BIOMARKERS IN RELAPSED/REFRACTORY DLBCL AND FL PATIENTS TREATED WITH POLATUZUMAB VEDOTIN: RESULTS FROM THE PHASE II CLINICAL TRIAL (ROMULUS)
(Abstract release date: 05/19/16)
EHA Library. Penuel E. 06/09/16; 132946; E1397
Dr. Elicia Penuel
Contributions
Contributions
Abstract
Abstract: E1397
Type: Eposter Presentation
Background
Polatuzumab vedotin (PoV) is an antibody drug conjugate (ADC) comprised of a monoclonal antibody targeting the B-cell marker, CD79b, linked to the microtubule-disrupting agent, monomethyl auristatin E (MMAE). PoV has shown clinical activity in patients with relapsed/refractory (R/R) non-Hodgkin lymphoma. Target expression, CD79b, and expression of anti-apoptotic factors, such as BCL-2, have the potential to mediate sensitivity and/or resistance to ADCs. Moreover, diffuse large B-cell lymphoma (DLBCL) is a heterogeneous disease in which distinct subtypes defined by gene expression profiles and, in some cases, prevalence of genetic variants, have been defined.
Aims
Perform a retrospective biomarker analysis on tumor samples at baseline (archival biopsies) from patients in the phase II trial (ROMULUS) who received PoV with rituximab, to correlate the activity of PoV with biomarkers in R/R DLBCL and follicular lymphoma (FL).
Methods
We evaluated target expression (CD79b) and potential for PoV resistance driven by BCL-2 expression by immunohistochemistry (IHC) and quantitative reverse transcription polymerase chain reaction (qRT-PCR) in 34 DLBCL and 19 FL patients with sufficient tissue for analysis. In DLBCL, cell of origin (COO) was evaluated by signature gene expression and a linear predictor score method described previously.1 Additionally, mutations (i.e., CD79b, CARD11, MYD88 and EZH2) enriched in COO DLBCL subtypes, and that may confer resistance to anti-lymphoma therapies, were evaluated using a multiplexed gene panel by next-generation sequencing.
Results
CD79b expression was comparable in DLBCL and FL by qRT-PCR and IHC. Consistent with the role of CD79b as a B-cell lineage marker, expression was seen in all samples. There was a range of CD79b expression, but ~90% of patients had expression at higher levels (IHC2/3+). Response to PoV was independent of CD79b expression, as responses were seen in patients with both high and lower levels. For BCL-2, there was no significant difference in expression across indications by qRT-PCR. However, while high BCL-2 expression (IHC 2/3+) was observed in ~90% of FL patients, expression was more distributed across levels in DLBCL. Importantly, there was no relationship between BCL-2 expression and response to PoV by IHC or qRT-PCR.PoV showed activity in both GCB and the more aggressive ABC DLBCL subtypes. Moreover, we observed mutations associated with COO, including EZH2 (n=2) in GCB patients and dual CD79b/MYD88 (n=2) in ABC patients. Tumor shrinkage and clinical response to PoV were observed in these patients. Similarly, mutations, such as MYD88 (n=2), associated with resistance to ABC targeting agents were also observed but clinical response was variable.
Conclusion
These analyses demonstrate broad activity of PoV in R/R DLBCL and FL. CD79b was expressed across B-cell malignancies; while a majority of samples expressed high levels of CD79b, even minimal expression was sufficient for PoV activity. Though anti-apoptotic regulators, like BCL-2, have potential to drive resistance to microtubule-disrupting agents, this was not observed with PoV. While the DLBCL treatment landscape is evolving to account for biologic subtypes, PoV showed activity independent of subtype, in contrast to other targeted therapies. Overall, the robust and expansive activity observed with PoV may position it as an effective component of therapy across DLBCL subtypes and FL. Studies of PoV combined with other anti-lymphoma agents in multiple indications, including in newly diagnosed DLBCL patients, are ongoing.1. Pfeifer, et al. Leukemia. 2015;29:1578-86.
Session topic: E-poster
Keyword(s): BCL2, DLBCL, Follicular lymphoma, NHL
Type: Eposter Presentation
Background
Polatuzumab vedotin (PoV) is an antibody drug conjugate (ADC) comprised of a monoclonal antibody targeting the B-cell marker, CD79b, linked to the microtubule-disrupting agent, monomethyl auristatin E (MMAE). PoV has shown clinical activity in patients with relapsed/refractory (R/R) non-Hodgkin lymphoma. Target expression, CD79b, and expression of anti-apoptotic factors, such as BCL-2, have the potential to mediate sensitivity and/or resistance to ADCs. Moreover, diffuse large B-cell lymphoma (DLBCL) is a heterogeneous disease in which distinct subtypes defined by gene expression profiles and, in some cases, prevalence of genetic variants, have been defined.
Aims
Perform a retrospective biomarker analysis on tumor samples at baseline (archival biopsies) from patients in the phase II trial (ROMULUS) who received PoV with rituximab, to correlate the activity of PoV with biomarkers in R/R DLBCL and follicular lymphoma (FL).
Methods
We evaluated target expression (CD79b) and potential for PoV resistance driven by BCL-2 expression by immunohistochemistry (IHC) and quantitative reverse transcription polymerase chain reaction (qRT-PCR) in 34 DLBCL and 19 FL patients with sufficient tissue for analysis. In DLBCL, cell of origin (COO) was evaluated by signature gene expression and a linear predictor score method described previously.1 Additionally, mutations (i.e., CD79b, CARD11, MYD88 and EZH2) enriched in COO DLBCL subtypes, and that may confer resistance to anti-lymphoma therapies, were evaluated using a multiplexed gene panel by next-generation sequencing.
Results
CD79b expression was comparable in DLBCL and FL by qRT-PCR and IHC. Consistent with the role of CD79b as a B-cell lineage marker, expression was seen in all samples. There was a range of CD79b expression, but ~90% of patients had expression at higher levels (IHC2/3+). Response to PoV was independent of CD79b expression, as responses were seen in patients with both high and lower levels. For BCL-2, there was no significant difference in expression across indications by qRT-PCR. However, while high BCL-2 expression (IHC 2/3+) was observed in ~90% of FL patients, expression was more distributed across levels in DLBCL. Importantly, there was no relationship between BCL-2 expression and response to PoV by IHC or qRT-PCR.PoV showed activity in both GCB and the more aggressive ABC DLBCL subtypes. Moreover, we observed mutations associated with COO, including EZH2 (n=2) in GCB patients and dual CD79b/MYD88 (n=2) in ABC patients. Tumor shrinkage and clinical response to PoV were observed in these patients. Similarly, mutations, such as MYD88 (n=2), associated with resistance to ABC targeting agents were also observed but clinical response was variable.
Conclusion
These analyses demonstrate broad activity of PoV in R/R DLBCL and FL. CD79b was expressed across B-cell malignancies; while a majority of samples expressed high levels of CD79b, even minimal expression was sufficient for PoV activity. Though anti-apoptotic regulators, like BCL-2, have potential to drive resistance to microtubule-disrupting agents, this was not observed with PoV. While the DLBCL treatment landscape is evolving to account for biologic subtypes, PoV showed activity independent of subtype, in contrast to other targeted therapies. Overall, the robust and expansive activity observed with PoV may position it as an effective component of therapy across DLBCL subtypes and FL. Studies of PoV combined with other anti-lymphoma agents in multiple indications, including in newly diagnosed DLBCL patients, are ongoing.1. Pfeifer, et al. Leukemia. 2015;29:1578-86.
Session topic: E-poster
Keyword(s): BCL2, DLBCL, Follicular lymphoma, NHL
Abstract: E1397
Type: Eposter Presentation
Background
Polatuzumab vedotin (PoV) is an antibody drug conjugate (ADC) comprised of a monoclonal antibody targeting the B-cell marker, CD79b, linked to the microtubule-disrupting agent, monomethyl auristatin E (MMAE). PoV has shown clinical activity in patients with relapsed/refractory (R/R) non-Hodgkin lymphoma. Target expression, CD79b, and expression of anti-apoptotic factors, such as BCL-2, have the potential to mediate sensitivity and/or resistance to ADCs. Moreover, diffuse large B-cell lymphoma (DLBCL) is a heterogeneous disease in which distinct subtypes defined by gene expression profiles and, in some cases, prevalence of genetic variants, have been defined.
Aims
Perform a retrospective biomarker analysis on tumor samples at baseline (archival biopsies) from patients in the phase II trial (ROMULUS) who received PoV with rituximab, to correlate the activity of PoV with biomarkers in R/R DLBCL and follicular lymphoma (FL).
Methods
We evaluated target expression (CD79b) and potential for PoV resistance driven by BCL-2 expression by immunohistochemistry (IHC) and quantitative reverse transcription polymerase chain reaction (qRT-PCR) in 34 DLBCL and 19 FL patients with sufficient tissue for analysis. In DLBCL, cell of origin (COO) was evaluated by signature gene expression and a linear predictor score method described previously.1 Additionally, mutations (i.e., CD79b, CARD11, MYD88 and EZH2) enriched in COO DLBCL subtypes, and that may confer resistance to anti-lymphoma therapies, were evaluated using a multiplexed gene panel by next-generation sequencing.
Results
CD79b expression was comparable in DLBCL and FL by qRT-PCR and IHC. Consistent with the role of CD79b as a B-cell lineage marker, expression was seen in all samples. There was a range of CD79b expression, but ~90% of patients had expression at higher levels (IHC2/3+). Response to PoV was independent of CD79b expression, as responses were seen in patients with both high and lower levels. For BCL-2, there was no significant difference in expression across indications by qRT-PCR. However, while high BCL-2 expression (IHC 2/3+) was observed in ~90% of FL patients, expression was more distributed across levels in DLBCL. Importantly, there was no relationship between BCL-2 expression and response to PoV by IHC or qRT-PCR.PoV showed activity in both GCB and the more aggressive ABC DLBCL subtypes. Moreover, we observed mutations associated with COO, including EZH2 (n=2) in GCB patients and dual CD79b/MYD88 (n=2) in ABC patients. Tumor shrinkage and clinical response to PoV were observed in these patients. Similarly, mutations, such as MYD88 (n=2), associated with resistance to ABC targeting agents were also observed but clinical response was variable.
Conclusion
These analyses demonstrate broad activity of PoV in R/R DLBCL and FL. CD79b was expressed across B-cell malignancies; while a majority of samples expressed high levels of CD79b, even minimal expression was sufficient for PoV activity. Though anti-apoptotic regulators, like BCL-2, have potential to drive resistance to microtubule-disrupting agents, this was not observed with PoV. While the DLBCL treatment landscape is evolving to account for biologic subtypes, PoV showed activity independent of subtype, in contrast to other targeted therapies. Overall, the robust and expansive activity observed with PoV may position it as an effective component of therapy across DLBCL subtypes and FL. Studies of PoV combined with other anti-lymphoma agents in multiple indications, including in newly diagnosed DLBCL patients, are ongoing.1. Pfeifer, et al. Leukemia. 2015;29:1578-86.
Session topic: E-poster
Keyword(s): BCL2, DLBCL, Follicular lymphoma, NHL
Type: Eposter Presentation
Background
Polatuzumab vedotin (PoV) is an antibody drug conjugate (ADC) comprised of a monoclonal antibody targeting the B-cell marker, CD79b, linked to the microtubule-disrupting agent, monomethyl auristatin E (MMAE). PoV has shown clinical activity in patients with relapsed/refractory (R/R) non-Hodgkin lymphoma. Target expression, CD79b, and expression of anti-apoptotic factors, such as BCL-2, have the potential to mediate sensitivity and/or resistance to ADCs. Moreover, diffuse large B-cell lymphoma (DLBCL) is a heterogeneous disease in which distinct subtypes defined by gene expression profiles and, in some cases, prevalence of genetic variants, have been defined.
Aims
Perform a retrospective biomarker analysis on tumor samples at baseline (archival biopsies) from patients in the phase II trial (ROMULUS) who received PoV with rituximab, to correlate the activity of PoV with biomarkers in R/R DLBCL and follicular lymphoma (FL).
Methods
We evaluated target expression (CD79b) and potential for PoV resistance driven by BCL-2 expression by immunohistochemistry (IHC) and quantitative reverse transcription polymerase chain reaction (qRT-PCR) in 34 DLBCL and 19 FL patients with sufficient tissue for analysis. In DLBCL, cell of origin (COO) was evaluated by signature gene expression and a linear predictor score method described previously.1 Additionally, mutations (i.e., CD79b, CARD11, MYD88 and EZH2) enriched in COO DLBCL subtypes, and that may confer resistance to anti-lymphoma therapies, were evaluated using a multiplexed gene panel by next-generation sequencing.
Results
CD79b expression was comparable in DLBCL and FL by qRT-PCR and IHC. Consistent with the role of CD79b as a B-cell lineage marker, expression was seen in all samples. There was a range of CD79b expression, but ~90% of patients had expression at higher levels (IHC2/3+). Response to PoV was independent of CD79b expression, as responses were seen in patients with both high and lower levels. For BCL-2, there was no significant difference in expression across indications by qRT-PCR. However, while high BCL-2 expression (IHC 2/3+) was observed in ~90% of FL patients, expression was more distributed across levels in DLBCL. Importantly, there was no relationship between BCL-2 expression and response to PoV by IHC or qRT-PCR.PoV showed activity in both GCB and the more aggressive ABC DLBCL subtypes. Moreover, we observed mutations associated with COO, including EZH2 (n=2) in GCB patients and dual CD79b/MYD88 (n=2) in ABC patients. Tumor shrinkage and clinical response to PoV were observed in these patients. Similarly, mutations, such as MYD88 (n=2), associated with resistance to ABC targeting agents were also observed but clinical response was variable.
Conclusion
These analyses demonstrate broad activity of PoV in R/R DLBCL and FL. CD79b was expressed across B-cell malignancies; while a majority of samples expressed high levels of CD79b, even minimal expression was sufficient for PoV activity. Though anti-apoptotic regulators, like BCL-2, have potential to drive resistance to microtubule-disrupting agents, this was not observed with PoV. While the DLBCL treatment landscape is evolving to account for biologic subtypes, PoV showed activity independent of subtype, in contrast to other targeted therapies. Overall, the robust and expansive activity observed with PoV may position it as an effective component of therapy across DLBCL subtypes and FL. Studies of PoV combined with other anti-lymphoma agents in multiple indications, including in newly diagnosed DLBCL patients, are ongoing.1. Pfeifer, et al. Leukemia. 2015;29:1578-86.
Session topic: E-poster
Keyword(s): BCL2, DLBCL, Follicular lymphoma, NHL
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