The FDA based the approval on the results of the phase 3 CLL14 trial, which will be presented at the 2019 annual meeting of the American Society of Clinical Oncology.

Researchers randomized 432 patients to either a 12-month duration of venetoclax with a 6-month duration of obinutuzumab or to a 6-month duration of obinutuzumab plus chlorambucil and another 6-month duration of chlorambucil.

The newly approved combination reduced the risk of disease progression or death (progression-free survival as assessed by an independent review committee) by 67%, compared with obinutuzumab/chlorambucil (hazard ratio, 0.33; P less than .0001).

Venetoclax/obinutuzumab also had a higher rate of minimal residual disease negativity in bone marrow and peripheral blood, compared to the other combination, according to Genentech.

The most common adverse reactions of any grade reported for venetoclax/obinutuzumab were neutropenia, diarrhea, fatigue, nausea, anemia, and upper respiratory tract infection.

[email protected]

For patients with relapsed/refractory chronic lymphocytic leukemia (CLL), long-term treatment with the phosphoinositol 3-kinase inhibitor idelalisib appears safe and effective, according to investigators.

Final results from a phase 3 trial confirmed survival advantages when idelalisib is used in combination with rituximab, reported lead author Jeff P. Sharman, MD, of Willamette Valley Cancer Institute and Research Center in Springfield, Ore., and colleagues.

During follow-up, which exceeded 5 years in some patients, no new idelalisib-related adverse events were encountered, supporting the safety of long-term use, the investigators noted. The report is in the Journal of Clinical Oncology.

This study was “pivotal” for treating elderly patients with relapsed CLL, the investigators wrote, as these patients previously had few treatment options beyond supportive or palliative care.

Earlier results from the study showed that adding idelalisib to rituximab raised overall response rates from about 15.5% to 83.6% and median progression-free survival from 6.5 months to 19.4 months, resulting in “significantly better clinical outcomes compared with those seen with rituximab alone,” leading to approval by the Food and Drug Administration.

During the primary study, 110 patients received a combination of idelalisib and rituximab, while 108 patients received rituximab and placebo. The median patient age was 71 years, with a median of three lines of prior therapy. The present analysis focused on the 110 patients in the combination group who received at least one dose of idelalisib, whether or not they elected to participate in the extension phase.

After a median follow-up of 18 months, ranging from 0.3 months to 67.6 months, the overall response rate was 85.5% and the median progression-free survival was 20.3 months, both of which are similar to earlier findings. Median overall survival was 40.6 months.

With a median duration of exposure of 16.2 months, the safety analysis revealed no new idelalisib-related adverse events.

However, the investigators pointed out that prolonged therapy often led to diarrhea, which ultimately occurred in about half of patients (46.4%). Roughly equal amounts of patients experienced grade 2 (17.3%) or grade 3 or greater diarrhea (16.4%). In cases of grade 3 or greater diarrhea, steroid therapy was recommended, typically resulting in symptom resolution within 2 weeks; however, “there were insufficient numbers of patients to determine if steroid therapy affected the duration of symptoms,” the investigators wrote.

“The longer-term data presented here confirm the previously reported efficacy of targeting PI3K with idelalisib in patients with relapsed/refractory CLL and support the use of [idelalisib and rituximab] in this patient population with careful management of potential [adverse events],” they wrote.

Gilead Sciences funded the study. Dr. Sharman reported financial relationships with Gilead and other companies.

SOURCE: Sharman JP et al. J Clin Oncol. 2019 Apr 17. doi: 10.1200/JCO.18.01460.

For patients with relapsed/refractory chronic lymphocytic leukemia (CLL), long-term treatment with the phosphoinositol 3-kinase inhibitor idelalisib appears safe and effective, according to investigators.

Final results from a phase 3 trial confirmed survival advantages when idelalisib is used in combination with rituximab, reported lead author Jeff P. Sharman, MD, of Willamette Valley Cancer Institute and Research Center in Springfield, Ore., and colleagues.

During follow-up, which exceeded 5 years in some patients, no new idelalisib-related adverse events were encountered, supporting the safety of long-term use, the investigators noted. The report is in the Journal of Clinical Oncology.

This study was “pivotal” for treating elderly patients with relapsed CLL, the investigators wrote, as these patients previously had few treatment options beyond supportive or palliative care.

Earlier results from the study showed that adding idelalisib to rituximab raised overall response rates from about 15.5% to 83.6% and median progression-free survival from 6.5 months to 19.4 months, resulting in “significantly better clinical outcomes compared with those seen with rituximab alone,” leading to approval by the Food and Drug Administration.

During the primary study, 110 patients received a combination of idelalisib and rituximab, while 108 patients received rituximab and placebo. The median patient age was 71 years, with a median of three lines of prior therapy. The present analysis focused on the 110 patients in the combination group who received at least one dose of idelalisib, whether or not they elected to participate in the extension phase.

After a median follow-up of 18 months, ranging from 0.3 months to 67.6 months, the overall response rate was 85.5% and the median progression-free survival was 20.3 months, both of which are similar to earlier findings. Median overall survival was 40.6 months.

With a median duration of exposure of 16.2 months, the safety analysis revealed no new idelalisib-related adverse events.

However, the investigators pointed out that prolonged therapy often led to diarrhea, which ultimately occurred in about half of patients (46.4%). Roughly equal amounts of patients experienced grade 2 (17.3%) or grade 3 or greater diarrhea (16.4%). In cases of grade 3 or greater diarrhea, steroid therapy was recommended, typically resulting in symptom resolution within 2 weeks; however, “there were insufficient numbers of patients to determine if steroid therapy affected the duration of symptoms,” the investigators wrote.

“The longer-term data presented here confirm the previously reported efficacy of targeting PI3K with idelalisib in patients with relapsed/refractory CLL and support the use of [idelalisib and rituximab] in this patient population with careful management of potential [adverse events],” they wrote.

Gilead Sciences funded the study. Dr. Sharman reported financial relationships with Gilead and other companies.

SOURCE: Sharman JP et al. J Clin Oncol. 2019 Apr 17. doi: 10.1200/JCO.18.01460.

For patients with relapsed/refractory chronic lymphocytic leukemia (CLL), long-term treatment with the phosphoinositol 3-kinase inhibitor idelalisib appears safe and effective, according to investigators.

Final results from a phase 3 trial confirmed survival advantages when idelalisib is used in combination with rituximab, reported lead author Jeff P. Sharman, MD, of Willamette Valley Cancer Institute and Research Center in Springfield, Ore., and colleagues.

During follow-up, which exceeded 5 years in some patients, no new idelalisib-related adverse events were encountered, supporting the safety of long-term use, the investigators noted. The report is in the Journal of Clinical Oncology.

This study was “pivotal” for treating elderly patients with relapsed CLL, the investigators wrote, as these patients previously had few treatment options beyond supportive or palliative care.

Earlier results from the study showed that adding idelalisib to rituximab raised overall response rates from about 15.5% to 83.6% and median progression-free survival from 6.5 months to 19.4 months, resulting in “significantly better clinical outcomes compared with those seen with rituximab alone,” leading to approval by the Food and Drug Administration.

During the primary study, 110 patients received a combination of idelalisib and rituximab, while 108 patients received rituximab and placebo. The median patient age was 71 years, with a median of three lines of prior therapy. The present analysis focused on the 110 patients in the combination group who received at least one dose of idelalisib, whether or not they elected to participate in the extension phase.

After a median follow-up of 18 months, ranging from 0.3 months to 67.6 months, the overall response rate was 85.5% and the median progression-free survival was 20.3 months, both of which are similar to earlier findings. Median overall survival was 40.6 months.

With a median duration of exposure of 16.2 months, the safety analysis revealed no new idelalisib-related adverse events.

However, the investigators pointed out that prolonged therapy often led to diarrhea, which ultimately occurred in about half of patients (46.4%). Roughly equal amounts of patients experienced grade 2 (17.3%) or grade 3 or greater diarrhea (16.4%). In cases of grade 3 or greater diarrhea, steroid therapy was recommended, typically resulting in symptom resolution within 2 weeks; however, “there were insufficient numbers of patients to determine if steroid therapy affected the duration of symptoms,” the investigators wrote.

“The longer-term data presented here confirm the previously reported efficacy of targeting PI3K with idelalisib in patients with relapsed/refractory CLL and support the use of [idelalisib and rituximab] in this patient population with careful management of potential [adverse events],” they wrote.

Gilead Sciences funded the study. Dr. Sharman reported financial relationships with Gilead and other companies.

SOURCE: Sharman JP et al. J Clin Oncol. 2019 Apr 17. doi: 10.1200/JCO.18.01460.

A combination of bendamustine and rituximab generated an 88% overall response rate and 96% overall survival rate at 2 years among patients with chronic lymphocytic leukemia (CLL) in a study of 83 patients aged 53-83 years.

Although combined fludarabine, cyclophosphamide, and rituximab has demonstrated success in younger patients with CLL, this therapy is often considered too aggressive for the majority of CLL patients, who tend to be older and have multiple comorbidities, wrote Martin Špacek, MD, of Charles University and General University Hospital in Prague and his colleagues.

The alternative treatment combination of bendamustine and rituximab (BR) has not been well studied in patients with comorbidities, they said.

In a study published in Leukemia Research, the researchers enrolled 83 previously untreated adults with progressive CLL. The average age of the participants was 71 years, and 61% were men. The median creatinine clearance for the study population was 65 mL/min, and all patients had comorbidities, defined as scores greater than 6 on the Cumulative Illness Rating Scale (CIRS).

All patients were prescribed 90 mg/m² bendamustine on days 1 and 2 combined with 375 mg/m² rituximab on day 0 of the first course, and 500 mg/m² rituximab on day 1 during subsequent courses every 28 days for a maximum of six cycles.

The overall response rate to BR was 88.0%, with a complete response rate of 20.5%. At 2 years, progression-free survival and overall survival rates were 69.9% and 96.2%, respectively.

A total of 51 patients (61.4%) experienced at least one grade 3 or 4 adverse event. The most common hematologic effects were neutropenia (40 patients), thrombocytopenia (14 patients), and anemia (8 patients). The most common nonhematologic effects were grade 3– or grade 4–level infections in 12 patients. Six patients developed severe skin rash.

Additionally, one patient developed sepsis during treatment and died after the first course of therapy.

“Age and CIRS failed to predict any severe toxicities or BR dose reduction,” the researchers noted.

The findings support data from previous studies and represent the largest study of CLL patients with significant comorbidities to be treated with BR, the researchers said.

More prospective research is needed, but the results demonstrate that “chemoimmunotherapy with BR is an effective therapeutic option with manageable toxicity for the initial treatment of CLL patients with significant comorbidities,” the investigators wrote.

The study was supported by the Ministry of Health, Czech Republic, the Charles University Progres program, and the Czech CLL Study Group. Researchers reported honoraria and travel grants from Mundipharma and Roche.
 

SOURCE: Spacek M et al. Leuk Res. 2019;79:17-21.

A combination of bendamustine and rituximab generated an 88% overall response rate and 96% overall survival rate at 2 years among patients with chronic lymphocytic leukemia (CLL) in a study of 83 patients aged 53-83 years.

Although combined fludarabine, cyclophosphamide, and rituximab has demonstrated success in younger patients with CLL, this therapy is often considered too aggressive for the majority of CLL patients, who tend to be older and have multiple comorbidities, wrote Martin Špacek, MD, of Charles University and General University Hospital in Prague and his colleagues.

The alternative treatment combination of bendamustine and rituximab (BR) has not been well studied in patients with comorbidities, they said.

In a study published in Leukemia Research, the researchers enrolled 83 previously untreated adults with progressive CLL. The average age of the participants was 71 years, and 61% were men. The median creatinine clearance for the study population was 65 mL/min, and all patients had comorbidities, defined as scores greater than 6 on the Cumulative Illness Rating Scale (CIRS).

All patients were prescribed 90 mg/m² bendamustine on days 1 and 2 combined with 375 mg/m² rituximab on day 0 of the first course, and 500 mg/m² rituximab on day 1 during subsequent courses every 28 days for a maximum of six cycles.

The overall response rate to BR was 88.0%, with a complete response rate of 20.5%. At 2 years, progression-free survival and overall survival rates were 69.9% and 96.2%, respectively.

A total of 51 patients (61.4%) experienced at least one grade 3 or 4 adverse event. The most common hematologic effects were neutropenia (40 patients), thrombocytopenia (14 patients), and anemia (8 patients). The most common nonhematologic effects were grade 3– or grade 4–level infections in 12 patients. Six patients developed severe skin rash.

Additionally, one patient developed sepsis during treatment and died after the first course of therapy.

“Age and CIRS failed to predict any severe toxicities or BR dose reduction,” the researchers noted.

The findings support data from previous studies and represent the largest study of CLL patients with significant comorbidities to be treated with BR, the researchers said.

More prospective research is needed, but the results demonstrate that “chemoimmunotherapy with BR is an effective therapeutic option with manageable toxicity for the initial treatment of CLL patients with significant comorbidities,” the investigators wrote.

The study was supported by the Ministry of Health, Czech Republic, the Charles University Progres program, and the Czech CLL Study Group. Researchers reported honoraria and travel grants from Mundipharma and Roche.
 

SOURCE: Spacek M et al. Leuk Res. 2019;79:17-21.

A combination of bendamustine and rituximab generated an 88% overall response rate and 96% overall survival rate at 2 years among patients with chronic lymphocytic leukemia (CLL) in a study of 83 patients aged 53-83 years.

Although combined fludarabine, cyclophosphamide, and rituximab has demonstrated success in younger patients with CLL, this therapy is often considered too aggressive for the majority of CLL patients, who tend to be older and have multiple comorbidities, wrote Martin Špacek, MD, of Charles University and General University Hospital in Prague and his colleagues.

The alternative treatment combination of bendamustine and rituximab (BR) has not been well studied in patients with comorbidities, they said.

In a study published in Leukemia Research, the researchers enrolled 83 previously untreated adults with progressive CLL. The average age of the participants was 71 years, and 61% were men. The median creatinine clearance for the study population was 65 mL/min, and all patients had comorbidities, defined as scores greater than 6 on the Cumulative Illness Rating Scale (CIRS).

All patients were prescribed 90 mg/m² bendamustine on days 1 and 2 combined with 375 mg/m² rituximab on day 0 of the first course, and 500 mg/m² rituximab on day 1 during subsequent courses every 28 days for a maximum of six cycles.

The overall response rate to BR was 88.0%, with a complete response rate of 20.5%. At 2 years, progression-free survival and overall survival rates were 69.9% and 96.2%, respectively.

A total of 51 patients (61.4%) experienced at least one grade 3 or 4 adverse event. The most common hematologic effects were neutropenia (40 patients), thrombocytopenia (14 patients), and anemia (8 patients). The most common nonhematologic effects were grade 3– or grade 4–level infections in 12 patients. Six patients developed severe skin rash.

Additionally, one patient developed sepsis during treatment and died after the first course of therapy.

“Age and CIRS failed to predict any severe toxicities or BR dose reduction,” the researchers noted.

The findings support data from previous studies and represent the largest study of CLL patients with significant comorbidities to be treated with BR, the researchers said.

More prospective research is needed, but the results demonstrate that “chemoimmunotherapy with BR is an effective therapeutic option with manageable toxicity for the initial treatment of CLL patients with significant comorbidities,” the investigators wrote.

The study was supported by the Ministry of Health, Czech Republic, the Charles University Progres program, and the Czech CLL Study Group. Researchers reported honoraria and travel grants from Mundipharma and Roche.
 

SOURCE: Spacek M et al. Leuk Res. 2019;79:17-21.

Prolonged exposure to ibrutinib showed sustained progression-free and overall survival and had tolerable safety outcomes in patients with relapsed or refractory chronic lymphocytic leukemia, according to a post hoc analysis of the phase 3 RESONATE trial.

Courtesy Wikimedia Commons/Nephron/Creative Commons BY-SA-3.0

“This study ... provides further evidence for efficacy and safety with prolonged treatment across multiple high-risk genomic and clinical disease features and with increasing depth of response,” John C. Byrd, MD, of the Ohio State University, Columbus, and his colleagues wrote in Blood.

RESONATE included 391 high-risk patients with relapsed or refractory chronic lymphocytic leukemia (CLL). Study participants were randomized in a 1:1 fashion to receive ibrutinib 420 mg daily or ofatumumab (initial infusion of 300 mg followed by seven weekly infusions and four monthly infusions of 2,000 mg) for a maximum of 24 weeks. Drug therapy was continued until cancer progression or intolerable toxicity of either agent was seen.

“Primary analysis at median follow-up of 9.7 months demonstrated superiority of ibrutinib over ofatumumab in PFS [progression-free survival], OS [overall survival], and overall response,” the researchers wrote. “With extended follow-up of median 44 months, these same results persist; a plateau of PFS has not yet been reached in this long-term follow-up. We also observe very durable remissions among patients of all genomic groups, including those with del(17)(p13.1), del(11)(q22.3), or unmutated IgHV [immunoglobulin heavy chain gene], who are traditionally considered high-risk populations.”

After an extended follow-up (median, 44 months), the team found that the PFS benefit with ibrutinib was sustained, compared with ofatumumab (hazard ratio, 0.133; 95% confidence interval, 0.099-0.178; P less than .0001). The 3-year PFS rate was 59% for ibrutinib, compared with 3% for ofatumumab. Similar PFS benefits were seen among subgroups of high- and very high–risk patients, based on their scores on the International Prognostic Index for CLL.

The OS benefit was also sustained in those randomized to ibrutinib (HR, 0.591; 95% CI, 0.378-0.926; P = .0208). The continued OS benefit with ibrutinib versus ofatumumab continued even after a sensitivity analysis adjusted for crossover of patients to ibrutinib.

With respect to safety, adverse events of any grade were similar to previous reports of ibrutinib. In fact, the prevalence of adverse events (grade 3 or higher) decreased over time for participants that continued on ibrutinib.

“Multiple studies are ongoing to investigate ibrutinib earlier in the course of CLL therapy, including phase 3 studies of first-line ibrutinib [or ibrutinib combined with anti-CD20 therapy], compared with standard chemoimmunotherapy regimens,” they wrote.

The study was sponsored by Pharmacyclics and Janssen. The authors reported financial disclosures related to the sponsors and several other companies.

SOURCE: Byrd JC et al. Blood. 2019 Mar 6. doi: 10.1182/blood-2018-08-870238.

Prolonged exposure to ibrutinib showed sustained progression-free and overall survival and had tolerable safety outcomes in patients with relapsed or refractory chronic lymphocytic leukemia, according to a post hoc analysis of the phase 3 RESONATE trial.

Courtesy Wikimedia Commons/Nephron/Creative Commons BY-SA-3.0

“This study ... provides further evidence for efficacy and safety with prolonged treatment across multiple high-risk genomic and clinical disease features and with increasing depth of response,” John C. Byrd, MD, of the Ohio State University, Columbus, and his colleagues wrote in Blood.

RESONATE included 391 high-risk patients with relapsed or refractory chronic lymphocytic leukemia (CLL). Study participants were randomized in a 1:1 fashion to receive ibrutinib 420 mg daily or ofatumumab (initial infusion of 300 mg followed by seven weekly infusions and four monthly infusions of 2,000 mg) for a maximum of 24 weeks. Drug therapy was continued until cancer progression or intolerable toxicity of either agent was seen.

“Primary analysis at median follow-up of 9.7 months demonstrated superiority of ibrutinib over ofatumumab in PFS [progression-free survival], OS [overall survival], and overall response,” the researchers wrote. “With extended follow-up of median 44 months, these same results persist; a plateau of PFS has not yet been reached in this long-term follow-up. We also observe very durable remissions among patients of all genomic groups, including those with del(17)(p13.1), del(11)(q22.3), or unmutated IgHV [immunoglobulin heavy chain gene], who are traditionally considered high-risk populations.”

After an extended follow-up (median, 44 months), the team found that the PFS benefit with ibrutinib was sustained, compared with ofatumumab (hazard ratio, 0.133; 95% confidence interval, 0.099-0.178; P less than .0001). The 3-year PFS rate was 59% for ibrutinib, compared with 3% for ofatumumab. Similar PFS benefits were seen among subgroups of high- and very high–risk patients, based on their scores on the International Prognostic Index for CLL.

The OS benefit was also sustained in those randomized to ibrutinib (HR, 0.591; 95% CI, 0.378-0.926; P = .0208). The continued OS benefit with ibrutinib versus ofatumumab continued even after a sensitivity analysis adjusted for crossover of patients to ibrutinib.

With respect to safety, adverse events of any grade were similar to previous reports of ibrutinib. In fact, the prevalence of adverse events (grade 3 or higher) decreased over time for participants that continued on ibrutinib.

“Multiple studies are ongoing to investigate ibrutinib earlier in the course of CLL therapy, including phase 3 studies of first-line ibrutinib [or ibrutinib combined with anti-CD20 therapy], compared with standard chemoimmunotherapy regimens,” they wrote.

The study was sponsored by Pharmacyclics and Janssen. The authors reported financial disclosures related to the sponsors and several other companies.

SOURCE: Byrd JC et al. Blood. 2019 Mar 6. doi: 10.1182/blood-2018-08-870238.

Prolonged exposure to ibrutinib showed sustained progression-free and overall survival and had tolerable safety outcomes in patients with relapsed or refractory chronic lymphocytic leukemia, according to a post hoc analysis of the phase 3 RESONATE trial.

Courtesy Wikimedia Commons/Nephron/Creative Commons BY-SA-3.0

“This study ... provides further evidence for efficacy and safety with prolonged treatment across multiple high-risk genomic and clinical disease features and with increasing depth of response,” John C. Byrd, MD, of the Ohio State University, Columbus, and his colleagues wrote in Blood.

RESONATE included 391 high-risk patients with relapsed or refractory chronic lymphocytic leukemia (CLL). Study participants were randomized in a 1:1 fashion to receive ibrutinib 420 mg daily or ofatumumab (initial infusion of 300 mg followed by seven weekly infusions and four monthly infusions of 2,000 mg) for a maximum of 24 weeks. Drug therapy was continued until cancer progression or intolerable toxicity of either agent was seen.

“Primary analysis at median follow-up of 9.7 months demonstrated superiority of ibrutinib over ofatumumab in PFS [progression-free survival], OS [overall survival], and overall response,” the researchers wrote. “With extended follow-up of median 44 months, these same results persist; a plateau of PFS has not yet been reached in this long-term follow-up. We also observe very durable remissions among patients of all genomic groups, including those with del(17)(p13.1), del(11)(q22.3), or unmutated IgHV [immunoglobulin heavy chain gene], who are traditionally considered high-risk populations.”

After an extended follow-up (median, 44 months), the team found that the PFS benefit with ibrutinib was sustained, compared with ofatumumab (hazard ratio, 0.133; 95% confidence interval, 0.099-0.178; P less than .0001). The 3-year PFS rate was 59% for ibrutinib, compared with 3% for ofatumumab. Similar PFS benefits were seen among subgroups of high- and very high–risk patients, based on their scores on the International Prognostic Index for CLL.

The OS benefit was also sustained in those randomized to ibrutinib (HR, 0.591; 95% CI, 0.378-0.926; P = .0208). The continued OS benefit with ibrutinib versus ofatumumab continued even after a sensitivity analysis adjusted for crossover of patients to ibrutinib.

With respect to safety, adverse events of any grade were similar to previous reports of ibrutinib. In fact, the prevalence of adverse events (grade 3 or higher) decreased over time for participants that continued on ibrutinib.

“Multiple studies are ongoing to investigate ibrutinib earlier in the course of CLL therapy, including phase 3 studies of first-line ibrutinib [or ibrutinib combined with anti-CD20 therapy], compared with standard chemoimmunotherapy regimens,” they wrote.

The study was sponsored by Pharmacyclics and Janssen. The authors reported financial disclosures related to the sponsors and several other companies.

SOURCE: Byrd JC et al. Blood. 2019 Mar 6. doi: 10.1182/blood-2018-08-870238.

The combination of venetoclax and obinutuzumab provided high response rates and deep remissions regardless of cytogenetic risk factors in patients with chronic lymphocytic leukemia, according to recently reported results of a phase 1b study.

The regimen elicited high rates of undetectable minimal residual disease in peripheral blood and had an acceptable safety profile with manageable toxicities in the study reported in Blood, which included patients with previously untreated or relapsed/refractory chronic lymphocytic leukemia (CLL).

“The deep remission rates we observed with venetoclax-obinutuzumab have not been reported with previously available CLL treatments, including FCR [fludarabine, cyclophosphamide, and rituximab], which is currently considered the most efficacious regimen with limited-duration therapy,” wrote the investigators, led by Ian W. Flinn, MD, PhD, of Sarah Cannon Research Institute/Tennessee Oncology, Nashville.

Venetoclax-obinutuzumab combinations are meanwhile being tested in other studies – including the phase 3 CLL13 and CLL14 studies – which have enrolled previously untreated fit or unfit CLL patients, respectively.

“If the primary endpoints of these large-scale trials are met, venetoclax-obinutuzumab may become a new standard treatment option in [first-line] CLL, irrespective of clinical fitness,” Dr. Flinn and his colleagues wrote in their report.

The present phase 1b, dose-escalation study enrolled 32 patients who were previously untreated (median age, 63 years) and 46 patients who were relapsed or refractory to previous treatments (median age, 61 years).

Doses of venetoclax were escalated from 100 mg to 400 mg to determine its maximum tolerated dose when combined with obinutuzumab, the investigators wrote. Some patients received venetoclax first, while others received obinutuzumab first, for a total of 1 year of treatment.

The study confirmed favorable risk-benefit treatment used a dose of 400 mg venetoclax plus the standard dose of obinutuzumab, according to the researchers.

The overall best response rate was 95% for relapsed/refractory patients, including a 37% rate of complete response or complete response with incomplete marrow recovery. In previously untreated patients, the overall best response rate was 100%, including a 78% rate of complete responses by those criteria.

Undetectable minimal residual disease was observed in 64% of relapsed/refractory patients and 91% of previously untreated patients at 3 months after the last obinutuzumab dose, the investigators reported.

There were no dose-limiting toxicities in the study, no clinical tumor lysis syndrome, and no differences between the two schedules (venetoclax first or obinutuzumab first) in terms of adverse events, the investigators wrote.

Neutropenia was the most common serious (grade 3-4) adverse event, occurring in 58% of relapsed/refractory patients and 53% of patients treated in the first line. Grade 3-4 infections were seen in 29% and 13% of the relapsed/refractory and previously untreated patients, respectively.

There were no fatal infections among previously untreated patients, while three relapsed/refractory patients (7%) had fatal adverse events, including one case of acute respiratory failure in a patient with suspected Richter’s transformation, pneumonia in a patient with metastatic squamous cell lung carcinoma, and another case of pneumonia occurring about 3 months after the last dose of venetoclax.

Genentech and AbbVie provided financial support for the study. Dr. Flinn reported receiving research funding for his institution from Genentech, AbbVie, and several other companies.

SOURCE: Flinn IW et al. Blood. 2019 Mar 12. doi: 10.1182/blood-2019-01-896290.

The combination of venetoclax and obinutuzumab provided high response rates and deep remissions regardless of cytogenetic risk factors in patients with chronic lymphocytic leukemia, according to recently reported results of a phase 1b study.

The regimen elicited high rates of undetectable minimal residual disease in peripheral blood and had an acceptable safety profile with manageable toxicities in the study reported in Blood, which included patients with previously untreated or relapsed/refractory chronic lymphocytic leukemia (CLL).

“The deep remission rates we observed with venetoclax-obinutuzumab have not been reported with previously available CLL treatments, including FCR [fludarabine, cyclophosphamide, and rituximab], which is currently considered the most efficacious regimen with limited-duration therapy,” wrote the investigators, led by Ian W. Flinn, MD, PhD, of Sarah Cannon Research Institute/Tennessee Oncology, Nashville.

Venetoclax-obinutuzumab combinations are meanwhile being tested in other studies – including the phase 3 CLL13 and CLL14 studies – which have enrolled previously untreated fit or unfit CLL patients, respectively.

“If the primary endpoints of these large-scale trials are met, venetoclax-obinutuzumab may become a new standard treatment option in [first-line] CLL, irrespective of clinical fitness,” Dr. Flinn and his colleagues wrote in their report.

The present phase 1b, dose-escalation study enrolled 32 patients who were previously untreated (median age, 63 years) and 46 patients who were relapsed or refractory to previous treatments (median age, 61 years).

Doses of venetoclax were escalated from 100 mg to 400 mg to determine its maximum tolerated dose when combined with obinutuzumab, the investigators wrote. Some patients received venetoclax first, while others received obinutuzumab first, for a total of 1 year of treatment.

The study confirmed favorable risk-benefit treatment used a dose of 400 mg venetoclax plus the standard dose of obinutuzumab, according to the researchers.

The overall best response rate was 95% for relapsed/refractory patients, including a 37% rate of complete response or complete response with incomplete marrow recovery. In previously untreated patients, the overall best response rate was 100%, including a 78% rate of complete responses by those criteria.

Undetectable minimal residual disease was observed in 64% of relapsed/refractory patients and 91% of previously untreated patients at 3 months after the last obinutuzumab dose, the investigators reported.

There were no dose-limiting toxicities in the study, no clinical tumor lysis syndrome, and no differences between the two schedules (venetoclax first or obinutuzumab first) in terms of adverse events, the investigators wrote.

Neutropenia was the most common serious (grade 3-4) adverse event, occurring in 58% of relapsed/refractory patients and 53% of patients treated in the first line. Grade 3-4 infections were seen in 29% and 13% of the relapsed/refractory and previously untreated patients, respectively.

There were no fatal infections among previously untreated patients, while three relapsed/refractory patients (7%) had fatal adverse events, including one case of acute respiratory failure in a patient with suspected Richter’s transformation, pneumonia in a patient with metastatic squamous cell lung carcinoma, and another case of pneumonia occurring about 3 months after the last dose of venetoclax.

Genentech and AbbVie provided financial support for the study. Dr. Flinn reported receiving research funding for his institution from Genentech, AbbVie, and several other companies.

SOURCE: Flinn IW et al. Blood. 2019 Mar 12. doi: 10.1182/blood-2019-01-896290.

The combination of venetoclax and obinutuzumab provided high response rates and deep remissions regardless of cytogenetic risk factors in patients with chronic lymphocytic leukemia, according to recently reported results of a phase 1b study.

The regimen elicited high rates of undetectable minimal residual disease in peripheral blood and had an acceptable safety profile with manageable toxicities in the study reported in Blood, which included patients with previously untreated or relapsed/refractory chronic lymphocytic leukemia (CLL).

“The deep remission rates we observed with venetoclax-obinutuzumab have not been reported with previously available CLL treatments, including FCR [fludarabine, cyclophosphamide, and rituximab], which is currently considered the most efficacious regimen with limited-duration therapy,” wrote the investigators, led by Ian W. Flinn, MD, PhD, of Sarah Cannon Research Institute/Tennessee Oncology, Nashville.

Venetoclax-obinutuzumab combinations are meanwhile being tested in other studies – including the phase 3 CLL13 and CLL14 studies – which have enrolled previously untreated fit or unfit CLL patients, respectively.

“If the primary endpoints of these large-scale trials are met, venetoclax-obinutuzumab may become a new standard treatment option in [first-line] CLL, irrespective of clinical fitness,” Dr. Flinn and his colleagues wrote in their report.

The present phase 1b, dose-escalation study enrolled 32 patients who were previously untreated (median age, 63 years) and 46 patients who were relapsed or refractory to previous treatments (median age, 61 years).

Doses of venetoclax were escalated from 100 mg to 400 mg to determine its maximum tolerated dose when combined with obinutuzumab, the investigators wrote. Some patients received venetoclax first, while others received obinutuzumab first, for a total of 1 year of treatment.

The study confirmed favorable risk-benefit treatment used a dose of 400 mg venetoclax plus the standard dose of obinutuzumab, according to the researchers.

The overall best response rate was 95% for relapsed/refractory patients, including a 37% rate of complete response or complete response with incomplete marrow recovery. In previously untreated patients, the overall best response rate was 100%, including a 78% rate of complete responses by those criteria.

Undetectable minimal residual disease was observed in 64% of relapsed/refractory patients and 91% of previously untreated patients at 3 months after the last obinutuzumab dose, the investigators reported.

There were no dose-limiting toxicities in the study, no clinical tumor lysis syndrome, and no differences between the two schedules (venetoclax first or obinutuzumab first) in terms of adverse events, the investigators wrote.

Neutropenia was the most common serious (grade 3-4) adverse event, occurring in 58% of relapsed/refractory patients and 53% of patients treated in the first line. Grade 3-4 infections were seen in 29% and 13% of the relapsed/refractory and previously untreated patients, respectively.

There were no fatal infections among previously untreated patients, while three relapsed/refractory patients (7%) had fatal adverse events, including one case of acute respiratory failure in a patient with suspected Richter’s transformation, pneumonia in a patient with metastatic squamous cell lung carcinoma, and another case of pneumonia occurring about 3 months after the last dose of venetoclax.

Genentech and AbbVie provided financial support for the study. Dr. Flinn reported receiving research funding for his institution from Genentech, AbbVie, and several other companies.

SOURCE: Flinn IW et al. Blood. 2019 Mar 12. doi: 10.1182/blood-2019-01-896290.

A telomere-length analysis tool appears to identify reliably which chronic lymphocytic leukemia (CLL) patients will benefit from frontline chemotherapy, according to an analysis of 260 patients across two separate trials.

VashiDonsk/Wikimedia Commons/Creative Commons BY-SA 3.0

The analysis compared the use of high-throughput, single telomere–length analysis (HTSTELA) with other commonly used markers including beta-2 microglobulin, fluorescence-in-situ hybridization (FISH) cytogenetics, CD38 expression, ZAP70 expression, and IGHV mutation status. The researchers looked specifically at whether telomere length could predict response to frontline treatment with fludarabine, cyclophosphamide, rituximab (FCR)–based regimens.

“[T]elomere length is a powerful predictor of both [progression-free survival] and [overall survival] in patients treated with FCR-based therapies. In contrast, CD38 expression and beta-2 microglobulin expression were not predictive, and IGHV mutation status was only predictive of PFS (progression-free survival),” Kevin Norris, PhD, of Cardiff (Wales) University and his colleagues wrote in Leukemia.

Previous studies have shown that telomere-length analysis offers independent prognostic information in all stages of CLL. In the present study, the researchers used HTSTELA to analyze patient samples taken from two concurrent, phase 2 clinical trials of frontline FCR-based treatment – ARCTIC and ADMIRE.

The researchers divided the cohort based on a threshold of telomere dysfunction – the point at which the chromosome end-capping function is lost and there is genomic instability. Shorter telomeres are inside the fusogenic range (TL-IFR) and longer telomeres are outside fusogenic range (TL-OFR).

Patients with TL-IFR had significantly shorter PFS on FCR-based treatment (P less than .0001). They also had reduced overall survival (OS; P = .0002). In the same cohort of patients, IGHV mutation status was predictive of PFS (P = .0016), but it was not predictive for OS (P = .38), while CD38 and beta-2 microglobulin were not predictive of PFS or OS.

The researchers also looked at the value of telomere length in predicting outcomes among IGHV-mutated and -unmutated patients.

Patients with IGHV-mutated disease and TL-IFR had worse PFS and OS than did patients with TL-OFR. TL-IFR patients in this cohort were more likely to progress (hazard ratio, 4.35; P less than .0001) and more likely to die from their disease (HR, 3.81; P = .006).

“Although the number of IGHV-mutated patients with TL-IFR was relatively small (n = 16), our data suggests that telomere length can identify a subset of “bad risk” IGHV-mutated patients who do not respond well to FCR,” the researchers wrote.

Among IGHV unmutated patients, those with short telomeres had worse PFS (HR, 1.48; P = .08) and OS (HR, 2.18; P = .025) than did those with longer telomeres.

In multivariate modeling of all the potential markers, telomere length was the statistically significant dominant covariable for both PFS and OS.

The study was funded by a Bloodwise grant and the Wales Cancer Research Center. Dr. Norris and three coauthors reported that they are coinventors of patents relevant to the study and hold shares in a company set to provide telomere length testing.

[email protected]

SOURCE: Norris K et al. Leukemia. 2019 Jan 30. doi: 10.1038/s41375-019-0389-9.
 

A telomere-length analysis tool appears to identify reliably which chronic lymphocytic leukemia (CLL) patients will benefit from frontline chemotherapy, according to an analysis of 260 patients across two separate trials.

VashiDonsk/Wikimedia Commons/Creative Commons BY-SA 3.0

The analysis compared the use of high-throughput, single telomere–length analysis (HTSTELA) with other commonly used markers including beta-2 microglobulin, fluorescence-in-situ hybridization (FISH) cytogenetics, CD38 expression, ZAP70 expression, and IGHV mutation status. The researchers looked specifically at whether telomere length could predict response to frontline treatment with fludarabine, cyclophosphamide, rituximab (FCR)–based regimens.

“[T]elomere length is a powerful predictor of both [progression-free survival] and [overall survival] in patients treated with FCR-based therapies. In contrast, CD38 expression and beta-2 microglobulin expression were not predictive, and IGHV mutation status was only predictive of PFS (progression-free survival),” Kevin Norris, PhD, of Cardiff (Wales) University and his colleagues wrote in Leukemia.

Previous studies have shown that telomere-length analysis offers independent prognostic information in all stages of CLL. In the present study, the researchers used HTSTELA to analyze patient samples taken from two concurrent, phase 2 clinical trials of frontline FCR-based treatment – ARCTIC and ADMIRE.

The researchers divided the cohort based on a threshold of telomere dysfunction – the point at which the chromosome end-capping function is lost and there is genomic instability. Shorter telomeres are inside the fusogenic range (TL-IFR) and longer telomeres are outside fusogenic range (TL-OFR).

Patients with TL-IFR had significantly shorter PFS on FCR-based treatment (P less than .0001). They also had reduced overall survival (OS; P = .0002). In the same cohort of patients, IGHV mutation status was predictive of PFS (P = .0016), but it was not predictive for OS (P = .38), while CD38 and beta-2 microglobulin were not predictive of PFS or OS.

The researchers also looked at the value of telomere length in predicting outcomes among IGHV-mutated and -unmutated patients.

Patients with IGHV-mutated disease and TL-IFR had worse PFS and OS than did patients with TL-OFR. TL-IFR patients in this cohort were more likely to progress (hazard ratio, 4.35; P less than .0001) and more likely to die from their disease (HR, 3.81; P = .006).

“Although the number of IGHV-mutated patients with TL-IFR was relatively small (n = 16), our data suggests that telomere length can identify a subset of “bad risk” IGHV-mutated patients who do not respond well to FCR,” the researchers wrote.

Among IGHV unmutated patients, those with short telomeres had worse PFS (HR, 1.48; P = .08) and OS (HR, 2.18; P = .025) than did those with longer telomeres.

In multivariate modeling of all the potential markers, telomere length was the statistically significant dominant covariable for both PFS and OS.

The study was funded by a Bloodwise grant and the Wales Cancer Research Center. Dr. Norris and three coauthors reported that they are coinventors of patents relevant to the study and hold shares in a company set to provide telomere length testing.

[email protected]

SOURCE: Norris K et al. Leukemia. 2019 Jan 30. doi: 10.1038/s41375-019-0389-9.
 

A telomere-length analysis tool appears to identify reliably which chronic lymphocytic leukemia (CLL) patients will benefit from frontline chemotherapy, according to an analysis of 260 patients across two separate trials.

VashiDonsk/Wikimedia Commons/Creative Commons BY-SA 3.0

The analysis compared the use of high-throughput, single telomere–length analysis (HTSTELA) with other commonly used markers including beta-2 microglobulin, fluorescence-in-situ hybridization (FISH) cytogenetics, CD38 expression, ZAP70 expression, and IGHV mutation status. The researchers looked specifically at whether telomere length could predict response to frontline treatment with fludarabine, cyclophosphamide, rituximab (FCR)–based regimens.

“[T]elomere length is a powerful predictor of both [progression-free survival] and [overall survival] in patients treated with FCR-based therapies. In contrast, CD38 expression and beta-2 microglobulin expression were not predictive, and IGHV mutation status was only predictive of PFS (progression-free survival),” Kevin Norris, PhD, of Cardiff (Wales) University and his colleagues wrote in Leukemia.

Previous studies have shown that telomere-length analysis offers independent prognostic information in all stages of CLL. In the present study, the researchers used HTSTELA to analyze patient samples taken from two concurrent, phase 2 clinical trials of frontline FCR-based treatment – ARCTIC and ADMIRE.

The researchers divided the cohort based on a threshold of telomere dysfunction – the point at which the chromosome end-capping function is lost and there is genomic instability. Shorter telomeres are inside the fusogenic range (TL-IFR) and longer telomeres are outside fusogenic range (TL-OFR).

Patients with TL-IFR had significantly shorter PFS on FCR-based treatment (P less than .0001). They also had reduced overall survival (OS; P = .0002). In the same cohort of patients, IGHV mutation status was predictive of PFS (P = .0016), but it was not predictive for OS (P = .38), while CD38 and beta-2 microglobulin were not predictive of PFS or OS.

The researchers also looked at the value of telomere length in predicting outcomes among IGHV-mutated and -unmutated patients.

Patients with IGHV-mutated disease and TL-IFR had worse PFS and OS than did patients with TL-OFR. TL-IFR patients in this cohort were more likely to progress (hazard ratio, 4.35; P less than .0001) and more likely to die from their disease (HR, 3.81; P = .006).

“Although the number of IGHV-mutated patients with TL-IFR was relatively small (n = 16), our data suggests that telomere length can identify a subset of “bad risk” IGHV-mutated patients who do not respond well to FCR,” the researchers wrote.

Among IGHV unmutated patients, those with short telomeres had worse PFS (HR, 1.48; P = .08) and OS (HR, 2.18; P = .025) than did those with longer telomeres.

In multivariate modeling of all the potential markers, telomere length was the statistically significant dominant covariable for both PFS and OS.

The study was funded by a Bloodwise grant and the Wales Cancer Research Center. Dr. Norris and three coauthors reported that they are coinventors of patents relevant to the study and hold shares in a company set to provide telomere length testing.

[email protected]

SOURCE: Norris K et al. Leukemia. 2019 Jan 30. doi: 10.1038/s41375-019-0389-9.