7. Treatment

Treatment for DLBCL includes chemo-immunotherapy with an anthracycline backbone. Options differ for patients with limited vs. advanced disease.

remained the standard of care for two decades until the introduction of first monoclonal antibody Rituximab which improved the OS by 10–15%. In the landmark GELA trial, 399 DLBCL patients 60–80 years old were randomly assigned to receive either 8 cycles of CHOP every 3 weeks vs. 8 cycles of CHOP plus rituximab every 3 weeks. There was an improvement in all endpoints including complete response rate, event-free and overall survival without significant increase in toxicity. R-CHOP became the standard of care [66]. (Table 4). Recent follow up of the study reported 10 year OS of 43.5%. The Mabthera International trial (MlnT) studied R-CHOP for 6 cycles vs. CHOP for 6 cycles in young patients 18–60 years who had IPI score of 0 or 1, advanced disease or stage I bulky disease. The EFS was 79 vs. 58% and OS of 93 vs. 84% which established 6 cycles of R-CHOP as the standard of care in advanced stage disease. Eight cycles of R-CHOP 21 has not been compared with 6 cycles of R-CHOP 21, 6

Recent Advances in Diffuse Large B Cell Lymphoma http://dx.doi.org/10.5772/intechopen.74263 55

An attempt to intensify R-CHOP-21 by giving it every 14 days in a dose dense manner has been tried in several trials. The first trial by Cunningham et al. assigned 1080 patients to R-CHOP 21 8 or R-CHOP 14 6 along with two more infusions of rituximab along with G-CSF support. There was no significant improvement in OS and PFS [67]. Another study, LNH03-6B also showed no difference in EFS in elderly patients treated with R-CHOP-14. R-

Maintenance Rituximab has shown some benefit in some subtypes of lymphoma. This was tested in ECOG intergroup 4494 study comparing CHOP vs. R-CHOP in elderly patients. Patient who had a CR had a second randomization to maintenance rituximab every 6 months for 2 years vs. no maintenance. There was no difference in OS or PFS. The maintenance was only useful in patients who did not receive it during induction. Based on these results, there is

High-dose therapy with autologous stem cell rescue (HDT/ASCR) has shown significant improvement in OS and PFS in pre-rituximab era [69, 70]. However in the era of chemoimmunotherapy with addition of rituximab to chemotherapy, the indication for HDT/ASCR has significantly become limited with many studies showing no statistical significant advantage of proceeding to transplant in first remission except may be in patients with high risk

Conventionally, very elderly patients are not considered candidates for aggressive therapy for various reasons. This population is not represented well in the clinical trials that form the basis for standard treatment. To address this issue GELA study group undertook a phase II study where 149 patients age 80 years and above were administered reduced dose CHOP with conventional dose rituximab (so-called R-mini-CHOP). The extended follow up from this study revealed 4-year OS and PFS rates of 49 and 41% with neutropenia being most frequent

cycles is recommended in most patients (NCCN guidelines).

CHOP-21 has thus remained the standard of care.

7.3. Role of transplant

7.4. Treatment in the elderly

score [71, 72].

no role for maintenance Rituximab in DLBCL therapy [68].

#### 7.1. Initial treatment of limited stage DLBCL

Limited stage DLBCL which is usually Ann Arbor stage I or II ( usually non-bulky stage II which may be included in one irradiation field) accounts for 30-40% of patients with DLBCL. Combined modality therapy is considered the standard of care for these patients. This was initially established by a large randomized SWOG 8736 trial which was conducted in the prerituximab era. The trial compared 3 cycles of CHOP plus RT (radiotherapy) vs. 8 cycles of CHOP alone in localized stage IE, non-bulky stage IIE aggressive lymphoma. The PFS for patients receiving CHOP plus RT and for patients receiving CHOP alone were 77 and 64%, p = 0.03, respectively. The 5 year OS for patients receiving CHOP plus RT vs. CHOP alone were 82 and 72%, p = 0.02, respectively [61]. However, further follow up showed that the advantage negated. Patients with RT had more late relapses while patients with CHOP alone had increased toxicity. Addition of rituximab to combination chemo showed improved responses in patients with early stage disease. In a multicenter randomized clinical trial, MInT, which comprised of atleast 2/3rd early stage patients, 3-year event-free survival (EFS) in R-Chemo arm (79% [95% CI 75–83]) was higher as compared to chemo alone arm (59% [54–64]) and 3 year overall survival (OS) in R-chemo arm was also higher than the chemo alone arm (93 vs. 84%) [62]. The SWOG S0014 study [63] was a phase II study where patients with limited stage disease and at least 1 adverse feature, based on stage modified-IPI were given rituximab with 3 cycles of CHOP followed by involved field radiation therapy (IFRT). The study showed 2-year PFS of 93% and 4 years PFS of 88%. OS was 95% at 2 years and 93% at 4 years. These results were better than SWOG 8736 trial where CHOP+ RT without rituximab was given. R-CHOP 3 followed by RT remains the standard of care for patients with limited stage non-bulky disease while R-CHOP 6 cycles with or without RT remains the standard for patients with limited stage bulky disease (NCCN guidelines).

#### 7.2. Initial treatment of advanced stage DLBCL

60–70% of patients present with advanced disease. R-CHOP every 21 days is the standard of care for this group of patients. About 60% of patients are cured with this approach. The beginnings of modern chemotherapy dates back to the use of nitrogen mustard with remarkable tumor response in a patient at Yale in 1942. The initial use of Adriamycin containing drug combinations (CHOP) was reported in 1979 by Miller et al. in 45 patients with localized NHL [61]. In Phase III trials, a complete remission (CR) rate was 53% and the survival rate was 30% after 12 years of follow up [64]. Several intense regimens such as m-BACOD; proMACe-CytaBOM and MACOP-B were investigated to improve on the results of CHOP. SWOG and ECOG did a prospective randomized phase III trial to compare these with CHOP and found no difference between these regimens but higher toxicity with the intense regimens [65]. It remained the standard of care for two decades until the introduction of first monoclonal antibody Rituximab which improved the OS by 10–15%. In the landmark GELA trial, 399 DLBCL patients 60–80 years old were randomly assigned to receive either 8 cycles of CHOP every 3 weeks vs. 8 cycles of CHOP plus rituximab every 3 weeks. There was an improvement in all endpoints including complete response rate, event-free and overall survival without significant increase in toxicity. R-CHOP became the standard of care [66]. (Table 4). Recent follow up of the study reported 10 year OS of 43.5%. The Mabthera International trial (MlnT) studied R-CHOP for 6 cycles vs. CHOP for 6 cycles in young patients 18–60 years who had IPI score of 0 or 1, advanced disease or stage I bulky disease. The EFS was 79 vs. 58% and OS of 93 vs. 84% which established 6 cycles of R-CHOP as the standard of care in advanced stage disease. Eight cycles of R-CHOP 21 has not been compared with 6 cycles of R-CHOP 21, 6 cycles is recommended in most patients (NCCN guidelines).

An attempt to intensify R-CHOP-21 by giving it every 14 days in a dose dense manner has been tried in several trials. The first trial by Cunningham et al. assigned 1080 patients to R-CHOP 21 8 or R-CHOP 14 6 along with two more infusions of rituximab along with G-CSF support. There was no significant improvement in OS and PFS [67]. Another study, LNH03-6B also showed no difference in EFS in elderly patients treated with R-CHOP-14. R-CHOP-21 has thus remained the standard of care.

Maintenance Rituximab has shown some benefit in some subtypes of lymphoma. This was tested in ECOG intergroup 4494 study comparing CHOP vs. R-CHOP in elderly patients. Patient who had a CR had a second randomization to maintenance rituximab every 6 months for 2 years vs. no maintenance. There was no difference in OS or PFS. The maintenance was only useful in patients who did not receive it during induction. Based on these results, there is no role for maintenance Rituximab in DLBCL therapy [68].
