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non-Hodgkin lymphomar-GDP LeSS TOXIC THaN r-DHaP IN reLaPSeD/reFraCTOry NHL

Douglas Stewart, MD, FRCPC, Chief, Division of Hematology & Hematological Malignancies, university of Calgary. Provincial Leader, Hematology Tumour Team, alberta Cancer Care.

TRIAL SUMMARY: GDP less toxic but equally effective relative to DHAP.Crump M, Kuruvilla J, Couban S, et al. Gemcitabine, dexamethasone, cisplatin (GDP) compared to dexamethasone, cytarabine, cisplatin (DHaP) chemotherapy prior to autologous stem cell transplantation for relapsed and refractory aggressive lymphomas: final results of the randomized Phase III NCIC CTG study Ly12. Presented at aSH 2012. Blood 2012;120:abstr 745.

The optimum chemotherapy combination prior to autologous stem cell transplantation (ASCT) for patients with relapsed or refractory aggressive non-Hodgkin lymphomas (NHL) has not been defined. The safety and efficacy of outpatient treatment with GDP was established in a Phase II study (Crump et al, Cancer 2004) leading to this Phase III trial testing the hypothesis that GDP is as effective as and less toxic than standard DHAP, and potentially associated with better quality of life (QoL) and lower resource utilization.

Patients with relapsed/refractory aggressive NHL were strati-fied by IPI (International Prognostic Index) score at relapse (0, 1, 2 ≥3 risk factors), immunophenotype (B vs T cell), disease status following initial treatment (response duration <1 year vs duration >1 year vs no response/PD) and prior treatment with rituximab (R), and were randomized to 2–3 21-day cycles of G 1000 mg/m2 day 1 & 8, D 40 mg day 1–4, P 75 mg/m2 day 1 or standard DHAP, followed by PBSC (peripheral blood stem cell) collection and ASCT. The protocol was amended 11/2005 to include R with GDP or DHAP for patients with CD20+ lymphoma. Co-primary endpoints were response rate (RR) after 2 cycles and transplantation rate; 18F-FDG PET (F-fluorodeoxyglucose positron emission tomography) was not used to determine response. Other endpoints included toxicity, event-free (EFS) and overall survival (OS), QoL and an economic analysis. Results of a second randomization to post-ASCT rituximab consolidation vs observation for patients with CD20+ lymphoma will be reported subsequently.

The trial enrolled 619 patients at 52 centres in Canada, Italy, Australia and the US (GDP 310 DHAP 309). Median age was 55 yrs; histology: DLBCL (diffuse large B-cell lym-

phoma) 71%, PTCL (peripheral T-cell lymphoma) 4%, ALCL (anaplastic large-cell lymphoma) 4%, transformed 14%; IPI risk factors: 0,1: 38%, 2: 29%; >3: 33%; elevated LDH 59%; prior R treatment 67%; refractory to initial therapy 31%; all baseline characteristics were balanced between treatment arms. In the intention-to-treat (ITT) population, RR for GDP was 45.2% and for DHAP 44.0%. Protocol-stated criteria for declaring GDP non-inferior to DHAP were met (p=0.005). RRs were similar between arms in patients with and without prior R exposure, and with and without R added to GDP or DHAP. The transplantation rate was 51.8% for GDP vs 49.3% for DHAP (per-protocol analysis; p=0.49); 6 patients in each arm could not mobilize adequate PBSCs. At a median followup of 53 months, 4-year EFS was 25.6% and 26.1% (HR 0.99, p=0.95) and 4-year OS 39.0% and 39.1% (HR 1.03, p=0.78) for GDP and DHAP, respectively. Patients receiving GDP experienced less Grade 3-4 toxicity (47 vs 61%, p=0.0003), including febrile neutropenia (9 vs 23%, p<0.0001), platelet transfusion during the first 2 treatment cycles (18% vs 32%, p < 0.0001) and adverse events (AEs) requiring hospitalization (18 vs 30%, p=0.0005). One patient in each arm died from infection during GDP/DHAP therapy (0.3%). Compared to baseline, superior mean and greater-than-minimally-important change scores for QoL were seen during and/or after 2 treatment cycles in the GDP group when assessed using FACT-Lym (Functional Assessment of Cancer Therapy–Lymphoma). Stratified by important baseline characteristics, in univariate analysis no variables were asso-ciated with response; in multivariate analysis, ECOG PS, stage and number of sites of disease were significantly asso-ciated with OS; age and stage were associated with EFS.

The response rate to GDP is not inferior to the standard regimen of DHAP prior to ASCT for aggressive lymphomas, and GDP resulted in similar rates of transplantation, EFS and OS. GDP can be given in the outpatient setting with signifi-cantly less toxicity, superior QoL scores and reduced need for hospitalization. This study supports the use of GDP as a new standard in practice and in future studies focused on improving salvage therapy approaches.

COMMENTARY: Treatment outcomes remain poor for the majority of patients who suffer from relapsed or refractory aggressive-histology non-Hodgkin Lymphoma (aNHL). Such patients who are not transplant-eligible because of significant comorbidities have very short survival rates, often less than 6 months. Even young healthy patients must undergo repeated cycles of a salvage chemotherapy regimen, and then proceed to myeloablative high-dose therapy (HDT) with ASCT if

their disease proves chemosensitive. Over the past 2 decades, conventional salvage chemotherapy options for NHL have included regimens such as DHAP (methylprednisolone), ESHAP (etoposide, high-dose ara-C, cisplatin), or ICE (ifos-famide, carboplatin, etoposide). These regimens are usually administered on an inpatient basis, and are associated with substantial toxicity in terms of febrile neutropenic infection, cytopenias, alopecia, nausea and malaise. There was no

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In BrIefAlready known• Salvage chemotherapy regimens r-ICe and r-DHaP

confer similar outcomes for relapsed or refractory DLbCL patients.

What this study showed• r-GDP results in non-inferior response rates, trans-

plantation rates and PFS compared to r-DHaP, but with lower toxicity and superior QoL. r-GDP should now be considered a new standard of care for relapsed aggressive-histology NHL patients.

Next steps• Improve upon r-GDP outcomes by incorporating

or substituting novel, noncytotoxic or targeted agents, or comparing new or high-dose regimens to standard r-GDP in future Phase III or random-ized Phase II trials.

• use correlative science to identify and validate biomarker models that can predict benefit or futility of r-GDP salvage, and guide appropriate patients to studies investigating novel agents or approaches.

prospective randomized controlled trial (RCT) comparing these regimens until the Collaborative Trial in Relapsed Aggressive Lymphoma (CORAL study), which compared R-DHAP to R-ICE for 396 patients with relapsed or refractory DLBCL.1 Results of the CORAL study found no significant differences between R-DHAP and R-ICE with almost two-thirds of patients responding to treatment, approximately half pro-ceeding to ASCT and one-third achieving 3-year PFS. How-ever, PFS was approximately 20% for patients who had ini-tially received prior rituximab-containing induction therapy, had initial time to progression (TTP) <1 year, or had age-adjusted IPI scores=2–3.

Dr. Crump and other investigators for the NCIC CTG LY12 study need to be commended for completing the largest Phase III RCT ever performed comparing two salvage chemo-therapy regimens for relapsed/refractory aNHL.2 Although the study had a long accrual period, from 2003–2011, treat-ment of relapsed aNHL changed little over this time except for the addition of rituximab to the salvage therapy,3-5 a modification that was incorporated into the LY12 protocol after 2005. NCIC LY12 randomized 619 patients to R-GDP or R-DHAP salvage therapy. Responding patients were then to proceed to HDT/ASCT. Using a non-inferiority design, co-primary endpoints were response and transplantation rates. Because R-GDP could more easily be administered on an outpatient basis and was thought to be less toxic, impor-tant secondary endpoints of the LY12 study included toxicity and QoL. A second randomization was performed post-ASCT

to either rituximab consolidation or observation for patients with CD20+ NHL, however results are not available.

The results of LY12 were reported in an oral presentation at the 2012 American Society of Hematology meeting.2 The main findings of LY12 were non-inferior response rates (45% and 44%), transplantation rates (52% and 49%), and 4-year PFS rates (25.6% and 26.1%) for R-GDP compared to R-DHAP. Also of importance, R-GDP resulted in less Grade 3-4 toxicity (47 vs 61%), less febrile neutropenia (9 vs 23%), less need for platelet transfusions (18% vs 32%) and fewer AEs requiring hospitalization (18 vs 30%), with better QoL. Although the response rates and PFS rates are numeri-cally higher in the CORAL study, it needs to be recognized that inter-trial comparisons are unreliable because differences in treatment outcomes between trials are often due to differ-ences in baseline patient characteristics. For example, the CORAL study only included DLBCL whereas LY12 also included T-cell NHL. In addition, only 44% of patients in the CORAL study had initial TTP <1 year compared to 73% in LY12. In opposition to the CORAL study, an important finding of the NCIC LY12 study was that patients who failed prior R-CHOP did not have worse outcomes following re-induction. This finding is supported by other reports.6,7 The authors reasonably conclude that R-GDP should be considered a new standard in practice for relapsed/refractory aNHL.

Although we may accept that R-GDP is the new standard of care for relapsed/refractory aNHL in Canada, the ques-tion is “Where do we go from here?” The main advantage of R-GDP is that it can easily be given on an outpatient basis, with similar outcomes but less toxicity than other salvage therapy options. It needs to be stated, however, that the results of all of these salvage regimens are unsatisfactory. Only 50% of patients eventually undergo HDT/ASCT and only 25–30% of patients achieve cure. Reasons for not receiving HDCT/ASCT include: chemoresistant disease; development of CNS lymphoma; organ dysfunction from comorbid illness, treatment complications or rapid disease progression; and inability to collect adequate stem cell graft secondary to marrow damage from lymphoma, chemotherapy or radio-therapy. Following R-ICE or R-DHAP in the CORAL study, 9–10% of patients failed stem cell mobilization, whereas following R-GDP or R-DHAP in the NCIC LY12 study, 12% and 18% of patients, respectively, failed to collect >2 million CD34+ cells/kg.

Similar to the many negative studies comparing front-line CHOP to other multidrug regimens, the NCIC LY12, the CORAL study, and a nonrandomized comparison of R-ESHAP to R-ICE all demonstrate that changing cytotoxic drug combinations is an ineffective strategy to improve results of salvage therapy for aNHL.1,2,8 Other strategies, there-fore, must be explored, such as high-dose salvage therapy,9,10 use of novel agents including lenalidomide, inotuzumab ozo-gamicin, or bendamustine, possibly with inhibitors of DNA damage repair such as infusional gemcitabine or bortezomib plus PARP (poly [ADP-ribose] polymerase) inhibition.

Future research should also investigate whether biomarkers

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can correctly predict which patients will benefit from conven-tional salvage chemotherapy and HDT/ASCT, and which patients should instead be offered investigational approaches described above. For example, it is known that non-germinal centre B-cell (non-GCB) DLBCL is associated with lower PFS and OS than GCB DLBCL following initial R-CHOP induction therapy. In the BioCORAL study GCB was signifi-cantly associated with a better PFS in the R-DHAP arm.11 Interestingly, HDT/ASCT outcomes are generally not asso-ciated with GCB vs non-GCB status, suggesting that non-GCB might benefit from higher-dose salvage therapy.12 Lenalido-mide has been reported to give higher response rates for relapsed non-GCB than GCB DLBCL (53% vs 9%, respec-tively).13 Bortezomib may also be a useful agent specifically for non-GCB relapsed DLBCL, based on the known NFkB activation in this subgroup. Also, assessment of Myc, Bcl-2, and p53 status may further prognosticate relapsed aNHL patients. In the BioCORAL study, the 17% of patients whose DLBCL contained Myc rearrangements had 4-year PFS rates of only 18% compared to 42% for other patients.14 These biomarkers should be evaluated in the LY12 patients. More recent technologies such as microRNA profiling and genome sequencing studies may one day shed more light on the best management approaches for these difficult disease situations.

Disclosure: Dr. Stewart reports no conflicts of interest relevant to this article.

References:1. Gisselbrecht C, Glass B, Mounier N et al. Salvage regimens with autologous trans-

plantation for relapsed large B-cell lymphoma in the rituximab era. J Clin Oncol 2010;28:4184-90.

2. Crump M, Kuruvilla J, Couban S et al. Gemcitabine, dexamethasone, cisplatin (GDP) compared to dexamethasone, cytarabine, cisplatin (DHAP) chemotherapy prior to autologous stem cell transplantation for relapsed and refractory aggressive lymphomas: final results of the randomized Phase III NCIC CTG study LY12. Blood 2012; 120: abstr 745.

3. Kewalramani T, Zelenetz AD, Nimer SD et al. Rituximab and ICE as second-line therapy before autologous stem cell transplantation for relapsed or primary refractory diffuse large B-cell lymphoma. Blood 2004;103:3684-88.

4. Vellenga E, van Putten WLJ, van’t Veer MB et al. Rituximab improves the treatment results of DHAP-VIM-DHAP and ASCT in relapsed/progressive aggressive CD20+ NHL: a prospective randomized HOVON trial. Blood 2008;111:537-43.

5. Tarella C, Zanni M, Magni M et al. Rituximab improves the efficacy of high-dose chemotherapy with autograft for high-risk follicular and diffuse large B-cell lymphoma: a multicenter Gruppo Italiano Terapie Innnovative nei Linfomi Survey. J Clin Oncol 2008;26:3166-75.

6. Moore S, Peggs K, Thomson K et al. Autologous stem cell transplantation remains beneficial for patients relapsing after R-CHOP chemotherapy and who respond to salvage chemotherapy. British Journal of Haematology 2012;156:142-3.

7. Smith SD, Bolwell BJ, Rybicki LA et al. Comparison of outcomes after auto-SCT for patients with relapsed diffuse large B-cell lymphoma according to previous therapy with rituximab. Bone Marrow Transplantation 2011;46:262-6.

8. Freyer C, George T, Price S et al. R-ICE versus R-ESHAP for salvage therapy in aggressive B-cell non-Hodgkin lymphoma. J Clin Oncol 2012;30:(suppl; abstr e18509).

9. Cortelazzo S, Rambaldi A, Rossi A, Oldani E, Ghielmini M, Benedetti F et al. Inten-sification of salvage treatment with high-dose sequential chemotherapy improves the outcome of patients with refractory or relapsed aggressive non-Hodgkin’s lymphoma. Br J Haematol 2001;114(2):333-41.

10. Henning J-W, Duan Q, Bahlis N et al. Dose-intensive cyclophosphamide, etoposide, cisplatin reinduction for relapsed/refractory aggressive non-Hodgkin lymphoma (r/r-aNHL). J Clin Oncol 2012;30 (abstr # 6548).

11. Thieblemont C, Briere J, Mounier N et al. The germinal center/activated B-cell subclassification has a prognostic impact for response to salvage therapy in relapsed/refractory diffuse large B-cell lymphoma: a bio-CORAL study. J Clin Oncol 2011;29:4079-87.

12. Costa LJ. Feldman AL. Micallef IN et al. Germinal center B (GCB) and non-GCB cell-like diffuse large B cell lymphomas have similar outcomes following autolo-gous haematopoietic stem cell transplantation. British Journal of Haematology 2008;142(3):404-12.

13. Hernandez-Ilizaliturri FJ. Deeb G. Zinzani PL et al. Higher response to lenalidomide in relapsed/refractory diffuse large B-cell lymphoma in nongerminal center B-cell-like than in germinal center B-cell-like phenotype. Cancer 2011;117(22):5058-66.

14. Cuccuini W, Briere J, Mounier N et al. MYC+ diffuse large B-cell lymphoma is not salvaged by classical R-ICE or R-DHAP followed by BEAM plus autologous stem cell transplantation. Blood 2012;119:4619-24.

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