CLL

SAN DIEGO – The combination of ibrutinib and rituximab was associated with a two-thirds reduction in chronic lymphocytic leukemia (CLL) progression, compared with standard chemoimmunotherapy in patients younger than 70 years old, interim results of a phase 3 randomized trial showed.

Among 529 patients with previously untreated, symptomatic CLL randomly assigned to ibrutinib-rituximab (IR) or to chemoimmunotherapy with fludarabine, cyclophosphamide, and rituximab (FCR), the IR regimen was associated with a 65% reduction in risk for disease progression, which was the trial’s primary endpoint.

The IR regimen was also associated with better overall survival out to 4 years of follow-up, reported Tait D. Shanafelt, MD, of Stanford (Calif.) University.

“This establishes ibrutinib-based therapy as the most effective treatment tested to date in this disease for untreated patients,” he said at a media briefing prior at the annual meeting of the American Society of Hematology.

The study results are likely to dethrone FCR as the most active chemoimmunotherapy regimen against CLL, Dr. Shanafelt said.

In the ECOG-ACRIN Cancer Research Group E1912 trial, 529 patients aged 70 or younger with previously untreated CLL were enrolled and randomly assigned on a 2:1 basis to either standard therapy with six cycles of FCR according to standard protocols (175 patients), or IR, with ibrutinib 420 mg daily for each cycle, and rituximab delivered 50 mg/m² intravenously on day 1 of cycle 2, and 325 mg/m² on day 2 of the same cycle, and 500 mg/m² on day 1 for all remaining cycles (354 patients).

From cycle 8 until progression, patients in the IR arm received daily ibrutinib 420 mg.

Dr. Shanafelt presented results from both an intention-to-treat analysis and a per-protocol analysis excluding 22 patients in the IR arm and 9 patients in the FCR arm who were randomized but later found not to meet eligibility criteria.

After a mean follow-up of 34 months, there were 37 PFS events in the IR arm, compared with 40 events in the FCR arm in an intention-to-treat analysis. The difference translated into a hazard ratio for progression of 0.35 with IR (P less than .00001).

The results were similar in the per-protocol analysis, with an HR of 0.32 favoring IR (P less than .00001).*

There were four deaths in the IR arm, compared with 10 in the FCR arm at the time of the data lock, translating into a hazard ratio (HR) for overall survival of 0.17 (P less than .0003) in the intention-to-treat analysis, and 0.13 in the per-protocol analysis (P less than .0001).

Dr. Shanafelt noted that although the overall number of deaths was relatively small, there were twice as many patients enrolled in the IR arm as in the FCR arm, meaning that the rate of deaths in the FCR arm was fivefold higher than in the IR arm.

In a subgroup analysis of PFS, IR was superior to FCR regardless of patient age, sex, performance status, disease stage, or the presence or absence of the 11q23.3 deletion.

PFS was also significantly better with IR in patients with unmutated immunoglobulin heavy chain variable (IGHV) regions (HR 0.26, P less than .00001), but not in patients with mutated IGHV.*

Grade 3 or greater treatment-related adverse events occurred in 58.5% of patients in the IR arm, compared with 72.1% of patients in the FCR arm. Specific events that occurred significantly less often with IR included neutropenia (22.7% vs. 43.7%), anemia (2.6% vs. 12.0%), thrombocytopenia (2.9% vs. 13.9%), any infection (7.1% vs. 19.0%), and neutropenic fever (2.3% vs. 15.8%; P less than .001 for all comparisons).

Events that occurred more frequently with IR than FCR included atrial fibrillation (2.9% vs. 0%, P = .04), and hypertension (7.4% vs. 1.9%, P = .01).

Dr. Shanafelt acknowledged that one possible barrier to the IR regimen is cost; the monthly cost of ibrutinib maintenance is about $10,000, he said, although he noted that cost considerations were not studied in the trial.

“Future trials testing novel agent combinations to see if we can eliminate the need for chronic therapy should be pursued,” he said.

The trial was sponsored by the National Cancer Institute with additional support from Pharmacyclics. Dr. Shanafelt reported patents and royalties from the Mayo Clinic, and research funding from Celgene, GlaxoSmithKline, Genentech, Abbvie, Pharmacyclics, and Janssen.

SOURCE: Shanafelt TD et al. ASH 2018, Abstract LBA-4.

*Correction, 12/12/2018: An earlier version of this story misstated the P value in two comparisons.

SAN DIEGO – The combination of ibrutinib and rituximab was associated with a two-thirds reduction in chronic lymphocytic leukemia (CLL) progression, compared with standard chemoimmunotherapy in patients younger than 70 years old, interim results of a phase 3 randomized trial showed.

Among 529 patients with previously untreated, symptomatic CLL randomly assigned to ibrutinib-rituximab (IR) or to chemoimmunotherapy with fludarabine, cyclophosphamide, and rituximab (FCR), the IR regimen was associated with a 65% reduction in risk for disease progression, which was the trial’s primary endpoint.

The IR regimen was also associated with better overall survival out to 4 years of follow-up, reported Tait D. Shanafelt, MD, of Stanford (Calif.) University.

“This establishes ibrutinib-based therapy as the most effective treatment tested to date in this disease for untreated patients,” he said at a media briefing prior at the annual meeting of the American Society of Hematology.

The study results are likely to dethrone FCR as the most active chemoimmunotherapy regimen against CLL, Dr. Shanafelt said.

In the ECOG-ACRIN Cancer Research Group E1912 trial, 529 patients aged 70 or younger with previously untreated CLL were enrolled and randomly assigned on a 2:1 basis to either standard therapy with six cycles of FCR according to standard protocols (175 patients), or IR, with ibrutinib 420 mg daily for each cycle, and rituximab delivered 50 mg/m² intravenously on day 1 of cycle 2, and 325 mg/m² on day 2 of the same cycle, and 500 mg/m² on day 1 for all remaining cycles (354 patients).

From cycle 8 until progression, patients in the IR arm received daily ibrutinib 420 mg.

Dr. Shanafelt presented results from both an intention-to-treat analysis and a per-protocol analysis excluding 22 patients in the IR arm and 9 patients in the FCR arm who were randomized but later found not to meet eligibility criteria.

After a mean follow-up of 34 months, there were 37 PFS events in the IR arm, compared with 40 events in the FCR arm in an intention-to-treat analysis. The difference translated into a hazard ratio for progression of 0.35 with IR (P less than .00001).

The results were similar in the per-protocol analysis, with an HR of 0.32 favoring IR (P less than .00001).*

There were four deaths in the IR arm, compared with 10 in the FCR arm at the time of the data lock, translating into a hazard ratio (HR) for overall survival of 0.17 (P less than .0003) in the intention-to-treat analysis, and 0.13 in the per-protocol analysis (P less than .0001).

Dr. Shanafelt noted that although the overall number of deaths was relatively small, there were twice as many patients enrolled in the IR arm as in the FCR arm, meaning that the rate of deaths in the FCR arm was fivefold higher than in the IR arm.

In a subgroup analysis of PFS, IR was superior to FCR regardless of patient age, sex, performance status, disease stage, or the presence or absence of the 11q23.3 deletion.

PFS was also significantly better with IR in patients with unmutated immunoglobulin heavy chain variable (IGHV) regions (HR 0.26, P less than .00001), but not in patients with mutated IGHV.*

Grade 3 or greater treatment-related adverse events occurred in 58.5% of patients in the IR arm, compared with 72.1% of patients in the FCR arm. Specific events that occurred significantly less often with IR included neutropenia (22.7% vs. 43.7%), anemia (2.6% vs. 12.0%), thrombocytopenia (2.9% vs. 13.9%), any infection (7.1% vs. 19.0%), and neutropenic fever (2.3% vs. 15.8%; P less than .001 for all comparisons).

Events that occurred more frequently with IR than FCR included atrial fibrillation (2.9% vs. 0%, P = .04), and hypertension (7.4% vs. 1.9%, P = .01).

Dr. Shanafelt acknowledged that one possible barrier to the IR regimen is cost; the monthly cost of ibrutinib maintenance is about $10,000, he said, although he noted that cost considerations were not studied in the trial.

“Future trials testing novel agent combinations to see if we can eliminate the need for chronic therapy should be pursued,” he said.

The trial was sponsored by the National Cancer Institute with additional support from Pharmacyclics. Dr. Shanafelt reported patents and royalties from the Mayo Clinic, and research funding from Celgene, GlaxoSmithKline, Genentech, Abbvie, Pharmacyclics, and Janssen.

SOURCE: Shanafelt TD et al. ASH 2018, Abstract LBA-4.

*Correction, 12/12/2018: An earlier version of this story misstated the P value in two comparisons.

SAN DIEGO – The combination of ibrutinib and rituximab was associated with a two-thirds reduction in chronic lymphocytic leukemia (CLL) progression, compared with standard chemoimmunotherapy in patients younger than 70 years old, interim results of a phase 3 randomized trial showed.

Among 529 patients with previously untreated, symptomatic CLL randomly assigned to ibrutinib-rituximab (IR) or to chemoimmunotherapy with fludarabine, cyclophosphamide, and rituximab (FCR), the IR regimen was associated with a 65% reduction in risk for disease progression, which was the trial’s primary endpoint.

The IR regimen was also associated with better overall survival out to 4 years of follow-up, reported Tait D. Shanafelt, MD, of Stanford (Calif.) University.

“This establishes ibrutinib-based therapy as the most effective treatment tested to date in this disease for untreated patients,” he said at a media briefing prior at the annual meeting of the American Society of Hematology.

The study results are likely to dethrone FCR as the most active chemoimmunotherapy regimen against CLL, Dr. Shanafelt said.

In the ECOG-ACRIN Cancer Research Group E1912 trial, 529 patients aged 70 or younger with previously untreated CLL were enrolled and randomly assigned on a 2:1 basis to either standard therapy with six cycles of FCR according to standard protocols (175 patients), or IR, with ibrutinib 420 mg daily for each cycle, and rituximab delivered 50 mg/m² intravenously on day 1 of cycle 2, and 325 mg/m² on day 2 of the same cycle, and 500 mg/m² on day 1 for all remaining cycles (354 patients).

From cycle 8 until progression, patients in the IR arm received daily ibrutinib 420 mg.

Dr. Shanafelt presented results from both an intention-to-treat analysis and a per-protocol analysis excluding 22 patients in the IR arm and 9 patients in the FCR arm who were randomized but later found not to meet eligibility criteria.

After a mean follow-up of 34 months, there were 37 PFS events in the IR arm, compared with 40 events in the FCR arm in an intention-to-treat analysis. The difference translated into a hazard ratio for progression of 0.35 with IR (P less than .00001).

The results were similar in the per-protocol analysis, with an HR of 0.32 favoring IR (P less than .00001).*

There were four deaths in the IR arm, compared with 10 in the FCR arm at the time of the data lock, translating into a hazard ratio (HR) for overall survival of 0.17 (P less than .0003) in the intention-to-treat analysis, and 0.13 in the per-protocol analysis (P less than .0001).

Dr. Shanafelt noted that although the overall number of deaths was relatively small, there were twice as many patients enrolled in the IR arm as in the FCR arm, meaning that the rate of deaths in the FCR arm was fivefold higher than in the IR arm.

In a subgroup analysis of PFS, IR was superior to FCR regardless of patient age, sex, performance status, disease stage, or the presence or absence of the 11q23.3 deletion.

PFS was also significantly better with IR in patients with unmutated immunoglobulin heavy chain variable (IGHV) regions (HR 0.26, P less than .00001), but not in patients with mutated IGHV.*

Grade 3 or greater treatment-related adverse events occurred in 58.5% of patients in the IR arm, compared with 72.1% of patients in the FCR arm. Specific events that occurred significantly less often with IR included neutropenia (22.7% vs. 43.7%), anemia (2.6% vs. 12.0%), thrombocytopenia (2.9% vs. 13.9%), any infection (7.1% vs. 19.0%), and neutropenic fever (2.3% vs. 15.8%; P less than .001 for all comparisons).

Events that occurred more frequently with IR than FCR included atrial fibrillation (2.9% vs. 0%, P = .04), and hypertension (7.4% vs. 1.9%, P = .01).

Dr. Shanafelt acknowledged that one possible barrier to the IR regimen is cost; the monthly cost of ibrutinib maintenance is about $10,000, he said, although he noted that cost considerations were not studied in the trial.

“Future trials testing novel agent combinations to see if we can eliminate the need for chronic therapy should be pursued,” he said.

The trial was sponsored by the National Cancer Institute with additional support from Pharmacyclics. Dr. Shanafelt reported patents and royalties from the Mayo Clinic, and research funding from Celgene, GlaxoSmithKline, Genentech, Abbvie, Pharmacyclics, and Janssen.

SOURCE: Shanafelt TD et al. ASH 2018, Abstract LBA-4.

*Correction, 12/12/2018: An earlier version of this story misstated the P value in two comparisons.

SAN DIEGO – It was banner year for new hematology drug approvals, according to R. Angelo de Claro, MD, of the Food and Drug Administration.

So far in 2018 there have been 32 new malignant hematology and nonmalignant hematology drug approvals by the FDA, including 12 first-time approvals, 5 new biosimilars, and 15 new indications for previously approved drugs, Dr. de Claro, clinical team leader in the FDA’s division of hematology products in Silver Spring, Md., said during an overview of the approvals at the annual meeting of the American Society of Hematology.

These include six new approvals for first-line treatment, and eight for pediatric indications, he said.

Highlights were discussed at two ASH-FDA joint symposia at the meeting, including one focused on the malignant hematology approvals, and another on the nonmalignant hematology approvals. In a video interview, Dr. de Claro provides some additional insight into their importance and about what might lie ahead.

“I think what’s exciting is that you have drug development occurring in more common conditions such as chronic lymphocytic leukemia, as well as in rare conditions, including hairy cell leukemia – and the first-ever approval in hemophagocytic lymphohistiocytosis,” he said. “It’s been very busy at the FDA; stay tuned ... the year’s not done yet. There could be more coming and we certainly anticipate more applications in the future.”

Dr. de Claro is an FDA employee. He reported having no other relevant disclosures.

[email protected]

SAN DIEGO – It was banner year for new hematology drug approvals, according to R. Angelo de Claro, MD, of the Food and Drug Administration.

So far in 2018 there have been 32 new malignant hematology and nonmalignant hematology drug approvals by the FDA, including 12 first-time approvals, 5 new biosimilars, and 15 new indications for previously approved drugs, Dr. de Claro, clinical team leader in the FDA’s division of hematology products in Silver Spring, Md., said during an overview of the approvals at the annual meeting of the American Society of Hematology.

These include six new approvals for first-line treatment, and eight for pediatric indications, he said.

Highlights were discussed at two ASH-FDA joint symposia at the meeting, including one focused on the malignant hematology approvals, and another on the nonmalignant hematology approvals. In a video interview, Dr. de Claro provides some additional insight into their importance and about what might lie ahead.

“I think what’s exciting is that you have drug development occurring in more common conditions such as chronic lymphocytic leukemia, as well as in rare conditions, including hairy cell leukemia – and the first-ever approval in hemophagocytic lymphohistiocytosis,” he said. “It’s been very busy at the FDA; stay tuned ... the year’s not done yet. There could be more coming and we certainly anticipate more applications in the future.”

Dr. de Claro is an FDA employee. He reported having no other relevant disclosures.

[email protected]

SAN DIEGO – It was banner year for new hematology drug approvals, according to R. Angelo de Claro, MD, of the Food and Drug Administration.

So far in 2018 there have been 32 new malignant hematology and nonmalignant hematology drug approvals by the FDA, including 12 first-time approvals, 5 new biosimilars, and 15 new indications for previously approved drugs, Dr. de Claro, clinical team leader in the FDA’s division of hematology products in Silver Spring, Md., said during an overview of the approvals at the annual meeting of the American Society of Hematology.

These include six new approvals for first-line treatment, and eight for pediatric indications, he said.

Highlights were discussed at two ASH-FDA joint symposia at the meeting, including one focused on the malignant hematology approvals, and another on the nonmalignant hematology approvals. In a video interview, Dr. de Claro provides some additional insight into their importance and about what might lie ahead.

“I think what’s exciting is that you have drug development occurring in more common conditions such as chronic lymphocytic leukemia, as well as in rare conditions, including hairy cell leukemia – and the first-ever approval in hemophagocytic lymphohistiocytosis,” he said. “It’s been very busy at the FDA; stay tuned ... the year’s not done yet. There could be more coming and we certainly anticipate more applications in the future.”

Dr. de Claro is an FDA employee. He reported having no other relevant disclosures.

[email protected]

SAN DIEGO – A recurrent mutation in BCL2, the therapeutic target of venetoclax (Venclexta), appears to be a major contributor to drug resistance in patients with chronic lymphocytic leukemia (CLL), investigators reported.

The mutation has been detected in some patients with CLL up to 2 years before resistance to venetoclax actually develops, said lead author Piers Blombery, MBBS, from the Peter MacCallum Cancer Center in Melbourne.

“We have identified the first acquired BCL2 mutation developed in patients clinically treated with venetoclax,” he said in a late-breaking oral abstract session at the annual meeting of the American Society of Hematology.

The mutation, which the investigators have labeled BCL2 Gly101Val, “is a recurrent and frequent mediator of resistance and may be detected years before clinical relapse occurs,” he added.

The paper was published online in Cancer Discovery (2018 Dec 4. doi: 10.1158/2159-8290.CD-18-1119) to coincide with the presentation at ASH.

Despite the demonstrated efficacy of venetoclax as continuous therapy in patients with relapsed or refractory CLL, the majority of patients experience disease progression, prompting the investigators to explore molecular mechanisms of secondary resistance.

To do this, they analyzed paired samples from 15 patients with CLL, enrolled in clinical trials of venetoclax, collected both before the start of venetoclax therapy and at the time of disease progression.

In seven of the patients, they identified a novel mutation that showed up at the time of progression, but was absent from the pre-venetoclax samples. The mutation first became detectable from about 19 to 42 months after the start of therapy and preceded clinical progression by as much as 25 months, the investigators found.

They pinned the mutation down to the BH3-binding groove on BCL2, the same molecular site targeted by venetoclax. They found that the mutation was not present in samples from 96 patients with venetoclax-naive CLL nor in any other B-cell malignancies. Searches for references to the mutation in both a cancer database (COSMIC) and a population database (gnomAD) came up empty.

In other experiments, they determined that cell lines overexpressing BCL2 Gly101Val are resistant to venetoclax, and that in the presence of venetoclax in vitro, BCL2 Gly101Val-expressing cells have a growth advantage, compared with wild type cells.

Additionally, they showed that the mutation results in impaired venetoclax binding in vitro.

“BCL2 Gly101Val is observed subclonally, implicating multiple mechanisms of venetoclax resistance in the same patient,” Dr. Blombery said.

In an interview, Dr. Blombery said that the identification of the resistance mutation is a strong rationale for using combination therapy to treat patients with relapsed or refractory CLL to help prevent or attenuate selection pressures that lead to resistance.

The investigators were supported by the Wilson Center for Lymphoma Genomics, Snowdome Foundation, National Health Medical Research Council, Leukemia and Lymphoma Society, Leukemia Foundation, Cancer Council of Victoria, and Australian Cancer Research Foundation. Dr. Blombery reported having no relevant disclosures.

SOURCE: Blombery P et al. ASH 2018, Abstract LBA-7.

SAN DIEGO – A recurrent mutation in BCL2, the therapeutic target of venetoclax (Venclexta), appears to be a major contributor to drug resistance in patients with chronic lymphocytic leukemia (CLL), investigators reported.

The mutation has been detected in some patients with CLL up to 2 years before resistance to venetoclax actually develops, said lead author Piers Blombery, MBBS, from the Peter MacCallum Cancer Center in Melbourne.

“We have identified the first acquired BCL2 mutation developed in patients clinically treated with venetoclax,” he said in a late-breaking oral abstract session at the annual meeting of the American Society of Hematology.

The mutation, which the investigators have labeled BCL2 Gly101Val, “is a recurrent and frequent mediator of resistance and may be detected years before clinical relapse occurs,” he added.

The paper was published online in Cancer Discovery (2018 Dec 4. doi: 10.1158/2159-8290.CD-18-1119) to coincide with the presentation at ASH.

Despite the demonstrated efficacy of venetoclax as continuous therapy in patients with relapsed or refractory CLL, the majority of patients experience disease progression, prompting the investigators to explore molecular mechanisms of secondary resistance.

To do this, they analyzed paired samples from 15 patients with CLL, enrolled in clinical trials of venetoclax, collected both before the start of venetoclax therapy and at the time of disease progression.

In seven of the patients, they identified a novel mutation that showed up at the time of progression, but was absent from the pre-venetoclax samples. The mutation first became detectable from about 19 to 42 months after the start of therapy and preceded clinical progression by as much as 25 months, the investigators found.

They pinned the mutation down to the BH3-binding groove on BCL2, the same molecular site targeted by venetoclax. They found that the mutation was not present in samples from 96 patients with venetoclax-naive CLL nor in any other B-cell malignancies. Searches for references to the mutation in both a cancer database (COSMIC) and a population database (gnomAD) came up empty.

In other experiments, they determined that cell lines overexpressing BCL2 Gly101Val are resistant to venetoclax, and that in the presence of venetoclax in vitro, BCL2 Gly101Val-expressing cells have a growth advantage, compared with wild type cells.

Additionally, they showed that the mutation results in impaired venetoclax binding in vitro.

“BCL2 Gly101Val is observed subclonally, implicating multiple mechanisms of venetoclax resistance in the same patient,” Dr. Blombery said.

In an interview, Dr. Blombery said that the identification of the resistance mutation is a strong rationale for using combination therapy to treat patients with relapsed or refractory CLL to help prevent or attenuate selection pressures that lead to resistance.

The investigators were supported by the Wilson Center for Lymphoma Genomics, Snowdome Foundation, National Health Medical Research Council, Leukemia and Lymphoma Society, Leukemia Foundation, Cancer Council of Victoria, and Australian Cancer Research Foundation. Dr. Blombery reported having no relevant disclosures.

SOURCE: Blombery P et al. ASH 2018, Abstract LBA-7.

SAN DIEGO – A recurrent mutation in BCL2, the therapeutic target of venetoclax (Venclexta), appears to be a major contributor to drug resistance in patients with chronic lymphocytic leukemia (CLL), investigators reported.

The mutation has been detected in some patients with CLL up to 2 years before resistance to venetoclax actually develops, said lead author Piers Blombery, MBBS, from the Peter MacCallum Cancer Center in Melbourne.

“We have identified the first acquired BCL2 mutation developed in patients clinically treated with venetoclax,” he said in a late-breaking oral abstract session at the annual meeting of the American Society of Hematology.

The mutation, which the investigators have labeled BCL2 Gly101Val, “is a recurrent and frequent mediator of resistance and may be detected years before clinical relapse occurs,” he added.

The paper was published online in Cancer Discovery (2018 Dec 4. doi: 10.1158/2159-8290.CD-18-1119) to coincide with the presentation at ASH.

Despite the demonstrated efficacy of venetoclax as continuous therapy in patients with relapsed or refractory CLL, the majority of patients experience disease progression, prompting the investigators to explore molecular mechanisms of secondary resistance.

To do this, they analyzed paired samples from 15 patients with CLL, enrolled in clinical trials of venetoclax, collected both before the start of venetoclax therapy and at the time of disease progression.

In seven of the patients, they identified a novel mutation that showed up at the time of progression, but was absent from the pre-venetoclax samples. The mutation first became detectable from about 19 to 42 months after the start of therapy and preceded clinical progression by as much as 25 months, the investigators found.

They pinned the mutation down to the BH3-binding groove on BCL2, the same molecular site targeted by venetoclax. They found that the mutation was not present in samples from 96 patients with venetoclax-naive CLL nor in any other B-cell malignancies. Searches for references to the mutation in both a cancer database (COSMIC) and a population database (gnomAD) came up empty.

In other experiments, they determined that cell lines overexpressing BCL2 Gly101Val are resistant to venetoclax, and that in the presence of venetoclax in vitro, BCL2 Gly101Val-expressing cells have a growth advantage, compared with wild type cells.

Additionally, they showed that the mutation results in impaired venetoclax binding in vitro.

“BCL2 Gly101Val is observed subclonally, implicating multiple mechanisms of venetoclax resistance in the same patient,” Dr. Blombery said.

In an interview, Dr. Blombery said that the identification of the resistance mutation is a strong rationale for using combination therapy to treat patients with relapsed or refractory CLL to help prevent or attenuate selection pressures that lead to resistance.

The investigators were supported by the Wilson Center for Lymphoma Genomics, Snowdome Foundation, National Health Medical Research Council, Leukemia and Lymphoma Society, Leukemia Foundation, Cancer Council of Victoria, and Australian Cancer Research Foundation. Dr. Blombery reported having no relevant disclosures.

SOURCE: Blombery P et al. ASH 2018, Abstract LBA-7.

SAN DIEGO – Ibrutinib alone or in combination with rituximab resulted in superior progression-free survival (PFS) when compared with bendamustine plus rituximab in the randomized, phase 3 Alliance A041202 trial of older patients with previously untreated chronic lymphocytic leukemia (CLL).

Sharon Worcester/MDedge News

[email protected]

SOURCE: Woyach JA et al. ASH 2018, Abstract 6.

SAN DIEGO – Ibrutinib alone or in combination with rituximab resulted in superior progression-free survival (PFS) when compared with bendamustine plus rituximab in the randomized, phase 3 Alliance A041202 trial of older patients with previously untreated chronic lymphocytic leukemia (CLL).

Sharon Worcester/MDedge News

[email protected]

SOURCE: Woyach JA et al. ASH 2018, Abstract 6.

SAN DIEGO – Ibrutinib alone or in combination with rituximab resulted in superior progression-free survival (PFS) when compared with bendamustine plus rituximab in the randomized, phase 3 Alliance A041202 trial of older patients with previously untreated chronic lymphocytic leukemia (CLL).

Sharon Worcester/MDedge News

[email protected]

SOURCE: Woyach JA et al. ASH 2018, Abstract 6.

The presence or absence in tumor cells of cortactin, a cytoskeleton-remodeling adapter protein, may be a marker to help pathologists distinguish between chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL), investigators suggest.

A study of cortactin expression in tumor samples from patients with B-cell CLL, MCL, and other hematologic malignancies showed that while cortactin was present in 14 of 17 CLL samples, it was not expressed on any of 16 MCL samples, reported Marco Pizzi, MD, PhD, from the University of Padova (Italy) and his colleagues.

“In particular, cortactin may contribute to the differential diagnosis between CLL and MCL, two neoplasms with similar histological features but very different clinical outcome. Further studies are needed to clarify the molecular mechanisms of deranged cortactin expression in MCL and CLL and to investigate any possible relationship between cortactin status and the biological features of these lymphomas,” they wrote in Human Pathology.

Overexpression of cortactin has been reported in several solid tumors, and increased expression of CTTN, the gene encoding for cortactin, has been associated with aggressive, poor prognosis disease, the investigators noted.

To characterize cortactin expression in lymphoid and hematopoietic cells and detect potential associations between cortactin and virulence of hematologic malignancies, the investigators performed immunohistochemical analysis on samples from 131 patients treated at their center. The samples included 17 cases of CLL, 16 of MCL, 25 of follicular lymphoma (FL), 30 of marginal zone lymphoma (MZL), 10 of hairy cell leukemia, three of splenic diffuse red pulp small B-cell lymphomas (SDRPBL), and 30 of diffuse large B-cell lymphoma (DLBCL).

They found that cortactin was expressed in 14 of the 17 CLL samples, all 10 of the HCL samples, and 22 of the 30 DLBCL samples. In contrast, there was no cortactin expression detected in any of either 16 MCL or three SDRPBL samples. The researchers found that 13 of 30 MZL samples had low-level staining. In FL, cortactin was expressed in 2 of the samples but in the remaining 23 cases the researchers found only scattered cortactin-positive lymphoid elements of non–B-cell lineage.

The investigators also found that cortactin expression in CLL correlated with other CLL-specific markers, and found that expression of two or more of the markers had 89.1% sensitivity, 100% specificity, a 100% positive predictive value, and 90.5% negative predictive value for a diagnosis of CLL.

In addition, they saw that the immunohistochemical results were similar to those for CTTN gene expression assessed by in silico analysis.

The investigators noted that CLL and MCL are challenging to differentiate from one another because of morphologic similarities and partially overlapping immunophenotypes.

“In this context, cortactin expression would strongly sustain a diagnosis of CLL over MCL, particularly in association with other CLL markers (i.e., LEF1 and CD200),” they wrote.

The study was internally supported. The authors declared no conflicts of interest.

SOURCE: Pizzi M et al. Hum Pathol. 2018 Nov 17. doi: 10.1016/j.humpath.2018.10.038.
 

The presence or absence in tumor cells of cortactin, a cytoskeleton-remodeling adapter protein, may be a marker to help pathologists distinguish between chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL), investigators suggest.

A study of cortactin expression in tumor samples from patients with B-cell CLL, MCL, and other hematologic malignancies showed that while cortactin was present in 14 of 17 CLL samples, it was not expressed on any of 16 MCL samples, reported Marco Pizzi, MD, PhD, from the University of Padova (Italy) and his colleagues.

“In particular, cortactin may contribute to the differential diagnosis between CLL and MCL, two neoplasms with similar histological features but very different clinical outcome. Further studies are needed to clarify the molecular mechanisms of deranged cortactin expression in MCL and CLL and to investigate any possible relationship between cortactin status and the biological features of these lymphomas,” they wrote in Human Pathology.

Overexpression of cortactin has been reported in several solid tumors, and increased expression of CTTN, the gene encoding for cortactin, has been associated with aggressive, poor prognosis disease, the investigators noted.

To characterize cortactin expression in lymphoid and hematopoietic cells and detect potential associations between cortactin and virulence of hematologic malignancies, the investigators performed immunohistochemical analysis on samples from 131 patients treated at their center. The samples included 17 cases of CLL, 16 of MCL, 25 of follicular lymphoma (FL), 30 of marginal zone lymphoma (MZL), 10 of hairy cell leukemia, three of splenic diffuse red pulp small B-cell lymphomas (SDRPBL), and 30 of diffuse large B-cell lymphoma (DLBCL).

They found that cortactin was expressed in 14 of the 17 CLL samples, all 10 of the HCL samples, and 22 of the 30 DLBCL samples. In contrast, there was no cortactin expression detected in any of either 16 MCL or three SDRPBL samples. The researchers found that 13 of 30 MZL samples had low-level staining. In FL, cortactin was expressed in 2 of the samples but in the remaining 23 cases the researchers found only scattered cortactin-positive lymphoid elements of non–B-cell lineage.

The investigators also found that cortactin expression in CLL correlated with other CLL-specific markers, and found that expression of two or more of the markers had 89.1% sensitivity, 100% specificity, a 100% positive predictive value, and 90.5% negative predictive value for a diagnosis of CLL.

In addition, they saw that the immunohistochemical results were similar to those for CTTN gene expression assessed by in silico analysis.

The investigators noted that CLL and MCL are challenging to differentiate from one another because of morphologic similarities and partially overlapping immunophenotypes.

“In this context, cortactin expression would strongly sustain a diagnosis of CLL over MCL, particularly in association with other CLL markers (i.e., LEF1 and CD200),” they wrote.

The study was internally supported. The authors declared no conflicts of interest.

SOURCE: Pizzi M et al. Hum Pathol. 2018 Nov 17. doi: 10.1016/j.humpath.2018.10.038.
 

The presence or absence in tumor cells of cortactin, a cytoskeleton-remodeling adapter protein, may be a marker to help pathologists distinguish between chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL), investigators suggest.

A study of cortactin expression in tumor samples from patients with B-cell CLL, MCL, and other hematologic malignancies showed that while cortactin was present in 14 of 17 CLL samples, it was not expressed on any of 16 MCL samples, reported Marco Pizzi, MD, PhD, from the University of Padova (Italy) and his colleagues.

“In particular, cortactin may contribute to the differential diagnosis between CLL and MCL, two neoplasms with similar histological features but very different clinical outcome. Further studies are needed to clarify the molecular mechanisms of deranged cortactin expression in MCL and CLL and to investigate any possible relationship between cortactin status and the biological features of these lymphomas,” they wrote in Human Pathology.

Overexpression of cortactin has been reported in several solid tumors, and increased expression of CTTN, the gene encoding for cortactin, has been associated with aggressive, poor prognosis disease, the investigators noted.

To characterize cortactin expression in lymphoid and hematopoietic cells and detect potential associations between cortactin and virulence of hematologic malignancies, the investigators performed immunohistochemical analysis on samples from 131 patients treated at their center. The samples included 17 cases of CLL, 16 of MCL, 25 of follicular lymphoma (FL), 30 of marginal zone lymphoma (MZL), 10 of hairy cell leukemia, three of splenic diffuse red pulp small B-cell lymphomas (SDRPBL), and 30 of diffuse large B-cell lymphoma (DLBCL).

They found that cortactin was expressed in 14 of the 17 CLL samples, all 10 of the HCL samples, and 22 of the 30 DLBCL samples. In contrast, there was no cortactin expression detected in any of either 16 MCL or three SDRPBL samples. The researchers found that 13 of 30 MZL samples had low-level staining. In FL, cortactin was expressed in 2 of the samples but in the remaining 23 cases the researchers found only scattered cortactin-positive lymphoid elements of non–B-cell lineage.

The investigators also found that cortactin expression in CLL correlated with other CLL-specific markers, and found that expression of two or more of the markers had 89.1% sensitivity, 100% specificity, a 100% positive predictive value, and 90.5% negative predictive value for a diagnosis of CLL.

In addition, they saw that the immunohistochemical results were similar to those for CTTN gene expression assessed by in silico analysis.

The investigators noted that CLL and MCL are challenging to differentiate from one another because of morphologic similarities and partially overlapping immunophenotypes.

“In this context, cortactin expression would strongly sustain a diagnosis of CLL over MCL, particularly in association with other CLL markers (i.e., LEF1 and CD200),” they wrote.

The study was internally supported. The authors declared no conflicts of interest.

SOURCE: Pizzi M et al. Hum Pathol. 2018 Nov 17. doi: 10.1016/j.humpath.2018.10.038.
 

In the closest thing the medical world has to movie trailers, the American Society of Hematology held a press conference offering a peek into the much anticipated (and much hyped) clinical and research abstracts that will be presented at the 2018 ASH annual meeting.

Shorter R-CHOP regimen for DLBCL

Under the heading “Big Trials, Big Results” will be data from the FLYER trial, a phase 3, randomized, deescalation trial in 592 patients aged 18-60 years with favorable-prognosis diffuse large B-cell lymphoma. The investigators report that both progression-free survival and overall survival with four cycles of R-CHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine and prednisone) were noninferior to those for patients treated with six cycles of R-CHOP (abstract 781).

Ibrutinib mastery in CLL

Also on the program are results of a study showing that ibrutinib (Imbruvica), either alone or in combination with rituximab, is associated with superior progression-free survival than bendamustine and rituximab in older patients with chronic lymphocytic leukemia (CLL).

The trial, the Alliance North American Intergroup Study A041202 (abstract 6) is the first major trial to pit ibrutinib against the modern standard of immunochemotherapy rather than the older standard of chlorambucil, Dr. Brodsky noted.

Anemia support in beta-thalassemia, MDS

In nonmalignant disease, investigators in the randomized, phase 3 BELIEVE trial are reporting results of their study showing that the first-in-class erythroid maturation agent luspatercept was associated with significant reductions in the need for RBC transfusion in adults with transfusion-dependent beta-thalassemia.

The investigators report that the experimental agent was “generally well tolerated” (abstract 163).

“Beyond a proof of principle, [this is] certainly a very exciting advancement in this group of patients who otherwise had very few treatment options,” said Alexis A. Thompson, MD, associate director of equity and minority health at the Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, and the current ASH president.

Dr. Thompson also highlighted the MEDALIST trial (abstract 1), a phase 3, randomized study showing that luspatercept significantly reduced transfusion burden, compared with placebo, in patients with anemia caused by very low–, low-, or intermediate-risk myelodysplastic syndrome with ring sideroblasts who require RBC transfusions.

“This group of patients were individuals who were refractory or were not responders or did not tolerate erythropoietic stimulating agents and therefore were requiring regular transfusion,” Dr. Thompson said.

Worth the wait

The late-breaking abstract program was stretched from the usual six abstracts to seven this year because of the unusually high quality of the science, Dr. Brodsky said.

Among these star attractions are results of a phase 3, randomized study of daratumumab (Darzalex) plus lenalidomide and dexamethasone versus lenalidomide-dexamethasone alone for patients with newly diagnosed multiple myeloma who are ineligible for transplant.

The investigators found that adding daratumumab reduced the risk of disease progression or death by close to 50%, supporting the combination as a new standard of care in these patients, according to Thierry Facon, MD, from the Hospital Claude Huriez in Lille, France, and colleagues (abstract LBA-2).

Two other late-breakers deal with CLL. The first, a randomized, phase 3 study of ibrutinib-based therapy versus standard fludarabine, cyclophosphamide, and rituximab chemoimmunotherapy in younger patients with untreated CLL, found that ibrutinib and rituximab provided significantly better progression-free survival and overall survival (abstract LBA-4).

“These findings have immediate practice-changing implications and establish ibrutinib-based therapy as the most efficacious first-line therapy for patients with CLL,” wrote Tait D. Shanafelt, MD, from Stanford (Calif.) University, and colleagues.

On a less positive note, Australian researchers report their discovery of a recurrent mutation in BCL2 that confers resistance to venetoclax (Venclexta) in patients with progressive CLL (abstract LBA-7).

“This mutation provides new insights into the pathobiology of venetoclax resistance and provides a potential biomarker of impending clinical relapse,” wrote Piers Blombery, MBBS, from the University of Melbourne, and colleagues.

Finally, investigators from children’s hospitals in the United States and Europe report promising findings on the safety and efficacy of emapalumab for the treatment of patients with the rare genetic disorder primary hemophagocytic lymphohistiocytosis (HLH).

The drug, newly approved by the Food and Drug Administration, was able to control HLH’s hyperinflammatory activity, and allowed a substantial proportion of patients to survive to hematopoietic stem cell transplantation, the investigators said (abstract LBA-6­).

In the closest thing the medical world has to movie trailers, the American Society of Hematology held a press conference offering a peek into the much anticipated (and much hyped) clinical and research abstracts that will be presented at the 2018 ASH annual meeting.

Shorter R-CHOP regimen for DLBCL

Under the heading “Big Trials, Big Results” will be data from the FLYER trial, a phase 3, randomized, deescalation trial in 592 patients aged 18-60 years with favorable-prognosis diffuse large B-cell lymphoma. The investigators report that both progression-free survival and overall survival with four cycles of R-CHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine and prednisone) were noninferior to those for patients treated with six cycles of R-CHOP (abstract 781).

Ibrutinib mastery in CLL

Also on the program are results of a study showing that ibrutinib (Imbruvica), either alone or in combination with rituximab, is associated with superior progression-free survival than bendamustine and rituximab in older patients with chronic lymphocytic leukemia (CLL).

The trial, the Alliance North American Intergroup Study A041202 (abstract 6) is the first major trial to pit ibrutinib against the modern standard of immunochemotherapy rather than the older standard of chlorambucil, Dr. Brodsky noted.

Anemia support in beta-thalassemia, MDS

In nonmalignant disease, investigators in the randomized, phase 3 BELIEVE trial are reporting results of their study showing that the first-in-class erythroid maturation agent luspatercept was associated with significant reductions in the need for RBC transfusion in adults with transfusion-dependent beta-thalassemia.

The investigators report that the experimental agent was “generally well tolerated” (abstract 163).

“Beyond a proof of principle, [this is] certainly a very exciting advancement in this group of patients who otherwise had very few treatment options,” said Alexis A. Thompson, MD, associate director of equity and minority health at the Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, and the current ASH president.

Dr. Thompson also highlighted the MEDALIST trial (abstract 1), a phase 3, randomized study showing that luspatercept significantly reduced transfusion burden, compared with placebo, in patients with anemia caused by very low–, low-, or intermediate-risk myelodysplastic syndrome with ring sideroblasts who require RBC transfusions.

“This group of patients were individuals who were refractory or were not responders or did not tolerate erythropoietic stimulating agents and therefore were requiring regular transfusion,” Dr. Thompson said.

Worth the wait

The late-breaking abstract program was stretched from the usual six abstracts to seven this year because of the unusually high quality of the science, Dr. Brodsky said.

Among these star attractions are results of a phase 3, randomized study of daratumumab (Darzalex) plus lenalidomide and dexamethasone versus lenalidomide-dexamethasone alone for patients with newly diagnosed multiple myeloma who are ineligible for transplant.

The investigators found that adding daratumumab reduced the risk of disease progression or death by close to 50%, supporting the combination as a new standard of care in these patients, according to Thierry Facon, MD, from the Hospital Claude Huriez in Lille, France, and colleagues (abstract LBA-2).

Two other late-breakers deal with CLL. The first, a randomized, phase 3 study of ibrutinib-based therapy versus standard fludarabine, cyclophosphamide, and rituximab chemoimmunotherapy in younger patients with untreated CLL, found that ibrutinib and rituximab provided significantly better progression-free survival and overall survival (abstract LBA-4).

“These findings have immediate practice-changing implications and establish ibrutinib-based therapy as the most efficacious first-line therapy for patients with CLL,” wrote Tait D. Shanafelt, MD, from Stanford (Calif.) University, and colleagues.

On a less positive note, Australian researchers report their discovery of a recurrent mutation in BCL2 that confers resistance to venetoclax (Venclexta) in patients with progressive CLL (abstract LBA-7).

“This mutation provides new insights into the pathobiology of venetoclax resistance and provides a potential biomarker of impending clinical relapse,” wrote Piers Blombery, MBBS, from the University of Melbourne, and colleagues.

Finally, investigators from children’s hospitals in the United States and Europe report promising findings on the safety and efficacy of emapalumab for the treatment of patients with the rare genetic disorder primary hemophagocytic lymphohistiocytosis (HLH).

The drug, newly approved by the Food and Drug Administration, was able to control HLH’s hyperinflammatory activity, and allowed a substantial proportion of patients to survive to hematopoietic stem cell transplantation, the investigators said (abstract LBA-6­).

In the closest thing the medical world has to movie trailers, the American Society of Hematology held a press conference offering a peek into the much anticipated (and much hyped) clinical and research abstracts that will be presented at the 2018 ASH annual meeting.

Shorter R-CHOP regimen for DLBCL

Under the heading “Big Trials, Big Results” will be data from the FLYER trial, a phase 3, randomized, deescalation trial in 592 patients aged 18-60 years with favorable-prognosis diffuse large B-cell lymphoma. The investigators report that both progression-free survival and overall survival with four cycles of R-CHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine and prednisone) were noninferior to those for patients treated with six cycles of R-CHOP (abstract 781).

Ibrutinib mastery in CLL

Also on the program are results of a study showing that ibrutinib (Imbruvica), either alone or in combination with rituximab, is associated with superior progression-free survival than bendamustine and rituximab in older patients with chronic lymphocytic leukemia (CLL).

The trial, the Alliance North American Intergroup Study A041202 (abstract 6) is the first major trial to pit ibrutinib against the modern standard of immunochemotherapy rather than the older standard of chlorambucil, Dr. Brodsky noted.

Anemia support in beta-thalassemia, MDS

In nonmalignant disease, investigators in the randomized, phase 3 BELIEVE trial are reporting results of their study showing that the first-in-class erythroid maturation agent luspatercept was associated with significant reductions in the need for RBC transfusion in adults with transfusion-dependent beta-thalassemia.

The investigators report that the experimental agent was “generally well tolerated” (abstract 163).

“Beyond a proof of principle, [this is] certainly a very exciting advancement in this group of patients who otherwise had very few treatment options,” said Alexis A. Thompson, MD, associate director of equity and minority health at the Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, and the current ASH president.

Dr. Thompson also highlighted the MEDALIST trial (abstract 1), a phase 3, randomized study showing that luspatercept significantly reduced transfusion burden, compared with placebo, in patients with anemia caused by very low–, low-, or intermediate-risk myelodysplastic syndrome with ring sideroblasts who require RBC transfusions.

“This group of patients were individuals who were refractory or were not responders or did not tolerate erythropoietic stimulating agents and therefore were requiring regular transfusion,” Dr. Thompson said.

Worth the wait

The late-breaking abstract program was stretched from the usual six abstracts to seven this year because of the unusually high quality of the science, Dr. Brodsky said.

Among these star attractions are results of a phase 3, randomized study of daratumumab (Darzalex) plus lenalidomide and dexamethasone versus lenalidomide-dexamethasone alone for patients with newly diagnosed multiple myeloma who are ineligible for transplant.

The investigators found that adding daratumumab reduced the risk of disease progression or death by close to 50%, supporting the combination as a new standard of care in these patients, according to Thierry Facon, MD, from the Hospital Claude Huriez in Lille, France, and colleagues (abstract LBA-2).

Two other late-breakers deal with CLL. The first, a randomized, phase 3 study of ibrutinib-based therapy versus standard fludarabine, cyclophosphamide, and rituximab chemoimmunotherapy in younger patients with untreated CLL, found that ibrutinib and rituximab provided significantly better progression-free survival and overall survival (abstract LBA-4).

“These findings have immediate practice-changing implications and establish ibrutinib-based therapy as the most efficacious first-line therapy for patients with CLL,” wrote Tait D. Shanafelt, MD, from Stanford (Calif.) University, and colleagues.

On a less positive note, Australian researchers report their discovery of a recurrent mutation in BCL2 that confers resistance to venetoclax (Venclexta) in patients with progressive CLL (abstract LBA-7).

“This mutation provides new insights into the pathobiology of venetoclax resistance and provides a potential biomarker of impending clinical relapse,” wrote Piers Blombery, MBBS, from the University of Melbourne, and colleagues.

Finally, investigators from children’s hospitals in the United States and Europe report promising findings on the safety and efficacy of emapalumab for the treatment of patients with the rare genetic disorder primary hemophagocytic lymphohistiocytosis (HLH).

The drug, newly approved by the Food and Drug Administration, was able to control HLH’s hyperinflammatory activity, and allowed a substantial proportion of patients to survive to hematopoietic stem cell transplantation, the investigators said (abstract LBA-6­).

CHICAGO – Asymptomatic chronic lymphocytic leukemia (CLL) patients should be observed, but consider therapy when symptoms develop, said Paul M. Barr, MD.

Courtesy Matt Wittmeyer/University of Rochester Medical Center

He described a patient who had been observed for 7 years when he began to complain of increasing fatigue and lost work time. A complete blood count (CBC) showed thrombocytopenia.

The recently updated International Workshop on Chronic Lymphocytic Leukemia (iwCLL) guidelines state that assessments before treatment in this type of patient should include history and physical, evaluation of infectious disease status, and routine laboratory testing – including CBC and differential, chemistry, serum immunoglobulin, and direct antiglobulin test.

“Bone marrow biopsies and [computed tomography] scans are listed as ‘not necessarily required,’ ” Dr. Barr, medical director of the Clinical Trials Office for Wilmot Cancer Institute at the University of Rochester (N.Y.) said during a presentation at the American Society of Hematology Meeting on Hematologic Malignancies.

He added that he opts for CT scans prior to therapy “to understand the patient’s disease burden and potentially to compare to later” and that bone marrow biopsy is “still very reasonable” for understanding the source of a patient’s cytopenias.

“Is it marrow failure or [immune thrombocytopenia]? Could the patient have [myelodysplastic syndrome]? All important considerations,” he said.

Positron emission tomography (PET) scans, however, are only considered when there is concern about transformation, he noted.

Predictive tests that should be conducted before initiating therapy, and that could help in guiding therapy decisions, include TP53 mutation testing and immunoglobulin heavy chain variable region gene (IGHV) mutational status testing (although this doesn’t need to be repeated if it was done at diagnosis because mutational status doesn’t change). Another helpful test is molecular cytogenetics using fluorescence in situ hybridization (FISH) for del(13q), del(17p), and trisomy 12 in peripheral blood lymphocytes. This should be repeated even it was done at diagnosis because patients can acquire additional molecular aberrations over time, Dr. Barr said.

Among the data that justify this advice for predictive testing are studies showing the curative potential of fludarabine/cyclophosphamide/rituximab (FCR) in mutated IGHV CLL, the progression-free survival (PFS) benefits of ibrutinib for patients with del(17p), and the activity of idelalisib in relapsed/refractory CLL patients, including those with TP53 dysfunction.

“The IGHV mutation status is useful to know what to expect from chemoimmunotherapy over time,” Dr. Barr said, explaining that several analyses demonstrate that patients with mutated IGHV genes (patients with low-risk disease) respond exceptionally well to chemoimmunotherapy, especially FCR.

In fact, studies, including a 2016 study by Philip A. Thompson and his colleagues and another by Kirsten Fischer and her colleagues, show that nearly 60% of patients with IGHV mutation remain in remission 10 years after FCR treatment, he said. However, the same is not necessarily true for bendamustine/rituximab (BR); the CLL10 study showed a significantly greater PFS with FCR, compared with that seen with BR.

Unmutated patients in that study had lower PFS, but the outcomes were still better with FCR than with BR, he said.

Studies of novel agents, including ibrutinib and idelalisib, suggest they may have particular benefit in higher-risk patients.

Ibrutinib was shown in a phase 2 study to be of benefit regardless of IGHV status, and this was replicated in the first-line RESONATE 2 study, which compared ibrutinib with chlorambucil and showed it had better PFS than that seen in unmutated patients treated with FCR in other studies, said Dr. Barr, the first author on that study.

“So you can see how the treatment paradigms are starting to evolve. It does look like ... comparing across trials, that ibrutinib leads to better remission durations, compared to chemoimmunotherapy, so far,” he said.

Ibrutinib has also been shown to be of benefit for patients with del(17p). A single-arm phase 2 study showed 79% PFS in relapsed, high-risk patients, which is much better than has been seen with chemoimmunotherapy, he noted.

“Venetoclax is also a very good option for this patient population in the relapse setting,” he said, adding that the PFS with venetoclax has been shown to be very similar to that with ibrutinib.

Similarly, idelalisib has been shown to provide comparable benefit in relapsed/refractory CLL patients, with and without del(17p)/TP53 mutation, he said.

Dr. Barr is a consultant for Pharmacyclics, AbbVie, Celgene, Gilead, Infinity, Novartis, and Seattle Genetics and has received research funding from Pharmacyclics and AbbVie.

[email protected]

CHICAGO – Asymptomatic chronic lymphocytic leukemia (CLL) patients should be observed, but consider therapy when symptoms develop, said Paul M. Barr, MD.

Courtesy Matt Wittmeyer/University of Rochester Medical Center

He described a patient who had been observed for 7 years when he began to complain of increasing fatigue and lost work time. A complete blood count (CBC) showed thrombocytopenia.

The recently updated International Workshop on Chronic Lymphocytic Leukemia (iwCLL) guidelines state that assessments before treatment in this type of patient should include history and physical, evaluation of infectious disease status, and routine laboratory testing – including CBC and differential, chemistry, serum immunoglobulin, and direct antiglobulin test.

“Bone marrow biopsies and [computed tomography] scans are listed as ‘not necessarily required,’ ” Dr. Barr, medical director of the Clinical Trials Office for Wilmot Cancer Institute at the University of Rochester (N.Y.) said during a presentation at the American Society of Hematology Meeting on Hematologic Malignancies.

He added that he opts for CT scans prior to therapy “to understand the patient’s disease burden and potentially to compare to later” and that bone marrow biopsy is “still very reasonable” for understanding the source of a patient’s cytopenias.

“Is it marrow failure or [immune thrombocytopenia]? Could the patient have [myelodysplastic syndrome]? All important considerations,” he said.

Positron emission tomography (PET) scans, however, are only considered when there is concern about transformation, he noted.

Predictive tests that should be conducted before initiating therapy, and that could help in guiding therapy decisions, include TP53 mutation testing and immunoglobulin heavy chain variable region gene (IGHV) mutational status testing (although this doesn’t need to be repeated if it was done at diagnosis because mutational status doesn’t change). Another helpful test is molecular cytogenetics using fluorescence in situ hybridization (FISH) for del(13q), del(17p), and trisomy 12 in peripheral blood lymphocytes. This should be repeated even it was done at diagnosis because patients can acquire additional molecular aberrations over time, Dr. Barr said.

Among the data that justify this advice for predictive testing are studies showing the curative potential of fludarabine/cyclophosphamide/rituximab (FCR) in mutated IGHV CLL, the progression-free survival (PFS) benefits of ibrutinib for patients with del(17p), and the activity of idelalisib in relapsed/refractory CLL patients, including those with TP53 dysfunction.

“The IGHV mutation status is useful to know what to expect from chemoimmunotherapy over time,” Dr. Barr said, explaining that several analyses demonstrate that patients with mutated IGHV genes (patients with low-risk disease) respond exceptionally well to chemoimmunotherapy, especially FCR.

In fact, studies, including a 2016 study by Philip A. Thompson and his colleagues and another by Kirsten Fischer and her colleagues, show that nearly 60% of patients with IGHV mutation remain in remission 10 years after FCR treatment, he said. However, the same is not necessarily true for bendamustine/rituximab (BR); the CLL10 study showed a significantly greater PFS with FCR, compared with that seen with BR.

Unmutated patients in that study had lower PFS, but the outcomes were still better with FCR than with BR, he said.

Studies of novel agents, including ibrutinib and idelalisib, suggest they may have particular benefit in higher-risk patients.

Ibrutinib was shown in a phase 2 study to be of benefit regardless of IGHV status, and this was replicated in the first-line RESONATE 2 study, which compared ibrutinib with chlorambucil and showed it had better PFS than that seen in unmutated patients treated with FCR in other studies, said Dr. Barr, the first author on that study.

“So you can see how the treatment paradigms are starting to evolve. It does look like ... comparing across trials, that ibrutinib leads to better remission durations, compared to chemoimmunotherapy, so far,” he said.

Ibrutinib has also been shown to be of benefit for patients with del(17p). A single-arm phase 2 study showed 79% PFS in relapsed, high-risk patients, which is much better than has been seen with chemoimmunotherapy, he noted.

“Venetoclax is also a very good option for this patient population in the relapse setting,” he said, adding that the PFS with venetoclax has been shown to be very similar to that with ibrutinib.

Similarly, idelalisib has been shown to provide comparable benefit in relapsed/refractory CLL patients, with and without del(17p)/TP53 mutation, he said.

Dr. Barr is a consultant for Pharmacyclics, AbbVie, Celgene, Gilead, Infinity, Novartis, and Seattle Genetics and has received research funding from Pharmacyclics and AbbVie.

[email protected]

CHICAGO – Asymptomatic chronic lymphocytic leukemia (CLL) patients should be observed, but consider therapy when symptoms develop, said Paul M. Barr, MD.

Courtesy Matt Wittmeyer/University of Rochester Medical Center

He described a patient who had been observed for 7 years when he began to complain of increasing fatigue and lost work time. A complete blood count (CBC) showed thrombocytopenia.

The recently updated International Workshop on Chronic Lymphocytic Leukemia (iwCLL) guidelines state that assessments before treatment in this type of patient should include history and physical, evaluation of infectious disease status, and routine laboratory testing – including CBC and differential, chemistry, serum immunoglobulin, and direct antiglobulin test.

“Bone marrow biopsies and [computed tomography] scans are listed as ‘not necessarily required,’ ” Dr. Barr, medical director of the Clinical Trials Office for Wilmot Cancer Institute at the University of Rochester (N.Y.) said during a presentation at the American Society of Hematology Meeting on Hematologic Malignancies.

He added that he opts for CT scans prior to therapy “to understand the patient’s disease burden and potentially to compare to later” and that bone marrow biopsy is “still very reasonable” for understanding the source of a patient’s cytopenias.

“Is it marrow failure or [immune thrombocytopenia]? Could the patient have [myelodysplastic syndrome]? All important considerations,” he said.

Positron emission tomography (PET) scans, however, are only considered when there is concern about transformation, he noted.

Predictive tests that should be conducted before initiating therapy, and that could help in guiding therapy decisions, include TP53 mutation testing and immunoglobulin heavy chain variable region gene (IGHV) mutational status testing (although this doesn’t need to be repeated if it was done at diagnosis because mutational status doesn’t change). Another helpful test is molecular cytogenetics using fluorescence in situ hybridization (FISH) for del(13q), del(17p), and trisomy 12 in peripheral blood lymphocytes. This should be repeated even it was done at diagnosis because patients can acquire additional molecular aberrations over time, Dr. Barr said.

Among the data that justify this advice for predictive testing are studies showing the curative potential of fludarabine/cyclophosphamide/rituximab (FCR) in mutated IGHV CLL, the progression-free survival (PFS) benefits of ibrutinib for patients with del(17p), and the activity of idelalisib in relapsed/refractory CLL patients, including those with TP53 dysfunction.

“The IGHV mutation status is useful to know what to expect from chemoimmunotherapy over time,” Dr. Barr said, explaining that several analyses demonstrate that patients with mutated IGHV genes (patients with low-risk disease) respond exceptionally well to chemoimmunotherapy, especially FCR.

In fact, studies, including a 2016 study by Philip A. Thompson and his colleagues and another by Kirsten Fischer and her colleagues, show that nearly 60% of patients with IGHV mutation remain in remission 10 years after FCR treatment, he said. However, the same is not necessarily true for bendamustine/rituximab (BR); the CLL10 study showed a significantly greater PFS with FCR, compared with that seen with BR.

Unmutated patients in that study had lower PFS, but the outcomes were still better with FCR than with BR, he said.

Studies of novel agents, including ibrutinib and idelalisib, suggest they may have particular benefit in higher-risk patients.

Ibrutinib was shown in a phase 2 study to be of benefit regardless of IGHV status, and this was replicated in the first-line RESONATE 2 study, which compared ibrutinib with chlorambucil and showed it had better PFS than that seen in unmutated patients treated with FCR in other studies, said Dr. Barr, the first author on that study.

“So you can see how the treatment paradigms are starting to evolve. It does look like ... comparing across trials, that ibrutinib leads to better remission durations, compared to chemoimmunotherapy, so far,” he said.

Ibrutinib has also been shown to be of benefit for patients with del(17p). A single-arm phase 2 study showed 79% PFS in relapsed, high-risk patients, which is much better than has been seen with chemoimmunotherapy, he noted.

“Venetoclax is also a very good option for this patient population in the relapse setting,” he said, adding that the PFS with venetoclax has been shown to be very similar to that with ibrutinib.

Similarly, idelalisib has been shown to provide comparable benefit in relapsed/refractory CLL patients, with and without del(17p)/TP53 mutation, he said.

Dr. Barr is a consultant for Pharmacyclics, AbbVie, Celgene, Gilead, Infinity, Novartis, and Seattle Genetics and has received research funding from Pharmacyclics and AbbVie.

[email protected]

CHICAGO – A 50-year old otherwise healthy man was found on routine history and physical to have lymphocytosis and was referred for additional work-up. He denied recent infection, had no lymphadenopathy, organomegaly, or rash or other concerning skin lesions. A complete blood count showed a white cell count of 23 x 10⁹/Land absolute lymphocyte count of 19 x 10⁹/L and normal hemoglobin and platelets.

Based on recently updated International Workshop on Chronic Lymphocytic Leukemia (iwCLL) guidelines, additional work-up for this patient might include peripheral smear and flow cytometry, according to Paul Barr, MD.

“A peripheral smear is still useful in this day and age just to ensure that a patient has a typical look under the microscope. We expect to see small mature lymphocytes, smudge cells, and perhaps a smaller number of prolymphocytes. But to mark CLL based on flow cytometry we need to see greater than 5 x 10⁹/L clonal B lymphocytes in the peripheral blood sustained over time,” Dr. Barr, medical director of the clinical trials office for Wilmot Cancer Institute at the University of Rochester (N.Y.), said during a presentation at the American Society of Hematology Meeting on Hematologic Malignancies.

A nuance in the iwCLL guidelines is that CLL also can be defined by a cytopenia caused by a typical marrow infiltrate, regardless of the number of circulating B lymphocytes, he noted.

Immunophenotype

As for CLL immunophenotype, the cells are CD5- and CD23-positive, and additional B cell markers like CD20 are “often dim, and – understandably – the cells are light-chain restricted,” he said.

A subtle difference between the World Health Organization classification of CLL and the iwCLL guidelines is that, by the former, patients can have “a somewhat atypical immunophenotype.”


“So our pathologists, I like to think, use a commonsense approach where, if there are very minor differences, they will still call it CLL, but not if there are major differences in the immunophenotype,” Dr. Barr said.

Patients with lymphadenopathy, without the critical threshold of circulating B lymphocytes, are considered to have small lymphocytic lymphoma (SLL).

“In this day and age we treat CLL and SLL relatively similarly, however, monoclonal B lymphocytosis (MBL) is the precursor lesion to CLL where we see less than 5 x 10⁹/L of circulating B lymphocytes and an absence of adenopathy and disease-related cytopenias,” he noted.

Staging

It is still common practice to stage patients given the prognostic value of staging and given that treatment is provided in advanced disease, Dr. Barr said.

“This is simple, easy to apply, applicable worldwide, and only requires laboratory testing and a physical exam,” he said.

The stages include:

• Stage 0: Lymphocytosis, peripheral lymphocyte count greater than 15,000/mcL and greater than 40% lymphocytes in bone marrow (low-risk disease status).
• Stage I: Stage 0 disease plus enlarged lymph nodes (intermediate-risk disease status).
• Stage II: Stage 0-I disease with splenomegaly and/or hepatomegaly (intermediate-risk disease status).
• Stage III: Stage 0-II disease with hemoglobin less than 11g/dL or hematocrit less than 33% (high-risk disease status).
• Stage IV: Stage 0-III disease with platelet count less than 100,000/mcL (high-risk disease status).

Prognostic testing

Once a patient is diagnosed with CLL, as was the case with the 50-year-old patient Dr. Barr described, a number of tests can be considered to assess prognosis.

There’s no “perfect answer” when it comes to which tests are considered a reasonable standard of care, he noted.

“I would typically perform [immunoglobulin variable heavy-chain gene] mutation testing, a [fluorescence in situ hybridization] panel, and TP53 mutation testing,” he said.

Scoring systems such as CLL-IPI, which combine prognostic factors to divide patients into various risk categories, can be useful.

For example, such systems may identify high-risk patients who might be appropriate candidates for clinical trials, or low-risk patients who could be expected to do well over time despite having advanced stage disease, he explained.

“I do think it’s a useful process to go through to understand a patient’s risk over time,” he added.

However, treatment for CLL still is not based on molecular aberrations/prognostic features. In fact, the treatment indications according to the updated iwCLL guidelines remain exactly the same, he said.

Therefore, the case of the 50-year-old man described earlier would be observed as long as he remained asymptomatic.

Dr. Barr is a consultant for Pharmacyclics, AbbVie, Celgene, Gilead, Infinity, Novartis, and Seattle Genetics and has received research funding from Pharmacyclics and AbbVie.

[email protected]

CHICAGO – A 50-year old otherwise healthy man was found on routine history and physical to have lymphocytosis and was referred for additional work-up. He denied recent infection, had no lymphadenopathy, organomegaly, or rash or other concerning skin lesions. A complete blood count showed a white cell count of 23 x 10⁹/Land absolute lymphocyte count of 19 x 10⁹/L and normal hemoglobin and platelets.

Based on recently updated International Workshop on Chronic Lymphocytic Leukemia (iwCLL) guidelines, additional work-up for this patient might include peripheral smear and flow cytometry, according to Paul Barr, MD.

“A peripheral smear is still useful in this day and age just to ensure that a patient has a typical look under the microscope. We expect to see small mature lymphocytes, smudge cells, and perhaps a smaller number of prolymphocytes. But to mark CLL based on flow cytometry we need to see greater than 5 x 10⁹/L clonal B lymphocytes in the peripheral blood sustained over time,” Dr. Barr, medical director of the clinical trials office for Wilmot Cancer Institute at the University of Rochester (N.Y.), said during a presentation at the American Society of Hematology Meeting on Hematologic Malignancies.

A nuance in the iwCLL guidelines is that CLL also can be defined by a cytopenia caused by a typical marrow infiltrate, regardless of the number of circulating B lymphocytes, he noted.

Immunophenotype

As for CLL immunophenotype, the cells are CD5- and CD23-positive, and additional B cell markers like CD20 are “often dim, and – understandably – the cells are light-chain restricted,” he said.

A subtle difference between the World Health Organization classification of CLL and the iwCLL guidelines is that, by the former, patients can have “a somewhat atypical immunophenotype.”


“So our pathologists, I like to think, use a commonsense approach where, if there are very minor differences, they will still call it CLL, but not if there are major differences in the immunophenotype,” Dr. Barr said.

Patients with lymphadenopathy, without the critical threshold of circulating B lymphocytes, are considered to have small lymphocytic lymphoma (SLL).

“In this day and age we treat CLL and SLL relatively similarly, however, monoclonal B lymphocytosis (MBL) is the precursor lesion to CLL where we see less than 5 x 10⁹/L of circulating B lymphocytes and an absence of adenopathy and disease-related cytopenias,” he noted.

Staging

It is still common practice to stage patients given the prognostic value of staging and given that treatment is provided in advanced disease, Dr. Barr said.

“This is simple, easy to apply, applicable worldwide, and only requires laboratory testing and a physical exam,” he said.

The stages include:

• Stage 0: Lymphocytosis, peripheral lymphocyte count greater than 15,000/mcL and greater than 40% lymphocytes in bone marrow (low-risk disease status).
• Stage I: Stage 0 disease plus enlarged lymph nodes (intermediate-risk disease status).
• Stage II: Stage 0-I disease with splenomegaly and/or hepatomegaly (intermediate-risk disease status).
• Stage III: Stage 0-II disease with hemoglobin less than 11g/dL or hematocrit less than 33% (high-risk disease status).
• Stage IV: Stage 0-III disease with platelet count less than 100,000/mcL (high-risk disease status).

Prognostic testing

Once a patient is diagnosed with CLL, as was the case with the 50-year-old patient Dr. Barr described, a number of tests can be considered to assess prognosis.

There’s no “perfect answer” when it comes to which tests are considered a reasonable standard of care, he noted.

“I would typically perform [immunoglobulin variable heavy-chain gene] mutation testing, a [fluorescence in situ hybridization] panel, and TP53 mutation testing,” he said.

Scoring systems such as CLL-IPI, which combine prognostic factors to divide patients into various risk categories, can be useful.

For example, such systems may identify high-risk patients who might be appropriate candidates for clinical trials, or low-risk patients who could be expected to do well over time despite having advanced stage disease, he explained.

“I do think it’s a useful process to go through to understand a patient’s risk over time,” he added.

However, treatment for CLL still is not based on molecular aberrations/prognostic features. In fact, the treatment indications according to the updated iwCLL guidelines remain exactly the same, he said.

Therefore, the case of the 50-year-old man described earlier would be observed as long as he remained asymptomatic.

Dr. Barr is a consultant for Pharmacyclics, AbbVie, Celgene, Gilead, Infinity, Novartis, and Seattle Genetics and has received research funding from Pharmacyclics and AbbVie.

[email protected]

CHICAGO – A 50-year old otherwise healthy man was found on routine history and physical to have lymphocytosis and was referred for additional work-up. He denied recent infection, had no lymphadenopathy, organomegaly, or rash or other concerning skin lesions. A complete blood count showed a white cell count of 23 x 10⁹/Land absolute lymphocyte count of 19 x 10⁹/L and normal hemoglobin and platelets.

Based on recently updated International Workshop on Chronic Lymphocytic Leukemia (iwCLL) guidelines, additional work-up for this patient might include peripheral smear and flow cytometry, according to Paul Barr, MD.

“A peripheral smear is still useful in this day and age just to ensure that a patient has a typical look under the microscope. We expect to see small mature lymphocytes, smudge cells, and perhaps a smaller number of prolymphocytes. But to mark CLL based on flow cytometry we need to see greater than 5 x 10⁹/L clonal B lymphocytes in the peripheral blood sustained over time,” Dr. Barr, medical director of the clinical trials office for Wilmot Cancer Institute at the University of Rochester (N.Y.), said during a presentation at the American Society of Hematology Meeting on Hematologic Malignancies.

A nuance in the iwCLL guidelines is that CLL also can be defined by a cytopenia caused by a typical marrow infiltrate, regardless of the number of circulating B lymphocytes, he noted.

Immunophenotype

As for CLL immunophenotype, the cells are CD5- and CD23-positive, and additional B cell markers like CD20 are “often dim, and – understandably – the cells are light-chain restricted,” he said.

A subtle difference between the World Health Organization classification of CLL and the iwCLL guidelines is that, by the former, patients can have “a somewhat atypical immunophenotype.”


“So our pathologists, I like to think, use a commonsense approach where, if there are very minor differences, they will still call it CLL, but not if there are major differences in the immunophenotype,” Dr. Barr said.

Patients with lymphadenopathy, without the critical threshold of circulating B lymphocytes, are considered to have small lymphocytic lymphoma (SLL).

“In this day and age we treat CLL and SLL relatively similarly, however, monoclonal B lymphocytosis (MBL) is the precursor lesion to CLL where we see less than 5 x 10⁹/L of circulating B lymphocytes and an absence of adenopathy and disease-related cytopenias,” he noted.

Staging

It is still common practice to stage patients given the prognostic value of staging and given that treatment is provided in advanced disease, Dr. Barr said.

“This is simple, easy to apply, applicable worldwide, and only requires laboratory testing and a physical exam,” he said.

The stages include:

• Stage 0: Lymphocytosis, peripheral lymphocyte count greater than 15,000/mcL and greater than 40% lymphocytes in bone marrow (low-risk disease status).
• Stage I: Stage 0 disease plus enlarged lymph nodes (intermediate-risk disease status).
• Stage II: Stage 0-I disease with splenomegaly and/or hepatomegaly (intermediate-risk disease status).
• Stage III: Stage 0-II disease with hemoglobin less than 11g/dL or hematocrit less than 33% (high-risk disease status).
• Stage IV: Stage 0-III disease with platelet count less than 100,000/mcL (high-risk disease status).

Prognostic testing

Once a patient is diagnosed with CLL, as was the case with the 50-year-old patient Dr. Barr described, a number of tests can be considered to assess prognosis.

There’s no “perfect answer” when it comes to which tests are considered a reasonable standard of care, he noted.

“I would typically perform [immunoglobulin variable heavy-chain gene] mutation testing, a [fluorescence in situ hybridization] panel, and TP53 mutation testing,” he said.

Scoring systems such as CLL-IPI, which combine prognostic factors to divide patients into various risk categories, can be useful.

For example, such systems may identify high-risk patients who might be appropriate candidates for clinical trials, or low-risk patients who could be expected to do well over time despite having advanced stage disease, he explained.

“I do think it’s a useful process to go through to understand a patient’s risk over time,” he added.

However, treatment for CLL still is not based on molecular aberrations/prognostic features. In fact, the treatment indications according to the updated iwCLL guidelines remain exactly the same, he said.

Therefore, the case of the 50-year-old man described earlier would be observed as long as he remained asymptomatic.

Dr. Barr is a consultant for Pharmacyclics, AbbVie, Celgene, Gilead, Infinity, Novartis, and Seattle Genetics and has received research funding from Pharmacyclics and AbbVie.

[email protected]

DUBROVNIK, CROATIA – New research suggests there is no association between the PTPN22 R620W polymorphism and chronic lymphocytic leukemia (CLL) or autoimmune hematologic disorders in patients from the Republic of Macedonia.

Past studies have shown an association between the PTPN22 R620W variant and both CLL and autoimmune diseases in patients from Northwest Europe. However, a new study of Macedonian patients suggests there is no association between the variant and CLL, autoimmune hemolytic anemia (AIHA), or idiopathic thrombocytopenic purpura (ITP) for patients from Southeast Europe.

Irina Panovska-Stavridis, PhD, of Ss. Cyril and Methodius University in Skopje, Republic of Macedonia, and her colleagues presented this finding at Leukemia and Lymphoma, a meeting jointly sponsored by the University of Texas MD Anderson Cancer Center and the School of Medicine at the University of Zagreb, Croatia.

“A lot of data from the literature suggests [the PTPN22 R620W variant ] has a role in developing multiple immune diseases, but it is validated just in patients from Northwest Europe,” Dr. Panovska-Stavridis noted.

She and her colleagues decided to assess the frequency of the PTPN22 R620W variant (C1858T, rs2476601) in individuals from Southeast Europe, particularly the Republic of Macedonia.

The researchers evaluated 320 patients – 168 with CLL, 66 with AIHA, and 86 with ITP – and 182 age- and sex-matched control subjects with no history of malignant or autoimmune disease.

The team found a similar frequency of the minor T allele and genotype distribution in control subjects and patients. For example, minor T allele was 0.107 in CLL, 0.067 in AIHA, 0.036 in ITP, and 0.05 in controls. Similarly, the frequency of the CC genotype was 0.809 in CLL, 0.166 in AIHA, 0.023 in ITP, and 0.901 in controls.

Dr. Panovska-Stavridis said these results suggest the PTPN22 R620W variant is not a risk factor for the development of CLL, AIHA, or ITP in patients from Southeast Europe.

She also said the results suggest the influence of the variant on lymphocytic homeostasis is affected by certain genetic and environmental factors, and the development of CLL and autoimmune diseases is influenced by race/ethnicity-based variations in the germline composition of the IGHV locus in correlation with environmental factors.

Dr. Panovska-Stavridis did not declare any conflicts of interest.

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

[email protected]

DUBROVNIK, CROATIA – New research suggests there is no association between the PTPN22 R620W polymorphism and chronic lymphocytic leukemia (CLL) or autoimmune hematologic disorders in patients from the Republic of Macedonia.

Past studies have shown an association between the PTPN22 R620W variant and both CLL and autoimmune diseases in patients from Northwest Europe. However, a new study of Macedonian patients suggests there is no association between the variant and CLL, autoimmune hemolytic anemia (AIHA), or idiopathic thrombocytopenic purpura (ITP) for patients from Southeast Europe.

Irina Panovska-Stavridis, PhD, of Ss. Cyril and Methodius University in Skopje, Republic of Macedonia, and her colleagues presented this finding at Leukemia and Lymphoma, a meeting jointly sponsored by the University of Texas MD Anderson Cancer Center and the School of Medicine at the University of Zagreb, Croatia.

“A lot of data from the literature suggests [the PTPN22 R620W variant ] has a role in developing multiple immune diseases, but it is validated just in patients from Northwest Europe,” Dr. Panovska-Stavridis noted.

She and her colleagues decided to assess the frequency of the PTPN22 R620W variant (C1858T, rs2476601) in individuals from Southeast Europe, particularly the Republic of Macedonia.

The researchers evaluated 320 patients – 168 with CLL, 66 with AIHA, and 86 with ITP – and 182 age- and sex-matched control subjects with no history of malignant or autoimmune disease.

The team found a similar frequency of the minor T allele and genotype distribution in control subjects and patients. For example, minor T allele was 0.107 in CLL, 0.067 in AIHA, 0.036 in ITP, and 0.05 in controls. Similarly, the frequency of the CC genotype was 0.809 in CLL, 0.166 in AIHA, 0.023 in ITP, and 0.901 in controls.

Dr. Panovska-Stavridis said these results suggest the PTPN22 R620W variant is not a risk factor for the development of CLL, AIHA, or ITP in patients from Southeast Europe.

She also said the results suggest the influence of the variant on lymphocytic homeostasis is affected by certain genetic and environmental factors, and the development of CLL and autoimmune diseases is influenced by race/ethnicity-based variations in the germline composition of the IGHV locus in correlation with environmental factors.

Dr. Panovska-Stavridis did not declare any conflicts of interest.

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

[email protected]

DUBROVNIK, CROATIA – New research suggests there is no association between the PTPN22 R620W polymorphism and chronic lymphocytic leukemia (CLL) or autoimmune hematologic disorders in patients from the Republic of Macedonia.

Past studies have shown an association between the PTPN22 R620W variant and both CLL and autoimmune diseases in patients from Northwest Europe. However, a new study of Macedonian patients suggests there is no association between the variant and CLL, autoimmune hemolytic anemia (AIHA), or idiopathic thrombocytopenic purpura (ITP) for patients from Southeast Europe.

Irina Panovska-Stavridis, PhD, of Ss. Cyril and Methodius University in Skopje, Republic of Macedonia, and her colleagues presented this finding at Leukemia and Lymphoma, a meeting jointly sponsored by the University of Texas MD Anderson Cancer Center and the School of Medicine at the University of Zagreb, Croatia.

“A lot of data from the literature suggests [the PTPN22 R620W variant ] has a role in developing multiple immune diseases, but it is validated just in patients from Northwest Europe,” Dr. Panovska-Stavridis noted.

She and her colleagues decided to assess the frequency of the PTPN22 R620W variant (C1858T, rs2476601) in individuals from Southeast Europe, particularly the Republic of Macedonia.

The researchers evaluated 320 patients – 168 with CLL, 66 with AIHA, and 86 with ITP – and 182 age- and sex-matched control subjects with no history of malignant or autoimmune disease.

The team found a similar frequency of the minor T allele and genotype distribution in control subjects and patients. For example, minor T allele was 0.107 in CLL, 0.067 in AIHA, 0.036 in ITP, and 0.05 in controls. Similarly, the frequency of the CC genotype was 0.809 in CLL, 0.166 in AIHA, 0.023 in ITP, and 0.901 in controls.

Dr. Panovska-Stavridis said these results suggest the PTPN22 R620W variant is not a risk factor for the development of CLL, AIHA, or ITP in patients from Southeast Europe.

She also said the results suggest the influence of the variant on lymphocytic homeostasis is affected by certain genetic and environmental factors, and the development of CLL and autoimmune diseases is influenced by race/ethnicity-based variations in the germline composition of the IGHV locus in correlation with environmental factors.

Dr. Panovska-Stavridis did not declare any conflicts of interest.

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

[email protected]

Sandoz has decided not to pursue U.S. approval for its rituximab product (GP2013), a proposed biosimilar of Rituxan.

Sandoz, a division of Novartis, was seeking Food and Drug Administration approval of GP2013 for all the same indications as the reference product – B-cell non-Hodgkin lymphoma, chronic lymphocytic leukemia, rheumatoid arthritis, granulomatosis with polyangiitis, microscopic polyangiitis, and pemphigus vulgaris.

GP2013 already is approved in the European Union and elsewhere.

The FDA had accepted the biologics license application (BLA) for GP2013 in September 2017. In May 2018, the agency issued a complete response letter saying it could not approve GP2013. The agency also requested additional information to complement the BLA submission.

At the time of the complete response letter, Sandoz said it was still committed to bringing GP2013 to the U.S. market.

“We appreciate the important conversations with the FDA, which have provided specific requirements for our potential U.S. biosimilar rituximab but believe the patient and marketplace needs in the U.S. will be satisfied before we can generate the data required,” Stefan Hendriks, global head of biopharmaceuticals at Sandoz, said in a statement.

“We are disappointed to have to make this decision and stand behind the safety, efficacy, and quality of our medicine, which met the stringent criteria for approval in the European Union, Switzerland, Japan, New Zealand, and Australia.”

The BLA for GP2013 was supported, in part, by results from the ASSIST-FL trial, in which researchers compared GP2013 with the reference product (Lancet Haematol. 2017 Aug;4[8]:e350-61).

The phase 3 trial included adults with previously untreated, advanced-stage follicular lymphoma. Patients received eight cycles of cyclophosphamide, vincristine, and prednisone with either GP2013 or reference rituximab. Responders then received GP2013 or rituximab monotherapy as maintenance for up to 2 years.

At a median follow-up of 11.6 months, the overall response rate was 87% in the GP2013 arm and 88% in the rituximab arm.

[email protected]

Sandoz has decided not to pursue U.S. approval for its rituximab product (GP2013), a proposed biosimilar of Rituxan.

Sandoz, a division of Novartis, was seeking Food and Drug Administration approval of GP2013 for all the same indications as the reference product – B-cell non-Hodgkin lymphoma, chronic lymphocytic leukemia, rheumatoid arthritis, granulomatosis with polyangiitis, microscopic polyangiitis, and pemphigus vulgaris.

GP2013 already is approved in the European Union and elsewhere.

The FDA had accepted the biologics license application (BLA) for GP2013 in September 2017. In May 2018, the agency issued a complete response letter saying it could not approve GP2013. The agency also requested additional information to complement the BLA submission.

At the time of the complete response letter, Sandoz said it was still committed to bringing GP2013 to the U.S. market.

“We appreciate the important conversations with the FDA, which have provided specific requirements for our potential U.S. biosimilar rituximab but believe the patient and marketplace needs in the U.S. will be satisfied before we can generate the data required,” Stefan Hendriks, global head of biopharmaceuticals at Sandoz, said in a statement.

“We are disappointed to have to make this decision and stand behind the safety, efficacy, and quality of our medicine, which met the stringent criteria for approval in the European Union, Switzerland, Japan, New Zealand, and Australia.”

The BLA for GP2013 was supported, in part, by results from the ASSIST-FL trial, in which researchers compared GP2013 with the reference product (Lancet Haematol. 2017 Aug;4[8]:e350-61).

The phase 3 trial included adults with previously untreated, advanced-stage follicular lymphoma. Patients received eight cycles of cyclophosphamide, vincristine, and prednisone with either GP2013 or reference rituximab. Responders then received GP2013 or rituximab monotherapy as maintenance for up to 2 years.

At a median follow-up of 11.6 months, the overall response rate was 87% in the GP2013 arm and 88% in the rituximab arm.

[email protected]

Sandoz has decided not to pursue U.S. approval for its rituximab product (GP2013), a proposed biosimilar of Rituxan.

Sandoz, a division of Novartis, was seeking Food and Drug Administration approval of GP2013 for all the same indications as the reference product – B-cell non-Hodgkin lymphoma, chronic lymphocytic leukemia, rheumatoid arthritis, granulomatosis with polyangiitis, microscopic polyangiitis, and pemphigus vulgaris.

GP2013 already is approved in the European Union and elsewhere.

The FDA had accepted the biologics license application (BLA) for GP2013 in September 2017. In May 2018, the agency issued a complete response letter saying it could not approve GP2013. The agency also requested additional information to complement the BLA submission.

At the time of the complete response letter, Sandoz said it was still committed to bringing GP2013 to the U.S. market.

“We appreciate the important conversations with the FDA, which have provided specific requirements for our potential U.S. biosimilar rituximab but believe the patient and marketplace needs in the U.S. will be satisfied before we can generate the data required,” Stefan Hendriks, global head of biopharmaceuticals at Sandoz, said in a statement.

“We are disappointed to have to make this decision and stand behind the safety, efficacy, and quality of our medicine, which met the stringent criteria for approval in the European Union, Switzerland, Japan, New Zealand, and Australia.”

The BLA for GP2013 was supported, in part, by results from the ASSIST-FL trial, in which researchers compared GP2013 with the reference product (Lancet Haematol. 2017 Aug;4[8]:e350-61).

The phase 3 trial included adults with previously untreated, advanced-stage follicular lymphoma. Patients received eight cycles of cyclophosphamide, vincristine, and prednisone with either GP2013 or reference rituximab. Responders then received GP2013 or rituximab monotherapy as maintenance for up to 2 years.

At a median follow-up of 11.6 months, the overall response rate was 87% in the GP2013 arm and 88% in the rituximab arm.

[email protected]