Brentuximab-AVD Treatment for a Patient with Hodgkin Lymphoma and Cystic Fibrosis

    

    

    Figure 1:  Patient’s imaging: (A) Chest Rx at time of the diagnosis; (B) PET scan after chest surgery; (C) PET scan after two cycles IGEV; (D) PET scan after two
cycles of Brentuximab AVD.
    
    

Discussion

The prognosis of patients with classical Hodgkin Lymphoma is improving during the last 20 years [2]. Unfortunately, these successes are limited by treatment toxicities [3]. Short-term toxicity is related to dose intensity and is relevant for aggressive schedules. Indeed, leukopenia and infections are common in patients during treatment. On contrary, long-term toxicities can arise after years and include second malignancies and heart and lung dysfunctions. In order to reduce short and long-term side effects aggressive chemotherapy is reserved for lymphomas with a poor prognosis and BEACOPP is currently the most active schedule [4]. BEACOPP prolongs PFS compared to ABVD, in patients with a high IPS, but carries a worse toxicity profile [5]. Modified ABVD schedules with only three chemotherapeutic agents are inferior to the use of the 4 drugs. Indeed, in the GHSG HD13 trial, modified ABVD without either decarbonize or bleomycin obtained inferior results compared to the full schedule [6]. A common bleomycin side effect is pulmonary fibrosis. In animal models, the bleomycin damage to basement membrane was induced by epithelial cell death, epithelial to mesenchymal transition and fibroblastic differentiation. At the biochemical level, chemokines, interleukins and the production of reactive oxygen species are responsible for bleomycin induced lung fibrosis [7]. In mice, the maximum lung fibrosis is obtained in 14 days after intratracheal instillation of bleomycin. However, 6 days after instillation of bleomycin early signs of fibrosis are already detectable [8]. In earlier studies, 53% of patients treated with ABVD developed respiratory symptoms. These symptoms usually regress with the discontinuation of therapy but 37% of patients have a decline in pulmonary function. After 6 ABVD cycles have been accomplished a progressive decline in FVC is observed until 15 months. However, it has been suggested that subsequently most patients recover their lung function. Interestingly, the baseline FVC, FEV1, and DLCO correlate with the impairment of FEV observed after therapy, suggesting that basal pulmonary diseases may increase the bleomycin toxicity [9].

Therefore, bleomycin should be used with caution in patients with impaired lung function especially in those with pulmonary fibrosis. In patients with Hodgkin lymphoma and concomitant pulmonary disorders alternative schedules without bleomycin but with a similar efficacy are advocated.

Brentuximab vedotin is a chimeric monoclonal anti-CD30 antibody conjugated with the antimitotic agent vedotin that has shown promising results in relapsed Hodgkin lymphoma [10]. Currently, several trials are evaluating brentuximab vedotin in relapsed/refractory Hodgkin lymphoma [11] and combination schedules with different chemotherapy regimens have been tested in phase I-II clinical trials [12]. Whereas the activity of brentuximab vedotin in association with ABV compared to classical ABVD is under investigation, the absence of significant toxicity of brentuximab vedotin-AVD has been already reported in phase I trial. However, not all the schedules including brentuximab vedotin have a favorable safety profile. Indeed, the schedule including brentuximab vedotin and ABVD is hampered by a relevant toxicity [13] and the combination of the anti CD30 antibody with gemcitabine, vinorelbine, Pegylated liposomal doxorubicin (GEV) has shown unacceptable lung toxicity leading to the premature closure of the trial [14].

Therefore, brentuximab vedotin-AVD could be an alternative treatment for patients with pulmonary dysfunction in order to avoid bleomycin. Brentuximab vedotin-AVD could be tested in patients with Hodgkin lymphoma and cystic fibrosis that spontaneously develop pulmonary insufficiency and recurrent infections. Indeed, patients with cystic fibrosis are fragile and careful considerations on safety are necessary for the choice of the most appropriate treatment.

Cystic fibrosis is the most frequent autosomal recessive disorder in Caucasian. Mutations of the CFTR gene (Fibrosis Transmembrane Conductance Regulator) that impair protein function cause cystic fibrosis. CFTR is an ABC-class transmembrane channel that conducts chloride and thiocyanate across the membrane of epithelial cells regulating the viscosity of mucous secretions. Over 15000 mutations have been reported in CFTR. Different mutations determine different degrees of protein dysfunction, which is reflected in the severity of the disease. A fluid mucous secretion is request for the proper function of several organs including lungs and pancreas. The viscous mucus secretions of patients with cystic fibrosis determine severe damage to the pancreas and lungs with consequent malabsorption, lung infections and fibrosis responsible for the breathing impairment. The disease evolves to a respiratory insufficiency that may lead to lung transplantation or death [15].

This case remarks that not all patients with Hodgkin lymphomas can receive standard chemotherapy. Bleomycin related lung-toxicity is harmful for patients with lung disorders especially for those with a preexisting pulmonary fibrosis. Moreover, chemotherapy toxicity includes leukopenia and neutropenia that predispose to infections, which can worsen the extension of reactive fibrosis. These considerations become extremely relevant for patients with cystic fibrosis because of the risk of a respiratory function decline and septic lung infections. Moreover, the patient described in this report had been colonized by Pseudomonas Aeruginosa, a common condition in cystic fibrosis, that further increase the risk of infection’s reactivation. Brentuximab vedotin is successfully used in relapsed Hodgkin lymphoma and is becoming a promising drug also in front line therapy for patients that require a schedule modification for the risk of toxicity. In this case report, we showed that brentuximab vedotin- AVD combination may be safely and successfully administered to a very frail patient After 15 months, there were not evidences of increased lung fibrosis or infections related to Pseudomonas Aeruginosa. In the absence of designed phase III clinical trial we suggest that patients affected by lung fibrosis could be candidate to brentuximab vedotin-AVD schedule.

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