In 1988 Velasquez et al showed that DHAP (cisplatin, high dose cytarabine and dexamethasone) was shown to be an effective salvage regimen for recurrent non Hodgkin lymphoma (NHL).r Of the 90 patients reported in this study, 58 had diffuse large B cell histology (DLBCL). Seventeen of these patients achieved CR and fourteen achieved PR1.
DHAP was employed as the salvage chemotherapy regimen in the pivotal PARMA trial published in NEJM in 1995. This randomized phase 3 trial examined the role of autologous bone marrow transplantation (ABMT) compared to conventional salvage chemotherapy in relapsed, but chemotherapy sensitive NHL.r
Patients were randomised after two 21 days cycles of DHAP to receive either 4 additional courses of DHAP or to ABMT. (Those who showed no response after the 2 cycles were excluded from randomisation). A total of 215 patients were enrolled, with a median age of 43 and median follow up of 63 months. There were 163 with ‘intermediate grade’ histology (DLBCL in 37), and 52 with ‘high grade’ histology. There was a highly significant advantage in favour of ABMT in both EFS and OS.r
The PARMA trial provided excellent data on the role of DHAP in treatment of relapsed NHL, with or without high dose chemotherapy followed by ABMT. At the end of the first two cycles of DHAP, 109 patients (41% in CR, and 59% in PR) were randomised to either BEAC followed by ABMT, or continuing with up to 4 more cycles of DHAP.r Time to first relapse was correlated with response after the first two cycles of DHAP, as well as 8-year survival rates.r
In the PARMA trial, there were no early toxic deaths in 54 patients in the DHAP arm, while there were 6 (out of 55 patients) early toxic deaths in the BEAC arm. As expected, the BEAC arm also had much higher adverse events such as infections and mucositis, one case of septic shock, and one had grade 4 cardiac toxicity.r
In a review in 1993, Vose commented that DHAP followed by high dose chemotherapy and autologous haemopoietic stem cell transplant was then the standard of care for relapsed or refractory high grade NHL.r
Furthermore, DHAP is the standard salvage regimen for HL (see below) and CD20-negative NHL in many countries in Europe.
Only 50% of patients with relapsed Hodgkin lymphoma (HL) can be cured with intensive induction chemotherapy, followed by high-dose chemotherapy (HDCT) and autologous stem cell transplant (ASCT).r
The randomized HDR2 trial aimed at increasing the efficacy of induction chemotherapy by incorporating sequential high-dose chemotherapy.r However, sequential high-dose chemotherapy failed to improve the outcome compared to the standard treatment.r Therefore, two courses of DHAP followed by HDCT with BEAM and ASCT are still regarded as standard treatment in transplant-eligible relapsed HL patients.rr Besides testing the benefit of single-agent high-dose chemotherapy, shortening of the DHAP cycle interval from 21 to 14 days was recommended in the HDR2 trial. That recommendation was based on preliminary clinical data from patients with relapsed HL or aggressive non-Hodgkin lymphoma (NHL) suggesting a correlation of dose density and outcome.r
In that study among 102 relapsed/refractory Hodgkin Lymphoma patients, Josting et al confirmed the efficacy and tolerability of DHAP given every 14 days.r The overall and complete response rates were 89% and 22% respectively. Grade IV neutropenia and thrombocytopenia were 43% and 48% respectively and there were no toxic deaths.
In a retrospective multivariate analysis of the HDR2 trial (N=266), in addition to four risk factors (early or multiple relapse, stage IV disease or anemia at relapse, and grade IV hematotoxicity during the first cycle of DHAP) a delayed start of the second cycle of DHAP at > day 22 predicted a significantly poorer progression-free survival (PFS, P = 0.0356) and overall survival (OS, P = 0.0025).r That analysis strongly suggested that dose density of DHAP has a relevant impact on the outcome of relapsed HL patients.r
Toxicities of DHAP, DHAC, DHAOX:
Optimal salvage chemotherapy regimen for patients with relapsed or refractory Hodgkin and non-Hodgkin lymphoma remains unclear but often based on platinum regimens. In a retrospective study, the real life toxicity profiles were assessed among patients with relapsed or refractory lymphoma treated with DHA (dexamethasone, high dose aracytine cytarabine) plus platinum salt (dexamethasone-High dose aracytine (cis)platin (DHAP), dexamethasone-High dose aracytine carboplatin (DHAC), or dexamethasone-High dose aracytine Oxaliplatin (DHAOX)), from February 2007 to May 2013 in 2 French hospitals.r
A total of 276 patients were treated: 168 with DHAP (60.9%), 79 with DHAOX (28.6%), and 29 with DHAC (10.5%). Rituximab was associated in 80.1% of patients (n = 221). Renal failure was reported in 97 patients, mainly with cisplatin regimen (86.6%) leading to 8.9% grade III to IV renal failure (P = 0.001). Renal insufficiency was reversible in most patients but remained persistent in 24, with all of them being treated with DHAP except 1. Cisplatin-based regimen (50.0% versus 12.0%, P < 0.05) and female (44.6% versus 29.7%, P < 0.05) appeared to be at higher risks of renal failure.9 Platinum cumulative dose is a significant risk factor of nephrotoxicity. Hematologic toxicity was more frequent with carboplatin and cisplatin with at least 1 event (all toxicity grade) respectively in 79.3% and 71.4% of patients treated (P < 0.005). Auditory toxicity was mainly reported with cisplatin (n = 19; 4 grade I-II and 15 grade III-IV). Oxaliplatin was implicated in 77.6% of neurotoxicity (n = 59), mainly moderate (grade I-II). In conclusion, DHAOX and DHAC regimens have more favorable toxicity profile than DHAP regimen. Their lack of renal toxicity makes them attractive regimens, which may be interesting for patients eligible for autologous stem cell transplantation. Nevertheless, these results have to be confirmed by the therapeutic efficacy of these 3 regimens.