Evaluation of pulmonary toxicities in lymphoma patients receiving brentuximab vedotin

Brentuximab vedotin (BV) is an antibody–drug conjugate which targets CD30-positive cells [1]. BV has demonstrated clinical efficacy as both monotherapy and combination therapy and is approved for the treatment of previously untreated or relapsed/refractory Hodgkin lymphoma (HL) [2–4], consolidation post-autologous hematopoietic stem cell transplantation (aHSCT) [5], untreated or relapsed anaplastic large cell lymphoma (ALCL), and previously untreated CD30-expressing peripheral T-cell lymphoma [6–8].

Patients receiving BV therapy often experience adverse events resulting in acute and long-term complications. The most common adverse events include peripheral neuropathy, neutropenia, nausea, vomiting, and fatigue [1]. Pulmonary toxicities have been reported as a rare but serious complication following BV-containing therapies. The ECHELON-1 trial reported pulmonary toxicities in 2% of patients receiving AAVD (BV, doxorubicin, vinblastine, and dacarbazine) for treatment of HL [9]. A subsequent study reported a fourfold increase in pulmonary toxicities in pediatric patients exposed to BV compared to unexposed patients [10]. Several case reports have also reported BV-induced pneumonitis [11,12]. BV-induced pneumonitis is a potentially life-threatening complication and incidence may be underreported. Real-world studies are warranted to further characterize BV-induced pulmonary toxicities.

We reviewed medical records of adult and pediatric patients with a confirmed diagnosis of lymphoma treated with at least one cycle of a BV-containing regimen at two medical centers between 1 June 2015 and 30 September 2020. The primary endpoint was the incidence of BV-induced pulmonary toxicities as characterized by the development of respiratory symptoms including, but not limited to, cough, shortness of breath (SOB), dyspnea on exertion (DOE), wheezing, or chest pain not attributable to infection during or six months following BV therapy. The provider’s certainty in attributing pulmonary symptoms to BV exposure was categorized as ‘likely’ (highest certainty – symptoms not justified by a competing cause), ‘possibly’ (mid-level certainty – symptoms potentially justified by an alternate cause), or ‘not likely’ (lowest certainty – symptoms justified by a competing cause). Secondary endpoints included the incidence of BV-associated pulmonary toxicities resulting in BV dose reduction, delay, or discontinuation. Risk factors assessed as potentially associated with developing pulmonary toxicities included history of chronic pulmonary disorders, disease staging at the time of BV therapy, presence of bulky mediastinal disease, parenchymal lung involvement, BV cumulative dose, and prior use of pulmonary toxic medications.

A total of 123 patients were treated with BV during the study period (114 adult (92.7%), nine pediatric (7.3%)) with 96 patients meeting inclusion criteria (Figure 1). The median age at BV initiation was 34.5 years; 61% patients were male, and 47% were Caucasian. Most patients (n = 66, 69%) received BV for the treatment of HL. Eight (8%) patients had ALCL, six (6%) mycosis fungoides, 10 (10%) peripheral T-cell lymphoma, five (5%) CD30-positive diffuse large B-cell lymphoma, and one (1%) gray zone lymphoma. The stage of disease at the time of BV initiation was most commonly IV (42%) and II (31%). At the time of BV initiation, 25% of patients had bulky mediastinal disease and 5% had parenchymal lung involvement.

Figure 1. Consort flow diagram.

In terms of potential predisposing risk factors, 18 (19%) patients had asthma, five (5%) had COPD, and four (4%) had eczema. One-third of patients had a history of smoking tobacco products with five (5%) patients reported as active tobacco smokers at the time of BV initiation. With regards to prior exposure to other pulmonary toxic agents, 15% of patients received carmustine as part of a conditioning regimen for aHSCT, 41% received bleomycin as a prior line of therapy, and 7% received gemcitabine.

Nineteen of 96 (20%) patients developed pulmonary symptoms following BV administration. Patients with pulmonary symptoms attributable to infectious etiologies (e.g. COVID, influenza, and pneumonia) were excluded from final analysis. Subsequently, four (4.2%) patients were identified to have developed symptoms concerning for BV-induced pneumonitis. Pulmonary symptoms of three patients were categorized as ‘likely related’ and one patient as ‘possibly related’ to BV. Patient characteristics are detailed in Table 1.

Table 1. Characteristics of patients who developed BV-induced pulmonary toxicities.

	Case 1	Case 2	Case 3	Case 4
Age/gender	28/male	76/male	53/female	47/male
BV-induced pneumonitis classification	Likely	Likely	Likely	Possibly
Pulmonary symptoms	Dry cough, SOB, decrease in DLCO	Dry cough, hypoxic respiratory failure	Dry cough, DOE, fatigue	Persistent cough, SOB, DOE
BV indication	HL (previously untreated, stage IV)	HL (previously untreated, stage II)	ALCL (previously untreated, stage II)	ALCL (relapsed, stage IV)
Timing of symptoms relative to BV treatment	During therapy after cycle 3 of AAVD	<2 months after completion of AAVD	During therapy after cycle 2 of BV-CHP	<2 months after completion of BV
BV doses prior to pulmonary symptoms	7	6	2	21
Cumulative BV dose (mg/kg)	10.6	8.8	16.1	30.4
Smoking history	No	Yes	Yes	No
Prior pulmonary toxic agents (cumulative dose)	No	No	No	Gemcitabine (6000 mg/m^2), carmustine (525 mg/m^2)
Dose changes	Dose decrease followed by discontinuation	N/A	Discontinued	N/A
Required steroids	Yes	Yes	Yes	No
Chest X-ray	Nonsignificant	Ground glass opacities	Nonsignificant	Retrocardiac consolidation
DLCO (%)	Before BV: 89 After BV: 73	N/A	After BV: 40 With steroids: 49	N/A

Abbreviations: BV: brentuximab vedotin, SOB: shortness of breath, DLCO: diffusing capacity for carbon monoxide; DOE: dyspnea on exertion; HL: Hodgkin's lymphoma; ALCL: anaplastic large cell lymphoma; AAVD: brentuximab vedotin, doxorubicin, vinblastine, dacarbazine; BV-CHP: brentuximab vedotin, cyclophosphamide, doxorubicin, prednisone.

Case 1 was a 28-year-old male patient with stage IVB nodular sclerosing HL who developed a persistent dry cough after cycle 3 of AAVD. The cough worsened during cycle 4 and pulmonary function tests (PFTs) were ordered. The patient’s baseline DLCO prior to initiating BV therapy was 89%. His DLCO following cycle 4 was 73%, representing an 18% reduction. Chest X-ray (CXR) was nonsignificant, but the decrease in DLCO coupled with a worsening cough was highly concerning for BV-induced pneumonitis. BV was dose-decreased from 1.2 mg/kg to 0.9 mg/kg to complete cycle 4 of AAVD. Prednisone 1 mg/kg was initiated, after which his cough resolved. BV was discontinued from the last two cycles of therapy.

Case 2 was a 76-year-old male patient with stage III HL who underwent treatment with six cycles of AAVD. Two months after completing therapy, the patient reported development of a cough. He was noted to have low O₂ saturations but was afebrile with robust blood counts. He was admitted to the ICU for worsening hypoxic respiratory failure requiring high-flow oxygen. Despite aggressive diuresis and empiric treatment for pneumonia, his respiratory status continued to worsen. Computed tomography (CT) imaging did not show evidence of pulmonary embolism (PE) but illustrated diffuse symmetric ground-glass opacities representative of a possible drug reaction. The cause of respiratory failure was determined to be BV-induced pneumonitis. Prednisone 1 mg/kg daily was initiated with a prolonged taper course. He reported complete resolution of his cough and DOE one week following initiation of steroid therapy.

Case 3 was a 53-year-old female patient with systemic stage IE ALK-negative CD30-positive ALCL was initiated on BV-CHP (BV, cyclophosphamide, doxorubicin, and prednisone). She developed a persistent dry cough and DOE following cycle 2 with symptoms worsening after completing cycle 5. CXR was nonsignificant and the cause of her symptoms was determined to be BV-induced pneumonitis. The cough resolved after initiating prednisone 1 mg/kg. Baseline PFTs were unavailable, but DLCO was documented as 40% prior to initiating steroid therapy. DLCO improved to 49% following one week of prednisone.

Case 4 was a 47-year-old male patient with stage IV ALK-negative ALCL initially achieved complete metabolic remission following upfront chemotherapy consolidation by aHSCT. The patient experienced a relapse 27 months later, for which he received eight cycles of BV monotherapy, achieving clinical remission after three cycles. Three years following completion of BV therapy, he experienced a second relapse and was re-treated with 13 cycles of BV. Two months following completion of the second course of BV, he developed a persistent cough. Comprehensive infectious and gastrointestinal work-ups were unyielding. CXR illustrated retrocardiac consolidations. In the next three months, patient’s cough continued to worsen, and he developed DOE. Further work-up revealed an acute right lower lobe PE and disease progression not involving mediastinum and lungs. This case was categorized as pulmonary symptoms possibly related to BV since PE could potentially be the competing cause for cough, although cough symptoms preceded the diagnosis of PE and earlier imaging studies around the time of developing cough had not shown evidence of PE. The patient opted for hospice care, and no further diagnostic work-up was pursued.

In these four cases, pulmonary symptoms developed after a median of 6.5 doses (range 2, 21). Most regimens recommend a maximum of 16 cycles of BV, but case 4 received BV on two separate occasions, in total receiving 21 cycles; this may have contributed to his risk of developing BV-induced pneumonitis [13]. Pulmonary toxicities were noted to develop either during or shortly after BV discontinuation. High-dose steroids were effective for managing pulmonary symptoms. Discontinuation of BV was necessary to completely resolve symptoms for the two patients who developed pneumonitis during therapy (cases 1 and 3).

History of smoking tobacco products was identified as a potential risk factor as 50% of patients who developed pulmonary toxicities had a history of smoking tobacco products. Prior history of pulmonary toxic agents was not a strong risk factor as only one patient had previous exposure to other pulmonary toxic agents.

This study identified a 4.2% incidence of pulmonary toxicity in patients treated with BV, with one patient requiring ICU care. None of the eight pediatric patients included in the study developed pneumonitis. This information is consistent with current literature illustrating that pulmonary toxicities are a concern with BV [9]. The 4.2% incidence rate identified in this study is higher than 2% reported in the ECHELON-1 trial. To our knowledge, this is the first study to characterize BV-induced pulmonary toxicities in the real-world lymphoma population and the first to include both pediatric and adult patients.

The study is limited by the small sample size and the inherent constraints associated with a retrospective study design. Incidence of pulmonary toxicities could be underreported as BV-induced pneumonitis may not have been on clinician’s differentials and diagnostic work-up processes for respiratory symptoms may vary. Additionally, pulmonary toxicity assessments utilizing CTCAE criteria were infrequently documented and baseline PFTs were not routinely performed, potentially resulting in inconsistent analysis.

Our study highlights BV-associated pulmonary toxicities as a rare but serious complication. When initiating BV-containing therapy, clinicians might consider ordering baseline PFTs and monitoring for potential pulmonary complications. Larger multicenter studies are necessary to further characterize the incidence and risk factors associated with BV-induced pulmonary toxicities, including associated short- and long-term complications.

Disclosure statement

No potential conflict of interest was reported by the author(s).