B-Cell Lymphoma ICYMI

Early-career researchers who are interested in studying mantle cell lymphoma can now apply for a $50,000 grant from the American Society of Clinical Oncology’s Conquer Cancer foundation.

The young investigator grant is for a 1-year period and the award is used to fund a project focused on clinical or translational research on the clinical biology, natural history, prevention, screening, diagnosis, therapy, or epidemiology of MCL.

The purpose of this annual award, according to ASCO, is to fund physicians during the transition from a fellowship program to a faculty appointment.

Eligible applicants must be physicians currently in the last 2 years of final subspecialty training and within 10 years of having obtained his or her medical degree. Additionally, applicants must be planning a research career in clinical oncology, with a focus on MCL.

The grant selection committee’s primary criteria include the significance and originality of the proposed study and hypothesis, the feasibility of the experiment and methodology, whether it has an appropriate and detailed statistical analysis plan, and if the research is patient oriented.

The application deadline is Jan. 7, 2020, and the award term is July 1, 2020–June 30, 2021.

Application instructions are available on the ASCO website.

[email protected]

Early-career researchers who are interested in studying mantle cell lymphoma can now apply for a $50,000 grant from the American Society of Clinical Oncology’s Conquer Cancer foundation.

The young investigator grant is for a 1-year period and the award is used to fund a project focused on clinical or translational research on the clinical biology, natural history, prevention, screening, diagnosis, therapy, or epidemiology of MCL.

The purpose of this annual award, according to ASCO, is to fund physicians during the transition from a fellowship program to a faculty appointment.

Eligible applicants must be physicians currently in the last 2 years of final subspecialty training and within 10 years of having obtained his or her medical degree. Additionally, applicants must be planning a research career in clinical oncology, with a focus on MCL.

The grant selection committee’s primary criteria include the significance and originality of the proposed study and hypothesis, the feasibility of the experiment and methodology, whether it has an appropriate and detailed statistical analysis plan, and if the research is patient oriented.

The application deadline is Jan. 7, 2020, and the award term is July 1, 2020–June 30, 2021.

Application instructions are available on the ASCO website.

[email protected]

Early-career researchers who are interested in studying mantle cell lymphoma can now apply for a $50,000 grant from the American Society of Clinical Oncology’s Conquer Cancer foundation.

The young investigator grant is for a 1-year period and the award is used to fund a project focused on clinical or translational research on the clinical biology, natural history, prevention, screening, diagnosis, therapy, or epidemiology of MCL.

The purpose of this annual award, according to ASCO, is to fund physicians during the transition from a fellowship program to a faculty appointment.

Eligible applicants must be physicians currently in the last 2 years of final subspecialty training and within 10 years of having obtained his or her medical degree. Additionally, applicants must be planning a research career in clinical oncology, with a focus on MCL.

The grant selection committee’s primary criteria include the significance and originality of the proposed study and hypothesis, the feasibility of the experiment and methodology, whether it has an appropriate and detailed statistical analysis plan, and if the research is patient oriented.

The application deadline is Jan. 7, 2020, and the award term is July 1, 2020–June 30, 2021.

Application instructions are available on the ASCO website.

[email protected]

Primary central nervous system lymphoma (PCNSL) is a rare and aggressive form of non-Hodgkin lymphoma solely confined to the CNS. The majority of PCNSL histologically presents as diffuse large B-cell lymphoma (DLBCL). However, outcomes in these patients are notably inferior, compared with nodal or other extranodal DLBCL. In order to achieve long-term progression-free survival, high-dose methotrexate (HD-MTX)–based chemotherapy followed by consolidation is needed. However, this treatment is associated with high toxicity burden and it is restricted to a select patient population – the young and fit – and requires administration at specialized hematological centers.

In the 1990s, the conventional DLBCL treatment regimen with CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) was tested in PCNSL patients. The results were rather disappointing. The addition of CHOP to whole brain radiation or HD-MTX could not improve survival.^1-3 The reason for CHOP failure was poor CNS penetration of doxorubicin and cyclophosphamide because of their high molecular weight. Consequently, it was concluded that there is no role for CHOP-like chemotherapy in the treatment of PCNSL.⁴

But is this really the case? Twenty years later, this traditional view has been challenged by Andres J.M. Ferreri, MD, and colleagues in the INGRID trial.⁵ Dr. Ferreri presented findings from the trial at the International Conference on Malignant Lymphoma in Lugano, Switzerland, which was greeted with much excitement.⁶

INGRID is a phase 2 trial conducted on patients with refractory/relapsed PCNSL. It consisted of a CHOP plus rituximab (R-CHOP) regimen, which was upgraded by engineered tumor necrosis factor–alpha (TNF-alpha). The idea was to enhance the blood-brain barrier (BBB) permeability and consequently improve the efficacy of R-CHOP in PCNSL. The use of human TNF-alpha is limited by relevant toxicities. In order to avoid that, a fusion of human TNF-alpha and CNGRCG peptide (called NGR-TNF) was developed.

CNGRCG peptide is a ligand of CD13, an aminopeptidase that is expressed almost exclusively on tumor blood vessels. Preclinical data showed that binding of CNGRCG to CD13 results in targeted – local, not systemic – delivery of TNF-alpha to the tumor blood vessels. Consequently, TNF-alpha led to increased vascular permeability in tumor tissue and enabled higher penetration of chemotherapeutic agents.^7,8

Altogether, 12 heavily pretreated PCNSL patients were included in the INGRID trial. Seven patients had two or more previous treatment regimens. Within this trial, patients received R-CHOP with NGR-TNF (0.8 mcg/m²) applied 2 hours prior to R-CHOP. The great majority of grade 3/4 adverse events were hematological toxicities. Importantly, no neurological side effects of any grade occurred.

The primary aim of this study was to investigate the CD13 expression on tumor tissue and provide a proof of concept for the use of NGR-TNF/R-CHOP. Indeed, CD13 expression was observed on tumor vessels in all patients. Consequently, increased BBB permeability in tumor tissue after NGR-TNF infusion was observed using dynamic contrast-enhanced MRI and by brain scintigraphy (SPECT). This was assessed 1 day after NGR-TNF/R-CHOP treatment. More importantly, this effect on BBB seems to be sustained because it was also observed after the last cycle of NGR-TNF/R-CHOP. The fact that there was no change of drug concentrations of R-CHOP components in plasma or cerebrospinal fluid suggests that the effect of NGR-TNF is restricted to tumor vessels.

The authors also reported preliminary results regarding response rates to NGR-TNF/R-CHOP. The overall response rate was 75%. Of note, six patients achieved complete remission and one patient achieved a partial remission. The median duration of response was 10 months (range, 7-14 months), and nine patients were able to proceed to consolidation treatment.

These preliminary results are encouraging and open a new window for the treatment strategies in PCNSL patients. NGR-TNF/R-CHOP treatment induced responses in 75% of these heavily pretreated patients. The low toxicity profile and feasibility of this regimen could allow clinicians to carry out this treatment approach in outpatient settings, as well as in older and comorbid patients. Extensive supportive therapy – such as intensive hydration or leucovorin-rescue by HD-MTX – is not needed.

These results will need to be confirmed through testing in a larger patient population. Dr. Ferreri and colleagues are currently conducting the extended phase of this study and aim to recruit 28 patients. If they report positive results from that study, evaluation of NGR-TNF/R-CHOP as a first-line treatment of PCNSL seems to be the next reasonable step.

Dr. Zeremski and Dr. Fischer are both in the department of hematology/oncology and affiliated with the Health Campus Immunology, Infectiology and Inflammation at Otto-von-Guericke University Magdeburg (Germany). Dr. Fischer is a member of the editorial advisory board of Hematology News. The authors reported having no conflicts of interest.

References

1. J Clin Oncol. 1996;14:556-64.

2. Cancer. 2000;89:1359-70.

3. J Neurooncol. 1996;30:257-65.

4. Guidelines on the diagnosis and management of adult patients with primary CNS lymphoma (PCNSL) and primary intra-ocular lymphoma (PIOL). British Society for Haematology/British Committee for Standards in Haematology; HO/016, 2009.

5. Blood. 2019;134:252-62.

6. Hematol Oncol. 2019; 37:159.

7. BioDrugs. 2013;27:591-603.

8. J Clin Invest. 2002;110:475-82.

Primary central nervous system lymphoma (PCNSL) is a rare and aggressive form of non-Hodgkin lymphoma solely confined to the CNS. The majority of PCNSL histologically presents as diffuse large B-cell lymphoma (DLBCL). However, outcomes in these patients are notably inferior, compared with nodal or other extranodal DLBCL. In order to achieve long-term progression-free survival, high-dose methotrexate (HD-MTX)–based chemotherapy followed by consolidation is needed. However, this treatment is associated with high toxicity burden and it is restricted to a select patient population – the young and fit – and requires administration at specialized hematological centers.

In the 1990s, the conventional DLBCL treatment regimen with CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) was tested in PCNSL patients. The results were rather disappointing. The addition of CHOP to whole brain radiation or HD-MTX could not improve survival.^1-3 The reason for CHOP failure was poor CNS penetration of doxorubicin and cyclophosphamide because of their high molecular weight. Consequently, it was concluded that there is no role for CHOP-like chemotherapy in the treatment of PCNSL.⁴

But is this really the case? Twenty years later, this traditional view has been challenged by Andres J.M. Ferreri, MD, and colleagues in the INGRID trial.⁵ Dr. Ferreri presented findings from the trial at the International Conference on Malignant Lymphoma in Lugano, Switzerland, which was greeted with much excitement.⁶

INGRID is a phase 2 trial conducted on patients with refractory/relapsed PCNSL. It consisted of a CHOP plus rituximab (R-CHOP) regimen, which was upgraded by engineered tumor necrosis factor–alpha (TNF-alpha). The idea was to enhance the blood-brain barrier (BBB) permeability and consequently improve the efficacy of R-CHOP in PCNSL. The use of human TNF-alpha is limited by relevant toxicities. In order to avoid that, a fusion of human TNF-alpha and CNGRCG peptide (called NGR-TNF) was developed.

CNGRCG peptide is a ligand of CD13, an aminopeptidase that is expressed almost exclusively on tumor blood vessels. Preclinical data showed that binding of CNGRCG to CD13 results in targeted – local, not systemic – delivery of TNF-alpha to the tumor blood vessels. Consequently, TNF-alpha led to increased vascular permeability in tumor tissue and enabled higher penetration of chemotherapeutic agents.^7,8

Altogether, 12 heavily pretreated PCNSL patients were included in the INGRID trial. Seven patients had two or more previous treatment regimens. Within this trial, patients received R-CHOP with NGR-TNF (0.8 mcg/m²) applied 2 hours prior to R-CHOP. The great majority of grade 3/4 adverse events were hematological toxicities. Importantly, no neurological side effects of any grade occurred.

The primary aim of this study was to investigate the CD13 expression on tumor tissue and provide a proof of concept for the use of NGR-TNF/R-CHOP. Indeed, CD13 expression was observed on tumor vessels in all patients. Consequently, increased BBB permeability in tumor tissue after NGR-TNF infusion was observed using dynamic contrast-enhanced MRI and by brain scintigraphy (SPECT). This was assessed 1 day after NGR-TNF/R-CHOP treatment. More importantly, this effect on BBB seems to be sustained because it was also observed after the last cycle of NGR-TNF/R-CHOP. The fact that there was no change of drug concentrations of R-CHOP components in plasma or cerebrospinal fluid suggests that the effect of NGR-TNF is restricted to tumor vessels.

The authors also reported preliminary results regarding response rates to NGR-TNF/R-CHOP. The overall response rate was 75%. Of note, six patients achieved complete remission and one patient achieved a partial remission. The median duration of response was 10 months (range, 7-14 months), and nine patients were able to proceed to consolidation treatment.

These preliminary results are encouraging and open a new window for the treatment strategies in PCNSL patients. NGR-TNF/R-CHOP treatment induced responses in 75% of these heavily pretreated patients. The low toxicity profile and feasibility of this regimen could allow clinicians to carry out this treatment approach in outpatient settings, as well as in older and comorbid patients. Extensive supportive therapy – such as intensive hydration or leucovorin-rescue by HD-MTX – is not needed.

These results will need to be confirmed through testing in a larger patient population. Dr. Ferreri and colleagues are currently conducting the extended phase of this study and aim to recruit 28 patients. If they report positive results from that study, evaluation of NGR-TNF/R-CHOP as a first-line treatment of PCNSL seems to be the next reasonable step.

Dr. Zeremski and Dr. Fischer are both in the department of hematology/oncology and affiliated with the Health Campus Immunology, Infectiology and Inflammation at Otto-von-Guericke University Magdeburg (Germany). Dr. Fischer is a member of the editorial advisory board of Hematology News. The authors reported having no conflicts of interest.

References

1. J Clin Oncol. 1996;14:556-64.

2. Cancer. 2000;89:1359-70.

3. J Neurooncol. 1996;30:257-65.

4. Guidelines on the diagnosis and management of adult patients with primary CNS lymphoma (PCNSL) and primary intra-ocular lymphoma (PIOL). British Society for Haematology/British Committee for Standards in Haematology; HO/016, 2009.

5. Blood. 2019;134:252-62.

6. Hematol Oncol. 2019; 37:159.

7. BioDrugs. 2013;27:591-603.

8. J Clin Invest. 2002;110:475-82.

Primary central nervous system lymphoma (PCNSL) is a rare and aggressive form of non-Hodgkin lymphoma solely confined to the CNS. The majority of PCNSL histologically presents as diffuse large B-cell lymphoma (DLBCL). However, outcomes in these patients are notably inferior, compared with nodal or other extranodal DLBCL. In order to achieve long-term progression-free survival, high-dose methotrexate (HD-MTX)–based chemotherapy followed by consolidation is needed. However, this treatment is associated with high toxicity burden and it is restricted to a select patient population – the young and fit – and requires administration at specialized hematological centers.

In the 1990s, the conventional DLBCL treatment regimen with CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) was tested in PCNSL patients. The results were rather disappointing. The addition of CHOP to whole brain radiation or HD-MTX could not improve survival.^1-3 The reason for CHOP failure was poor CNS penetration of doxorubicin and cyclophosphamide because of their high molecular weight. Consequently, it was concluded that there is no role for CHOP-like chemotherapy in the treatment of PCNSL.⁴

But is this really the case? Twenty years later, this traditional view has been challenged by Andres J.M. Ferreri, MD, and colleagues in the INGRID trial.⁵ Dr. Ferreri presented findings from the trial at the International Conference on Malignant Lymphoma in Lugano, Switzerland, which was greeted with much excitement.⁶

INGRID is a phase 2 trial conducted on patients with refractory/relapsed PCNSL. It consisted of a CHOP plus rituximab (R-CHOP) regimen, which was upgraded by engineered tumor necrosis factor–alpha (TNF-alpha). The idea was to enhance the blood-brain barrier (BBB) permeability and consequently improve the efficacy of R-CHOP in PCNSL. The use of human TNF-alpha is limited by relevant toxicities. In order to avoid that, a fusion of human TNF-alpha and CNGRCG peptide (called NGR-TNF) was developed.

CNGRCG peptide is a ligand of CD13, an aminopeptidase that is expressed almost exclusively on tumor blood vessels. Preclinical data showed that binding of CNGRCG to CD13 results in targeted – local, not systemic – delivery of TNF-alpha to the tumor blood vessels. Consequently, TNF-alpha led to increased vascular permeability in tumor tissue and enabled higher penetration of chemotherapeutic agents.^7,8

Altogether, 12 heavily pretreated PCNSL patients were included in the INGRID trial. Seven patients had two or more previous treatment regimens. Within this trial, patients received R-CHOP with NGR-TNF (0.8 mcg/m²) applied 2 hours prior to R-CHOP. The great majority of grade 3/4 adverse events were hematological toxicities. Importantly, no neurological side effects of any grade occurred.

The primary aim of this study was to investigate the CD13 expression on tumor tissue and provide a proof of concept for the use of NGR-TNF/R-CHOP. Indeed, CD13 expression was observed on tumor vessels in all patients. Consequently, increased BBB permeability in tumor tissue after NGR-TNF infusion was observed using dynamic contrast-enhanced MRI and by brain scintigraphy (SPECT). This was assessed 1 day after NGR-TNF/R-CHOP treatment. More importantly, this effect on BBB seems to be sustained because it was also observed after the last cycle of NGR-TNF/R-CHOP. The fact that there was no change of drug concentrations of R-CHOP components in plasma or cerebrospinal fluid suggests that the effect of NGR-TNF is restricted to tumor vessels.

The authors also reported preliminary results regarding response rates to NGR-TNF/R-CHOP. The overall response rate was 75%. Of note, six patients achieved complete remission and one patient achieved a partial remission. The median duration of response was 10 months (range, 7-14 months), and nine patients were able to proceed to consolidation treatment.

These preliminary results are encouraging and open a new window for the treatment strategies in PCNSL patients. NGR-TNF/R-CHOP treatment induced responses in 75% of these heavily pretreated patients. The low toxicity profile and feasibility of this regimen could allow clinicians to carry out this treatment approach in outpatient settings, as well as in older and comorbid patients. Extensive supportive therapy – such as intensive hydration or leucovorin-rescue by HD-MTX – is not needed.

These results will need to be confirmed through testing in a larger patient population. Dr. Ferreri and colleagues are currently conducting the extended phase of this study and aim to recruit 28 patients. If they report positive results from that study, evaluation of NGR-TNF/R-CHOP as a first-line treatment of PCNSL seems to be the next reasonable step.

Dr. Zeremski and Dr. Fischer are both in the department of hematology/oncology and affiliated with the Health Campus Immunology, Infectiology and Inflammation at Otto-von-Guericke University Magdeburg (Germany). Dr. Fischer is a member of the editorial advisory board of Hematology News. The authors reported having no conflicts of interest.

References

1. J Clin Oncol. 1996;14:556-64.

2. Cancer. 2000;89:1359-70.

3. J Neurooncol. 1996;30:257-65.

4. Guidelines on the diagnosis and management of adult patients with primary CNS lymphoma (PCNSL) and primary intra-ocular lymphoma (PIOL). British Society for Haematology/British Committee for Standards in Haematology; HO/016, 2009.

5. Blood. 2019;134:252-62.

6. Hematol Oncol. 2019; 37:159.

7. BioDrugs. 2013;27:591-603.

8. J Clin Invest. 2002;110:475-82.

EDINBURGH – Routine empiric prophylaxis against pneumocystis jiroveci pneumonia (PJP) may be unwarranted in chronic lymphocytic leukemia patients initiating Bruton tyrosine kinase (BTK) inhibitor therapy, a retrospective chart review suggests.

Among 212 patients with chronic lymphocytic leukemia (CLL) who were treated with ibrutinib or acalabrutinib either as monotherapy or as part of a combination regimen for at least 30 days between Jan. 1, 2010, and Feb. 1, 2019, at Dana-Farber Cancer Institute and Brigham and Women’s Hospital in Boston, 125 (59%) received PJP prophylaxis, including either trimethoprim-sulfamethoxazole (74%) or atovaquone (26%), Christine Ryan, MD, reported at the International Workshop on CLL.

Two PJP cases occurred in the 120 patients on single-agent ibrutinib, including one in a previously untreated patient and one in a patient with relapsed/refractory CLL. Neither patient had received PJP prophylaxis, said Dr. Ryan, a senior resident at Brigham and Women’s Hospital.

No PJP cases occurred in the 21 patients who received acalabrutinib monotherapy or in the 14 patients who received acalabrutinib combination therapy, and 1 occurred in a trial cohort of 57 patients receiving frontline ibrutinib plus fludarabine-based chemotherapy (FCR). The latter had been prescribed PJP prophylaxis, but “unfortunately self-discontinued the prophylaxis” 2 months prior to the infection, Dr. Ryan said.

“The overall prevalence of PJP in patients not on prophylaxis was 3.4%, there were no cases of PJP in patients on prophylaxis, and the incidence rate in patients not on prophylaxis was 1.9 per 100 person-years, with a number needed to treat to prevent 1 case of PJP calculated to be 42 patients,” she said.

In addition to PJP, three cases of proven or probable invasive fungal infections (IFI) occurred, including one case of pulmonary histoplasmosis in the ibrutinib plus FCR trial cohort and two cases of aspergillosis, including a pulmonary case and a brain abscess, in an ibrutinib plus umbralisib trial cohort.

“The overall prevalence of aspergillosis or histoplasmosis in our entire cohort was 1.4%, and notably there were no cases of IFI in the single-agent therapy cohort, but the prevalence in the ibrutinib-combination therapy patients was 4.2%,” Dr. Ryan said.

Patients included in the review were adults with a median age of 64.8 years, and 64% were men. The median duration of BTK inhibitor therapy was 23.2 months.

“We know that CLL patients treated with fludarabine have an increased risk of PJP,” she said. “As such, it is routinely recommended that patients receiving fludarabine-containing chemotherapy regimens are prescribed PJP prophylaxis.”

Additionally, the increasing use of oral BTK inhibitors has raised concerns about the potential risk of PJP or other IFIs in patients on those agents, Dr. Ryan explained, noting that existing case reports and case series looking at PJP have shown varying prevalence rates, and little is known about the effects of prophylaxis.

“At present, there are no international guidelines regarding the use of antimicrobial prophylaxis in CLL patients treated with BTK inhibitors, and prophylaxis practices vary widely across countries and institutions,” she said.

The findings of the current study demonstrate that such variation exists “even within our own institution,” Dr. Ryan added.

The findings also show an overall low PJP prevalence of 3.4% in patients not receiving prophylaxis, which falls below the “commonly accepted threshold of 5%, above which routine prophylaxis becomes recommended,” she said.

“Overall, our data suggest that routine PJP or IFI prophylaxis in patients receiving BTK inhibitors may not be needed, but this is definitely an area that requires further study, ideally with a prospective trial with a larger sample size and multiple institutions, to support the development of consensus guidelines on this issue,” she said.

Dr. Ryan reported having no financial disclosures.

[email protected]

EDINBURGH – Routine empiric prophylaxis against pneumocystis jiroveci pneumonia (PJP) may be unwarranted in chronic lymphocytic leukemia patients initiating Bruton tyrosine kinase (BTK) inhibitor therapy, a retrospective chart review suggests.

Among 212 patients with chronic lymphocytic leukemia (CLL) who were treated with ibrutinib or acalabrutinib either as monotherapy or as part of a combination regimen for at least 30 days between Jan. 1, 2010, and Feb. 1, 2019, at Dana-Farber Cancer Institute and Brigham and Women’s Hospital in Boston, 125 (59%) received PJP prophylaxis, including either trimethoprim-sulfamethoxazole (74%) or atovaquone (26%), Christine Ryan, MD, reported at the International Workshop on CLL.

Two PJP cases occurred in the 120 patients on single-agent ibrutinib, including one in a previously untreated patient and one in a patient with relapsed/refractory CLL. Neither patient had received PJP prophylaxis, said Dr. Ryan, a senior resident at Brigham and Women’s Hospital.

No PJP cases occurred in the 21 patients who received acalabrutinib monotherapy or in the 14 patients who received acalabrutinib combination therapy, and 1 occurred in a trial cohort of 57 patients receiving frontline ibrutinib plus fludarabine-based chemotherapy (FCR). The latter had been prescribed PJP prophylaxis, but “unfortunately self-discontinued the prophylaxis” 2 months prior to the infection, Dr. Ryan said.

“The overall prevalence of PJP in patients not on prophylaxis was 3.4%, there were no cases of PJP in patients on prophylaxis, and the incidence rate in patients not on prophylaxis was 1.9 per 100 person-years, with a number needed to treat to prevent 1 case of PJP calculated to be 42 patients,” she said.

In addition to PJP, three cases of proven or probable invasive fungal infections (IFI) occurred, including one case of pulmonary histoplasmosis in the ibrutinib plus FCR trial cohort and two cases of aspergillosis, including a pulmonary case and a brain abscess, in an ibrutinib plus umbralisib trial cohort.

“The overall prevalence of aspergillosis or histoplasmosis in our entire cohort was 1.4%, and notably there were no cases of IFI in the single-agent therapy cohort, but the prevalence in the ibrutinib-combination therapy patients was 4.2%,” Dr. Ryan said.

Patients included in the review were adults with a median age of 64.8 years, and 64% were men. The median duration of BTK inhibitor therapy was 23.2 months.

“We know that CLL patients treated with fludarabine have an increased risk of PJP,” she said. “As such, it is routinely recommended that patients receiving fludarabine-containing chemotherapy regimens are prescribed PJP prophylaxis.”

Additionally, the increasing use of oral BTK inhibitors has raised concerns about the potential risk of PJP or other IFIs in patients on those agents, Dr. Ryan explained, noting that existing case reports and case series looking at PJP have shown varying prevalence rates, and little is known about the effects of prophylaxis.

“At present, there are no international guidelines regarding the use of antimicrobial prophylaxis in CLL patients treated with BTK inhibitors, and prophylaxis practices vary widely across countries and institutions,” she said.

The findings of the current study demonstrate that such variation exists “even within our own institution,” Dr. Ryan added.

The findings also show an overall low PJP prevalence of 3.4% in patients not receiving prophylaxis, which falls below the “commonly accepted threshold of 5%, above which routine prophylaxis becomes recommended,” she said.

“Overall, our data suggest that routine PJP or IFI prophylaxis in patients receiving BTK inhibitors may not be needed, but this is definitely an area that requires further study, ideally with a prospective trial with a larger sample size and multiple institutions, to support the development of consensus guidelines on this issue,” she said.

Dr. Ryan reported having no financial disclosures.

[email protected]

EDINBURGH – Routine empiric prophylaxis against pneumocystis jiroveci pneumonia (PJP) may be unwarranted in chronic lymphocytic leukemia patients initiating Bruton tyrosine kinase (BTK) inhibitor therapy, a retrospective chart review suggests.

Among 212 patients with chronic lymphocytic leukemia (CLL) who were treated with ibrutinib or acalabrutinib either as monotherapy or as part of a combination regimen for at least 30 days between Jan. 1, 2010, and Feb. 1, 2019, at Dana-Farber Cancer Institute and Brigham and Women’s Hospital in Boston, 125 (59%) received PJP prophylaxis, including either trimethoprim-sulfamethoxazole (74%) or atovaquone (26%), Christine Ryan, MD, reported at the International Workshop on CLL.

Two PJP cases occurred in the 120 patients on single-agent ibrutinib, including one in a previously untreated patient and one in a patient with relapsed/refractory CLL. Neither patient had received PJP prophylaxis, said Dr. Ryan, a senior resident at Brigham and Women’s Hospital.

No PJP cases occurred in the 21 patients who received acalabrutinib monotherapy or in the 14 patients who received acalabrutinib combination therapy, and 1 occurred in a trial cohort of 57 patients receiving frontline ibrutinib plus fludarabine-based chemotherapy (FCR). The latter had been prescribed PJP prophylaxis, but “unfortunately self-discontinued the prophylaxis” 2 months prior to the infection, Dr. Ryan said.

“The overall prevalence of PJP in patients not on prophylaxis was 3.4%, there were no cases of PJP in patients on prophylaxis, and the incidence rate in patients not on prophylaxis was 1.9 per 100 person-years, with a number needed to treat to prevent 1 case of PJP calculated to be 42 patients,” she said.

In addition to PJP, three cases of proven or probable invasive fungal infections (IFI) occurred, including one case of pulmonary histoplasmosis in the ibrutinib plus FCR trial cohort and two cases of aspergillosis, including a pulmonary case and a brain abscess, in an ibrutinib plus umbralisib trial cohort.

“The overall prevalence of aspergillosis or histoplasmosis in our entire cohort was 1.4%, and notably there were no cases of IFI in the single-agent therapy cohort, but the prevalence in the ibrutinib-combination therapy patients was 4.2%,” Dr. Ryan said.

Patients included in the review were adults with a median age of 64.8 years, and 64% were men. The median duration of BTK inhibitor therapy was 23.2 months.

“We know that CLL patients treated with fludarabine have an increased risk of PJP,” she said. “As such, it is routinely recommended that patients receiving fludarabine-containing chemotherapy regimens are prescribed PJP prophylaxis.”

Additionally, the increasing use of oral BTK inhibitors has raised concerns about the potential risk of PJP or other IFIs in patients on those agents, Dr. Ryan explained, noting that existing case reports and case series looking at PJP have shown varying prevalence rates, and little is known about the effects of prophylaxis.

“At present, there are no international guidelines regarding the use of antimicrobial prophylaxis in CLL patients treated with BTK inhibitors, and prophylaxis practices vary widely across countries and institutions,” she said.

The findings of the current study demonstrate that such variation exists “even within our own institution,” Dr. Ryan added.

The findings also show an overall low PJP prevalence of 3.4% in patients not receiving prophylaxis, which falls below the “commonly accepted threshold of 5%, above which routine prophylaxis becomes recommended,” she said.

“Overall, our data suggest that routine PJP or IFI prophylaxis in patients receiving BTK inhibitors may not be needed, but this is definitely an area that requires further study, ideally with a prospective trial with a larger sample size and multiple institutions, to support the development of consensus guidelines on this issue,” she said.

Dr. Ryan reported having no financial disclosures.

[email protected]

The incidence and severity of hypertension was considerably higher in patients with B-cell malignancies treated with ibrutinib, according to a retrospective analysis.

Additionally, new or worsening hypertension was associated with a greater risk of major adverse cardiac events (MACE), including stroke, myocardial infarction, and cardiovascular-related death (hazard ratio, 2.17; 95% confidence interval, 1.08-4.38; P = .03).

“Despite ibrutinib’s benefits, cardiotoxicity has emerged as an increasingly important complication of this life-saving therapy,” Tyler Dickerson, PhD, of the Ohio State University, Columbus, and colleagues wrote in Blood.

The researchers retrospectively studied 562 consecutive patients with a lymphoid malignancy who received ibrutinib. Data was collected from patients treated at The Ohio State University’s Comprehensive Cancer Center during 2009-2016.

The mean age of study participants was 63.8 years, with a mean body mass index of 28.0 kg/m². Most of the patients included in the analysis were men.

The team assessed rates of new or worsening hypertension, as well as rates of other MACE. The observed rates were compared with Framingham Heart Study–predicted incident-hypertension rates. The effects of various antihypertensive drugs on ibrutinib-linked hypertension were also evaluated.

After a median follow-up of 30 months, 78.3% of patients who received ibrutinib had new or worsening hypertension using a systolic blood pressure cutoff of 130 mm Hg. Of these, 84.8% of cases had an “at least probable association with ibrutinib,” they reported.

Among the 215 patients with no baseline hypertension, 71.6% developed hypertension while on ibrutinib, with a mean increase in systolic blood pressure of 13.4 mm Hg. Among the 347 patients with baseline hypertension, 82.4% experienced a worsening of their hypertension.

“This relationship remained even after accounting for ibrutinib dose, and was not attenuated by the use of any specific anti-hypertensive class,” the researchers wrote.

The researchers observed MACE among 93 patients. This included 84 patients with new or worsening hypertension and 9 patients with stable or no hypertension. Most MACE events were of at least probable ibrutinib association, the researchers reported.

Overall, the cumulative incidence of new hypertension at 1 year was 442 per 1,000 person-years in the current study. This value is 12.9-fold higher than the Framingham Heart Study risk–predicted rate of 34 per 1,000 person-years.

“Given the expected continued increase in ibrutinib use, further studies characterizing the mechanisms, treatment, and implications of [hypertension] during ibrutinib use are needed,” the researchers wrote.

The study was funded by the National Institutes of Health, the D. Warren Brown Family Foundation, the Four Winds Foundation, and the Connie Brown CLL Research Fund. The authors reported financial affiliations with Janssen, Pharmacyclics, and other companies.

SOURCE: Dickerson T et al. Blood. 2019 Oct 3. doi: 10.1182/blood.2019000840.

The incidence and severity of hypertension was considerably higher in patients with B-cell malignancies treated with ibrutinib, according to a retrospective analysis.

Additionally, new or worsening hypertension was associated with a greater risk of major adverse cardiac events (MACE), including stroke, myocardial infarction, and cardiovascular-related death (hazard ratio, 2.17; 95% confidence interval, 1.08-4.38; P = .03).

“Despite ibrutinib’s benefits, cardiotoxicity has emerged as an increasingly important complication of this life-saving therapy,” Tyler Dickerson, PhD, of the Ohio State University, Columbus, and colleagues wrote in Blood.

The researchers retrospectively studied 562 consecutive patients with a lymphoid malignancy who received ibrutinib. Data was collected from patients treated at The Ohio State University’s Comprehensive Cancer Center during 2009-2016.

The mean age of study participants was 63.8 years, with a mean body mass index of 28.0 kg/m². Most of the patients included in the analysis were men.

The team assessed rates of new or worsening hypertension, as well as rates of other MACE. The observed rates were compared with Framingham Heart Study–predicted incident-hypertension rates. The effects of various antihypertensive drugs on ibrutinib-linked hypertension were also evaluated.

After a median follow-up of 30 months, 78.3% of patients who received ibrutinib had new or worsening hypertension using a systolic blood pressure cutoff of 130 mm Hg. Of these, 84.8% of cases had an “at least probable association with ibrutinib,” they reported.

Among the 215 patients with no baseline hypertension, 71.6% developed hypertension while on ibrutinib, with a mean increase in systolic blood pressure of 13.4 mm Hg. Among the 347 patients with baseline hypertension, 82.4% experienced a worsening of their hypertension.

“This relationship remained even after accounting for ibrutinib dose, and was not attenuated by the use of any specific anti-hypertensive class,” the researchers wrote.

The researchers observed MACE among 93 patients. This included 84 patients with new or worsening hypertension and 9 patients with stable or no hypertension. Most MACE events were of at least probable ibrutinib association, the researchers reported.

Overall, the cumulative incidence of new hypertension at 1 year was 442 per 1,000 person-years in the current study. This value is 12.9-fold higher than the Framingham Heart Study risk–predicted rate of 34 per 1,000 person-years.

“Given the expected continued increase in ibrutinib use, further studies characterizing the mechanisms, treatment, and implications of [hypertension] during ibrutinib use are needed,” the researchers wrote.

The study was funded by the National Institutes of Health, the D. Warren Brown Family Foundation, the Four Winds Foundation, and the Connie Brown CLL Research Fund. The authors reported financial affiliations with Janssen, Pharmacyclics, and other companies.

SOURCE: Dickerson T et al. Blood. 2019 Oct 3. doi: 10.1182/blood.2019000840.

The incidence and severity of hypertension was considerably higher in patients with B-cell malignancies treated with ibrutinib, according to a retrospective analysis.

Additionally, new or worsening hypertension was associated with a greater risk of major adverse cardiac events (MACE), including stroke, myocardial infarction, and cardiovascular-related death (hazard ratio, 2.17; 95% confidence interval, 1.08-4.38; P = .03).

“Despite ibrutinib’s benefits, cardiotoxicity has emerged as an increasingly important complication of this life-saving therapy,” Tyler Dickerson, PhD, of the Ohio State University, Columbus, and colleagues wrote in Blood.

The researchers retrospectively studied 562 consecutive patients with a lymphoid malignancy who received ibrutinib. Data was collected from patients treated at The Ohio State University’s Comprehensive Cancer Center during 2009-2016.

The mean age of study participants was 63.8 years, with a mean body mass index of 28.0 kg/m². Most of the patients included in the analysis were men.

The team assessed rates of new or worsening hypertension, as well as rates of other MACE. The observed rates were compared with Framingham Heart Study–predicted incident-hypertension rates. The effects of various antihypertensive drugs on ibrutinib-linked hypertension were also evaluated.

After a median follow-up of 30 months, 78.3% of patients who received ibrutinib had new or worsening hypertension using a systolic blood pressure cutoff of 130 mm Hg. Of these, 84.8% of cases had an “at least probable association with ibrutinib,” they reported.

Among the 215 patients with no baseline hypertension, 71.6% developed hypertension while on ibrutinib, with a mean increase in systolic blood pressure of 13.4 mm Hg. Among the 347 patients with baseline hypertension, 82.4% experienced a worsening of their hypertension.

“This relationship remained even after accounting for ibrutinib dose, and was not attenuated by the use of any specific anti-hypertensive class,” the researchers wrote.

The researchers observed MACE among 93 patients. This included 84 patients with new or worsening hypertension and 9 patients with stable or no hypertension. Most MACE events were of at least probable ibrutinib association, the researchers reported.

Overall, the cumulative incidence of new hypertension at 1 year was 442 per 1,000 person-years in the current study. This value is 12.9-fold higher than the Framingham Heart Study risk–predicted rate of 34 per 1,000 person-years.

“Given the expected continued increase in ibrutinib use, further studies characterizing the mechanisms, treatment, and implications of [hypertension] during ibrutinib use are needed,” the researchers wrote.

The study was funded by the National Institutes of Health, the D. Warren Brown Family Foundation, the Four Winds Foundation, and the Connie Brown CLL Research Fund. The authors reported financial affiliations with Janssen, Pharmacyclics, and other companies.

SOURCE: Dickerson T et al. Blood. 2019 Oct 3. doi: 10.1182/blood.2019000840.

An international panel of neurologists has drafted a consensus statement on the diagnosis, prognosis, and treatment of stridor in patients with multiple system atrophy (MSA). The statement was published Oct. 1 in Neurology. In addition to reviewing the literature on the topic and providing recommendations, the authors described several areas for future research.

MSA is a rare neurodegenerative disorder that entails autonomic failure, cerebellar ataxia, and parkinsonism. Laryngeal stridor has a high positive predictive value in the diagnosis of MSA, but consensus about its definition and clinical implications had not been established previously. The Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) delle Scienze Neurologiche di Bologna (Italy) convened a consensus conference of experts in 2017 to determine diagnostic criteria for stridor in MSA, define its prognostic value, suggest treatment options, and indicate subjects for future research. The neurologists reviewed studies of any design that reported original data. They based their statements on 34 published articles, most of which were class III or IV.

The authors defined stridor in MSA as “a strained, high-pitched, harsh respiratory sound, mainly inspiratory, caused by laryngeal dysfunction leading to narrowing of the rima glottidis.” Stridor may occur exclusively during sleep or during sleep and wakefulness. It may be recognized during a clinical examination, through witness report, or through an audio recording. Neurologists may consider laryngoscopy to exclude mechanical lesions or functional vocal cord abnormalities related to other neurologic conditions, wrote the authors. Drug-induced sleep endoscopy and video polysomnography also may be considered.

Whether stridor, or certain features of stridor, affects survival in MSA is uncertain. “Stridor within 3 years of motor or autonomic symptom onset may shorten survival,” according to the statement. “However, identification of stridor onset may be difficult.” Moreover, stridor during wakefulness is considered to reflect a more advanced stage of disease, compared with stridor during sleep. Although stridor can be distressing for the patient and his or her caregivers, its influence on health-related quality of life has yet to be determined, according to the statement.

Continuous positive airway pressure (CPAP) during sleep can be a useful symptomatic treatment and should be considered a first-line therapy for stridor, wrote the authors. Tracheostomy, another effective symptomatic treatment, bypasses upper-airway obstruction at the larynx. “Persistent and severe stridor may require tracheostomy,” according to the statement. It is not certain whether CPAP improves survival in patients with MSA and stridor, and tracheostomy may improve survival. The literature contains insufficient evidence about whether minimally invasive procedures or botulinum toxin injections are effective symptomatic treatments for stridor, wrote the authors.

During their review of the literature, the authors identified what they considered to be several research gaps. The diagnosis of stridor remains challenging, and investigators should develop a questionnaire for detecting stridor, they wrote. A smartphone application also could be developed to recognize stridor automatically. “The relationship between stridor and other breathing disorders (i.e., central apneas and breathing rate abnormalities) and their respective contributions to disease prognosis and survival should be determined through a multicenter prospective study,” according to the statement. Finally, randomized controlled trials comparing CPAP and tracheostomy for various degrees of stridor could guide physicians’ choice of treatment.

The IRCCS funded the study. One of the authors is a section editor for Neurology, and other authors reported receiving honoraria from various companies such as Novartis, Sanofi, and UCB.

[email protected]

SOURCE: Cortelli P et al. Neurology. 2019;93(14):630-9.

An international panel of neurologists has drafted a consensus statement on the diagnosis, prognosis, and treatment of stridor in patients with multiple system atrophy (MSA). The statement was published Oct. 1 in Neurology. In addition to reviewing the literature on the topic and providing recommendations, the authors described several areas for future research.

MSA is a rare neurodegenerative disorder that entails autonomic failure, cerebellar ataxia, and parkinsonism. Laryngeal stridor has a high positive predictive value in the diagnosis of MSA, but consensus about its definition and clinical implications had not been established previously. The Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) delle Scienze Neurologiche di Bologna (Italy) convened a consensus conference of experts in 2017 to determine diagnostic criteria for stridor in MSA, define its prognostic value, suggest treatment options, and indicate subjects for future research. The neurologists reviewed studies of any design that reported original data. They based their statements on 34 published articles, most of which were class III or IV.

The authors defined stridor in MSA as “a strained, high-pitched, harsh respiratory sound, mainly inspiratory, caused by laryngeal dysfunction leading to narrowing of the rima glottidis.” Stridor may occur exclusively during sleep or during sleep and wakefulness. It may be recognized during a clinical examination, through witness report, or through an audio recording. Neurologists may consider laryngoscopy to exclude mechanical lesions or functional vocal cord abnormalities related to other neurologic conditions, wrote the authors. Drug-induced sleep endoscopy and video polysomnography also may be considered.

Whether stridor, or certain features of stridor, affects survival in MSA is uncertain. “Stridor within 3 years of motor or autonomic symptom onset may shorten survival,” according to the statement. “However, identification of stridor onset may be difficult.” Moreover, stridor during wakefulness is considered to reflect a more advanced stage of disease, compared with stridor during sleep. Although stridor can be distressing for the patient and his or her caregivers, its influence on health-related quality of life has yet to be determined, according to the statement.

Continuous positive airway pressure (CPAP) during sleep can be a useful symptomatic treatment and should be considered a first-line therapy for stridor, wrote the authors. Tracheostomy, another effective symptomatic treatment, bypasses upper-airway obstruction at the larynx. “Persistent and severe stridor may require tracheostomy,” according to the statement. It is not certain whether CPAP improves survival in patients with MSA and stridor, and tracheostomy may improve survival. The literature contains insufficient evidence about whether minimally invasive procedures or botulinum toxin injections are effective symptomatic treatments for stridor, wrote the authors.

During their review of the literature, the authors identified what they considered to be several research gaps. The diagnosis of stridor remains challenging, and investigators should develop a questionnaire for detecting stridor, they wrote. A smartphone application also could be developed to recognize stridor automatically. “The relationship between stridor and other breathing disorders (i.e., central apneas and breathing rate abnormalities) and their respective contributions to disease prognosis and survival should be determined through a multicenter prospective study,” according to the statement. Finally, randomized controlled trials comparing CPAP and tracheostomy for various degrees of stridor could guide physicians’ choice of treatment.

The IRCCS funded the study. One of the authors is a section editor for Neurology, and other authors reported receiving honoraria from various companies such as Novartis, Sanofi, and UCB.

[email protected]

SOURCE: Cortelli P et al. Neurology. 2019;93(14):630-9.

An international panel of neurologists has drafted a consensus statement on the diagnosis, prognosis, and treatment of stridor in patients with multiple system atrophy (MSA). The statement was published Oct. 1 in Neurology. In addition to reviewing the literature on the topic and providing recommendations, the authors described several areas for future research.

MSA is a rare neurodegenerative disorder that entails autonomic failure, cerebellar ataxia, and parkinsonism. Laryngeal stridor has a high positive predictive value in the diagnosis of MSA, but consensus about its definition and clinical implications had not been established previously. The Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) delle Scienze Neurologiche di Bologna (Italy) convened a consensus conference of experts in 2017 to determine diagnostic criteria for stridor in MSA, define its prognostic value, suggest treatment options, and indicate subjects for future research. The neurologists reviewed studies of any design that reported original data. They based their statements on 34 published articles, most of which were class III or IV.

The authors defined stridor in MSA as “a strained, high-pitched, harsh respiratory sound, mainly inspiratory, caused by laryngeal dysfunction leading to narrowing of the rima glottidis.” Stridor may occur exclusively during sleep or during sleep and wakefulness. It may be recognized during a clinical examination, through witness report, or through an audio recording. Neurologists may consider laryngoscopy to exclude mechanical lesions or functional vocal cord abnormalities related to other neurologic conditions, wrote the authors. Drug-induced sleep endoscopy and video polysomnography also may be considered.

Whether stridor, or certain features of stridor, affects survival in MSA is uncertain. “Stridor within 3 years of motor or autonomic symptom onset may shorten survival,” according to the statement. “However, identification of stridor onset may be difficult.” Moreover, stridor during wakefulness is considered to reflect a more advanced stage of disease, compared with stridor during sleep. Although stridor can be distressing for the patient and his or her caregivers, its influence on health-related quality of life has yet to be determined, according to the statement.

Continuous positive airway pressure (CPAP) during sleep can be a useful symptomatic treatment and should be considered a first-line therapy for stridor, wrote the authors. Tracheostomy, another effective symptomatic treatment, bypasses upper-airway obstruction at the larynx. “Persistent and severe stridor may require tracheostomy,” according to the statement. It is not certain whether CPAP improves survival in patients with MSA and stridor, and tracheostomy may improve survival. The literature contains insufficient evidence about whether minimally invasive procedures or botulinum toxin injections are effective symptomatic treatments for stridor, wrote the authors.

During their review of the literature, the authors identified what they considered to be several research gaps. The diagnosis of stridor remains challenging, and investigators should develop a questionnaire for detecting stridor, they wrote. A smartphone application also could be developed to recognize stridor automatically. “The relationship between stridor and other breathing disorders (i.e., central apneas and breathing rate abnormalities) and their respective contributions to disease prognosis and survival should be determined through a multicenter prospective study,” according to the statement. Finally, randomized controlled trials comparing CPAP and tracheostomy for various degrees of stridor could guide physicians’ choice of treatment.

The IRCCS funded the study. One of the authors is a section editor for Neurology, and other authors reported receiving honoraria from various companies such as Novartis, Sanofi, and UCB.

[email protected]

SOURCE: Cortelli P et al. Neurology. 2019;93(14):630-9.

Patients with bipolar disorder may be at increased risk of Parkinson’s disease in later life, according to a systematic review and meta-analysis published in JAMA Neurology.

Patrícia R. Faustino, MD, from the faculty of medicine at the University of Lisboa (Portgual), and coauthors reviewed and analyzed seven articles – four cohort studies and three cross-sectional studies – that reported data on idiopathic Parkinson’s disease in patients with bipolar disorder, compared with those without. The meta-analysis found that individuals with a previous diagnosis of bipolar disorder had a 235% higher risk of being later diagnosed with Parkinson’s disease. Even after removing studies with a high risk of bias, the risk was still 3.21 times higher in those with bipolar disorder, compared with those without.

“The pathophysiological rationale between bipolar disorder and Parkinson’s disease might be explained by the dopamine dysregulation hypothesis, which states that the cyclical process of bipolar disorder in manic states leads to a down-regulation of dopamine receptor sensitivity (depression phase), which is later compensated by up-regulation (manic state),” the authors wrote. “Over time, this phenomenon may lead to an overall reduction of dopaminergic activity, the prototypical Parkinson’s disease state.”

Subgroup analysis revealed that subgroups with shorter follow-up periods – less than 9 years – had a greater increase in the risk of a later Parkinson’s disease diagnosis. The authors noted that this could represent misdiagnosis of parkinsonism – possibly drug induced – as Parkinson’s disease. The researchers also raised the possibility that the increased risk of Parkinson’s disease in patients with bipolar disorder could relate to long-term lithium use, rather than being a causal relationship. “However, treatment with lithium is foundational in bipolar disorder, and so to separate the causal effect from a potential confounder would be particularly difficult,” they wrote.

One of the studies included did explore the use of lithium, and found that lithium monotherapy was associated with a significant increase in the risk of being diagnosed with Parkinson’s disease or taking antiparkinsonism medication, compared with antidepressant therapy. However the authors commented that the diagnostic code may not differentiate Parkinson’s disease from other causes of parkinsonism.

Given their findings, the authors suggested that, if patients with bipolar disorder present with parkinsonism features, it may not necessarily be drug induced. In these patients, they recommended an investigation for Parkinson’s disease, perhaps using functional neuroimaging “as Parkinson’s disease classically presents with nigrostriatal degeneration while drug-induced parkinsonism does not.”

Two authors declared grants and personal fees from the pharmaceutical sector. No other conflicts of interest were reported.

SOURCE: Faustino PR et al. JAMA Neurol. 2019 Oct 14. doi: 10.1001/jamaneurol.2019.3446.

Patients with bipolar disorder may be at increased risk of Parkinson’s disease in later life, according to a systematic review and meta-analysis published in JAMA Neurology.

Patrícia R. Faustino, MD, from the faculty of medicine at the University of Lisboa (Portgual), and coauthors reviewed and analyzed seven articles – four cohort studies and three cross-sectional studies – that reported data on idiopathic Parkinson’s disease in patients with bipolar disorder, compared with those without. The meta-analysis found that individuals with a previous diagnosis of bipolar disorder had a 235% higher risk of being later diagnosed with Parkinson’s disease. Even after removing studies with a high risk of bias, the risk was still 3.21 times higher in those with bipolar disorder, compared with those without.

“The pathophysiological rationale between bipolar disorder and Parkinson’s disease might be explained by the dopamine dysregulation hypothesis, which states that the cyclical process of bipolar disorder in manic states leads to a down-regulation of dopamine receptor sensitivity (depression phase), which is later compensated by up-regulation (manic state),” the authors wrote. “Over time, this phenomenon may lead to an overall reduction of dopaminergic activity, the prototypical Parkinson’s disease state.”

Subgroup analysis revealed that subgroups with shorter follow-up periods – less than 9 years – had a greater increase in the risk of a later Parkinson’s disease diagnosis. The authors noted that this could represent misdiagnosis of parkinsonism – possibly drug induced – as Parkinson’s disease. The researchers also raised the possibility that the increased risk of Parkinson’s disease in patients with bipolar disorder could relate to long-term lithium use, rather than being a causal relationship. “However, treatment with lithium is foundational in bipolar disorder, and so to separate the causal effect from a potential confounder would be particularly difficult,” they wrote.

One of the studies included did explore the use of lithium, and found that lithium monotherapy was associated with a significant increase in the risk of being diagnosed with Parkinson’s disease or taking antiparkinsonism medication, compared with antidepressant therapy. However the authors commented that the diagnostic code may not differentiate Parkinson’s disease from other causes of parkinsonism.

Given their findings, the authors suggested that, if patients with bipolar disorder present with parkinsonism features, it may not necessarily be drug induced. In these patients, they recommended an investigation for Parkinson’s disease, perhaps using functional neuroimaging “as Parkinson’s disease classically presents with nigrostriatal degeneration while drug-induced parkinsonism does not.”

Two authors declared grants and personal fees from the pharmaceutical sector. No other conflicts of interest were reported.

SOURCE: Faustino PR et al. JAMA Neurol. 2019 Oct 14. doi: 10.1001/jamaneurol.2019.3446.

Patients with bipolar disorder may be at increased risk of Parkinson’s disease in later life, according to a systematic review and meta-analysis published in JAMA Neurology.

Patrícia R. Faustino, MD, from the faculty of medicine at the University of Lisboa (Portgual), and coauthors reviewed and analyzed seven articles – four cohort studies and three cross-sectional studies – that reported data on idiopathic Parkinson’s disease in patients with bipolar disorder, compared with those without. The meta-analysis found that individuals with a previous diagnosis of bipolar disorder had a 235% higher risk of being later diagnosed with Parkinson’s disease. Even after removing studies with a high risk of bias, the risk was still 3.21 times higher in those with bipolar disorder, compared with those without.

“The pathophysiological rationale between bipolar disorder and Parkinson’s disease might be explained by the dopamine dysregulation hypothesis, which states that the cyclical process of bipolar disorder in manic states leads to a down-regulation of dopamine receptor sensitivity (depression phase), which is later compensated by up-regulation (manic state),” the authors wrote. “Over time, this phenomenon may lead to an overall reduction of dopaminergic activity, the prototypical Parkinson’s disease state.”

Subgroup analysis revealed that subgroups with shorter follow-up periods – less than 9 years – had a greater increase in the risk of a later Parkinson’s disease diagnosis. The authors noted that this could represent misdiagnosis of parkinsonism – possibly drug induced – as Parkinson’s disease. The researchers also raised the possibility that the increased risk of Parkinson’s disease in patients with bipolar disorder could relate to long-term lithium use, rather than being a causal relationship. “However, treatment with lithium is foundational in bipolar disorder, and so to separate the causal effect from a potential confounder would be particularly difficult,” they wrote.

One of the studies included did explore the use of lithium, and found that lithium monotherapy was associated with a significant increase in the risk of being diagnosed with Parkinson’s disease or taking antiparkinsonism medication, compared with antidepressant therapy. However the authors commented that the diagnostic code may not differentiate Parkinson’s disease from other causes of parkinsonism.

Given their findings, the authors suggested that, if patients with bipolar disorder present with parkinsonism features, it may not necessarily be drug induced. In these patients, they recommended an investigation for Parkinson’s disease, perhaps using functional neuroimaging “as Parkinson’s disease classically presents with nigrostriatal degeneration while drug-induced parkinsonism does not.”

Two authors declared grants and personal fees from the pharmaceutical sector. No other conflicts of interest were reported.

SOURCE: Faustino PR et al. JAMA Neurol. 2019 Oct 14. doi: 10.1001/jamaneurol.2019.3446.

Applying diagnostic criteria for amnestic mild cognitive impairment (aMCI) that do not account for sex differences in verbal memory performance leads to an approximately 20% rate of misdiagnosis, according to an investigation published Oct. 9 in Neurology. Using sex-specific cut scores to define verbal memory impairment improves diagnostic accuracy and “may result in earlier detection of memory impairment in women and avoid false diagnoses in men,” wrote Erin E. Sundermann, PhD, assistant project scientist in psychiatry at the University of California, San Diego, and colleagues.

A diagnosis of aMCI generally requires a verbal memory deficit. Ample research demonstrates a female advantage on verbal memory tests, but normative data for these tests usually do not adjust for sex. Dr. Sundermann and colleagues previously showed that among men and women with aMCI and similar disease burden, women perform better on tests of verbal memory. Given these results, the investigators initiated a new study to test the hypothesis that using sex-specific norms and cut scores to identify memory impairment improves the accuracy of aMCI diagnosis, compared with non–sex-specific norms and cut scores.
 

An examination of ADNI data

Dr. Sundermann’s group extracted cross-sectional data from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database in October 2016. They included participants without dementia for whom neuropsychologic and Alzheimer’s disease pathologic marker data were available at baseline. They excluded patients with a non-aMCI diagnosis based on typical and sex-specific criteria.

The researchers’ primary outcome was the Rey Auditory Verbal Learning Test (RAVLT). They also determined the presence or absence of the APOE e4 allele for each participant. Biomarker outcomes included the CSF ratio of hyperphosphorylated tau (p-tau) to beta-amyloid (A-beta), and cortical A-beta deposition.

Dr. Sundermann and colleagues applied the Jak/Bondi actuarial neuropsychologic diagnostic method to baseline data. This method relies on six neuropsychologic tests, including the RAVLT Learning and Delayed Recall. They subsequently derived two sets of normative data for the RAVLT outcomes in a normative sample of 1,620 patients enrolled in the Mayo Clinic Study of Aging (MCSA). The latter patients were considered normal controls at baseline and at least two follow-up visits at 15 months apart. One set of normative data was specific for age and education, and the other was specific for age, education, and sex. Dr. Sundermann’s group next applied the typical Jak/Bondi method and the sex-specific Jak/Bondi method to all ADNI participants’ data.
 

Biomarker analysis supported the hypothesis

The researchers included 985 participants (453 women) in their final sample. Approximately 94% of the population was white. Mean age was 72.9 years, and mean education duration was 16.3 years. Overall, women had a significantly lower mean age (71.9 years vs. 73.6 years), significantly fewer mean years of education (15.7 years vs. 16.7 years), and a significantly higher mean Mini-Mental State Examination score (28 vs. 28.1) compared with men. Compared with men’s scores, women’s scores on the RAVLT Learning (mean 42.3 vs. mean 35.6) and Delayed Recall (mean 6.2 vs. mean 4.5) were significantly higher.

When Dr. Sundermann and colleagues used typical cut scores, the frequency of aMCI diagnosis was significantly higher in men. Using sex-specific cut scores eliminated this sex difference, however. Among men, 184 (35%) were categorized as true positive, 293 (55%) as true negative, and 55 (10%) as false positive. No men were categorized as false negative. Among women, 120 (26%) were categorized as true positive, 288 (64%) as true negative, and 45 (10%) as false negative. No women were categorized as false positive.

The likelihood of cortical amyloid positivity in false negative women was 3.6 times greater than in true negative women but did not differ from that in true positive women. The likelihood of positivity for the CSF p-tau/A-beta ratio in false negative women was more than two times higher than in true negative women but did not differ from that in true positive women. The likelihood of having an APOE e4 allele in false negative women was almost fivefold higher than in true negative women but did not differ from that in true positive women.

The likelihood of cortical amyloid positivity in false positive men was less than that in true positive men (odds ratio [OR], 0.45) but did not differ from that in true negative men. The likelihood of positivity for CSF p-tau/A-beta ratio in false positive men was significantly less than in true positive men (OR, 0.47) but did not differ from that in true negative men. The likelihood of having the APOE e4 allele in false positive men was lower than that in true positive men (OR, 0.63) and higher than that in true negative men (OR, 1.50), but not significantly.
 

Results have implications for treatment

“If these results are confirmed, they have vital implications,” Dr. Sundermann said in a press release. “If women are inaccurately identified as having no problems with memory and thinking skills when they actually have MCI, then treatments are not being started, and they and their families are not planning ahead for their care or their financial or legal situations. And for men who are inaccurately diagnosed with MCI, they can be exposed to unneeded medications along with undue stress for them and their families.”

Among the limitations that the investigators acknowledged was the study’s cross-sectional, rather than longitudinal, design. In addition, the ADNI population that the researchers examined is a convenience sample of predominantly white and well-educated volunteers. The results therefore may not be generalizable to the broader U.S. population, wrote the authors.

Grants from the National Institutes of Health funded the study. Several of the investigators reported receiving honoraria from various pharmaceutical companies such as Mylan. One investigator sits on the editorial board for Neurology.

[email protected]

SOURCE: Sundermann EE et al. Neurology. 2019 Oct 9.

Applying diagnostic criteria for amnestic mild cognitive impairment (aMCI) that do not account for sex differences in verbal memory performance leads to an approximately 20% rate of misdiagnosis, according to an investigation published Oct. 9 in Neurology. Using sex-specific cut scores to define verbal memory impairment improves diagnostic accuracy and “may result in earlier detection of memory impairment in women and avoid false diagnoses in men,” wrote Erin E. Sundermann, PhD, assistant project scientist in psychiatry at the University of California, San Diego, and colleagues.

A diagnosis of aMCI generally requires a verbal memory deficit. Ample research demonstrates a female advantage on verbal memory tests, but normative data for these tests usually do not adjust for sex. Dr. Sundermann and colleagues previously showed that among men and women with aMCI and similar disease burden, women perform better on tests of verbal memory. Given these results, the investigators initiated a new study to test the hypothesis that using sex-specific norms and cut scores to identify memory impairment improves the accuracy of aMCI diagnosis, compared with non–sex-specific norms and cut scores.
 

An examination of ADNI data

Dr. Sundermann’s group extracted cross-sectional data from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database in October 2016. They included participants without dementia for whom neuropsychologic and Alzheimer’s disease pathologic marker data were available at baseline. They excluded patients with a non-aMCI diagnosis based on typical and sex-specific criteria.

The researchers’ primary outcome was the Rey Auditory Verbal Learning Test (RAVLT). They also determined the presence or absence of the APOE e4 allele for each participant. Biomarker outcomes included the CSF ratio of hyperphosphorylated tau (p-tau) to beta-amyloid (A-beta), and cortical A-beta deposition.

Dr. Sundermann and colleagues applied the Jak/Bondi actuarial neuropsychologic diagnostic method to baseline data. This method relies on six neuropsychologic tests, including the RAVLT Learning and Delayed Recall. They subsequently derived two sets of normative data for the RAVLT outcomes in a normative sample of 1,620 patients enrolled in the Mayo Clinic Study of Aging (MCSA). The latter patients were considered normal controls at baseline and at least two follow-up visits at 15 months apart. One set of normative data was specific for age and education, and the other was specific for age, education, and sex. Dr. Sundermann’s group next applied the typical Jak/Bondi method and the sex-specific Jak/Bondi method to all ADNI participants’ data.
 

Biomarker analysis supported the hypothesis

The researchers included 985 participants (453 women) in their final sample. Approximately 94% of the population was white. Mean age was 72.9 years, and mean education duration was 16.3 years. Overall, women had a significantly lower mean age (71.9 years vs. 73.6 years), significantly fewer mean years of education (15.7 years vs. 16.7 years), and a significantly higher mean Mini-Mental State Examination score (28 vs. 28.1) compared with men. Compared with men’s scores, women’s scores on the RAVLT Learning (mean 42.3 vs. mean 35.6) and Delayed Recall (mean 6.2 vs. mean 4.5) were significantly higher.

When Dr. Sundermann and colleagues used typical cut scores, the frequency of aMCI diagnosis was significantly higher in men. Using sex-specific cut scores eliminated this sex difference, however. Among men, 184 (35%) were categorized as true positive, 293 (55%) as true negative, and 55 (10%) as false positive. No men were categorized as false negative. Among women, 120 (26%) were categorized as true positive, 288 (64%) as true negative, and 45 (10%) as false negative. No women were categorized as false positive.

The likelihood of cortical amyloid positivity in false negative women was 3.6 times greater than in true negative women but did not differ from that in true positive women. The likelihood of positivity for the CSF p-tau/A-beta ratio in false negative women was more than two times higher than in true negative women but did not differ from that in true positive women. The likelihood of having an APOE e4 allele in false negative women was almost fivefold higher than in true negative women but did not differ from that in true positive women.

The likelihood of cortical amyloid positivity in false positive men was less than that in true positive men (odds ratio [OR], 0.45) but did not differ from that in true negative men. The likelihood of positivity for CSF p-tau/A-beta ratio in false positive men was significantly less than in true positive men (OR, 0.47) but did not differ from that in true negative men. The likelihood of having the APOE e4 allele in false positive men was lower than that in true positive men (OR, 0.63) and higher than that in true negative men (OR, 1.50), but not significantly.
 

Results have implications for treatment

“If these results are confirmed, they have vital implications,” Dr. Sundermann said in a press release. “If women are inaccurately identified as having no problems with memory and thinking skills when they actually have MCI, then treatments are not being started, and they and their families are not planning ahead for their care or their financial or legal situations. And for men who are inaccurately diagnosed with MCI, they can be exposed to unneeded medications along with undue stress for them and their families.”

Among the limitations that the investigators acknowledged was the study’s cross-sectional, rather than longitudinal, design. In addition, the ADNI population that the researchers examined is a convenience sample of predominantly white and well-educated volunteers. The results therefore may not be generalizable to the broader U.S. population, wrote the authors.

Grants from the National Institutes of Health funded the study. Several of the investigators reported receiving honoraria from various pharmaceutical companies such as Mylan. One investigator sits on the editorial board for Neurology.

[email protected]

SOURCE: Sundermann EE et al. Neurology. 2019 Oct 9.

Applying diagnostic criteria for amnestic mild cognitive impairment (aMCI) that do not account for sex differences in verbal memory performance leads to an approximately 20% rate of misdiagnosis, according to an investigation published Oct. 9 in Neurology. Using sex-specific cut scores to define verbal memory impairment improves diagnostic accuracy and “may result in earlier detection of memory impairment in women and avoid false diagnoses in men,” wrote Erin E. Sundermann, PhD, assistant project scientist in psychiatry at the University of California, San Diego, and colleagues.

A diagnosis of aMCI generally requires a verbal memory deficit. Ample research demonstrates a female advantage on verbal memory tests, but normative data for these tests usually do not adjust for sex. Dr. Sundermann and colleagues previously showed that among men and women with aMCI and similar disease burden, women perform better on tests of verbal memory. Given these results, the investigators initiated a new study to test the hypothesis that using sex-specific norms and cut scores to identify memory impairment improves the accuracy of aMCI diagnosis, compared with non–sex-specific norms and cut scores.
 

An examination of ADNI data

Dr. Sundermann’s group extracted cross-sectional data from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database in October 2016. They included participants without dementia for whom neuropsychologic and Alzheimer’s disease pathologic marker data were available at baseline. They excluded patients with a non-aMCI diagnosis based on typical and sex-specific criteria.

The researchers’ primary outcome was the Rey Auditory Verbal Learning Test (RAVLT). They also determined the presence or absence of the APOE e4 allele for each participant. Biomarker outcomes included the CSF ratio of hyperphosphorylated tau (p-tau) to beta-amyloid (A-beta), and cortical A-beta deposition.

Dr. Sundermann and colleagues applied the Jak/Bondi actuarial neuropsychologic diagnostic method to baseline data. This method relies on six neuropsychologic tests, including the RAVLT Learning and Delayed Recall. They subsequently derived two sets of normative data for the RAVLT outcomes in a normative sample of 1,620 patients enrolled in the Mayo Clinic Study of Aging (MCSA). The latter patients were considered normal controls at baseline and at least two follow-up visits at 15 months apart. One set of normative data was specific for age and education, and the other was specific for age, education, and sex. Dr. Sundermann’s group next applied the typical Jak/Bondi method and the sex-specific Jak/Bondi method to all ADNI participants’ data.
 

Biomarker analysis supported the hypothesis

The researchers included 985 participants (453 women) in their final sample. Approximately 94% of the population was white. Mean age was 72.9 years, and mean education duration was 16.3 years. Overall, women had a significantly lower mean age (71.9 years vs. 73.6 years), significantly fewer mean years of education (15.7 years vs. 16.7 years), and a significantly higher mean Mini-Mental State Examination score (28 vs. 28.1) compared with men. Compared with men’s scores, women’s scores on the RAVLT Learning (mean 42.3 vs. mean 35.6) and Delayed Recall (mean 6.2 vs. mean 4.5) were significantly higher.

When Dr. Sundermann and colleagues used typical cut scores, the frequency of aMCI diagnosis was significantly higher in men. Using sex-specific cut scores eliminated this sex difference, however. Among men, 184 (35%) were categorized as true positive, 293 (55%) as true negative, and 55 (10%) as false positive. No men were categorized as false negative. Among women, 120 (26%) were categorized as true positive, 288 (64%) as true negative, and 45 (10%) as false negative. No women were categorized as false positive.

The likelihood of cortical amyloid positivity in false negative women was 3.6 times greater than in true negative women but did not differ from that in true positive women. The likelihood of positivity for the CSF p-tau/A-beta ratio in false negative women was more than two times higher than in true negative women but did not differ from that in true positive women. The likelihood of having an APOE e4 allele in false negative women was almost fivefold higher than in true negative women but did not differ from that in true positive women.

The likelihood of cortical amyloid positivity in false positive men was less than that in true positive men (odds ratio [OR], 0.45) but did not differ from that in true negative men. The likelihood of positivity for CSF p-tau/A-beta ratio in false positive men was significantly less than in true positive men (OR, 0.47) but did not differ from that in true negative men. The likelihood of having the APOE e4 allele in false positive men was lower than that in true positive men (OR, 0.63) and higher than that in true negative men (OR, 1.50), but not significantly.
 

Results have implications for treatment

“If these results are confirmed, they have vital implications,” Dr. Sundermann said in a press release. “If women are inaccurately identified as having no problems with memory and thinking skills when they actually have MCI, then treatments are not being started, and they and their families are not planning ahead for their care or their financial or legal situations. And for men who are inaccurately diagnosed with MCI, they can be exposed to unneeded medications along with undue stress for them and their families.”

Among the limitations that the investigators acknowledged was the study’s cross-sectional, rather than longitudinal, design. In addition, the ADNI population that the researchers examined is a convenience sample of predominantly white and well-educated volunteers. The results therefore may not be generalizable to the broader U.S. population, wrote the authors.

Grants from the National Institutes of Health funded the study. Several of the investigators reported receiving honoraria from various pharmaceutical companies such as Mylan. One investigator sits on the editorial board for Neurology.

[email protected]

SOURCE: Sundermann EE et al. Neurology. 2019 Oct 9.

Randomized trials are needed to determine the optimal treatment approach for early stage follicular lymphoma (FL), according to researchers.

Patho/Wikimedia Commons/CC BY-SA 3.0(http://creativecommons.org/licenses/by-sa/3.0)], via Wikimedia Commons

A retrospective study showed similar outcomes among patients who received radiotherapy, immunochemotherapy, combined modality treatment (CMT), and watchful waiting (WW).

There were some differences in progression-free survival (PFS) according to treatment approach. However, there were no significant differences in overall survival (OS) between any of the active treatments or between patients who received active treatment and those managed with WW.

Joshua W. D. Tobin, MD, of Princess Alexandra Hospital in Brisbane, Queensland, Australia, and colleagues conducted this research and reported the results in Blood Advances.

The researchers analyzed 365 patients with newly diagnosed, stage I/II FL. The patients had a median age of 63 years and more than half were men. They were diagnosed between 2005 and 2017, and the median follow-up was 45 months.

Most patients (n = 280) received active treatment, but 85 were managed with WW. The WW patients were older and had more extranodal involvement.

Types of active treatment included radiotherapy alone (n = 171), immunochemotherapy alone (n = 63), and CMT (n = 46). Compared with the other groups, patients who received radiotherapy alone had less bulk, fewer nodal sites, and fewer B symptoms, and were more likely to have stage I disease. Patients who received CMT had fewer B symptoms and lower FLIPI scores compared with patients who received immunochemotherapy.

The immunochemotherapy regimens used were largely rituximab based. In all, 106 patients received rituximab (alone or in combination) for induction, and 49 received maintenance rituximab (37 in the immunochemotherapy group and 12 in the CMT group).

Results

Response rates were similar among the active treatment groups. The overall response rate was 95% in the radiotherapy group, 96% in the immunochemotherapy group, and 95% in the CMT group (P = .87).

There was a significant difference in PFS between the radiotherapy, immunochemotherapy, and CMT groups (P = .023), but there was no difference in OS between these groups (P = .38).

There was no significant difference in PFS between the immunochemotherapy and CMT groups (hazard ratio [HR], 1.78; P = .24), so the researchers combined these groups into a single group called “systemic therapy.” The patients treated with systemic therapy had PFS (HR, 1.32; P = .96) and OS (HR, 0.46; P = .21) similar to that of patients treated with radiotherapy alone.

Maintenance rituximab was associated with prolonged PFS among patients treated with systemic therapy (HR, 0.24; P = .017). However, there was no significant difference in OS between patients who received maintenance and those who did not (HR, 0.89; P = .90).

Relapse was less common among patients who received maintenance, and there were no cases of transformation in that group. Relapse occurred in 24.6% of the radiotherapy group, 18.3% of the systemic therapy group, and 4.1% of the group that received systemic therapy plus maintenance (P = .006). Transformation was less likely in the systemic therapy group (1.8%) than in the radiotherapy (6.4%) and WW (9.4%) groups (HR, 0.20; P = .034).

Overall, the active treatment group had better PFS than the WW group (HR, 0.52; P = .002), but there was no significant difference in OS between the groups (HR, 0.94; P = .90).

“Based on our comparable OS between WW and actively treated patients, WW could be considered as an initial management strategy in early stage FL,” Dr. Tobin and colleagues wrote. “However, long-term follow-up is required to determine if a survival benefit exists favoring active treatment.”

The researchers reported relationships with many pharmaceutical companies.

[email protected]

SOURCE: Tobin JWD et al. Blood Adv. 2019 Oct 8;3(19):2804-11.

Randomized trials are needed to determine the optimal treatment approach for early stage follicular lymphoma (FL), according to researchers.

Patho/Wikimedia Commons/CC BY-SA 3.0(http://creativecommons.org/licenses/by-sa/3.0)], via Wikimedia Commons

A retrospective study showed similar outcomes among patients who received radiotherapy, immunochemotherapy, combined modality treatment (CMT), and watchful waiting (WW).

There were some differences in progression-free survival (PFS) according to treatment approach. However, there were no significant differences in overall survival (OS) between any of the active treatments or between patients who received active treatment and those managed with WW.

Joshua W. D. Tobin, MD, of Princess Alexandra Hospital in Brisbane, Queensland, Australia, and colleagues conducted this research and reported the results in Blood Advances.

The researchers analyzed 365 patients with newly diagnosed, stage I/II FL. The patients had a median age of 63 years and more than half were men. They were diagnosed between 2005 and 2017, and the median follow-up was 45 months.

Most patients (n = 280) received active treatment, but 85 were managed with WW. The WW patients were older and had more extranodal involvement.

Types of active treatment included radiotherapy alone (n = 171), immunochemotherapy alone (n = 63), and CMT (n = 46). Compared with the other groups, patients who received radiotherapy alone had less bulk, fewer nodal sites, and fewer B symptoms, and were more likely to have stage I disease. Patients who received CMT had fewer B symptoms and lower FLIPI scores compared with patients who received immunochemotherapy.

The immunochemotherapy regimens used were largely rituximab based. In all, 106 patients received rituximab (alone or in combination) for induction, and 49 received maintenance rituximab (37 in the immunochemotherapy group and 12 in the CMT group).

Results

Response rates were similar among the active treatment groups. The overall response rate was 95% in the radiotherapy group, 96% in the immunochemotherapy group, and 95% in the CMT group (P = .87).

There was a significant difference in PFS between the radiotherapy, immunochemotherapy, and CMT groups (P = .023), but there was no difference in OS between these groups (P = .38).

There was no significant difference in PFS between the immunochemotherapy and CMT groups (hazard ratio [HR], 1.78; P = .24), so the researchers combined these groups into a single group called “systemic therapy.” The patients treated with systemic therapy had PFS (HR, 1.32; P = .96) and OS (HR, 0.46; P = .21) similar to that of patients treated with radiotherapy alone.

Maintenance rituximab was associated with prolonged PFS among patients treated with systemic therapy (HR, 0.24; P = .017). However, there was no significant difference in OS between patients who received maintenance and those who did not (HR, 0.89; P = .90).

Relapse was less common among patients who received maintenance, and there were no cases of transformation in that group. Relapse occurred in 24.6% of the radiotherapy group, 18.3% of the systemic therapy group, and 4.1% of the group that received systemic therapy plus maintenance (P = .006). Transformation was less likely in the systemic therapy group (1.8%) than in the radiotherapy (6.4%) and WW (9.4%) groups (HR, 0.20; P = .034).

Overall, the active treatment group had better PFS than the WW group (HR, 0.52; P = .002), but there was no significant difference in OS between the groups (HR, 0.94; P = .90).

“Based on our comparable OS between WW and actively treated patients, WW could be considered as an initial management strategy in early stage FL,” Dr. Tobin and colleagues wrote. “However, long-term follow-up is required to determine if a survival benefit exists favoring active treatment.”

The researchers reported relationships with many pharmaceutical companies.

[email protected]

SOURCE: Tobin JWD et al. Blood Adv. 2019 Oct 8;3(19):2804-11.

Randomized trials are needed to determine the optimal treatment approach for early stage follicular lymphoma (FL), according to researchers.

Patho/Wikimedia Commons/CC BY-SA 3.0(http://creativecommons.org/licenses/by-sa/3.0)], via Wikimedia Commons

A retrospective study showed similar outcomes among patients who received radiotherapy, immunochemotherapy, combined modality treatment (CMT), and watchful waiting (WW).

There were some differences in progression-free survival (PFS) according to treatment approach. However, there were no significant differences in overall survival (OS) between any of the active treatments or between patients who received active treatment and those managed with WW.

Joshua W. D. Tobin, MD, of Princess Alexandra Hospital in Brisbane, Queensland, Australia, and colleagues conducted this research and reported the results in Blood Advances.

The researchers analyzed 365 patients with newly diagnosed, stage I/II FL. The patients had a median age of 63 years and more than half were men. They were diagnosed between 2005 and 2017, and the median follow-up was 45 months.

Most patients (n = 280) received active treatment, but 85 were managed with WW. The WW patients were older and had more extranodal involvement.

Types of active treatment included radiotherapy alone (n = 171), immunochemotherapy alone (n = 63), and CMT (n = 46). Compared with the other groups, patients who received radiotherapy alone had less bulk, fewer nodal sites, and fewer B symptoms, and were more likely to have stage I disease. Patients who received CMT had fewer B symptoms and lower FLIPI scores compared with patients who received immunochemotherapy.

The immunochemotherapy regimens used were largely rituximab based. In all, 106 patients received rituximab (alone or in combination) for induction, and 49 received maintenance rituximab (37 in the immunochemotherapy group and 12 in the CMT group).

Results

Response rates were similar among the active treatment groups. The overall response rate was 95% in the radiotherapy group, 96% in the immunochemotherapy group, and 95% in the CMT group (P = .87).

There was a significant difference in PFS between the radiotherapy, immunochemotherapy, and CMT groups (P = .023), but there was no difference in OS between these groups (P = .38).

There was no significant difference in PFS between the immunochemotherapy and CMT groups (hazard ratio [HR], 1.78; P = .24), so the researchers combined these groups into a single group called “systemic therapy.” The patients treated with systemic therapy had PFS (HR, 1.32; P = .96) and OS (HR, 0.46; P = .21) similar to that of patients treated with radiotherapy alone.

Maintenance rituximab was associated with prolonged PFS among patients treated with systemic therapy (HR, 0.24; P = .017). However, there was no significant difference in OS between patients who received maintenance and those who did not (HR, 0.89; P = .90).

Relapse was less common among patients who received maintenance, and there were no cases of transformation in that group. Relapse occurred in 24.6% of the radiotherapy group, 18.3% of the systemic therapy group, and 4.1% of the group that received systemic therapy plus maintenance (P = .006). Transformation was less likely in the systemic therapy group (1.8%) than in the radiotherapy (6.4%) and WW (9.4%) groups (HR, 0.20; P = .034).

Overall, the active treatment group had better PFS than the WW group (HR, 0.52; P = .002), but there was no significant difference in OS between the groups (HR, 0.94; P = .90).

“Based on our comparable OS between WW and actively treated patients, WW could be considered as an initial management strategy in early stage FL,” Dr. Tobin and colleagues wrote. “However, long-term follow-up is required to determine if a survival benefit exists favoring active treatment.”

The researchers reported relationships with many pharmaceutical companies.

[email protected]

SOURCE: Tobin JWD et al. Blood Adv. 2019 Oct 8;3(19):2804-11.

Acalabrutinib monotherapy can produce durable responses in relapsed/refractory mantle cell lymphoma (MCL), according to updated results from a phase 2 trial.

Wikimedia Commons/TexasPathologistMSW/CC-ASA 4.0 International

The drug produced an overall response rate (ORR) of 81%, and the median duration of response was 26 months.

These are the highest such figures reported “among all approved single-agent therapies for the treatment of relapsed/refractory MCL,” Michael Wang, MD, of the MD Anderson Cancer Center at the University of Texas in Houston and colleagues wrote in a letter in Leukemia.

Dr. Wang and colleagues reported updated results in 124 patients treated on the ACE-LY-004 trial. At baseline, the patients had a median age of 68 years (range, 42-90 years), and 80% were men. Three-quarters of patients had stage IV disease, 72% had extranodal disease, 21% had blastoid/pleomorphic MCL, and 26% had a Ki-67 proliferation index of 50% or greater.

At a median follow-up of 26 months, 40% (n = 49) of patients were still on acalabrutinib, and 61% (n = 76) were still in follow-up for survival. Six patients went on to allogeneic transplant at a median of 19 days after stopping acalabrutinib.

The ORR was 81% (100/124), and the complete response (CR) rate was 43% (n = 53). Four patients who initially had a partial response converted to a CR with longer follow-up. The estimated 24-month duration of response was 52.4%.

“ORR was consistent across patients with refractory disease and those with blastoid/pleomorphic MCL, despite those patients having a higher mean Ki-67 index [of 50% or greater], suggesting that some patients with poorer prognosis may also benefit from acalabrutinib,” Dr. Wang and colleagues wrote.

There were 29 patients evaluable for minimal residual disease (MRD) assessment. Seven patients (24%) had MRD-negative disease in the peripheral blood after they achieved a CR. An additional patient with a CR became MRD negative when a second blood sample was taken about 6 months after the first.

“Despite limited samples, these results demonstrate that continued use of acalabrutinib can lead to undetectable MRD in patients with CR,” Dr. Wang and his colleagues wrote. “Since most patients with MRD data are still on treatment (27/29), relationships between MRD negativity and durability of response cannot be made at this time.”

The median progression-free survival was 20 months, and the median overall survival was not reached. The estimated 24-month progression-free survival rate was 49.0%, and the estimated 24-month overall survival rate was 72.4%. Patients with low/intermediate Mantle Cell Lymphoma International Prognostic Index scores, classical MCL, and a Ki-67 index less than 50% had a longer duration of response and survival.

The adverse event profile was “largely consistent with earlier reporting,” Dr. Wang and colleagues wrote. The most frequent adverse events were headache (38%), diarrhea (36%), fatigue (28%), cough (22%), and myalgia (21%). The most common grade 3/4 adverse events were anemia (10%), neutropenia (10%), and pneumonia (6%).

Ten patients developed second primary cancers. There were no new atrial fibrillation events and no new hypertension events. The frequency of infections decreased over time, as did the number of bleeding events. However, two of three major hemorrhage events occurred after the previous report was published.

There were 43 deaths (35%), 29 of them because of disease progression. Six patients died of adverse events, two died of unknown causes, and two died of secondary acute myeloid leukemia. Other causes of death included multiorgan failure, intestinal obstruction, lung cancer, and graft-versus-host disease.

This study was sponsored by Acerta Pharma, a member of the AstraZeneca Group. The researchers reported relationships with AstraZeneca/Acerta Pharma and many other companies.

[email protected]

SOURCE: Wang M et al. Leukemia. 2019 Sep 26. doi: 10.1038/s41375-019-0575-9.

Acalabrutinib monotherapy can produce durable responses in relapsed/refractory mantle cell lymphoma (MCL), according to updated results from a phase 2 trial.

Wikimedia Commons/TexasPathologistMSW/CC-ASA 4.0 International

The drug produced an overall response rate (ORR) of 81%, and the median duration of response was 26 months.

These are the highest such figures reported “among all approved single-agent therapies for the treatment of relapsed/refractory MCL,” Michael Wang, MD, of the MD Anderson Cancer Center at the University of Texas in Houston and colleagues wrote in a letter in Leukemia.

Dr. Wang and colleagues reported updated results in 124 patients treated on the ACE-LY-004 trial. At baseline, the patients had a median age of 68 years (range, 42-90 years), and 80% were men. Three-quarters of patients had stage IV disease, 72% had extranodal disease, 21% had blastoid/pleomorphic MCL, and 26% had a Ki-67 proliferation index of 50% or greater.

At a median follow-up of 26 months, 40% (n = 49) of patients were still on acalabrutinib, and 61% (n = 76) were still in follow-up for survival. Six patients went on to allogeneic transplant at a median of 19 days after stopping acalabrutinib.

The ORR was 81% (100/124), and the complete response (CR) rate was 43% (n = 53). Four patients who initially had a partial response converted to a CR with longer follow-up. The estimated 24-month duration of response was 52.4%.

“ORR was consistent across patients with refractory disease and those with blastoid/pleomorphic MCL, despite those patients having a higher mean Ki-67 index [of 50% or greater], suggesting that some patients with poorer prognosis may also benefit from acalabrutinib,” Dr. Wang and colleagues wrote.

There were 29 patients evaluable for minimal residual disease (MRD) assessment. Seven patients (24%) had MRD-negative disease in the peripheral blood after they achieved a CR. An additional patient with a CR became MRD negative when a second blood sample was taken about 6 months after the first.

“Despite limited samples, these results demonstrate that continued use of acalabrutinib can lead to undetectable MRD in patients with CR,” Dr. Wang and his colleagues wrote. “Since most patients with MRD data are still on treatment (27/29), relationships between MRD negativity and durability of response cannot be made at this time.”

The median progression-free survival was 20 months, and the median overall survival was not reached. The estimated 24-month progression-free survival rate was 49.0%, and the estimated 24-month overall survival rate was 72.4%. Patients with low/intermediate Mantle Cell Lymphoma International Prognostic Index scores, classical MCL, and a Ki-67 index less than 50% had a longer duration of response and survival.

The adverse event profile was “largely consistent with earlier reporting,” Dr. Wang and colleagues wrote. The most frequent adverse events were headache (38%), diarrhea (36%), fatigue (28%), cough (22%), and myalgia (21%). The most common grade 3/4 adverse events were anemia (10%), neutropenia (10%), and pneumonia (6%).

Ten patients developed second primary cancers. There were no new atrial fibrillation events and no new hypertension events. The frequency of infections decreased over time, as did the number of bleeding events. However, two of three major hemorrhage events occurred after the previous report was published.

There were 43 deaths (35%), 29 of them because of disease progression. Six patients died of adverse events, two died of unknown causes, and two died of secondary acute myeloid leukemia. Other causes of death included multiorgan failure, intestinal obstruction, lung cancer, and graft-versus-host disease.

This study was sponsored by Acerta Pharma, a member of the AstraZeneca Group. The researchers reported relationships with AstraZeneca/Acerta Pharma and many other companies.

[email protected]

SOURCE: Wang M et al. Leukemia. 2019 Sep 26. doi: 10.1038/s41375-019-0575-9.

Acalabrutinib monotherapy can produce durable responses in relapsed/refractory mantle cell lymphoma (MCL), according to updated results from a phase 2 trial.

Wikimedia Commons/TexasPathologistMSW/CC-ASA 4.0 International

The drug produced an overall response rate (ORR) of 81%, and the median duration of response was 26 months.

These are the highest such figures reported “among all approved single-agent therapies for the treatment of relapsed/refractory MCL,” Michael Wang, MD, of the MD Anderson Cancer Center at the University of Texas in Houston and colleagues wrote in a letter in Leukemia.

Dr. Wang and colleagues reported updated results in 124 patients treated on the ACE-LY-004 trial. At baseline, the patients had a median age of 68 years (range, 42-90 years), and 80% were men. Three-quarters of patients had stage IV disease, 72% had extranodal disease, 21% had blastoid/pleomorphic MCL, and 26% had a Ki-67 proliferation index of 50% or greater.

At a median follow-up of 26 months, 40% (n = 49) of patients were still on acalabrutinib, and 61% (n = 76) were still in follow-up for survival. Six patients went on to allogeneic transplant at a median of 19 days after stopping acalabrutinib.

The ORR was 81% (100/124), and the complete response (CR) rate was 43% (n = 53). Four patients who initially had a partial response converted to a CR with longer follow-up. The estimated 24-month duration of response was 52.4%.

“ORR was consistent across patients with refractory disease and those with blastoid/pleomorphic MCL, despite those patients having a higher mean Ki-67 index [of 50% or greater], suggesting that some patients with poorer prognosis may also benefit from acalabrutinib,” Dr. Wang and colleagues wrote.

There were 29 patients evaluable for minimal residual disease (MRD) assessment. Seven patients (24%) had MRD-negative disease in the peripheral blood after they achieved a CR. An additional patient with a CR became MRD negative when a second blood sample was taken about 6 months after the first.

“Despite limited samples, these results demonstrate that continued use of acalabrutinib can lead to undetectable MRD in patients with CR,” Dr. Wang and his colleagues wrote. “Since most patients with MRD data are still on treatment (27/29), relationships between MRD negativity and durability of response cannot be made at this time.”

The median progression-free survival was 20 months, and the median overall survival was not reached. The estimated 24-month progression-free survival rate was 49.0%, and the estimated 24-month overall survival rate was 72.4%. Patients with low/intermediate Mantle Cell Lymphoma International Prognostic Index scores, classical MCL, and a Ki-67 index less than 50% had a longer duration of response and survival.

The adverse event profile was “largely consistent with earlier reporting,” Dr. Wang and colleagues wrote. The most frequent adverse events were headache (38%), diarrhea (36%), fatigue (28%), cough (22%), and myalgia (21%). The most common grade 3/4 adverse events were anemia (10%), neutropenia (10%), and pneumonia (6%).

Ten patients developed second primary cancers. There were no new atrial fibrillation events and no new hypertension events. The frequency of infections decreased over time, as did the number of bleeding events. However, two of three major hemorrhage events occurred after the previous report was published.

There were 43 deaths (35%), 29 of them because of disease progression. Six patients died of adverse events, two died of unknown causes, and two died of secondary acute myeloid leukemia. Other causes of death included multiorgan failure, intestinal obstruction, lung cancer, and graft-versus-host disease.

This study was sponsored by Acerta Pharma, a member of the AstraZeneca Group. The researchers reported relationships with AstraZeneca/Acerta Pharma and many other companies.

[email protected]

SOURCE: Wang M et al. Leukemia. 2019 Sep 26. doi: 10.1038/s41375-019-0575-9.