Reduced-Intensity Conditioning and Allogeneic Stem Cell Transplantation For Relapsed/Refractory Hodgkin Lymphoma In The Brentuximab Vedotin Era

Progressive disease (PD) remains the main cause of treatment failure following reduced-intensity conditioning (RIC) allogeneic stem cell transplantation (allo-SCT) in Hodgkin lymphoma (HL). In 08/2007 we elected to add gemcitabine (G) to our standard fludarabine (F) - melphalan (M) RIC (Anderlini et al, Haematol  93:257, 2008) in patients with relapsed/refractory HL undergoing allo-SCT. Subsequently, brentuximab vedotin (BV) was introduced as salvage therapy prior to allo-SCT. Main G-associated non-hematologic toxicities are pulmonary, skin toxicity and mucositis. Between 8/07 and 04/13, twenty-seven HL patients underwent an allo-SCT with the G-FM regimen. The median age was 31 years (20-46). Disease status at SCT was complete remission (CR) or undetermined (CRu) (n=17; 63%), partial remission (n=9; 33%), and other (n=1; 4%). The median time to PD after auto-SCT was 5 months (range 1-68). Fourteen patients (52%) received BV prior to allo-SCT, and in seven (50%) it was the last therapy prior to allo-SCT. In these seven patients the CR rate after BV was 100%. The donor was an HLA-identical sibling (n=16) or matched unrelated donor (n=11). The conditioning regimen was G 800 mg/m sq IV x1; F (33 mg/m sq IV x4), M (70 mg/m sq x2). There were three early (ie before day 30) deaths and one case of graft failure. Cumulative incidence of day 100 and overall transplant-related mortality (TRM) was 15% (both). Pulmonary toxicity (NCI CTC v3) was seen in 9 patients (33%). Grade 4-5 pulmonary toxicity was seen in 3 patients (13%). Otherwise it was grade 1-3 (n=6). Cutaneous toxicity (skin rash) was seen in 5 patients (19%: grade 3 n=1; grade 1-2 n=4). Mucositis was seen in 13 patients (48%). It was grade 3 (n=1) and grade 1-2 (n=12). The overall response rate (CR/CRu) prior to allo-SCT was 79% (11/14) in BV-treated patients vs. 46% (6/13) in BV-naïve patients (p=0.12; Fisher’s exact). The overall response rate (CR/CRu) after allo-SCT was 85%, both in BV+ and in BV- patients. Six patients expired (TRM n=4; PD n=2). Twenty-one patients are alive with a median follow-up of 18 months (range 4-55). At the last f/up, actuarial estimates of overall survival (OS) and progression-free survival (PFS) are 69% and 55%, respectively. Cumulative overall PD incidence is 30%. The median time to PD after allo-SCT is 13 mo (2-22). The seven patients who received BV as last line of therapy prior to allo-SCT are all alive and in CR/CRu. The G-FM140 regimen continues to show promise in this high-risk patient group. The inclusion of G may affect pulmonary toxicity, but TRM remained low. With the current BV-supported  approach, the CR rate pretransplant may be improved. PFS (18-mo) in CR/CRu patients seems to compare favorably to our FM140 experience in complete responders (80% vs 57%, p=0.2). While this BV-based transplant strategy needs further evaluation, the role of RIC allo-SCT in HL may need reassessment in the BV era.