Gemcitabine is a cytarabine analogue which has synergistic activity with cisplatin in vitro. These two agents, along with the dexamethasone dose used in DHAP were combined with intent to develop an efficacious outpatient regimen that does not adversely impact stem cell mobilisation capacity.r
Hodgkin lymphoma (HL)
In a Canadian study of relapsed/refractory Hodgkin Lymphoma,r 131 patients were treated with GDP (27% relapsed less than 12 months after upfront therapy; 33% relapsed greater than 12 months after upfront therapy; 40% primary refractory disease). After 2 cycles, 15% achieved complete response (CR) and 61% achieved partial response (PR) (overall response rate 76%). These patients were each able to mobilise adequate stem cells to proceed to BEAM ASCT, the standard ultimate goal in relapsed/refractory HL.r In a smaller preceding analysis of 34 patients receiving GDP,r there were response rates of 3/34 in CR (9%), 18/34 in PR (53%) and 9/34 (26%) with stable disease (30/34 in total with non-progressive disease). These patients were all able to proceed to BEAM ASCT, with OS (at 1.5 years) and PFS (at 1.2 years) of 90% and 76% respectively. Baetz and colleaguesr reported comparable findings in 23 patients with relapsed/refractory HL.
Ramzi et alr published a small, randomized study comparing GDP and ESHAP as salvage chemotherapy for relapsed/refractory Hodgkin lymphoma. Twenty-two patients were recruited to each arm. Overall response rates were 54.1% in the GDP group and 50.0% in the ESHAP group, with complete responses identical in the two groups (38.1%).
Non-Hodgkin lymphoma (NHL)
In a Canadian phase 2 study, 51 patients with aggressive non-Hodgkin lymphoma (40 DLBCL) were treated with 2 cycles of GDP.r Response rates were 8/51 in CR (16%) and 17/51 in PR (33%), with an overall response rate of 49%. 22 of the 23 patients who were eligible to proceed to ASCT were able to mobilise a target CD34 dose of 2 x 106/kg, indicating that capacity for stem cell mobilisation was not substantially impaired by this regimen.
The NCIC-CTG LY.12. study randomized patients with relapsed and refractory aggressive lymphomas to receive either GDP or DHAP, followed by autologous stem cell transplantation. In this studyr, Crump and colleagues studied 619 patients, with several aggressive histological entities included - DLBCL (n=419), transformed indolent (n=87), PTCL (n=27), ALCL (n=23), and primary mediastinal B-cell lymphoma (n=18). An amendment in 2005 allowed patients with CD20+ diseases to receive rituximab in addition to the chemotherapy backbone. The patients were poor-risk with approximately 70% in each arm experiencing relapse within 1 year of primary therapy or having no response to primary therapy. At least 2 cycles of therapy were administered to 90% of the GDP group and 87% of the DHAP group. The rates of response were similar in the two groups (45.1% v 44.1%), meeting the prespecified criteria for non-inferiority. 52.1% of the GDP arm and 49.3% of the DHAP group proceeded to subsequent stem cell transplantation. 6 patients in the GDP arm and 7 patients in the DHAP arm failed to collect stem cells sufficient for subsequent transplantation. After a median follow-up of 53 months, the 4 year progression-free survival and overall survival were similar.
Progression free survival and overall survival in the NCIC-CTG LY.12 study
© Journal of Clinical Oncology 2014
The British Columbia group recently published a retrospective analysis of patients treated with GDP between Sep 2002 and Jun 2010. In the paper by Moccia and colleagues,r 152 patients with DLBCL and 83 patients with Hodgkin lymphoma were identified. Overall response rates in these two groups were 49% and 71% respectively, with 52% and 96% of patients respectively proceeding to transplant (in those patients eligible for transplantation). The 2 year progression-free and overall survivals were 21% and 28% in the DLBCL group respectively, and 58% and 85% in the HL group respectively.
Peripheral T-cell lymphoma (PTCL)
Several small studies have evaluated GDP specifically in the setting of PTCL. Jia et alr evaluated the role of 3 different front-line protocols. In this retrospective study, 93 patients were treated with CHOP (n=40), CHOPE (n=42), and GDP (n=11). GDP appeared to have similar complete response rates to CHOPE, and overall response rate of 90.9%. Median PFS was 9.7 months in the GDP arm, with a 100% overall survival (OS) at 1 year which was significantly higher than the CHOP-treated group (p=0.024).
In the relapsed setting, Park et alr demonstrated a 72% overall response rate after a median of 4 cycles, with 12 of 25 patients studied achieving a complete response to GDP. In this study, cisplatin was administered at a lower dose of 70mg/m2. At a median follow-up of 27.1 months, median progression free survival (PFS) was 9.3 months. Qi et alr published the Chinese experience of GDP in 25 patients treated with a median on 4 cycles. An overall response rate of 64.0% was demonstrated, with 5 patients achieving a complete response. After a median follow-up of 9 months, median overall survival and progression free survival were 9.3 and 5.4 months respectively.
Phase 2 studiesrr in stage I-II nasal type extranodal NK/T-cell lymphoma deliver 3-4 cycles of GDP following radiotherapy or concurrent radiotherapy and cisplatin. In the study by Qi et al. the cisplatin dose was divided and given daily D1-D3. CR rates (90-95%) and 3-year PFS 84% and OS 87% are comparable to similar sized phase 2 studies of other regimens including concurrent chemoradiotherapy followed by VIPD, concurrent DeVIC and radiotherapy, and GELOX followed by radiotherapy.
Note that rituximab is routinely incorporated into salvage regimens for B-cell lymphomas. This is based on randomised evidence in follicular lymphomar and more limited evidence in diffuse large B-cell lymphoma.r Rituximab was included as a protocol amendment in the Crump 2012 abstract in each arm, 318 patients received rituximab in combination with GDP, 96 did not.r The rituximab group had better ORR (46% vs 25%) and higher transplant rates (52% vs 31%), however there was no difference in PFS and OS between groups. Where patients who relapse within 1 year of primary therapy were excluded, the inclusion of rituximab at salvage significantly improved OS with a trend towards improved PFS. These data support the use of R+GDP in relapsed B-cell NHL.
||Study & Year Published
||Is the dose and regimen consistent with the protocol?
|Phase III trials
||Crump et al. 2014
|Phase II trials
Baetz et al. 2003
Villa et al. 2012
Kuruvilla et al. 2006
Ke et al. 2014
|Park et al. 2015
Qi et al. 2018
|cisplatin 70 mg/m2
cisplatin 25mg/m2 D1-D3
Moccia et al. 2017
Qi et al. 2017
Jia et al. 2016
The paper by Crump et alr demonstrated that Grade 3 or 4 adverse events were observed significantly less frequently during the first two cycles of chemotherapy among patients receiving GDP (47% v 61%; P < .001), including fewer episodes of febrile neutropenia (9% v 23%; P < .001). Furthermore, hospitalisations were less frequent in the GDP group (47% v 99%, P<0.001).
© Journal of Clinical Oncology 2014