CHEMOTERAPY, MONOCLONAL ANTİBODY, STEM CELL TRANSPLANTATION: HOW CAN WE COMBINE BEST ALL THESE MODALITIES IN THE TREATMENT OF HIGH GRADE LYMPHOMAS
Burhan FERHANOGLU, MD, Professor of Hematology
Non-Hodgkin Lymphoma (NHL) is the most prevalent hematologic malignancy all over the world. Several different subtypes are included within NHL. Diffuse large B-cell lymphoma (DLBCL) is the most common NHL histology, representing 30% of new cases annually. NHLs are composed of a clinically and pathologically heterogeneous group of lymphoproliferative malignancies, most of which are of B-cell origin. The specific clinical, morphologic, and molecular characteristics have been established by the 2008 World Health Organization (WHO) Classification of Hematopoietic and Lymphoid Tissue to further subtype DLBCL (Table 1) (1)
Patients often present with a rapidly enlarging mass in a lymphatic region. Extranodal involvement or constitutional symptoms are uncommon.
The ability to cure patients with DLBCL improved dramatically in the past 40 years.
Predicting the Treatment Outcome
The prognosis varies among DLBCL patients. Overall survival rates with the standart therapy in the rituximab era range from 30% to 50% over 5 years for all patients with DLBCL, indicating that there is a clinical spectrum of sensitivity to the standard R-CHOP treatment.
The International Prognostic Index (IPI) was developed to predict response, based on a retrospective analysis of more than 2000 patients with aggressive lymphomas. Two major modifications to the IPI have been implemented over time and have been validated in rituximab era: the age-adjusted model for patients aged 60 and younger and revised IPI that consolidates five prognostic risk into-three-tumor stage, performance status and LDH level (2, 3). Although IPI has been accepted into the standard practice, the revised IPI is being still assessed in large prospective trials and has not yet been completely established for daily practice.
In our series based on the cohort consisted of newly diagnosed 312 DLBCL patients with a median age of 52, two third of the patients had IPI scores of 2 or less. Bulky mass at the diagnosis (lymph node mass > 5cm) was present in 129 (42%) patients. Fifty-four and 258 patients received CHOP and rituximab added to CHOP based treatments, respectively. Rituximab was found to increase the 3- and 5-year overall survival (OS) rates from 71% to 77.3% and %67 to 74.5%, respectively (p=0.264). Rituximab significantly improved the 3- and 5-year progression free survival (PFS) rates (41% vs. 70% and 36% vs.65%, respectively; p<0.001). The cell of origin data was available in 190 patients. The mortality rate was found significantly lower in the germinal center B cell (GC) subgroup (p=0.023). The 3-year OS rates in GC and non-GC subgroups were 79% and 64%, respectively. The 3- and 5- year overall survival rates were significantly better in GC group (p=0.014). The difference was independent of rituximab usage (p=0.007). In multivariate analysis all IPI parameters except extranodal involvement were significantly associated with prognosis (study in the process of submission to scientific journal).
Fig 1 and 2
In 2002, Rosenwald et al. reported that DNA expression analysis in 160 patients identified three distinct subtypes of DLBCL: 1) Germinal Center B-celltype (GCB), 2) activated B-cell type (ABC) and 3) Type 3 DLBCL. The outcome of patients with GCB vs nonGCB subtypes were statistically different; 59 vs 30% (4). Hans et al. proposed a small set of immunohistochemical markers including CD10, bcl-6, and MUM1 that demonstrated an 80% concordance to DNA expression analysis (5).
Recently published data on DLBCL recognized a new biological model based on nongerminal center B-cell-like subtype, SPARC (secreted protein, acidic, and rich in cysteine) <5%, and microvascular density quartile 4. This new model delineates two groups of patients 1 with low biologic score (0-1), and good survival and other with a high score (2-3) and poor survival (Figure 3) (6).
Current Treatment Strategies
If left untreated, DLBCL has a median survival of less than 1 year (7, 8, 9). Prior to rituximab era, anthracycline based chemotherapy regimens alongside involved field irradiation formed the basis of treatment. The introduction of the chimeric monoclonal antiCD20 antibody rituximab a decade ago was a milestone in the treatment of B-cell lymphomas including DLBCL, greatly improving progression free and overall survival (10, 11, 12).
A) Localized DLBCL
In patients with ‘limited stage disease’ (generally defined as stage I or non-bulky stage II disease), the use of abbreviated chemotherapy followed by involved field radiotherapy (IFRT) has been applied. The SWOG initially demonstrated that three cycles of CHOP followed by IFRT was superior to eight cycles of CHOP but the initial superiority of the combined approach disappeared with longer follow-up. There are few to no formal prospective evaluations of the efficacy of the multimodal therapy in the rituximab era. A new study conducted by the SWOG showed that the addition of four cycles of rituximab in combination with IFRT resulted even higher PFS and OS rates than CHOP alone (PFS;93% at 2 years and 88% at 4 years; OS: 95% at 2 years and 92% at 4 years. However, in this trial a continuing pattern of relapse without a plateau in either PFS or OS curves was noted, suggesting that the abbreviated immunochemotherapy regimen may have failed to eradicate the malignant clone (13).
Recently, Sehn et al. presented data from 134 patients with non-bulky, limited stage I and II disease using PET-based approach to tailor therapy: patients with negative PET scan (n:103) following three cycles of R-CHOP received only one additional cycle of R-CHOP, whereas PET-positive patients received IFRT. After median follow-up of 30 months, seven of 103 patients have relapsed and three year OS was 86%. However, in the group of patients with a positive PET scan after three cycles of R-CHOP, treatment with IFRT was unsatisfactory with high (9/30 patients) distant relapse rates (7). The result from this investigation suggested that in those with localized disease, PET scan might be helpful to identify patients who may benefit from abbreviated chemotherapy. However, the appropriate treatment for patients with a positive PET scan after immunotherapy remains to be validated.
In our cohort, we had 108 patients with stage I or non-bulky (mass<5cm) stage II disease. In the analysis of 88 R-CHOP and 20 CHOP treated patients, the mortality was significantly higher in CHOP group (p=0.006). In this subgroup of patient, the addition of rituximab to chemotherapy resulted in a significant improvement of the 3- (92% vs 70%, p=0.012) and 5- year OS (90% vs 70%, p=0.012) and PFS at 3- (92% vs 74%, p<0.001) and 5-year (92% vs 65%, p<0.001) (study in the process of submission to scientific journal).
B-Advanced stage DLBCL and elderly patients
Groupe d’Etudes des Lymphomes de l’Adulte (GELA) conducted phase III study comparing eight cycles of R-CHOP versus eight cycles of CHOP alone administered every 21 days in patients over 60 years age. R-CHOP21 resulted in significantly higher CR rates (76% vs 63%). Ten year follow up showed statistically significant benefits in favor of R-CHOP in terms of PFS, OS, EFS and DFS. US intergroup study and RICOVER-60 trial also confirmed the benefit of R-CHOP 14 in elderly patients (14).
Although the RICOVER-60 trial was based on a dose dense R-CHOP regimen (15), the superiority of R-CHOP14 versus the standard R-CHOP21 regimen still lacks formal clinical validation. Surprisingly data from a trial from the UK NCRI did not indicate the superiority of dose dense R-CHOP (16, 17).
Within our cohort, we had 80 patients who were older than 60 years and who had stage 2 or 3 or 4 disease. Seventy patients had R-CHOP and 10 received CHOP. The CHOP group was too small to perform subgroup analysis. The overall survival rate in our older population was 59% at three and 49% at five years. The progression free survival rates were 67% and 51% at three and five years, respectively (study in the process of submission to scientific journal).
C-Young, low-risk patients (18-60 years)
In the MInT trial, a total of 824 patients aged 18-60 years with 0-1 risk factors according to aaIPI were randomized to six cycles of CHOP or CHOP like chemotherapy with or without rituximab followed by radiotherapy for bulky and extranodal sites. In a recent update, the improvement in PFS (79.9 vs 63.8%; p<0.0001) and OS (89.8% vs 80%; p=0.001) for immunotherapy was maintained after a median follow-up of 70 months (18).
In our cohort of 312 DLBCL patients, we ran a subgroup analysis and compared our data to that of MinT trial. We included all low risk patients from our cohort that met the patient inclusion criteria of the MinT trial. One-hundred and twenty-eight patients entered the analysis. Of those 22 were treated with CHOP and 106 received R-CHOP. In this subgroup of patient addition of rituximab to chemotherapy resulted in a significant improvement in the early OS (78% vs 73%, p=0.048) and PFS (82% vs 54%, p<0.001) rates, though lower than the rates reported in the original study (study in the process of submission to scientific journal).
D- Young, high-risk patients
There is currently no consensus on the optimal treatment for younger patients with unfavorable aaIPI scores (aaIPI 2-3).
In our cohort, we performed a subgroup analysis by including young patients (age ≤ 60 years) with aaIPI scores of 2-3. A total of 71 patients with the aforementioned characteristics were identified in the cohort. The 3- and 5-year OS and PFS rates were higher than the elderly population with same IPI scores but no significant difference could be demonstrated between CHOP and R-CHOP treatment groups (OS at 3 years: 71% vs 77% and at 5 years 67% vs 75% p=0.532, PFS at 3 years 55% vs 81% and at 5 years 47% vs 76% p=0.234) (study in the process of submission to scientific journal).
In a recent population based study from Danish Lymphoma study group, the R-CHOEP14 regimen was compared with R-CHOP14 in young high risk patients with 2-3 risk factors according to the aaIPI (4 year OS 75% vs 62% p=0.04 respectively) (19).
To assess the clinical outcome and influence of various biomarkers in a group of patients treated with dose adjusted R-EPOCH, the CALGB is investigating germinal center B-cell (GCB) and post-GCB subtypes by immunohistochemistry (20). The combination of R-CHOP with bortezomib is being tested in those with the ABC subtype (21).
Compared with standard R-CHOP, intensified immunochemotherapy with ACVBP significantly improves survival in DLBCL patients aged 18 to 59 year-old with low-intermediate IPI score. Hematologic toxicity of intensive regimen was found to be increased (22).
One of the most extensively debated issues in the high risk young DLBCL is the role of up-front high dose chemotherapy (HDT) followed by autologous stem cell transplantation (ASCT). A meta analysis of 15 randomized controlled trials failed to demonstrate a clear benefit for HDT with ASCT as first-line therapy (23).
Recently, the results of four randomized trials incorporating rituximab have been presented. In the GOELAMS075 trial, eight cycles of R-CHOP14 resulted in a similar three year PFS/DFS compared to rituximab plus HDT (76% vs 83% respectively, for both treatment arms) but CHOP-14 was better tolerated (24).
In the DSHNHL Phase III trial including young high-risk DLBCL patients with 2-3 risk factors according to aaIPI; HDT with MegaCHOEP14 followed by ASCT was no more effective than eight cycles of R-CHOEP14 but was associated with a much higher incidence of infections .Overall, the R-CHOEP14 regimen resulted in an excellent PFS (73.7%) and OS (84.6) in this poor-prognosis population (25).
In contrast, HDT followed by ASCT after four cycles of R-CHOP14 or R-MegaCHOEP resulted in a superior 2 year PFS compared to the pooled population of standard R-CHOP14 or R-MegaCHOEP14 in the DLC04 trial conducted by the FIL. So far, this advantage has not been resulted into an OS benefit and longer follow-up data is needed to clarify the role of HDT (26).
Finally, the results of SWOG S9704 (U.S/Canadian Intergroup trial) have recently been presented. In this study, after induction therapy with five cycles of CHOP21 (with or without rituximab) were randomly assigned to either three additional cycles of CHOP (+/-R) or one additional cycle of CHOP followed by HDT with ASCT. Two year PFS was 69 vs 56 respectively (p=0.005) in favor of HDT over conventional therapy. However there was no difference in OS (p=0.32). The majority of clinical benefits occurred in the high risk group (aaIPI=3) (27).
According to current ESMO guidelines these new regimens still remain experimental.
E-Treatment of relapsed disease
In 1991, the Parma international trial demonstrated that lymphoma patients with relapsed or refractory disease could be induced a durable remission after high-dose chemotherapy followed by autologous stem cell rescue (20). Twenty percent of the patients who entered the pilot study are long-term survivors without disease progression. Further prospective studies have validated these data by demonstrating that approximately 50% of patients undergoing transplant achieved a durable remission after 3 years. Thus, hematopoietic stem cell transplantation (HSCT) is the only option for a durable remission at this point for patients with relapsed or refractory DLBCL. In many cases, HSCT availability is limited by patients’ age, treatment related morbidities and poor performance status (28, 29).
The clinical impact of relapsing disease has been re-evaluated in the rituximab era. The high efficacy of R-CHOP as a first-line therapy has led to a smaller proportion of relapses, but those who relapsed presented a significant clinical challenge. The choice of salvage therapy in patients who failed first-line therapy was explored in the phase III CORAL trial (30). A total of 396 relapsing DLBCL patients were randomized to receive three courses of either R-ICE or R-DHAP salvage therapy; responders were given HDT and autologous SCT. No significant differences were indicated between R-ICE and R-DHAP in terms of overall response rate, three-year PFS and OS. Multivariate analysis revealed three main factors that influenced OS; second-line aaIPI ≥ 2, relapse occurring The following table summarizes the chemotherapy regimens applied to the patients who are candidates and who are not candidates for HSCT (32).
Allogeneic SCT is being explored as an alternative in the subset of patients who relapsed after first-line therapy and who did not respond to salvage regimens. In general this treatment is preserved only for refractory disease, or failed autologous SCT. Although some studies have shown lower relapse rates and better survival outcomes with allogeneic compared to autologous SCT, the high treatment related mortality renders this option less preferable (33). Recently, the use of reduced-intensity conditioning regimens has shown promising results (34).
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