Key clinical point: The rituximab, bendamustine, and low-dose cytarabine (R-BAC) regimen, not succeeded by maintenance therapy, induces long-term responses in previously untreated elderly patients with mantle cell lymphoma (MCL).

Major finding: After a median follow-up of 86 months, the median overall survival (OS) and progression-free survival (PFS) were not reached; the 7-year PFS and OS rates were 55% (95% CI 41%-67%) and 63% (95% CI 49%-74%), respectively. The 7-year duration of response rate among the 52 responding patients was 59% (95% CI 44%-71%). No signal of late toxicity was reported.

Study details: Findings are from a long-term analysis of the FIL-RBAC500 trial that included 57 previously untreated elderly patients with MCL who received the R-BAC regimen.

Disclosures: This study was supported by Progetto di Ricerca Sanitaria Finalizzata (Italy) grants and other sources. Some authors declared serving as advisory board members or consultants and receiving research funding, speaker honoraria, or travel expenses and accommodations from various sources.

Source: Tisi MC et al. Long term follow-up of rituximab plus bendamustine and cytarabine (R-BAC) in elderly patients with newly diagnosed MCL. Blood Adv. 2023 (May 12). doi: 10.1182/bloodadvances.2023009744

Key clinical point: The rituximab, bendamustine, and low-dose cytarabine (R-BAC) regimen, not succeeded by maintenance therapy, induces long-term responses in previously untreated elderly patients with mantle cell lymphoma (MCL).

Major finding: After a median follow-up of 86 months, the median overall survival (OS) and progression-free survival (PFS) were not reached; the 7-year PFS and OS rates were 55% (95% CI 41%-67%) and 63% (95% CI 49%-74%), respectively. The 7-year duration of response rate among the 52 responding patients was 59% (95% CI 44%-71%). No signal of late toxicity was reported.

Study details: Findings are from a long-term analysis of the FIL-RBAC500 trial that included 57 previously untreated elderly patients with MCL who received the R-BAC regimen.

Disclosures: This study was supported by Progetto di Ricerca Sanitaria Finalizzata (Italy) grants and other sources. Some authors declared serving as advisory board members or consultants and receiving research funding, speaker honoraria, or travel expenses and accommodations from various sources.

Source: Tisi MC et al. Long term follow-up of rituximab plus bendamustine and cytarabine (R-BAC) in elderly patients with newly diagnosed MCL. Blood Adv. 2023 (May 12). doi: 10.1182/bloodadvances.2023009744

Key clinical point: The rituximab, bendamustine, and low-dose cytarabine (R-BAC) regimen, not succeeded by maintenance therapy, induces long-term responses in previously untreated elderly patients with mantle cell lymphoma (MCL).

Major finding: After a median follow-up of 86 months, the median overall survival (OS) and progression-free survival (PFS) were not reached; the 7-year PFS and OS rates were 55% (95% CI 41%-67%) and 63% (95% CI 49%-74%), respectively. The 7-year duration of response rate among the 52 responding patients was 59% (95% CI 44%-71%). No signal of late toxicity was reported.

Study details: Findings are from a long-term analysis of the FIL-RBAC500 trial that included 57 previously untreated elderly patients with MCL who received the R-BAC regimen.

Disclosures: This study was supported by Progetto di Ricerca Sanitaria Finalizzata (Italy) grants and other sources. Some authors declared serving as advisory board members or consultants and receiving research funding, speaker honoraria, or travel expenses and accommodations from various sources.

Source: Tisi MC et al. Long term follow-up of rituximab plus bendamustine and cytarabine (R-BAC) in elderly patients with newly diagnosed MCL. Blood Adv. 2023 (May 12). doi: 10.1182/bloodadvances.2023009744

Key clinical point: First-line ibrutinib+venetoclax led to high response and survival rates in patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) regardless of high-risk genomic features generally associated with poor outcomes.

Major finding: Overall response and 36-month overall survival rates were >95% regardless of high-risk features. Patients with and without high-risk features had similar complete response (61% [95% CI 53%-70%] and 53% [95% CI 41%-65%], respectively) and 36-month progression-free survival (88% [95% CI 81%-93%] and 92% [95% CI 82%-97%], respectively) rates.

Study details: This post hoc analysis of the CAPTIVATE trial analyzed the pooled data of 195 patients with previously untreated CLL/SLL and known status of high-risk features [del(17p), TP53 mutation, and unmutated immunoglobulin heavy chain] treated with fixed-duration ibrutinib+venetoclax, of which 129 had ≥1 high-risk feature.

Disclosures: This study was funded by Pharmacyclics LLC, an AbbVie Company. Some authors declared receiving grants, personal fees, or other support from Pharmacyclics, AbbVie, or others. Two authors declared being employees of Pharmacyclics or AbbVie or having stock or other ownership interests in AbbVie.

Source: Allan JN et al. Outcomes in patients with high-risk features after fixed-duration ibrutinib plus venetoclax: Phase II CAPTIVATE study in first-line chronic lymphocytic leukemia. Clin Cancer Res. 2023 (Jun 7). doi: 10.1158/1078-0432.CCR-22-2779

Key clinical point: First-line ibrutinib+venetoclax led to high response and survival rates in patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) regardless of high-risk genomic features generally associated with poor outcomes.

Major finding: Overall response and 36-month overall survival rates were >95% regardless of high-risk features. Patients with and without high-risk features had similar complete response (61% [95% CI 53%-70%] and 53% [95% CI 41%-65%], respectively) and 36-month progression-free survival (88% [95% CI 81%-93%] and 92% [95% CI 82%-97%], respectively) rates.

Study details: This post hoc analysis of the CAPTIVATE trial analyzed the pooled data of 195 patients with previously untreated CLL/SLL and known status of high-risk features [del(17p), TP53 mutation, and unmutated immunoglobulin heavy chain] treated with fixed-duration ibrutinib+venetoclax, of which 129 had ≥1 high-risk feature.

Disclosures: This study was funded by Pharmacyclics LLC, an AbbVie Company. Some authors declared receiving grants, personal fees, or other support from Pharmacyclics, AbbVie, or others. Two authors declared being employees of Pharmacyclics or AbbVie or having stock or other ownership interests in AbbVie.

Source: Allan JN et al. Outcomes in patients with high-risk features after fixed-duration ibrutinib plus venetoclax: Phase II CAPTIVATE study in first-line chronic lymphocytic leukemia. Clin Cancer Res. 2023 (Jun 7). doi: 10.1158/1078-0432.CCR-22-2779

Key clinical point: First-line ibrutinib+venetoclax led to high response and survival rates in patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) regardless of high-risk genomic features generally associated with poor outcomes.

Major finding: Overall response and 36-month overall survival rates were >95% regardless of high-risk features. Patients with and without high-risk features had similar complete response (61% [95% CI 53%-70%] and 53% [95% CI 41%-65%], respectively) and 36-month progression-free survival (88% [95% CI 81%-93%] and 92% [95% CI 82%-97%], respectively) rates.

Study details: This post hoc analysis of the CAPTIVATE trial analyzed the pooled data of 195 patients with previously untreated CLL/SLL and known status of high-risk features [del(17p), TP53 mutation, and unmutated immunoglobulin heavy chain] treated with fixed-duration ibrutinib+venetoclax, of which 129 had ≥1 high-risk feature.

Disclosures: This study was funded by Pharmacyclics LLC, an AbbVie Company. Some authors declared receiving grants, personal fees, or other support from Pharmacyclics, AbbVie, or others. Two authors declared being employees of Pharmacyclics or AbbVie or having stock or other ownership interests in AbbVie.

Source: Allan JN et al. Outcomes in patients with high-risk features after fixed-duration ibrutinib plus venetoclax: Phase II CAPTIVATE study in first-line chronic lymphocytic leukemia. Clin Cancer Res. 2023 (Jun 7). doi: 10.1158/1078-0432.CCR-22-2779

Key clinical point: The preexistence of depression, anxiety, or both is associated with shorter survival in older patients with diffuse large B-cell lymphoma (DLBCL).

Major finding: At a median follow-up of 2.0 years, patients with depression, anxiety, or both vs without any mental disorder had significantly lower 5-year overall survival rates (27.0% vs 37.4%; hazard ratio [HR] 1.37; 95% CI 1.29-1.44), with those with preexisting depression vs without any mental disorder having the worst rate (23.4% vs 38.0%; HR 1.37; P < .0001).

Study details: This retrospective cohort study analyzed the data of 13,244 patients age ≥ 67 years with DLBCL from the Surveillance, Epidemiology, and End Results-Medicare (SEER) registry, of which 2094 had depression, anxiety, or both at the time of their DLBCL diagnosis.

Disclosures: This study was funded by the American Society of Hematology and others. Some authors declared participating on Data Safety Monitoring or Advisory Boards or receiving financial support, royalties or licenses, or payments or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing, or educational events from various organizations.

Source: Kuczmarski TM et al. Mental health disorders and survival among older patients with diffuse large B-cell lymphoma in the USA: A population-based study. Lancet Haematol. 2023 (Jun 1). doi: 10.1016/S2352-3026(23)00094-7

Key clinical point: The preexistence of depression, anxiety, or both is associated with shorter survival in older patients with diffuse large B-cell lymphoma (DLBCL).

Major finding: At a median follow-up of 2.0 years, patients with depression, anxiety, or both vs without any mental disorder had significantly lower 5-year overall survival rates (27.0% vs 37.4%; hazard ratio [HR] 1.37; 95% CI 1.29-1.44), with those with preexisting depression vs without any mental disorder having the worst rate (23.4% vs 38.0%; HR 1.37; P < .0001).

Study details: This retrospective cohort study analyzed the data of 13,244 patients age ≥ 67 years with DLBCL from the Surveillance, Epidemiology, and End Results-Medicare (SEER) registry, of which 2094 had depression, anxiety, or both at the time of their DLBCL diagnosis.

Disclosures: This study was funded by the American Society of Hematology and others. Some authors declared participating on Data Safety Monitoring or Advisory Boards or receiving financial support, royalties or licenses, or payments or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing, or educational events from various organizations.

Source: Kuczmarski TM et al. Mental health disorders and survival among older patients with diffuse large B-cell lymphoma in the USA: A population-based study. Lancet Haematol. 2023 (Jun 1). doi: 10.1016/S2352-3026(23)00094-7

Key clinical point: The preexistence of depression, anxiety, or both is associated with shorter survival in older patients with diffuse large B-cell lymphoma (DLBCL).

Major finding: At a median follow-up of 2.0 years, patients with depression, anxiety, or both vs without any mental disorder had significantly lower 5-year overall survival rates (27.0% vs 37.4%; hazard ratio [HR] 1.37; 95% CI 1.29-1.44), with those with preexisting depression vs without any mental disorder having the worst rate (23.4% vs 38.0%; HR 1.37; P < .0001).

Study details: This retrospective cohort study analyzed the data of 13,244 patients age ≥ 67 years with DLBCL from the Surveillance, Epidemiology, and End Results-Medicare (SEER) registry, of which 2094 had depression, anxiety, or both at the time of their DLBCL diagnosis.

Disclosures: This study was funded by the American Society of Hematology and others. Some authors declared participating on Data Safety Monitoring or Advisory Boards or receiving financial support, royalties or licenses, or payments or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing, or educational events from various organizations.

Source: Kuczmarski TM et al. Mental health disorders and survival among older patients with diffuse large B-cell lymphoma in the USA: A population-based study. Lancet Haematol. 2023 (Jun 1). doi: 10.1016/S2352-3026(23)00094-7

Key clinical point: Compared with the current standard-of-care chemoimmunotherapy, second-line axicabtagene ciloleucel (axi-cel) significantly prolongs the overall survival of patients with early relapsed or refractory large B-cell lymphoma (LBCL).

Major finding: At a median follow-up of 47.2 months, patients receiving axi-cel vs standard care had a significantly longer median overall survival (not reached vs 31.1 months; hazard ratio 0.73; P = .03) and an absolute improvement in overall survival (8.6 percentage points at 4 years). No new treatment-related deaths were reported since the primary event-free survival analysis.

Study details: This primary overall survival analysis of the phase 3 ZUMA-7 trial included 359 adults with LBCL (refractory to or relapsed after first-line treatment) who were randomly assigned to receive axi-cel (n = 180) or standard care (n = 179).

Disclosures: This study was funded by Kite Pharma. Some authors, including the lead author, declared serving as advisory board members, consultants, or speakers for; receiving research support, speaker fees, travel expenses, or honoraria from; or owning stock or stock options in various sources, including Kite.

Source: Westin JR et al. Survival with axicabtagene ciloleucel in large B-cell lymphoma. N Engl J Med. 2023 (Jun 5). doi: 10.1056/NEJMoa2301665

Key clinical point: Compared with the current standard-of-care chemoimmunotherapy, second-line axicabtagene ciloleucel (axi-cel) significantly prolongs the overall survival of patients with early relapsed or refractory large B-cell lymphoma (LBCL).

Major finding: At a median follow-up of 47.2 months, patients receiving axi-cel vs standard care had a significantly longer median overall survival (not reached vs 31.1 months; hazard ratio 0.73; P = .03) and an absolute improvement in overall survival (8.6 percentage points at 4 years). No new treatment-related deaths were reported since the primary event-free survival analysis.

Study details: This primary overall survival analysis of the phase 3 ZUMA-7 trial included 359 adults with LBCL (refractory to or relapsed after first-line treatment) who were randomly assigned to receive axi-cel (n = 180) or standard care (n = 179).

Disclosures: This study was funded by Kite Pharma. Some authors, including the lead author, declared serving as advisory board members, consultants, or speakers for; receiving research support, speaker fees, travel expenses, or honoraria from; or owning stock or stock options in various sources, including Kite.

Source: Westin JR et al. Survival with axicabtagene ciloleucel in large B-cell lymphoma. N Engl J Med. 2023 (Jun 5). doi: 10.1056/NEJMoa2301665

Key clinical point: Compared with the current standard-of-care chemoimmunotherapy, second-line axicabtagene ciloleucel (axi-cel) significantly prolongs the overall survival of patients with early relapsed or refractory large B-cell lymphoma (LBCL).

Major finding: At a median follow-up of 47.2 months, patients receiving axi-cel vs standard care had a significantly longer median overall survival (not reached vs 31.1 months; hazard ratio 0.73; P = .03) and an absolute improvement in overall survival (8.6 percentage points at 4 years). No new treatment-related deaths were reported since the primary event-free survival analysis.

Study details: This primary overall survival analysis of the phase 3 ZUMA-7 trial included 359 adults with LBCL (refractory to or relapsed after first-line treatment) who were randomly assigned to receive axi-cel (n = 180) or standard care (n = 179).

Disclosures: This study was funded by Kite Pharma. Some authors, including the lead author, declared serving as advisory board members, consultants, or speakers for; receiving research support, speaker fees, travel expenses, or honoraria from; or owning stock or stock options in various sources, including Kite.

Source: Westin JR et al. Survival with axicabtagene ciloleucel in large B-cell lymphoma. N Engl J Med. 2023 (Jun 5). doi: 10.1056/NEJMoa2301665

Key clinical point: Pirtobrutinib demonstrated durable efficacy and a favorable safety profile in patients with covalent Bruton tyrosine kinase inhibitor (cBTKi) pretreated relapsed or refractory mantle cell lymphoma (MCL).

Major finding: The overall response rate was 57.8% (95% CI 46.9%-68.1%), with the complete response rate being 20.0%. At a median follow-up of 12 months, the median duration of response was 21.6 (95% CI 7.5-not reached) months. Grade ≥3 treatment-related adverse events were not frequent, with neutropenia (8.5%) being the most common.

Study details: This multicenter phase 1/2 BRUIN trial included 90 cBTKi pretreated patients with relapsed or refractory MCL in the primary efficacy cohort who received 25-300 mg and 200 mg pirtobrutinib once daily orally in the phases 1 and 2 of the trial, respectively.

Disclosures: This study was sponsored by Loxo Oncology Inc., a wholly owned subsidiary of Eli Lilly and Company. Some authors reported ties with Eli Lilly and others. Seven authors declared being employees of or stockholders in Eli Lilly.

Source: Wang ML et al. Pirtobrutinib in covalent BTK-inhibitor pre-treated mantle cell lymphoma. J Clin Oncol. 2023 (May 16). doi: 10.1200/JCO.23.00562

Key clinical point: Pirtobrutinib demonstrated durable efficacy and a favorable safety profile in patients with covalent Bruton tyrosine kinase inhibitor (cBTKi) pretreated relapsed or refractory mantle cell lymphoma (MCL).

Major finding: The overall response rate was 57.8% (95% CI 46.9%-68.1%), with the complete response rate being 20.0%. At a median follow-up of 12 months, the median duration of response was 21.6 (95% CI 7.5-not reached) months. Grade ≥3 treatment-related adverse events were not frequent, with neutropenia (8.5%) being the most common.

Study details: This multicenter phase 1/2 BRUIN trial included 90 cBTKi pretreated patients with relapsed or refractory MCL in the primary efficacy cohort who received 25-300 mg and 200 mg pirtobrutinib once daily orally in the phases 1 and 2 of the trial, respectively.

Disclosures: This study was sponsored by Loxo Oncology Inc., a wholly owned subsidiary of Eli Lilly and Company. Some authors reported ties with Eli Lilly and others. Seven authors declared being employees of or stockholders in Eli Lilly.

Source: Wang ML et al. Pirtobrutinib in covalent BTK-inhibitor pre-treated mantle cell lymphoma. J Clin Oncol. 2023 (May 16). doi: 10.1200/JCO.23.00562

Key clinical point: Pirtobrutinib demonstrated durable efficacy and a favorable safety profile in patients with covalent Bruton tyrosine kinase inhibitor (cBTKi) pretreated relapsed or refractory mantle cell lymphoma (MCL).

Major finding: The overall response rate was 57.8% (95% CI 46.9%-68.1%), with the complete response rate being 20.0%. At a median follow-up of 12 months, the median duration of response was 21.6 (95% CI 7.5-not reached) months. Grade ≥3 treatment-related adverse events were not frequent, with neutropenia (8.5%) being the most common.

Study details: This multicenter phase 1/2 BRUIN trial included 90 cBTKi pretreated patients with relapsed or refractory MCL in the primary efficacy cohort who received 25-300 mg and 200 mg pirtobrutinib once daily orally in the phases 1 and 2 of the trial, respectively.

Disclosures: This study was sponsored by Loxo Oncology Inc., a wholly owned subsidiary of Eli Lilly and Company. Some authors reported ties with Eli Lilly and others. Seven authors declared being employees of or stockholders in Eli Lilly.

Source: Wang ML et al. Pirtobrutinib in covalent BTK-inhibitor pre-treated mantle cell lymphoma. J Clin Oncol. 2023 (May 16). doi: 10.1200/JCO.23.00562

THE DIAGNOSIS: Neutrophilic Eccrine Hidradenitis

A biopsy from the left preauricular cheek demonstrated dermal neutrophilic inflammation around eccrine coils with focal necrosis (Figure). No notable diffuse dermal neutrophilic infiltrate was present, ruling out Sweet syndrome, and no notable interstitial neutrophilic infiltrate was present, making cellulitis and erysipelas less likely; panculture of tissue also was negative.^1,2 Atypical cells in the deep dermis were positive for CD163 and negative for CD117, CD34, CD123, and myeloperoxidase, consistent with a diagnosis of neutrophilic eccrine hidradenitis (NEH) and reactive histiocytes.³ Treatment with oral prednisone resulted in rapid improvement of symptoms.

Neutrophilic eccrine hidradenitis is a rare reactive neutrophilic dermatosis characterized by eccrine gland involvement. This benign and self-limited condition presents as asymmetric erythematous papules and plaques.² Among 8 granulocytopenic patients with neutrophilic dermatoses, 5 were diagnosed with NEH.⁴ Although first identified in 1982, NEH remains poorly understood.² Initial theories suggested that NEH developed due to cytotoxic substances secreted in sweat glands causing necrosis and neutrophil chemotaxis; however, chemotherapy exposure cannot be linked to every case of NEH. Neutrophilic eccrine hidradenitis can be extremely difficult to differentiate clinically from conditions such as cellulitis and Sweet syndrome.

A patient history can be helpful in identifying triggering factors. Neutrophilic eccrine hidradenitis most commonly is associated with malignant, drug-induced, or infectious triggers, while Sweet syndrome has a broad range of associations including infections, vaccines, inflammatory bowel disease, pregnancy, malignancy, and drug-induced etiologies (Table).¹ On average, NEH presents 10 days after chemotherapy induction, with 70% of cases presenting after the first chemotherapy cycle.⁵ Bacterial cellulitis or erysipelas have an infectious etiology, and patients may report symptoms such as fever, chills, or malaise. Immunosuppressed patients are at greater risk for infection; therefore, clinical signs of infection in a granulocytopenic patient should be addressed urgently.

Physical examination may have limited value in differentiating between these diagnoses, as neutrophilic dermatoses notoriously mimic infection. Cutaneous lesions can appear as pruritic or tender erythematous plaques, papules, or nodules in these conditions, though cellulitis and erysipelas tend to be unilateral and may have associated purulence or inflamed skin lymphatics. Given the potential for misdiagnosis, approaching patients with a broad differential can be helpful. In our patient, the differential diagnosis included Sweet syndrome, NEH, bacterial cellulitis, erysipelas, leukemia cutis, sarcoid, and eosinophilic cellulitis.

Leukemia cutis refers to the infiltration of neoplastic leukocytes in the skin and often occurs in patients with peripheral leukemia, most often acute myeloid leukemia or chronic lymphocytic leukemia. Patients with leukemia cutis often have a worse prognosis, as this finding signifies extramedullary spread of disease.⁶ Clinically, lesions can appear similar to those seen in our patient, though they typically are not symptomatic, can be nodular, tend to exhibit a violaceous hue, and occasionally may be hemorrhagic. Wells syndrome (also known as eosinophilic cellulitis) is an inflammatory dermatosis that presents as painful or pruritic, edematous and erythematous plaques.^7,8 A green hue on resolution is present in some cases and may help clinicians differentiate this disease from mimickers.⁷ Often, eosinophilic cellulitis is misdiagnosed as bacterial cellulitis and treated with antibiotics. The presence of systemic symptoms such as fever or arthralgia is more typical of bacterial cellulitis, erysipelas, eosinophilic cellulitis, or Sweet syndrome than of NEH.¹ Additionally, inflammatory markers (ie, C-reactive protein) and white blood cell counts tend to be elevated in bacterial cellulitis and Sweet syndrome, while leukopenia often is seen in NEH.

Histopathology is crucial in distinguishing these disease etiologies. Neutrophilic eccrine hidradenitis is diagnosed by the characteristic neutrophilic infiltrate and necrosis surrounding eccrine glands and coils. There also may be occasional intraductal abscesses and syringosquamous metaplasia of the sweat glands along with fibrosis of the adjacent dermis. In contrast, histologic sections of Sweet syndrome show numerous mature neutrophils infiltrating the dermis with marked papillary dermal edema. The histopathology of bacterial cellulitis and erysipelas is less specific, but common features include dermal edema, lymphatic dilation, and a diffuse neutrophilic infiltrate surrounding blood vessels. Pathogenic organisms may be seen on histopathology but are not required for the diagnosis of bacterial cellulitis or erysipelas.² Additionally, blood and tissue culture can assist in identification of both the source of infection and the causative organism, but cultures may not always be positive. 

Comparatively, the histopathologic features of eosinophilic cellulitis include dermal edema, eosinophilic infiltration, and flame figures that form when eosinophils degranulate and coat collagen fibers with major basic protein. Flame figures are characteristic but not pathognomonic for eosinophilic cellulitis.⁷ The histopathology of leukemia cutis varies based on the leukemia classification; generally, in acute myeloid leukemia the infiltrate is composed of neoplastic cells in the early stages of development that are positive for myeloid markers such as myeloperoxidase. Atypical and immature granulocytes within the leukocytic infiltrate differentiate this condition from the other diagnoses. Treatment may entail chemotherapy or radiotherapy, and this diagnosis generally carries the worst prognosis of all the conditions in the differential.⁶

Differentiating between these conditions is important in guiding treatment, especially in patients with febrile neutropenia. Unnecessary steroids in immunosuppressed patients can be dangerous, especially if the patient has an infection such as bacterial cellulitis. Furthermore, unwarranted antibiotic use for noninfectious conditions may expose patients to substantial side effects and not improve the condition. Neutrophilic eccrine hidradenitis typically is self-limited and treated symptomatically with systemic corticosteroids and nonsteroidal anti-inflammatory drugs.³ Sweet syndrome often requires a longer course of oral steroids. Leukemia cutis worsens as the leukemia advances, and treatment of the underlying malignancy is the most effective treatment.⁹

Early and accurate recognition of the diagnosis can prevent harmful diagnostic delay, unnecessary antibiotic use, or extended steroid taper in neutropenic patients. Appreciating the differences between these diagnoses can assist clinicians in investigating and tailoring a broad differential to specific patient presentations, which is especially critical when considering common mimickers for life-threatening conditions.

THE DIAGNOSIS: Neutrophilic Eccrine Hidradenitis

A biopsy from the left preauricular cheek demonstrated dermal neutrophilic inflammation around eccrine coils with focal necrosis (Figure). No notable diffuse dermal neutrophilic infiltrate was present, ruling out Sweet syndrome, and no notable interstitial neutrophilic infiltrate was present, making cellulitis and erysipelas less likely; panculture of tissue also was negative.^1,2 Atypical cells in the deep dermis were positive for CD163 and negative for CD117, CD34, CD123, and myeloperoxidase, consistent with a diagnosis of neutrophilic eccrine hidradenitis (NEH) and reactive histiocytes.³ Treatment with oral prednisone resulted in rapid improvement of symptoms.

Neutrophilic eccrine hidradenitis is a rare reactive neutrophilic dermatosis characterized by eccrine gland involvement. This benign and self-limited condition presents as asymmetric erythematous papules and plaques.² Among 8 granulocytopenic patients with neutrophilic dermatoses, 5 were diagnosed with NEH.⁴ Although first identified in 1982, NEH remains poorly understood.² Initial theories suggested that NEH developed due to cytotoxic substances secreted in sweat glands causing necrosis and neutrophil chemotaxis; however, chemotherapy exposure cannot be linked to every case of NEH. Neutrophilic eccrine hidradenitis can be extremely difficult to differentiate clinically from conditions such as cellulitis and Sweet syndrome.

A patient history can be helpful in identifying triggering factors. Neutrophilic eccrine hidradenitis most commonly is associated with malignant, drug-induced, or infectious triggers, while Sweet syndrome has a broad range of associations including infections, vaccines, inflammatory bowel disease, pregnancy, malignancy, and drug-induced etiologies (Table).¹ On average, NEH presents 10 days after chemotherapy induction, with 70% of cases presenting after the first chemotherapy cycle.⁵ Bacterial cellulitis or erysipelas have an infectious etiology, and patients may report symptoms such as fever, chills, or malaise. Immunosuppressed patients are at greater risk for infection; therefore, clinical signs of infection in a granulocytopenic patient should be addressed urgently.

Physical examination may have limited value in differentiating between these diagnoses, as neutrophilic dermatoses notoriously mimic infection. Cutaneous lesions can appear as pruritic or tender erythematous plaques, papules, or nodules in these conditions, though cellulitis and erysipelas tend to be unilateral and may have associated purulence or inflamed skin lymphatics. Given the potential for misdiagnosis, approaching patients with a broad differential can be helpful. In our patient, the differential diagnosis included Sweet syndrome, NEH, bacterial cellulitis, erysipelas, leukemia cutis, sarcoid, and eosinophilic cellulitis.

Leukemia cutis refers to the infiltration of neoplastic leukocytes in the skin and often occurs in patients with peripheral leukemia, most often acute myeloid leukemia or chronic lymphocytic leukemia. Patients with leukemia cutis often have a worse prognosis, as this finding signifies extramedullary spread of disease.⁶ Clinically, lesions can appear similar to those seen in our patient, though they typically are not symptomatic, can be nodular, tend to exhibit a violaceous hue, and occasionally may be hemorrhagic. Wells syndrome (also known as eosinophilic cellulitis) is an inflammatory dermatosis that presents as painful or pruritic, edematous and erythematous plaques.^7,8 A green hue on resolution is present in some cases and may help clinicians differentiate this disease from mimickers.⁷ Often, eosinophilic cellulitis is misdiagnosed as bacterial cellulitis and treated with antibiotics. The presence of systemic symptoms such as fever or arthralgia is more typical of bacterial cellulitis, erysipelas, eosinophilic cellulitis, or Sweet syndrome than of NEH.¹ Additionally, inflammatory markers (ie, C-reactive protein) and white blood cell counts tend to be elevated in bacterial cellulitis and Sweet syndrome, while leukopenia often is seen in NEH.

Histopathology is crucial in distinguishing these disease etiologies. Neutrophilic eccrine hidradenitis is diagnosed by the characteristic neutrophilic infiltrate and necrosis surrounding eccrine glands and coils. There also may be occasional intraductal abscesses and syringosquamous metaplasia of the sweat glands along with fibrosis of the adjacent dermis. In contrast, histologic sections of Sweet syndrome show numerous mature neutrophils infiltrating the dermis with marked papillary dermal edema. The histopathology of bacterial cellulitis and erysipelas is less specific, but common features include dermal edema, lymphatic dilation, and a diffuse neutrophilic infiltrate surrounding blood vessels. Pathogenic organisms may be seen on histopathology but are not required for the diagnosis of bacterial cellulitis or erysipelas.² Additionally, blood and tissue culture can assist in identification of both the source of infection and the causative organism, but cultures may not always be positive. 

Comparatively, the histopathologic features of eosinophilic cellulitis include dermal edema, eosinophilic infiltration, and flame figures that form when eosinophils degranulate and coat collagen fibers with major basic protein. Flame figures are characteristic but not pathognomonic for eosinophilic cellulitis.⁷ The histopathology of leukemia cutis varies based on the leukemia classification; generally, in acute myeloid leukemia the infiltrate is composed of neoplastic cells in the early stages of development that are positive for myeloid markers such as myeloperoxidase. Atypical and immature granulocytes within the leukocytic infiltrate differentiate this condition from the other diagnoses. Treatment may entail chemotherapy or radiotherapy, and this diagnosis generally carries the worst prognosis of all the conditions in the differential.⁶

Differentiating between these conditions is important in guiding treatment, especially in patients with febrile neutropenia. Unnecessary steroids in immunosuppressed patients can be dangerous, especially if the patient has an infection such as bacterial cellulitis. Furthermore, unwarranted antibiotic use for noninfectious conditions may expose patients to substantial side effects and not improve the condition. Neutrophilic eccrine hidradenitis typically is self-limited and treated symptomatically with systemic corticosteroids and nonsteroidal anti-inflammatory drugs.³ Sweet syndrome often requires a longer course of oral steroids. Leukemia cutis worsens as the leukemia advances, and treatment of the underlying malignancy is the most effective treatment.⁹

Early and accurate recognition of the diagnosis can prevent harmful diagnostic delay, unnecessary antibiotic use, or extended steroid taper in neutropenic patients. Appreciating the differences between these diagnoses can assist clinicians in investigating and tailoring a broad differential to specific patient presentations, which is especially critical when considering common mimickers for life-threatening conditions.

THE DIAGNOSIS: Neutrophilic Eccrine Hidradenitis

A biopsy from the left preauricular cheek demonstrated dermal neutrophilic inflammation around eccrine coils with focal necrosis (Figure). No notable diffuse dermal neutrophilic infiltrate was present, ruling out Sweet syndrome, and no notable interstitial neutrophilic infiltrate was present, making cellulitis and erysipelas less likely; panculture of tissue also was negative.^1,2 Atypical cells in the deep dermis were positive for CD163 and negative for CD117, CD34, CD123, and myeloperoxidase, consistent with a diagnosis of neutrophilic eccrine hidradenitis (NEH) and reactive histiocytes.³ Treatment with oral prednisone resulted in rapid improvement of symptoms.

Neutrophilic eccrine hidradenitis is a rare reactive neutrophilic dermatosis characterized by eccrine gland involvement. This benign and self-limited condition presents as asymmetric erythematous papules and plaques.² Among 8 granulocytopenic patients with neutrophilic dermatoses, 5 were diagnosed with NEH.⁴ Although first identified in 1982, NEH remains poorly understood.² Initial theories suggested that NEH developed due to cytotoxic substances secreted in sweat glands causing necrosis and neutrophil chemotaxis; however, chemotherapy exposure cannot be linked to every case of NEH. Neutrophilic eccrine hidradenitis can be extremely difficult to differentiate clinically from conditions such as cellulitis and Sweet syndrome.

A patient history can be helpful in identifying triggering factors. Neutrophilic eccrine hidradenitis most commonly is associated with malignant, drug-induced, or infectious triggers, while Sweet syndrome has a broad range of associations including infections, vaccines, inflammatory bowel disease, pregnancy, malignancy, and drug-induced etiologies (Table).¹ On average, NEH presents 10 days after chemotherapy induction, with 70% of cases presenting after the first chemotherapy cycle.⁵ Bacterial cellulitis or erysipelas have an infectious etiology, and patients may report symptoms such as fever, chills, or malaise. Immunosuppressed patients are at greater risk for infection; therefore, clinical signs of infection in a granulocytopenic patient should be addressed urgently.

Physical examination may have limited value in differentiating between these diagnoses, as neutrophilic dermatoses notoriously mimic infection. Cutaneous lesions can appear as pruritic or tender erythematous plaques, papules, or nodules in these conditions, though cellulitis and erysipelas tend to be unilateral and may have associated purulence or inflamed skin lymphatics. Given the potential for misdiagnosis, approaching patients with a broad differential can be helpful. In our patient, the differential diagnosis included Sweet syndrome, NEH, bacterial cellulitis, erysipelas, leukemia cutis, sarcoid, and eosinophilic cellulitis.

Leukemia cutis refers to the infiltration of neoplastic leukocytes in the skin and often occurs in patients with peripheral leukemia, most often acute myeloid leukemia or chronic lymphocytic leukemia. Patients with leukemia cutis often have a worse prognosis, as this finding signifies extramedullary spread of disease.⁶ Clinically, lesions can appear similar to those seen in our patient, though they typically are not symptomatic, can be nodular, tend to exhibit a violaceous hue, and occasionally may be hemorrhagic. Wells syndrome (also known as eosinophilic cellulitis) is an inflammatory dermatosis that presents as painful or pruritic, edematous and erythematous plaques.^7,8 A green hue on resolution is present in some cases and may help clinicians differentiate this disease from mimickers.⁷ Often, eosinophilic cellulitis is misdiagnosed as bacterial cellulitis and treated with antibiotics. The presence of systemic symptoms such as fever or arthralgia is more typical of bacterial cellulitis, erysipelas, eosinophilic cellulitis, or Sweet syndrome than of NEH.¹ Additionally, inflammatory markers (ie, C-reactive protein) and white blood cell counts tend to be elevated in bacterial cellulitis and Sweet syndrome, while leukopenia often is seen in NEH.

Histopathology is crucial in distinguishing these disease etiologies. Neutrophilic eccrine hidradenitis is diagnosed by the characteristic neutrophilic infiltrate and necrosis surrounding eccrine glands and coils. There also may be occasional intraductal abscesses and syringosquamous metaplasia of the sweat glands along with fibrosis of the adjacent dermis. In contrast, histologic sections of Sweet syndrome show numerous mature neutrophils infiltrating the dermis with marked papillary dermal edema. The histopathology of bacterial cellulitis and erysipelas is less specific, but common features include dermal edema, lymphatic dilation, and a diffuse neutrophilic infiltrate surrounding blood vessels. Pathogenic organisms may be seen on histopathology but are not required for the diagnosis of bacterial cellulitis or erysipelas.² Additionally, blood and tissue culture can assist in identification of both the source of infection and the causative organism, but cultures may not always be positive. 

Comparatively, the histopathologic features of eosinophilic cellulitis include dermal edema, eosinophilic infiltration, and flame figures that form when eosinophils degranulate and coat collagen fibers with major basic protein. Flame figures are characteristic but not pathognomonic for eosinophilic cellulitis.⁷ The histopathology of leukemia cutis varies based on the leukemia classification; generally, in acute myeloid leukemia the infiltrate is composed of neoplastic cells in the early stages of development that are positive for myeloid markers such as myeloperoxidase. Atypical and immature granulocytes within the leukocytic infiltrate differentiate this condition from the other diagnoses. Treatment may entail chemotherapy or radiotherapy, and this diagnosis generally carries the worst prognosis of all the conditions in the differential.⁶

Differentiating between these conditions is important in guiding treatment, especially in patients with febrile neutropenia. Unnecessary steroids in immunosuppressed patients can be dangerous, especially if the patient has an infection such as bacterial cellulitis. Furthermore, unwarranted antibiotic use for noninfectious conditions may expose patients to substantial side effects and not improve the condition. Neutrophilic eccrine hidradenitis typically is self-limited and treated symptomatically with systemic corticosteroids and nonsteroidal anti-inflammatory drugs.³ Sweet syndrome often requires a longer course of oral steroids. Leukemia cutis worsens as the leukemia advances, and treatment of the underlying malignancy is the most effective treatment.⁹

Early and accurate recognition of the diagnosis can prevent harmful diagnostic delay, unnecessary antibiotic use, or extended steroid taper in neutropenic patients. Appreciating the differences between these diagnoses can assist clinicians in investigating and tailoring a broad differential to specific patient presentations, which is especially critical when considering common mimickers for life-threatening conditions.

A novel agent has shown promise in the treatment of chronic myelomonocytic leukemia (CMML), a rare, aggressive malignancy of myeloid cells with an inherent risk of transforming into acute myeloid leukemia in about 15%-20% of patients. 

There is currently no international standard of care for patients with CMML, but given its overlap with other myelodysplastic and myeloproliferative syndromes, CMML is usually treated with the hypomethylating agent azacitidine (Vidaza, Onureg), which is associated with objective response rates of 40%-50% and a complete response rate of less than 20%. Alternatively, some patients are treated with the antimetabolite hydroxurea in the palliative setting.

CMML is “insidious, it’s rare, but we think the incidence is increasing because more patients are now getting sequencing done by their doctors, and therapy [related] cases, patients that have survived chemo in the last 10 years, can also develop this disease,” said Daniel Thomas, MD, PhD, from the South Australian Health and Medical Research Institute, Adelaide, in an interview.

Dr. Thomas is a co-investigator of the ongoing phase 2/3 PREACH-M trial, which is testing a novel strategy of treating CMML with mutations in the RAS pathway with a combination of azacitidine and the investigational antibody lenzilumab, which is a targeted inhibitor of granulocyte-macrophage colony-stimulating factor (GM-CSF).

Preliminary results from the trial, reported at the European Hematology Association (EHA) annual meeting, showed that among 10 patients with CMML bearing mutations in the RAS pathway, the combination was associated with durable decreases in monocyte counts, increases in platelet counts and hemoglobin levels, and reductions in both spleen size and C-reactive protein level.
 

Targeting GM-CSF

More than 90% of cases of CMML carry somatic mutations that are thought to be leukemogenic, with an estimated 46%-60% of cases having mutations in TET2, a tumor suppressor, and an estimated 40% having mutations in KRAS, NRAS, or CBL, all of which are involved in cellular proliferation, and which, research suggests, are sensitive to GM-CSF inhibition.

“I was very surprised that the RAS-mutant arm – so, patients that have KRAS, NRAS, or CBL mutations – are just responding beautifully to [lenzilumab], ” Dr. Thomas said.

“It’s [in the] early days, but if what we’re seeing is durable across the next 10 patients, then I think we’re looking at a game changer,” he added.

Cameron Durrant, MD, DRCOG, MRCGP, chairman and CEO of lenzilumab’s maker Humanigen, said in an interview that the development of the antibody for CMML was spurred in part by research from investigators at the Mayo Clinic, showing that patients with mutations that increased sensitivity to GM-CSF seemed to have better clinical outcomes when the growth factor was blocked.

In addition, Dr. Durrant said, preclinical research from investigators at the Moffitt Cancer Center, Tampa, found that myeloid and monocytic progenitors “fed” on GM-CSF and were sensitive to GM-CSF signal inhibition.

“The biological idea that’s being explored here in the clinic in this study is that by blocking, or starving, if you will, those cells of that food, then you can prevent this overgrowth of certain blood cells that lead to chronic myelomonocytic leukemia,” he said.
 

PREACH-M details

Lenzilumab is an engineered human immunoglobulin G1-kappa monoclonal antibody with high affinity for human GM-CSF.

In the open label, nonrandomized PREACH-M trial, 72 patients with CMML were enrolled and were assigned to receive 24 monthly cycles of therapy depending on mutational status.

Patients with RAS pathway mutations were assigned to receive azacitidine delivered subcutaneously 75 mg/m² for 7 days, plus intravenous lenzilumab 552 mg on days 1 and 15 of cycle 1 and on day 1 only of all subsequent cycles.

Patients with TET2 mutations only were assigned to receive azacitidine on the same schedule, plus IV sodium ascorbate 30 g for 7 days, with the first dose 15 g, and subsequent doses 30 g if there is no evidence of tumor lysis syndrome. Following IV administration, patients continue on oral sodium ascorbate 1.1 g on all other days.

The primary endpoint of complete and partial responses any time during the first 12 cycles is planned for reporting at the annual meeting of the American Society of Hematology in December, Dr. Thomas said.

At EHA 2023, the investigators reported available data on 10 patients enrolled in the lenzilumab arm and one enrolled in the azacitidine-sodium ascorbate arm.

Among patients in the lenzilumab arm there was a 5.1-fold decrease in monocyte counts (P = .03) and 2.4-fold decrease in blast counts (P = .04) at 12 months of follow-up.

In addition there was a trend toward increased platelet counts over baseline at 12 months, a significant increase in blood hemoglobin concentration (P = .024), a significant reduction in spleen size (P = .03) and a trend toward lower levels of the inflammatory marker C-reactive protein.

There were 21 grade 3 or 4 adverse events reported, of which 5 were deemed to be possibly related to lenzilumab.

Dr. Thomas told this news organization that the investigators have been “pleasantly surprised” at how well patients tolerated the monoclonal antibody.

“We haven’t had any infusion reactions, we haven’t had any pulmonary alveolar proteinosis, [and] we haven’t had any fevers from the infusion, from the antibody,” he said.

There were some instances of neutropenia and thrombocytopenia that the investigators think may have been related to azacitidine, he noted.

The study is sponsored by the National Health and Medical Research Council of Australia. Dr. Thomas reported no relevant financial relationships. Dr. Durrant is an employee and director of Humanigen.

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

A novel agent has shown promise in the treatment of chronic myelomonocytic leukemia (CMML), a rare, aggressive malignancy of myeloid cells with an inherent risk of transforming into acute myeloid leukemia in about 15%-20% of patients. 

There is currently no international standard of care for patients with CMML, but given its overlap with other myelodysplastic and myeloproliferative syndromes, CMML is usually treated with the hypomethylating agent azacitidine (Vidaza, Onureg), which is associated with objective response rates of 40%-50% and a complete response rate of less than 20%. Alternatively, some patients are treated with the antimetabolite hydroxurea in the palliative setting.

CMML is “insidious, it’s rare, but we think the incidence is increasing because more patients are now getting sequencing done by their doctors, and therapy [related] cases, patients that have survived chemo in the last 10 years, can also develop this disease,” said Daniel Thomas, MD, PhD, from the South Australian Health and Medical Research Institute, Adelaide, in an interview.

Dr. Thomas is a co-investigator of the ongoing phase 2/3 PREACH-M trial, which is testing a novel strategy of treating CMML with mutations in the RAS pathway with a combination of azacitidine and the investigational antibody lenzilumab, which is a targeted inhibitor of granulocyte-macrophage colony-stimulating factor (GM-CSF).

Preliminary results from the trial, reported at the European Hematology Association (EHA) annual meeting, showed that among 10 patients with CMML bearing mutations in the RAS pathway, the combination was associated with durable decreases in monocyte counts, increases in platelet counts and hemoglobin levels, and reductions in both spleen size and C-reactive protein level.
 

Targeting GM-CSF

More than 90% of cases of CMML carry somatic mutations that are thought to be leukemogenic, with an estimated 46%-60% of cases having mutations in TET2, a tumor suppressor, and an estimated 40% having mutations in KRAS, NRAS, or CBL, all of which are involved in cellular proliferation, and which, research suggests, are sensitive to GM-CSF inhibition.

“I was very surprised that the RAS-mutant arm – so, patients that have KRAS, NRAS, or CBL mutations – are just responding beautifully to [lenzilumab], ” Dr. Thomas said.

“It’s [in the] early days, but if what we’re seeing is durable across the next 10 patients, then I think we’re looking at a game changer,” he added.

Cameron Durrant, MD, DRCOG, MRCGP, chairman and CEO of lenzilumab’s maker Humanigen, said in an interview that the development of the antibody for CMML was spurred in part by research from investigators at the Mayo Clinic, showing that patients with mutations that increased sensitivity to GM-CSF seemed to have better clinical outcomes when the growth factor was blocked.

In addition, Dr. Durrant said, preclinical research from investigators at the Moffitt Cancer Center, Tampa, found that myeloid and monocytic progenitors “fed” on GM-CSF and were sensitive to GM-CSF signal inhibition.

“The biological idea that’s being explored here in the clinic in this study is that by blocking, or starving, if you will, those cells of that food, then you can prevent this overgrowth of certain blood cells that lead to chronic myelomonocytic leukemia,” he said.
 

PREACH-M details

Lenzilumab is an engineered human immunoglobulin G1-kappa monoclonal antibody with high affinity for human GM-CSF.

In the open label, nonrandomized PREACH-M trial, 72 patients with CMML were enrolled and were assigned to receive 24 monthly cycles of therapy depending on mutational status.

Patients with RAS pathway mutations were assigned to receive azacitidine delivered subcutaneously 75 mg/m² for 7 days, plus intravenous lenzilumab 552 mg on days 1 and 15 of cycle 1 and on day 1 only of all subsequent cycles.

Patients with TET2 mutations only were assigned to receive azacitidine on the same schedule, plus IV sodium ascorbate 30 g for 7 days, with the first dose 15 g, and subsequent doses 30 g if there is no evidence of tumor lysis syndrome. Following IV administration, patients continue on oral sodium ascorbate 1.1 g on all other days.

The primary endpoint of complete and partial responses any time during the first 12 cycles is planned for reporting at the annual meeting of the American Society of Hematology in December, Dr. Thomas said.

At EHA 2023, the investigators reported available data on 10 patients enrolled in the lenzilumab arm and one enrolled in the azacitidine-sodium ascorbate arm.

Among patients in the lenzilumab arm there was a 5.1-fold decrease in monocyte counts (P = .03) and 2.4-fold decrease in blast counts (P = .04) at 12 months of follow-up.

In addition there was a trend toward increased platelet counts over baseline at 12 months, a significant increase in blood hemoglobin concentration (P = .024), a significant reduction in spleen size (P = .03) and a trend toward lower levels of the inflammatory marker C-reactive protein.

There were 21 grade 3 or 4 adverse events reported, of which 5 were deemed to be possibly related to lenzilumab.

Dr. Thomas told this news organization that the investigators have been “pleasantly surprised” at how well patients tolerated the monoclonal antibody.

“We haven’t had any infusion reactions, we haven’t had any pulmonary alveolar proteinosis, [and] we haven’t had any fevers from the infusion, from the antibody,” he said.

There were some instances of neutropenia and thrombocytopenia that the investigators think may have been related to azacitidine, he noted.

The study is sponsored by the National Health and Medical Research Council of Australia. Dr. Thomas reported no relevant financial relationships. Dr. Durrant is an employee and director of Humanigen.

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

A novel agent has shown promise in the treatment of chronic myelomonocytic leukemia (CMML), a rare, aggressive malignancy of myeloid cells with an inherent risk of transforming into acute myeloid leukemia in about 15%-20% of patients. 

There is currently no international standard of care for patients with CMML, but given its overlap with other myelodysplastic and myeloproliferative syndromes, CMML is usually treated with the hypomethylating agent azacitidine (Vidaza, Onureg), which is associated with objective response rates of 40%-50% and a complete response rate of less than 20%. Alternatively, some patients are treated with the antimetabolite hydroxurea in the palliative setting.

CMML is “insidious, it’s rare, but we think the incidence is increasing because more patients are now getting sequencing done by their doctors, and therapy [related] cases, patients that have survived chemo in the last 10 years, can also develop this disease,” said Daniel Thomas, MD, PhD, from the South Australian Health and Medical Research Institute, Adelaide, in an interview.

Dr. Thomas is a co-investigator of the ongoing phase 2/3 PREACH-M trial, which is testing a novel strategy of treating CMML with mutations in the RAS pathway with a combination of azacitidine and the investigational antibody lenzilumab, which is a targeted inhibitor of granulocyte-macrophage colony-stimulating factor (GM-CSF).

Preliminary results from the trial, reported at the European Hematology Association (EHA) annual meeting, showed that among 10 patients with CMML bearing mutations in the RAS pathway, the combination was associated with durable decreases in monocyte counts, increases in platelet counts and hemoglobin levels, and reductions in both spleen size and C-reactive protein level.
 

Targeting GM-CSF

More than 90% of cases of CMML carry somatic mutations that are thought to be leukemogenic, with an estimated 46%-60% of cases having mutations in TET2, a tumor suppressor, and an estimated 40% having mutations in KRAS, NRAS, or CBL, all of which are involved in cellular proliferation, and which, research suggests, are sensitive to GM-CSF inhibition.

“I was very surprised that the RAS-mutant arm – so, patients that have KRAS, NRAS, or CBL mutations – are just responding beautifully to [lenzilumab], ” Dr. Thomas said.

“It’s [in the] early days, but if what we’re seeing is durable across the next 10 patients, then I think we’re looking at a game changer,” he added.

Cameron Durrant, MD, DRCOG, MRCGP, chairman and CEO of lenzilumab’s maker Humanigen, said in an interview that the development of the antibody for CMML was spurred in part by research from investigators at the Mayo Clinic, showing that patients with mutations that increased sensitivity to GM-CSF seemed to have better clinical outcomes when the growth factor was blocked.

In addition, Dr. Durrant said, preclinical research from investigators at the Moffitt Cancer Center, Tampa, found that myeloid and monocytic progenitors “fed” on GM-CSF and were sensitive to GM-CSF signal inhibition.

“The biological idea that’s being explored here in the clinic in this study is that by blocking, or starving, if you will, those cells of that food, then you can prevent this overgrowth of certain blood cells that lead to chronic myelomonocytic leukemia,” he said.
 

PREACH-M details

Lenzilumab is an engineered human immunoglobulin G1-kappa monoclonal antibody with high affinity for human GM-CSF.

In the open label, nonrandomized PREACH-M trial, 72 patients with CMML were enrolled and were assigned to receive 24 monthly cycles of therapy depending on mutational status.

Patients with RAS pathway mutations were assigned to receive azacitidine delivered subcutaneously 75 mg/m² for 7 days, plus intravenous lenzilumab 552 mg on days 1 and 15 of cycle 1 and on day 1 only of all subsequent cycles.

Patients with TET2 mutations only were assigned to receive azacitidine on the same schedule, plus IV sodium ascorbate 30 g for 7 days, with the first dose 15 g, and subsequent doses 30 g if there is no evidence of tumor lysis syndrome. Following IV administration, patients continue on oral sodium ascorbate 1.1 g on all other days.

The primary endpoint of complete and partial responses any time during the first 12 cycles is planned for reporting at the annual meeting of the American Society of Hematology in December, Dr. Thomas said.

At EHA 2023, the investigators reported available data on 10 patients enrolled in the lenzilumab arm and one enrolled in the azacitidine-sodium ascorbate arm.

Among patients in the lenzilumab arm there was a 5.1-fold decrease in monocyte counts (P = .03) and 2.4-fold decrease in blast counts (P = .04) at 12 months of follow-up.

In addition there was a trend toward increased platelet counts over baseline at 12 months, a significant increase in blood hemoglobin concentration (P = .024), a significant reduction in spleen size (P = .03) and a trend toward lower levels of the inflammatory marker C-reactive protein.

There were 21 grade 3 or 4 adverse events reported, of which 5 were deemed to be possibly related to lenzilumab.

Dr. Thomas told this news organization that the investigators have been “pleasantly surprised” at how well patients tolerated the monoclonal antibody.

“We haven’t had any infusion reactions, we haven’t had any pulmonary alveolar proteinosis, [and] we haven’t had any fevers from the infusion, from the antibody,” he said.

There were some instances of neutropenia and thrombocytopenia that the investigators think may have been related to azacitidine, he noted.

The study is sponsored by the National Health and Medical Research Council of Australia. Dr. Thomas reported no relevant financial relationships. Dr. Durrant is an employee and director of Humanigen.

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

The Sexual Health Initiative to Foster Transformation (SHIFT)¹ is a landmark study about sexual assault at college, which has generated 20 scientific articles and several chapters in books, but unfortunately, has not made its way into the psychiatric literature.

“Sexual Citizens: Sex, Power and Assault on Campus,” by Jennifer Hirsch and Shamus Khan, (available in audio book and paperback) was written as a follow up to the SHIFT study, so the rest of us can absorb the findings.² This mixed-methods study included a survey of over 1,600 students aged 18-29 from Columbia University and Barnard College regarding their relationships and sexual histories, including assault. Data were collected using daily diaries, focus groups, and hundreds of hours of field work observation by young researchers. One- to 3-hour in-depth interviews exploring sexual experiences on campus were conducted with 151 students. These interviews are the focus of the book. It is a well-written, provocative story brimming with insights for those of us who lack the time to scour social science literature.

Dr. Higgins

“Sexual Citizens” and the SHIFT study confirmed much of what we know. Sexual assault is common and has enduring effects. The study found that 36% of women and 15% of men had experienced unwanted, nonconsensual sexual contact by senior year. Twenty percent of women and 6% of men were rape survivors. Freshman, LGBTQ, and minority students were found at highest risk of assault. SHIFT reaffirmed that abstinence-only education is not a protective factor against college sexual assault, but neither was knowledge of affirmative consent (the practice of “ongoing and explicit” checking-in with partners) which few students ever employed. Encouragingly, students taught refusal skills were less likely to experience sexual assault.

Many of the book’s valuable lessons fall under the umbrella of failures of language and communication. For example, after drinking, they went to his room. She was expecting a social interaction, but with no other place to sit, they sat on his bed where she was coaxed or pressured into a sexual encounter. Afterward, she leaves, and it is never discussed again. One partner desires emotional intimacy, and the other, bragging rights in the fraternity or at the girls’ weekly brunch. Numerous personal stories like these, though at times heart wrenching, provide perspective on the barriers to addressing assault.

Subjects relayed experiences of assault by strangers or friends, and some provided details of their own actions as perpetrators. Stumbling around words and emotions, an avoidance of explicit language stemmed from shame, a fear of personal responsibility, the desire to maintain social cohesion, and concern for potential consequences for the perpetrator. Many subjects were resistant to calling nonconsensual sexual activity rape or even assault. Some who had perpetrated were unaware their behavior may have been experienced as assault, with recognition of this fact dawning during interviews.

This apparent limitation in self-reflective capacity may be in part due to the conceptualization of what assault is. Focus groups identified a discernible difference in how men and women understood assaults, with men believing rapes looked like a woman fighting back and screaming for help ... which is rarely what happens.

Notably absent among the interviewed are any flagrant perpetrators. The methodology section theorizes that individuals who intentionally harmed their peers were unlikely to choose to participate in this study. In addition, the characterization of assailants as “sociopathic predators” is based in a history of racialized imagery that leads us astray from the truth about campus sexual assault. Most assaults do not involve force, and SHIFT data showed 75% of victims knew their assailants. Ultimately, a major aim of the research was to study assault alongside healthy sex to “understand those pivotal moments when encounters change from being sex, to being assault.” Doing this requires understanding the where, how, and why students have sex, a more complicated undertaking than we may think.

In discussing their sexual lives, subjects frequently noted they did not have space to talk about their assaults. Though 81% of students discussed their experiences with someone, friend groups were often overburdened with stories, which minimized the victim’s experience. Furthermore, most had not sought help from the student counseling centers. Students navigating this complex field were frequently doing so in isolation. SHIFT found subjects to be eager to participate; they would often express thankfulness, and a sense of freedom in sharing with researchers. Commonly, students expressly did not want retribution for perpetrators, but simply a place to be heard without challenge. The current legal system precludes that possibility, leaving individuals without the option to confront perpetrators, and perpetrators often not knowing the extent of the damage they caused.

Where can psychiatrists have an impact right now? “Sexual Citizens” identifies four key areas for intervention to work toward a world with less sexual assault. These are:

• Improving diversity, inequality, and power distortions.
• Education about sex and sexual assault.
• Substance use.
• Mental health.

Substance use and mental health are especially relevant for psychiatrists (That substance use contributes to sexual assault is known by approximately ... everybody!). “Sexual Citizens” notes that mental illness is likely “both a cause and a consequence of sexual assault.” Unwanted sexual contact prior to college (20% of students) increased the odds of experiencing assault during college. Harm reduction strategies should be introduced before college, according to the SHIFT research, particularly in skills-based training on how to say “No” to unwanted sex. Psychiatrists are likely used to asking brief history questions related to sexual assault and rape. “Sexual Citizens” highlights the inadequacy of this blunt language and guides the reader toward a refined knowledge of the language needed to address sexual assault.

Dr. Whisler is a child and adolescent psychiatry fellow at the Stanford (Calif.) University. Dr. Higgins is affiliate associate professor of psychiatry and family medicine at the Medical University of South Carolina, Charleston.

References

1. Hirsch JS et al. Social dimensions of sexual consent among cisgender heterosexual college students: Insights from ethnographic research. J Adolesc Health. 2019 Jan;64(1):26-35. doi: 10.1016/j.jadohealth.2018.06.011.

2. Hirsch JS and Khan S. Sexual citizens: Sex, power, and assault on campus. New York: W.W. Norton & Company, 2020.

The Sexual Health Initiative to Foster Transformation (SHIFT)¹ is a landmark study about sexual assault at college, which has generated 20 scientific articles and several chapters in books, but unfortunately, has not made its way into the psychiatric literature.

“Sexual Citizens: Sex, Power and Assault on Campus,” by Jennifer Hirsch and Shamus Khan, (available in audio book and paperback) was written as a follow up to the SHIFT study, so the rest of us can absorb the findings.² This mixed-methods study included a survey of over 1,600 students aged 18-29 from Columbia University and Barnard College regarding their relationships and sexual histories, including assault. Data were collected using daily diaries, focus groups, and hundreds of hours of field work observation by young researchers. One- to 3-hour in-depth interviews exploring sexual experiences on campus were conducted with 151 students. These interviews are the focus of the book. It is a well-written, provocative story brimming with insights for those of us who lack the time to scour social science literature.

Dr. Higgins

“Sexual Citizens” and the SHIFT study confirmed much of what we know. Sexual assault is common and has enduring effects. The study found that 36% of women and 15% of men had experienced unwanted, nonconsensual sexual contact by senior year. Twenty percent of women and 6% of men were rape survivors. Freshman, LGBTQ, and minority students were found at highest risk of assault. SHIFT reaffirmed that abstinence-only education is not a protective factor against college sexual assault, but neither was knowledge of affirmative consent (the practice of “ongoing and explicit” checking-in with partners) which few students ever employed. Encouragingly, students taught refusal skills were less likely to experience sexual assault.

Many of the book’s valuable lessons fall under the umbrella of failures of language and communication. For example, after drinking, they went to his room. She was expecting a social interaction, but with no other place to sit, they sat on his bed where she was coaxed or pressured into a sexual encounter. Afterward, she leaves, and it is never discussed again. One partner desires emotional intimacy, and the other, bragging rights in the fraternity or at the girls’ weekly brunch. Numerous personal stories like these, though at times heart wrenching, provide perspective on the barriers to addressing assault.

Subjects relayed experiences of assault by strangers or friends, and some provided details of their own actions as perpetrators. Stumbling around words and emotions, an avoidance of explicit language stemmed from shame, a fear of personal responsibility, the desire to maintain social cohesion, and concern for potential consequences for the perpetrator. Many subjects were resistant to calling nonconsensual sexual activity rape or even assault. Some who had perpetrated were unaware their behavior may have been experienced as assault, with recognition of this fact dawning during interviews.

This apparent limitation in self-reflective capacity may be in part due to the conceptualization of what assault is. Focus groups identified a discernible difference in how men and women understood assaults, with men believing rapes looked like a woman fighting back and screaming for help ... which is rarely what happens.

Notably absent among the interviewed are any flagrant perpetrators. The methodology section theorizes that individuals who intentionally harmed their peers were unlikely to choose to participate in this study. In addition, the characterization of assailants as “sociopathic predators” is based in a history of racialized imagery that leads us astray from the truth about campus sexual assault. Most assaults do not involve force, and SHIFT data showed 75% of victims knew their assailants. Ultimately, a major aim of the research was to study assault alongside healthy sex to “understand those pivotal moments when encounters change from being sex, to being assault.” Doing this requires understanding the where, how, and why students have sex, a more complicated undertaking than we may think.

In discussing their sexual lives, subjects frequently noted they did not have space to talk about their assaults. Though 81% of students discussed their experiences with someone, friend groups were often overburdened with stories, which minimized the victim’s experience. Furthermore, most had not sought help from the student counseling centers. Students navigating this complex field were frequently doing so in isolation. SHIFT found subjects to be eager to participate; they would often express thankfulness, and a sense of freedom in sharing with researchers. Commonly, students expressly did not want retribution for perpetrators, but simply a place to be heard without challenge. The current legal system precludes that possibility, leaving individuals without the option to confront perpetrators, and perpetrators often not knowing the extent of the damage they caused.

Where can psychiatrists have an impact right now? “Sexual Citizens” identifies four key areas for intervention to work toward a world with less sexual assault. These are:

• Improving diversity, inequality, and power distortions.
• Education about sex and sexual assault.
• Substance use.
• Mental health.

Substance use and mental health are especially relevant for psychiatrists (That substance use contributes to sexual assault is known by approximately ... everybody!). “Sexual Citizens” notes that mental illness is likely “both a cause and a consequence of sexual assault.” Unwanted sexual contact prior to college (20% of students) increased the odds of experiencing assault during college. Harm reduction strategies should be introduced before college, according to the SHIFT research, particularly in skills-based training on how to say “No” to unwanted sex. Psychiatrists are likely used to asking brief history questions related to sexual assault and rape. “Sexual Citizens” highlights the inadequacy of this blunt language and guides the reader toward a refined knowledge of the language needed to address sexual assault.

Dr. Whisler is a child and adolescent psychiatry fellow at the Stanford (Calif.) University. Dr. Higgins is affiliate associate professor of psychiatry and family medicine at the Medical University of South Carolina, Charleston.

References

1. Hirsch JS et al. Social dimensions of sexual consent among cisgender heterosexual college students: Insights from ethnographic research. J Adolesc Health. 2019 Jan;64(1):26-35. doi: 10.1016/j.jadohealth.2018.06.011.

2. Hirsch JS and Khan S. Sexual citizens: Sex, power, and assault on campus. New York: W.W. Norton & Company, 2020.

The Sexual Health Initiative to Foster Transformation (SHIFT)¹ is a landmark study about sexual assault at college, which has generated 20 scientific articles and several chapters in books, but unfortunately, has not made its way into the psychiatric literature.

“Sexual Citizens: Sex, Power and Assault on Campus,” by Jennifer Hirsch and Shamus Khan, (available in audio book and paperback) was written as a follow up to the SHIFT study, so the rest of us can absorb the findings.² This mixed-methods study included a survey of over 1,600 students aged 18-29 from Columbia University and Barnard College regarding their relationships and sexual histories, including assault. Data were collected using daily diaries, focus groups, and hundreds of hours of field work observation by young researchers. One- to 3-hour in-depth interviews exploring sexual experiences on campus were conducted with 151 students. These interviews are the focus of the book. It is a well-written, provocative story brimming with insights for those of us who lack the time to scour social science literature.

Dr. Higgins

“Sexual Citizens” and the SHIFT study confirmed much of what we know. Sexual assault is common and has enduring effects. The study found that 36% of women and 15% of men had experienced unwanted, nonconsensual sexual contact by senior year. Twenty percent of women and 6% of men were rape survivors. Freshman, LGBTQ, and minority students were found at highest risk of assault. SHIFT reaffirmed that abstinence-only education is not a protective factor against college sexual assault, but neither was knowledge of affirmative consent (the practice of “ongoing and explicit” checking-in with partners) which few students ever employed. Encouragingly, students taught refusal skills were less likely to experience sexual assault.

Many of the book’s valuable lessons fall under the umbrella of failures of language and communication. For example, after drinking, they went to his room. She was expecting a social interaction, but with no other place to sit, they sat on his bed where she was coaxed or pressured into a sexual encounter. Afterward, she leaves, and it is never discussed again. One partner desires emotional intimacy, and the other, bragging rights in the fraternity or at the girls’ weekly brunch. Numerous personal stories like these, though at times heart wrenching, provide perspective on the barriers to addressing assault.

Subjects relayed experiences of assault by strangers or friends, and some provided details of their own actions as perpetrators. Stumbling around words and emotions, an avoidance of explicit language stemmed from shame, a fear of personal responsibility, the desire to maintain social cohesion, and concern for potential consequences for the perpetrator. Many subjects were resistant to calling nonconsensual sexual activity rape or even assault. Some who had perpetrated were unaware their behavior may have been experienced as assault, with recognition of this fact dawning during interviews.

This apparent limitation in self-reflective capacity may be in part due to the conceptualization of what assault is. Focus groups identified a discernible difference in how men and women understood assaults, with men believing rapes looked like a woman fighting back and screaming for help ... which is rarely what happens.

Notably absent among the interviewed are any flagrant perpetrators. The methodology section theorizes that individuals who intentionally harmed their peers were unlikely to choose to participate in this study. In addition, the characterization of assailants as “sociopathic predators” is based in a history of racialized imagery that leads us astray from the truth about campus sexual assault. Most assaults do not involve force, and SHIFT data showed 75% of victims knew their assailants. Ultimately, a major aim of the research was to study assault alongside healthy sex to “understand those pivotal moments when encounters change from being sex, to being assault.” Doing this requires understanding the where, how, and why students have sex, a more complicated undertaking than we may think.

In discussing their sexual lives, subjects frequently noted they did not have space to talk about their assaults. Though 81% of students discussed their experiences with someone, friend groups were often overburdened with stories, which minimized the victim’s experience. Furthermore, most had not sought help from the student counseling centers. Students navigating this complex field were frequently doing so in isolation. SHIFT found subjects to be eager to participate; they would often express thankfulness, and a sense of freedom in sharing with researchers. Commonly, students expressly did not want retribution for perpetrators, but simply a place to be heard without challenge. The current legal system precludes that possibility, leaving individuals without the option to confront perpetrators, and perpetrators often not knowing the extent of the damage they caused.

Where can psychiatrists have an impact right now? “Sexual Citizens” identifies four key areas for intervention to work toward a world with less sexual assault. These are:

• Improving diversity, inequality, and power distortions.
• Education about sex and sexual assault.
• Substance use.
• Mental health.

Substance use and mental health are especially relevant for psychiatrists (That substance use contributes to sexual assault is known by approximately ... everybody!). “Sexual Citizens” notes that mental illness is likely “both a cause and a consequence of sexual assault.” Unwanted sexual contact prior to college (20% of students) increased the odds of experiencing assault during college. Harm reduction strategies should be introduced before college, according to the SHIFT research, particularly in skills-based training on how to say “No” to unwanted sex. Psychiatrists are likely used to asking brief history questions related to sexual assault and rape. “Sexual Citizens” highlights the inadequacy of this blunt language and guides the reader toward a refined knowledge of the language needed to address sexual assault.

Dr. Whisler is a child and adolescent psychiatry fellow at the Stanford (Calif.) University. Dr. Higgins is affiliate associate professor of psychiatry and family medicine at the Medical University of South Carolina, Charleston.

References

1. Hirsch JS et al. Social dimensions of sexual consent among cisgender heterosexual college students: Insights from ethnographic research. J Adolesc Health. 2019 Jan;64(1):26-35. doi: 10.1016/j.jadohealth.2018.06.011.

2. Hirsch JS and Khan S. Sexual citizens: Sex, power, and assault on campus. New York: W.W. Norton & Company, 2020.

The Food and Drug Administration has approved the anti-inflammatory drug colchicine 0.5 mg tablets (Lodoco) as the first specific anti-inflammatory drug demonstrated to reduce the risk for myocardial infarction, stroke, coronary revascularization, and cardiovascular death in adult patients with established atherosclerotic disease or with multiple risk factors for cardiovascular disease.

The drug, which targets residual inflammation as an underlying cause of atherosclerotic cardiovascular disease, has a dosage of 0.5 mg once daily, and can be used alone or in combination with cholesterol-lowering medications. 

Olivier Le Moal/Getty Images

The drug’s manufacturer, Agepha Pharma, said it anticipates that Lodoco will be available for prescription in the second half of 2023.

Colchicine has been available for many years and used at higher doses for the acute treatment of gout and pericarditis, but the current formulation is a much lower dose for long-term use in patients with atherosclerotic heart disease.

Data supporting the approval has come from two major randomized trials, LoDoCo-2 and COLCOT.

In the LoDoCo-2 trial, the anti-inflammatory drug cut the risk of cardiovascular events by one third when added to standard prevention therapies in patients with chronic coronary disease. And in the COLCOT study, use of colchicine reduced cardiovascular events by 23% compared with placebo in patients with a recent MI. 

Paul Ridker, MD, director of the Center for Cardiovascular Disease Prevention at Brigham and Women’s Hospital in Boston, who has been a pioneer in establishing inflammation as an underlying cause of atherosclerotic cardiovascular disease, welcomed the Lodoco approval.
 

‘A very big day for cardiology’

“This is a very big day for cardiology,” Dr. Ridker said in an interview.

“The FDA approval of colchicine for patients with atherosclerotic disease is a huge signal that physicians need to be aware of inflammation as a key player in cardiovascular disease,” he said.

Dr. Ridker was the lead author of a recent study showing that among patients receiving contemporary statins, inflammation assessed by high-sensitivity C-reactive protein (hsCRP) was a stronger predictor for risk of future cardiovascular events and death than LDL cholesterol.

He pointed out that the indication for Lodoco was very broad, simply stating that it can be used in adult patients with established atherosclerotic disease or with multiple risk factors for cardiovascular disease.

“That is virtually identical to the indication approved for statin therapy. That shows just how important the FDA thinks this is,” he commented.

But Dr. Ridker added that, while the label does not specify that Lodoco has to be used in addition to statin therapy, he believes that it will be used as additional therapy to statins in the vast majority of patients.

“This is not an alternative to statin therapy. In the randomized trials, the benefits were seen on top of statins,” he stressed.

Dr. Ridker believes that physicians will need time to feel comfortable with this new approach. 

“Initially, I think, it will be used mainly by cardiologists who know about inflammation, but I believe over time it will be widely prescribed by internists, in much the same way as statins are used today,” he commented.

Dr. Ridker said he already uses low dose colchicine in his high-risk patients who have high levels of inflammation as seen on hsCRP testing. He believes this is where the drug will mostly be used initially, as this is where it is likely to be most effective.

The prescribing information states that Lodoco is contraindicated in patients who are taking strong CYP3A4 inhibitors or P-glycoprotein inhibitors, such as ketoconazole, fluconazole, and clarithromycin, and in patients with preexisting blood dyscrasias, renal failure, and severe hepatic impairment.

Common side effects reported in published clinical studies and literature with the use of colchicine are gastrointestinal symptoms (diarrhea, vomiting, abdominal cramping) and myalgia.

More serious adverse effects are listed as blood dyscrasias such as myelosuppression, leukopenia, granulocytopenia, thrombocytopenia, pancytopenia, and aplastic anemia; and neuromuscular toxicity in the form of myotoxicity including rhabdomyolysis, which may occur, especially in combination with other drugs known to cause this effect. If these adverse effects occur, it is recommended that the drug be stopped.

The prescribing information also notes that Lodoco may rarely and transiently impair fertility in males; and that patients with renal or hepatic impairment should be monitored closely for adverse effects of colchicine.

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

The Food and Drug Administration has approved the anti-inflammatory drug colchicine 0.5 mg tablets (Lodoco) as the first specific anti-inflammatory drug demonstrated to reduce the risk for myocardial infarction, stroke, coronary revascularization, and cardiovascular death in adult patients with established atherosclerotic disease or with multiple risk factors for cardiovascular disease.

The drug, which targets residual inflammation as an underlying cause of atherosclerotic cardiovascular disease, has a dosage of 0.5 mg once daily, and can be used alone or in combination with cholesterol-lowering medications. 

Olivier Le Moal/Getty Images

The drug’s manufacturer, Agepha Pharma, said it anticipates that Lodoco will be available for prescription in the second half of 2023.

Colchicine has been available for many years and used at higher doses for the acute treatment of gout and pericarditis, but the current formulation is a much lower dose for long-term use in patients with atherosclerotic heart disease.

Data supporting the approval has come from two major randomized trials, LoDoCo-2 and COLCOT.

In the LoDoCo-2 trial, the anti-inflammatory drug cut the risk of cardiovascular events by one third when added to standard prevention therapies in patients with chronic coronary disease. And in the COLCOT study, use of colchicine reduced cardiovascular events by 23% compared with placebo in patients with a recent MI. 

Paul Ridker, MD, director of the Center for Cardiovascular Disease Prevention at Brigham and Women’s Hospital in Boston, who has been a pioneer in establishing inflammation as an underlying cause of atherosclerotic cardiovascular disease, welcomed the Lodoco approval.
 

‘A very big day for cardiology’

“This is a very big day for cardiology,” Dr. Ridker said in an interview.

“The FDA approval of colchicine for patients with atherosclerotic disease is a huge signal that physicians need to be aware of inflammation as a key player in cardiovascular disease,” he said.

Dr. Ridker was the lead author of a recent study showing that among patients receiving contemporary statins, inflammation assessed by high-sensitivity C-reactive protein (hsCRP) was a stronger predictor for risk of future cardiovascular events and death than LDL cholesterol.

He pointed out that the indication for Lodoco was very broad, simply stating that it can be used in adult patients with established atherosclerotic disease or with multiple risk factors for cardiovascular disease.

“That is virtually identical to the indication approved for statin therapy. That shows just how important the FDA thinks this is,” he commented.

But Dr. Ridker added that, while the label does not specify that Lodoco has to be used in addition to statin therapy, he believes that it will be used as additional therapy to statins in the vast majority of patients.

“This is not an alternative to statin therapy. In the randomized trials, the benefits were seen on top of statins,” he stressed.

Dr. Ridker believes that physicians will need time to feel comfortable with this new approach. 

“Initially, I think, it will be used mainly by cardiologists who know about inflammation, but I believe over time it will be widely prescribed by internists, in much the same way as statins are used today,” he commented.

Dr. Ridker said he already uses low dose colchicine in his high-risk patients who have high levels of inflammation as seen on hsCRP testing. He believes this is where the drug will mostly be used initially, as this is where it is likely to be most effective.

The prescribing information states that Lodoco is contraindicated in patients who are taking strong CYP3A4 inhibitors or P-glycoprotein inhibitors, such as ketoconazole, fluconazole, and clarithromycin, and in patients with preexisting blood dyscrasias, renal failure, and severe hepatic impairment.

Common side effects reported in published clinical studies and literature with the use of colchicine are gastrointestinal symptoms (diarrhea, vomiting, abdominal cramping) and myalgia.

More serious adverse effects are listed as blood dyscrasias such as myelosuppression, leukopenia, granulocytopenia, thrombocytopenia, pancytopenia, and aplastic anemia; and neuromuscular toxicity in the form of myotoxicity including rhabdomyolysis, which may occur, especially in combination with other drugs known to cause this effect. If these adverse effects occur, it is recommended that the drug be stopped.

The prescribing information also notes that Lodoco may rarely and transiently impair fertility in males; and that patients with renal or hepatic impairment should be monitored closely for adverse effects of colchicine.

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

The Food and Drug Administration has approved the anti-inflammatory drug colchicine 0.5 mg tablets (Lodoco) as the first specific anti-inflammatory drug demonstrated to reduce the risk for myocardial infarction, stroke, coronary revascularization, and cardiovascular death in adult patients with established atherosclerotic disease or with multiple risk factors for cardiovascular disease.

The drug, which targets residual inflammation as an underlying cause of atherosclerotic cardiovascular disease, has a dosage of 0.5 mg once daily, and can be used alone or in combination with cholesterol-lowering medications. 

Olivier Le Moal/Getty Images

The drug’s manufacturer, Agepha Pharma, said it anticipates that Lodoco will be available for prescription in the second half of 2023.

Colchicine has been available for many years and used at higher doses for the acute treatment of gout and pericarditis, but the current formulation is a much lower dose for long-term use in patients with atherosclerotic heart disease.

Data supporting the approval has come from two major randomized trials, LoDoCo-2 and COLCOT.

In the LoDoCo-2 trial, the anti-inflammatory drug cut the risk of cardiovascular events by one third when added to standard prevention therapies in patients with chronic coronary disease. And in the COLCOT study, use of colchicine reduced cardiovascular events by 23% compared with placebo in patients with a recent MI. 

Paul Ridker, MD, director of the Center for Cardiovascular Disease Prevention at Brigham and Women’s Hospital in Boston, who has been a pioneer in establishing inflammation as an underlying cause of atherosclerotic cardiovascular disease, welcomed the Lodoco approval.
 

‘A very big day for cardiology’

“This is a very big day for cardiology,” Dr. Ridker said in an interview.

“The FDA approval of colchicine for patients with atherosclerotic disease is a huge signal that physicians need to be aware of inflammation as a key player in cardiovascular disease,” he said.

Dr. Ridker was the lead author of a recent study showing that among patients receiving contemporary statins, inflammation assessed by high-sensitivity C-reactive protein (hsCRP) was a stronger predictor for risk of future cardiovascular events and death than LDL cholesterol.

He pointed out that the indication for Lodoco was very broad, simply stating that it can be used in adult patients with established atherosclerotic disease or with multiple risk factors for cardiovascular disease.

“That is virtually identical to the indication approved for statin therapy. That shows just how important the FDA thinks this is,” he commented.

But Dr. Ridker added that, while the label does not specify that Lodoco has to be used in addition to statin therapy, he believes that it will be used as additional therapy to statins in the vast majority of patients.

“This is not an alternative to statin therapy. In the randomized trials, the benefits were seen on top of statins,” he stressed.

Dr. Ridker believes that physicians will need time to feel comfortable with this new approach. 

“Initially, I think, it will be used mainly by cardiologists who know about inflammation, but I believe over time it will be widely prescribed by internists, in much the same way as statins are used today,” he commented.

Dr. Ridker said he already uses low dose colchicine in his high-risk patients who have high levels of inflammation as seen on hsCRP testing. He believes this is where the drug will mostly be used initially, as this is where it is likely to be most effective.

The prescribing information states that Lodoco is contraindicated in patients who are taking strong CYP3A4 inhibitors or P-glycoprotein inhibitors, such as ketoconazole, fluconazole, and clarithromycin, and in patients with preexisting blood dyscrasias, renal failure, and severe hepatic impairment.

Common side effects reported in published clinical studies and literature with the use of colchicine are gastrointestinal symptoms (diarrhea, vomiting, abdominal cramping) and myalgia.

More serious adverse effects are listed as blood dyscrasias such as myelosuppression, leukopenia, granulocytopenia, thrombocytopenia, pancytopenia, and aplastic anemia; and neuromuscular toxicity in the form of myotoxicity including rhabdomyolysis, which may occur, especially in combination with other drugs known to cause this effect. If these adverse effects occur, it is recommended that the drug be stopped.

The prescribing information also notes that Lodoco may rarely and transiently impair fertility in males; and that patients with renal or hepatic impairment should be monitored closely for adverse effects of colchicine.

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

People with nonalcoholic fatty liver disease (NAFLD) are more likely to develop severe infections requiring hospitalization, according to findings from a large Swedish cohort study.

The increased risk was equal to one extra severe infection in every six patients with NAFLD by 20 years after diagnosis, wrote Fahim Ebrahimi, MD, of the Karolinska Institute in Stockholm, and coauthors.

“Accumulating evidence suggests that NAFLD can affect multiple organ systems, which is not surprising, as the liver has multiple functions – regulating metabolism and being a central organ of the immune system,” Dr. Ebrahimi said in an interview.

The study was published online in Clinical Gastroenterology and Hepatology.

“Up to a fifth of cells in the liver are immune cells that process numerous antigens and pathogens from the gastrointestinal tract,” Dr. Ebrahimi noted. “We were intrigued by experimental studies showing that, in NAFLD, many of these key immune cells become dysfunctional at various levels, which may affect disease progression, but at the same time also increase the susceptibility to viral, bacterial, and fungal infections.”

Patients with NAFLD have metabolic risk factors known to increase infection risk, but a smaller study by a different research group had found that NAFLD could independently predispose patients to bacterial infections.

To further explore a connection between NAFLD and infection risk, the researchers looked at data for 12,133 Swedish adults with simple steatosis, nonfibrotic steatohepatitis, noncirrhotic fibrosis, or cirrhosis caused by NAFLD confirmed by liver biopsies performed between 1969 and 2017.

Each patient was matched to five or more contemporary controls from the general population by age, sex, and region of residence. The authors conducted an additional analysis that also adjusted for education, country of birth, and baseline clinical comorbidities, including diabetes, obesity, dyslipidemia, and hypertension, as well as hospitalization preceding the biopsy and chronic obstructive pulmonary disease.

The primary endpoint was severe infections requiring hospital admission. Secondary endpoints included seven prespecified infection subgroups: sepsis; respiratory tract; most gastrointestinal infections; bacterial peritonitis; urogenital; muscle, skin, and soft tissue; and other infections.
 

Elevated risk at all NAFLD stages

Dr. Ebrahimi and colleagues found that over a median follow-up of 14 years, patients with NAFLD had a higher incidence of severe infections – most often respiratory or urinary tract infections – compared with those without NAFLD (32% vs. 17%, respectively).

Biopsy-confirmed NAFLD was also associated with a 71% higher hazard and a 20-year absolute excess risk of 17.3% for severe infections requiring hospital admission versus comparators. The elevated risk showed up in patients with steatosis and increased with the severity of NAFLD. Simple steatosis saw a 64% higher risk (adjusted hazard ratio, 1.64; 95% confidence interval, 1.55-1.73), whereas patients with cirrhosis saw a more than twofold higher risk, compared with controls (aHR, 2.32; 95% CI, 1.92-2.82).

When Dr. Ebrahimi and colleagues adjusted for parameters of the metabolic syndrome, they found an independent increased risk for severe infection. For patients with NAFLD, the increased risk may come from greater susceptibility to infections in general or to a more severe course of infections.

“Our study clearly demonstrates the complexity and high disease burden associated with NAFLD,” Dr. Ebrahimi said. “We are beginning to understand the different layers involved and will eventually move away from a liver-centric view to a more holistic view of the disease.”

Clinicians caring for patients with NAFLD need to be aware of the increased risk for infection, Dr. Ebrahimi said. They also should assess their patients’ vaccination status, and seek to control modifiable risk factors, such as diabetes.

Nancy Reau, MD, of Rush University, Chicago, described the study’s message as important.

“Patients with NAFLD and advancing liver disease are at risk for severe infections,” Dr. Reau said. “When we consider the fact that patients with advanced liver disease tend to die from infectious complications, awareness leading to early recognition and efficient treatment is imperative.”

The authors acknowledged the following limitations: only severe infections requiring hospitalization could be captured; whether infection led to decompensation or vice versa among patients with cirrhosis could not be determined; and detailed data on smoking, alcohol, vaccinations, body mass, and other potentially relevant measures were not available.

The Swiss National Science Foundation, Syskonen Svensson Foundation, and Bengt Ihre Foundation provided grants to Dr. Ebrahimi or coauthors. One coauthor disclosed previous research funding from Janssen and MSD. Dr. Reau disclosed receiving research support and consulting fees from AbbVie and Gilead, as well as consulting fees from Arbutus, Intercept, and Salix.

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

People with nonalcoholic fatty liver disease (NAFLD) are more likely to develop severe infections requiring hospitalization, according to findings from a large Swedish cohort study.

The increased risk was equal to one extra severe infection in every six patients with NAFLD by 20 years after diagnosis, wrote Fahim Ebrahimi, MD, of the Karolinska Institute in Stockholm, and coauthors.

“Accumulating evidence suggests that NAFLD can affect multiple organ systems, which is not surprising, as the liver has multiple functions – regulating metabolism and being a central organ of the immune system,” Dr. Ebrahimi said in an interview.

The study was published online in Clinical Gastroenterology and Hepatology.

“Up to a fifth of cells in the liver are immune cells that process numerous antigens and pathogens from the gastrointestinal tract,” Dr. Ebrahimi noted. “We were intrigued by experimental studies showing that, in NAFLD, many of these key immune cells become dysfunctional at various levels, which may affect disease progression, but at the same time also increase the susceptibility to viral, bacterial, and fungal infections.”

Patients with NAFLD have metabolic risk factors known to increase infection risk, but a smaller study by a different research group had found that NAFLD could independently predispose patients to bacterial infections.

To further explore a connection between NAFLD and infection risk, the researchers looked at data for 12,133 Swedish adults with simple steatosis, nonfibrotic steatohepatitis, noncirrhotic fibrosis, or cirrhosis caused by NAFLD confirmed by liver biopsies performed between 1969 and 2017.

Each patient was matched to five or more contemporary controls from the general population by age, sex, and region of residence. The authors conducted an additional analysis that also adjusted for education, country of birth, and baseline clinical comorbidities, including diabetes, obesity, dyslipidemia, and hypertension, as well as hospitalization preceding the biopsy and chronic obstructive pulmonary disease.

The primary endpoint was severe infections requiring hospital admission. Secondary endpoints included seven prespecified infection subgroups: sepsis; respiratory tract; most gastrointestinal infections; bacterial peritonitis; urogenital; muscle, skin, and soft tissue; and other infections.
 

Elevated risk at all NAFLD stages

Dr. Ebrahimi and colleagues found that over a median follow-up of 14 years, patients with NAFLD had a higher incidence of severe infections – most often respiratory or urinary tract infections – compared with those without NAFLD (32% vs. 17%, respectively).

Biopsy-confirmed NAFLD was also associated with a 71% higher hazard and a 20-year absolute excess risk of 17.3% for severe infections requiring hospital admission versus comparators. The elevated risk showed up in patients with steatosis and increased with the severity of NAFLD. Simple steatosis saw a 64% higher risk (adjusted hazard ratio, 1.64; 95% confidence interval, 1.55-1.73), whereas patients with cirrhosis saw a more than twofold higher risk, compared with controls (aHR, 2.32; 95% CI, 1.92-2.82).

When Dr. Ebrahimi and colleagues adjusted for parameters of the metabolic syndrome, they found an independent increased risk for severe infection. For patients with NAFLD, the increased risk may come from greater susceptibility to infections in general or to a more severe course of infections.

“Our study clearly demonstrates the complexity and high disease burden associated with NAFLD,” Dr. Ebrahimi said. “We are beginning to understand the different layers involved and will eventually move away from a liver-centric view to a more holistic view of the disease.”

Clinicians caring for patients with NAFLD need to be aware of the increased risk for infection, Dr. Ebrahimi said. They also should assess their patients’ vaccination status, and seek to control modifiable risk factors, such as diabetes.

Nancy Reau, MD, of Rush University, Chicago, described the study’s message as important.

“Patients with NAFLD and advancing liver disease are at risk for severe infections,” Dr. Reau said. “When we consider the fact that patients with advanced liver disease tend to die from infectious complications, awareness leading to early recognition and efficient treatment is imperative.”

The authors acknowledged the following limitations: only severe infections requiring hospitalization could be captured; whether infection led to decompensation or vice versa among patients with cirrhosis could not be determined; and detailed data on smoking, alcohol, vaccinations, body mass, and other potentially relevant measures were not available.

The Swiss National Science Foundation, Syskonen Svensson Foundation, and Bengt Ihre Foundation provided grants to Dr. Ebrahimi or coauthors. One coauthor disclosed previous research funding from Janssen and MSD. Dr. Reau disclosed receiving research support and consulting fees from AbbVie and Gilead, as well as consulting fees from Arbutus, Intercept, and Salix.

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

People with nonalcoholic fatty liver disease (NAFLD) are more likely to develop severe infections requiring hospitalization, according to findings from a large Swedish cohort study.

The increased risk was equal to one extra severe infection in every six patients with NAFLD by 20 years after diagnosis, wrote Fahim Ebrahimi, MD, of the Karolinska Institute in Stockholm, and coauthors.

“Accumulating evidence suggests that NAFLD can affect multiple organ systems, which is not surprising, as the liver has multiple functions – regulating metabolism and being a central organ of the immune system,” Dr. Ebrahimi said in an interview.

The study was published online in Clinical Gastroenterology and Hepatology.

“Up to a fifth of cells in the liver are immune cells that process numerous antigens and pathogens from the gastrointestinal tract,” Dr. Ebrahimi noted. “We were intrigued by experimental studies showing that, in NAFLD, many of these key immune cells become dysfunctional at various levels, which may affect disease progression, but at the same time also increase the susceptibility to viral, bacterial, and fungal infections.”

Patients with NAFLD have metabolic risk factors known to increase infection risk, but a smaller study by a different research group had found that NAFLD could independently predispose patients to bacterial infections.

To further explore a connection between NAFLD and infection risk, the researchers looked at data for 12,133 Swedish adults with simple steatosis, nonfibrotic steatohepatitis, noncirrhotic fibrosis, or cirrhosis caused by NAFLD confirmed by liver biopsies performed between 1969 and 2017.

Each patient was matched to five or more contemporary controls from the general population by age, sex, and region of residence. The authors conducted an additional analysis that also adjusted for education, country of birth, and baseline clinical comorbidities, including diabetes, obesity, dyslipidemia, and hypertension, as well as hospitalization preceding the biopsy and chronic obstructive pulmonary disease.

The primary endpoint was severe infections requiring hospital admission. Secondary endpoints included seven prespecified infection subgroups: sepsis; respiratory tract; most gastrointestinal infections; bacterial peritonitis; urogenital; muscle, skin, and soft tissue; and other infections.
 

Elevated risk at all NAFLD stages

Dr. Ebrahimi and colleagues found that over a median follow-up of 14 years, patients with NAFLD had a higher incidence of severe infections – most often respiratory or urinary tract infections – compared with those without NAFLD (32% vs. 17%, respectively).

Biopsy-confirmed NAFLD was also associated with a 71% higher hazard and a 20-year absolute excess risk of 17.3% for severe infections requiring hospital admission versus comparators. The elevated risk showed up in patients with steatosis and increased with the severity of NAFLD. Simple steatosis saw a 64% higher risk (adjusted hazard ratio, 1.64; 95% confidence interval, 1.55-1.73), whereas patients with cirrhosis saw a more than twofold higher risk, compared with controls (aHR, 2.32; 95% CI, 1.92-2.82).

When Dr. Ebrahimi and colleagues adjusted for parameters of the metabolic syndrome, they found an independent increased risk for severe infection. For patients with NAFLD, the increased risk may come from greater susceptibility to infections in general or to a more severe course of infections.

“Our study clearly demonstrates the complexity and high disease burden associated with NAFLD,” Dr. Ebrahimi said. “We are beginning to understand the different layers involved and will eventually move away from a liver-centric view to a more holistic view of the disease.”

Clinicians caring for patients with NAFLD need to be aware of the increased risk for infection, Dr. Ebrahimi said. They also should assess their patients’ vaccination status, and seek to control modifiable risk factors, such as diabetes.

Nancy Reau, MD, of Rush University, Chicago, described the study’s message as important.

“Patients with NAFLD and advancing liver disease are at risk for severe infections,” Dr. Reau said. “When we consider the fact that patients with advanced liver disease tend to die from infectious complications, awareness leading to early recognition and efficient treatment is imperative.”

The authors acknowledged the following limitations: only severe infections requiring hospitalization could be captured; whether infection led to decompensation or vice versa among patients with cirrhosis could not be determined; and detailed data on smoking, alcohol, vaccinations, body mass, and other potentially relevant measures were not available.

The Swiss National Science Foundation, Syskonen Svensson Foundation, and Bengt Ihre Foundation provided grants to Dr. Ebrahimi or coauthors. One coauthor disclosed previous research funding from Janssen and MSD. Dr. Reau disclosed receiving research support and consulting fees from AbbVie and Gilead, as well as consulting fees from Arbutus, Intercept, and Salix.

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