First‐line treatment of stage IIB to stage IV classical Hodgkin lymphoma in Italy, Israel, and Spain: Patient characteristics, treatment patterns, and clinical outcomes

Abstract Classical Hodgkin lymphoma (cHL) is curable in 90% of cases, but advanced stage patients who do not respond well to first‐line (1L) therapy have poorer outcomes. This retrospective study examines patient characteristics, treatment patterns, clinical outcomes, and safety management of 1L cHL therapies in common clinical practice in Italy (IT), Israel (IL), and Spain (SP). The overall sample (n = 256) included patients with stage IIb to IV cHL, of which 86.3% received ABVD as 1L therapy (n = 221). Clinical outcomes were similar for the overall population and ABVD subsample: complete response (CR) in 75% and 76.5%; 30‐month (30‐mo) survival (OS) of 92.5% and 93.6%; and 30‐mo progression‐free survival (PFS) of 70.7% and 72.6%. Thirty‐month PFS was significantly lower for patients ≥ 60 years and/or with high (4–7) IPS. Treatment‐induced pulmonary and cardiac toxicities, and febrile neutropenia occurred, respectively, in 10%, 2.3%, and 6.8% of ABVD‐treated patients. Interim PET or PET‐CT scans were performed after two cycles of 1L therapy (PET2) for 70.3% and 66.6% of the overall and ABVD cohorts, respectively. PET2 positive rates were nearly 30% (49/173), yet PET‐adapted strategy of dose modification only occurred in a small fraction of patients.

Physician treatment choice is currently made according to risk stratification provided by the International Prognostic Score (IPS), age, disease stage and, more recently is being adjusted by interim response assessment commonly provided by positron emission tomography (PET) and/or computed tomography (CT) scans [15,16]. Results from PET/CT performed after 2 cycles of therapy (PET2) are used for response-adapted therapy management, offering a balance between risk of AE and survival outcomes [17]. When PET2 findings are deemed negative, the most commonly adopted approach is to discontinue the compound with the weakest anti-lymphoma activity, bleomycin, in order to reduce the risk of pulmonary toxicity [18] or to reduce the number of treatment cycles [19]). Conversely, the treatment intensity of PET2-positive patients may be increased, most often by switching to eBEACOPP, but at the cost of an increased rate of acute toxicity [20], gonadal damage, and second malignancies [21]. Nonetheless, PET2-driven strategies have certain limitations. PET scans are not always easily interpretable and PET2-negative patients do not always display long-term remissions [21,22].
Evidence from clinical practice allows to review the effectiveness and safety of cHL treatments in cohorts representative of the general population, including patients with comorbidities who may not be included in clinical trials. The aim of this study was to examine patient characteristics, treatment patterns, safety management, and clinical outcomes associated with 1L systemic regimens used to treat advanced stage cHL in Israel (IL), Italy (IT), and Spain (SP).

Patient characteristics
The demographic and baseline disease characteristics of the study population by systemic 1L therapies are listed in

Treatment modalities
The 1L treatments are shown in Table 2   RT was undertaken by 12.9% (n = 33) of the overall population, nearly all of them (n = 32) following 1L ABVD chemotherapy. The anatomical site of radiation was localized (72%), regional (25%), or extensive (3%). RT was mostly given as a consolidation therapy in 65.6% (n = 21) of ABVD patients, or to treat residual disease in 31.3% (n = 10).
Utilization of RT appeared to vary within countries, with only 3.3% (n = 2) of advanced stage cHL patients receiving RT in IL, against 19.1% (n = 17) in IT and 13.1% (n = 14) in SP.
As expected, these values were significantly lower for patients with high IPS (4-7) compared to those with low to intermediate scores at diagnosis, both in the overall study sample (62% vs. 78%; P = 0.04) and in the 1L ABVD subgroup (64% vs. 79%; P = 0.02, Figure 2A)

Safety and patient management
Overall, 31 patients interrupted 1L treatment, 26 of whom belonging to the ABVD cohort. The reasons for interruption of ABVD included pulmonary toxicity (n = 3), infection (n = 2), neutropenia (n = 1), and febrile neutropenia (n = 1). Moreover, ABVD dose was reduced for six patients suffering from pulmonary toxicity and one patient with neutropenia.
A total of 216 (84.4%) patients experienced at least one AE ( Table 3).

TA B L E 3
Treatment-emergent adverse events (AEs) in the overall study population and the ABVD subgroup. In each cohort, AEs are presented by age (< and ≥ 60 years old). *Chi-square test, Fisher exact P < 0.05  Notes: Age at initiation of 1L; *Chi-square test, Fisher exact p < 0.05.

DISCUSSION
Data collected retrospectively from the charts review of patients diagnosed with cHL over a 4-year period up to August 2018, showed that ABVD was the most prevalent 1L systemic therapy used across three countries: IL, IT, and SP. High IPS and age ≥ 60 years were indicative of lower PFS both in the overall study population and the ABVD subgroup.
Other factors generally associated with poorer prognosis, such as stage IV or the presence of extra-nodal disease, were also associated with a decrease of 30-mo PFS in both cohorts, though this difference was not statistically significant.
It has been suggested that PET2 assessments hold a superior prognosis potential to IPS [22][23][24]. There continues to be a debate The observed rate of PET2-positive scans (30%) was higher than in clinical trials [14,18], as often reported in studies in clinical practice settings [26]. This may reflect the higher proportion of stage IV cHL patients included in clinical practice [27]. We observed PET-adapted strategy of treatment intensity modification occurred in a small fraction of patients. This study reflects patient management in clinical practice and as such, age of patients and higher rates of comorbidity in the clinical practice setting may have influenced the decision to skip treatment escalation. Of note, our retrospective study also included a higher number of stage IV cHL patients (51.2%) than in previous real world studies (28.9% [26]; 11.8% [28] [18,20,28]. Increasing treatment intensity, most often from ABVD to eBEA-COPP, which showed better initial results and is supported by data from several clinical trials [11,13,18,20,21,28,29], exacerbates acute toxicity and long-term organ damage [20,28]. High rates of febrile neutropenia are generally attributed to doxorubicin and dacarbazine, while bleomycin also increases the risk of irreversible pulmonary damage [9,[30][31][32]. Brentuximab vedotin (A) in combination with AVD, an alternative 1L treatment option, is associated with substantially less pulmonary toxicity than ABVD, however myelotoxicity and neurotoxicity are increased (although myelotoxicity can be ameliorated with prophylactic G-CSF and neurotoxicity is largely reversible). The A+AVD combination appears to be more effective than ABVD for 1L treatment of advanced-stage cHL [14,33,34], and may have a role in treatment of older cHL patients and those with high IPS stage [35,36], who tend to have less favorable outcomes as shown in this study.
Even in patients with standard of care treatment (ABVD), the use of supportive therapies, especially G-CSF is extensive. Neutropenia, including febrile neutropenia, was greatly reduced when G-CSF was used as a primary prophylactic treatment, in line with prior reports [14]. Accordingly, prophylactic G-CSF was suggested to improve survival outcomes [33]).
In the present study in common clinical practice settings in IL,

STATEMENT OF SIGNIFICANCE
Patients with higher IPS consistently presented with poorer survival outcomes. Most of the patients were treated with ABVD as 1L chemotherapy across all centers in three countries.
Despite being recommended after two cycles of 1L chemotherapy in advanced cHL treatment guidelines, evidence for use of PET scan assessments and consequently, PET-guided treatment modification, was limited in common clinical practice in the three included countries during the study period.
There remains an unmet need for both safer and more efficient 1L therapy for advanced cHL patients presenting with unfavorable prognostic factors and low therapeutic response after two cycles of 1L chemotherapy.

ACKNOWLEDGMENTS
All authors have contributed substantially to the research design, analysis and interpretation of data, to the drafting of the paper and its revisions. All authors have approved the submitted and final version of the manuscript. Medical writing and editorial assistance, funded by Takeda, was provided by Patricia Viard.

Funding for this research was provided by Takeda Pharmaceuticals
International AG.

CONFLICT OF INTEREST
The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.

ETHICAL APPROVAL
This observational study was conducted in accordance with the Declaration of Helsinki, other legal and regulatory requirements, as well as with scientific purpose, value and rigor and following generally accepted research practices described in Good Pharmacoepidemiology Practices (GPP) guidelines issued by the International Society for Pharmacoepidemiology (ISPE). All data were handled in strictest confidence in conformity with national and international data protection regulations (such as Directive 95/46/EC). Good Epidemiological Practice (GEP) recommends the study design and data protection aspects be approved by an EC, and, for publication in peer-reviewed journals or other purposes, approval of an EC is recommended. However, some countries only require EC submission for interventional research only. Where required, the study protocol was reviewed and approved by a duly constituted independent ethics committee at a local level before initiation of data collection.

CONSENT TO PARTICIPATE
Respondents were informed about confidentiality in the statement of informed consent.

CONSENT TO PUBLICATION
Not applicable.