Lymphoma & Plasma Cell Disorders

Photo by Bill Branson

The U.S. Food and Drug Administration (FDA) has approved a biosimilar rituximab product for the treatment of non-Hodgkin lymphoma (NHL).

Celltrion’s Truxima (rituximab-abbs) is a biosimilar of Genentech’s Rituxan and the first biosimilar approved in the United States to treat NHL.

Truxima (formerly CT-P10) is approved to treat adults with CD20-positive, B-cell NHL, either as a single agent or in combination with chemotherapy.

Specifically, Truxima is approved as a single agent to treat relapsed or refractory, low grade or follicular, CD20-positive, B-cell NHL.

Truxima is approved in combination with first-line chemotherapy to treat previously untreated follicular, CD20-positive, B-cell NHL.

Truxima is approved as single-agent maintenance therapy in patients with follicular, CD20-positive, B-cell NHL who achieve a complete or partial response to a rituximab product in combination with chemotherapy.

And Truxima is approved as a single agent to treat non-progressing, low-grade, CD20­-positive, B-cell NHL after first-line treatment with cyclophosphamide, vincristine, and prednisone.

The label for Truxima contains a boxed warning detailing the risk of fatal infusion reactions, severe skin and mouth reactions (some with fatal outcomes), hepatitis B virus reactivation that may cause serious liver problems (including liver failure and death), and progressive multifocal leukoencephalopathy.

The FDA said its approval of Truxima is “based on a review of evidence that included extensive structural and functional characterization, animal study data, human pharmacokinetic data, clinical immunogenicity data, and other clinical data that demonstrates Truxima is biosimilar to Rituxan.”

A phase 3 trial recently published in The Lancet Haematology suggested that Truxima is equivalent to the reference product in patients with low-tumor-burden follicular lymphoma.

For more details on Truxima, see the prescribing information.

Photo by Bill Branson

The U.S. Food and Drug Administration (FDA) has approved a biosimilar rituximab product for the treatment of non-Hodgkin lymphoma (NHL).

Celltrion’s Truxima (rituximab-abbs) is a biosimilar of Genentech’s Rituxan and the first biosimilar approved in the United States to treat NHL.

Truxima (formerly CT-P10) is approved to treat adults with CD20-positive, B-cell NHL, either as a single agent or in combination with chemotherapy.

Specifically, Truxima is approved as a single agent to treat relapsed or refractory, low grade or follicular, CD20-positive, B-cell NHL.

Truxima is approved in combination with first-line chemotherapy to treat previously untreated follicular, CD20-positive, B-cell NHL.

Truxima is approved as single-agent maintenance therapy in patients with follicular, CD20-positive, B-cell NHL who achieve a complete or partial response to a rituximab product in combination with chemotherapy.

And Truxima is approved as a single agent to treat non-progressing, low-grade, CD20­-positive, B-cell NHL after first-line treatment with cyclophosphamide, vincristine, and prednisone.

The label for Truxima contains a boxed warning detailing the risk of fatal infusion reactions, severe skin and mouth reactions (some with fatal outcomes), hepatitis B virus reactivation that may cause serious liver problems (including liver failure and death), and progressive multifocal leukoencephalopathy.

The FDA said its approval of Truxima is “based on a review of evidence that included extensive structural and functional characterization, animal study data, human pharmacokinetic data, clinical immunogenicity data, and other clinical data that demonstrates Truxima is biosimilar to Rituxan.”

A phase 3 trial recently published in The Lancet Haematology suggested that Truxima is equivalent to the reference product in patients with low-tumor-burden follicular lymphoma.

For more details on Truxima, see the prescribing information.

Photo by Bill Branson

The U.S. Food and Drug Administration (FDA) has approved a biosimilar rituximab product for the treatment of non-Hodgkin lymphoma (NHL).

Celltrion’s Truxima (rituximab-abbs) is a biosimilar of Genentech’s Rituxan and the first biosimilar approved in the United States to treat NHL.

Truxima (formerly CT-P10) is approved to treat adults with CD20-positive, B-cell NHL, either as a single agent or in combination with chemotherapy.

Specifically, Truxima is approved as a single agent to treat relapsed or refractory, low grade or follicular, CD20-positive, B-cell NHL.

Truxima is approved in combination with first-line chemotherapy to treat previously untreated follicular, CD20-positive, B-cell NHL.

Truxima is approved as single-agent maintenance therapy in patients with follicular, CD20-positive, B-cell NHL who achieve a complete or partial response to a rituximab product in combination with chemotherapy.

And Truxima is approved as a single agent to treat non-progressing, low-grade, CD20­-positive, B-cell NHL after first-line treatment with cyclophosphamide, vincristine, and prednisone.

The label for Truxima contains a boxed warning detailing the risk of fatal infusion reactions, severe skin and mouth reactions (some with fatal outcomes), hepatitis B virus reactivation that may cause serious liver problems (including liver failure and death), and progressive multifocal leukoencephalopathy.

The FDA said its approval of Truxima is “based on a review of evidence that included extensive structural and functional characterization, animal study data, human pharmacokinetic data, clinical immunogenicity data, and other clinical data that demonstrates Truxima is biosimilar to Rituxan.”

A phase 3 trial recently published in The Lancet Haematology suggested that Truxima is equivalent to the reference product in patients with low-tumor-burden follicular lymphoma.

For more details on Truxima, see the prescribing information.

The Food and Drug Administration has approved a biosimilar rituximab product for the treatment of non-Hodgkin lymphoma (NHL).

Celltrion’s Truxima (rituximab-abbs) is a biosimilar of Genentech’s Rituxan (rituximab) and the first biosimilar approved in the United States to treat NHL.

Truxima (formerly CT-P10) is approved to treat adults with CD20-positive, B-cell NHL, either as a single agent or in combination with chemotherapy. Truxima is approved as a single agent to treat relapsed or refractory, low grade or follicular, CD20-positive, B-cell NHL. Truxima is approved in combination with first-line chemotherapy to treat previously untreated follicular, CD20-positive, B-cell NHL.

Truxima is approved as single-agent maintenance therapy in patients with follicular, CD20-positive, B-cell NHL who achieve a complete or partial response to a rituximab product in combination with chemotherapy. Truxima also is approved as a single agent to treat nonprogressing, low-grade, CD20-positive, B-cell NHL after first-line treatment with cyclophosphamide, vincristine, and prednisone.The label for Truxima contains a boxed warning detailing the risk of fatal infusion reactions, severe skin and mouth reactions (some with fatal outcomes), hepatitis B virus reactivation that may cause serious liver problems (including liver failure and death), and progressive multifocal leukoencephalopathy.

The FDA said its approval of Truxima is “based on a review of evidence that included extensive structural and functional characterization, animal study data, human pharmacokinetic data, clinical immunogenicity data, and other clinical data that demonstrates Truxima is biosimilar to Rituxan.”

Findings from a phase 3 trial suggested that Truxima is equivalent to the reference product in patients with low-tumor-burden follicular lymphoma (Lancet Haematol. 2018 Nov;5[11]:e543-53).

[email protected]

The Food and Drug Administration has approved a biosimilar rituximab product for the treatment of non-Hodgkin lymphoma (NHL).

Celltrion’s Truxima (rituximab-abbs) is a biosimilar of Genentech’s Rituxan (rituximab) and the first biosimilar approved in the United States to treat NHL.

Truxima (formerly CT-P10) is approved to treat adults with CD20-positive, B-cell NHL, either as a single agent or in combination with chemotherapy. Truxima is approved as a single agent to treat relapsed or refractory, low grade or follicular, CD20-positive, B-cell NHL. Truxima is approved in combination with first-line chemotherapy to treat previously untreated follicular, CD20-positive, B-cell NHL.

Truxima is approved as single-agent maintenance therapy in patients with follicular, CD20-positive, B-cell NHL who achieve a complete or partial response to a rituximab product in combination with chemotherapy. Truxima also is approved as a single agent to treat nonprogressing, low-grade, CD20-positive, B-cell NHL after first-line treatment with cyclophosphamide, vincristine, and prednisone.The label for Truxima contains a boxed warning detailing the risk of fatal infusion reactions, severe skin and mouth reactions (some with fatal outcomes), hepatitis B virus reactivation that may cause serious liver problems (including liver failure and death), and progressive multifocal leukoencephalopathy.

The FDA said its approval of Truxima is “based on a review of evidence that included extensive structural and functional characterization, animal study data, human pharmacokinetic data, clinical immunogenicity data, and other clinical data that demonstrates Truxima is biosimilar to Rituxan.”

Findings from a phase 3 trial suggested that Truxima is equivalent to the reference product in patients with low-tumor-burden follicular lymphoma (Lancet Haematol. 2018 Nov;5[11]:e543-53).

[email protected]

The Food and Drug Administration has approved a biosimilar rituximab product for the treatment of non-Hodgkin lymphoma (NHL).

Celltrion’s Truxima (rituximab-abbs) is a biosimilar of Genentech’s Rituxan (rituximab) and the first biosimilar approved in the United States to treat NHL.

Truxima (formerly CT-P10) is approved to treat adults with CD20-positive, B-cell NHL, either as a single agent or in combination with chemotherapy. Truxima is approved as a single agent to treat relapsed or refractory, low grade or follicular, CD20-positive, B-cell NHL. Truxima is approved in combination with first-line chemotherapy to treat previously untreated follicular, CD20-positive, B-cell NHL.

Truxima is approved as single-agent maintenance therapy in patients with follicular, CD20-positive, B-cell NHL who achieve a complete or partial response to a rituximab product in combination with chemotherapy. Truxima also is approved as a single agent to treat nonprogressing, low-grade, CD20-positive, B-cell NHL after first-line treatment with cyclophosphamide, vincristine, and prednisone.The label for Truxima contains a boxed warning detailing the risk of fatal infusion reactions, severe skin and mouth reactions (some with fatal outcomes), hepatitis B virus reactivation that may cause serious liver problems (including liver failure and death), and progressive multifocal leukoencephalopathy.

The FDA said its approval of Truxima is “based on a review of evidence that included extensive structural and functional characterization, animal study data, human pharmacokinetic data, clinical immunogenicity data, and other clinical data that demonstrates Truxima is biosimilar to Rituxan.”

Findings from a phase 3 trial suggested that Truxima is equivalent to the reference product in patients with low-tumor-burden follicular lymphoma (Lancet Haematol. 2018 Nov;5[11]:e543-53).

[email protected]

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.
 

mycosis fungoides

The European Commission (EC) has granted marketing authorization for mogamulizumab (Poteligeo), a humanized monoclonal antibody directed against CCR4.

This means mogamulizumab is approved for use in adults with mycosis fungoides (MF) or Sézary syndrome (SS) who have received at least one prior systemic therapy.

This approval is valid in all countries of the European Union as well as Norway, Iceland, and Liechtenstein.

Kyowa Kirin plans to launch mogamulizumab in various European markets starting next year.

The EC’s decision to approve mogamulizumab was supported by the phase 3 MAVORIC trial. Results from this trial were published in The Lancet Oncology in August.

MAVORIC was a comparison of mogamulizumab and vorinostat in 372 adults with MF or SS who had received at least one prior systemic therapy.

Mogamulizumab provided a significant improvement in progression-free survival (PFS), the study’s primary endpoint.

According to investigators, the median PFS was 7.7 months with mogamulizumab and 3.1 months with vorinostat (hazard ratio=0.53, P<0.0001).

According to an independent review committee, the median PFS was 6.7 months and 3.8 months, respectively (hazard ratio=0.64, P<0.0007).

There was a significant improvement in overall response rate (ORR) with mogamulizumab.

According to independent review, the global ORR was 23% (43/186) in the mogamulizumab arm and 4% (7/186) in the vorinostat arm (risk ratio=19.4, P<0.0001).

According to investigators, the global ORR was 28% (52/186) and 5% (9/186), respectively (risk ratio=23.1, P<0.0001).

For patients with MF, the investigator-assessed ORR was 21% (22/105) with mogamulizumab and 7% (7/99) with vorinostat.

For SS patients, the investigator-assessed ORR was 37% (30/81) and 2% (2/87), respectively.

Grade 3 adverse events (AEs) in the mogamulizumab arm included drug eruptions (n=8), hypertension (n=8), pneumonia (n=6), fatigue (n=3), cellulitis (n=3), infusion-related reactions (n=3), sepsis (n=2), decreased appetite (n=2), AST increase (n=2), weight decrease (n=1), pyrexia (n=1), constipation (n=1), nausea (n=1), and diarrhea (n=1).

Grade 4 AEs with mogamulizumab were cellulitis (n=1) and pneumonia (n=1). Grade 5 AEs included pneumonia (n=1) and sepsis (n=1).

mycosis fungoides

The European Commission (EC) has granted marketing authorization for mogamulizumab (Poteligeo), a humanized monoclonal antibody directed against CCR4.

This means mogamulizumab is approved for use in adults with mycosis fungoides (MF) or Sézary syndrome (SS) who have received at least one prior systemic therapy.

This approval is valid in all countries of the European Union as well as Norway, Iceland, and Liechtenstein.

Kyowa Kirin plans to launch mogamulizumab in various European markets starting next year.

The EC’s decision to approve mogamulizumab was supported by the phase 3 MAVORIC trial. Results from this trial were published in The Lancet Oncology in August.

MAVORIC was a comparison of mogamulizumab and vorinostat in 372 adults with MF or SS who had received at least one prior systemic therapy.

Mogamulizumab provided a significant improvement in progression-free survival (PFS), the study’s primary endpoint.

According to investigators, the median PFS was 7.7 months with mogamulizumab and 3.1 months with vorinostat (hazard ratio=0.53, P<0.0001).

According to an independent review committee, the median PFS was 6.7 months and 3.8 months, respectively (hazard ratio=0.64, P<0.0007).

There was a significant improvement in overall response rate (ORR) with mogamulizumab.

According to independent review, the global ORR was 23% (43/186) in the mogamulizumab arm and 4% (7/186) in the vorinostat arm (risk ratio=19.4, P<0.0001).

According to investigators, the global ORR was 28% (52/186) and 5% (9/186), respectively (risk ratio=23.1, P<0.0001).

For patients with MF, the investigator-assessed ORR was 21% (22/105) with mogamulizumab and 7% (7/99) with vorinostat.

For SS patients, the investigator-assessed ORR was 37% (30/81) and 2% (2/87), respectively.

Grade 3 adverse events (AEs) in the mogamulizumab arm included drug eruptions (n=8), hypertension (n=8), pneumonia (n=6), fatigue (n=3), cellulitis (n=3), infusion-related reactions (n=3), sepsis (n=2), decreased appetite (n=2), AST increase (n=2), weight decrease (n=1), pyrexia (n=1), constipation (n=1), nausea (n=1), and diarrhea (n=1).

Grade 4 AEs with mogamulizumab were cellulitis (n=1) and pneumonia (n=1). Grade 5 AEs included pneumonia (n=1) and sepsis (n=1).

mycosis fungoides

The European Commission (EC) has granted marketing authorization for mogamulizumab (Poteligeo), a humanized monoclonal antibody directed against CCR4.

This means mogamulizumab is approved for use in adults with mycosis fungoides (MF) or Sézary syndrome (SS) who have received at least one prior systemic therapy.

This approval is valid in all countries of the European Union as well as Norway, Iceland, and Liechtenstein.

Kyowa Kirin plans to launch mogamulizumab in various European markets starting next year.

The EC’s decision to approve mogamulizumab was supported by the phase 3 MAVORIC trial. Results from this trial were published in The Lancet Oncology in August.

MAVORIC was a comparison of mogamulizumab and vorinostat in 372 adults with MF or SS who had received at least one prior systemic therapy.

Mogamulizumab provided a significant improvement in progression-free survival (PFS), the study’s primary endpoint.

According to investigators, the median PFS was 7.7 months with mogamulizumab and 3.1 months with vorinostat (hazard ratio=0.53, P<0.0001).

According to an independent review committee, the median PFS was 6.7 months and 3.8 months, respectively (hazard ratio=0.64, P<0.0007).

There was a significant improvement in overall response rate (ORR) with mogamulizumab.

According to independent review, the global ORR was 23% (43/186) in the mogamulizumab arm and 4% (7/186) in the vorinostat arm (risk ratio=19.4, P<0.0001).

According to investigators, the global ORR was 28% (52/186) and 5% (9/186), respectively (risk ratio=23.1, P<0.0001).

For patients with MF, the investigator-assessed ORR was 21% (22/105) with mogamulizumab and 7% (7/99) with vorinostat.

For SS patients, the investigator-assessed ORR was 37% (30/81) and 2% (2/87), respectively.

Grade 3 adverse events (AEs) in the mogamulizumab arm included drug eruptions (n=8), hypertension (n=8), pneumonia (n=6), fatigue (n=3), cellulitis (n=3), infusion-related reactions (n=3), sepsis (n=2), decreased appetite (n=2), AST increase (n=2), weight decrease (n=1), pyrexia (n=1), constipation (n=1), nausea (n=1), and diarrhea (n=1).

Grade 4 AEs with mogamulizumab were cellulitis (n=1) and pneumonia (n=1). Grade 5 AEs included pneumonia (n=1) and sepsis (n=1).

Photo by Rhoda Baer

The European Commission (EC) has granted marketing authorization for Sandoz’s pegfilgrastim product Ziextenzo®, a biosimilar of Amgen’s Neulasta.

Ziextenzo is approved for the same use as the reference medicine—to reduce the duration of neutropenia and the incidence of febrile neutropenia in adults receiving cytotoxic chemotherapy for malignancies except chronic myeloid leukemia and myelodysplastic syndromes.

The approval is valid in all countries of the European Union as well as Norway, Iceland, and Liechtenstein.

The EC’s approval was based on research suggesting Ziextenzo is comparable to Neulasta in terms of safety, efficacy, pharmacokinetics, and pharmacodynamics.^1,2,3,4

1. Blackwell K. et al. Pooled analysis of two randomized, double-blind trials comparing proposed biosimilar LA-EP2006 with reference pegfilgrastim in breast cancer. Ann Oncol 28, 2272-2277 (2017).

2. Nakov R. et al. Proposed biosimilar pegfilgrastim LA-EP2006 shows similarity in pharmacokinetics and pharmacodynamics to reference pegfilgrastim in healthy subjects. 2017 San Antonio Breast Cancer Symposium, abstract P3-14-10.

3. Blackwell K. et al. A Comparison of Proposed Biosimilar LA-EP2006 and Reference Pegfilgrastim for the Prevention of Neutropenia in Patients With Early-Stage Breast Cancer Receiving Myelosuppressive Adjuvant or Neoadjuvant Chemotherapy: Pegfilgrastim Randomized Oncology (Supportive Care) Trial to Evaluate Comparative Treatment (PROTECT-2), a Phase III, Randomized, Double-Blind Trial. Oncologist 21, 789-794 (2016).

4. Harbeck N. et al. Randomized, double-blind study comparing proposed biosimilar LA-EP2006 with reference pegfilgrastim in breast cancer. Future Oncol 12, 1359-1367 (2016).

Photo by Rhoda Baer

The European Commission (EC) has granted marketing authorization for Sandoz’s pegfilgrastim product Ziextenzo®, a biosimilar of Amgen’s Neulasta.

Ziextenzo is approved for the same use as the reference medicine—to reduce the duration of neutropenia and the incidence of febrile neutropenia in adults receiving cytotoxic chemotherapy for malignancies except chronic myeloid leukemia and myelodysplastic syndromes.

The approval is valid in all countries of the European Union as well as Norway, Iceland, and Liechtenstein.

The EC’s approval was based on research suggesting Ziextenzo is comparable to Neulasta in terms of safety, efficacy, pharmacokinetics, and pharmacodynamics.^1,2,3,4

1. Blackwell K. et al. Pooled analysis of two randomized, double-blind trials comparing proposed biosimilar LA-EP2006 with reference pegfilgrastim in breast cancer. Ann Oncol 28, 2272-2277 (2017).

2. Nakov R. et al. Proposed biosimilar pegfilgrastim LA-EP2006 shows similarity in pharmacokinetics and pharmacodynamics to reference pegfilgrastim in healthy subjects. 2017 San Antonio Breast Cancer Symposium, abstract P3-14-10.

3. Blackwell K. et al. A Comparison of Proposed Biosimilar LA-EP2006 and Reference Pegfilgrastim for the Prevention of Neutropenia in Patients With Early-Stage Breast Cancer Receiving Myelosuppressive Adjuvant or Neoadjuvant Chemotherapy: Pegfilgrastim Randomized Oncology (Supportive Care) Trial to Evaluate Comparative Treatment (PROTECT-2), a Phase III, Randomized, Double-Blind Trial. Oncologist 21, 789-794 (2016).

4. Harbeck N. et al. Randomized, double-blind study comparing proposed biosimilar LA-EP2006 with reference pegfilgrastim in breast cancer. Future Oncol 12, 1359-1367 (2016).

Photo by Rhoda Baer

The European Commission (EC) has granted marketing authorization for Sandoz’s pegfilgrastim product Ziextenzo®, a biosimilar of Amgen’s Neulasta.

Ziextenzo is approved for the same use as the reference medicine—to reduce the duration of neutropenia and the incidence of febrile neutropenia in adults receiving cytotoxic chemotherapy for malignancies except chronic myeloid leukemia and myelodysplastic syndromes.

The approval is valid in all countries of the European Union as well as Norway, Iceland, and Liechtenstein.

The EC’s approval was based on research suggesting Ziextenzo is comparable to Neulasta in terms of safety, efficacy, pharmacokinetics, and pharmacodynamics.^1,2,3,4

1. Blackwell K. et al. Pooled analysis of two randomized, double-blind trials comparing proposed biosimilar LA-EP2006 with reference pegfilgrastim in breast cancer. Ann Oncol 28, 2272-2277 (2017).

2. Nakov R. et al. Proposed biosimilar pegfilgrastim LA-EP2006 shows similarity in pharmacokinetics and pharmacodynamics to reference pegfilgrastim in healthy subjects. 2017 San Antonio Breast Cancer Symposium, abstract P3-14-10.

3. Blackwell K. et al. A Comparison of Proposed Biosimilar LA-EP2006 and Reference Pegfilgrastim for the Prevention of Neutropenia in Patients With Early-Stage Breast Cancer Receiving Myelosuppressive Adjuvant or Neoadjuvant Chemotherapy: Pegfilgrastim Randomized Oncology (Supportive Care) Trial to Evaluate Comparative Treatment (PROTECT-2), a Phase III, Randomized, Double-Blind Trial. Oncologist 21, 789-794 (2016).

4. Harbeck N. et al. Randomized, double-blind study comparing proposed biosimilar LA-EP2006 with reference pegfilgrastim in breast cancer. Future Oncol 12, 1359-1367 (2016).

India has the third largest HIV epidemic in the world because of its large population size, with 0.3% of the adult population infected with HIV. That translates to 2.1 million infected people, posing a significant challenge in the management of these individuals.¹ In all, 43% of the infected are currently on highly active antiretroviral therapy (HAART).¹ There has been a significant decrease in the number of HIV-AIDS–related deaths in recent years because of the remarkable increase in the use of antiretroviral therapy.² However, the prolonged life expectancy in these patients has resulted in an increase in the risk of various new diseases such as cancers. With the complex interactions between altered immunity and infections, the risk of cancers is markedly increased in patients with HIV-AIDS.³ The spectrum of malignancies in this group of patients differs from that in the general population. In addition, the pattern and the magnitude of malignancies differ in different parts of the world.⁴ In this study, we have analyzed the pattern of malignancies in patients with HIV-AIDS in a regional cancer center in India. The aim of the study was to analyze the pattern of malignancies in patients with HIV-AIDS based on their age and sex and to document the CD4 counts at the time the malignancy was diagnosed.

Methods

We retrieved data from our institution’s medical records department on all patients who had HIV-AIDS and had been diagnosed with a malignancy. Data of all patients presenting with a malignancy and coexisting HIV-AIDS from January 2013 through December 2016 were analyzed initially. Only patients for whom there was a documented CD4 count were included in the final retrospective analysis. We analyzed the correlation between the patients’ CD4 counts and malignancies subclassified as AIDS-defining malignancies (ADMs; aggressive B-cell non-Hodgkin lymphoma [NHL] and cervical cancer) or non–AIDS-defining malignancies (NADMs; all other malignancies other than aggressive NHL and carcinoma cervix were defined as NADM). We also analyzed the correlation between the CD4 count and NHL and other malignancies. A statistical analysis was performed using SPSS Statistics for Windows, version 23 (IBM Corp, Armonk, NY). The independent sample Mann-Whitney U or Kruskal-Wallis tests were used for comparing the CD4 counts between the various subgroups of malignancies. The study was carried out in accordance with the Declaration of Helsinki and Good Clinical Practice Guidelines.
 

Results

A total of 370 patients who were diagnosed with malignancy and have coexisting HIV-AIDS were identified. In all, 85 patients were excluded because there were no CD4 counts available for them, and the remaining 285 patients were included in the final analysis. Of that total, 136 patients (48%) were men, and 149 (52%) were women.

The median age of the population was 44.8 years (5-80 years) at the time of diagnosis with malignancy. The mean CD4 count of the entire population was 235.4 cells/mm³ (50-734 cells/mm³). There were 104 patients with CD4 counts of ≤200 cells/mm³, and 181 patients had CD4 counts of >200 cells/mm³ (Table 1). All patients received the HAART regimen, efavirenz-lamuvidine-tenofovir (600 mg/300 mg/300 mg Telura).

Discussion

In 2015, a report from the Indian government estimated the prevalence of HIV in the country as 0.26% (0.22%-0.32%).⁵ The report also noted a decreasing trend in the number of new cases of HIV diagnosed and a decrease in the number of AIDS-related deaths.⁵ The decrease in deaths from AIDS is primarily attributed to the widespread use of HAART. With the introduction of HAART therapy, the survival of patients diagnosed with HIV-AIDS has increased markedly.⁶ However, newer challenges have emerged with improved survival, such as an increasing number of patients being diagnosed with malignancies. In the current HAART era, the pattern of malignancies in people living with HIV-AIDS has changed compared with the pre-HAART era.⁷ The literature suggests that worldwide, malignancies are encountered in about 30% patients with HIV-AIDS, but that percentage differs sharply from that encountered in India, where it is less than 5%.⁸ This may partly be explained by opportunistic infections such as tuberculosis in Indian patients, which remains the leading cause of death in the HIV-AIDS population. In our study, we retrospectively analyzed the pattern of malignancies in patients with HIV-AIDS.

Although few studies have quoted NHL as the predominant malignancy in their patients with HIV-AIDS, the predominant malignancy was cervical cancer in our patient population, as seen in few other studies.^8-10 Head and neck malignancies also continue to be common malignancies in men with HIV-AIDS.¹⁰ Thus, an increase in malignancies induced by the human papillomavirus (HPV) can be seen in this group of patients. Only a few pediatric malignancies were noted in our study, and all of those patients had a vertical transmission of HIV.

Kaposi sarcoma is quite rare in the Indian population, and no case of Kaposi sarcoma was diagnosed in our study population. A similar finding was seen in several earlier publications from India. In the largest published series from India by Dhir and colleagues, evaluating 251 patients with HIV-AIDS and malignancy, no case of Kaposi sarcoma was reported.¹⁰ The authors mentioned that this finding might be because of the low seroprevalence of Kaposi sarcoma-associated herpesvirus in the Asian population.¹⁰ Three different studies from southern India have also not reported the incidence of Kaposi Sarcoma in their series of HIV-AIDS patients with malignancies,^11-13 and similar findings were also reported in a study from northern India.⁹ The incidence of other immunodeficiency-related malignancies was identical to those reported in other studies in the literature.^10,14

As seen in other studies, the CD4 counts in patients with ADM were significantly lower compared with those of patients with NADM, and that difference was not seen when CD4 counts of patients with cervical cancer were compared with patients in the NADM subgroup. The risk of NHL increases proportionally to the degree of immune suppression. The increased susceptibility to various infections in patients with low CD4 counts may also contribute to the occurrence of NHL in patients with low CD4 counts. The occurrence of various other rare cancers in patients with HIV-AIDS may be because of confounding rather than a direct HIV or immunosuppression effect.

An increasing incidence of NADMs has been noted in the Western literature.^7,14 ADMs remain the most common malignancies in the HIV-AIDS population, accounting for about 48% of all malignancies.⁸ This is in concordance with previous publications from India.^8,10 With the widespread availability of generic HAART, the incidence of ADMs may decrease even more in the future. In developing countries where the screening procedures for malignancies in both the general population and patients with HIV-AIDS have not yet been implemented at a national level, premalignant lesions of the cervix are not detected.¹⁰ Cervical cancer is the most common malignancy in our study population, which underscores the importance of cervical cancer screening in patients with HIV-AIDS.

In the developed countries, following the introduction of HAART in HIV-AIDS management, the incidence of Kaposi sarcoma decreased by 60% to 70%, and the incidence of NHL decreased by 30% to 50%, whereas the rates of cervical cancer remained either stable or declined.^15,16 Despite the declining trend, the incidence of these malignancies continues to be high among patients with HIV-AIDS compared with the general population.¹⁷ A study from the United States showed increasing trends in various NADMs (such as anal, lung, and liver cancers and Hodgkin lymphoma) from 2006 to 2010.¹⁷ In 2003, the number of patients with NADM were higher than the number of patients with ADM in the United States.¹⁴ In a population-based study from Brazil, ADMs were the most common malignancies diagnosed in patients with HIV-AIDS. A declining trend was noted in the incidence of ADMs in the population and an increasing trend in the incidence of NADMs. This increase in NADM incidence was contributed by anal and lung cancers.¹⁸ Studies from developing countries such as Uganda and Botswana have also shown a decrease in the incidence of Kaposi sarcoma after the introduction of HAART.^19-21

Kaposi sarcoma, cervical cancer, NHL (including Burkitt lymphoma, immunoblastic lymphoma, and primary CNS lymphoma [PCNSL]) comprise ADMs. All 3 ADMs have an underlying viral infection as the causative agent.²² Kaposi sarcoma is caused by the Kaposi sarcoma herpes virus, for which seroprevalence varies worldwide.²³ As already noted in this article, the incidence of Kaposi sarcoma among the HIV-AIDS population has decreased worldwide since the introduction of HAART. The preinvasive uterine cervix lesions and carcinoma cervix are caused by HPV. NHL in patients with HIV-AIDS is a predominantly aggressive B-cell neoplasm. Epstein-Barr virus is implicated for most of the ADM NHLs.²⁴ PCNSL occurs in patients with low CD4 counts and poses a diagnostic challenge. The treatment outcomes for patients with PCNSL before the HAART era were dismal. With the widespread use of HAART, the treatment outcomes of patients with HIV-AIDS and NHL improved, and, currently, these patients are managed the same way as other patients with NHL.²²

The increasing incidence of the NADM is partly attributed to the increasing incidence of these malignancies in the general population. An elevated risk of certain NADMs is also attributable to viral infections. The common NADMs in the United States are lung, anal, oropharyngeal, and hepatocellular cancers and Hodgkin lymphoma.¹⁴ The common NADMs in our study population were oral, oropharyngeal, colon, and breast cancers and Hodgkin lymphoma. One-third of head and neck cancers, including most oropharyngeal cancers, and cervical and anal cancers in patients with HIV-AIDS are related to HPV.²⁵ Patients with HIV-AIDS are at increased risk for chronic HPV infection from immunosuppression. Chronic HPV infections and prolonged immunosuppression cause premalignant high-grade squamous intraepithelial lesions and invasive cancers.²² The initiation of and adherence to HAART leads to immune recovery and reduces high-risk HPV-associated morbidity.²⁶ Findings from previous studies have demonstrated the benefits of screening for cervical cancer in patients with HIV-AIDS.²⁷ The HPV vaccine is immunogenic in patients with HIV-AIDS and might help prevent HPV-associated malignancies.²⁸

Conclusions

With the wide use of HAART by patients with HIV-AIDS, we can expect an increase in the survival of that population. The incidence of malignancies may also increase significantly in these patients, and further longitudinal studies are needed, as malignancies may emerge as the most common cause of death in patients with HIV-AIDS. In addition, the extensive use of HAART therapy and implementation of screening programs for cervical cancer in patients with HIV-AIDS could result in a decrease in the incidence of ADMs.

India has the third largest HIV epidemic in the world because of its large population size, with 0.3% of the adult population infected with HIV. That translates to 2.1 million infected people, posing a significant challenge in the management of these individuals.¹ In all, 43% of the infected are currently on highly active antiretroviral therapy (HAART).¹ There has been a significant decrease in the number of HIV-AIDS–related deaths in recent years because of the remarkable increase in the use of antiretroviral therapy.² However, the prolonged life expectancy in these patients has resulted in an increase in the risk of various new diseases such as cancers. With the complex interactions between altered immunity and infections, the risk of cancers is markedly increased in patients with HIV-AIDS.³ The spectrum of malignancies in this group of patients differs from that in the general population. In addition, the pattern and the magnitude of malignancies differ in different parts of the world.⁴ In this study, we have analyzed the pattern of malignancies in patients with HIV-AIDS in a regional cancer center in India. The aim of the study was to analyze the pattern of malignancies in patients with HIV-AIDS based on their age and sex and to document the CD4 counts at the time the malignancy was diagnosed.

Methods

We retrieved data from our institution’s medical records department on all patients who had HIV-AIDS and had been diagnosed with a malignancy. Data of all patients presenting with a malignancy and coexisting HIV-AIDS from January 2013 through December 2016 were analyzed initially. Only patients for whom there was a documented CD4 count were included in the final retrospective analysis. We analyzed the correlation between the patients’ CD4 counts and malignancies subclassified as AIDS-defining malignancies (ADMs; aggressive B-cell non-Hodgkin lymphoma [NHL] and cervical cancer) or non–AIDS-defining malignancies (NADMs; all other malignancies other than aggressive NHL and carcinoma cervix were defined as NADM). We also analyzed the correlation between the CD4 count and NHL and other malignancies. A statistical analysis was performed using SPSS Statistics for Windows, version 23 (IBM Corp, Armonk, NY). The independent sample Mann-Whitney U or Kruskal-Wallis tests were used for comparing the CD4 counts between the various subgroups of malignancies. The study was carried out in accordance with the Declaration of Helsinki and Good Clinical Practice Guidelines.
 

Results

A total of 370 patients who were diagnosed with malignancy and have coexisting HIV-AIDS were identified. In all, 85 patients were excluded because there were no CD4 counts available for them, and the remaining 285 patients were included in the final analysis. Of that total, 136 patients (48%) were men, and 149 (52%) were women.

The median age of the population was 44.8 years (5-80 years) at the time of diagnosis with malignancy. The mean CD4 count of the entire population was 235.4 cells/mm³ (50-734 cells/mm³). There were 104 patients with CD4 counts of ≤200 cells/mm³, and 181 patients had CD4 counts of >200 cells/mm³ (Table 1). All patients received the HAART regimen, efavirenz-lamuvidine-tenofovir (600 mg/300 mg/300 mg Telura).

Discussion

In 2015, a report from the Indian government estimated the prevalence of HIV in the country as 0.26% (0.22%-0.32%).⁵ The report also noted a decreasing trend in the number of new cases of HIV diagnosed and a decrease in the number of AIDS-related deaths.⁵ The decrease in deaths from AIDS is primarily attributed to the widespread use of HAART. With the introduction of HAART therapy, the survival of patients diagnosed with HIV-AIDS has increased markedly.⁶ However, newer challenges have emerged with improved survival, such as an increasing number of patients being diagnosed with malignancies. In the current HAART era, the pattern of malignancies in people living with HIV-AIDS has changed compared with the pre-HAART era.⁷ The literature suggests that worldwide, malignancies are encountered in about 30% patients with HIV-AIDS, but that percentage differs sharply from that encountered in India, where it is less than 5%.⁸ This may partly be explained by opportunistic infections such as tuberculosis in Indian patients, which remains the leading cause of death in the HIV-AIDS population. In our study, we retrospectively analyzed the pattern of malignancies in patients with HIV-AIDS.

Although few studies have quoted NHL as the predominant malignancy in their patients with HIV-AIDS, the predominant malignancy was cervical cancer in our patient population, as seen in few other studies.^8-10 Head and neck malignancies also continue to be common malignancies in men with HIV-AIDS.¹⁰ Thus, an increase in malignancies induced by the human papillomavirus (HPV) can be seen in this group of patients. Only a few pediatric malignancies were noted in our study, and all of those patients had a vertical transmission of HIV.

Kaposi sarcoma is quite rare in the Indian population, and no case of Kaposi sarcoma was diagnosed in our study population. A similar finding was seen in several earlier publications from India. In the largest published series from India by Dhir and colleagues, evaluating 251 patients with HIV-AIDS and malignancy, no case of Kaposi sarcoma was reported.¹⁰ The authors mentioned that this finding might be because of the low seroprevalence of Kaposi sarcoma-associated herpesvirus in the Asian population.¹⁰ Three different studies from southern India have also not reported the incidence of Kaposi Sarcoma in their series of HIV-AIDS patients with malignancies,^11-13 and similar findings were also reported in a study from northern India.⁹ The incidence of other immunodeficiency-related malignancies was identical to those reported in other studies in the literature.^10,14

As seen in other studies, the CD4 counts in patients with ADM were significantly lower compared with those of patients with NADM, and that difference was not seen when CD4 counts of patients with cervical cancer were compared with patients in the NADM subgroup. The risk of NHL increases proportionally to the degree of immune suppression. The increased susceptibility to various infections in patients with low CD4 counts may also contribute to the occurrence of NHL in patients with low CD4 counts. The occurrence of various other rare cancers in patients with HIV-AIDS may be because of confounding rather than a direct HIV or immunosuppression effect.

An increasing incidence of NADMs has been noted in the Western literature.^7,14 ADMs remain the most common malignancies in the HIV-AIDS population, accounting for about 48% of all malignancies.⁸ This is in concordance with previous publications from India.^8,10 With the widespread availability of generic HAART, the incidence of ADMs may decrease even more in the future. In developing countries where the screening procedures for malignancies in both the general population and patients with HIV-AIDS have not yet been implemented at a national level, premalignant lesions of the cervix are not detected.¹⁰ Cervical cancer is the most common malignancy in our study population, which underscores the importance of cervical cancer screening in patients with HIV-AIDS.

In the developed countries, following the introduction of HAART in HIV-AIDS management, the incidence of Kaposi sarcoma decreased by 60% to 70%, and the incidence of NHL decreased by 30% to 50%, whereas the rates of cervical cancer remained either stable or declined.^15,16 Despite the declining trend, the incidence of these malignancies continues to be high among patients with HIV-AIDS compared with the general population.¹⁷ A study from the United States showed increasing trends in various NADMs (such as anal, lung, and liver cancers and Hodgkin lymphoma) from 2006 to 2010.¹⁷ In 2003, the number of patients with NADM were higher than the number of patients with ADM in the United States.¹⁴ In a population-based study from Brazil, ADMs were the most common malignancies diagnosed in patients with HIV-AIDS. A declining trend was noted in the incidence of ADMs in the population and an increasing trend in the incidence of NADMs. This increase in NADM incidence was contributed by anal and lung cancers.¹⁸ Studies from developing countries such as Uganda and Botswana have also shown a decrease in the incidence of Kaposi sarcoma after the introduction of HAART.^19-21

Kaposi sarcoma, cervical cancer, NHL (including Burkitt lymphoma, immunoblastic lymphoma, and primary CNS lymphoma [PCNSL]) comprise ADMs. All 3 ADMs have an underlying viral infection as the causative agent.²² Kaposi sarcoma is caused by the Kaposi sarcoma herpes virus, for which seroprevalence varies worldwide.²³ As already noted in this article, the incidence of Kaposi sarcoma among the HIV-AIDS population has decreased worldwide since the introduction of HAART. The preinvasive uterine cervix lesions and carcinoma cervix are caused by HPV. NHL in patients with HIV-AIDS is a predominantly aggressive B-cell neoplasm. Epstein-Barr virus is implicated for most of the ADM NHLs.²⁴ PCNSL occurs in patients with low CD4 counts and poses a diagnostic challenge. The treatment outcomes for patients with PCNSL before the HAART era were dismal. With the widespread use of HAART, the treatment outcomes of patients with HIV-AIDS and NHL improved, and, currently, these patients are managed the same way as other patients with NHL.²²

The increasing incidence of the NADM is partly attributed to the increasing incidence of these malignancies in the general population. An elevated risk of certain NADMs is also attributable to viral infections. The common NADMs in the United States are lung, anal, oropharyngeal, and hepatocellular cancers and Hodgkin lymphoma.¹⁴ The common NADMs in our study population were oral, oropharyngeal, colon, and breast cancers and Hodgkin lymphoma. One-third of head and neck cancers, including most oropharyngeal cancers, and cervical and anal cancers in patients with HIV-AIDS are related to HPV.²⁵ Patients with HIV-AIDS are at increased risk for chronic HPV infection from immunosuppression. Chronic HPV infections and prolonged immunosuppression cause premalignant high-grade squamous intraepithelial lesions and invasive cancers.²² The initiation of and adherence to HAART leads to immune recovery and reduces high-risk HPV-associated morbidity.²⁶ Findings from previous studies have demonstrated the benefits of screening for cervical cancer in patients with HIV-AIDS.²⁷ The HPV vaccine is immunogenic in patients with HIV-AIDS and might help prevent HPV-associated malignancies.²⁸

Conclusions

With the wide use of HAART by patients with HIV-AIDS, we can expect an increase in the survival of that population. The incidence of malignancies may also increase significantly in these patients, and further longitudinal studies are needed, as malignancies may emerge as the most common cause of death in patients with HIV-AIDS. In addition, the extensive use of HAART therapy and implementation of screening programs for cervical cancer in patients with HIV-AIDS could result in a decrease in the incidence of ADMs.

India has the third largest HIV epidemic in the world because of its large population size, with 0.3% of the adult population infected with HIV. That translates to 2.1 million infected people, posing a significant challenge in the management of these individuals.¹ In all, 43% of the infected are currently on highly active antiretroviral therapy (HAART).¹ There has been a significant decrease in the number of HIV-AIDS–related deaths in recent years because of the remarkable increase in the use of antiretroviral therapy.² However, the prolonged life expectancy in these patients has resulted in an increase in the risk of various new diseases such as cancers. With the complex interactions between altered immunity and infections, the risk of cancers is markedly increased in patients with HIV-AIDS.³ The spectrum of malignancies in this group of patients differs from that in the general population. In addition, the pattern and the magnitude of malignancies differ in different parts of the world.⁴ In this study, we have analyzed the pattern of malignancies in patients with HIV-AIDS in a regional cancer center in India. The aim of the study was to analyze the pattern of malignancies in patients with HIV-AIDS based on their age and sex and to document the CD4 counts at the time the malignancy was diagnosed.

Methods

We retrieved data from our institution’s medical records department on all patients who had HIV-AIDS and had been diagnosed with a malignancy. Data of all patients presenting with a malignancy and coexisting HIV-AIDS from January 2013 through December 2016 were analyzed initially. Only patients for whom there was a documented CD4 count were included in the final retrospective analysis. We analyzed the correlation between the patients’ CD4 counts and malignancies subclassified as AIDS-defining malignancies (ADMs; aggressive B-cell non-Hodgkin lymphoma [NHL] and cervical cancer) or non–AIDS-defining malignancies (NADMs; all other malignancies other than aggressive NHL and carcinoma cervix were defined as NADM). We also analyzed the correlation between the CD4 count and NHL and other malignancies. A statistical analysis was performed using SPSS Statistics for Windows, version 23 (IBM Corp, Armonk, NY). The independent sample Mann-Whitney U or Kruskal-Wallis tests were used for comparing the CD4 counts between the various subgroups of malignancies. The study was carried out in accordance with the Declaration of Helsinki and Good Clinical Practice Guidelines.
 

Results

A total of 370 patients who were diagnosed with malignancy and have coexisting HIV-AIDS were identified. In all, 85 patients were excluded because there were no CD4 counts available for them, and the remaining 285 patients were included in the final analysis. Of that total, 136 patients (48%) were men, and 149 (52%) were women.

The median age of the population was 44.8 years (5-80 years) at the time of diagnosis with malignancy. The mean CD4 count of the entire population was 235.4 cells/mm³ (50-734 cells/mm³). There were 104 patients with CD4 counts of ≤200 cells/mm³, and 181 patients had CD4 counts of >200 cells/mm³ (Table 1). All patients received the HAART regimen, efavirenz-lamuvidine-tenofovir (600 mg/300 mg/300 mg Telura).

Discussion

In 2015, a report from the Indian government estimated the prevalence of HIV in the country as 0.26% (0.22%-0.32%).⁵ The report also noted a decreasing trend in the number of new cases of HIV diagnosed and a decrease in the number of AIDS-related deaths.⁵ The decrease in deaths from AIDS is primarily attributed to the widespread use of HAART. With the introduction of HAART therapy, the survival of patients diagnosed with HIV-AIDS has increased markedly.⁶ However, newer challenges have emerged with improved survival, such as an increasing number of patients being diagnosed with malignancies. In the current HAART era, the pattern of malignancies in people living with HIV-AIDS has changed compared with the pre-HAART era.⁷ The literature suggests that worldwide, malignancies are encountered in about 30% patients with HIV-AIDS, but that percentage differs sharply from that encountered in India, where it is less than 5%.⁸ This may partly be explained by opportunistic infections such as tuberculosis in Indian patients, which remains the leading cause of death in the HIV-AIDS population. In our study, we retrospectively analyzed the pattern of malignancies in patients with HIV-AIDS.

Although few studies have quoted NHL as the predominant malignancy in their patients with HIV-AIDS, the predominant malignancy was cervical cancer in our patient population, as seen in few other studies.^8-10 Head and neck malignancies also continue to be common malignancies in men with HIV-AIDS.¹⁰ Thus, an increase in malignancies induced by the human papillomavirus (HPV) can be seen in this group of patients. Only a few pediatric malignancies were noted in our study, and all of those patients had a vertical transmission of HIV.

Kaposi sarcoma is quite rare in the Indian population, and no case of Kaposi sarcoma was diagnosed in our study population. A similar finding was seen in several earlier publications from India. In the largest published series from India by Dhir and colleagues, evaluating 251 patients with HIV-AIDS and malignancy, no case of Kaposi sarcoma was reported.¹⁰ The authors mentioned that this finding might be because of the low seroprevalence of Kaposi sarcoma-associated herpesvirus in the Asian population.¹⁰ Three different studies from southern India have also not reported the incidence of Kaposi Sarcoma in their series of HIV-AIDS patients with malignancies,^11-13 and similar findings were also reported in a study from northern India.⁹ The incidence of other immunodeficiency-related malignancies was identical to those reported in other studies in the literature.^10,14

As seen in other studies, the CD4 counts in patients with ADM were significantly lower compared with those of patients with NADM, and that difference was not seen when CD4 counts of patients with cervical cancer were compared with patients in the NADM subgroup. The risk of NHL increases proportionally to the degree of immune suppression. The increased susceptibility to various infections in patients with low CD4 counts may also contribute to the occurrence of NHL in patients with low CD4 counts. The occurrence of various other rare cancers in patients with HIV-AIDS may be because of confounding rather than a direct HIV or immunosuppression effect.

An increasing incidence of NADMs has been noted in the Western literature.^7,14 ADMs remain the most common malignancies in the HIV-AIDS population, accounting for about 48% of all malignancies.⁸ This is in concordance with previous publications from India.^8,10 With the widespread availability of generic HAART, the incidence of ADMs may decrease even more in the future. In developing countries where the screening procedures for malignancies in both the general population and patients with HIV-AIDS have not yet been implemented at a national level, premalignant lesions of the cervix are not detected.¹⁰ Cervical cancer is the most common malignancy in our study population, which underscores the importance of cervical cancer screening in patients with HIV-AIDS.

In the developed countries, following the introduction of HAART in HIV-AIDS management, the incidence of Kaposi sarcoma decreased by 60% to 70%, and the incidence of NHL decreased by 30% to 50%, whereas the rates of cervical cancer remained either stable or declined.^15,16 Despite the declining trend, the incidence of these malignancies continues to be high among patients with HIV-AIDS compared with the general population.¹⁷ A study from the United States showed increasing trends in various NADMs (such as anal, lung, and liver cancers and Hodgkin lymphoma) from 2006 to 2010.¹⁷ In 2003, the number of patients with NADM were higher than the number of patients with ADM in the United States.¹⁴ In a population-based study from Brazil, ADMs were the most common malignancies diagnosed in patients with HIV-AIDS. A declining trend was noted in the incidence of ADMs in the population and an increasing trend in the incidence of NADMs. This increase in NADM incidence was contributed by anal and lung cancers.¹⁸ Studies from developing countries such as Uganda and Botswana have also shown a decrease in the incidence of Kaposi sarcoma after the introduction of HAART.^19-21

Kaposi sarcoma, cervical cancer, NHL (including Burkitt lymphoma, immunoblastic lymphoma, and primary CNS lymphoma [PCNSL]) comprise ADMs. All 3 ADMs have an underlying viral infection as the causative agent.²² Kaposi sarcoma is caused by the Kaposi sarcoma herpes virus, for which seroprevalence varies worldwide.²³ As already noted in this article, the incidence of Kaposi sarcoma among the HIV-AIDS population has decreased worldwide since the introduction of HAART. The preinvasive uterine cervix lesions and carcinoma cervix are caused by HPV. NHL in patients with HIV-AIDS is a predominantly aggressive B-cell neoplasm. Epstein-Barr virus is implicated for most of the ADM NHLs.²⁴ PCNSL occurs in patients with low CD4 counts and poses a diagnostic challenge. The treatment outcomes for patients with PCNSL before the HAART era were dismal. With the widespread use of HAART, the treatment outcomes of patients with HIV-AIDS and NHL improved, and, currently, these patients are managed the same way as other patients with NHL.²²

The increasing incidence of the NADM is partly attributed to the increasing incidence of these malignancies in the general population. An elevated risk of certain NADMs is also attributable to viral infections. The common NADMs in the United States are lung, anal, oropharyngeal, and hepatocellular cancers and Hodgkin lymphoma.¹⁴ The common NADMs in our study population were oral, oropharyngeal, colon, and breast cancers and Hodgkin lymphoma. One-third of head and neck cancers, including most oropharyngeal cancers, and cervical and anal cancers in patients with HIV-AIDS are related to HPV.²⁵ Patients with HIV-AIDS are at increased risk for chronic HPV infection from immunosuppression. Chronic HPV infections and prolonged immunosuppression cause premalignant high-grade squamous intraepithelial lesions and invasive cancers.²² The initiation of and adherence to HAART leads to immune recovery and reduces high-risk HPV-associated morbidity.²⁶ Findings from previous studies have demonstrated the benefits of screening for cervical cancer in patients with HIV-AIDS.²⁷ The HPV vaccine is immunogenic in patients with HIV-AIDS and might help prevent HPV-associated malignancies.²⁸

Conclusions

With the wide use of HAART by patients with HIV-AIDS, we can expect an increase in the survival of that population. The incidence of malignancies may also increase significantly in these patients, and further longitudinal studies are needed, as malignancies may emerge as the most common cause of death in patients with HIV-AIDS. In addition, the extensive use of HAART therapy and implementation of screening programs for cervical cancer in patients with HIV-AIDS could result in a decrease in the incidence of ADMs.

Photo by Rhoda Baer

The European Commission (EC) has approved Mundipharma’s pegfilgrastim product Pelmeg, a biosimilar of Amgen’s Neulasta.

Pelmeg is approved for use in reducing the duration of neutropenia and the incidence of febrile neutropenia in adults who receive cytotoxic chemotherapy for malignancies, with the exceptions of chronic myeloid leukemia and myelodysplastic syndromes.

The approval is valid in all countries of the European Union as well as Norway, Iceland, and Liechtenstein.

The EC’s approval of Pelmeg was supported by research showing pharmacokinetic comparability between Pelmeg and Neulasta at a dose of 6 mg, pharmacodynamic comparability at doses of 6 mg and 3 mg, and no clinically meaningful differences in the safety and immunogenicity profiles of Pelmeg and Neulasta.^1,2,3

1. Roth K. et al. Demonstration of pharmacokinetic and pharmacodynamic comparability in healthy volunteers for B12019, a proposed pegfilgrastim biosimilar. ECCO 2017, abstract 241.

2. Roth K. et al. Comparability of pharmacodynamics and immunogenicity of B12019, a proposed pegfilgrastim biosimilar to Neulasta®. ASH 2017, abstract 1002.

3. Roth K. et al. Pharmacokinetic and pharmacodynamic comparability of B12019, a proposed pegfilgrastim biosimilar. ESMO 2017, poster 1573.

Photo by Rhoda Baer

The European Commission (EC) has approved Mundipharma’s pegfilgrastim product Pelmeg, a biosimilar of Amgen’s Neulasta.

Pelmeg is approved for use in reducing the duration of neutropenia and the incidence of febrile neutropenia in adults who receive cytotoxic chemotherapy for malignancies, with the exceptions of chronic myeloid leukemia and myelodysplastic syndromes.

The approval is valid in all countries of the European Union as well as Norway, Iceland, and Liechtenstein.

The EC’s approval of Pelmeg was supported by research showing pharmacokinetic comparability between Pelmeg and Neulasta at a dose of 6 mg, pharmacodynamic comparability at doses of 6 mg and 3 mg, and no clinically meaningful differences in the safety and immunogenicity profiles of Pelmeg and Neulasta.^1,2,3

1. Roth K. et al. Demonstration of pharmacokinetic and pharmacodynamic comparability in healthy volunteers for B12019, a proposed pegfilgrastim biosimilar. ECCO 2017, abstract 241.

2. Roth K. et al. Comparability of pharmacodynamics and immunogenicity of B12019, a proposed pegfilgrastim biosimilar to Neulasta®. ASH 2017, abstract 1002.

3. Roth K. et al. Pharmacokinetic and pharmacodynamic comparability of B12019, a proposed pegfilgrastim biosimilar. ESMO 2017, poster 1573.

Photo by Rhoda Baer

The European Commission (EC) has approved Mundipharma’s pegfilgrastim product Pelmeg, a biosimilar of Amgen’s Neulasta.

Pelmeg is approved for use in reducing the duration of neutropenia and the incidence of febrile neutropenia in adults who receive cytotoxic chemotherapy for malignancies, with the exceptions of chronic myeloid leukemia and myelodysplastic syndromes.

The approval is valid in all countries of the European Union as well as Norway, Iceland, and Liechtenstein.

The EC’s approval of Pelmeg was supported by research showing pharmacokinetic comparability between Pelmeg and Neulasta at a dose of 6 mg, pharmacodynamic comparability at doses of 6 mg and 3 mg, and no clinically meaningful differences in the safety and immunogenicity profiles of Pelmeg and Neulasta.^1,2,3

1. Roth K. et al. Demonstration of pharmacokinetic and pharmacodynamic comparability in healthy volunteers for B12019, a proposed pegfilgrastim biosimilar. ECCO 2017, abstract 241.

2. Roth K. et al. Comparability of pharmacodynamics and immunogenicity of B12019, a proposed pegfilgrastim biosimilar to Neulasta®. ASH 2017, abstract 1002.

3. Roth K. et al. Pharmacokinetic and pharmacodynamic comparability of B12019, a proposed pegfilgrastim biosimilar. ESMO 2017, poster 1573.

Multiple myeloma is the most common plasma cell neoplasm, with an estimated 24,000 cases occurring annually.¹ Symptomatic multiple myeloma most commonly presents with one or more of the cardinal CRAB phenomena of hypercalcemia, renal dysfunction, anemia, or lytic bone lesions.² Less commonly, patients may present with plasmacytomas (focal lesions of malignant plasma cells), which may involve bony or soft tissues.¹

Plasma cell neoplasms occasionally involve the joints, including the elbows, typically as plasmacytomas. The elbow is an unusual but reported location of plasmacytomas.^3,4 A case of multiple myeloma and amyloid light-chain (AL) amyloidosis has been reported, with manifestations including pseudomyopathy, bone marrow plasmacytosis, and bilateral trochanteric bursitis.⁵Bursitis is defined as inflammation of the synovial-fluid–containing sacs that lubricate joints. The olecranon bursa is commonly affected. Etiologies include infection, inflammatory disease, trauma, and malignancy. Furthermore, there is an association between bursitis and immunosuppression.^6,7 The most common modes of therapy used to treat bursitis are nonsteroidal anti-inflammatory drugs, corticosteroid injections, and surgical management.

Trochanteric bursitis has been attributed to multiple myeloma in one previous case report, but we are not aware of any previous cases of olecranon bursitis caused by multiple myeloma. Here, we present the case of a 46-year-old man with heavily pretreated multiple myeloma and amyloidosis who developed left olecranon bursitis contemporaneously with disease relapse; flow cytometric analysis of the bursal fluid demonstrated an abnormal plasma cell population, establishing the etiology.

Case presentation and summary

A 46-year-old man with a longstanding history of multiple myeloma developed swelling of the left elbow that was initially painless in September 2016. He had been diagnosed with IgA kappa multiple myeloma and AL deposition in 2011. Over the course of his disease, he was treated with the following sequence of therapies: cyclophosphamide, bortezomib, and dexamethasone, followed by melphalan-conditioned autologous peripheral blood stem cell transplant; lenalidomide and dexamethasone; carfilzomib and dexamethasone; pomalidomide, bortezomib, and dexamethasone; and bortezomib, lenalidomide, dexamethasone, doxorubicin, cyclophosphamide, and etoposide, followed by second melphalan-conditioned autologous peripheral blood stem cell transplant. In addition to treatment with numerous novel and chemotherapeutic agents, his disease course was notable for amyloid deposition in the liver, bone marrow, and kidneys, which resulted in dialysis dependence.

After the second autologous transplant, he achieved a very good partial response and experienced about 9 months of remission, after which laboratory evaluation indicated recurrence of IgA kappa monoclonal protein and free kappa light-chains, which increased slowly over several months without focal symptoms, cytopenias, or decline in organ function (Figure 1).

Discussion

Our patient experienced left olecranon bursitis simultaneously with relapse of multiple myeloma and AL amyloidosis. Evaluation for infectious causes was negative, and the bursal fluid did not have strongly inflammatory characteristics. Furthermore, a small plasma cell population was isolated from the fluid. Imaging did not reveal an underlying dominant lytic lesion. Although we do not have direct pathologic confirmation, the clinical scenario and flow cytometry findings support our interpretation that the patient’s bursitis was caused by or at least related to underlying multiple myeloma. While reactive plasma cells are also CD38 positive and CD138 positive, they maintain the expression of CD19 and CD45 without aberrant expression of CD56 or CD117 and do not show loss of expression of CD81 or CD27. In this situation, we suspect that either a plasmacytoma involving the soft tissue of the bursa or amyloid infiltration of the synovium may have occurred. Anti-myeloma therapies and radiation therapy did not result in control of the bursitis, though it should be noted that the patient’s highly refractory disease progressed despite treatment with a combination of later-generation immunomodulatory imide and proteasome inhibitor therapies.

Cases of malignant bursitis have been reported several times in the literature, though nearly all of the instances involved connective tissue or metastatic tumors. Tumor histologies include osteochondroma,^8,9 malignant fibrous histiocytoma,¹⁰ synovial sarcoma,¹¹ and metastatic breast cancer.¹²

Hematologic malignancies are more rare causes of bursitis; our literature search identified a report of 2 cases of non-Hodgkin lymphoma mimicking rheumatoid arthritis. The joints were the knee and elbow. Synovial fluid from one case was clear and yellow, with leukocytosis with a neutrophilic predominance (similar to our case). In both cases, pathology confirmed lymphomatous infiltration of the synovium.¹³ Notably, we identified a case of a previously healthy 35-year-old woman with bilateral trochanteric bursitis. Biopsy of tissue from the right trochanteric bursa demonstrated positive birefringence, diagnostic of AL amyloidosis. The patient also had a biclonal paraprotein accompanied by calvarial lytic lesions. She was treated with a corticosteroid pulse and bisphosphonates, followed by autologous hematopoietic stem cell transplant. ⁵ Our case shares features with the above case, including the relatively young age of the patient and the presence of AL amyloidosis.

Our patient wished to avoid a surgical biopsy procedure, and therefore we utilized flow cytometry of the bursal fluid to establish that the etiology of fluid collection was consistent with his concurrent relapse of multiple myeloma. We believe that we are reporting the second case of multiple myeloma-associated bursitis and the first case associated with multiple myeloma relapse; to our knowledge, it is the first to be diagnosed with the aid of flow cytometry.

Because of our patient’s reliance on hemodialysis beginning one year prior to his presentation with olecranon bursitis, we entertain “dialysis elbow” within the differential diagnosis. Dialysis elbow is a relatively uncommon complication of dialysis, in which patients develop olecranon bursitis on the same side as the hemodialysis access after a prolonged (months to years) duration of hemodialysis. Serositis and mechanical forces are the hypothesized etiologies¹⁴; infectious and rheumatologic causes were excluded from the reported cases. Nevertheless, we favor a malignant cause based upon the flow cytometry findings indicating involvement by immunophenotypically abnormal plasma cells.

Our patient was treated initially with serial drainage and nonsteroidals, which had little impact. After diagnosis of a plasma cell population in the fluid, we offered local treatment with radiation and systemic treatment of multiple myeloma, which offered better but suboptimal control. Possible treatments for olecranon bursitis include surgery, corticosteroid injections, anti-inflammatories, and serial drainage. Nonsurgical management may be more effective than surgical management, and corticosteroid injection carries significant risks. On the other hand, serial drainage does not confer additional infection risk in cases with aseptic etiology.¹⁵ We combined conservative measures as well as treatment of the underlying disease, but we believe that our patient did not derive significant benefit because of the refractory nature of his disease; he also expressed a preference to avoid surgical intervention.
 

Conclusion

Bursitis is a rare but thought-provoking potential manifestation of multiple myeloma and AL amyloidosis; we believe that our patient’s bursitis was related to plasma cell neoplasia based upon co-occurrence with disease relapse. His bursitis turned out to be an early indicator of impending systemic relapse. In this particular case, in which the patient wished to avoid surgical intervention, flow cytometry was of great value, and we believe that our case is the first report of malignant bursitis being diagnosed by flow cytometry. Our patient’s case shares similarities with other biopsy-confirmed cases of malignant bursitis, but we were able to avoid the need for surgical biopsy or bursal stripping.

The authors thank Jennifer Wilham MT (ASCP), Pat Byrd MT (ASCP), and Darlene Mann MT (ASCP) for their technical support.

Multiple myeloma is the most common plasma cell neoplasm, with an estimated 24,000 cases occurring annually.¹ Symptomatic multiple myeloma most commonly presents with one or more of the cardinal CRAB phenomena of hypercalcemia, renal dysfunction, anemia, or lytic bone lesions.² Less commonly, patients may present with plasmacytomas (focal lesions of malignant plasma cells), which may involve bony or soft tissues.¹

Plasma cell neoplasms occasionally involve the joints, including the elbows, typically as plasmacytomas. The elbow is an unusual but reported location of plasmacytomas.^3,4 A case of multiple myeloma and amyloid light-chain (AL) amyloidosis has been reported, with manifestations including pseudomyopathy, bone marrow plasmacytosis, and bilateral trochanteric bursitis.⁵Bursitis is defined as inflammation of the synovial-fluid–containing sacs that lubricate joints. The olecranon bursa is commonly affected. Etiologies include infection, inflammatory disease, trauma, and malignancy. Furthermore, there is an association between bursitis and immunosuppression.^6,7 The most common modes of therapy used to treat bursitis are nonsteroidal anti-inflammatory drugs, corticosteroid injections, and surgical management.

Trochanteric bursitis has been attributed to multiple myeloma in one previous case report, but we are not aware of any previous cases of olecranon bursitis caused by multiple myeloma. Here, we present the case of a 46-year-old man with heavily pretreated multiple myeloma and amyloidosis who developed left olecranon bursitis contemporaneously with disease relapse; flow cytometric analysis of the bursal fluid demonstrated an abnormal plasma cell population, establishing the etiology.

Case presentation and summary

A 46-year-old man with a longstanding history of multiple myeloma developed swelling of the left elbow that was initially painless in September 2016. He had been diagnosed with IgA kappa multiple myeloma and AL deposition in 2011. Over the course of his disease, he was treated with the following sequence of therapies: cyclophosphamide, bortezomib, and dexamethasone, followed by melphalan-conditioned autologous peripheral blood stem cell transplant; lenalidomide and dexamethasone; carfilzomib and dexamethasone; pomalidomide, bortezomib, and dexamethasone; and bortezomib, lenalidomide, dexamethasone, doxorubicin, cyclophosphamide, and etoposide, followed by second melphalan-conditioned autologous peripheral blood stem cell transplant. In addition to treatment with numerous novel and chemotherapeutic agents, his disease course was notable for amyloid deposition in the liver, bone marrow, and kidneys, which resulted in dialysis dependence.

After the second autologous transplant, he achieved a very good partial response and experienced about 9 months of remission, after which laboratory evaluation indicated recurrence of IgA kappa monoclonal protein and free kappa light-chains, which increased slowly over several months without focal symptoms, cytopenias, or decline in organ function (Figure 1).

Discussion

Our patient experienced left olecranon bursitis simultaneously with relapse of multiple myeloma and AL amyloidosis. Evaluation for infectious causes was negative, and the bursal fluid did not have strongly inflammatory characteristics. Furthermore, a small plasma cell population was isolated from the fluid. Imaging did not reveal an underlying dominant lytic lesion. Although we do not have direct pathologic confirmation, the clinical scenario and flow cytometry findings support our interpretation that the patient’s bursitis was caused by or at least related to underlying multiple myeloma. While reactive plasma cells are also CD38 positive and CD138 positive, they maintain the expression of CD19 and CD45 without aberrant expression of CD56 or CD117 and do not show loss of expression of CD81 or CD27. In this situation, we suspect that either a plasmacytoma involving the soft tissue of the bursa or amyloid infiltration of the synovium may have occurred. Anti-myeloma therapies and radiation therapy did not result in control of the bursitis, though it should be noted that the patient’s highly refractory disease progressed despite treatment with a combination of later-generation immunomodulatory imide and proteasome inhibitor therapies.

Cases of malignant bursitis have been reported several times in the literature, though nearly all of the instances involved connective tissue or metastatic tumors. Tumor histologies include osteochondroma,^8,9 malignant fibrous histiocytoma,¹⁰ synovial sarcoma,¹¹ and metastatic breast cancer.¹²

Hematologic malignancies are more rare causes of bursitis; our literature search identified a report of 2 cases of non-Hodgkin lymphoma mimicking rheumatoid arthritis. The joints were the knee and elbow. Synovial fluid from one case was clear and yellow, with leukocytosis with a neutrophilic predominance (similar to our case). In both cases, pathology confirmed lymphomatous infiltration of the synovium.¹³ Notably, we identified a case of a previously healthy 35-year-old woman with bilateral trochanteric bursitis. Biopsy of tissue from the right trochanteric bursa demonstrated positive birefringence, diagnostic of AL amyloidosis. The patient also had a biclonal paraprotein accompanied by calvarial lytic lesions. She was treated with a corticosteroid pulse and bisphosphonates, followed by autologous hematopoietic stem cell transplant. ⁵ Our case shares features with the above case, including the relatively young age of the patient and the presence of AL amyloidosis.

Our patient wished to avoid a surgical biopsy procedure, and therefore we utilized flow cytometry of the bursal fluid to establish that the etiology of fluid collection was consistent with his concurrent relapse of multiple myeloma. We believe that we are reporting the second case of multiple myeloma-associated bursitis and the first case associated with multiple myeloma relapse; to our knowledge, it is the first to be diagnosed with the aid of flow cytometry.

Because of our patient’s reliance on hemodialysis beginning one year prior to his presentation with olecranon bursitis, we entertain “dialysis elbow” within the differential diagnosis. Dialysis elbow is a relatively uncommon complication of dialysis, in which patients develop olecranon bursitis on the same side as the hemodialysis access after a prolonged (months to years) duration of hemodialysis. Serositis and mechanical forces are the hypothesized etiologies¹⁴; infectious and rheumatologic causes were excluded from the reported cases. Nevertheless, we favor a malignant cause based upon the flow cytometry findings indicating involvement by immunophenotypically abnormal plasma cells.

Our patient was treated initially with serial drainage and nonsteroidals, which had little impact. After diagnosis of a plasma cell population in the fluid, we offered local treatment with radiation and systemic treatment of multiple myeloma, which offered better but suboptimal control. Possible treatments for olecranon bursitis include surgery, corticosteroid injections, anti-inflammatories, and serial drainage. Nonsurgical management may be more effective than surgical management, and corticosteroid injection carries significant risks. On the other hand, serial drainage does not confer additional infection risk in cases with aseptic etiology.¹⁵ We combined conservative measures as well as treatment of the underlying disease, but we believe that our patient did not derive significant benefit because of the refractory nature of his disease; he also expressed a preference to avoid surgical intervention.
 

Conclusion

Bursitis is a rare but thought-provoking potential manifestation of multiple myeloma and AL amyloidosis; we believe that our patient’s bursitis was related to plasma cell neoplasia based upon co-occurrence with disease relapse. His bursitis turned out to be an early indicator of impending systemic relapse. In this particular case, in which the patient wished to avoid surgical intervention, flow cytometry was of great value, and we believe that our case is the first report of malignant bursitis being diagnosed by flow cytometry. Our patient’s case shares similarities with other biopsy-confirmed cases of malignant bursitis, but we were able to avoid the need for surgical biopsy or bursal stripping.

The authors thank Jennifer Wilham MT (ASCP), Pat Byrd MT (ASCP), and Darlene Mann MT (ASCP) for their technical support.

Multiple myeloma is the most common plasma cell neoplasm, with an estimated 24,000 cases occurring annually.¹ Symptomatic multiple myeloma most commonly presents with one or more of the cardinal CRAB phenomena of hypercalcemia, renal dysfunction, anemia, or lytic bone lesions.² Less commonly, patients may present with plasmacytomas (focal lesions of malignant plasma cells), which may involve bony or soft tissues.¹

Plasma cell neoplasms occasionally involve the joints, including the elbows, typically as plasmacytomas. The elbow is an unusual but reported location of plasmacytomas.^3,4 A case of multiple myeloma and amyloid light-chain (AL) amyloidosis has been reported, with manifestations including pseudomyopathy, bone marrow plasmacytosis, and bilateral trochanteric bursitis.⁵Bursitis is defined as inflammation of the synovial-fluid–containing sacs that lubricate joints. The olecranon bursa is commonly affected. Etiologies include infection, inflammatory disease, trauma, and malignancy. Furthermore, there is an association between bursitis and immunosuppression.^6,7 The most common modes of therapy used to treat bursitis are nonsteroidal anti-inflammatory drugs, corticosteroid injections, and surgical management.

Trochanteric bursitis has been attributed to multiple myeloma in one previous case report, but we are not aware of any previous cases of olecranon bursitis caused by multiple myeloma. Here, we present the case of a 46-year-old man with heavily pretreated multiple myeloma and amyloidosis who developed left olecranon bursitis contemporaneously with disease relapse; flow cytometric analysis of the bursal fluid demonstrated an abnormal plasma cell population, establishing the etiology.

Case presentation and summary

A 46-year-old man with a longstanding history of multiple myeloma developed swelling of the left elbow that was initially painless in September 2016. He had been diagnosed with IgA kappa multiple myeloma and AL deposition in 2011. Over the course of his disease, he was treated with the following sequence of therapies: cyclophosphamide, bortezomib, and dexamethasone, followed by melphalan-conditioned autologous peripheral blood stem cell transplant; lenalidomide and dexamethasone; carfilzomib and dexamethasone; pomalidomide, bortezomib, and dexamethasone; and bortezomib, lenalidomide, dexamethasone, doxorubicin, cyclophosphamide, and etoposide, followed by second melphalan-conditioned autologous peripheral blood stem cell transplant. In addition to treatment with numerous novel and chemotherapeutic agents, his disease course was notable for amyloid deposition in the liver, bone marrow, and kidneys, which resulted in dialysis dependence.

After the second autologous transplant, he achieved a very good partial response and experienced about 9 months of remission, after which laboratory evaluation indicated recurrence of IgA kappa monoclonal protein and free kappa light-chains, which increased slowly over several months without focal symptoms, cytopenias, or decline in organ function (Figure 1).

Discussion

Our patient experienced left olecranon bursitis simultaneously with relapse of multiple myeloma and AL amyloidosis. Evaluation for infectious causes was negative, and the bursal fluid did not have strongly inflammatory characteristics. Furthermore, a small plasma cell population was isolated from the fluid. Imaging did not reveal an underlying dominant lytic lesion. Although we do not have direct pathologic confirmation, the clinical scenario and flow cytometry findings support our interpretation that the patient’s bursitis was caused by or at least related to underlying multiple myeloma. While reactive plasma cells are also CD38 positive and CD138 positive, they maintain the expression of CD19 and CD45 without aberrant expression of CD56 or CD117 and do not show loss of expression of CD81 or CD27. In this situation, we suspect that either a plasmacytoma involving the soft tissue of the bursa or amyloid infiltration of the synovium may have occurred. Anti-myeloma therapies and radiation therapy did not result in control of the bursitis, though it should be noted that the patient’s highly refractory disease progressed despite treatment with a combination of later-generation immunomodulatory imide and proteasome inhibitor therapies.

Cases of malignant bursitis have been reported several times in the literature, though nearly all of the instances involved connective tissue or metastatic tumors. Tumor histologies include osteochondroma,^8,9 malignant fibrous histiocytoma,¹⁰ synovial sarcoma,¹¹ and metastatic breast cancer.¹²

Hematologic malignancies are more rare causes of bursitis; our literature search identified a report of 2 cases of non-Hodgkin lymphoma mimicking rheumatoid arthritis. The joints were the knee and elbow. Synovial fluid from one case was clear and yellow, with leukocytosis with a neutrophilic predominance (similar to our case). In both cases, pathology confirmed lymphomatous infiltration of the synovium.¹³ Notably, we identified a case of a previously healthy 35-year-old woman with bilateral trochanteric bursitis. Biopsy of tissue from the right trochanteric bursa demonstrated positive birefringence, diagnostic of AL amyloidosis. The patient also had a biclonal paraprotein accompanied by calvarial lytic lesions. She was treated with a corticosteroid pulse and bisphosphonates, followed by autologous hematopoietic stem cell transplant. ⁵ Our case shares features with the above case, including the relatively young age of the patient and the presence of AL amyloidosis.

Our patient wished to avoid a surgical biopsy procedure, and therefore we utilized flow cytometry of the bursal fluid to establish that the etiology of fluid collection was consistent with his concurrent relapse of multiple myeloma. We believe that we are reporting the second case of multiple myeloma-associated bursitis and the first case associated with multiple myeloma relapse; to our knowledge, it is the first to be diagnosed with the aid of flow cytometry.

Because of our patient’s reliance on hemodialysis beginning one year prior to his presentation with olecranon bursitis, we entertain “dialysis elbow” within the differential diagnosis. Dialysis elbow is a relatively uncommon complication of dialysis, in which patients develop olecranon bursitis on the same side as the hemodialysis access after a prolonged (months to years) duration of hemodialysis. Serositis and mechanical forces are the hypothesized etiologies¹⁴; infectious and rheumatologic causes were excluded from the reported cases. Nevertheless, we favor a malignant cause based upon the flow cytometry findings indicating involvement by immunophenotypically abnormal plasma cells.

Our patient was treated initially with serial drainage and nonsteroidals, which had little impact. After diagnosis of a plasma cell population in the fluid, we offered local treatment with radiation and systemic treatment of multiple myeloma, which offered better but suboptimal control. Possible treatments for olecranon bursitis include surgery, corticosteroid injections, anti-inflammatories, and serial drainage. Nonsurgical management may be more effective than surgical management, and corticosteroid injection carries significant risks. On the other hand, serial drainage does not confer additional infection risk in cases with aseptic etiology.¹⁵ We combined conservative measures as well as treatment of the underlying disease, but we believe that our patient did not derive significant benefit because of the refractory nature of his disease; he also expressed a preference to avoid surgical intervention.
 

Conclusion

Bursitis is a rare but thought-provoking potential manifestation of multiple myeloma and AL amyloidosis; we believe that our patient’s bursitis was related to plasma cell neoplasia based upon co-occurrence with disease relapse. His bursitis turned out to be an early indicator of impending systemic relapse. In this particular case, in which the patient wished to avoid surgical intervention, flow cytometry was of great value, and we believe that our case is the first report of malignant bursitis being diagnosed by flow cytometry. Our patient’s case shares similarities with other biopsy-confirmed cases of malignant bursitis, but we were able to avoid the need for surgical biopsy or bursal stripping.

The authors thank Jennifer Wilham MT (ASCP), Pat Byrd MT (ASCP), and Darlene Mann MT (ASCP) for their technical support.

© Todd Buchanan 2017

An additional presentation has been added to the late-breaking abstract session of the 2018 ASH Annual Meeting.

The session was expanded from six abstracts to seven this year because of a record number of “exciting” submissions, according to ASH Secretary Robert A. Brodsky, MD, of Johns Hopkins University in Baltimore, Maryland.

“We received 98 late-breaking abstracts, which is a record,” Dr. Brodsky said.

“They were so exciting this year that we added a seventh, and, quite frankly, we could have added several more, but we just didn’t have time in the meeting.”

Dr. Brodsky discussed this year’s late-breaking abstracts during a recent press briefing.

Abstract LBA-1 reports results of rivaroxaban thromboprophylaxis in cancer patients with an increased risk of venous thromboembolism (VTE). Compared to placebo, rivaroxaban significantly reduced VTE and VTE-related death during treatment but not over the entire study period.

Abstract LBA-2 describes a phase 3, randomized trial comparing daratumumab plus lenalidomide and dexamethasone to lenalidomide and dexamethasone in patients with newly diagnosed multiple myeloma who are ineligible for transplant. The addition of daratumumab reduced the risk of disease progression or death by 45%.

Abstract LBA-3 details results with HemoTypeSC, a test used to detect sickle cell trait and sickle cell disease. The test correctly identified all phenotypes in the 1,000 children studied.

Abstract LBA-4 describes a randomized, phase 3 study comparing ibrutinib plus rituximab to fludarabine, cyclophosphamide, and rituximab in younger patients with untreated chronic lymphocytic leukemia (CLL). Investigators found that ibrutinib plus rituximab provided significantly better progression-free and overall survival than the three-drug combination.

Abstract LBA-5 details a strategy for direct oral anticoagulant use in patients with atrial fibrillation undergoing surgery. Investigators say the strategy is likely to be “practice-changing” and incorporated into guidelines.

Abstract LBA-6 ­covers a trial of emapalumab in patients with primary hemophagocytic lymphohistiocytosis. Emapalumab, which was recently approved by the U.S. Food and Drug Administration, produced responses in most of the 34 patients studied and had a favorable safety profile, according to investigators.

Abstract LBA-7 reports the discovery of a recurrent mutation in BCL2 that confers resistance to venetoclax in patients with progressive CLL. Investigators say this mutation could be a biomarker of CLL relapse.

© Todd Buchanan 2017

An additional presentation has been added to the late-breaking abstract session of the 2018 ASH Annual Meeting.

The session was expanded from six abstracts to seven this year because of a record number of “exciting” submissions, according to ASH Secretary Robert A. Brodsky, MD, of Johns Hopkins University in Baltimore, Maryland.

“We received 98 late-breaking abstracts, which is a record,” Dr. Brodsky said.

“They were so exciting this year that we added a seventh, and, quite frankly, we could have added several more, but we just didn’t have time in the meeting.”

Dr. Brodsky discussed this year’s late-breaking abstracts during a recent press briefing.

Abstract LBA-1 reports results of rivaroxaban thromboprophylaxis in cancer patients with an increased risk of venous thromboembolism (VTE). Compared to placebo, rivaroxaban significantly reduced VTE and VTE-related death during treatment but not over the entire study period.

Abstract LBA-2 describes a phase 3, randomized trial comparing daratumumab plus lenalidomide and dexamethasone to lenalidomide and dexamethasone in patients with newly diagnosed multiple myeloma who are ineligible for transplant. The addition of daratumumab reduced the risk of disease progression or death by 45%.

Abstract LBA-3 details results with HemoTypeSC, a test used to detect sickle cell trait and sickle cell disease. The test correctly identified all phenotypes in the 1,000 children studied.

Abstract LBA-4 describes a randomized, phase 3 study comparing ibrutinib plus rituximab to fludarabine, cyclophosphamide, and rituximab in younger patients with untreated chronic lymphocytic leukemia (CLL). Investigators found that ibrutinib plus rituximab provided significantly better progression-free and overall survival than the three-drug combination.

Abstract LBA-5 details a strategy for direct oral anticoagulant use in patients with atrial fibrillation undergoing surgery. Investigators say the strategy is likely to be “practice-changing” and incorporated into guidelines.

Abstract LBA-6 ­covers a trial of emapalumab in patients with primary hemophagocytic lymphohistiocytosis. Emapalumab, which was recently approved by the U.S. Food and Drug Administration, produced responses in most of the 34 patients studied and had a favorable safety profile, according to investigators.

Abstract LBA-7 reports the discovery of a recurrent mutation in BCL2 that confers resistance to venetoclax in patients with progressive CLL. Investigators say this mutation could be a biomarker of CLL relapse.

© Todd Buchanan 2017

An additional presentation has been added to the late-breaking abstract session of the 2018 ASH Annual Meeting.

The session was expanded from six abstracts to seven this year because of a record number of “exciting” submissions, according to ASH Secretary Robert A. Brodsky, MD, of Johns Hopkins University in Baltimore, Maryland.

“We received 98 late-breaking abstracts, which is a record,” Dr. Brodsky said.

“They were so exciting this year that we added a seventh, and, quite frankly, we could have added several more, but we just didn’t have time in the meeting.”

Dr. Brodsky discussed this year’s late-breaking abstracts during a recent press briefing.

Abstract LBA-1 reports results of rivaroxaban thromboprophylaxis in cancer patients with an increased risk of venous thromboembolism (VTE). Compared to placebo, rivaroxaban significantly reduced VTE and VTE-related death during treatment but not over the entire study period.

Abstract LBA-2 describes a phase 3, randomized trial comparing daratumumab plus lenalidomide and dexamethasone to lenalidomide and dexamethasone in patients with newly diagnosed multiple myeloma who are ineligible for transplant. The addition of daratumumab reduced the risk of disease progression or death by 45%.

Abstract LBA-3 details results with HemoTypeSC, a test used to detect sickle cell trait and sickle cell disease. The test correctly identified all phenotypes in the 1,000 children studied.

Abstract LBA-4 describes a randomized, phase 3 study comparing ibrutinib plus rituximab to fludarabine, cyclophosphamide, and rituximab in younger patients with untreated chronic lymphocytic leukemia (CLL). Investigators found that ibrutinib plus rituximab provided significantly better progression-free and overall survival than the three-drug combination.

Abstract LBA-5 details a strategy for direct oral anticoagulant use in patients with atrial fibrillation undergoing surgery. Investigators say the strategy is likely to be “practice-changing” and incorporated into guidelines.

Abstract LBA-6 ­covers a trial of emapalumab in patients with primary hemophagocytic lymphohistiocytosis. Emapalumab, which was recently approved by the U.S. Food and Drug Administration, produced responses in most of the 34 patients studied and had a favorable safety profile, according to investigators.

Abstract LBA-7 reports the discovery of a recurrent mutation in BCL2 that confers resistance to venetoclax in patients with progressive CLL. Investigators say this mutation could be a biomarker of CLL relapse.

Infection with certain viruses has been causally linked to the development of cancer. In recent years, an improved understanding of the unique pathology and molecular underpinnings of these virally associated cancers has prompted the development of more personalized treatment strategies, with a particular focus on immunotherapy. Here, we describe some of the latest developments.

The link between viruses and cancer

Suspicions about a possible role of viral infections in the development of cancer were first aroused in the early 1900s. The seminal discovery is traced back to Peyton Rous, who showed that a malignant tumor growing in a chicken could be transferred to a healthy bird by injecting it with tumor extracts that contained no actual tumor cells.¹

The infectious etiology of human cancer, however, remained controversial until many years later when the first cancer-causing virus, Epstein-Barr virus (EBV), was identified in cell cultures from patients with Burkitt lymphoma. Shortly afterward, the Rous sarcoma virus was unveiled as the oncogenic agent behind Rous’ observations.²Seven viruses have now been linked to the development of cancers and are thought to be responsible for around 12% of all cancer cases worldwide. The burden is likely to increase as technological advancements make it easier to establish a causal link between viruses and cancer development.³

In addition to making these links, researchers have also made significant headway in understanding how viruses cause cancer. Cancerous transformation of host cells occurs in only a minority of those who are infected with oncogenic viruses and often occurs in the setting of chronic infection.

Viruses can mediate carcinogenesis by direct and/or indirect mechanisms (Figure 1). Many of the hallmarks of cancer, the key attributes that drive the transformation from a normal cell to a malignant one, are compatible with the virus’s needs, such as needing to avoid cell death, increasing cell proliferation, and avoiding detection by the immune system.

Vaccines lead the charge in HPV-driven cancers

German virologist Harald zur Hausen received the Nobel Prize in 2008 for his discovery of the oncogenic role of human papillomaviruses (HPVs), a large family of more than 100 DNA viruses that infect the epithelial cells of the skin and mucous membranes. They are responsible for the largest number of virally associated cancer cases globally – around 5% (Table 1).

A number of different cancer types are linked to HPV infection, but it is best known as the cause of cervical cancer. The development of diagnostic blood tests and prophylactic vaccines for prevention and early intervention in HPV infection has helped to reduce the incidence of cervical cancer. Conversely, another type of HPV-associated cancer, head and neck squamous cell carcinoma (HNSCC), has seen increased incidence in recent years.

HPVs are categorized according to their oncogenic potential as high, intermediate, or low risk. The high-risk HPV16 and HPV18 strains are most commonly associated with cancer. They are thought to cause cancer predominantly through integration into the host genome. The HPV genome is composed of 8 genes encoding proteins that regulate viral replication and assembly. The E6 and E7 genes are the most highly oncogenic; as the HPV DNA is inserted into the host genome, the transcriptional regulator of E6/E7 is lost, leading to their increased expression. These genes have significant oncogenic potential because of their interaction with 2 tumor suppressor proteins, p53 and pRb.^6,7

The largest investment in therapeutic development for HPV-positive cancers has been in the realm of immunotherapy in an effort to boost the anti-tumor immune response. In particular, there has been a focus on the development of therapeutic vaccines, designed to prime the anti-tumor immune response to recognize viral antigens. A variety of different types of vaccines are being developed, including live, attenuated and inactivated vaccines that are protein, DNA, or peptide based. Most developed to date target the E6/E7 proteins from the HPV16/18 strains (Table 2).^8,9

Hepatocellular carcinoma: a tale of two viruses

The hepatitis viruses are a group of 5 unrelated viruses that causes inflammation of the liver. Hepatitis B (HBV), a DNA virus, and hepatitis C (HCV), an RNA virus, are also oncoviruses; HBV in particular is one of the main causes of hepatocellular carcinoma (HCC), the most common type of liver cancer.

The highly inflammatory environment fostered by HBV and HCV infection causes liver damage that often leads to cirrhosis. Continued infection can drive permanent damage to the hepatocytes, leading to genetic and epigenetic damage and driving oncogenesis. As an RNA virus, HCV doesn’t integrate into the genome and no confirmed viral oncoproteins have been identified to date, therefore it mostly drives cancer through these indirect mechanisms, which is also reflected in the fact that HCV-associated HCC predominantly occurs against a backdrop of liver cirrhosis.

HBV does integrate into the host genome. Genome sequencing studies revealed hundreds of integration sites, but most commonly they disrupted host genes involved in telomere stability and cell cycle regulation, providing some insight into the mechanisms by which HBV-associated HCC develops. In addition, HBV produces several oncoproteins, including HBx, which disrupts gene transcription, cell signaling pathways, cell cycle progress, apoptosis and other cellular processes.^15,16

Multitargeted tyrosine kinase inhibitors (TKIs) have been the focal point of therapeutic development in HCC. However, following the approval of sorafenib in 2008, there was a dearth of effective new treatment options despite substantial efforts and numerous phase 3 trials. More recently, immunotherapy has also come to the forefront, especially immune checkpoint inhibitors.

Last year marked the first new drug approvals in nearly a decade – the TKI regorafenib (Stivarga) and immune checkpoint inhibitor nivolumab (Opdivo), both in the second-line setting after failure of sorafenib. Treatment options in this setting may continue to expand, with the TKIs cabozantinib and lenvatinib and the immune checkpoint inhibitor pembrolizumab and the combination of durvalumab and tremelimumab hot on their heels.^17-20 Many of these drugs are also being evaluated in the front-line setting in comparison with sorafenib (Table 3).

Adoptive cell therapy promising in EBV-positive cancers

More than 90% of the global population is infected with EBV, making it one of the most common human viruses. It is a member of the herpesvirus family that is probably best known as the cause of infectious mononucleosis. On rare occasions, however, EBV can cause tumor development, though our understanding of its exact pathogenic role in cancer is still incomplete.

EBV is a DNA virus that doesn’t tend to integrate into the host genome, but instead remains in the nucleus in the form of episomes and produces several oncoproteins, including latent membrane protein-1. It is associated with a range of different cancer types, including Burkitt lymphoma and other B-cell malignancies. It also infects epithelial cells and can cause nasopharyngeal carcinoma and gastric cancer, however, much less is known about the molecular underpinnings of these EBV-positive cancer types.^26,27Gastric cancers actually comprise the largest group of EBV-associated tumors because of the global incidence of this cancer type. The Cancer Genome Atlas Research Network recently characterized gastric cancer on a molecular level and identified an EBV-positive subgroup as a distinct clinical entity with unique molecular characteristics.²⁹

The focus of therapeutic development has again been on immunotherapy, however in this case the idea of collecting the patients T cells, engineering them to recognize EBV, and then reinfusing them into the patient – adoptive cell therapy – has gained the most traction (Table 4).

Newest oncovirus on the block

The most recently discovered cancer-associated virus is Merkel cell polyomavirus (MCV), a DNA virus that was identified in 2008. Like EBV, virtually the whole global adult population is infected with MCV. It is linked to the development of a highly aggressive and lethal, though rare, form of skin cancer – Merkel cell carcinoma.

MCV is found in around 80% of MCC cases and in fewer than 10% of melanomas and other skin cancers. Thus far, several direct mechanisms of oncogenesis have been described, including integration of MCV into the host genome and the production of viral oncogenes, though their precise function is as yet unclear.^32-34

The American Cancer Society estimates that only 1500 cases of MCC are diagnosed each year in the United States.³⁵ Its rarity makes it difficult to conduct clinical trials with sufficient power, yet some headway has still been made.

Around half of MCCs express the programmed cell death ligand 1 (PD-L1) on their surface, making them a logical candidate for immune checkpoint inhibition. In 2017, avelumab became the first FDA-approved drug for the treatment of MCC. Approval was based on the JAVELIN Merkel 200 study in which 88 patients received avelumab. After 1 year of follow-up the ORR was 31.8%, with a CR rate of 9%.³⁶

Genome sequencing studies suggest that the mutational profile of MCV-positive tumors is quite different to those that are MCV-negative, which could have therapeutic implications. To date, these implications have not been delineated, given the challenge of small patient numbers, however an ongoing phase 1/2 trial is evaluating the combination of avelumab and radiation therapy or recombinant interferon beta, with or without MCV-specific cytotoxic T cells in patients with MCC and MCV infection.

The 2 other known cancer-causing viruses are human T-lymphotropic virus 1 (HTLV-1), a retrovirus associated with adult T-cell leukemia/lymphoma (ATL) and Kaposi sarcoma herpesvirus (KSHV). The latter is the causative agent of Kaposi sarcoma, often in combination with human immunodeficiency virus (HIV), a rare skin tumor that became renowned in the 1980s as an AIDS-defining illness.

The incidence of HTLV-1- and KSHV-positive tumors is substantially lower than the other virally associated cancers and, like MCC, this makes studying them and conducting clinical trials of novel therapeutic options a challenge. Nonetheless, several trials of targeted therapies and immunotherapies are underway.

Infection with certain viruses has been causally linked to the development of cancer. In recent years, an improved understanding of the unique pathology and molecular underpinnings of these virally associated cancers has prompted the development of more personalized treatment strategies, with a particular focus on immunotherapy. Here, we describe some of the latest developments.

The link between viruses and cancer

Suspicions about a possible role of viral infections in the development of cancer were first aroused in the early 1900s. The seminal discovery is traced back to Peyton Rous, who showed that a malignant tumor growing in a chicken could be transferred to a healthy bird by injecting it with tumor extracts that contained no actual tumor cells.¹

The infectious etiology of human cancer, however, remained controversial until many years later when the first cancer-causing virus, Epstein-Barr virus (EBV), was identified in cell cultures from patients with Burkitt lymphoma. Shortly afterward, the Rous sarcoma virus was unveiled as the oncogenic agent behind Rous’ observations.²Seven viruses have now been linked to the development of cancers and are thought to be responsible for around 12% of all cancer cases worldwide. The burden is likely to increase as technological advancements make it easier to establish a causal link between viruses and cancer development.³

In addition to making these links, researchers have also made significant headway in understanding how viruses cause cancer. Cancerous transformation of host cells occurs in only a minority of those who are infected with oncogenic viruses and often occurs in the setting of chronic infection.

Viruses can mediate carcinogenesis by direct and/or indirect mechanisms (Figure 1). Many of the hallmarks of cancer, the key attributes that drive the transformation from a normal cell to a malignant one, are compatible with the virus’s needs, such as needing to avoid cell death, increasing cell proliferation, and avoiding detection by the immune system.

Vaccines lead the charge in HPV-driven cancers

German virologist Harald zur Hausen received the Nobel Prize in 2008 for his discovery of the oncogenic role of human papillomaviruses (HPVs), a large family of more than 100 DNA viruses that infect the epithelial cells of the skin and mucous membranes. They are responsible for the largest number of virally associated cancer cases globally – around 5% (Table 1).

A number of different cancer types are linked to HPV infection, but it is best known as the cause of cervical cancer. The development of diagnostic blood tests and prophylactic vaccines for prevention and early intervention in HPV infection has helped to reduce the incidence of cervical cancer. Conversely, another type of HPV-associated cancer, head and neck squamous cell carcinoma (HNSCC), has seen increased incidence in recent years.

HPVs are categorized according to their oncogenic potential as high, intermediate, or low risk. The high-risk HPV16 and HPV18 strains are most commonly associated with cancer. They are thought to cause cancer predominantly through integration into the host genome. The HPV genome is composed of 8 genes encoding proteins that regulate viral replication and assembly. The E6 and E7 genes are the most highly oncogenic; as the HPV DNA is inserted into the host genome, the transcriptional regulator of E6/E7 is lost, leading to their increased expression. These genes have significant oncogenic potential because of their interaction with 2 tumor suppressor proteins, p53 and pRb.^6,7

The largest investment in therapeutic development for HPV-positive cancers has been in the realm of immunotherapy in an effort to boost the anti-tumor immune response. In particular, there has been a focus on the development of therapeutic vaccines, designed to prime the anti-tumor immune response to recognize viral antigens. A variety of different types of vaccines are being developed, including live, attenuated and inactivated vaccines that are protein, DNA, or peptide based. Most developed to date target the E6/E7 proteins from the HPV16/18 strains (Table 2).^8,9

Hepatocellular carcinoma: a tale of two viruses

The hepatitis viruses are a group of 5 unrelated viruses that causes inflammation of the liver. Hepatitis B (HBV), a DNA virus, and hepatitis C (HCV), an RNA virus, are also oncoviruses; HBV in particular is one of the main causes of hepatocellular carcinoma (HCC), the most common type of liver cancer.

The highly inflammatory environment fostered by HBV and HCV infection causes liver damage that often leads to cirrhosis. Continued infection can drive permanent damage to the hepatocytes, leading to genetic and epigenetic damage and driving oncogenesis. As an RNA virus, HCV doesn’t integrate into the genome and no confirmed viral oncoproteins have been identified to date, therefore it mostly drives cancer through these indirect mechanisms, which is also reflected in the fact that HCV-associated HCC predominantly occurs against a backdrop of liver cirrhosis.

HBV does integrate into the host genome. Genome sequencing studies revealed hundreds of integration sites, but most commonly they disrupted host genes involved in telomere stability and cell cycle regulation, providing some insight into the mechanisms by which HBV-associated HCC develops. In addition, HBV produces several oncoproteins, including HBx, which disrupts gene transcription, cell signaling pathways, cell cycle progress, apoptosis and other cellular processes.^15,16

Multitargeted tyrosine kinase inhibitors (TKIs) have been the focal point of therapeutic development in HCC. However, following the approval of sorafenib in 2008, there was a dearth of effective new treatment options despite substantial efforts and numerous phase 3 trials. More recently, immunotherapy has also come to the forefront, especially immune checkpoint inhibitors.

Last year marked the first new drug approvals in nearly a decade – the TKI regorafenib (Stivarga) and immune checkpoint inhibitor nivolumab (Opdivo), both in the second-line setting after failure of sorafenib. Treatment options in this setting may continue to expand, with the TKIs cabozantinib and lenvatinib and the immune checkpoint inhibitor pembrolizumab and the combination of durvalumab and tremelimumab hot on their heels.^17-20 Many of these drugs are also being evaluated in the front-line setting in comparison with sorafenib (Table 3).

Adoptive cell therapy promising in EBV-positive cancers

More than 90% of the global population is infected with EBV, making it one of the most common human viruses. It is a member of the herpesvirus family that is probably best known as the cause of infectious mononucleosis. On rare occasions, however, EBV can cause tumor development, though our understanding of its exact pathogenic role in cancer is still incomplete.

EBV is a DNA virus that doesn’t tend to integrate into the host genome, but instead remains in the nucleus in the form of episomes and produces several oncoproteins, including latent membrane protein-1. It is associated with a range of different cancer types, including Burkitt lymphoma and other B-cell malignancies. It also infects epithelial cells and can cause nasopharyngeal carcinoma and gastric cancer, however, much less is known about the molecular underpinnings of these EBV-positive cancer types.^26,27Gastric cancers actually comprise the largest group of EBV-associated tumors because of the global incidence of this cancer type. The Cancer Genome Atlas Research Network recently characterized gastric cancer on a molecular level and identified an EBV-positive subgroup as a distinct clinical entity with unique molecular characteristics.²⁹

The focus of therapeutic development has again been on immunotherapy, however in this case the idea of collecting the patients T cells, engineering them to recognize EBV, and then reinfusing them into the patient – adoptive cell therapy – has gained the most traction (Table 4).

Newest oncovirus on the block

The most recently discovered cancer-associated virus is Merkel cell polyomavirus (MCV), a DNA virus that was identified in 2008. Like EBV, virtually the whole global adult population is infected with MCV. It is linked to the development of a highly aggressive and lethal, though rare, form of skin cancer – Merkel cell carcinoma.

MCV is found in around 80% of MCC cases and in fewer than 10% of melanomas and other skin cancers. Thus far, several direct mechanisms of oncogenesis have been described, including integration of MCV into the host genome and the production of viral oncogenes, though their precise function is as yet unclear.^32-34

The American Cancer Society estimates that only 1500 cases of MCC are diagnosed each year in the United States.³⁵ Its rarity makes it difficult to conduct clinical trials with sufficient power, yet some headway has still been made.

Around half of MCCs express the programmed cell death ligand 1 (PD-L1) on their surface, making them a logical candidate for immune checkpoint inhibition. In 2017, avelumab became the first FDA-approved drug for the treatment of MCC. Approval was based on the JAVELIN Merkel 200 study in which 88 patients received avelumab. After 1 year of follow-up the ORR was 31.8%, with a CR rate of 9%.³⁶

Genome sequencing studies suggest that the mutational profile of MCV-positive tumors is quite different to those that are MCV-negative, which could have therapeutic implications. To date, these implications have not been delineated, given the challenge of small patient numbers, however an ongoing phase 1/2 trial is evaluating the combination of avelumab and radiation therapy or recombinant interferon beta, with or without MCV-specific cytotoxic T cells in patients with MCC and MCV infection.

The 2 other known cancer-causing viruses are human T-lymphotropic virus 1 (HTLV-1), a retrovirus associated with adult T-cell leukemia/lymphoma (ATL) and Kaposi sarcoma herpesvirus (KSHV). The latter is the causative agent of Kaposi sarcoma, often in combination with human immunodeficiency virus (HIV), a rare skin tumor that became renowned in the 1980s as an AIDS-defining illness.

The incidence of HTLV-1- and KSHV-positive tumors is substantially lower than the other virally associated cancers and, like MCC, this makes studying them and conducting clinical trials of novel therapeutic options a challenge. Nonetheless, several trials of targeted therapies and immunotherapies are underway.

Infection with certain viruses has been causally linked to the development of cancer. In recent years, an improved understanding of the unique pathology and molecular underpinnings of these virally associated cancers has prompted the development of more personalized treatment strategies, with a particular focus on immunotherapy. Here, we describe some of the latest developments.

The link between viruses and cancer

Suspicions about a possible role of viral infections in the development of cancer were first aroused in the early 1900s. The seminal discovery is traced back to Peyton Rous, who showed that a malignant tumor growing in a chicken could be transferred to a healthy bird by injecting it with tumor extracts that contained no actual tumor cells.¹

The infectious etiology of human cancer, however, remained controversial until many years later when the first cancer-causing virus, Epstein-Barr virus (EBV), was identified in cell cultures from patients with Burkitt lymphoma. Shortly afterward, the Rous sarcoma virus was unveiled as the oncogenic agent behind Rous’ observations.²Seven viruses have now been linked to the development of cancers and are thought to be responsible for around 12% of all cancer cases worldwide. The burden is likely to increase as technological advancements make it easier to establish a causal link between viruses and cancer development.³

In addition to making these links, researchers have also made significant headway in understanding how viruses cause cancer. Cancerous transformation of host cells occurs in only a minority of those who are infected with oncogenic viruses and often occurs in the setting of chronic infection.

Viruses can mediate carcinogenesis by direct and/or indirect mechanisms (Figure 1). Many of the hallmarks of cancer, the key attributes that drive the transformation from a normal cell to a malignant one, are compatible with the virus’s needs, such as needing to avoid cell death, increasing cell proliferation, and avoiding detection by the immune system.

Vaccines lead the charge in HPV-driven cancers

German virologist Harald zur Hausen received the Nobel Prize in 2008 for his discovery of the oncogenic role of human papillomaviruses (HPVs), a large family of more than 100 DNA viruses that infect the epithelial cells of the skin and mucous membranes. They are responsible for the largest number of virally associated cancer cases globally – around 5% (Table 1).

A number of different cancer types are linked to HPV infection, but it is best known as the cause of cervical cancer. The development of diagnostic blood tests and prophylactic vaccines for prevention and early intervention in HPV infection has helped to reduce the incidence of cervical cancer. Conversely, another type of HPV-associated cancer, head and neck squamous cell carcinoma (HNSCC), has seen increased incidence in recent years.

HPVs are categorized according to their oncogenic potential as high, intermediate, or low risk. The high-risk HPV16 and HPV18 strains are most commonly associated with cancer. They are thought to cause cancer predominantly through integration into the host genome. The HPV genome is composed of 8 genes encoding proteins that regulate viral replication and assembly. The E6 and E7 genes are the most highly oncogenic; as the HPV DNA is inserted into the host genome, the transcriptional regulator of E6/E7 is lost, leading to their increased expression. These genes have significant oncogenic potential because of their interaction with 2 tumor suppressor proteins, p53 and pRb.^6,7

The largest investment in therapeutic development for HPV-positive cancers has been in the realm of immunotherapy in an effort to boost the anti-tumor immune response. In particular, there has been a focus on the development of therapeutic vaccines, designed to prime the anti-tumor immune response to recognize viral antigens. A variety of different types of vaccines are being developed, including live, attenuated and inactivated vaccines that are protein, DNA, or peptide based. Most developed to date target the E6/E7 proteins from the HPV16/18 strains (Table 2).^8,9

Hepatocellular carcinoma: a tale of two viruses

The hepatitis viruses are a group of 5 unrelated viruses that causes inflammation of the liver. Hepatitis B (HBV), a DNA virus, and hepatitis C (HCV), an RNA virus, are also oncoviruses; HBV in particular is one of the main causes of hepatocellular carcinoma (HCC), the most common type of liver cancer.

The highly inflammatory environment fostered by HBV and HCV infection causes liver damage that often leads to cirrhosis. Continued infection can drive permanent damage to the hepatocytes, leading to genetic and epigenetic damage and driving oncogenesis. As an RNA virus, HCV doesn’t integrate into the genome and no confirmed viral oncoproteins have been identified to date, therefore it mostly drives cancer through these indirect mechanisms, which is also reflected in the fact that HCV-associated HCC predominantly occurs against a backdrop of liver cirrhosis.

HBV does integrate into the host genome. Genome sequencing studies revealed hundreds of integration sites, but most commonly they disrupted host genes involved in telomere stability and cell cycle regulation, providing some insight into the mechanisms by which HBV-associated HCC develops. In addition, HBV produces several oncoproteins, including HBx, which disrupts gene transcription, cell signaling pathways, cell cycle progress, apoptosis and other cellular processes.^15,16

Multitargeted tyrosine kinase inhibitors (TKIs) have been the focal point of therapeutic development in HCC. However, following the approval of sorafenib in 2008, there was a dearth of effective new treatment options despite substantial efforts and numerous phase 3 trials. More recently, immunotherapy has also come to the forefront, especially immune checkpoint inhibitors.

Last year marked the first new drug approvals in nearly a decade – the TKI regorafenib (Stivarga) and immune checkpoint inhibitor nivolumab (Opdivo), both in the second-line setting after failure of sorafenib. Treatment options in this setting may continue to expand, with the TKIs cabozantinib and lenvatinib and the immune checkpoint inhibitor pembrolizumab and the combination of durvalumab and tremelimumab hot on their heels.^17-20 Many of these drugs are also being evaluated in the front-line setting in comparison with sorafenib (Table 3).

Adoptive cell therapy promising in EBV-positive cancers

More than 90% of the global population is infected with EBV, making it one of the most common human viruses. It is a member of the herpesvirus family that is probably best known as the cause of infectious mononucleosis. On rare occasions, however, EBV can cause tumor development, though our understanding of its exact pathogenic role in cancer is still incomplete.

EBV is a DNA virus that doesn’t tend to integrate into the host genome, but instead remains in the nucleus in the form of episomes and produces several oncoproteins, including latent membrane protein-1. It is associated with a range of different cancer types, including Burkitt lymphoma and other B-cell malignancies. It also infects epithelial cells and can cause nasopharyngeal carcinoma and gastric cancer, however, much less is known about the molecular underpinnings of these EBV-positive cancer types.^26,27Gastric cancers actually comprise the largest group of EBV-associated tumors because of the global incidence of this cancer type. The Cancer Genome Atlas Research Network recently characterized gastric cancer on a molecular level and identified an EBV-positive subgroup as a distinct clinical entity with unique molecular characteristics.²⁹

The focus of therapeutic development has again been on immunotherapy, however in this case the idea of collecting the patients T cells, engineering them to recognize EBV, and then reinfusing them into the patient – adoptive cell therapy – has gained the most traction (Table 4).

Newest oncovirus on the block

The most recently discovered cancer-associated virus is Merkel cell polyomavirus (MCV), a DNA virus that was identified in 2008. Like EBV, virtually the whole global adult population is infected with MCV. It is linked to the development of a highly aggressive and lethal, though rare, form of skin cancer – Merkel cell carcinoma.

MCV is found in around 80% of MCC cases and in fewer than 10% of melanomas and other skin cancers. Thus far, several direct mechanisms of oncogenesis have been described, including integration of MCV into the host genome and the production of viral oncogenes, though their precise function is as yet unclear.^32-34

The American Cancer Society estimates that only 1500 cases of MCC are diagnosed each year in the United States.³⁵ Its rarity makes it difficult to conduct clinical trials with sufficient power, yet some headway has still been made.

Around half of MCCs express the programmed cell death ligand 1 (PD-L1) on their surface, making them a logical candidate for immune checkpoint inhibition. In 2017, avelumab became the first FDA-approved drug for the treatment of MCC. Approval was based on the JAVELIN Merkel 200 study in which 88 patients received avelumab. After 1 year of follow-up the ORR was 31.8%, with a CR rate of 9%.³⁶

Genome sequencing studies suggest that the mutational profile of MCV-positive tumors is quite different to those that are MCV-negative, which could have therapeutic implications. To date, these implications have not been delineated, given the challenge of small patient numbers, however an ongoing phase 1/2 trial is evaluating the combination of avelumab and radiation therapy or recombinant interferon beta, with or without MCV-specific cytotoxic T cells in patients with MCC and MCV infection.

The 2 other known cancer-causing viruses are human T-lymphotropic virus 1 (HTLV-1), a retrovirus associated with adult T-cell leukemia/lymphoma (ATL) and Kaposi sarcoma herpesvirus (KSHV). The latter is the causative agent of Kaposi sarcoma, often in combination with human immunodeficiency virus (HIV), a rare skin tumor that became renowned in the 1980s as an AIDS-defining illness.

The incidence of HTLV-1- and KSHV-positive tumors is substantially lower than the other virally associated cancers and, like MCC, this makes studying them and conducting clinical trials of novel therapeutic options a challenge. Nonetheless, several trials of targeted therapies and immunotherapies are underway.