The Lancet Haematology

2019

DOI: 10.1016/s2352-3026(18)30175-3

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Haematological immune-related adverse events induced by anti-PD-1 or anti-PD-L1 immunotherapy: a descriptive observational study

Nicolas Delanoy

¹

,

Jean‐Marie Michot

²

,

et al.

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Cited by 200 publications

(280 citation statements)

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“…In some patients, AIHA relapses after premature cessation of steroids, but reapplication is still effective. Although AIHA presents a benign process as a whole, ICIs should be discontinued during the administration of steroids . Other immune suppressor therapies are not recommended because most cases of AIHA recover with single steroid treatment.…”

Section: Introductionmentioning

confidence: 99%

“…Most cases had severe TCP. Usually not until grade 4 TCP develops can it cause severe spontaneous bleeding, such as the skin mucosa which can be life‐threatening . Mortality was reported in 11% of cases in the report by Delyon et al …”

Section: Introductionmentioning

confidence: 99%

“…If the PLT count responses quickly, the steroids can be gradually reduced after a standard administration of two to four weeks. If first‐line treatment fails, rituximab, splenectomy, thrombopoietin receptor agonists or second‐line immunosuppressive drugs such as cyclosporine, azathioprine, etc can be considered …”

Section: Introductionmentioning

confidence: 99%

“…The rechallenge of ICIs after the remission of TCP is still inconclusive. In three readministered cases, one patient had a recurrence of thrombocytopenia, so the risk and benefit of rechallenge need to be fully balanced …”

Section: Introductionmentioning

confidence: 99%

“…Neutropenia is a rare irAE, with up to nine cases reported in a meta‐analyses, among which ipilimumab was the most commonly used, followed by nivolumab and pembrolizumab . The underlying cancers were melanoma, NSCLC and prostate cancer.…”

Section: Introductionmentioning

confidence: 99%

See 4 more Smart Citations

Clinical diagnosis and treatment recommendations for immune checkpoint inhibitor‐related hematological adverse events

¹

,

²

,

³

et al. 2020

Thoracic Cancer

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Immune checkpoint inhibitors (ICIs) are able to reactivate the immune system, thereby enhancing the anti‐tumor effects. However, over‐activated T cells may induce immune‐related adverse events (irAEs). Hematological irAEs are rarely reported which mainly represent monolineage cytopenia or pancytopenia, including autoimmune hemolytic anemia (AIHA), immune thrombocytopenia (ITP), neutropenia and aplastic anemia, sometimes even life‐threatening diseases such as hemophagocytic lymphohistiocytosis. Here, the clinical manifestations of hematological irAEs are summarized and recommendations for diagnosis and treatment proposed. Key points Significant findings of the study• Hematological immune‐related adverse events (irAEs) caused by checkpoint inhibitors are rare and may sometimes be life‐threatening. This study summarizes the manifestations of hematological irAEs and proposes preliminary recommendations for diagnosis and treatment. What this study adds• Much still remains unknown regarding hematological irAEs caused by checkpoint inhibitors. This study delineates the overview of hematological irAEs, and provides practical treatment suggestions, in particular addressing the issue of rechallenge.

“…In some patients, AIHA relapses after premature cessation of steroids, but reapplication is still effective. Although AIHA presents a benign process as a whole, ICIs should be discontinued during the administration of steroids . Other immune suppressor therapies are not recommended because most cases of AIHA recover with single steroid treatment.…”

Section: Introductionmentioning

confidence: 99%

“…Most cases had severe TCP. Usually not until grade 4 TCP develops can it cause severe spontaneous bleeding, such as the skin mucosa which can be life‐threatening . Mortality was reported in 11% of cases in the report by Delyon et al …”

Section: Introductionmentioning

confidence: 99%

“…If the PLT count responses quickly, the steroids can be gradually reduced after a standard administration of two to four weeks. If first‐line treatment fails, rituximab, splenectomy, thrombopoietin receptor agonists or second‐line immunosuppressive drugs such as cyclosporine, azathioprine, etc can be considered …”

Section: Introductionmentioning

confidence: 99%

“…The rechallenge of ICIs after the remission of TCP is still inconclusive. In three readministered cases, one patient had a recurrence of thrombocytopenia, so the risk and benefit of rechallenge need to be fully balanced …”

Section: Introductionmentioning

confidence: 99%

“…Neutropenia is a rare irAE, with up to nine cases reported in a meta‐analyses, among which ipilimumab was the most commonly used, followed by nivolumab and pembrolizumab . The underlying cancers were melanoma, NSCLC and prostate cancer.…”

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Clinical diagnosis and treatment recommendations for immune checkpoint inhibitor‐related hematological adverse events

¹

,

²

,

³

et al. 2020

Thoracic Cancer

View full text Add to dashboard Cite

Immune checkpoint inhibitors (ICIs) are able to reactivate the immune system, thereby enhancing the anti‐tumor effects. However, over‐activated T cells may induce immune‐related adverse events (irAEs). Hematological irAEs are rarely reported which mainly represent monolineage cytopenia or pancytopenia, including autoimmune hemolytic anemia (AIHA), immune thrombocytopenia (ITP), neutropenia and aplastic anemia, sometimes even life‐threatening diseases such as hemophagocytic lymphohistiocytosis. Here, the clinical manifestations of hematological irAEs are summarized and recommendations for diagnosis and treatment proposed. Key points Significant findings of the study• Hematological immune‐related adverse events (irAEs) caused by checkpoint inhibitors are rare and may sometimes be life‐threatening. This study summarizes the manifestations of hematological irAEs and proposes preliminary recommendations for diagnosis and treatment. What this study adds• Much still remains unknown regarding hematological irAEs caused by checkpoint inhibitors. This study delineates the overview of hematological irAEs, and provides practical treatment suggestions, in particular addressing the issue of rechallenge.

Immune Thrombocytopenia—A Neglected Adverse Event of PD-1 and PD-L1 Inhibitors in Clinical Trials

¹

,

²

,

³

2019

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In Reply We appreciate the letter by Yang and the opportunity to comment on the safety of immune checkpoint blockade (ICB) in breast cancer. This important subject was not addressed extensively in our original article due to space limitations. 1 However, since that publication, a comprehensive review by D'Abreo and Adams 2 on the incidence of adverse events (AEs) with particular emphasis on immune-related adverse events (irAEs) in patients with breast cancer has been published. That review describes more than 1000 patients with triple-negative breast cancer included in published clinical trials of ICB alone or in combination with chemotherapy. The most common organspecific irAEs were pruritus or rash occurring in 18% of patients, followed by hypothyroidism in 12%, and hepatitis or elevated transaminases in 10%. Less frequent events with an incidence greater than 1% were hyperthyroidism (5%), autoimmune hematologic abnormalities (4%), pneumonitis (3%), and diarrhea or colitis (2.5%). Grade 3 or higher irAEs were observed in 7% of patients with breast cancer.In a recently published meta-analysis of irAEs that included more than 12 800 patients from 46 studies evaluating different anti-programmed cell death 1/programmed cell death ligand 1 (anti-PD-1/PD-L1) agents as monotherapy in multiple tumor types, the rate of irAEs of any grade was 26.82%, with 6.1% of irAEs identified as severe (grade ≥3). 3 When the authors evaluated AEs by the specific agent, the rate of any grade irAEs in patients who received atezolizumab was 16.67% (95% CI, 4.75-44.5), 18.50% (95% CI, 15.41-22.06) in those who received pembrolizumab, and 48% (95% CI, 40.13-55.98) in those who received nivolumab. Consistent with these findings, in the largest single-agent ICB trial in triple-negative breast cancer that evaluated pembrolizumab, the irAE incidence was 18.5% (14 of 84 patients in cohort B 4 and 33 of 170 patients in cohort A 5 ). These data suggest that the incidence of irAEs is not different in patients with breast cancer compared with patients with different tumor types when treated with ICB monotherapy.In combination trials of ICB with chemotherapy enrolling patients with breast cancer, irAEs are more frequent than in trials of ICB monotherapy. Interestingly, irAEs are also documented in a substantial number of patients on the control arm treated with chemotherapy alone. In IMpassion130, a phase 3 trial that demonstrated the benefit of atezolizumab with nabpaclitaxel, predefined AEs of special interest of any grade were observed in 57.3% of patients in the atezolizumab plus nabpaclitaxel arm and in 41.8% in the nab-paclitaxel monotherapy arm. 6 These rates, mainly driven by immune-related rashes (34.1% vs 26.0%), hypothyroidism (17.3% vs 4.3%), hyperthyroidism (4.4% vs 1.4%), pneumonitis (3.1% vs 0.3%), and immune-related hepatitis (2.2% vs 1.6%) suggest that better understanding of irAEs is necessary.We agree with Yang that the identification of predictive biomarkers beyond PD-L1 remains a priority in breast cancer. At this time, the oc...

Immune Thrombocytopenia—A Neglected Adverse Event of PD-1 and PD-L1 Inhibitors in Clinical Trials—In Reply

¹

,

²

,

³

2019

View full text Add to dashboard Cite

In Reply We appreciate the letter by Yang and the opportunity to comment on the safety of immune checkpoint blockade (ICB) in breast cancer. This important subject was not addressed extensively in our original article due to space limitations. 1 However, since that publication, a comprehensive review by D'Abreo and Adams 2 on the incidence of adverse events (AEs) with particular emphasis on immune-related adverse events (irAEs) in patients with breast cancer has been published. That review describes more than 1000 patients with triple-negative breast cancer included in published clinical trials of ICB alone or in combination with chemotherapy. The most common organspecific irAEs were pruritus or rash occurring in 18% of patients, followed by hypothyroidism in 12%, and hepatitis or elevated transaminases in 10%. Less frequent events with an incidence greater than 1% were hyperthyroidism (5%), autoimmune hematologic abnormalities (4%), pneumonitis (3%), and diarrhea or colitis (2.5%). Grade 3 or higher irAEs were observed in 7% of patients with breast cancer.In a recently published meta-analysis of irAEs that included more than 12 800 patients from 46 studies evaluating different anti-programmed cell death 1/programmed cell death ligand 1 (anti-PD-1/PD-L1) agents as monotherapy in multiple tumor types, the rate of irAEs of any grade was 26.82%, with 6.1% of irAEs identified as severe (grade ≥3). 3 When the authors evaluated AEs by the specific agent, the rate of any grade irAEs in patients who received atezolizumab was 16.67% (95% CI, 4.75-44.5), 18.50% (95% CI, 15.41-22.06) in those who received pembrolizumab, and 48% (95% CI, 40.13-55.98) in those who received nivolumab. Consistent with these findings, in the largest single-agent ICB trial in triple-negative breast cancer that evaluated pembrolizumab, the irAE incidence was 18.5% (14 of 84 patients in cohort B 4 and 33 of 170 patients in cohort A 5 ). These data suggest that the incidence of irAEs is not different in patients with breast cancer compared with patients with different tumor types when treated with ICB monotherapy.In combination trials of ICB with chemotherapy enrolling patients with breast cancer, irAEs are more frequent than in trials of ICB monotherapy. Interestingly, irAEs are also documented in a substantial number of patients on the control arm treated with chemotherapy alone. In IMpassion130, a phase 3 trial that demonstrated the benefit of atezolizumab with nabpaclitaxel, predefined AEs of special interest of any grade were observed in 57.3% of patients in the atezolizumab plus nabpaclitaxel arm and in 41.8% in the nab-paclitaxel monotherapy arm. 6 These rates, mainly driven by immune-related rashes (34.1% vs 26.0%), hypothyroidism (17.3% vs 4.3%), hyperthyroidism (4.4% vs 1.4%), pneumonitis (3.1% vs 0.3%), and immune-related hepatitis (2.2% vs 1.6%) suggest that better understanding of irAEs is necessary.We agree with Yang that the identification of predictive biomarkers beyond PD-L1 remains a priority in breast cancer. At this time, the oc...

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