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Treatment: First-Line Strategy

Chapter 09 - Diffuse Large B-Cell Lymphoma in the Elderly: R-CHOP or Adapted Strategy?

Therapeutic decisions in elderly patients should be based on the aaIPI score and a CGA. Many of these patients present with a good PS, allowing the administration of standard-dose chemotherapy regimens. Several studies agree that, with an optimal treatment strategy, elderly patients can have a similar outcome to younger patients. There is now a consensus that most patients, in the absence of specific contraindications and regardless of their age, should be treated with regimens that include anthracyclines. Active supportive care, such as nutrition, neutropaenia prophylaxis, and, if absolutely necessary, reduced dose intensity, should always be combined with chemotherapy.

Treatment of Fit Elderly Patients with Localised DLBCL

In the population of elderly patients with localised disease and no adverse prognostic factors (aaIPI = 0), the question of radiotherapy efficacy has been raised in a randomised trial performed by GELA (Groupe d’Etudes des Lymphomes de l’Adulte). The results did not show any benefit of adding radiotherapy to the CHOP regimen for these patients (Bonnet et al, 2007).

In the immunochemotherapy era and based on results from a phase III prospective trial, 6 cycles of R-CHOP every 3 weeks is the recommended regimen. Central nervous system (CNS) prophylaxis is not recommended and lumbar puncture can be stopped after a normal initial evaluation.

Treatment of Fit Elderly Patients with Poor-Risk Disease

In 1998, GELA conducted the first phase III study that randomised fit elderly patients (i.e. 60 to 80 years, median 70 years) with stage II to IV disease to receive either 8 cycles of CHOP or rituximab plus 8 cycles of CHOP. The trial successfully showed that the R-CHOP regimen improved complete response (Cr) rate, progression-free survival (PFS) and overall survival (OS), with a benefit still present after 10 years. Additional phase III studies confirmed these results, without any increase in benefit shown for R-CHOP every 2 weeks compared to every 3 weeks. 

A phase II study of lenalidomide plus R-CHOP conducted by the Fondazione Italiana Linfomi (FIL) in patients 60 to 80 years with diagnosed and untreated AA stage II-IV DLBCL showed an overall response (OR) of 92% and a CR of 86% without grade 4 haematological toxicities or toxic deaths. These results have been confirmed by another study carried out at the Mayo Clinic.

Maintenance strategies have also been evaluated in this population of patients. Rituximab maintenance did not show any benefit. However, it might improve outcome in the subgroup of male elderly patients, as shown in the NHL13 study. A maintenance strategy with lenalidomide is currently being evaluated in the LYSA REMARC trial (NCT01122472).

If there is no initial CNS involvement, prophylaxis should be reserved for patients with high risk of CNS relapse (those who present with aaIPI>1) or special localisation (vertebra, testis or breast, cavum, sinus and ethmoid).

Treatment with a Regimen Adapted to the CGA

Few studies have investigated the results of adapting the treatment strategy according to the outcome of an initial evaluation including a CGA.
An Intergruppo Italiano Lymphoma (IIL) prospective study of 100 patients (aged ≥70 years) aimed to evaluate the feasibility of chemotherapy dose modulation based on ADL and IADL scales, evaluated by a CGA (Spina et al, 2012). Treatment resulted in a CR rate of 81%, and OS was 60% at 5 years. Overall, this study showed that chemotherapy dose modulation based on a CGA is associated with manageable toxicity and excellent outcomes in elderly patients with DLBCL. Results from other studies underlined the fact that frail patients who received less intensive regimens have a poorer outcome. The benefits of adapting treatment regimens according to the outcomes of a CGA are difficult to evaluate as the different studies included a variable, and frequently low, number of frail patients. Therefore, dose modification conditions cannot yet be standardised.

Very Elderly Patients (> 80 years)

This population is the one with the most important unmet medical need. A retrospective analysis in 278 patients aged over 80 years with NHL from the GELA group reported a similar clinical and biological presentation as observed in younger patients but huge differences in terms of disease management, with only 32% of patients treated with anthracyclines. Comorbidities were found in 87% of patients, but only 14% had a high Charlson Index. The decision to not treat the patient relied on a subjective estimation of physiological age in 19% of cases. The median OS was 2.2 years and NHL remained as the main cause of death. In multivariate analysis, the presence of comorbidities was not a relevant Prognostic factor.

GELA conducted the first prospective phase II trial in patients older than 80 years with DLBCL using an attenuated regimen containing an anthracycline and rituximab: R-miniCHOP (doses of doxorubicin, vincristine, and cyclophosphamide reduced by 50%). The study included 150 patients with a median age of 83 years. Two-year PFS and OS were 47% and 59%, respectively, with 20% of deaths related to toxicities and 60% to lymphoma. The full planned dose regimen was administered to 72% of patients. Serum albumin level was the strongest prognostic factor for survival.

The same group recently published a retrospective analysis of lymphoma occurring in patients over 90 years of age. The median age was 92 years and more than 80% had DLBCL. The OS in patients who received a systemic treatment (57%) was longer compared to untreated patients in the group of patients with aggressive lymphoma but not for indolent lymphoma. Low albumin level was a strong prognostic factor.

Based on these different studies, R-miniCHOP without CNS prophylaxis is the standard of care for very elderly patients. An initial prephase with prednisone or vincristine may be considered.

Different studies have evaluated the efficacy of regimens with a reduced dose intensity (described in Table below). These regimens show acceptable results for the very elderly or for frail elderly with comorbidities, although the evaluation of the studies is not easy as they included different percentages of frail patients and very elderly patients.

Prospective studies with a reduced dose intensity in the rituximab era

StudyNAgeRegimenRDICREFSOS
Peyrade
 (2011)
14983 (80-95)R-miniCHOPDoxorubicin 50%
Endoxan 53%
63%2y 47%2y 59%
Spina
 (2012)
10075 (70-89)RCHOPFit 100%
 Frail 75%
 unfit 50%
70-80y: 83%
 >80y: 80%
5y 60%5y 80%
Olivieri
 (2012)
9174 (65-92)RCHOP
 RCDOP
 miniCHOP
Fit RCHOP 100%
 Comorbidities:
    RCDOP, LD 40%
 Frail:
   Endoxan 50%
   Doxorubicine50%
   Vincristine 40%
81%
 64%
 
 50%
2y 72 %
 2y 65%
 
 2y 52%
2y 70 %
 2y 48%
 
 2y 48%
Gimeno
 (2011)
3576 (61-88)RCMyOPNPLD 40%
 Vincristine 24%
69%2y 58%2y 70%
Meguro (2012)6170+R-CHOP70%75%3y 45%3y 58%
Musolino (2011)2377 (70-90)DA-POCH-RDoxorubicin and endoxan 20% based on NADIR57%3y 54%3y 56%
Shin (2012)
8560+RD-RCHOP

Endoxan 20%

Doxorubicin 60%
 Vincristine 40%

67%72%83%
Merli (2012)22472 (64-86)RminiCEOP vs
 RCHOP
Epirubicin, vinblastine 0%68%
 
 73%
5y 46%
 
 5y 48%
5y 66%
 
 5y 68%

RDI: % of reduced dose intensity
CR, complete response; EFS, event-free survival; OS, overall survival
CHOP, cyclophosphamide, doxorubicin, vincristine, and prednisone
RCHOP, rituximab plus CHOP
RCDOP: doxorubicin replaced by pegylated liposomal doxorubicin (LD) at 30 mg/m2
R-miniCEOP: cyclophosphamide, epirubicin, vinblastine, prednisone, rituximab
RCMyOP: intermediate dose of non-pegylated liposomal doxorubicin
R-miniCHOP, doses of doxorubicin, vincristine, and cyclophosphamide reduced by 50% compared with RCHOP
NPLD, non-pegylated liposomal doxorubicin
DA-POCH-R, rituximab plus dose-adjusted infusional CHOP
RD-RCHOP, reduced-dose CHOP plus rituximab

Treatment of Patients with a Contraindication to Anthracyclines

The main contraindication to anthracyclines is cardiac dysfunction (LVEF<50%). A recent American study from the SEER medicare database suggests that elderly patients with DLBCL and contraindication to anthracyclines can be efficiently treated.

A non-pegylated liposomal doxorubicin may be an option in this patient population, as it seems to induce less cardiotoxicity than doxorubicin. A recent Italian phase II study evaluated the R-COMP regimen, in which doxorubicin is replaced by non-pegylated liposomal-encapsulated doxorubicin (NPLD) in untreated elderly patients with poor-risk DLBCL and moderate to high 'life threat' impact NIA/NCI cardiac comorbidity. Results were similar or slightly inferior to those obtained with R-CHOP in the study by Coiffier et al: the CR rate was 68% compared to 76%. Cardiotoxicity was not prevented: the incidence of cardiac events was 17%, making this drug less appealing.

Other analogues of doxorubicin, such as piparubicin, have also been evaluated, although no differences in outcome were observed in these studies. These results must be taken with caution as the CR rates observed with the R-CHOP regimen were lower than in other studies.

Different chemotherapies have been tested as a replacement for doxorubicin. Doxorubicin was substituted for etoposide in the CHOP regimen in a trial by the British Columbia group. This resulted in a 5-year OS of 49%, which is certainly lower than that observed with R-CHOP but satisfying in this patient population. In this indication, bendamustine showed disappointing results in association with rituximab.

Finally, the use of dexrazoxane (an iron chelator) with anthracyclines to prevent the risk of congestive heart failure is not universally recommended due to concerns over its efficacy and safety. 

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