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BV-DHAP in relapsed or refractory Hodgkin lymphoma
AB
Figure 2. Kaplan-Meier survival analysis. Kaplan-Meier survival analysis for all 55 phase II patients by intention-to-treat, including the number of patients at risk at 1, 2 and 3 years with regard to (A) progression-free survival and (B) overall survival, measured from enrollment.
cal morphological and/or immunohistochemical features, including cases with high numbers of Epstein Barr virus- encoded RNA (EBER)-positive atypical large cells and/or small lymphocytes (n=16), extensive immunohistochemical and molecular T-cell receptor and immunoglobulin heavy and light chain gene rearrangement assays (BIOMED) were performed (Online Supplementary Table S6). In eight patients, cHL could not be confirmed. Of these, five patients were diagnosed with peripheral T-cell lymphoma (PTCL) not otherwise specified (NOS), one patient with angioimmunoblastic T-cell lymphoma (AITL), and one patient with immunodeficiency-associated B-lymphoprolif- erative disorder (IA-B-LPD).25 In one patient, a classifying diagnosis could not be made due to lack of representative material in the biopsy sample. Additionally, in one patient, a composite lymphoma of cHL and lymphoplasmacytic lymphoma (LPL) was diagnosed. In all cases, high CD30 expression was present. Of the seven patients with PTCL, AITL or IA-B-LPD, six had an mCR after three cycles of BV- DHAP. One patient with PTCL had PD after cycle 2, one with AITL had PD after auto-PBSCT, and one patient with PTCL died due to unrelated head-trauma. When excluding the patient with unrelated death, there was no significant difference in PFS between patients with confirmed cHL versus patients with another diagnosis (2-year PFS 81% vs. 67%, log-rank P=0.36).
Discussion
In this international, prospective phase II study, we investigated the efficacy and safety of BV-DHAP as first salvage treatment for patients with R/R cHL. This study is the first to investigate this combination. Treatment with BV-DHAP resulted in a high proportion of patients with an mCR prior to HDC/auto-PBSCT, and toxicity was mostly reversible.
Data on FDG-PET-CT results following treatment with DHAP are scarce, but generally only about 25% of patients achieved a CR as assessed by CT scan.4,26 Other trials have recently investigated BV in combination with other salvage chemotherapy combinations, such as ben- damustine, ICE (ifosfamide, carboplatin, etoposide) or
ESHAP (etoposide, methylprednisolone, high-dose cytara- bine and cisplatin), and have shown mCR rates up to 76% prior to HDC/auto-PBSCT.15-18,27 The administration schedule of BV differed among these studies, and most studies used more than three administrations of BV in total.15-18,27 In the current study, three cycles of BV-DHAP resulted in a high mCR rate with only three administra- tions of BV. This makes it a less ‘financially toxic’ therapy than using BV in first line for all patients or to use it as con- solidation therapy after auto-PBSCT.
In R/R cHL patients treated with salvage chemotherapy followed by HDC and auto-PBSCT, historical studies demonstrate a 5-year PFS of approximately 50%.1-4,26,28,29 In 97 patients treated with ICE, 2-year event-free survival was 70%.6 Another regimen consisting of bendamustine, gemcitabine and vinorelbine (in 59 patients) resulted in a 2- year PFS of 63%.30 With the present treatment protocol, we have been able to achieve a high 2-year PFS rate of 74%. A total of 14 events occurred (including 3 deaths), and at the present median follow-up of 27 months, no relapses have occurred beyond 18 months from enrollment. Longer fol- low-up is needed to confirm that the majority of patients in remission after 2 years are indeed cured.3,28,31
The unprecedented high response rate and prolonged PFS of this treatment regimen were achieved at the cost of higher toxicity in comparison to other salvage regimens. However, most of the observed toxicities, including neu- tropenia, thrombocytopenia, fever, nausea/vomiting, oto- toxicity and nephrotoxicity are toxicities of specific con- cern during treatment with DHAP.4,26,32,33 Other regimens of BV with bendamustine, nivolumab, ICE or ESHAP seem to induce fewer AE, with most toxicities consisting of hematologic toxicity.15,16,18,19,34 While the occurrence of grade 3/4 non-hematologic toxicity was low with BV-ben- damustine, a substantial proportion of the patients (25%) did not undergo auto-PBSCT, resulting in a lower 2-year PFS of 62.6%.16 Another recent study with BV-bendamus- tine in 40 patients had a 3-year PFS of 67.3%, and 82.5% of patients underwent auto-PBSCT.19 The combination of BV with nivolumab resulted in an mCR rate of 61% with almost all patients experiencing grade 1/2 toxicity and 31% having grade 3/4 toxicity; however, these AE were also manageable.34
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