Diffuse large B-cell non-Hodgkin lymphomas: treatment paradigms and unmet medical needs





Philippe SOLAL-CELIGNY MD, PhD
Institut de Cancérologie de l’Ouest
Nantes/Angers
FRANCE

Diffuse large B-cell non-Hodgkin lymphomas: treatment paradigms and unmet medical needs


by P. Solal-Celigny, France



Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of non-Hodgkin lymphomas. Recently, molecular studies have revealed some DLBCL subtypes that have distinct clinical courses, responses to treatment, and prognoses. DLBCL is associated with an aggressive natural medical history, but the combination of chemotherapy—eg, CHOP regimen (cyclophosphamide, hydroxydaunorubicin, vincristine [Oncovin], and prednisone)— with anti-CD20 monoclonal antibody therapy has greatly improved the outcome of the disease and has enabled approximately 70% of patients to be cured. However, substantial progress is still required, particularly for relapsed/refractory disease and in the frontline treatment of elderly and frail patients. Future approaches to DLBCL treatment will rely on new cytotoxic drugs with a high efficacy/toxicity ratio and therapies directed against the targets identified by the new genetic subclassification of DLBCL.

Medicographia. 2015;37:263-270 (see French abstract on page 270)



Diffuse large B-cell lymphoma (DLBCL) is the most common type of non- Hodgkin lymphomas (NHL) in the world and accounts for 30%-35% of all cases of adult NHL. The annual incidence of DLBCL is approximately 5 to 7 new cases/100 000 in Europe, Australia, and North and South America. DLBCL occurs more commonly in middle-aged or elderly patients, with the median age at diagnosis being 60-70 years. The incidence rises from 2 cases per 100 000 at 20- 24 years of age to 45 per 100 000 by 60-64 years and 112 per 100 000 at over 80 years of age.1 DLBCL is slightly more frequent in males than in females. According to the 2008 World Health Organization (WHO) classification of lymphomas, more than 15 subgroups of DLBCL have been distinguished based on morphologic, immunophenotypic, molecular, clinical, and evolutive characteristics.2 Modern treatment approaches—whose mainstay is a combination of chemotherapy and rituximab anti- CD20 monoclonal antibody therapy—enables approximately 70% of patients to be cured. Despite this remarkable progress in improving patient survival, clinical outcomes remain unsatisfactory for certain subsets of patients. This review outlines the current treatment strategies for DLBCL and discusses the main issues that affect clinical practice




Prognostic factors

Clinical prognostic factors
The International Prognostic Index (IPI) proposed more than 20 years ago includes 5 parameters that have an adverse influence on outcome, as well as at initial pres- entation and at relapse: age >60 years, performance status >1, Ann Arbor stage III-IV, number of extranodal involvement site(s) >1, and serum lactate dehydrogenase (LDH) level above normal, with 1 point given for each factor.3,4 Four risk groups have been identified: low (0-1 factor), low-intermediate (2 factors), high-intermediate (3 factors) and high risk (>3 factors), with 5-year overall survival (OS) ranging from 73% to 26% in the initial report carried out on patients treated with anthracycline- based chemotherapy only. A simplified score, the denominated age-adapted IPI (aaIPI), has been proposed for patients who are less than 60 years of age and relies on 3 parameters: an above-normal serum LDH level, Ann Arbor stage III-IV, and ECOG (Eastern Cooperative Oncology Group) performance status >1. The aaIPI stratifies patients into 4 discrete groups utilizing these parameters to elicit a score from 0 to 3 for adverse factors. It has also been validated in patients >60 years. Although constructed and validated in the pre-rituximab era, the validity of the IPI was also confirmed in patients treated with rituximab plus chemotherapy. For patients treated with a combination of chemotherapy and rituximab, a revised IPI (R-IPI) was proposed by redistributing the IPI factors into 3 prognostic subgroups: “very good” group (0 factors), “good” (1 or 2 factors) and “poor” (3 factors).5 The range of outcomes has narrowed substantially and all risk groups have at least a 50% chance of being cured. However, the IPI, whether in its initial or revised form, has only a limited ability to identify a subgroup with substantially poor outcome. Currently, the original IPI/aaIPI and the R-IPI remain the prospectively designed and validated measures for assessing DLBCL risk.

However, clinical indices are surrogate markers for underlying biological differences between patients and a large number of biological tools are now proposed to evaluate the risk and predict the outcome for patients.

Molecular and genetic prognostic factors
Gene-expression profiling (GEP) identifies 3 distinct forms of DLBCL: the germinal center B-cell (GCB), activated B-cell (ABC), and primary mediastinal B-cell subtypes. Approximately 15% of cases do not fit into any of these categories. Each of these categories have distinct counterparts in the normal maturation/activation B-cell development cycle. GCBs arise from centrogerminative centroblasts. ABCs arise from proplasmablastic B-cells and have always had a poorer prognosis than DLBCL with a GCB signature, even in the rituximab era.6 The primary mediastinal B-cell subtype arises from a rare and specific thymic B cell and has genetic commonalities with the cell of origin of classical Hodgkin lymphoma. As GEP techniques are costly and cumbersome, surrogate immunohistochemistry- based algorithms have been proposed. The Hans algorithm, based on the presence of 3 markers (CD10, B-cell chronic lymphocytic leukemia/lymphoma 6 [BCL6] and melanoma associated antigen (mutated) 1 [MUM1]), is the most widely used,7 although concordance with GEP does not exceed 80%. These molecular subtypes are associated with distinct oncogenic pathways that can be exploited differentially by new, targeted therapies. These include the GC-DLBCL–expressed genes normally detected in GCB cells such as CD10, LIM domain only 2 (LMO2), and the transcriptional repressor BCL6. The pathogenetic hallmark of ABC-DLBCL is the constitutive activation of the nuclear factor κB (NF-κB) signaling pathway.

GEP studies have also identified molecular signatures related to the microenvironment that correlated with outcome independently of lymphoma-cell GEP profile. The stromal-1 signature reflects extracellular matrix deposition and tumor infiltration by macrophages and is associated with a favorable outcome. The stromal-2 signature identifies tumors with a high level of angiogenesis and a high density of blood vessels and is associated with a poorer outcome.8

B-cell chronic lymphocytic leukemia/lymphoma 2 (BCL2) is an antiapoptotic protein that plays a major role in normal Bcell development. BCL2 overexpression has been reported in approximately 50% of DLBCL cases. Overexpression of BCL2 has a negative influence on clinical outcome for the GCB subtype, but not for the ABC subtype.

MYC protein overexpression—which is a constitutive hallmark of Burkitt lymphoma and related to MYC oncogene rearrangement— has been found in 5%-10% of DLBCLs and is associated with a poor outcome. DLBCL cases that overexpress both BCL2 and MYC proteins represent 5% of DLBCL cases and have always had a dramatically poorer outcome than the others, independently of the IPI and of the cell of origin, even in the rituximab era.9

Response to treatment
Complete remission (CR) after treatment is mandatory, but not sufficient, to reach the goal of cure in DLBCL patients. Consensual criteria for defining response to treatment, often reported as the Cheson criteria, were established in 2007, revised in 2014, and have to be used in routine practice and in clinical trials.10,11 CR rates are much lower after salvage treatment for progression/relapse than after initial treatment.

Among the criteria used for assessing response to treatment, positron emission tomography (PET)-computed tomography (CT) with18 fluorodeoxyglucose (FDG) has become the imaging standard. At presentation, DLBCL cases have a high uptake rate for FDG and PET-CT is the optimal method for evaluating the extent of the disease. At the end of therapy, measuring FDG uptake is the most accurate method to evaluate treatment efficacy. Results of final PET-CT can be evaluated either by visual assessment or using a semiquantitative method based on standardized uptake value (SUV). A positive PET-CT scan at the end of treatment is highly predictive of residual or recurrent disease and is associated with an inferior progression-free survival (PFS) and OS.12 Interim PETCT after 2 cycles of chemotherapy in DLBCL patients is used by many clinicians in order to assess efficacy as soon as possible, but results are conflicting and should not influence treatment outside a clinical trial.


Figure 1
Figure 1. Frontline treatment of diffuse large B-cell lymphoma patients aged 65 years
or less (outside a clinical trial).

: R, rituximab; R-ACVBP, chemotherapy regimen containing rituximab plus Adriamycin
(doxorubicin), cyclophosphamide, vindesine, bleomycin, and prednisone; R-CHOP14, rituximab-CHOP
regimen at 14-day intervals (rituximab plus cyclophosphamide, hydroxydaunorubicin [also called doxorubicin
or Adriamycin], vincristine [Oncovin], and prednisone); R-CHOP21, rituximab-CHOP regimen at
21-day intervals; RT, radiotherapy.


Frontline treatment

If left untreated, DLBCL has a median survival of less than 1 year. For the last 40 years, anthracycline-based chemotherapy regimens formed the basis of treatment. The introduction of the chimeric monoclonal anti-CD20 antibody 15 years ago was a milestone in the treatment of DLBCL, greatly improving both PFS and OS. This improvement in outcome for patients with DLBCL treated with a modern approach is illustrated by the observational study of 1366 patients treated in British Columbia in the rituximab era (2001-2011), which shows an OS of 60% at 10 years. Since very few relapses occur after this time lag, these patients can be considered cured.13 The paradigms of the most widely used treatments in adult patients are illustrated in Figure 1 and will be further detailed.14 The main chemotherapy regimens used in DLBCL patients are shown in Table I (page 266).

Treatment of “young” patients (aged 18-65 years)
The treatment is stratified according to disease risk assessed by the IPI score. In patients with no more than 1 risk factor, 6 cycles of R-CHOP (rituximab plus cyclophosphamide, hydroxydaunorubicin [also called doxorubicin or Adriamycin], Oncovin [vincristine], and prednisone) is the mainstay of most treatment regimens. R-CHOP21 (R-CHOP, at 21-day intervals) is the most widely used treatment, but in many centers, R-CHOP14 (R-CHOP, at 14-day intervals) is used, which allows a shorter treatment duration. However, the toxicity, particularly the myeloid toxicity, of R-CHOP14 is superior to that of R-CHOP21. Two randomized studies have compared these two regimens and reached the same conclusion; namely that R-CHOP14 was not superior to R-CHOP21 in terms of response rate and PFS, despite a higher dose-intensity of chemotherapy.15,16 There is much controversy over the benefits of consolidation involved-field radiotherapy in patients with low-risk IPI (0-1) and localized disease. Radiotherapy may be proposed to patients with initial site(s) of bulky disease (ie, >5 cm) and to site(s) which remain PET-positive at the end of treatment.17 In the MInT trial (MabThera International Trial), the 6-year PFS and OS of 824 patients with 0 or 1 risk factors were respectively 80% and 89.8%.17


Table I
Table I. Main chemotherapy regimens used in diffuse large B-cell
lymphoma.

Abbreviations: AUC, area under the curve; D, day.



Treatment of “young” patients with high-intermediate–risk or high-risk IPI score with R-CHOP yields less satisfactory results with a 3-year PFS that does not exceed 50%. Several options have been tested in order to improve these results, but none of them has clearly demonstrated its superiority and a consensus is difficult to reach. Schematically, 3 treatment methods have been tested separately or in combination:
Increasing dose
Several regimens that increase doses of cytotoxic drugs have been designed. The LNH03-2B conducted by GELA (Groupe d’Etudes des Lymphomes de l’Adulte) compared 8 cycles of R-CHOP21 with a R-ACVBP regimen (rituximab plus Adriamycin [doxorubicin], cyclophosphamide, vindesine, bleomycin, and prednisone; see Table I), which is much more intense than R-CHOP, in patients with 1 risk factor according to aaIPI. Patients treated with R-ACVBP had a better 3-year eventfree survival (EFS) and OS than those treated with R-CHOP (respectively 81% vs 67% and 92% vs 84%).18 However, the severe toxicities observed in patients treated with ACVBP limited its use. Other dose-dense regimens such as the R-Mega- CHOP (R-CHOP regimen, increasing doses from cycle to cycle) have also been proposed.
Increasing the number of drugs
Addition of etoposide to the CHOP regimen improved treatment efficacy compared with CHOP in the pre-rituximab era. Conflicting results for comparisons of R-CHOP14 and RCHOEP14 (R-CHOP plus etoposide regimen, 14-day intervals) have been reported in the rituximab era. R-EPOCH (rituximab plus etoposide, prednisone, vincristine [Oncovin], cyclophosphamide, and hydroxydaunorubicin [doxorubicin]) is a regimen that combines (i) addition of etoposide, and (ii) continuous infusion of cytotoxic drugs (Table I). Preliminary results suggest that this regimen could improve treatment results in patients with DLBCL and human immunodeficiency virus (HIV) infection, or in DLBCL patients with overexpression of the MYC gene, and in DLBCL of the non-GC subtype.
Including high-dose therapy with autologous stem cell transplantation
Consolidation with high-dose therapy (HDT) and autologous stem cell transplantation (ASCT) has been tested in several randomized trials in the pre-rituximab era with contradictory results. A meta-analysis of 13 randomized trials concluded that there was no benefit in terms of OS.19 In the rituximab era, 4 randomized trials have compared a conventional chemoimmunotherapy (a dose-intense R-CHOP–like regimen) to a R chemotherapy followed by HDT and ASCT. In all of these trials, no improvement in OS in patients treated with HDT and ASCT was observed. HDT and ASCT as frontline treatment remains a potentially useful option in “young” patients with high-risk DLBCL, but is not recommended to be used outside a clinical trial.

In contrast to follicular and mantle cell lymphomas, no available maintenance treatment demonstrated efficacy in DLBCL.

The issue of prophylaxis of central nervous system (CNS) relapse remains a subject of debate. Some patients are at higher risk of CNS relapse: patients with testicular, bone marrow, or head-and-neck involvement, more than 1 extranodal involvement site, or who are in a high-risk IPI group. These patients usually receive 4 intrathecal methotrexate injections for prophylaxis although there is no demonstration of the efficacy of this treatment. Intrathecal methotrexate does not prevent parenchymal CNS relapse. Some data suggest that systemic high-dose methotrexate may be more effective in the prevention of all types of CNS relapse.20


Figure 2
Figure 2. Proposal for
a treatment scheme of
DLBCL patients aged over
65 years.

Abbreviations: CHF, congestive
heart failure; CHOP, chemotherapy
regimen containing cyclophosphamide,
hydroxydaunorubicin
[also called doxorubicin or Adriamycin],
vincristine [Oncovin], and
prednisone; NHL, non-Hodgkin
lymphoma; PDN, prednisone;
R-miniCHOP, low-dose rituximab-
CHOP regimen; R-CXOP*, R-CHOP
with substitution of doxorubicin
(hydroxydaunorubicin) with another
drug (etoposide, mitoxantrone,
gemcitabine, etc.); VCR, vincristine.



Treatment of patients aged over 65 years
Figure 2 shows a proposed treatment scheme for DLBCL patients who are over 65 years of age. Age is a major adverse prognostic factor in DLBCL. This effect is related to:
♦ Intrinsic factors of DLBCL in elderly patients, such as a greater proportion of non-GC DLBCL and a high frequency of Epstein-Barr virus (EBV)-related DLBCL, which has a poorer outcome than other de novo DLBCL.
♦ Age-related decline in renal and liver functions, with wellestablished consequences on drug metabolism and toxicity.
♦ Decrease in marrow reserve and increased risk of myelo suppression.
♦ Comorbidities whose incidence increases with age, especially in patients aged 75 years or older.
♦ Cardiovascular disease, often clinically asymptomatic, which increases the risk of anthracycline-related cardiomyopathy.

All these reasons justify a specific evaluation of DLBCL patients aged 70 years or older.21 The Comprehensive Geriatric Assessment (CGA) is an exhaustive evaluation of the medical, cognitive, socioeconomic, and psychological status of elderly patients, which provides an optimal proposal for a treatment plan and enables a supportive care program to be established in order to improve treatment tolerance.22 However, CGA takes up to 2 hours to be carried out and a far more simplified, score-dominated Geriatric 8 (G8) screening tool has recently been proposed that provides accurate detection of frail patients potentially unfit for optimal treatment and for whom a complete CGA assessment may be performed before choosing a treatment.23

An optimal frontline treatment regimen for DLBCL patients includes full-dose doxorubicin (Adriamycin), providing that the pretreatment evaluation suggests that it can be tolerated. This requires measurement of the left ventricular ejection fraction (LVEF) either by echocardiography or by multiple-gated acquisitions scanning. Only patients with an LVEF of at least 50%-55% may be able to tolerate full-dose doxorubicin (Adriamycin). Whenever feasible, R-CHOP21 is the best initial treatment, even in elderly patients.24 An initial prephase treatment with prednisone and low-dose vincristine may improve the performance status of elderly patients and enable full-dose R-CHOP immunochemotherapy to be subsequently administered.25

Several regimens have been tested in patients too frail to receive full-dose R-CHOP. In a study conducted by the LySA group (Lymphoma Study Association), carried out on 150 patients agedover 80 years, an R-CHOP regimen with decreased doses of doxorubicin (Adriamycin) and cyclophosphamide (R-miniCHOP) yielded a response rate of 73% and a median PFS of 21 months.26 Other cytotoxic drugs with low toxicity still need to be tested in this setting. Epirubicin and idarubicin have been tested and were less cardiotoxic than doxorubicin (Adriamycin) at doses used in clinical trials, but their equiva- lent antilymphoma efficacy has not been demonstrated. Pixantrone, a novel aza-anthracenedione, could play a role in the frontline treatment of elderly and/or frail DLBCL patients.27

Treatment of relapsed/refractory DLBCL

Despite overall improvements in the outcome of DLBCL, approximately 40% of patients develop relapsed/refractory (R/R) disease. Biopsy will be required in most cases of suspected R/R disease given the prognostic and therapeutic impact and the fact that some other disorders (sarcoidosis, carcinoma) may mimic R/R disease. After confirmation, patients should undergo restaging procedures.

R/R disease may be separated into 4 subgroups: (i) refractory with disease progression during treatment, which is associated with an extremely poor prognosis; (ii) partial response after treatment; (iii) early relapse, ie, relapse within 6-12 months after the end of previous treatment; (iv) late relapse with, in some cases, a more indolent histological type. In addition to these categories, the IPI at relapse has to be used to assess prognosis. It must be stated that the results of salvage treatments are poorer in patients previously treated with rituximab based immunochemotherapy in comparison with patients who are rituximab-naive. At the present time, almost all patients treated for DLBCL fall in this category.28

Firstly, it must be established whether or not the patient is eligible for HDT and ASCT.Age >70 years is a widely used threshold to rule out such a treatment. In patients aged less than 70 years, severe cardiac, pulmonary and/or liver comorbidities are contraindications to HDT. The PARMA trial (trial name not an acronym) conducted more than 20 years ago has clearly demonstrated the benefits of HDT and ASCT for patients whose relapse remains chemosensitive.29

For patients who are eligible for HDT, the first goal is to administer a non–cross-resistant salvage regimen. Although there is no clear demonstration that adding rituximab to salvage chemotherapy adds efficacy in patients previously treated with R-chemotherapy, most patients are treated with such a combination at the time of relapse. The most widely used chemotherapy regimens contain a platinum derivative: DHAP (dexamethasone, high-dose Aracytine [cytarabine], and Platinol [cisplatin]), ICE (ifosfamide, carboplatin, and etoposide) (Table I). Three to four cycles are given and stem cells are collected after the second and/or third cycle.

A PET scan is the most accurate means of evaluating chemosensitivity. In the CORAL study (COllaborative trial in Relapsed Aggressive Lymphoma),28 patients with R/R DLBCL were randomly allocated to R-ICE (rituximab plus ICE) or R-DHAP (rituximab plus DHAP). Overall, there was no difference in outcome between these 2 regimens. With R-DHAP or R-ICE, the response rate was 63% and only 50% were able to proceed to ASCT.

There is no standard conditioning regimen for ASCT in patients who have responded to salvage therapy. A combination of carmustine (BCNU), etoposide, cytarabine (Aracytine), and melphalan is the most widely used treatment. Approximately 30% of patients who are able to receive the whole procedure do not relapse. Maintenance treatment with rituximab after ASCT did not decrease the relapse rate.28

The outcome of patients who are not sensitive to salvage therapy or who relapse after HDT is very poor, with a median survival of less than 6 months. In patients less than 55-60 years of age, an allogeneic stem cell transplantation may be planned. For other patients, there is no demonstration that aggressive treatment improves survival.30 Less-intensive approaches or participation in a clinical trial are justified approaches.

The prognosis of patients who are not eligible for HDT and ASCT is also poor. After intensive salvage chemotherapy regimens such as R-DHAP or R-ICE, the relapse rate is higher than 80%. The toxicities of these regimens must be taken into account in this setting. Other regimens, such as combinations of gemcitabine and oxaliplatin have been tested, yielding a median PFS of less than 6 months.31 Monotherapy with pixantrone may be proposed to patients in second or subsequent relapse. Whenever possible, these patients should be referred for clinical trials of new drugs since treatment requirements have not been met within this context.

New therapies for DLBCL

The poor prognosis of DLBCL for patients who are not cured by frontline immunochemotherapy, as well as the increasing incidence of the disease in elderly patients who cannot be treated with conventional treatment, underline the fact that new approaches are clearly needed. The improving understanding of DLBCL subtypes with their specific signaling pathway disturbances has led to the development of new targeted drugs.32

Lenalidomide is an immunomodulatory agent that has numerous other mechanisms of action. It acts on the microenvironment, enhancing the cytotoxic activity of T and natural killer (NK) cells and decreases proliferation and angiogenesis. A clinical activity in heavily pretreated patients has been demonstrated in phase 1 and 2 trials. In a large phase 2 trial being carried out on 217 heavily pretreated patients, combinations of lenalidomide with R-CHOP or lenalidomide maintenance after R-CHOP in high-risk patients are currently being tested.

New anti-CD20 monoclonal antibodies (ofatumumab, obinutuzumab), which potentially have greater efficacy than rituximab, are under development in combination with CHOP chemotherapy. Antibody-drug conjugates combine a monoclonal antibody directed against a B-cell antigen closely linked to a cytotoxic agent. The antibody enables B cells to be tar geted specifically and, after internalization of the complex, the cytotoxic drug acts on DNA and/or microtubules. Inotuzumab ozogamicin is an antibody against CD22 conjugated with calicheamicin, a potent inhibitor of microtubule organization.

Enzastaurin is a protein-kinase Cβ inhibitor. GEP studies showed an overexpression of this kinase in relapsed DLBCL and early phase trials suggested efficacy. Unfortunately, a clinical trial of enzastaurin as a maintenance treatment in highrisk DLBCL patients who had responded to R-CHOP did not confirm efficacy in this setting.

The B-cell receptor (BCR) signaling pathway is critical to the development and maturation of normal B cells. Ibrutinib is a potent irreversible inhibitor of Bruton’s tyrosine kinase, a key kinase that plays a significant role in signal transduction in the BCR pathway. Ibrutinib has been tested in combination with R-CHOP in a phase 1b trial and has produced promising results. Bortezomib inhibits the NF-κB signaling pathway, which is constitutively activated in DLBCL of the ABC subtype. Preliminary studies have shown that bortezomib increases the response rate when combined with an R-CHOP regimen. A large phase 3 study is being conducted to evaluate the efficacy of adding bortezomib to standard immunochemotherapy in the R/R and frontline settings.

Conclusion

For over 40 years, no chemotherapy regimen has been produced having a better efficacy/toxicity than CHOP in the frontline treatment of DLBCL. In combination with rituximab, it enables approximately 70% of patients to be cured. However, unmet medical needs still exist for DLBCL, particularly in the frontline treatment of elderly and frail patients, and in the relapse setting for patients who are unfit for ASCT or who relapse afterwards. Improvements will be obtained from a better understanding of lymphomagenesis and better risk-stratification of patients taking into account molecular subtyping. A rational combination of new agents tested in well-designed clinical trials is needed.

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Keywords: chemotherapy; CHOP, DHAP; diffuse large B-cell lymphoma; EPOCH, gene-expression profiling; ICE; monoclonal antibody therapy; relapsed/refractory