Rituximab, cyclophosphamide-fractionated, vincristine, doxorubicin and dexamethasone alternating with rituximab, methotrexate and cytarabine overcomes risk features associated with inferior outcomes in treatment of newly diagnosed, high-risk diffuse large B-cell lymphoma

Abstract

Subtypes of diffuse large B-cell lymphoma (DLBCL) that have inferior outcomes after front-line therapy with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone) have been identified. While it is agreed that R-CHOP is probably not adequate in these patients, there is no standard treatment approach for patients with DLBCL with high-risk features. We present results of a retrospective cohort study of high-risk DLBCL (defined as having at least one unfavorable risk factor: non-germinal center [GC] subtype by immunohistochemistry [IHC], Ki-67 ≥ 80%, high International Prognostic Index [IPI], c-MYC rearrangement) treated with R-HCVAD/R-MTX-AraC (rituximab, cyclophosphamide-fractionated, vincristine, doxorubicin and dexamethasone alternating with rituximab, methotrexate and cytarabine; R-HCVAD) as front-line therapy. With a median follow-up of 25.3 months, the 3-year PFS and OS estimates are 79% (95% confidence interval [CI], 65-88%) and 76% (95% CI, 61-86%), respectively, which are higher than those for historical comparisons with R-CHOP data for high-risk patients. These data are in accord with other recent reports of dose-intense front-line therapy of high-risk DLBCL. This analysis represents the largest reported cohort of patients with DLBCL treated with R-HCVAD. These data suggest that R-HCVAD can overcome traditional poor risk features such as high IPI, high Ki-67 and non-GC IHC pattern. Future work will focus on identifying molecular markers for failure in patients with DLBCL treated with dose-intensive regimens.

Prospective phase II study of rituximab with alternating cycles of hyper‐CVAD and high‐dose methotrexate with cytarabine for young patients with high‐risk diffuse large B‐cell lymphoma

“…The primary intention of the study was to determine whether initial intensive chemotherapy with R-HCVAD/R-MA, compared with standard R-CHOP, could overcome the adverse biology and improve outcome in patients with high-risk DLBCL. The retrospective analyses on which our trial was based revealed promising efficacy data (Fayad et al, 2007) , (Mato et al, 2013). To prospectively compare the safety and efficacy of R-HCVAD/R-MA with R-CHOP, a randomized trial was considered necessary.…”

‘Double‐Hit’ cytogenetic status may not be predicted by baseline clinicopathological characteristics and is highly associated with overall survival in B cell lymphoma patients

“…Inferior rates of survival have been reported in diffuse large B cell lymphoma (DLBCL) patients harbouring MYC rearrangements compared to those without MYC rearrangements when treated with R‐CHOP (Savage et al , ) and (Barrans et al , ), and recent publications have suggested that the use of higher‐dose first‐line immunochemotherapy may result in improved outcomes in patients with MYC rearrangements (Mato et al , ; Oki et al , ). Accordingly, there is a strong rationale for offering intensive first‐line therapies to patients with MYC‐ rearranged DLBCL (including DH), and the use of dose‐adjusted EPOCH‐R (etoposide, predisone, vincristine, cyclophosphamide, doxorubicin, rituximab; NCT01092182) is currently being evaluated in a multi‐centre phase 2 clinical trial.…”

Excellent survival after R‐Hyper‐CVAD in hospitalized patients with high‐risk large B‐cell lymphoma: The Karolinska experience

“…When we applied the inclusion criteria of each respective trial on our R‐Hyper‐CVAD cohort and investigated outcomes, we found very similar outcome in our patients compared with these three trials, although it seems that treatment‐related mortality in our older patients was lower, which we believe might be due to the flexibility outside trials to switch between regimens, and partly because our patients were treated at a single‐centre with long experience with the regimen. This probably also explains the differences with multi‐centre [ 26 ] and the similarities with single‐centre [ 27 ] studies of R‐Hyper‐CVAD/R‐MA. Still, R‐Hyper‐CVAD/R‐MA causes considerable toxicity, and there were six toxic deaths during induction therapy among the 150 patients who received at least one cycle of R‐Hyper‐CVAD/R‐MA, all in patients aged 54–65.…”