Dose-adjusted EPOCH plus rituximab improves the clinical outcome of young patients affected by double expressor diffuse large B-cell lymphoma

1. Cairns RA, Mak TW. Oncogenic isocitrate dehydrogenase mutations: mechanisms, models, and clinical opportunities. Cancer Discov. 2013;3:730–41. 2. Ward PS, Patel J, Wise DR, Abdel-Wahab O, Bennett BD, Coller HA, et al. The common feature of leukemia-associated IDH1 and IDH2 mutations is a neomorphic enzyme activity converting alphaketoglutarate to 2-hydroxyglutarate. Cancer Cell. 2010;17:225–34. 3. Dang L, White DW, Gross S, Bennett BD, Bittinger MA, Driggers EM, et al. Cancer-associated IDH1 mutations produce 2hydroxyglutarate. Nature. 2009;462:739–44. 4. Gross S, Cairns RA, Minden MD, Driggers EM, Bittinger MA, Jang HG, et al. Cancer-associated metabolite 2-hydroxyglutarate accumulates in acute myelogenous leukemia with isocitrate dehydrogenase 1 and 2 mutations. J Exp Med. 2010;207:339–44. 5. Figueroa ME, Abdel-Wahab O, Lu C, Ward PS, Patel J, Shih A, et al. Leukemic IDH1 and IDH2 mutations result in a hypermethylation phenotype, disrupt TET2 function, and impair hematopoietic differentiation. Cancer Cell. 2010;18:553–67. 6. Schnittger S, Haferlach C, Ulke M, Alpermann T, Kern W, Haferlach T. IDH1 mutations are detected in 6.6% of 1414 AML patients and are associated with intermediate risk karyotype and unfavorable prognosis in adults younger than 60 years and unmutated NPM1 status. Blood. 2010;116:5486–96. 7. Paschka P, Schlenk RF, Gaidzik VI, Habdank M, Kronke J, Bullinger L, et al. IDH1 and IDH2 mutations are frequent genetic alterations in acute myeloid leukemia and confer adverse prognosis in cytogenetically normal acute myeloid leukemia with NPM1 mutation without FLT3 internal tandem duplication. J Clin Oncol. 2010;28:3636–43. 8. Capper D, Zentgraf H, Balss J, Hartmann C, von Deimling A. Monoclonal antibody specific for IDH1 R132H mutation. Acta Neuropathol. 2009;118:599–601. 9. Falini B, Mecucci C, Tiacci E, Alcalay M, Rosati R, Pasqualucci L, et al. Cytoplasmic nucleophosmin in acute myelogenous leukemia with a normal karyotype. N Engl J Med. 2005;352:254–66. 10. Falini B, Martelli MP, Bolli N, Bonasso R, Ghia E, Pallotta MT, et al. Immunohistochemistry predicts nucleophosmin (NPM) mutations in acute myeloid leukemia. Blood. 2006;108:1999–2005. 11. Meggendorfer M, Cappelli LV, Walter W, Haferlach C, Kern W, Falini B, et al. IDH1R132, IDH2R140 and IDH2R172 in AML: different genetic landscapes correlate with outcome and may influence targeted treatment strategies. Leukemia. 2018;32:1249–53. 12. Lindsley RC, Mar BG, Mazzola E, Grauman PV, Shareef S, Allen SL, et al. Acute myeloid leukemia ontogeny is defined by distinct somatic mutations. Blood. 2015;125:1367–76. 13. Papaemmanuil E, Gerstung M, Bullinger L, Gaidzik VI, Paschka P, Roberts ND, et al. Genomic classification and prognosis in acute myeloid leukemia. N Engl J Med. 2016;374:2209–21. 14. DiNardo CD, Stein EM, de Botton S, Roboz GJ, Altman JK, Mims AS, et al. Durable remissions with ivosidenib in IDH1mutated relapsed or refractory AML. N Engl J Med 2018;378:2386–98.

MYC and BCL2 (double expressor, DE) with or without concomitant translocations of MYC and BCL2, and/or BCL6 genes have a dismal prognosis. In patients affected by DE DLBCL without translocations, the 5-year overall survival (OS) is~40% with R-CHOP. In high grade B-cell lymphomas [i.e., double hit (DH) or triple hit (TH) lymphomas], the median OS is~12 months [1][2][3][4][5][6]. Therefore, no standard therapy for these disease entities exists, and their optimal treatment represents an urgent unmet clinical need.
At our Institution, the DA-EPOCH-R has been adopted for all DE DLBCL patients since 2013. The present study compared the outcome of patients treated in a similar period at three different Italian institutions with DA-EPOCH-R and R-CHOP. We estimated the propensity score (PS) as a balancing score to account for the biases consistent with a non-random treatment assignment. The treatment effect in the multivariable Cox models was estimated using an inverse-probability-of-treatment-weight (IPTW) based on PS [7].
Diagnosis was performed according to the WHO classification and was reviewed by two expert hematopathologists [patients with primary mediastinal and human immunodeficiency virus-associated lymphomas or central nervous system (CNS) disease were excluded]. Immunohistochemistry analysis and FISH were performed in all patients and are detailed in Supplementary Appendix. The cut-off levels for positivity for MYC and BCL2 were ≥40% and ≥50%, respectively [8]. In this analysis, we included stages II-IV or stage I disease with an International Prognostic Index (IPI) score ≥ 1 or bulky disease. The Ethical Committees of participating centers approved the study (INT55/17). Written informed consent was obtained from all patients.
The DA-EPOCH-R regimen was administered as previously described every 21 days for 6 cycles and doseadjustment was based on blood counts between cycles [9]. R-CHOP was administered every 21 days. CNS prophylaxis with lumbar puncture or intravenous methotrexate was administered according to institutional guidelines. Disease assessment during the study was described in Supplementary Appendix.
The primary objective of the study was to compare the 2year PFS and OS in the DA-EPOCH-R and R-CHOP cohorts. Secondary objectives included comparisons of survival according to different prognostic factors (age, stage, IPI, cell of origin and cytogenetic characterization). Statistical Methods are summarized in Supplementary Appendix.
A total of 114 consecutive patients were identified for the study. Table 1  Patients in the R-CHOP group received less CNS prophylaxis compared to those treated with DA-EPOCH-R  DA-EPOCH-R dose escalation was feasible in most patients aged ≤65 years with 73% of the patients being escalated to the 3rd dose level or above (Supplementary Figure 1). In contrast, the majority of the elderly patients (≥65 years) received therapy at level 1 (11 out of 14, 78%) due to comorbidities and toxicities. Supplementary Table 1 lists the primary toxicities observed during DA-EPOCH-R. Therapy discontinuation due to adverse events occurred in two patients per arm [DA-EPOCH-R: pneumonia (Grade 5) and infection (alive in CR); R-CHOP: toxicity (Grade 5, n = 2)].
Analyses with IPTW adjustment were also performed on the entire cohort according to treatment (DA-EPOCH-R vs R-CHOP) and absence or presence of genetic lesions (DEonly including patients lacking cytogenetic alterations, vs "other" including single-hit, DH/TH or atypical DH patients [10]). The subgroup of patients with any type of cytogenetic abnormality treated with R-CHOP, had a worse 2-year PFS compared to the other subgroups (41% vs 59%, p < 0.001) (Fig. 1e).
Survival analysis of the entire study population revealed similar OS and PFS for R-CHOP and DA-EPOCH-R patients. In contrast, patients younger than 65 years achieved a 2-year PFS of 82%, which was significantly better than the PFS observed with R-CHOP. Most of the patients older than 65 years were treated with the first dose level compared to the group of younger patients who generally received level 3 or above (73% of cases) (Supplementary Figure 1). This suggests that the efficacy of the treatment in the younger population might be ascribed to the higher cumulative dose of chemotherapy received and not only to the continuous infusion of the drugs.
A possible counfounding factor in this study relates to CNS prophylaxis which varied over time. Biomarkers influencing CNS relapse risk, independently from clinical risk model (CNS-IPI), are in fact a recent acquisition. However, the observed rate of CNS relapse is in line with previous publications describing a risk of 13% and 9.7% at 2 years in patients affected by DH/TH and DE lymphomas, respectively [11,12].
In this retrospective study, possible biases between R-CHOP and DA-EPOCH-R cohorts were balanced using stabilized IPTW based on the PS in all survival analyses.
Our results indicate the potential role of DA-EPOCH-R in the treatment of DE DLBCL patients mainly because of three relevant observations: (1) treatment with DA-EPOCH-R compared to R-CHOP was associated with a significant improvement of PFS and OS in patients younger than 65 years; (2) all patients with genetic abnormalities (single translocations, atypical DH, and DH/TH) had better PFS with DA-EPOCH-R; and (3) intensification with DA-EPOCH-R was feasible and safe in young patients.
It is clear that the optimal chemo-immunotherapy for patients affected by DE DLBCL with or without gene rearrangements is still a matter of debate. However, the results observed with R-CHOP are considered unsatisfactory, and most published studies using more intensive regimens were retrospective and limited to the DH/TH subgroup [13,14]. To our knowledge, this is the first report analyzing the survival of a consecutive cohort of genetically characterized DE patients treated with DA-EPOCH-R. In addition to DH/TH lymphomas,~30-50% of patients in both cohorts exhibited single translocations or were atypical DH. We observed that DE patients carrying any genetic abnormality had a poor PFS when treated with R-CHOP while they experienced a significantly better outcome with DA-EPOCH-R. Separate survival analyses according to single cytogenetic alteration or combining age and cytogenetic alterations were not possible because of the limited number of patients in each subgroup. It is true that the median follow-up for DA-EPOCH-R (20 months) cohort is shorter than R-CHOP (49 months), but recent studies showed that PFS at 24 months is a valuable surrogate end-point for OS in DLBCL patients [15]. The 2-year PFS following DA-EPOCH-R in younger patients is promising, but a prospective trial is required to confirm these findings.
In conclusion, the DA-EPOCH-R regimen is feasible in patients up to 79 years of age, but the advantage of using an intensive regimen is likely related to the dose escalation. The results of the present study suggest that intensive chemotherapy, such as DA-EPOCH-R, should be considered for patients with DE DLBCL aged less than 65 years.