CLL

An updated European Society for Medical Oncology (ESMO) clinical practice guidelines were released to provide key recommendations on the management of chronic lymphocytic leukemia (CLL).

The guidelines were developed by a multidisciplinary group of experts from different institutions and countries in Europe and provide levels of evidence and grades of recommendation where applicable for issues regarding prognosis and treatment decisions in CLL. Such decisions depend on genetic and clinical factors such as age, stage, and comorbidities. The guidelines also focus on new therapies targeting B-cell-receptor pathways or defect mechanism of apoptosis, which have been found to induce long-lasting remissions. The guidelines were endorsed by the European Hematology Association (EHA) through the Scientific Working Group on CLL/European Research Initiative on CLL (ERIC), according to the report published online the Annals of Oncology.

These clinical practice guidelines were developed in accordance with the ESMO standard operating procedures for clinical practice guidelines development with use of relevant literature selected by the expert authors. Statements without grading were considered justified as standard clinical practice by the experts and the ESMO faculty.

Below are some highlights of the guidelines, which cover a wide array of topics regarding the diagnosis, staging, treatment, and progression of CLL disease.
 

Diagnosis

The guidelines indicate that CLL diagnosis is usually possible by immunophenotyping of peripheral blood only and that lymph node (LN) biopsy and/or bone marrow biopsy may be helpful if immunophenotyping is not conclusive for the diagnosis of CLL, according to Barbara Eichhorst, MD, of the University of Cologne (Germany) and colleagues on behalf of the ESMO guidelines committee.

Staging and risk assessment

Early asymptomatic-stage disease does not need further risk assessment, but after the first year, when all patients should be seen at 3-monthly intervals, patients can be followed every 3-12 months. The interval would depend on burden and dynamics of the disease obtained by the using history and physical examinations, including a careful palpation of all LN areas, spleen, and liver, as well as assessing complete blood cell count and differential count, according to the report.

Advanced- and symptomatic-stage disease requires a broader examination including imaging, history and status of relevant infections, and fluorescent in situ hybridization (FISH) assays for the detection of deletion of the chromosome 17 (del[17p]) affecting the tumor protein p53 expression and, in the absence of del(17p), TP53 sequencing for detection of TP53 gene mutation, according to the authors.

Prognostication

Two clinical staging systems are typically used in CLL. Both Binet and Rai staging systems separate three groups of patients with different prognosis, although “as a consequence of more effective therapy, the overall survival (OS) of patients with advanced stage has improved and the relevance of the staging systems for prognostication has decreased,” according to the report.

The recent addition of genetic markers has also proved highly relevant to identifying patients with different prognoses and to guide treatment.
 

Therapy

Although CLL is an incurable disease, choice and application of treatment are strongly tied to the length of survival, according to the authors. The guidelines recommend Binet and Rai staging with clinical symptoms as relevant for treatment indication. In addition, the identification of del(17p), TP53 mutations, and IGHV status are relevant for choice of therapy and should be assessed prior to treatment.

The guidelines discuss specific treatment modalities for various stages of the disease, from early stages to relapse.

For frontline therapy, different treatment strategies are available including continuous treatment with Bruton tyrosine kinase (BTK)–inhibitors, such as ibrutinib, until progression or time-limited therapy with ChT backbone and CD20 antibodies. In addition, the Food and Drug Administration and European Medicines Agency have recently approved the combination of venetoclax plus obinutuzumab for first-line therapy of CLL.

Treatment decisions should include an assessment of IGHV and TP53 status, as well as patient-related factors such as comedication, comorbidities, preferences, drug availability, and potential of treatment adherence, according to the guidelines.

In case of symptomatic relapse within 3 years after fixed-duration therapy or nonresponse to therapy, the guidelines recommend that the therapeutic regimen should be changed, regardless of the type of first-line either to venetoclax plus rituximab for 24 months or to ibrutinib, acalabrutinib, or other BTK inhibitors (if available) as continuous therapy.

The guidelines also discuss the possible roles for hematopoietic stem cell transplantation and cellular therapies, as well as the treatment of the various complications that can arise in patients with CLL, and dealing with various aspects of disease progression.

No external funds were provided for the production of the guidelines. The authors of the report and members of the ESMO Guidelines Committee reported numerous disclosures regarding pharmaceutical and biotechnology companies.

[email protected]

SOURCE: Eichhorst B et al. Ann Oncol. 2020 Oct 19. doi: 10.1016/j.annonc.2020.09.019.

An updated European Society for Medical Oncology (ESMO) clinical practice guidelines were released to provide key recommendations on the management of chronic lymphocytic leukemia (CLL).

The guidelines were developed by a multidisciplinary group of experts from different institutions and countries in Europe and provide levels of evidence and grades of recommendation where applicable for issues regarding prognosis and treatment decisions in CLL. Such decisions depend on genetic and clinical factors such as age, stage, and comorbidities. The guidelines also focus on new therapies targeting B-cell-receptor pathways or defect mechanism of apoptosis, which have been found to induce long-lasting remissions. The guidelines were endorsed by the European Hematology Association (EHA) through the Scientific Working Group on CLL/European Research Initiative on CLL (ERIC), according to the report published online the Annals of Oncology.

These clinical practice guidelines were developed in accordance with the ESMO standard operating procedures for clinical practice guidelines development with use of relevant literature selected by the expert authors. Statements without grading were considered justified as standard clinical practice by the experts and the ESMO faculty.

Below are some highlights of the guidelines, which cover a wide array of topics regarding the diagnosis, staging, treatment, and progression of CLL disease.
 

Diagnosis

The guidelines indicate that CLL diagnosis is usually possible by immunophenotyping of peripheral blood only and that lymph node (LN) biopsy and/or bone marrow biopsy may be helpful if immunophenotyping is not conclusive for the diagnosis of CLL, according to Barbara Eichhorst, MD, of the University of Cologne (Germany) and colleagues on behalf of the ESMO guidelines committee.

Staging and risk assessment

Early asymptomatic-stage disease does not need further risk assessment, but after the first year, when all patients should be seen at 3-monthly intervals, patients can be followed every 3-12 months. The interval would depend on burden and dynamics of the disease obtained by the using history and physical examinations, including a careful palpation of all LN areas, spleen, and liver, as well as assessing complete blood cell count and differential count, according to the report.

Advanced- and symptomatic-stage disease requires a broader examination including imaging, history and status of relevant infections, and fluorescent in situ hybridization (FISH) assays for the detection of deletion of the chromosome 17 (del[17p]) affecting the tumor protein p53 expression and, in the absence of del(17p), TP53 sequencing for detection of TP53 gene mutation, according to the authors.

Prognostication

Two clinical staging systems are typically used in CLL. Both Binet and Rai staging systems separate three groups of patients with different prognosis, although “as a consequence of more effective therapy, the overall survival (OS) of patients with advanced stage has improved and the relevance of the staging systems for prognostication has decreased,” according to the report.

The recent addition of genetic markers has also proved highly relevant to identifying patients with different prognoses and to guide treatment.
 

Therapy

Although CLL is an incurable disease, choice and application of treatment are strongly tied to the length of survival, according to the authors. The guidelines recommend Binet and Rai staging with clinical symptoms as relevant for treatment indication. In addition, the identification of del(17p), TP53 mutations, and IGHV status are relevant for choice of therapy and should be assessed prior to treatment.

The guidelines discuss specific treatment modalities for various stages of the disease, from early stages to relapse.

For frontline therapy, different treatment strategies are available including continuous treatment with Bruton tyrosine kinase (BTK)–inhibitors, such as ibrutinib, until progression or time-limited therapy with ChT backbone and CD20 antibodies. In addition, the Food and Drug Administration and European Medicines Agency have recently approved the combination of venetoclax plus obinutuzumab for first-line therapy of CLL.

Treatment decisions should include an assessment of IGHV and TP53 status, as well as patient-related factors such as comedication, comorbidities, preferences, drug availability, and potential of treatment adherence, according to the guidelines.

In case of symptomatic relapse within 3 years after fixed-duration therapy or nonresponse to therapy, the guidelines recommend that the therapeutic regimen should be changed, regardless of the type of first-line either to venetoclax plus rituximab for 24 months or to ibrutinib, acalabrutinib, or other BTK inhibitors (if available) as continuous therapy.

The guidelines also discuss the possible roles for hematopoietic stem cell transplantation and cellular therapies, as well as the treatment of the various complications that can arise in patients with CLL, and dealing with various aspects of disease progression.

No external funds were provided for the production of the guidelines. The authors of the report and members of the ESMO Guidelines Committee reported numerous disclosures regarding pharmaceutical and biotechnology companies.

[email protected]

SOURCE: Eichhorst B et al. Ann Oncol. 2020 Oct 19. doi: 10.1016/j.annonc.2020.09.019.

An updated European Society for Medical Oncology (ESMO) clinical practice guidelines were released to provide key recommendations on the management of chronic lymphocytic leukemia (CLL).

The guidelines were developed by a multidisciplinary group of experts from different institutions and countries in Europe and provide levels of evidence and grades of recommendation where applicable for issues regarding prognosis and treatment decisions in CLL. Such decisions depend on genetic and clinical factors such as age, stage, and comorbidities. The guidelines also focus on new therapies targeting B-cell-receptor pathways or defect mechanism of apoptosis, which have been found to induce long-lasting remissions. The guidelines were endorsed by the European Hematology Association (EHA) through the Scientific Working Group on CLL/European Research Initiative on CLL (ERIC), according to the report published online the Annals of Oncology.

These clinical practice guidelines were developed in accordance with the ESMO standard operating procedures for clinical practice guidelines development with use of relevant literature selected by the expert authors. Statements without grading were considered justified as standard clinical practice by the experts and the ESMO faculty.

Below are some highlights of the guidelines, which cover a wide array of topics regarding the diagnosis, staging, treatment, and progression of CLL disease.
 

Diagnosis

The guidelines indicate that CLL diagnosis is usually possible by immunophenotyping of peripheral blood only and that lymph node (LN) biopsy and/or bone marrow biopsy may be helpful if immunophenotyping is not conclusive for the diagnosis of CLL, according to Barbara Eichhorst, MD, of the University of Cologne (Germany) and colleagues on behalf of the ESMO guidelines committee.

Staging and risk assessment

Early asymptomatic-stage disease does not need further risk assessment, but after the first year, when all patients should be seen at 3-monthly intervals, patients can be followed every 3-12 months. The interval would depend on burden and dynamics of the disease obtained by the using history and physical examinations, including a careful palpation of all LN areas, spleen, and liver, as well as assessing complete blood cell count and differential count, according to the report.

Advanced- and symptomatic-stage disease requires a broader examination including imaging, history and status of relevant infections, and fluorescent in situ hybridization (FISH) assays for the detection of deletion of the chromosome 17 (del[17p]) affecting the tumor protein p53 expression and, in the absence of del(17p), TP53 sequencing for detection of TP53 gene mutation, according to the authors.

Prognostication

Two clinical staging systems are typically used in CLL. Both Binet and Rai staging systems separate three groups of patients with different prognosis, although “as a consequence of more effective therapy, the overall survival (OS) of patients with advanced stage has improved and the relevance of the staging systems for prognostication has decreased,” according to the report.

The recent addition of genetic markers has also proved highly relevant to identifying patients with different prognoses and to guide treatment.
 

Therapy

Although CLL is an incurable disease, choice and application of treatment are strongly tied to the length of survival, according to the authors. The guidelines recommend Binet and Rai staging with clinical symptoms as relevant for treatment indication. In addition, the identification of del(17p), TP53 mutations, and IGHV status are relevant for choice of therapy and should be assessed prior to treatment.

The guidelines discuss specific treatment modalities for various stages of the disease, from early stages to relapse.

For frontline therapy, different treatment strategies are available including continuous treatment with Bruton tyrosine kinase (BTK)–inhibitors, such as ibrutinib, until progression or time-limited therapy with ChT backbone and CD20 antibodies. In addition, the Food and Drug Administration and European Medicines Agency have recently approved the combination of venetoclax plus obinutuzumab for first-line therapy of CLL.

Treatment decisions should include an assessment of IGHV and TP53 status, as well as patient-related factors such as comedication, comorbidities, preferences, drug availability, and potential of treatment adherence, according to the guidelines.

In case of symptomatic relapse within 3 years after fixed-duration therapy or nonresponse to therapy, the guidelines recommend that the therapeutic regimen should be changed, regardless of the type of first-line either to venetoclax plus rituximab for 24 months or to ibrutinib, acalabrutinib, or other BTK inhibitors (if available) as continuous therapy.

The guidelines also discuss the possible roles for hematopoietic stem cell transplantation and cellular therapies, as well as the treatment of the various complications that can arise in patients with CLL, and dealing with various aspects of disease progression.

No external funds were provided for the production of the guidelines. The authors of the report and members of the ESMO Guidelines Committee reported numerous disclosures regarding pharmaceutical and biotechnology companies.

[email protected]

SOURCE: Eichhorst B et al. Ann Oncol. 2020 Oct 19. doi: 10.1016/j.annonc.2020.09.019.

Acalabrutinib, given alone or in combination with obinutuzumab, showed favorable progression-free survival (PFS) and overall survival (OS), compared with other frontline therapies for chronic lymphocytic leukemia (CLL) in fludarabine-ineligible patients, according to the results of a meta-analysis comparing clinical trial results.

Researchers conducted a systematic literature review for applicable CLL studies that examined frontline treatments in order to compare the results with data on acalabrutinib (monotherapy and in combination with obinutuzumab) from patients in the ELEVATE-TN study (NCT02475681), according to a report published in Clinical Therapeutics.

Matthew S. Davids, MD, MMSc, of the Dana-Farber Cancer Institute in Boston, and colleagues performed a network meta-analysis (NMA) comparing acalabrutinib versus other standard frontline therapies for CLL in patients for whom fludarabine-based treatment is not appropriate.

“In the absence of head-to-head trial data, NMAs allow for simultaneous comparisons of a number of interventions with multiple comparators, by synthesizing direct and indirect evidence,” the authors stated.

Eight randomized controlled trials (RCTs) met the criteria for comparison.

The researchers constructed two evidence networks: Network A comprised solely RCTs that met the inclusion criteria, and Network B comprised seven RCTs and a published cross-trial comparison of ibrutinib from RESONATE-2 and chlorambucil plus obinutuzumab from iLLUMINATE. PFS and OS results were reported by using hazard ratios and 95% credible intervals.


 

Overall benefit

Both networks showed a significant improvement in PFS for acalabrutinib plus obinutuzumab over all comparators, according to the researchers. Both networks also showed a significant improvement in PFS for acalabrutinib monotherapy versus most comparators, with a significant difference to ibrutinib monotherapy found in Network A but not Network B.

Conversely, a significant difference in PFS was observed for acalabrutinib monotherapy versus venetoclax plus obinutuzumab in Network B but not Network A.

Overall survival hazard ratios ranged from 0.18 to 0.65 in favor of acalabrutinib-based treatment, but not all were significant. Acalabrutinib plus obinutuzumab ranked highest in terms of PFS and OS improvement, followed by acalabrutinib monotherapy.

“Although our NMAs provide useful insights into the relative efficacy of acalabrutinib, compared with other frontline treatments of CLL, the results cannot be considered confirmatory, and head-to-head randomized trials are needed, especially to compare the efficacy of acalabrutinib versus other targeted agents,” the researchers concluded.

AstraZeneca sponsored the study. The authors reported funding from AstraZeneca and numerous other pharmaceutical companies.

[email protected]

SOURCE: Davids MS et al. Clin Ther. 2020 Oct 5. doi: 10.1016/j.clinthera.2020.08.017.

Acalabrutinib, given alone or in combination with obinutuzumab, showed favorable progression-free survival (PFS) and overall survival (OS), compared with other frontline therapies for chronic lymphocytic leukemia (CLL) in fludarabine-ineligible patients, according to the results of a meta-analysis comparing clinical trial results.

Researchers conducted a systematic literature review for applicable CLL studies that examined frontline treatments in order to compare the results with data on acalabrutinib (monotherapy and in combination with obinutuzumab) from patients in the ELEVATE-TN study (NCT02475681), according to a report published in Clinical Therapeutics.

Matthew S. Davids, MD, MMSc, of the Dana-Farber Cancer Institute in Boston, and colleagues performed a network meta-analysis (NMA) comparing acalabrutinib versus other standard frontline therapies for CLL in patients for whom fludarabine-based treatment is not appropriate.

“In the absence of head-to-head trial data, NMAs allow for simultaneous comparisons of a number of interventions with multiple comparators, by synthesizing direct and indirect evidence,” the authors stated.

Eight randomized controlled trials (RCTs) met the criteria for comparison.

The researchers constructed two evidence networks: Network A comprised solely RCTs that met the inclusion criteria, and Network B comprised seven RCTs and a published cross-trial comparison of ibrutinib from RESONATE-2 and chlorambucil plus obinutuzumab from iLLUMINATE. PFS and OS results were reported by using hazard ratios and 95% credible intervals.


 

Overall benefit

Both networks showed a significant improvement in PFS for acalabrutinib plus obinutuzumab over all comparators, according to the researchers. Both networks also showed a significant improvement in PFS for acalabrutinib monotherapy versus most comparators, with a significant difference to ibrutinib monotherapy found in Network A but not Network B.

Conversely, a significant difference in PFS was observed for acalabrutinib monotherapy versus venetoclax plus obinutuzumab in Network B but not Network A.

Overall survival hazard ratios ranged from 0.18 to 0.65 in favor of acalabrutinib-based treatment, but not all were significant. Acalabrutinib plus obinutuzumab ranked highest in terms of PFS and OS improvement, followed by acalabrutinib monotherapy.

“Although our NMAs provide useful insights into the relative efficacy of acalabrutinib, compared with other frontline treatments of CLL, the results cannot be considered confirmatory, and head-to-head randomized trials are needed, especially to compare the efficacy of acalabrutinib versus other targeted agents,” the researchers concluded.

AstraZeneca sponsored the study. The authors reported funding from AstraZeneca and numerous other pharmaceutical companies.

[email protected]

SOURCE: Davids MS et al. Clin Ther. 2020 Oct 5. doi: 10.1016/j.clinthera.2020.08.017.

Acalabrutinib, given alone or in combination with obinutuzumab, showed favorable progression-free survival (PFS) and overall survival (OS), compared with other frontline therapies for chronic lymphocytic leukemia (CLL) in fludarabine-ineligible patients, according to the results of a meta-analysis comparing clinical trial results.

Researchers conducted a systematic literature review for applicable CLL studies that examined frontline treatments in order to compare the results with data on acalabrutinib (monotherapy and in combination with obinutuzumab) from patients in the ELEVATE-TN study (NCT02475681), according to a report published in Clinical Therapeutics.

Matthew S. Davids, MD, MMSc, of the Dana-Farber Cancer Institute in Boston, and colleagues performed a network meta-analysis (NMA) comparing acalabrutinib versus other standard frontline therapies for CLL in patients for whom fludarabine-based treatment is not appropriate.

“In the absence of head-to-head trial data, NMAs allow for simultaneous comparisons of a number of interventions with multiple comparators, by synthesizing direct and indirect evidence,” the authors stated.

Eight randomized controlled trials (RCTs) met the criteria for comparison.

The researchers constructed two evidence networks: Network A comprised solely RCTs that met the inclusion criteria, and Network B comprised seven RCTs and a published cross-trial comparison of ibrutinib from RESONATE-2 and chlorambucil plus obinutuzumab from iLLUMINATE. PFS and OS results were reported by using hazard ratios and 95% credible intervals.


 

Overall benefit

Both networks showed a significant improvement in PFS for acalabrutinib plus obinutuzumab over all comparators, according to the researchers. Both networks also showed a significant improvement in PFS for acalabrutinib monotherapy versus most comparators, with a significant difference to ibrutinib monotherapy found in Network A but not Network B.

Conversely, a significant difference in PFS was observed for acalabrutinib monotherapy versus venetoclax plus obinutuzumab in Network B but not Network A.

Overall survival hazard ratios ranged from 0.18 to 0.65 in favor of acalabrutinib-based treatment, but not all were significant. Acalabrutinib plus obinutuzumab ranked highest in terms of PFS and OS improvement, followed by acalabrutinib monotherapy.

“Although our NMAs provide useful insights into the relative efficacy of acalabrutinib, compared with other frontline treatments of CLL, the results cannot be considered confirmatory, and head-to-head randomized trials are needed, especially to compare the efficacy of acalabrutinib versus other targeted agents,” the researchers concluded.

AstraZeneca sponsored the study. The authors reported funding from AstraZeneca and numerous other pharmaceutical companies.

[email protected]

SOURCE: Davids MS et al. Clin Ther. 2020 Oct 5. doi: 10.1016/j.clinthera.2020.08.017.

Two new protein biomarkers may serve as prognostic indicators for outcomes in chronic lymphocytic leukemia (CLL) patients, according to the results of a proteomic assessment of patients’ serum compared to their event-free survival (EFS).

The results were published in Experimental Hematology.

The study attempted to validate the prognostic ability of known proteomic markers measured pretreatment and to search for new proteomic markers that might be related to treatment response in CLL, according to Fatemeh Saberi Hosnijeh, MD, of Erasmus MC, University Medical Center, Rotterdam, The Netherlands, and colleagues.

Baseline serum samples were taken from 51 CLL patients who were then treated with chemoimmunotherapy. The samples were analyzed for 360 proteomic markers, and those results were compared with patient EFS.

Study subjects were selected from patients enrolled in the HOVON 109 clinical trial, a phase 1/2 trial designed to assess the efficacy and safety of first-line therapy involving chlorambucil, rituximab,and lenalidomide in elderly patients and young frail patients with advanced CLL.

The patients assessed comprised 30 men and 21 women, and the median EFS for all patients was 23 months (ranging from 1.25 to 60.9 months).
 

Promising biomarkers

The researchers found that patients who had high serum levels of the proteins sCD23 (P = .026), sCD27 (P = .04), the serine peptidase inhibitor SPINT1 (P = .001), and the surface antigen protein LY9 (P = .0003) had a shorter EFS than those with marker levels below the median.

“Taken together, our results validate the prognostic impact of sCD23 and highlight SPINT1 and LY9 as possible promising markers for treatment response in CLL patients,” the researchers stated.

“Despite the relatively small number of available cases, which had an impact on statistical power, our pilot study identified SPINT1 and LY9 as promising independent prognostic proteomic markers next to sCD23 and sCD27 in patients treated for CLL. Further studies with larger sample sizes are required to validate these results,” the researchers concluded.

This research was supported by a grant from Gilead Sciences and an EU TRANSCAN/Dutch Cancer Society grant. The authors declared that they had no conflicts of interest.

[email protected]

SOURCE: Hosnijeh FS et al. Exp Hematol. 2020;89:55-60.

Two new protein biomarkers may serve as prognostic indicators for outcomes in chronic lymphocytic leukemia (CLL) patients, according to the results of a proteomic assessment of patients’ serum compared to their event-free survival (EFS).

The results were published in Experimental Hematology.

The study attempted to validate the prognostic ability of known proteomic markers measured pretreatment and to search for new proteomic markers that might be related to treatment response in CLL, according to Fatemeh Saberi Hosnijeh, MD, of Erasmus MC, University Medical Center, Rotterdam, The Netherlands, and colleagues.

Baseline serum samples were taken from 51 CLL patients who were then treated with chemoimmunotherapy. The samples were analyzed for 360 proteomic markers, and those results were compared with patient EFS.

Study subjects were selected from patients enrolled in the HOVON 109 clinical trial, a phase 1/2 trial designed to assess the efficacy and safety of first-line therapy involving chlorambucil, rituximab,and lenalidomide in elderly patients and young frail patients with advanced CLL.

The patients assessed comprised 30 men and 21 women, and the median EFS for all patients was 23 months (ranging from 1.25 to 60.9 months).
 

Promising biomarkers

The researchers found that patients who had high serum levels of the proteins sCD23 (P = .026), sCD27 (P = .04), the serine peptidase inhibitor SPINT1 (P = .001), and the surface antigen protein LY9 (P = .0003) had a shorter EFS than those with marker levels below the median.

“Taken together, our results validate the prognostic impact of sCD23 and highlight SPINT1 and LY9 as possible promising markers for treatment response in CLL patients,” the researchers stated.

“Despite the relatively small number of available cases, which had an impact on statistical power, our pilot study identified SPINT1 and LY9 as promising independent prognostic proteomic markers next to sCD23 and sCD27 in patients treated for CLL. Further studies with larger sample sizes are required to validate these results,” the researchers concluded.

This research was supported by a grant from Gilead Sciences and an EU TRANSCAN/Dutch Cancer Society grant. The authors declared that they had no conflicts of interest.

[email protected]

SOURCE: Hosnijeh FS et al. Exp Hematol. 2020;89:55-60.

Two new protein biomarkers may serve as prognostic indicators for outcomes in chronic lymphocytic leukemia (CLL) patients, according to the results of a proteomic assessment of patients’ serum compared to their event-free survival (EFS).

The results were published in Experimental Hematology.

The study attempted to validate the prognostic ability of known proteomic markers measured pretreatment and to search for new proteomic markers that might be related to treatment response in CLL, according to Fatemeh Saberi Hosnijeh, MD, of Erasmus MC, University Medical Center, Rotterdam, The Netherlands, and colleagues.

Baseline serum samples were taken from 51 CLL patients who were then treated with chemoimmunotherapy. The samples were analyzed for 360 proteomic markers, and those results were compared with patient EFS.

Study subjects were selected from patients enrolled in the HOVON 109 clinical trial, a phase 1/2 trial designed to assess the efficacy and safety of first-line therapy involving chlorambucil, rituximab,and lenalidomide in elderly patients and young frail patients with advanced CLL.

The patients assessed comprised 30 men and 21 women, and the median EFS for all patients was 23 months (ranging from 1.25 to 60.9 months).
 

Promising biomarkers

The researchers found that patients who had high serum levels of the proteins sCD23 (P = .026), sCD27 (P = .04), the serine peptidase inhibitor SPINT1 (P = .001), and the surface antigen protein LY9 (P = .0003) had a shorter EFS than those with marker levels below the median.

“Taken together, our results validate the prognostic impact of sCD23 and highlight SPINT1 and LY9 as possible promising markers for treatment response in CLL patients,” the researchers stated.

“Despite the relatively small number of available cases, which had an impact on statistical power, our pilot study identified SPINT1 and LY9 as promising independent prognostic proteomic markers next to sCD23 and sCD27 in patients treated for CLL. Further studies with larger sample sizes are required to validate these results,” the researchers concluded.

This research was supported by a grant from Gilead Sciences and an EU TRANSCAN/Dutch Cancer Society grant. The authors declared that they had no conflicts of interest.

[email protected]

SOURCE: Hosnijeh FS et al. Exp Hematol. 2020;89:55-60.

An international survey provides new insights into how COVID-19 has affected, and may continue to affect, the field of oncology.

The survey showed that “COVID-19 has had a major impact on the organization of patient care, on the well-being of caregivers, on continued medical education, and on clinical trial activities in oncology,” stated Guy Jerusalem, MD, PhD, of Centre Hospitalier Universitaire de Liège (Belgium).

Dr. Jerusalem presented these findings at the European Society for Medical Oncology Virtual Congress 2020.

The survey was distributed by 20 oncologists from 10 of the countries most affected by COVID-19. Responses were obtained from 109 oncologists representing centers in 18 countries. The responses were recorded between June 17 and July 14, 2020.

The survey consisted of 95 items intended to evaluate the impact of COVID-19 on the organization of oncologic care. Questions encompassed the capacity and service offered at each center, the magnitude of COVID-19–based care interruptions and the reasons for them, the ensuing challenges faced, interventions implemented, and the estimated harms to patients during the pandemic.

The 109 oncologists surveyed had a median of 20 years of oncology experience. A majority of respondents were men (61.5%), and the median age was 48.5 years.

The respondents had worked predominantly (62.4%) at academic hospitals, with 29.6% at community hospitals. Most respondents worked at general hospitals with an oncology unit (66.1%) rather than a specialized separate cancer center (32.1%).

The most common specialty was breast cancer (60.6%), followed by gastrointestinal cancer (10.1%), urogenital cancer (9.2%), and lung cancer (8.3%).
 

Impact on treatment

The treatment modalities affected by the pandemic – through cancellations or delays in more than 10% of patients – included surgery (in 34% of centers), chemotherapy (22%), radiotherapy (13.7%), checkpoint inhibitor therapy (9.1%), monoclonal antibodies (9%), and oral targeted therapy (3.7%).

Among oncologists treating breast cancer, cancellations/delays in more than 10% of patients were reported for everolimus (18%), CDK4/6 inhibitors (8.9%), and endocrine therapy (2.2%).

Overall, 34.8% of respondents reported increased use of granulocyte colony–stimulating factor, and 6.4% reported increased use of erythropoietin.

On the other hand, 11.1% of respondents reported a decrease in the use of double immunotherapy, and 21.9% reported decreased use of corticosteroids.

Not only can the immunosuppressive effects of steroid use increase infection risks, Dr. Jerusalem noted, fever suppression can lead to a delayed diagnosis of COVID-19.

“To circumvent potential higher infection risks or greater disease severity, we use lower doses of steroids, but this is not based on studies,” he said.

“Previous exposure to steroids or being on steroids at the time of COVID-19 infection is a detrimental factor for complications and mortality,” commented ESMO President Solange Peters, MD, PhD, of Centre Hospitalier Universitaire Vaudois in Lausanne, Switzerland.

Frontline Medical News

Dr. Peters noted that the observation was based on lung cancer registry findings. Furthermore, because data from smaller outbreaks of other coronavirus infections suggested worse prognosis and increased mortality, steroid use was already feared in the very early days of the COVID-19 pandemic.

Lastly, earlier cessation of palliative treatment was observed in 32.1% of centers, and 64.2% of respondents agreed that undertreatment because of COVID-19 is a major concern.

Dr. Jerusalem noted that the survey data do not explain the early cessation of palliative treatment. “I suspect that many patients died at home rather than alone in institutions because it was the only way they could die with their families around them.”
 

Telehealth, meetings, and trials

The survey also revealed rationales for the use of teleconsultation, including follow-up (94.5%), oral therapy (92.7%), immunotherapy (57.8%), and chemotherapy (55%).

Most respondents reported more frequent use of virtual meetings for continuing medical education (94%), oncologic team meetings (92%), and tumor boards (82%).

While about 82% of respondents said they were likely to continue the use of telemedicine, 45% said virtual conferences are not an acceptable alternative to live international conferences such as ESMO, Dr. Jerusalem said.

Finally, nearly three-quarters of respondents (72.5%) said all clinical trial activities are or will soon be activated, or never stopped, at their centers. On the other hand, 27.5% of respondents reported that their centers had major protocol violations or deviations, and 37% of respondents said they expect significant reductions in clinical trial activities this year.

Dr. Jerusalem concluded that COVID-19 is having a major, long-term impact on the organization of patient care, caregivers, continued medical education, and clinical trial activities in oncology.

He cautioned that “the risk of a delayed diagnosis of new cancers and economic consequences of COVID-19 on access to health care and cancer treatments have to be carefully evaluated.”

This research was funded by Fondation Léon Fredericq. Dr. Jerusalem disclosed relationships with Novartis, Roche, Lilly, Pfizer, Amgen, Bristol-Myers Squibb, AstraZeneca, Daiichi Sankyo, AbbVie, MedImmune, and Merck. Dr. Peters disclosed relationships with AbbVie, Amgen, AstraZeneca, and many other companies.

SOURCE: Jerusalem G et al. ESMO 2020, Abstract LBA76.

An international survey provides new insights into how COVID-19 has affected, and may continue to affect, the field of oncology.

The survey showed that “COVID-19 has had a major impact on the organization of patient care, on the well-being of caregivers, on continued medical education, and on clinical trial activities in oncology,” stated Guy Jerusalem, MD, PhD, of Centre Hospitalier Universitaire de Liège (Belgium).

Dr. Jerusalem presented these findings at the European Society for Medical Oncology Virtual Congress 2020.

The survey was distributed by 20 oncologists from 10 of the countries most affected by COVID-19. Responses were obtained from 109 oncologists representing centers in 18 countries. The responses were recorded between June 17 and July 14, 2020.

The survey consisted of 95 items intended to evaluate the impact of COVID-19 on the organization of oncologic care. Questions encompassed the capacity and service offered at each center, the magnitude of COVID-19–based care interruptions and the reasons for them, the ensuing challenges faced, interventions implemented, and the estimated harms to patients during the pandemic.

The 109 oncologists surveyed had a median of 20 years of oncology experience. A majority of respondents were men (61.5%), and the median age was 48.5 years.

The respondents had worked predominantly (62.4%) at academic hospitals, with 29.6% at community hospitals. Most respondents worked at general hospitals with an oncology unit (66.1%) rather than a specialized separate cancer center (32.1%).

The most common specialty was breast cancer (60.6%), followed by gastrointestinal cancer (10.1%), urogenital cancer (9.2%), and lung cancer (8.3%).
 

Impact on treatment

The treatment modalities affected by the pandemic – through cancellations or delays in more than 10% of patients – included surgery (in 34% of centers), chemotherapy (22%), radiotherapy (13.7%), checkpoint inhibitor therapy (9.1%), monoclonal antibodies (9%), and oral targeted therapy (3.7%).

Among oncologists treating breast cancer, cancellations/delays in more than 10% of patients were reported for everolimus (18%), CDK4/6 inhibitors (8.9%), and endocrine therapy (2.2%).

Overall, 34.8% of respondents reported increased use of granulocyte colony–stimulating factor, and 6.4% reported increased use of erythropoietin.

On the other hand, 11.1% of respondents reported a decrease in the use of double immunotherapy, and 21.9% reported decreased use of corticosteroids.

Not only can the immunosuppressive effects of steroid use increase infection risks, Dr. Jerusalem noted, fever suppression can lead to a delayed diagnosis of COVID-19.

“To circumvent potential higher infection risks or greater disease severity, we use lower doses of steroids, but this is not based on studies,” he said.

“Previous exposure to steroids or being on steroids at the time of COVID-19 infection is a detrimental factor for complications and mortality,” commented ESMO President Solange Peters, MD, PhD, of Centre Hospitalier Universitaire Vaudois in Lausanne, Switzerland.

Frontline Medical News

Dr. Peters noted that the observation was based on lung cancer registry findings. Furthermore, because data from smaller outbreaks of other coronavirus infections suggested worse prognosis and increased mortality, steroid use was already feared in the very early days of the COVID-19 pandemic.

Lastly, earlier cessation of palliative treatment was observed in 32.1% of centers, and 64.2% of respondents agreed that undertreatment because of COVID-19 is a major concern.

Dr. Jerusalem noted that the survey data do not explain the early cessation of palliative treatment. “I suspect that many patients died at home rather than alone in institutions because it was the only way they could die with their families around them.”
 

Telehealth, meetings, and trials

The survey also revealed rationales for the use of teleconsultation, including follow-up (94.5%), oral therapy (92.7%), immunotherapy (57.8%), and chemotherapy (55%).

Most respondents reported more frequent use of virtual meetings for continuing medical education (94%), oncologic team meetings (92%), and tumor boards (82%).

While about 82% of respondents said they were likely to continue the use of telemedicine, 45% said virtual conferences are not an acceptable alternative to live international conferences such as ESMO, Dr. Jerusalem said.

Finally, nearly three-quarters of respondents (72.5%) said all clinical trial activities are or will soon be activated, or never stopped, at their centers. On the other hand, 27.5% of respondents reported that their centers had major protocol violations or deviations, and 37% of respondents said they expect significant reductions in clinical trial activities this year.

Dr. Jerusalem concluded that COVID-19 is having a major, long-term impact on the organization of patient care, caregivers, continued medical education, and clinical trial activities in oncology.

He cautioned that “the risk of a delayed diagnosis of new cancers and economic consequences of COVID-19 on access to health care and cancer treatments have to be carefully evaluated.”

This research was funded by Fondation Léon Fredericq. Dr. Jerusalem disclosed relationships with Novartis, Roche, Lilly, Pfizer, Amgen, Bristol-Myers Squibb, AstraZeneca, Daiichi Sankyo, AbbVie, MedImmune, and Merck. Dr. Peters disclosed relationships with AbbVie, Amgen, AstraZeneca, and many other companies.

SOURCE: Jerusalem G et al. ESMO 2020, Abstract LBA76.

An international survey provides new insights into how COVID-19 has affected, and may continue to affect, the field of oncology.

The survey showed that “COVID-19 has had a major impact on the organization of patient care, on the well-being of caregivers, on continued medical education, and on clinical trial activities in oncology,” stated Guy Jerusalem, MD, PhD, of Centre Hospitalier Universitaire de Liège (Belgium).

Dr. Jerusalem presented these findings at the European Society for Medical Oncology Virtual Congress 2020.

The survey was distributed by 20 oncologists from 10 of the countries most affected by COVID-19. Responses were obtained from 109 oncologists representing centers in 18 countries. The responses were recorded between June 17 and July 14, 2020.

The survey consisted of 95 items intended to evaluate the impact of COVID-19 on the organization of oncologic care. Questions encompassed the capacity and service offered at each center, the magnitude of COVID-19–based care interruptions and the reasons for them, the ensuing challenges faced, interventions implemented, and the estimated harms to patients during the pandemic.

The 109 oncologists surveyed had a median of 20 years of oncology experience. A majority of respondents were men (61.5%), and the median age was 48.5 years.

The respondents had worked predominantly (62.4%) at academic hospitals, with 29.6% at community hospitals. Most respondents worked at general hospitals with an oncology unit (66.1%) rather than a specialized separate cancer center (32.1%).

The most common specialty was breast cancer (60.6%), followed by gastrointestinal cancer (10.1%), urogenital cancer (9.2%), and lung cancer (8.3%).
 

Impact on treatment

The treatment modalities affected by the pandemic – through cancellations or delays in more than 10% of patients – included surgery (in 34% of centers), chemotherapy (22%), radiotherapy (13.7%), checkpoint inhibitor therapy (9.1%), monoclonal antibodies (9%), and oral targeted therapy (3.7%).

Among oncologists treating breast cancer, cancellations/delays in more than 10% of patients were reported for everolimus (18%), CDK4/6 inhibitors (8.9%), and endocrine therapy (2.2%).

Overall, 34.8% of respondents reported increased use of granulocyte colony–stimulating factor, and 6.4% reported increased use of erythropoietin.

On the other hand, 11.1% of respondents reported a decrease in the use of double immunotherapy, and 21.9% reported decreased use of corticosteroids.

Not only can the immunosuppressive effects of steroid use increase infection risks, Dr. Jerusalem noted, fever suppression can lead to a delayed diagnosis of COVID-19.

“To circumvent potential higher infection risks or greater disease severity, we use lower doses of steroids, but this is not based on studies,” he said.

“Previous exposure to steroids or being on steroids at the time of COVID-19 infection is a detrimental factor for complications and mortality,” commented ESMO President Solange Peters, MD, PhD, of Centre Hospitalier Universitaire Vaudois in Lausanne, Switzerland.

Frontline Medical News

Dr. Peters noted that the observation was based on lung cancer registry findings. Furthermore, because data from smaller outbreaks of other coronavirus infections suggested worse prognosis and increased mortality, steroid use was already feared in the very early days of the COVID-19 pandemic.

Lastly, earlier cessation of palliative treatment was observed in 32.1% of centers, and 64.2% of respondents agreed that undertreatment because of COVID-19 is a major concern.

Dr. Jerusalem noted that the survey data do not explain the early cessation of palliative treatment. “I suspect that many patients died at home rather than alone in institutions because it was the only way they could die with their families around them.”
 

Telehealth, meetings, and trials

The survey also revealed rationales for the use of teleconsultation, including follow-up (94.5%), oral therapy (92.7%), immunotherapy (57.8%), and chemotherapy (55%).

Most respondents reported more frequent use of virtual meetings for continuing medical education (94%), oncologic team meetings (92%), and tumor boards (82%).

While about 82% of respondents said they were likely to continue the use of telemedicine, 45% said virtual conferences are not an acceptable alternative to live international conferences such as ESMO, Dr. Jerusalem said.

Finally, nearly three-quarters of respondents (72.5%) said all clinical trial activities are or will soon be activated, or never stopped, at their centers. On the other hand, 27.5% of respondents reported that their centers had major protocol violations or deviations, and 37% of respondents said they expect significant reductions in clinical trial activities this year.

Dr. Jerusalem concluded that COVID-19 is having a major, long-term impact on the organization of patient care, caregivers, continued medical education, and clinical trial activities in oncology.

He cautioned that “the risk of a delayed diagnosis of new cancers and economic consequences of COVID-19 on access to health care and cancer treatments have to be carefully evaluated.”

This research was funded by Fondation Léon Fredericq. Dr. Jerusalem disclosed relationships with Novartis, Roche, Lilly, Pfizer, Amgen, Bristol-Myers Squibb, AstraZeneca, Daiichi Sankyo, AbbVie, MedImmune, and Merck. Dr. Peters disclosed relationships with AbbVie, Amgen, AstraZeneca, and many other companies.

SOURCE: Jerusalem G et al. ESMO 2020, Abstract LBA76.

Oxidative stress may play a role in pathogenesis of B-cell chronic lymphocytic leukemia (B-CLL), according to the results of a biochemical and cytogenetic study of patients published online in Experimental and Molecular Pathology.

The study evaluated the serum levels of oxidative stress biomarkers [conjugated dienes (CD), malondialdehyde (MDA), and nitrite levels] and the levels of antioxidant biomarkers [ceruloplasmin (CP) and glutathione peroxidase (GPx)] in 64 B-CLL patients. The relationship between these biomarkers and the presence of cytogenetic abnormalities was examined, according to Tatiana Zhevak, MD, of Sechenov First Moscow (Russia) State Medical University, and colleagues.

Cytogenetic abnormalities have previously been determined to be linked to a poorer prognosis in CLL patients, and factors that increase the frequency of CA have been shown to increase the risk of rapid tumor progression, Dr. Zhevak and her colleagues stated.
 

Oxidative stress connection

Enhanced oxidative stress was detected in B-CLL patients as shown by their increased levels of serum CD, MDA, and nitrite, as well as a demonstrated imbalance in the antioxidant defense system as shown by an increased serum CP level and decreased serum GPx activity, according to the researchers.

In addition, these metabolic changes were found to be greater in those patients whose lymphocytes harbored specific cytogenetic abnormalities, and could be predicted by the serum levels of CD. Specifically, the odds of harboring a cytogenetic abnormality increased by a factor of 1.88 (P = .004) for every one-unit increase in serum CD level (mcmol/L), according to the authors.

“Collectively, the results support our hypothesis that oxidative stress and resulting lipid peroxidation play a role in pathogenesis of B-CLL and provide a rational basis for the use of agents regulating the pro-oxidant and antioxidant activity in the treatment of B-CLL patients,” the researchers concluded.

The research was unsponsored and the authors reported having no conflicts.

[email protected]

SOURCE: Zhevak T et al. Exp Mol Patholo. 2020 Oct;16:104524 doi: 10.1016/j.yexmp.2020.104524.

Oxidative stress may play a role in pathogenesis of B-cell chronic lymphocytic leukemia (B-CLL), according to the results of a biochemical and cytogenetic study of patients published online in Experimental and Molecular Pathology.

The study evaluated the serum levels of oxidative stress biomarkers [conjugated dienes (CD), malondialdehyde (MDA), and nitrite levels] and the levels of antioxidant biomarkers [ceruloplasmin (CP) and glutathione peroxidase (GPx)] in 64 B-CLL patients. The relationship between these biomarkers and the presence of cytogenetic abnormalities was examined, according to Tatiana Zhevak, MD, of Sechenov First Moscow (Russia) State Medical University, and colleagues.

Cytogenetic abnormalities have previously been determined to be linked to a poorer prognosis in CLL patients, and factors that increase the frequency of CA have been shown to increase the risk of rapid tumor progression, Dr. Zhevak and her colleagues stated.
 

Oxidative stress connection

Enhanced oxidative stress was detected in B-CLL patients as shown by their increased levels of serum CD, MDA, and nitrite, as well as a demonstrated imbalance in the antioxidant defense system as shown by an increased serum CP level and decreased serum GPx activity, according to the researchers.

In addition, these metabolic changes were found to be greater in those patients whose lymphocytes harbored specific cytogenetic abnormalities, and could be predicted by the serum levels of CD. Specifically, the odds of harboring a cytogenetic abnormality increased by a factor of 1.88 (P = .004) for every one-unit increase in serum CD level (mcmol/L), according to the authors.

“Collectively, the results support our hypothesis that oxidative stress and resulting lipid peroxidation play a role in pathogenesis of B-CLL and provide a rational basis for the use of agents regulating the pro-oxidant and antioxidant activity in the treatment of B-CLL patients,” the researchers concluded.

The research was unsponsored and the authors reported having no conflicts.

[email protected]

SOURCE: Zhevak T et al. Exp Mol Patholo. 2020 Oct;16:104524 doi: 10.1016/j.yexmp.2020.104524.

Oxidative stress may play a role in pathogenesis of B-cell chronic lymphocytic leukemia (B-CLL), according to the results of a biochemical and cytogenetic study of patients published online in Experimental and Molecular Pathology.

The study evaluated the serum levels of oxidative stress biomarkers [conjugated dienes (CD), malondialdehyde (MDA), and nitrite levels] and the levels of antioxidant biomarkers [ceruloplasmin (CP) and glutathione peroxidase (GPx)] in 64 B-CLL patients. The relationship between these biomarkers and the presence of cytogenetic abnormalities was examined, according to Tatiana Zhevak, MD, of Sechenov First Moscow (Russia) State Medical University, and colleagues.

Cytogenetic abnormalities have previously been determined to be linked to a poorer prognosis in CLL patients, and factors that increase the frequency of CA have been shown to increase the risk of rapid tumor progression, Dr. Zhevak and her colleagues stated.
 

Oxidative stress connection

Enhanced oxidative stress was detected in B-CLL patients as shown by their increased levels of serum CD, MDA, and nitrite, as well as a demonstrated imbalance in the antioxidant defense system as shown by an increased serum CP level and decreased serum GPx activity, according to the researchers.

In addition, these metabolic changes were found to be greater in those patients whose lymphocytes harbored specific cytogenetic abnormalities, and could be predicted by the serum levels of CD. Specifically, the odds of harboring a cytogenetic abnormality increased by a factor of 1.88 (P = .004) for every one-unit increase in serum CD level (mcmol/L), according to the authors.

“Collectively, the results support our hypothesis that oxidative stress and resulting lipid peroxidation play a role in pathogenesis of B-CLL and provide a rational basis for the use of agents regulating the pro-oxidant and antioxidant activity in the treatment of B-CLL patients,” the researchers concluded.

The research was unsponsored and the authors reported having no conflicts.

[email protected]

SOURCE: Zhevak T et al. Exp Mol Patholo. 2020 Oct;16:104524 doi: 10.1016/j.yexmp.2020.104524.

Three over-the-counter antihistamines, clemastine, desloratadine, and loratadine, preferentially induce cell death through lysosomal membrane permeabilization in chronic lymphocytic leukemia cells, compared with normal lymphocytes, according to the results of an in vitro study published in Leukemia Research.

In addition, the antihistamines showed a synergistic effect in killing off chronic lymphocytic leukemia (CLL) cells when combined with the tyrosine kinase inhibitor, ibrutinib, but not with chemotherapy, according to Aaron Chanas-Larue of CancerCare Manitoba, Winnipeg, Man., and colleagues.

Blood from CLL patients and age-matched healthy donors was collected, treated, and compared with two malignant B-cell lines. Cells were treated with the three different antihistamines at various concentrations alone and in the presence of ibrutinib. Cell death was determined by flow cytometry using fluorescent staining and EC50 (half-maximal effective concentration) values were calculated.

Of the three drugs, clemastine demonstrated the greatest degree of cytotoxicity, with a mean EC50 value of 12.3 mcmol in CLL cells. Desloratadine and loratadine also had a greater effect on leukemic cells, with mean EC50 values of 27.2 mcmol and 17.2 mcmol, respectively, according to the researchers.

Clemastine also showed the greatest tumor sensitivity, with an EC50 nearly three times lower for CLL cells (EC50, 12.3 mcmol) than for normal peripheral blood mononuclear cells (EC50, 32 mcmol). In addition, clemastine induced cell death over a 72-hour time course in CLL cells, and was equally effective against CLL cells with del17p, unmutated immunoglobulin heavy chain gene, or high Zeta-chain–associated protein kinase 70 expression.
 

Effective synergy

The researchers found that clemastine enhanced cell death when combined with targeted CLL therapies ibrutinib, idelalisib, or venetoclax, but did not enhance the activities of the chemotherapeutics fludarabine, chlorambucil, or bendamustine.

Ibrutinib increased cell death to the greatest degree when combined with antihistamines. The effect was demonstrated to be synergistic, showing “a unique interaction between the activities of the antihistamines and this inhibitor of the B-cell pathway, suggesting a clinical potential for this combination,” the authors stated.

“Repurposing well-characterized drugs such as antihistamines with defined mechanisms and toxicities allows for repositioning of these drugs to use in CLL treatment in the near future in the context of targeted therapies,” they concluded.

The study was supported by grants from the Cancer Research Society and the CancerCare Manitoba Foundation. The authors reported that they had no conflicts.

[email protected]

SOURCE: Chanas-Larue A et al. Leuk Res. 2020 Jul 17. doi: 10.1016/j.leukres.2020.106423.

Three over-the-counter antihistamines, clemastine, desloratadine, and loratadine, preferentially induce cell death through lysosomal membrane permeabilization in chronic lymphocytic leukemia cells, compared with normal lymphocytes, according to the results of an in vitro study published in Leukemia Research.

In addition, the antihistamines showed a synergistic effect in killing off chronic lymphocytic leukemia (CLL) cells when combined with the tyrosine kinase inhibitor, ibrutinib, but not with chemotherapy, according to Aaron Chanas-Larue of CancerCare Manitoba, Winnipeg, Man., and colleagues.

Blood from CLL patients and age-matched healthy donors was collected, treated, and compared with two malignant B-cell lines. Cells were treated with the three different antihistamines at various concentrations alone and in the presence of ibrutinib. Cell death was determined by flow cytometry using fluorescent staining and EC50 (half-maximal effective concentration) values were calculated.

Of the three drugs, clemastine demonstrated the greatest degree of cytotoxicity, with a mean EC50 value of 12.3 mcmol in CLL cells. Desloratadine and loratadine also had a greater effect on leukemic cells, with mean EC50 values of 27.2 mcmol and 17.2 mcmol, respectively, according to the researchers.

Clemastine also showed the greatest tumor sensitivity, with an EC50 nearly three times lower for CLL cells (EC50, 12.3 mcmol) than for normal peripheral blood mononuclear cells (EC50, 32 mcmol). In addition, clemastine induced cell death over a 72-hour time course in CLL cells, and was equally effective against CLL cells with del17p, unmutated immunoglobulin heavy chain gene, or high Zeta-chain–associated protein kinase 70 expression.
 

Effective synergy

The researchers found that clemastine enhanced cell death when combined with targeted CLL therapies ibrutinib, idelalisib, or venetoclax, but did not enhance the activities of the chemotherapeutics fludarabine, chlorambucil, or bendamustine.

Ibrutinib increased cell death to the greatest degree when combined with antihistamines. The effect was demonstrated to be synergistic, showing “a unique interaction between the activities of the antihistamines and this inhibitor of the B-cell pathway, suggesting a clinical potential for this combination,” the authors stated.

“Repurposing well-characterized drugs such as antihistamines with defined mechanisms and toxicities allows for repositioning of these drugs to use in CLL treatment in the near future in the context of targeted therapies,” they concluded.

The study was supported by grants from the Cancer Research Society and the CancerCare Manitoba Foundation. The authors reported that they had no conflicts.

[email protected]

SOURCE: Chanas-Larue A et al. Leuk Res. 2020 Jul 17. doi: 10.1016/j.leukres.2020.106423.

Three over-the-counter antihistamines, clemastine, desloratadine, and loratadine, preferentially induce cell death through lysosomal membrane permeabilization in chronic lymphocytic leukemia cells, compared with normal lymphocytes, according to the results of an in vitro study published in Leukemia Research.

In addition, the antihistamines showed a synergistic effect in killing off chronic lymphocytic leukemia (CLL) cells when combined with the tyrosine kinase inhibitor, ibrutinib, but not with chemotherapy, according to Aaron Chanas-Larue of CancerCare Manitoba, Winnipeg, Man., and colleagues.

Blood from CLL patients and age-matched healthy donors was collected, treated, and compared with two malignant B-cell lines. Cells were treated with the three different antihistamines at various concentrations alone and in the presence of ibrutinib. Cell death was determined by flow cytometry using fluorescent staining and EC50 (half-maximal effective concentration) values were calculated.

Of the three drugs, clemastine demonstrated the greatest degree of cytotoxicity, with a mean EC50 value of 12.3 mcmol in CLL cells. Desloratadine and loratadine also had a greater effect on leukemic cells, with mean EC50 values of 27.2 mcmol and 17.2 mcmol, respectively, according to the researchers.

Clemastine also showed the greatest tumor sensitivity, with an EC50 nearly three times lower for CLL cells (EC50, 12.3 mcmol) than for normal peripheral blood mononuclear cells (EC50, 32 mcmol). In addition, clemastine induced cell death over a 72-hour time course in CLL cells, and was equally effective against CLL cells with del17p, unmutated immunoglobulin heavy chain gene, or high Zeta-chain–associated protein kinase 70 expression.
 

Effective synergy

The researchers found that clemastine enhanced cell death when combined with targeted CLL therapies ibrutinib, idelalisib, or venetoclax, but did not enhance the activities of the chemotherapeutics fludarabine, chlorambucil, or bendamustine.

Ibrutinib increased cell death to the greatest degree when combined with antihistamines. The effect was demonstrated to be synergistic, showing “a unique interaction between the activities of the antihistamines and this inhibitor of the B-cell pathway, suggesting a clinical potential for this combination,” the authors stated.

“Repurposing well-characterized drugs such as antihistamines with defined mechanisms and toxicities allows for repositioning of these drugs to use in CLL treatment in the near future in the context of targeted therapies,” they concluded.

The study was supported by grants from the Cancer Research Society and the CancerCare Manitoba Foundation. The authors reported that they had no conflicts.

[email protected]

SOURCE: Chanas-Larue A et al. Leuk Res. 2020 Jul 17. doi: 10.1016/j.leukres.2020.106423.

The BALL score was able to identify a subset of patients with chronic lymphocytic leukemia (CLL) who particularly benefit from single-agent ibrutinib therapy, according to the results of a study of 111 patients followed from two different institutions.

The BALL model consists of four factors: serum beta₂-microglobulin at 5 mg/dL or greater, hemoglobin < 110 g/L for women or < 120 g/L for men, lactate dehydrogenase [LDH] > upper limit of normal [UNL], and time elapsed from last therapy less than 24 months. Each parameter was alloted 1 point, leading to a stratification of patients into three different prognostic groups: low risk (score 0-1), intermediate risk (2-3), and high risk (score 4), according to a report published online in Leukemia Research.

According to Stefano Molica, MD, of the Azienda Ospedaliera Pugliese-Ciaccio, Catanzaro, Italy, and his colleagues, the majority of patients (82%) were clinical Rai stage II-IV. The median patient age was 63 years and nearly 68% were men.

The researchers assessed four models for predicting overall survival. The modified version of CLL-International Prognostic Index (CLL-IPI) failed to provide prognostic information in relapsed/refractory (R/R) CLL (P = .77) as did the Ahn et al. model (P = .95) and a simplified BALL model (P = .09). In contrast, the full BALL score captured two groups of patients with significant differences in survival (hazard ratio, 0.240; 95 % confidence interval, 0.10-0.54; P = .0005); however, because of the low number of patients in the high-risk category, these cases were combined with the intermediate-risk group.

The BALL score identified a subset of patients, accounting for about 50% of the whole population, who particularly benefit from single-agent ibrutinib, according to Dr. Molica and his colleagues. These patients had a survival rate of 85% at 3 years.

“In contrast, the outcome of subjects with intermediate-high risk is disappointing. These patients should be considered for a combination of targeted drugs or cellular-based therapies,” the researchers concluded.

The authors reported that they had no conflicts.

[email protected]

SOURCE: Molica S et al. Leuk Res. 2020 Jun 10. https://doi.org/10.1016/j.leukres.2020.

The BALL score was able to identify a subset of patients with chronic lymphocytic leukemia (CLL) who particularly benefit from single-agent ibrutinib therapy, according to the results of a study of 111 patients followed from two different institutions.

The BALL model consists of four factors: serum beta₂-microglobulin at 5 mg/dL or greater, hemoglobin < 110 g/L for women or < 120 g/L for men, lactate dehydrogenase [LDH] > upper limit of normal [UNL], and time elapsed from last therapy less than 24 months. Each parameter was alloted 1 point, leading to a stratification of patients into three different prognostic groups: low risk (score 0-1), intermediate risk (2-3), and high risk (score 4), according to a report published online in Leukemia Research.

According to Stefano Molica, MD, of the Azienda Ospedaliera Pugliese-Ciaccio, Catanzaro, Italy, and his colleagues, the majority of patients (82%) were clinical Rai stage II-IV. The median patient age was 63 years and nearly 68% were men.

The researchers assessed four models for predicting overall survival. The modified version of CLL-International Prognostic Index (CLL-IPI) failed to provide prognostic information in relapsed/refractory (R/R) CLL (P = .77) as did the Ahn et al. model (P = .95) and a simplified BALL model (P = .09). In contrast, the full BALL score captured two groups of patients with significant differences in survival (hazard ratio, 0.240; 95 % confidence interval, 0.10-0.54; P = .0005); however, because of the low number of patients in the high-risk category, these cases were combined with the intermediate-risk group.

The BALL score identified a subset of patients, accounting for about 50% of the whole population, who particularly benefit from single-agent ibrutinib, according to Dr. Molica and his colleagues. These patients had a survival rate of 85% at 3 years.

“In contrast, the outcome of subjects with intermediate-high risk is disappointing. These patients should be considered for a combination of targeted drugs or cellular-based therapies,” the researchers concluded.

The authors reported that they had no conflicts.

[email protected]

SOURCE: Molica S et al. Leuk Res. 2020 Jun 10. https://doi.org/10.1016/j.leukres.2020.

The BALL score was able to identify a subset of patients with chronic lymphocytic leukemia (CLL) who particularly benefit from single-agent ibrutinib therapy, according to the results of a study of 111 patients followed from two different institutions.

The BALL model consists of four factors: serum beta₂-microglobulin at 5 mg/dL or greater, hemoglobin < 110 g/L for women or < 120 g/L for men, lactate dehydrogenase [LDH] > upper limit of normal [UNL], and time elapsed from last therapy less than 24 months. Each parameter was alloted 1 point, leading to a stratification of patients into three different prognostic groups: low risk (score 0-1), intermediate risk (2-3), and high risk (score 4), according to a report published online in Leukemia Research.

According to Stefano Molica, MD, of the Azienda Ospedaliera Pugliese-Ciaccio, Catanzaro, Italy, and his colleagues, the majority of patients (82%) were clinical Rai stage II-IV. The median patient age was 63 years and nearly 68% were men.

The researchers assessed four models for predicting overall survival. The modified version of CLL-International Prognostic Index (CLL-IPI) failed to provide prognostic information in relapsed/refractory (R/R) CLL (P = .77) as did the Ahn et al. model (P = .95) and a simplified BALL model (P = .09). In contrast, the full BALL score captured two groups of patients with significant differences in survival (hazard ratio, 0.240; 95 % confidence interval, 0.10-0.54; P = .0005); however, because of the low number of patients in the high-risk category, these cases were combined with the intermediate-risk group.

The BALL score identified a subset of patients, accounting for about 50% of the whole population, who particularly benefit from single-agent ibrutinib, according to Dr. Molica and his colleagues. These patients had a survival rate of 85% at 3 years.

“In contrast, the outcome of subjects with intermediate-high risk is disappointing. These patients should be considered for a combination of targeted drugs or cellular-based therapies,” the researchers concluded.

The authors reported that they had no conflicts.

[email protected]

SOURCE: Molica S et al. Leuk Res. 2020 Jun 10. https://doi.org/10.1016/j.leukres.2020.

The European Medicines Agency’s (EMA) Committee for Medicinal Products for Human Use (CHMP) has given a thumbs up to avapritinib and acalabrutinib, paving the way for the drugs’ approval in the European Union (EU). 

The CHMP recommended granting conditional marketing authorization for avapritinib (Ayvakit, Blueprint Medicines) for use in adults with unresectable or metastatic gastrointestinal stromal tumors (GIST) harboring a platelet-derived growth factor receptor alpha (PDGFRA) exon 18 mutation, including PDGFRA D842V mutations. About 6%-10% of GIST tumors harbor this mutation, and avapritinib is a selective and potent inhibitor of KIT and PDGFRA mutant kinases.

The CHMP also adopted a positive opinion for acalabrutinib (Calquence, AstraZeneca) for the treatment of chronic lymphocytic leukemia (CLL) as monotherapy in patients who are treatment-naive or have received at least one prior therapy.

The CHMP opinion on both drugs will be reviewed by the European Commission, which has the authority to grant marketing authorization for medicinal products in the EU.

Detailed recommendations for the use of both drugs will be provided in the summary of product characteristics, which will be published in the European public assessment report and made available in all official EU languages after the products receive marketing authorization by the European Commission.

First targeted therapy for mutation

If approved by the European Commission, avapritinib would be the first treatment in the EU indicated for patients with PDGFRA D842V-mutant GIST.

Avapritinib was approved by the US Food and Drug Administration (FDA) earlier this year for the aforementioned indication. The FDA approval was based on findings from the phase 1 NAVIGATOR trial, which included 43 patients with GIST harboring a PDGFRA exon 18 mutation, including 38 patients with the most common mutation, PDGFRA D842V.

For patients harboring a PDGFRA exon 18 mutation, the overall response rate (ORR) was 84%, with 7% having a complete response and 77% having a partial response. Patients with the PDGFRA D842V mutation achieved an ORR of 89%, with 8% having a complete response and 82% having a partial response.

“GIST harboring a PDGFRA exon 18 mutation do not respond to standard therapies ... Today’s approval provides patients with the first drug specifically approved for GIST harboring this mutation,” said Richard Pazdur, MD, director of the FDA’s Oncology Center of Excellence, in a statement at the time of approval.

The most common side effects (≥ 20% of patients) observed in patients taking avapritinib include nausea, fatigue, anemia, periorbital edema, face edema, hyperbilirubinemia, diarrhea, vomiting, peripheral edema, increased lacrimation, decreased appetite, and memory impairment. There may also be a risk of intracranial hemorrhage, in which case the dose should be reduced or the drug should be discontinued.

In the EU, conditional marketing authorization is granted to a medicinal product that fulfills an unmet medical need when the benefit to public health of immediate availability outweighs the risk inherent in the fact that additional data are still required, the CHMP notes on its website. 

Avapritinib had received an orphan medicine designation during development, which the EMA will review to determine if the designation can be maintained.

New treatment for CLL

Acalabrutinib is already approved in the United States, Canada, and Australia for the treatment of CLL and small lymphocytic lymphoma. The product was approved at the same time by all three regulatory authorities last year.  In the United States, acalabrutinib had previously been approved for use in mantle cell lymphoma.

The CHMP’s positive opinion of acalabrutinib is based on results from two phase 3 trials, ELEVATE TN and ASCEND.

In the ASCEND trial, acalabrutinib was compared with investigator’s choice of idelalisib or bendamustine with rituximab. The trial, which involved 310 patients with relapsed/refractory CLL, showed that acalabrutinib improved progression-free survival (PFS).

At a median follow-up of 16.1 months, the median PFS was not reached with acalabrutinib and was 16.5 months with investigator’s choice of therapy (P < .0001).

The most commonly reported adverse events seen with acalabrutinib were respiratory tract infections, headache, bruising, contusion, diarrhea, nausea, rash, musculoskeletal pain, fatigue, decreased hemoglobin, and decreased platelets.

In the ELEVATE TN trial, acalabrutinib was given alone or combined with obinutuzumab and compared to chlorambucil plus obinutuzumab in patients with previously untreated CLL. There were 535 patients randomized to receive acalabrutinib alone (n = 179), acalabrutinib plus obinutuzumab (n = 179), and chlorambucil plus obinutuzumab (n = 177).

At a median follow-up of 28 months, the median PFS was not reached with acalabrutinib alone or with acalabrutinib plus obinutuzumab, but the median PFS was 22.6 months in the chlorambucil-obinutuzumab arm (P < .0001 for both comparisons).

The most common adverse events in the acalabrutinib arms were headache, diarrhea, neutropenia, and nausea.
 

A version of this article first appeared on Medscape.com.

The European Medicines Agency’s (EMA) Committee for Medicinal Products for Human Use (CHMP) has given a thumbs up to avapritinib and acalabrutinib, paving the way for the drugs’ approval in the European Union (EU). 

The CHMP recommended granting conditional marketing authorization for avapritinib (Ayvakit, Blueprint Medicines) for use in adults with unresectable or metastatic gastrointestinal stromal tumors (GIST) harboring a platelet-derived growth factor receptor alpha (PDGFRA) exon 18 mutation, including PDGFRA D842V mutations. About 6%-10% of GIST tumors harbor this mutation, and avapritinib is a selective and potent inhibitor of KIT and PDGFRA mutant kinases.

The CHMP also adopted a positive opinion for acalabrutinib (Calquence, AstraZeneca) for the treatment of chronic lymphocytic leukemia (CLL) as monotherapy in patients who are treatment-naive or have received at least one prior therapy.

The CHMP opinion on both drugs will be reviewed by the European Commission, which has the authority to grant marketing authorization for medicinal products in the EU.

Detailed recommendations for the use of both drugs will be provided in the summary of product characteristics, which will be published in the European public assessment report and made available in all official EU languages after the products receive marketing authorization by the European Commission.

First targeted therapy for mutation

If approved by the European Commission, avapritinib would be the first treatment in the EU indicated for patients with PDGFRA D842V-mutant GIST.

Avapritinib was approved by the US Food and Drug Administration (FDA) earlier this year for the aforementioned indication. The FDA approval was based on findings from the phase 1 NAVIGATOR trial, which included 43 patients with GIST harboring a PDGFRA exon 18 mutation, including 38 patients with the most common mutation, PDGFRA D842V.

For patients harboring a PDGFRA exon 18 mutation, the overall response rate (ORR) was 84%, with 7% having a complete response and 77% having a partial response. Patients with the PDGFRA D842V mutation achieved an ORR of 89%, with 8% having a complete response and 82% having a partial response.

“GIST harboring a PDGFRA exon 18 mutation do not respond to standard therapies ... Today’s approval provides patients with the first drug specifically approved for GIST harboring this mutation,” said Richard Pazdur, MD, director of the FDA’s Oncology Center of Excellence, in a statement at the time of approval.

The most common side effects (≥ 20% of patients) observed in patients taking avapritinib include nausea, fatigue, anemia, periorbital edema, face edema, hyperbilirubinemia, diarrhea, vomiting, peripheral edema, increased lacrimation, decreased appetite, and memory impairment. There may also be a risk of intracranial hemorrhage, in which case the dose should be reduced or the drug should be discontinued.

In the EU, conditional marketing authorization is granted to a medicinal product that fulfills an unmet medical need when the benefit to public health of immediate availability outweighs the risk inherent in the fact that additional data are still required, the CHMP notes on its website. 

Avapritinib had received an orphan medicine designation during development, which the EMA will review to determine if the designation can be maintained.

New treatment for CLL

Acalabrutinib is already approved in the United States, Canada, and Australia for the treatment of CLL and small lymphocytic lymphoma. The product was approved at the same time by all three regulatory authorities last year.  In the United States, acalabrutinib had previously been approved for use in mantle cell lymphoma.

The CHMP’s positive opinion of acalabrutinib is based on results from two phase 3 trials, ELEVATE TN and ASCEND.

In the ASCEND trial, acalabrutinib was compared with investigator’s choice of idelalisib or bendamustine with rituximab. The trial, which involved 310 patients with relapsed/refractory CLL, showed that acalabrutinib improved progression-free survival (PFS).

At a median follow-up of 16.1 months, the median PFS was not reached with acalabrutinib and was 16.5 months with investigator’s choice of therapy (P < .0001).

The most commonly reported adverse events seen with acalabrutinib were respiratory tract infections, headache, bruising, contusion, diarrhea, nausea, rash, musculoskeletal pain, fatigue, decreased hemoglobin, and decreased platelets.

In the ELEVATE TN trial, acalabrutinib was given alone or combined with obinutuzumab and compared to chlorambucil plus obinutuzumab in patients with previously untreated CLL. There were 535 patients randomized to receive acalabrutinib alone (n = 179), acalabrutinib plus obinutuzumab (n = 179), and chlorambucil plus obinutuzumab (n = 177).

At a median follow-up of 28 months, the median PFS was not reached with acalabrutinib alone or with acalabrutinib plus obinutuzumab, but the median PFS was 22.6 months in the chlorambucil-obinutuzumab arm (P < .0001 for both comparisons).

The most common adverse events in the acalabrutinib arms were headache, diarrhea, neutropenia, and nausea.
 

A version of this article first appeared on Medscape.com.

The European Medicines Agency’s (EMA) Committee for Medicinal Products for Human Use (CHMP) has given a thumbs up to avapritinib and acalabrutinib, paving the way for the drugs’ approval in the European Union (EU). 

The CHMP recommended granting conditional marketing authorization for avapritinib (Ayvakit, Blueprint Medicines) for use in adults with unresectable or metastatic gastrointestinal stromal tumors (GIST) harboring a platelet-derived growth factor receptor alpha (PDGFRA) exon 18 mutation, including PDGFRA D842V mutations. About 6%-10% of GIST tumors harbor this mutation, and avapritinib is a selective and potent inhibitor of KIT and PDGFRA mutant kinases.

The CHMP also adopted a positive opinion for acalabrutinib (Calquence, AstraZeneca) for the treatment of chronic lymphocytic leukemia (CLL) as monotherapy in patients who are treatment-naive or have received at least one prior therapy.

The CHMP opinion on both drugs will be reviewed by the European Commission, which has the authority to grant marketing authorization for medicinal products in the EU.

Detailed recommendations for the use of both drugs will be provided in the summary of product characteristics, which will be published in the European public assessment report and made available in all official EU languages after the products receive marketing authorization by the European Commission.

First targeted therapy for mutation

If approved by the European Commission, avapritinib would be the first treatment in the EU indicated for patients with PDGFRA D842V-mutant GIST.

Avapritinib was approved by the US Food and Drug Administration (FDA) earlier this year for the aforementioned indication. The FDA approval was based on findings from the phase 1 NAVIGATOR trial, which included 43 patients with GIST harboring a PDGFRA exon 18 mutation, including 38 patients with the most common mutation, PDGFRA D842V.

For patients harboring a PDGFRA exon 18 mutation, the overall response rate (ORR) was 84%, with 7% having a complete response and 77% having a partial response. Patients with the PDGFRA D842V mutation achieved an ORR of 89%, with 8% having a complete response and 82% having a partial response.

“GIST harboring a PDGFRA exon 18 mutation do not respond to standard therapies ... Today’s approval provides patients with the first drug specifically approved for GIST harboring this mutation,” said Richard Pazdur, MD, director of the FDA’s Oncology Center of Excellence, in a statement at the time of approval.

The most common side effects (≥ 20% of patients) observed in patients taking avapritinib include nausea, fatigue, anemia, periorbital edema, face edema, hyperbilirubinemia, diarrhea, vomiting, peripheral edema, increased lacrimation, decreased appetite, and memory impairment. There may also be a risk of intracranial hemorrhage, in which case the dose should be reduced or the drug should be discontinued.

In the EU, conditional marketing authorization is granted to a medicinal product that fulfills an unmet medical need when the benefit to public health of immediate availability outweighs the risk inherent in the fact that additional data are still required, the CHMP notes on its website. 

Avapritinib had received an orphan medicine designation during development, which the EMA will review to determine if the designation can be maintained.

New treatment for CLL

Acalabrutinib is already approved in the United States, Canada, and Australia for the treatment of CLL and small lymphocytic lymphoma. The product was approved at the same time by all three regulatory authorities last year.  In the United States, acalabrutinib had previously been approved for use in mantle cell lymphoma.

The CHMP’s positive opinion of acalabrutinib is based on results from two phase 3 trials, ELEVATE TN and ASCEND.

In the ASCEND trial, acalabrutinib was compared with investigator’s choice of idelalisib or bendamustine with rituximab. The trial, which involved 310 patients with relapsed/refractory CLL, showed that acalabrutinib improved progression-free survival (PFS).

At a median follow-up of 16.1 months, the median PFS was not reached with acalabrutinib and was 16.5 months with investigator’s choice of therapy (P < .0001).

The most commonly reported adverse events seen with acalabrutinib were respiratory tract infections, headache, bruising, contusion, diarrhea, nausea, rash, musculoskeletal pain, fatigue, decreased hemoglobin, and decreased platelets.

In the ELEVATE TN trial, acalabrutinib was given alone or combined with obinutuzumab and compared to chlorambucil plus obinutuzumab in patients with previously untreated CLL. There were 535 patients randomized to receive acalabrutinib alone (n = 179), acalabrutinib plus obinutuzumab (n = 179), and chlorambucil plus obinutuzumab (n = 177).

At a median follow-up of 28 months, the median PFS was not reached with acalabrutinib alone or with acalabrutinib plus obinutuzumab, but the median PFS was 22.6 months in the chlorambucil-obinutuzumab arm (P < .0001 for both comparisons).

The most common adverse events in the acalabrutinib arms were headache, diarrhea, neutropenia, and nausea.
 

A version of this article first appeared on Medscape.com.

When a patient with cancer hears there isn’t much left that doctors can do, it always stays fresh in the mind.

Doug Olson was first diagnosed with chronic lymphocytic leukemia (CLL) over 20 years ago, in 1996. For several years, his doctors used the watch-and-wait approach. But then his cancer progressed and needed treatment. By 2010, it had mutated so much that it no longer responded to standard therapy.

He was rapidly running out of options. Back then, the only treatment left was a bone marrow transplant. Without one, his doctors said, he would have 1 or 2 years left to live.

“I was really trying to avoid a bone marrow transplant. You’re playing your last card if that doesn’t work. It’s a pretty rough procedure,” Olson told Medscape Medical News.

Looking back, Olson counts himself as lucky – for being in the right place, at the right time, with the right doctor. His oncologist was David Porter, MD, the principal investigator on a trial at the University of Pennsylvania that was investigating a brand new approach to treating cancer: chimeric antigen receptor (CAR) T-cell therapy.

CAR T-cell therapy uses a patient’s own T cells engineered to express a receptor that targets proteins on cancer cells. CAR T cells are considered “living drugs” because they expand inside the body and stick around for years – maybe for a lifetime – to fight the cancer if it tries to come back.

“I was certainly intrigued by the approach. It had worked in mice, and it was the sort of thing that looked like it would work,” Olson recalled.

Science is not a foreign language to Olson. He holds a PhD in medicinal chemistry, spent most of his career in the in vitro diagnostics industry, and currently acts as chief executive officer of Buhlmann Diagnostics Corp.

So he read the clinical protocol for the first in-human trial of CAR T cells and agreed to become patient number two.

Olson’s T cells were harvested, engineered to attack the CD19 antigen found on malignant and normal B lymphocytes, and then were expanded into millions in the lab. After undergoing preconditioning with chemotherapy to minimize rejection and boost the CAR T cells’ expansion inside the body, he received several infusions of the new therapy over the course of 3 days.

Nothing really happened for 2 weeks. Then he developed severe flu-like symptoms – so bad that he was hospitalized.

Ironically, getting sick was a sign that the CAR T cells were working. Olson was experiencing one of the main short-term effects of CAR T-cell therapy: cytokine release syndrome. Symptoms include extremely high fevers and dangerous drops in blood pressure that can potentially cause end-organ damage.

In the early trials of these products, some patients experienced such a severe reaction that they needed intensive care, and some died. With increasing clinical experience, doctors have learned to control the reaction with the use of steroids and interleukein-6 inhibitors such as tocilizumab (Actemra).

Fortunately for Olson, the reaction passed, and he was eventually discharged.

Then the “aha moment” happened. Four weeks after receiving the CAR T cells, Olson found out that he was cancer free.

“It still gives me shivers,” he said. “Dr Porter said, ‘Your bone marrow’s completely free. We just can’t find a cancer cell anywhere.’ “

The remission has lasted, and it is now 10 years later.
 

Balancing long-term risks vs benefits

Long-term data have been accumulating for these novel therapies since Olson’s treatment in 2010. This is particularly important for CAR T-cell therapy, because of its longevity. Because these are living cells and are expected to persist in the body for years, there is great interest in longer-term data, especially the risks for toxicity.

The FDA requires clinical follow-up for at least 15 years for patients treated with CAR T-cell therapy or any other genetically modified cells.

So far, most of the experience with CAR T cells comes from anti-CD19-directed therapy, which has shown “remarkable” remission rates in the 50% to 85% range, said Nirali Shah, MD, head of the hematologic malignancies section of the Pediatric Oncology Branch at the National Cancer Institute (NCI).

The most recent results presented at this year’s annual meeting of the American Society of Clinical Oncology support earlier efficacy data, she noted. In the longest follow-up to date, researchers reported remissions lasting over 9 years in patients with relapsed/refractory B-cell lymphoma or CLL treated with Kite›s axicaptagene cilleucel (Yescarta), one of two anti-CD19-directed CAR T-cell therapies approved by the FDA in 2017 (the other is Novartis’ tisagenlecleucel [Kymriah]).

This study included 43 patients and showed an overall remission rate of 76%. Complete remission was achieved in 54% of patients, and 22% had partial remission.

The other focus is long-term safety. Although some of the long-term adverse effects are known and are manageable, others fall into the theoretical realm. In early May 2020, the NCI held a multidisciplinary virtual conference on CAR T-cell therapy «to encourage collaborative research about the subacute and potentially long-term toxicity profile of these treatments.»

“We know just a little at this point about late- and long-term effects of CAR-T therapy, because we are relatively early in the era of CAR T cells,” said Merav Bar, MD, from the Fred Hutchinson Cancer Research Center in Seattle, Washington.
 

B-cell aplasia and risk for new infections

What is known is that B-cell aplasia represents the most common long-term adverse effect of CAR T-cell therapy. B-cell aplasia results when anti-CD19 CAR-T therapy wipes out healthy B cells as well as the malignant ones responsible for leukemia/lymphoma.

As major players in the immune system, B cells are a key defense against viruses. So B-cell aplasia represents a very specific type of immunosuppression. It is generally less severe than immunosuppression that occurs after organ transplant, which hits the immune system pretty much across the board and carries a much higher risk for infection.

The main concern is what happens when someone with B-cell aplasia encounters a new pathogen, such as SARS-CoV-2.

After infection, B cells generate memory cells, which are not killed off by anti-CD19 therapy and that stick around for life. So a patient such as Olson would still make antibodies that fight infections they experienced before receiving CAR-T therapy, such as childhood chickenpox. But now they are unable to make new memory cells, so these patients receive monthly immunoglobulin infusions to protect against pathogens they have not previously encountered.

Olson takes this in stride and says he isn’t overly worried about COVID-19. He follows the recommended precautions for a man his age. He wears a mask, washes his hands frequently, and tries to maintain social distancing. But he doesn’t stay locked up in his New Hampshire home.

“I took the attitude when I was diagnosed with cancer that I’m going to live my life,” he said. “Quality of life to me is more important than quantity.”
 

Neuropsychiatric toxicity

Another problem is the possibility of neuropsychiatric toxicity. Past studies have reported a wide range of such toxicities associated with CAR T-cell therapy, including seizures and hallucinations. Most have occurred early in the course of treatment and appear to be short-lived and reversible. However, there remain questions about long-term neuropsychiatric problems.

In a long-term study of 40 patients with relapsed/refractory CLL, non-Hodgkin lymphoma, and ALL, nearly half of patients (47.5%, 19/40) self-reported at least one clinically meaningful negative neuropsychiatric outcome (anxiety, depression, or cognitive difficulty) 1 to 5 years after anti-CD19 CAR T-cell therapy. In addition, 37.5% (15/40) self-reported cognitive difficulties.

“Patients with more severe neurotoxicity showed a trend for more cognitive difficulties afterwards,» said Bar, senior author of the study.

However, teasing out the role that CAR T-cell therapy plays in these problems poses a challenge. All of these patients had been heavily pretreated with previous cancer therapy, which has also been associated with neuropsychiatric problems.

“So far, we don’t know what caused it,” Bar said. “Nevertheless, people need to pay attention to neuropsychiatric symptoms in CAR T-cell therapy. It is important to continue to monitor these patients for these issues.”
 

Graft-vs-host disease

Another potential problem is graft-vs-host disease (GVHD). This is not uncommon after hematopoietic stem cell transplants. It develops when the donor T cells view antigens on healthy recipient cells as foreign and attack them.

For patients who are treated with CAR T cells, GVHD is mostly a concern among individuals who have previously had a transplant and who are already at increased risk for it.

In a study of late effects among 86 adults treated with anti-CD19 CAR T cells for relapsed/refractory non-Hodgkin lymphoma, Bar and colleagues found that GVHD occurred only among patients who had received a previous donor stem cell transplant. Of these, 20% (3/15) developed GVHD about 28 months after CAR-T therapy.

“The data for CAR T cells causing GVHD really hasn’t shown that it’s a huge problem, although we have seen it and are continuing to monitor for it,” the NCI’s Shah commented to Medscape Medical News.

Other Long-term Adverse Effects

A range of other long-term adverse effects have been reported with CAR-T therapy, including prolonged cytopenias (reduced mature blood cells), myelodysplasia (bone marrow failure), and second malignancies.

In the study with the longest follow-up to date, 16% (7/43) of patients developed second malignancies, which is comparable to data from Bar’s study in Seattle (15%, 13/86). The researchers in this study consider this rate to be no higher than expected: these patients had already received extensive chemotherapy, which increases the risk for other cancers, they point out.

However, this brings up theoretical concerns about the long-term effects of gene modification. CAR T cells are engineered using retroviruses (mainly lentiviruses), which randomly insert the CAR genes into the host genome. Doing so may cause mutations that could promote cancer. These lentiviruses also carry the theoretical risk of becoming capable of viral replication once inside the body.

To address these concerns, viruses used to engineer CAR T cells go through comprehensive safety testing. After therapy, patients are checked every few months during the first year and annually after that.

So far, there have been no reports of cancers associated with CAR T-cell therapy.

“Any type of cancer is a very theoretical risk,” Bar told Medscape Medical News. «Most likely the malignancies in our study were related to prior treatment that the patients received. None of them had any evidence of replication-competent lentivirus, or any other evidence that the malignancies were related to the CAR T cells.»

Another theoretical concern is the possibility of new-onset autoimmune disease, although, once again, no cases have been reported so far.

“We think of it as a theoretic possibility. Whenever you jack up the immune system, autoimmune disease is a potential risk,” said Carl June, MD, director of the Center for Cellular Immunotherapies at the University of Pennsylvania.

June was the co–principal investigator of the trial in which Olson participated. He is also the inventor on patents for CAR T cells licensed by the University of Pennsylvania to Novartis and Tmunity and is a scientific founder with equity in Tmunity.

Still, autoimmunity could occur, and scientists are looking out for it.

“We are continuing to be vigilant in our monitoring for autoimmune disease,” Shah added. “We’ve been doing CAR T-cell therapy since 2012, and I think we have yet to see true autoimmunity beyond GVHD.”
 

Future directions

In the 10 years since Olson received CAR T-cell therapy, an entire industry has sprung up. Over 100 companies worldwide are now developing CAR T-cell therapies targeting various antigens. These therapies are directed at about 60 different tumor types, including solid tumors. Nearly 200 clinical trials are underway, though most are still in early stages: as of September 2019, only 5% had reached phase 3.

Clinical data show promising results for CAR T-cell therapy directed against CD22 (overexpressed on ALL cells), and BCMA (found on almost all multiple myeloma cells). Yet questions remain as to whether CAR T cells will be as effective if they target antigens other than CD19 or cells other than B lymphocytes. One of the biggest research questions is whether they will be effective against solid tumors.

One research avenue being watched with great interest is the development of universal CAR T cells. So far, such products are at very early stages of development (phase 1 trials), but they are attractive because of the potential advantages they offer over bespoke CAR T cells. Automating the process holds the promise of immediate availability, standardizing production, expanding access, and lowering costs. And because the T cells for this universal product come from healthy donors, they may function better than T cells that have been battered and bruised by past cancer treatments, or even the cancer itself.

However, precisely because they are developed from healthy donor T cells, universal CAR T cells may pose increased risk for GVHD. Scientists are trying to get around this problem by engineering universal CAR T cells that lack the T-cell receptor involved in GVHD.

There are also other concerns. Nature has a penchant for mutation. Engineering CAR T cells without T-cell receptors means the body may no longer detect or reject a universal CAR T cell if it goes rogue. Also, gene insertion in universal CAR-T therapy is targeted rather than random (as in bespoke CAR T cells), which could create off-target effects. Both issues create a theoretical risk of such products inducing an untreatable CAR T-cell therapy–associated cancer.

“The theoretic risk with universal cells is that their safety profile may not be as good for long term,” June commented.
 

Hope for the future

From that first trial in which June and Porter used CAR T cells, two of three patients they treated are still alive 10 years later.

Olson is one of these two, and he still undergoes monitoring every 3 months to check for relapse. So far, none of his tests have shown signs of his cancer returning.

After going into remission, Doug spent the next 6 to 9 months regaining his health and strength.

“I figured if I had this amazing treatment that saved my life, I had an obligation to stay alive,” he said. “I’d better not die of something like a heart attack!”

He took up long distance running and has completed six half marathons. He became involved in the Leukemia and Lymphoma Society, participating in fund-raising and helping newly diagnosed patients. Over the years, he has also given talks for researchers, people with cancer, and healthcare providers.

Doug is now 73. Today, he marvels at how rapidly the CAR-T field has progressed.

“Twenty years ago, if you had cancer, your prospects weren’t nearly as good as these days. In 2010, people still didn’t believe in CAR T-cell therapy,” he said. “My goal always in telling my story is a message of hope.”

This article first appeared on Medscape.com.

When a patient with cancer hears there isn’t much left that doctors can do, it always stays fresh in the mind.

Doug Olson was first diagnosed with chronic lymphocytic leukemia (CLL) over 20 years ago, in 1996. For several years, his doctors used the watch-and-wait approach. But then his cancer progressed and needed treatment. By 2010, it had mutated so much that it no longer responded to standard therapy.

He was rapidly running out of options. Back then, the only treatment left was a bone marrow transplant. Without one, his doctors said, he would have 1 or 2 years left to live.

“I was really trying to avoid a bone marrow transplant. You’re playing your last card if that doesn’t work. It’s a pretty rough procedure,” Olson told Medscape Medical News.

Looking back, Olson counts himself as lucky – for being in the right place, at the right time, with the right doctor. His oncologist was David Porter, MD, the principal investigator on a trial at the University of Pennsylvania that was investigating a brand new approach to treating cancer: chimeric antigen receptor (CAR) T-cell therapy.

CAR T-cell therapy uses a patient’s own T cells engineered to express a receptor that targets proteins on cancer cells. CAR T cells are considered “living drugs” because they expand inside the body and stick around for years – maybe for a lifetime – to fight the cancer if it tries to come back.

“I was certainly intrigued by the approach. It had worked in mice, and it was the sort of thing that looked like it would work,” Olson recalled.

Science is not a foreign language to Olson. He holds a PhD in medicinal chemistry, spent most of his career in the in vitro diagnostics industry, and currently acts as chief executive officer of Buhlmann Diagnostics Corp.

So he read the clinical protocol for the first in-human trial of CAR T cells and agreed to become patient number two.

Olson’s T cells were harvested, engineered to attack the CD19 antigen found on malignant and normal B lymphocytes, and then were expanded into millions in the lab. After undergoing preconditioning with chemotherapy to minimize rejection and boost the CAR T cells’ expansion inside the body, he received several infusions of the new therapy over the course of 3 days.

Nothing really happened for 2 weeks. Then he developed severe flu-like symptoms – so bad that he was hospitalized.

Ironically, getting sick was a sign that the CAR T cells were working. Olson was experiencing one of the main short-term effects of CAR T-cell therapy: cytokine release syndrome. Symptoms include extremely high fevers and dangerous drops in blood pressure that can potentially cause end-organ damage.

In the early trials of these products, some patients experienced such a severe reaction that they needed intensive care, and some died. With increasing clinical experience, doctors have learned to control the reaction with the use of steroids and interleukein-6 inhibitors such as tocilizumab (Actemra).

Fortunately for Olson, the reaction passed, and he was eventually discharged.

Then the “aha moment” happened. Four weeks after receiving the CAR T cells, Olson found out that he was cancer free.

“It still gives me shivers,” he said. “Dr Porter said, ‘Your bone marrow’s completely free. We just can’t find a cancer cell anywhere.’ “

The remission has lasted, and it is now 10 years later.
 

Balancing long-term risks vs benefits

Long-term data have been accumulating for these novel therapies since Olson’s treatment in 2010. This is particularly important for CAR T-cell therapy, because of its longevity. Because these are living cells and are expected to persist in the body for years, there is great interest in longer-term data, especially the risks for toxicity.

The FDA requires clinical follow-up for at least 15 years for patients treated with CAR T-cell therapy or any other genetically modified cells.

So far, most of the experience with CAR T cells comes from anti-CD19-directed therapy, which has shown “remarkable” remission rates in the 50% to 85% range, said Nirali Shah, MD, head of the hematologic malignancies section of the Pediatric Oncology Branch at the National Cancer Institute (NCI).

The most recent results presented at this year’s annual meeting of the American Society of Clinical Oncology support earlier efficacy data, she noted. In the longest follow-up to date, researchers reported remissions lasting over 9 years in patients with relapsed/refractory B-cell lymphoma or CLL treated with Kite›s axicaptagene cilleucel (Yescarta), one of two anti-CD19-directed CAR T-cell therapies approved by the FDA in 2017 (the other is Novartis’ tisagenlecleucel [Kymriah]).

This study included 43 patients and showed an overall remission rate of 76%. Complete remission was achieved in 54% of patients, and 22% had partial remission.

The other focus is long-term safety. Although some of the long-term adverse effects are known and are manageable, others fall into the theoretical realm. In early May 2020, the NCI held a multidisciplinary virtual conference on CAR T-cell therapy «to encourage collaborative research about the subacute and potentially long-term toxicity profile of these treatments.»

“We know just a little at this point about late- and long-term effects of CAR-T therapy, because we are relatively early in the era of CAR T cells,” said Merav Bar, MD, from the Fred Hutchinson Cancer Research Center in Seattle, Washington.
 

B-cell aplasia and risk for new infections

What is known is that B-cell aplasia represents the most common long-term adverse effect of CAR T-cell therapy. B-cell aplasia results when anti-CD19 CAR-T therapy wipes out healthy B cells as well as the malignant ones responsible for leukemia/lymphoma.

As major players in the immune system, B cells are a key defense against viruses. So B-cell aplasia represents a very specific type of immunosuppression. It is generally less severe than immunosuppression that occurs after organ transplant, which hits the immune system pretty much across the board and carries a much higher risk for infection.

The main concern is what happens when someone with B-cell aplasia encounters a new pathogen, such as SARS-CoV-2.

After infection, B cells generate memory cells, which are not killed off by anti-CD19 therapy and that stick around for life. So a patient such as Olson would still make antibodies that fight infections they experienced before receiving CAR-T therapy, such as childhood chickenpox. But now they are unable to make new memory cells, so these patients receive monthly immunoglobulin infusions to protect against pathogens they have not previously encountered.

Olson takes this in stride and says he isn’t overly worried about COVID-19. He follows the recommended precautions for a man his age. He wears a mask, washes his hands frequently, and tries to maintain social distancing. But he doesn’t stay locked up in his New Hampshire home.

“I took the attitude when I was diagnosed with cancer that I’m going to live my life,” he said. “Quality of life to me is more important than quantity.”
 

Neuropsychiatric toxicity

Another problem is the possibility of neuropsychiatric toxicity. Past studies have reported a wide range of such toxicities associated with CAR T-cell therapy, including seizures and hallucinations. Most have occurred early in the course of treatment and appear to be short-lived and reversible. However, there remain questions about long-term neuropsychiatric problems.

In a long-term study of 40 patients with relapsed/refractory CLL, non-Hodgkin lymphoma, and ALL, nearly half of patients (47.5%, 19/40) self-reported at least one clinically meaningful negative neuropsychiatric outcome (anxiety, depression, or cognitive difficulty) 1 to 5 years after anti-CD19 CAR T-cell therapy. In addition, 37.5% (15/40) self-reported cognitive difficulties.

“Patients with more severe neurotoxicity showed a trend for more cognitive difficulties afterwards,» said Bar, senior author of the study.

However, teasing out the role that CAR T-cell therapy plays in these problems poses a challenge. All of these patients had been heavily pretreated with previous cancer therapy, which has also been associated with neuropsychiatric problems.

“So far, we don’t know what caused it,” Bar said. “Nevertheless, people need to pay attention to neuropsychiatric symptoms in CAR T-cell therapy. It is important to continue to monitor these patients for these issues.”
 

Graft-vs-host disease

Another potential problem is graft-vs-host disease (GVHD). This is not uncommon after hematopoietic stem cell transplants. It develops when the donor T cells view antigens on healthy recipient cells as foreign and attack them.

For patients who are treated with CAR T cells, GVHD is mostly a concern among individuals who have previously had a transplant and who are already at increased risk for it.

In a study of late effects among 86 adults treated with anti-CD19 CAR T cells for relapsed/refractory non-Hodgkin lymphoma, Bar and colleagues found that GVHD occurred only among patients who had received a previous donor stem cell transplant. Of these, 20% (3/15) developed GVHD about 28 months after CAR-T therapy.

“The data for CAR T cells causing GVHD really hasn’t shown that it’s a huge problem, although we have seen it and are continuing to monitor for it,” the NCI’s Shah commented to Medscape Medical News.

Other Long-term Adverse Effects

A range of other long-term adverse effects have been reported with CAR-T therapy, including prolonged cytopenias (reduced mature blood cells), myelodysplasia (bone marrow failure), and second malignancies.

In the study with the longest follow-up to date, 16% (7/43) of patients developed second malignancies, which is comparable to data from Bar’s study in Seattle (15%, 13/86). The researchers in this study consider this rate to be no higher than expected: these patients had already received extensive chemotherapy, which increases the risk for other cancers, they point out.

However, this brings up theoretical concerns about the long-term effects of gene modification. CAR T cells are engineered using retroviruses (mainly lentiviruses), which randomly insert the CAR genes into the host genome. Doing so may cause mutations that could promote cancer. These lentiviruses also carry the theoretical risk of becoming capable of viral replication once inside the body.

To address these concerns, viruses used to engineer CAR T cells go through comprehensive safety testing. After therapy, patients are checked every few months during the first year and annually after that.

So far, there have been no reports of cancers associated with CAR T-cell therapy.

“Any type of cancer is a very theoretical risk,” Bar told Medscape Medical News. «Most likely the malignancies in our study were related to prior treatment that the patients received. None of them had any evidence of replication-competent lentivirus, or any other evidence that the malignancies were related to the CAR T cells.»

Another theoretical concern is the possibility of new-onset autoimmune disease, although, once again, no cases have been reported so far.

“We think of it as a theoretic possibility. Whenever you jack up the immune system, autoimmune disease is a potential risk,” said Carl June, MD, director of the Center for Cellular Immunotherapies at the University of Pennsylvania.

June was the co–principal investigator of the trial in which Olson participated. He is also the inventor on patents for CAR T cells licensed by the University of Pennsylvania to Novartis and Tmunity and is a scientific founder with equity in Tmunity.

Still, autoimmunity could occur, and scientists are looking out for it.

“We are continuing to be vigilant in our monitoring for autoimmune disease,” Shah added. “We’ve been doing CAR T-cell therapy since 2012, and I think we have yet to see true autoimmunity beyond GVHD.”
 

Future directions

In the 10 years since Olson received CAR T-cell therapy, an entire industry has sprung up. Over 100 companies worldwide are now developing CAR T-cell therapies targeting various antigens. These therapies are directed at about 60 different tumor types, including solid tumors. Nearly 200 clinical trials are underway, though most are still in early stages: as of September 2019, only 5% had reached phase 3.

Clinical data show promising results for CAR T-cell therapy directed against CD22 (overexpressed on ALL cells), and BCMA (found on almost all multiple myeloma cells). Yet questions remain as to whether CAR T cells will be as effective if they target antigens other than CD19 or cells other than B lymphocytes. One of the biggest research questions is whether they will be effective against solid tumors.

One research avenue being watched with great interest is the development of universal CAR T cells. So far, such products are at very early stages of development (phase 1 trials), but they are attractive because of the potential advantages they offer over bespoke CAR T cells. Automating the process holds the promise of immediate availability, standardizing production, expanding access, and lowering costs. And because the T cells for this universal product come from healthy donors, they may function better than T cells that have been battered and bruised by past cancer treatments, or even the cancer itself.

However, precisely because they are developed from healthy donor T cells, universal CAR T cells may pose increased risk for GVHD. Scientists are trying to get around this problem by engineering universal CAR T cells that lack the T-cell receptor involved in GVHD.

There are also other concerns. Nature has a penchant for mutation. Engineering CAR T cells without T-cell receptors means the body may no longer detect or reject a universal CAR T cell if it goes rogue. Also, gene insertion in universal CAR-T therapy is targeted rather than random (as in bespoke CAR T cells), which could create off-target effects. Both issues create a theoretical risk of such products inducing an untreatable CAR T-cell therapy–associated cancer.

“The theoretic risk with universal cells is that their safety profile may not be as good for long term,” June commented.
 

Hope for the future

From that first trial in which June and Porter used CAR T cells, two of three patients they treated are still alive 10 years later.

Olson is one of these two, and he still undergoes monitoring every 3 months to check for relapse. So far, none of his tests have shown signs of his cancer returning.

After going into remission, Doug spent the next 6 to 9 months regaining his health and strength.

“I figured if I had this amazing treatment that saved my life, I had an obligation to stay alive,” he said. “I’d better not die of something like a heart attack!”

He took up long distance running and has completed six half marathons. He became involved in the Leukemia and Lymphoma Society, participating in fund-raising and helping newly diagnosed patients. Over the years, he has also given talks for researchers, people with cancer, and healthcare providers.

Doug is now 73. Today, he marvels at how rapidly the CAR-T field has progressed.

“Twenty years ago, if you had cancer, your prospects weren’t nearly as good as these days. In 2010, people still didn’t believe in CAR T-cell therapy,” he said. “My goal always in telling my story is a message of hope.”

This article first appeared on Medscape.com.

When a patient with cancer hears there isn’t much left that doctors can do, it always stays fresh in the mind.

Doug Olson was first diagnosed with chronic lymphocytic leukemia (CLL) over 20 years ago, in 1996. For several years, his doctors used the watch-and-wait approach. But then his cancer progressed and needed treatment. By 2010, it had mutated so much that it no longer responded to standard therapy.

He was rapidly running out of options. Back then, the only treatment left was a bone marrow transplant. Without one, his doctors said, he would have 1 or 2 years left to live.

“I was really trying to avoid a bone marrow transplant. You’re playing your last card if that doesn’t work. It’s a pretty rough procedure,” Olson told Medscape Medical News.

Looking back, Olson counts himself as lucky – for being in the right place, at the right time, with the right doctor. His oncologist was David Porter, MD, the principal investigator on a trial at the University of Pennsylvania that was investigating a brand new approach to treating cancer: chimeric antigen receptor (CAR) T-cell therapy.

CAR T-cell therapy uses a patient’s own T cells engineered to express a receptor that targets proteins on cancer cells. CAR T cells are considered “living drugs” because they expand inside the body and stick around for years – maybe for a lifetime – to fight the cancer if it tries to come back.

“I was certainly intrigued by the approach. It had worked in mice, and it was the sort of thing that looked like it would work,” Olson recalled.

Science is not a foreign language to Olson. He holds a PhD in medicinal chemistry, spent most of his career in the in vitro diagnostics industry, and currently acts as chief executive officer of Buhlmann Diagnostics Corp.

So he read the clinical protocol for the first in-human trial of CAR T cells and agreed to become patient number two.

Olson’s T cells were harvested, engineered to attack the CD19 antigen found on malignant and normal B lymphocytes, and then were expanded into millions in the lab. After undergoing preconditioning with chemotherapy to minimize rejection and boost the CAR T cells’ expansion inside the body, he received several infusions of the new therapy over the course of 3 days.

Nothing really happened for 2 weeks. Then he developed severe flu-like symptoms – so bad that he was hospitalized.

Ironically, getting sick was a sign that the CAR T cells were working. Olson was experiencing one of the main short-term effects of CAR T-cell therapy: cytokine release syndrome. Symptoms include extremely high fevers and dangerous drops in blood pressure that can potentially cause end-organ damage.

In the early trials of these products, some patients experienced such a severe reaction that they needed intensive care, and some died. With increasing clinical experience, doctors have learned to control the reaction with the use of steroids and interleukein-6 inhibitors such as tocilizumab (Actemra).

Fortunately for Olson, the reaction passed, and he was eventually discharged.

Then the “aha moment” happened. Four weeks after receiving the CAR T cells, Olson found out that he was cancer free.

“It still gives me shivers,” he said. “Dr Porter said, ‘Your bone marrow’s completely free. We just can’t find a cancer cell anywhere.’ “

The remission has lasted, and it is now 10 years later.
 

Balancing long-term risks vs benefits

Long-term data have been accumulating for these novel therapies since Olson’s treatment in 2010. This is particularly important for CAR T-cell therapy, because of its longevity. Because these are living cells and are expected to persist in the body for years, there is great interest in longer-term data, especially the risks for toxicity.

The FDA requires clinical follow-up for at least 15 years for patients treated with CAR T-cell therapy or any other genetically modified cells.

So far, most of the experience with CAR T cells comes from anti-CD19-directed therapy, which has shown “remarkable” remission rates in the 50% to 85% range, said Nirali Shah, MD, head of the hematologic malignancies section of the Pediatric Oncology Branch at the National Cancer Institute (NCI).

The most recent results presented at this year’s annual meeting of the American Society of Clinical Oncology support earlier efficacy data, she noted. In the longest follow-up to date, researchers reported remissions lasting over 9 years in patients with relapsed/refractory B-cell lymphoma or CLL treated with Kite›s axicaptagene cilleucel (Yescarta), one of two anti-CD19-directed CAR T-cell therapies approved by the FDA in 2017 (the other is Novartis’ tisagenlecleucel [Kymriah]).

This study included 43 patients and showed an overall remission rate of 76%. Complete remission was achieved in 54% of patients, and 22% had partial remission.

The other focus is long-term safety. Although some of the long-term adverse effects are known and are manageable, others fall into the theoretical realm. In early May 2020, the NCI held a multidisciplinary virtual conference on CAR T-cell therapy «to encourage collaborative research about the subacute and potentially long-term toxicity profile of these treatments.»

“We know just a little at this point about late- and long-term effects of CAR-T therapy, because we are relatively early in the era of CAR T cells,” said Merav Bar, MD, from the Fred Hutchinson Cancer Research Center in Seattle, Washington.
 

B-cell aplasia and risk for new infections

What is known is that B-cell aplasia represents the most common long-term adverse effect of CAR T-cell therapy. B-cell aplasia results when anti-CD19 CAR-T therapy wipes out healthy B cells as well as the malignant ones responsible for leukemia/lymphoma.

As major players in the immune system, B cells are a key defense against viruses. So B-cell aplasia represents a very specific type of immunosuppression. It is generally less severe than immunosuppression that occurs after organ transplant, which hits the immune system pretty much across the board and carries a much higher risk for infection.

The main concern is what happens when someone with B-cell aplasia encounters a new pathogen, such as SARS-CoV-2.

After infection, B cells generate memory cells, which are not killed off by anti-CD19 therapy and that stick around for life. So a patient such as Olson would still make antibodies that fight infections they experienced before receiving CAR-T therapy, such as childhood chickenpox. But now they are unable to make new memory cells, so these patients receive monthly immunoglobulin infusions to protect against pathogens they have not previously encountered.

Olson takes this in stride and says he isn’t overly worried about COVID-19. He follows the recommended precautions for a man his age. He wears a mask, washes his hands frequently, and tries to maintain social distancing. But he doesn’t stay locked up in his New Hampshire home.

“I took the attitude when I was diagnosed with cancer that I’m going to live my life,” he said. “Quality of life to me is more important than quantity.”
 

Neuropsychiatric toxicity

Another problem is the possibility of neuropsychiatric toxicity. Past studies have reported a wide range of such toxicities associated with CAR T-cell therapy, including seizures and hallucinations. Most have occurred early in the course of treatment and appear to be short-lived and reversible. However, there remain questions about long-term neuropsychiatric problems.

In a long-term study of 40 patients with relapsed/refractory CLL, non-Hodgkin lymphoma, and ALL, nearly half of patients (47.5%, 19/40) self-reported at least one clinically meaningful negative neuropsychiatric outcome (anxiety, depression, or cognitive difficulty) 1 to 5 years after anti-CD19 CAR T-cell therapy. In addition, 37.5% (15/40) self-reported cognitive difficulties.

“Patients with more severe neurotoxicity showed a trend for more cognitive difficulties afterwards,» said Bar, senior author of the study.

However, teasing out the role that CAR T-cell therapy plays in these problems poses a challenge. All of these patients had been heavily pretreated with previous cancer therapy, which has also been associated with neuropsychiatric problems.

“So far, we don’t know what caused it,” Bar said. “Nevertheless, people need to pay attention to neuropsychiatric symptoms in CAR T-cell therapy. It is important to continue to monitor these patients for these issues.”
 

Graft-vs-host disease

Another potential problem is graft-vs-host disease (GVHD). This is not uncommon after hematopoietic stem cell transplants. It develops when the donor T cells view antigens on healthy recipient cells as foreign and attack them.

For patients who are treated with CAR T cells, GVHD is mostly a concern among individuals who have previously had a transplant and who are already at increased risk for it.

In a study of late effects among 86 adults treated with anti-CD19 CAR T cells for relapsed/refractory non-Hodgkin lymphoma, Bar and colleagues found that GVHD occurred only among patients who had received a previous donor stem cell transplant. Of these, 20% (3/15) developed GVHD about 28 months after CAR-T therapy.

“The data for CAR T cells causing GVHD really hasn’t shown that it’s a huge problem, although we have seen it and are continuing to monitor for it,” the NCI’s Shah commented to Medscape Medical News.

Other Long-term Adverse Effects

A range of other long-term adverse effects have been reported with CAR-T therapy, including prolonged cytopenias (reduced mature blood cells), myelodysplasia (bone marrow failure), and second malignancies.

In the study with the longest follow-up to date, 16% (7/43) of patients developed second malignancies, which is comparable to data from Bar’s study in Seattle (15%, 13/86). The researchers in this study consider this rate to be no higher than expected: these patients had already received extensive chemotherapy, which increases the risk for other cancers, they point out.

However, this brings up theoretical concerns about the long-term effects of gene modification. CAR T cells are engineered using retroviruses (mainly lentiviruses), which randomly insert the CAR genes into the host genome. Doing so may cause mutations that could promote cancer. These lentiviruses also carry the theoretical risk of becoming capable of viral replication once inside the body.

To address these concerns, viruses used to engineer CAR T cells go through comprehensive safety testing. After therapy, patients are checked every few months during the first year and annually after that.

So far, there have been no reports of cancers associated with CAR T-cell therapy.

“Any type of cancer is a very theoretical risk,” Bar told Medscape Medical News. «Most likely the malignancies in our study were related to prior treatment that the patients received. None of them had any evidence of replication-competent lentivirus, or any other evidence that the malignancies were related to the CAR T cells.»

Another theoretical concern is the possibility of new-onset autoimmune disease, although, once again, no cases have been reported so far.

“We think of it as a theoretic possibility. Whenever you jack up the immune system, autoimmune disease is a potential risk,” said Carl June, MD, director of the Center for Cellular Immunotherapies at the University of Pennsylvania.

June was the co–principal investigator of the trial in which Olson participated. He is also the inventor on patents for CAR T cells licensed by the University of Pennsylvania to Novartis and Tmunity and is a scientific founder with equity in Tmunity.

Still, autoimmunity could occur, and scientists are looking out for it.

“We are continuing to be vigilant in our monitoring for autoimmune disease,” Shah added. “We’ve been doing CAR T-cell therapy since 2012, and I think we have yet to see true autoimmunity beyond GVHD.”
 

Future directions

In the 10 years since Olson received CAR T-cell therapy, an entire industry has sprung up. Over 100 companies worldwide are now developing CAR T-cell therapies targeting various antigens. These therapies are directed at about 60 different tumor types, including solid tumors. Nearly 200 clinical trials are underway, though most are still in early stages: as of September 2019, only 5% had reached phase 3.

Clinical data show promising results for CAR T-cell therapy directed against CD22 (overexpressed on ALL cells), and BCMA (found on almost all multiple myeloma cells). Yet questions remain as to whether CAR T cells will be as effective if they target antigens other than CD19 or cells other than B lymphocytes. One of the biggest research questions is whether they will be effective against solid tumors.

One research avenue being watched with great interest is the development of universal CAR T cells. So far, such products are at very early stages of development (phase 1 trials), but they are attractive because of the potential advantages they offer over bespoke CAR T cells. Automating the process holds the promise of immediate availability, standardizing production, expanding access, and lowering costs. And because the T cells for this universal product come from healthy donors, they may function better than T cells that have been battered and bruised by past cancer treatments, or even the cancer itself.

However, precisely because they are developed from healthy donor T cells, universal CAR T cells may pose increased risk for GVHD. Scientists are trying to get around this problem by engineering universal CAR T cells that lack the T-cell receptor involved in GVHD.

There are also other concerns. Nature has a penchant for mutation. Engineering CAR T cells without T-cell receptors means the body may no longer detect or reject a universal CAR T cell if it goes rogue. Also, gene insertion in universal CAR-T therapy is targeted rather than random (as in bespoke CAR T cells), which could create off-target effects. Both issues create a theoretical risk of such products inducing an untreatable CAR T-cell therapy–associated cancer.

“The theoretic risk with universal cells is that their safety profile may not be as good for long term,” June commented.
 

Hope for the future

From that first trial in which June and Porter used CAR T cells, two of three patients they treated are still alive 10 years later.

Olson is one of these two, and he still undergoes monitoring every 3 months to check for relapse. So far, none of his tests have shown signs of his cancer returning.

After going into remission, Doug spent the next 6 to 9 months regaining his health and strength.

“I figured if I had this amazing treatment that saved my life, I had an obligation to stay alive,” he said. “I’d better not die of something like a heart attack!”

He took up long distance running and has completed six half marathons. He became involved in the Leukemia and Lymphoma Society, participating in fund-raising and helping newly diagnosed patients. Over the years, he has also given talks for researchers, people with cancer, and healthcare providers.

Doug is now 73. Today, he marvels at how rapidly the CAR-T field has progressed.

“Twenty years ago, if you had cancer, your prospects weren’t nearly as good as these days. In 2010, people still didn’t believe in CAR T-cell therapy,” he said. “My goal always in telling my story is a message of hope.”

This article first appeared on Medscape.com.

In patients with previously untreated chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL), a once-daily oral regimen of ibrutinib and venetoclax was associated with deep molecular remissions in both bone marrow and peripheral blood, including in patients with high-risk disease, according to investigators in the phase 2 CAPTIVATE MRD trial.

An intention-to-treat analysis of 164 patients with CLL/SLL treated with the combination of ibrutinib (Imbruvica) and venetoclax (Venclexta) showed a 75% rate of minimal residual disease (MRD) negativity in peripheral blood, and a 68% rate of MRD negativity in bone marrow among patients who received up to 12 cycles of the combination, reported Tanya Siddiqi, MD, of City of Hope National Medical Center, Duarte, Calif., and colleagues.

“This phase 2 study supports synergistic antitumor activity of the combination with notable deep responses across multiple compartments,” she said in an oral presentation during the virtual annual congress of the European Hematology Association.
 

Not ready to change practice

A hematologist/oncologist who was not involved in the study said that the data from CAPTIVATE MRD look good, but it’s still not known whether concurrent or sequential administration of the agents is optimal, and whether other regimens may be more effective in the first line.

“I think this is promising, but the informative and practice-changing study would be to compare this combination to ibrutinib monotherapy or to venetoclax and obinutuzumab, and that’s actually the subject of the next large German cooperative group study, CLL17,” said Catherine C. Coombs, MD, assistant professor of medicine at the University of North Carolina, and the UNC Lineberger Cancer Center, Chapel Hill.

She noted that the combination of venetoclax and obinutuzumab (Gazyva) is also associated with high rates of MRD negativity in the first-line setting, and that use of this regimen allows clinicians to reserve ibrutinib or acalabrutinib (Calquence) for patients in the relapsed setting.
 

Prerandomization results

Dr. Siddiqi presented prerandomization results from the MRD cohort of the CAPTIVATE trial (NCT02910583), which is evaluating the combination of ibrutinib and venetoclax for depth of MRD response. Following 12 cycles of the combinations, patients in this cohort are then randomized based on confirmed MRD status, with patients who are MRD negative randomized to maintenance with either ibrutinib or placebo, and patients with residual disease (MRD positive) randomized to maintenance with either ibrutinib alone or with venetoclax.

A total of 164 patients with previously untreated CLL/SLL and active disease requiring treatment who were under age 70 and had good performance status were enrolled. Following an ibrutinib lead-in period with the drug given at 420 mg once daily for three cycles of 28 days, the patients were continued on ibrutinib, and were started on venetoclax with a ramp up to 400 mg once daily, for 12 additional cycles.

As planned, patients were assessed after 15 cycles for tumor lysis syndrome (TLS) risk assessment, MRD, and hematologic, clinical, imaging, and bone marrow exams for response.

The median patient age was 58, with poor-risk features such as deletion 17p seen in 16%, complex karyotype in 19%, and unmutated immunoglobulin heavy chain variable (IGHV) in 59%.

A total of 152 patients (90%) completed all 12 cycles of the combined agents, with a median treatment duration of 14.7 months on ibrutinib and 12 months on venetoclax. Eight patients had adverse events leading to discontinuation, but there were no treatment-related deaths.

A majority of patients had reductions in lymph node burden after the three-cycle ibrutinib lead in. TLS risk also decreased during the lead-in period, with 90% of patients who had a high baseline TLS risk shifting to medium or low-risk categories, and no patients moved into the high-risk category.

“Hospitalization because of this was no longer required in 66% of at-risk patients after three cycles of ibrutinib lead in, and 82% of patients initiated venetoclax ramp up without the need for hospitalization,” Dr. Siddiqi said.

The best response of undetectable MRD was seen in peripheral blood of 75% of 163 evaluable patients, and in bone marrow of 72% of 155 patients. As noted before, the respective rates of MRD negativity in the intention-to-treat population were 75% and 68%. The proportion of patients with undetectable MRD in peripheral blood increased over time, from 57% after six cycles of the combination, she said.

The overall response rate was 97%, including 51% complete responses (CR) or CR with incomplete bone marrow recovery (CRi), and 46% partial (PR) or nodular PR (nPR). Among patients with CR/CRi, 85% had undetectable MRD in peripheral blood and 80% were MRD negative in bone marrow. In patients with PR/nPR, the respective rates were 69% and 59%. The high rates of undetectable MRD were seen irrespective of baseline disease characteristics, including bulky disease, cytogenetic risk category, del(17p) or TP53 mutation, and complex karyotype.

The most common adverse events with the combination were grade 1 or 2 diarrhea, arthralgia, fatigue, headache, and nausea. Grade 3 neutropenia was seen in 17% of patients, and grade 4 neutropenia was seen in 16%. Grade 3 febrile neutropenia and laboratory confirmed TLS occurred in 2 patients each (1%), and there were no grade 4 instances of either adverse event.

Postrandomization follow-up and analyses are currently being conducted, and results will be reported at a future meeting, real or virtual. An analysis of data on a separate cohort of 159 patients treated with the ibrutinib-venetoclax combination for a fixed duration is currently ongoing.

Dr. Siddiqi disclosed research funding and speakers bureau activity for Pharmacyclics, which sponsored the study, and others, as well as consulting/advising for several companies. Dr. Coombs disclosed consulting for AbbVie.

SOURCE: Siddiqi T et al. EHA25. Abstract S158.

In patients with previously untreated chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL), a once-daily oral regimen of ibrutinib and venetoclax was associated with deep molecular remissions in both bone marrow and peripheral blood, including in patients with high-risk disease, according to investigators in the phase 2 CAPTIVATE MRD trial.

An intention-to-treat analysis of 164 patients with CLL/SLL treated with the combination of ibrutinib (Imbruvica) and venetoclax (Venclexta) showed a 75% rate of minimal residual disease (MRD) negativity in peripheral blood, and a 68% rate of MRD negativity in bone marrow among patients who received up to 12 cycles of the combination, reported Tanya Siddiqi, MD, of City of Hope National Medical Center, Duarte, Calif., and colleagues.

“This phase 2 study supports synergistic antitumor activity of the combination with notable deep responses across multiple compartments,” she said in an oral presentation during the virtual annual congress of the European Hematology Association.
 

Not ready to change practice

A hematologist/oncologist who was not involved in the study said that the data from CAPTIVATE MRD look good, but it’s still not known whether concurrent or sequential administration of the agents is optimal, and whether other regimens may be more effective in the first line.

“I think this is promising, but the informative and practice-changing study would be to compare this combination to ibrutinib monotherapy or to venetoclax and obinutuzumab, and that’s actually the subject of the next large German cooperative group study, CLL17,” said Catherine C. Coombs, MD, assistant professor of medicine at the University of North Carolina, and the UNC Lineberger Cancer Center, Chapel Hill.

She noted that the combination of venetoclax and obinutuzumab (Gazyva) is also associated with high rates of MRD negativity in the first-line setting, and that use of this regimen allows clinicians to reserve ibrutinib or acalabrutinib (Calquence) for patients in the relapsed setting.
 

Prerandomization results

Dr. Siddiqi presented prerandomization results from the MRD cohort of the CAPTIVATE trial (NCT02910583), which is evaluating the combination of ibrutinib and venetoclax for depth of MRD response. Following 12 cycles of the combinations, patients in this cohort are then randomized based on confirmed MRD status, with patients who are MRD negative randomized to maintenance with either ibrutinib or placebo, and patients with residual disease (MRD positive) randomized to maintenance with either ibrutinib alone or with venetoclax.

A total of 164 patients with previously untreated CLL/SLL and active disease requiring treatment who were under age 70 and had good performance status were enrolled. Following an ibrutinib lead-in period with the drug given at 420 mg once daily for three cycles of 28 days, the patients were continued on ibrutinib, and were started on venetoclax with a ramp up to 400 mg once daily, for 12 additional cycles.

As planned, patients were assessed after 15 cycles for tumor lysis syndrome (TLS) risk assessment, MRD, and hematologic, clinical, imaging, and bone marrow exams for response.

The median patient age was 58, with poor-risk features such as deletion 17p seen in 16%, complex karyotype in 19%, and unmutated immunoglobulin heavy chain variable (IGHV) in 59%.

A total of 152 patients (90%) completed all 12 cycles of the combined agents, with a median treatment duration of 14.7 months on ibrutinib and 12 months on venetoclax. Eight patients had adverse events leading to discontinuation, but there were no treatment-related deaths.

A majority of patients had reductions in lymph node burden after the three-cycle ibrutinib lead in. TLS risk also decreased during the lead-in period, with 90% of patients who had a high baseline TLS risk shifting to medium or low-risk categories, and no patients moved into the high-risk category.

“Hospitalization because of this was no longer required in 66% of at-risk patients after three cycles of ibrutinib lead in, and 82% of patients initiated venetoclax ramp up without the need for hospitalization,” Dr. Siddiqi said.

The best response of undetectable MRD was seen in peripheral blood of 75% of 163 evaluable patients, and in bone marrow of 72% of 155 patients. As noted before, the respective rates of MRD negativity in the intention-to-treat population were 75% and 68%. The proportion of patients with undetectable MRD in peripheral blood increased over time, from 57% after six cycles of the combination, she said.

The overall response rate was 97%, including 51% complete responses (CR) or CR with incomplete bone marrow recovery (CRi), and 46% partial (PR) or nodular PR (nPR). Among patients with CR/CRi, 85% had undetectable MRD in peripheral blood and 80% were MRD negative in bone marrow. In patients with PR/nPR, the respective rates were 69% and 59%. The high rates of undetectable MRD were seen irrespective of baseline disease characteristics, including bulky disease, cytogenetic risk category, del(17p) or TP53 mutation, and complex karyotype.

The most common adverse events with the combination were grade 1 or 2 diarrhea, arthralgia, fatigue, headache, and nausea. Grade 3 neutropenia was seen in 17% of patients, and grade 4 neutropenia was seen in 16%. Grade 3 febrile neutropenia and laboratory confirmed TLS occurred in 2 patients each (1%), and there were no grade 4 instances of either adverse event.

Postrandomization follow-up and analyses are currently being conducted, and results will be reported at a future meeting, real or virtual. An analysis of data on a separate cohort of 159 patients treated with the ibrutinib-venetoclax combination for a fixed duration is currently ongoing.

Dr. Siddiqi disclosed research funding and speakers bureau activity for Pharmacyclics, which sponsored the study, and others, as well as consulting/advising for several companies. Dr. Coombs disclosed consulting for AbbVie.

SOURCE: Siddiqi T et al. EHA25. Abstract S158.

In patients with previously untreated chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL), a once-daily oral regimen of ibrutinib and venetoclax was associated with deep molecular remissions in both bone marrow and peripheral blood, including in patients with high-risk disease, according to investigators in the phase 2 CAPTIVATE MRD trial.

An intention-to-treat analysis of 164 patients with CLL/SLL treated with the combination of ibrutinib (Imbruvica) and venetoclax (Venclexta) showed a 75% rate of minimal residual disease (MRD) negativity in peripheral blood, and a 68% rate of MRD negativity in bone marrow among patients who received up to 12 cycles of the combination, reported Tanya Siddiqi, MD, of City of Hope National Medical Center, Duarte, Calif., and colleagues.

“This phase 2 study supports synergistic antitumor activity of the combination with notable deep responses across multiple compartments,” she said in an oral presentation during the virtual annual congress of the European Hematology Association.
 

Not ready to change practice

A hematologist/oncologist who was not involved in the study said that the data from CAPTIVATE MRD look good, but it’s still not known whether concurrent or sequential administration of the agents is optimal, and whether other regimens may be more effective in the first line.

“I think this is promising, but the informative and practice-changing study would be to compare this combination to ibrutinib monotherapy or to venetoclax and obinutuzumab, and that’s actually the subject of the next large German cooperative group study, CLL17,” said Catherine C. Coombs, MD, assistant professor of medicine at the University of North Carolina, and the UNC Lineberger Cancer Center, Chapel Hill.

She noted that the combination of venetoclax and obinutuzumab (Gazyva) is also associated with high rates of MRD negativity in the first-line setting, and that use of this regimen allows clinicians to reserve ibrutinib or acalabrutinib (Calquence) for patients in the relapsed setting.
 

Prerandomization results

Dr. Siddiqi presented prerandomization results from the MRD cohort of the CAPTIVATE trial (NCT02910583), which is evaluating the combination of ibrutinib and venetoclax for depth of MRD response. Following 12 cycles of the combinations, patients in this cohort are then randomized based on confirmed MRD status, with patients who are MRD negative randomized to maintenance with either ibrutinib or placebo, and patients with residual disease (MRD positive) randomized to maintenance with either ibrutinib alone or with venetoclax.

A total of 164 patients with previously untreated CLL/SLL and active disease requiring treatment who were under age 70 and had good performance status were enrolled. Following an ibrutinib lead-in period with the drug given at 420 mg once daily for three cycles of 28 days, the patients were continued on ibrutinib, and were started on venetoclax with a ramp up to 400 mg once daily, for 12 additional cycles.

As planned, patients were assessed after 15 cycles for tumor lysis syndrome (TLS) risk assessment, MRD, and hematologic, clinical, imaging, and bone marrow exams for response.

The median patient age was 58, with poor-risk features such as deletion 17p seen in 16%, complex karyotype in 19%, and unmutated immunoglobulin heavy chain variable (IGHV) in 59%.

A total of 152 patients (90%) completed all 12 cycles of the combined agents, with a median treatment duration of 14.7 months on ibrutinib and 12 months on venetoclax. Eight patients had adverse events leading to discontinuation, but there were no treatment-related deaths.

A majority of patients had reductions in lymph node burden after the three-cycle ibrutinib lead in. TLS risk also decreased during the lead-in period, with 90% of patients who had a high baseline TLS risk shifting to medium or low-risk categories, and no patients moved into the high-risk category.

“Hospitalization because of this was no longer required in 66% of at-risk patients after three cycles of ibrutinib lead in, and 82% of patients initiated venetoclax ramp up without the need for hospitalization,” Dr. Siddiqi said.

The best response of undetectable MRD was seen in peripheral blood of 75% of 163 evaluable patients, and in bone marrow of 72% of 155 patients. As noted before, the respective rates of MRD negativity in the intention-to-treat population were 75% and 68%. The proportion of patients with undetectable MRD in peripheral blood increased over time, from 57% after six cycles of the combination, she said.

The overall response rate was 97%, including 51% complete responses (CR) or CR with incomplete bone marrow recovery (CRi), and 46% partial (PR) or nodular PR (nPR). Among patients with CR/CRi, 85% had undetectable MRD in peripheral blood and 80% were MRD negative in bone marrow. In patients with PR/nPR, the respective rates were 69% and 59%. The high rates of undetectable MRD were seen irrespective of baseline disease characteristics, including bulky disease, cytogenetic risk category, del(17p) or TP53 mutation, and complex karyotype.

The most common adverse events with the combination were grade 1 or 2 diarrhea, arthralgia, fatigue, headache, and nausea. Grade 3 neutropenia was seen in 17% of patients, and grade 4 neutropenia was seen in 16%. Grade 3 febrile neutropenia and laboratory confirmed TLS occurred in 2 patients each (1%), and there were no grade 4 instances of either adverse event.

Postrandomization follow-up and analyses are currently being conducted, and results will be reported at a future meeting, real or virtual. An analysis of data on a separate cohort of 159 patients treated with the ibrutinib-venetoclax combination for a fixed duration is currently ongoing.

Dr. Siddiqi disclosed research funding and speakers bureau activity for Pharmacyclics, which sponsored the study, and others, as well as consulting/advising for several companies. Dr. Coombs disclosed consulting for AbbVie.

SOURCE: Siddiqi T et al. EHA25. Abstract S158.