Insights into the Argentine experience with brentuximab vedotin and its combination with bendamustine in R/R cHL

At the 2017 American Society of Hematology (ASH) 59th Annual Meeting in Atlanta, an oral abstract #4089 was presented describing a retrospective analysis of the safety and efficacy of brentuximab (BV) and BV in combination with bendamustine (BV-B) in multiple centers across Argentina. This was the first study of its kind in this country to assess this treatment in patients with relapsed or refractory (R/R) classical Hodgkin lymphoma (cHL).

The study by Florencia Negri Aranguren, from GATLA, Instituto Hematologia y Hemoterapia, Parana, Argentina, and colleagues, retrospectively evaluated 93 patients treated with either BV monotherapy (n = 71) or BV-B (n = 22). The primary endpoints were overall response rate (ORR) and event-free survival (EFS). Secondary endpoints included overall survival (OS) and toxicity. The median follow-up with patients was 13 months.

Results for BV vs BV-B treated patients included; ORR 61% vs 86%, complete response (CR) 28% vs 55%, progression-free survival (PFS) 41% vs 42%, and OS 75% vs 95%. In a non-randomized comparison, and with a small number of patients, results were more favorable for the BV-B combination therapy. These results also showed longer PFS and OS for those who achieved CR (BV: PFS = 80% and OS =95%; BV-B: PFS = 62% and OS = 100%).

Astrid Pavlovsky, Medical Director of the Pavlovsky Center and staff member in the Hematology Department of FUNDALEU, Buenos Aires, Argentina, and one of the Negri Aranguren et al. study co-authors, discussed the results of this study in an interview with the Lymphoma Hub during the ASH 2017 meeting. She mentioned that the results were good, however, they were not in line with the results published from other trials and she also observed that “some centers or areas of the country had better results than other centers or areas.” She told the Hub at ASH that the research team is investigating the reasons for this discrepancy. They contacted all participating centers, and found that some clinicians in some regional areas were unable to provide the exact dosing at the exact proper time in the study treatment protocol as they “do not have the same access to drugs”. They will further analyze whether this influenced the efficacy of the treatment. She added that the research team will try to perform a prospective trial and potentially produce some country guidelines for patient treatment and evaluation hoping to “have better results in the future.”

Lymphoma Hub invited Astrid Pavlovsky, a scientific advisory board member of Lymphoma Hub, to follow-up on her study to gain further insight into the Argentine experience with BV and B therapy. 

What is the current standard of care for R/R cHL in Argentina? Is BV and/or the combination of BV-B routinely used in the treatment of R/R cHL in Argentina?

In Argentina, the current standard of care for R/R HL does not differ from international guidelines. At first relapse or primary refractory patients receive salvage chemotherapy which mainly includes ICE (ifosfamide, carboplatin, etoposide), ESHAP (etoposide, high dose ara-c and Cisplatin) and DHAP (dexamethasone, high-dose cytarabine, cisplatin) followed by autologous stem cell transplant (ASCT). 

Those patients achieving CR prior to proceeding to ASCT experienced improved OS. As such, CR prior to ASCT is considered an important determinant of outcome. Over the last decade, PET-CT has been widely incorporated both in first-line treatment and also in the relapse setting. A negative PET-CT before ASCT has shown to be of prognostic importance thus, it has been widely incorporated to try to achieve a negative PET-CT before consolidating with ASCT. For patients who relapse to ASCT, who are refractory to two lines of chemotherapy or ineligible for ASCT, brentuximab vedotin has been approved and reimbursed since 2016. 

What were the results from the other BV-B pivotal trials as a comparison? Is there a publication that presents these results?

Brentuximab vedotin (BV) and bendamustine (B) both showed activity in relapsed HL patients as monotherapy (Younes et al, 2012). Their combination in heavily pre-treated patients with multiply relapsed or refractory HL resulted in an ORR and CR rate of 67% and 19%, respectively (n = 42) (Sawas et al, 2015). Another study, in which BV+B was used in HL patients with primary refractory disease or at first relapse, reported ORR and CR rate of 93% and 73%, respectively (n = 55) (LaCasce et al, 2015).

Sawas et al (Blood 2015 126:586) published their experience with BV+B in 41 patients with HL; the median number of prior systemic therapies was 5 (range 1-16); with 26 patients having had prior ASCT and 14 patients receiving prior radiation therapy.

Thirty-six patients were evaluable for response. The overall response rate was 67%, with 7 patients (19%) attaining a complete response (CR). Eight patients had stable disease. The regimen showed an ORR of 67% with responses ≥ 50% in patients who had received either agent separately supporting the potential clinical synergy of the combination.

Our retrospective analysis of all indications of BV showed that the combination of BV with B is also a physician’s choice in Argentina, outside clinical trials. Our findings add to the growing body of evidence supporting the efficacy of BV as monotherapy and the high ORR and CR of its combination with Bendamustine. A non-randomized comparison favors the efficacy of this combination.

Nevertheless, in this cohort of patients treated with BV-B we describe unexpected grade III-IV CNS toxicity in 32% of patients. This toxicity has not been described in other published experiences. Hopefully, a future large randomized trial should address the risk and benefit of BV vs BV-B.

What are the possible reasons for discrepancies in access to drugs in different areas of Argentina?

Different areas in Argentina present a significant difference in income per capita and in formal employment, thus translating into a significant difference in effective coverage and access to drugs.

How does drug access for cHL in Argentina compare with other countries in Latin America?

 Many Latin American countries face the same inequality of medical resources within the country, concentrating better resources in main cities, sometimes far away from the rest of the country. 

What are the regulatory processes for reimbursement in Argentina? 

The Argentine health system is composed of three subsystems: the public, the Social Security and the private. Social security and Private Health insurance are regulated by our Plan Medico Obligatorio PMO (Compulsory Medical Plan). The PMO is modified by a decision of the Health Ministry. There is no official process for health technology assessment. Drugs become reimbursable by National Social Security and private health insurance companies either through official inclusion by the Health Ministry, by law sanctioned by the legislative power, or by a judicial decision made on an individual basis.

PAMI (Programa de Atencion Medica Integral) is a social health insurance under federal state control, for retirees and pensioners, people over 70 without retirement and ex-combats of Malvinas. Reimbursement by PAMI is an autonomous decision by PAMI, however, it is strongly influenced by judicial decisions and by the PMO. Reimbursement by Provincial Social Security is decided by each Province, either by a Provincial law or by the provincial health ministry. Judicial decisions on an individual basis also apply. 

How long does it usually take between approval and reimbursement? Is the regulatory body ANMAT involved in reimbursement?

Marketing approval by ANMAT is a necessary but not sufficient condition for reimbursement. ANMAT does not decide on reimbursement but it is closely related. Time from marketing approval to reimbursement is very variable. Many drugs become reimbursed immediately after ANMAT approval, even before they are officially declared as reimbursable. 

What are your plans for a prospective trial that will be conducted for further analysis? 

At the moment, and after a retrospective analysis of the indication of BV in Argentina, we plan to write the conclusions of its indications in our country and we believe it would be helpful to have a guideline on the time of evaluation, and the possible therapeutic decisions based on the response to treatment after BV.

You plan to produce country guidelines, can you elaborate further on what you want to include in them and what the current guidelines are? Would the guidelines be published by GATLA?

 The Argentine Society of Haematology (Sociedad Argentina de Hematologia/SAH) has its own guidelines on most hematological diseases which are updated every 2 years by a group of experts and are in concordance with international guidelines and what has been approved and reimbursed in Argentina. The latest guidelines were formulated last year and are available and published by the SAH (http://www.sah.org.ar/guias_hematolo.asp). 

The GATLA is a National Cooperative Group dedicated to clinical trials and is not involved in the elaboration of treatment guidelines. We hope our national experience is of help contributing to international knowledge in the treatment of relapsed, refractory Hodgkin lymphoma.