Diffuse Large Cell Lymphoma Treatment & Management

Updated: Feb 07, 2016
  • Author: Shipra Gandhi, MBBS; Chief Editor: Emmanuel C Besa, MD  more...
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Treatment

Approach Considerations

Therapy for aggressive non-Hodgkin lymphoma (NHL) has evolved significantly in the last 30 years. For example, high-dose chemotherapy in the setting of stem cell/bone marrow transplantation has become a useful treatment modality in the management of diffuse large cell lymphoma.

Chemotherapy is usually given on an outpatient basis, although patients should be admitted to the hospital if a treatment complication arises. Transfer to an appropriate facility may be necessary for further diagnostic evaluation and medical or surgical interventions.

In general, the role of surgery in the treatment of diffuse large cell lymphomas is limited. Treatment of these tumors is primarily with cytotoxic agents, with or without radiation therapy. However, surgery can be helpful in obtaining tissue for diagnosis or, rarely, to palliate a complication.

A study by Kim et al determined that although the quality of life (QOL) of patients with intestinal diffuse large B-cell lymphoma who underwent surgery and chemotherapy was lower than that of patients who underwent chemotherapy alone, the difference was acceptable. [69] Thus, surgical resection followed by chemotherapy may be an effective treatment strategy for these patients.

Unless contraindicated because of significant and preexisting comorbid conditions, the treatment of diffuse large B-cell lymphoma (DLBCL) should include the use of rituximab- and anthracycline-based-multiagent chemotherapy, and the goal should be to achieve a durable complete remission (ie, cure). The treatment is subsequently tailored according to stage or bulk of disease and response to therapy. In general, the frontline management of DLBCL can be divided according to disease stage in 2 groups: localized and advance stage.

R-CHOP regimen

The cyclophosphamide, vincristine, doxorubicin, and prednisone (CHOP) regimen was among the first combinations to produce complete response rates and long-term survivors. For patients with advanced diffuse large cell lymphoma, another standard therapy exists; specifically, the addition of rituximab (Rituxan; a chimeric antibody that targets CD20+ B cells) to CHOP (R-CHOP). [70, 71, 72]

Rituximab produces a 48% response rate in patients with low-grade lymphomas [73] and has activity in diffuse large cell lymphoma.

A phase II pilot study of rituximab in combination with CHOP in patients with previously untreated diffuse large cell lymphoma or high-grade NHL reported an overall response rate of 97% (32 of 33 patients), with a 61% complete remission rate, a 36% partial remission rate, and a 3% progressive disease rate. [70] Severe adverse events were similar to those observed with CHOP alone.

In a study of 435 patients with diffuse large cell lymphoma, Villa et al found that the risk of CNS relapse was significantly reduced with the addition of rituximab to the CHOP regimen compared with risk reduction for patients treated with CHOP alone. [74] This reduction was even more evident in patients who achieved a complete response.

A study by Phan et al found that overall survival and progression-free survival were significantly improved among patients who received consolidation radiation treatment after undergoing R-CHOP therapy. [75]

A study of 215 patients treated with R-CHOP revealed improved event-free survival (EFS) in patients treated with epratuzumab plus R-CHOP (ER-CHOP). ER-CHOP is well tolerated, and these results suggest that combination therapy is promising. [76]

Récher et al compared the efficacy of R-CHOP with that of treatment consisting of rituximab added to a regimen of doxorubicin, cyclophosphamide, vindesine, bleomycin, and prednisone (R-ACVBP) and found significant improvement in survival with the R-ACVBP regimen among patients aged 18-59 years with diffuse large B-cell lymphoma and low intermediate risk. [77]

Relapse therapy

At relapse, evidence suggests that the cell of origin has a better response to rituximab, dexamethasone, high-dose cytarabine, and cisplatin (R-DHAP) than to rituximab, ifosfamide, carboplatin, and etoposide (R-ICE) in patients with germinal center B (GCB)-like diffuse large B-cell lymphoma. [44]

Venous access devices

Because multiple chemotherapy cycles are usually administered, consult a surgeon regarding implantation of a venous access device, which is helpful for chemotherapy infusions and for the repeated blood samples required to monitor treatment toxicity.

Patient monitoring

Monitor patients very carefully while they are receiving chemotherapy, which is administered every 3 weeks. Order complete blood count (CBC) and chemistries frequently for outpatient monitoring. Immediately see patients if they develop any chemotherapy-related adverse effects.

Red blood cell transfusions or erythropoietin or darbepoetin alfa (Aranesp) injections may be required for patients with persistently low hemoglobin values due to disease or chemotherapy.

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Multidisciplinary Management of Early-Stage DLBCL

Approximately 25% of diffuse large B-cell lymphoma (DLBCL) cases present as early stage. Localized DLBCL is defined as Ann Arbor stage I or II nonbulky disease, and the management of such patients requires an abbreviated course of combined systemic chemoimmunotherapy following by involved-field radiation therapy (IF-XRT). [78, 79]

A phase II study conducted by the British Columbia Cancer Agency treated 308 DLBCL patients with 3 cycles of chemotherapy followed by IF-XRT. The overall progression-free survival (PFS) and overall survival (OS) rates were 80-81% at 5 years and 63-74% at 10 years, respectively. [80]

The Southwestern Oncology Group (SWOG) study 8736 randomly assigned 401 patients with nonbulky stage I or II aggressive B-cell lymphoma to receive either 3 cycles of the cyclophosphamide, vincristine, doxorubicin, and prednisone (CHOP) regimen followed by IF-XRT at 40-50 cGy versus 8 cycles of CHOP chemotherapy alone. [81] Patients managed with CHOP followed by IF-XRT had better PFS (77% and 64%, respectively, P =.03) and OS (82% and 72%, respectively, P =.02) than patients treated with 8 cycles of CHOP. [82]

An updated analysis after 10 years of follow up showed an increased frequency of late recurrences that explained the absence of a plateau effect in the survival curve.

Radiation therapy in early-stage DLBCL

The role of radiation therapy in the management of early-stage DLBCL had been challenged by 2 studies conducted by the Groupe d'Etude des Lymphomes de l'Adulte (GELA). The first study randomized patients younger than 60 years to either 3 cycles of CHOP chemotherapy followed by IF-XRT or an intense regimen consisting of doxorubicin, cyclophosphamide, vindesine, bleomycin, and prednisone (ACVBP) for 6 cycles. [82] After a median follow-up period of 7.7 years, OS and PFS were significantly better in the group given ACVBP than in the group given CHOP plus radiotherapy. The 5-year estimates of event-free survival were 82% for patients receiving chemotherapy alone and 74% for those receiving chemotherapy/radiotherapy. The respective 5-year estimates of OS were 90% and 8%. In contrast to previous clinical trials, this study included patients with bulky disease. [83]

On the other hand, the ACVBP regimen was associated with increased chemotherapy-related toxicity and a high frequency of hospitalizations. [83] Moreover, vindesine is not commercially available in the United States. Hence, chemotherapy was considered to be superior to chemo-radiotherapy.

In the second study, DLBCL patients older than 60 years with localized disease and no International Prognostic Index (IPI) factors were randomized to 4 cycles of CHOP plus IF-XRT or chemotherapy alone with 4 cycles of CHOP. After a median follow-up of 7 years, the median OS and PFS were not significantly different between the 2 treatment arms. The 5-year estimates of event-free survival were 61% for patients receiving chemotherapy alone and 64% for patients receiving CHOP plus radiotherapy; the 5-year estimates of OS were 72% and 68%, respectively. [84]

On the other hand, the Eastern Cooperative Oncology Group (ECOG) assessed the value of radiation as a consolidation after 8 cycles of standard chemotherapy in a randomized clinical trial. The study enrolled 352 patients older than 60 years with stage I or II bulky disease, who were assigned to receive CHOP chemotherapy and randomly selected to receive IF-XRT or no further treatment as consolidation in those who achieved complete response (CR). Among the 172 CR patients, the 6-year disease-free survival rate was 73% for low-dose radiotherapy versus 56% for observation. Although improvement occurred in the estimated disease-free survival after 6 years of follow up, no significant differences were noted in OS. [24]

Rituximab in early-stage DLBCL

The use of monoclonal antibodies, particularly rituximab, has changed the treatment paradigm of patients with B-cell non-Hodgkin lymphoma, including DLBCL. Rituximab is a chimeric monoclonal antibody that targets the CD20 antigen present in normal and most of the malignant B-cells. The mechanisms by which rituximab elucidates its antitumor activity has been characterized and includes antibody-dependent cellular cytotoxicity (ADCC), complement-mediated cytotoxicity (CMC), and activation of intracellular pathways leading to apoptosis. Preclinical models have demonstrated that rituximab potentiates the effect of several chemotherapeutic agents. [85] In contrast to what has been observed in low-grade lymphomas, rituximab monotherapy has limited activity in DLBCL. [86] The addition of rituximab to standard doses of chemotherapy in DLBCL has resulted in improved clinical outcomes without adding significant toxicity.

Only a few studies addressing the role of rituximab in the management of early-stage DLBCL have been conducted. The Mabthera International Trial (MInT) was studied the role of adding rituximab to standard therapy in young patients with stage I bulky or stage II-IV DLBCL. [87] The MInT enrolled 824 young patients (ie, < 60 y) with aggressive lymphoma and good IPI score (< 1 IPI risk factor). Patients were randomized to receive 6 cycles of CHOP-like chemotherapy with or without rituximab. After a median follow-up period of 3 years, the event-free survival (EFS) and OS were improved significantly by the addition of rituximab to systemic chemotherapy. Of interest, in a subset analysis of the patients with early stage or bulky disease, the addition of IF-XRT as consolidation following chemoimmunotherapy did not improve clinical endpoints. [87]

The addition of rituximab to combined-modality treatment in DLBCL was evaluated in a Southwest Oncology Group (SWOG) study and reported by Persky et al. [88] The SWOG conducted a phase II clinical trial evaluating the addition of rituximab to an abbreviated course of CHOP chemotherapy followed by IF-XRT. The study enrolled 60 patients with limited-stage DLBCL. PFS and OS were 88% and 92%, respectively, and were considered superior to historical (chemotherapy–IF-XRT) controls, for which PFS was 78% and OS was 88%. [88] The current literature supports the addition of rituximab in the management of early-stage DLBCL to standard doses of CHOP chemotherapy.

The length of therapy and the use of radiation continue to be a subject of debate. Some clinicians strongly recommend the use of a short course (usually 3 cycles) of systemic chemoimmunotherapy followed by IF-XRT, while other physicians consider 6 cycles of rituximab in combination with CHOP equivalent and thus avoid the delayed toxicity from IF-XRT. On the other hand, it is important to stress that the multidisciplinary approach of early-stage DLBCL should be tailored according to site of disease involvement (eg, mediastinum, stomach), disease response using functional imaging, and patient comorbid conditions in an attempt to optimize the achievement of a CR that can translate into improved OS.

As the addition of rituximab to CHOP chemotherapy increases the CR, PFS, and OS of DLBCL patients, clinicians are questioning again the role of IF-XRT in the post-rituximab era. Tomita et al demonstrated that a standard strategy of 3 cycles of rituximab/CHOP (R-CHOP) followed by IF-XRT for limited-stage DLBCL could be effectively replaced by 6 cycles of R-CHOP alone. A total of 190 previously untreated patients with limited-stage DLBCL were treated with R-CHOP alone and were studied retrospectively. IF-XRT was only administered to patients achieving a CR to R-CHOP (N=5). The 5-year PFS and OS were 84% and 90, respectively. [89]

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Treatment of Advanced-Stage Disease

Historical perspective

The use of systemic chemotherapy to successfully eradicate disseminated diffuse large B-cell lymphoma (DLBCL) was first described in the early 1970s. [90, 91] After these original reports, the cyclophosphamide, vincristine, doxorubicin, and prednisone (CHOP) regimen (given every 21 days, ie, CHOP-21) became the standard of care for aggressive lymphomas in the United States.

Multiple attempts to improve survival in DLBCL patients led investigators to evaluate more intensive regimens. Fisher et al on behalf of the Southwest Oncology Group (SWOG) reported the results of a large clinical trial conducted in the United States. [92] The study compared CHOP-21 chemotherapy with 3 intense chemotherapy regimens. The study failed to demonstrate any superiority with the intense regimens tested, and CHOP-21 was found to be equivalent but less toxic. After a follow up of 6 years, the overall survival (OS) and progression-free survival (PFS) rates were not statistically significantly different between the chemotherapeutic regimens tested.

Alternative chemotherapies evaluated against CHOP

In the last decade, 2 alternative chemotherapy regimens were evaluated against standard CHOP in patients with advanced DLBCL. The Groupe d'Etude des Lymphomes de l'Adulte (GELA) compared the efficacy of doxorubicin, cyclophosphamide, vindesine, bleomycin, and prednisone (ACVBP) against CHOP-21 in 635 patients aged 61-69 years with advanced-stage DLBCL with at least one International Prognostic Index (IPI) score risk factor. [92]

While the complete response rate was similar between the 2 groups (58% vs 56%), the event-free survival (EFS) and OS rates were significantly better in patients treated with ACVBP than in those treated with CHOP-21. At 5 years of follow up, the EFS was 39% in the ACVBP groups and 29% in the CHOP-21 group (P =.005) and the OS was significantly longer for patients treated with ACVBP (46%) than patients treated with CHOP-21 (38%, P =.036). Of interest, CNS progressions or relapses were more frequent in the CHOP-21 group (P =.004). [92]

The German Study Lymphoma Group (GSLG) evaluated the concept of dose-dense in DLBCL patients. Elderly patients with DLBCL were randomized into 4 cohorts and received CHOP-21 (given every 21 days) with or without etoposide (E) or dose-dense CHOP (given every 14 days, CHOP-14) with or without etoposide. The addition of etoposide to CHOP chemotherapy did not affect the clinical end points of the study. On the other hand, the delivery of CHOP in a dose-dense schema proved superior in terms of PFS and OS with a similar toxicity profile (43.8% vs 32.5%, P =.003 and 53.3% vs 40.6%, P < .001). [93]

A subsequent study, the NHL-B1, evaluated the same regimens in young patients with advanced DLBCL. The study confirmed the value of dose-dense CHOP, and, of interest, in younger patients with DLBCL, the addition of etoposide to CHOP (CHOEP-14 or CHOEP-21) was associated with better PFS and OS when compared with CHOP-21. In spite of an increased degree of myelosuppression, these regimens were well tolerated. [94]

Rituximab in advanced-stage DLBCL

Despite the clinical superiority of CHOEP-14 and ACVBP over CHOP-21 in patients with DLBCL, the parallel development and incorporation of rituximab into standard doses of CHOP-21 has challenged the clinical value of such toxic regimens in the post-rituximab era.

Based on results from clinical trials evaluating rituximab as monotherapy in aggressive lymphomas and the results reported by Czuczuman et al in patients with follicular lymphomas, [95] a phase II study evaluating the combination of rituximab and CHOP in aggressive B-cell lymphomas was conducted by Vose et al. [70] The overall response rate (ORR) to the combination of CHOP and rituximab was 94%, with 20 of 33 patients achieving a complete response (CR). At the time of the updated publication and after a median follow-up time of 63 months, the PFS rate was 82% and the OS rate was 88%.

The landmark study validating the addition of rituximab to CHOP chemotherapy was conducted by the GELA and presented by Coiffier et al. The GELA enrolled patients with newly diagnosed aggressive B-cell lymphomas who were older than 60 years and randomized them to receive either 8 cycles of CHOP or rituximab in combination with CHOP at 21-day intervals. [96] The study included patients with stage I-IV DLBCL, and 59% had 3 or more IPI score risk factors and 80% had Ann Arbor stage III or IV disease. The addition of rituximab to CHOP chemotherapy resulted in higher response rates than CHOP alone (76% vs 63%, respectively, P =.005). PFS and OS at the interim analysis (after 18-month follow-up) were significantly better in the R-CHOP arm (P < .001 and P =.007, respectively) when compared with CHOP.

A long-term analysis of the study after 5 years of follow up confirmed the efficacy of combining rituximab with systemic chemotherapy in terms of PFS (54% vs 30%; P < .0001) and OS (58% vs 45%; P =.0004). [96, 97]

The LNH-98.5 Study was recently updated after 10 years of follow up. [98] The 10-year PFS rate following therapy with R-CHOP or CHOP was 36.5% and 20%, respectively. Moreover, the 10-year OS rate was better in R-CHOP–treated DLBCL patients (43.5%) compared with patients treated with CHOP alone (27.6%). According to this study, the addition of rituximab to CHOP showed a clear benefit

Another study conducted primarily in the United States was conducted to try to validate the results from the GELA study. Data from the Eastern Cooperative Oncology Group (ECOG) study 4944 in previously untreated elderly DLBCL patients randomized to R-CHOP versus CHOP and in responders to subsequent observation versus rituximab maintenance showed that the addition of rituximab to chemotherapy either during induction treatment or during maintenance improved the time to progression (TTP) compared with patients treated with CHOP chemotherapy alone. [99] Similar findings were found in younger patients with DLBCL with 0-1 IPI score risk factors as described above.

Pfreundschuh et al reported a statistically significant benefit by adding rituximab to CHOP or CHOP-like chemotherapy in 824 patients with DLBCL in terms of PFS and OS. [87] After a follow-up period of 3 years, patients randomized to receive chemotherapy and rituximab had higher EFS (79% vs 59%, P < .0001) and had increased OS (93% vs 84%; P =.0001) than patients assigned to chemotherapy alone.

The benefit of adding rituximab to high-intermediate and high-risk DLBCL patients younger than 60 years has not been formally studied. The use of rituximab in combination with CHOP chemotherapy in this group of patients has been extrapolated from the results of the GELA and Mabthera International Trial (MInT) studies. While the addition of rituximab to standard doses of CHOP chemotherapy has improved the outcomes of patients with DLBCL, a significant number of patients do not to respond or relapse after initial responses, stressing the need to develop novel therapeutic strategies.

To further study the role of dose-dense chemotherapy in DLBCL in the post-rituximab era, the German High-Grade Non-Hodgkin Lymphoma Study Group (DSHNHL) evaluated the benefit of adding rituximab to CHOP-14 in elderly patients with DLBCL. Pfreundschuh et al reported the results of the rituximab with CHOP over age 60 years (RICOVER-60) trial. [100]

In this study, 1222 elderly patients (aged 61-80 years) were randomized to receive either 6 or 8 cycles of CHOP-14 with or without rituximab. Involved-field radiation therapy (IF-XRT) was planned for extranodal or bulky sites. The results of this study demonstrated that the addition of rituximab to systemic chemotherapy improved the EFS and OS in DLBCL patients and that 6 cycles of chemotherapy were as effective as 8 cycles. After a 3-year period of follow up, the EFS was 47.2% after 6 cycles of CHOP-14, 53% after 8 cycles of CHOP-14, 66.5% after 6 cycles of R-CHOP-14, and 63.1% after 8 cycles of R-CHOP-14. In addition, OS after 3 years of follow up was 67% and 66% in patients treated with 6 or 8 cycles of CHOP-14, in contrast to 78.1% or 72.5% for those patients treated with 6 or 8 cycles of R-CHOP-14, respectively.

Of the 4 regimens assessed in this study, 6 cycles of R-CHOP-14 was found to be the preferred treatment for elderly patients, with which other approaches should be compared.

A topic of debate continues to be if R-CHOP-14 is superior to R-CHOP-21. A quick glance to the data presented by the GELA or the RICOVER-60 trial could suggest that R-CHOP-14 appears to yield higher PFS and OS rates at 3-year follow-up. However, it is important to note that the DLBCL patients enrolled in both studies are different. The GELA study included more patients with DLBCL (84% vs 78%) stage I/II (20% vs 55%) and/or high-intermediate/high-risk IPI score categories (59% vs 39%) than the RICOVER-60 study. The GELA group recently completed the accrual of a randomized study comparing R-CHOP-21 to R-CHOP-14 in patients with DLBCL. Results from this study failed to demonstrate any clinical benefit from using R-CHOP-14 over R-CHOP-21 in the management of patients with DLBCL. [101]

Additional clinical trials have explored the combination of rituximab with other chemotherapy regimens. Wilson et al, from the National Cancer Institute, have studied dose-adjusted etoposide, doxorubicin, and cyclophosphamide with vincristine and prednisone (DA-EPOCH) in combination with rituximab in previously untreated DLBCL. [102] In this particular regimen, the doses of etoposide, vincristine, cyclophosphamide, and doxorubicin are adjusted with each cycle to achieve an absolute neutrophil count nadir of 500 cells/µL. The study enrolled 72 consecutive patients with untreated DLBCL who were aged at least 18 years and had stage II or higher disease. Patients received 6-8 cycles of rituximab and DA-EPOCH. IF-XRT was not permitted. Correlative studies were performed to address biomarkers of disease response by immunohistochemistry (IHC). At 5 years, PFS and OS were 79% and 80%, respectively. [102, 103]

An ongoing randomized phase III study from the Cancer and Leukemia Group B (CALGB) is comparing R-CHOP-21 to rituximab in combination with DA-EPOCH in previously untreated DLBCL. Correlative studies planned in this study will validate prospectively gene expression profiling (GEP) studies in DLBCL.

Four alternative strategies currently have been or are being evaluated in clinical studies, with promising activity in DLBCL patients: (1) the concept of dose-dense rituximab (ie, 12 doses of rituximab delivered concomitantly with 6 cycles of CHOP-14), (2) targeting of the ubiquitous proteasome with bortezomib as a means to potentiate the antitumor activity of chemoimmunotherapy, (3) the use of rituximab maintenance in the relapsed/refractory setting (CORAL study), and (4) the use of high dose-chemotherapy and autologous stem cell support (HDC-ASCS) in first remission, especially for those patients with high risk-disease. [104, 105, 106, 107, 108, 109]

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Treatment of R-CHOP Relapsed/Refractory DLBCL

As rituximab changed the treatment paradigm of patients with diffuse large B-cell lymphoma (DLBCL), it has been postulated that the current subset of patients with refractory or relapsed DLBCL represent a different patient population to the one studied in pre-rituximab clinical trials. Several investigators are questioning if the response to second-line chemotherapy or if the value of high-dose chemotherapy and autologous stem cell support (HDC-ASCS) in patients with relapsing or primary refractory DLBCL previously treated with rituximab and the cyclophosphamide, vincristine, doxorubicin, and prednisone (R-CHOP) regimen has decreased compared with historical controls.

HDC-ASCS in patients with R-CHOP relapsed/refractory DLBCL

The role of HDC-ASCS in the treatment of relapsed/refractory DLBCL was confirmed by the only international randomized phase III clinical trial known as the PARMA study. [110] In this particular study, patients with relapsed/refractory DLBCL underwent salvage chemotherapy for 2 cycles. Patients with chemotherapy-sensitive DLBCL were randomized to further salvage chemotherapy with cytarabine/platinum-based chemotherapy alone or in combination with ASCS. The results of this study demonstrated that event-free survival (EFS) and overall survival (OS) at 5 years in the transplant arm were 46% and 53%, respectively, compared with 12% and 32% in the chemotherapy alone arm.

Moreover, subset analysis for the patients revealed that response to salvage chemotherapy was associated with a 5-year progression-free survival (PFS) rate of 43%, in contrast to a 1-year OS rate of 22% for patients with chemotherapy-resistant disease. [110] Based on these results, salvage chemotherapy followed by HDC-ASCS has been adopted as the standard of care for transplant-eligible DLBCL patients.

Subsequent work was focused on the development of tools to predict which patients were most likely to benefit from HDC-ASCS, such as the value of age-adjusted the International Prognostic Index (IPI) score or positron emission tomography (PET) scanning after salvage chemotherapy. [111, 112, 113]

Rituximab in R-CHOP relapsed/refractory DLBCL

As rituximab changed the treatment paradigm of patients with DLBCL, it has been postulated that the current subset of patients with refractory or relapsed DLBCL represent a different patient population than the one studied in pre-rituximab clinical trials. Several investigators are questioning if the response to second-line chemotherapy or if the value of HDC-ASCS in patients with relapsing or primary refractory DLBCL previously treated with R-CHOP has decreased compared with historical controls.

Martin et al, on behalf of the Grupo Español de Linfomas/Trasplante Autólogo de Médula Osea (GEL/TAMO Cooperative Group), reported results from a retrospective analysis on the outcome of patients with DLBCL, evaluating the influence of rituximab on response rate to rituximab in combination with etoposide, methylprednisolone, cytarabine, and cisplatin (ESHAP) as salvage therapy. [114] Martin and colleagues studied 163 consecutive patients with relapsed/refractory DLBCL who received R-ESHAP as second-line therapy; 94 patients were previously treated with rituximab chemotherapy (R+ group) in the frontline setting and 69 patients received only chemotherapy alone (R- group).

Response rates were higher in patients who were not previously exposed to rituximab in a univariate analysis but not in a multivariate analysis. The OS and complete rates to R-ESHAP was 67% and 37% for DLBCL patients previously treated with rituximab-CHOP versus 81% and 56% for patients previously treated with CHOP (P =.045, P =.015), respectively. In addition, the PFS and OS rates at 3 years were significantly higher for the patients in the R- group (57% and 64%) compared with those patients in the R+ group (38% and 17%) (P < .0001, P =.0005). Of note, the same percentage of patients in both groups subsequently underwent HDC-ASCS.

In a multivariate analysis, prior exposure to rituximab was found to be a prognostic indicator of worse PFS and OS. [114] The results of this retrospective study suggest that DLBCL patients who relapse or do not respond to rituximab chemotherapy as first-line therapy have a more resistant type of disease and represent an emerging challenge for clinicians treating aggressive B-cell lymphomas. It also stresses the need to further study and define at the molecular level the mechanisms by which DLBCLs are developing resistance to chemoimmunotherapy.

On the other hand, it is uncertain if rituximab can enhance the antitumor activity of systemic chemotherapy in the salvage setting or to what extent the use of HDC-ASCS improves the cure rates in previously R-CHOP–treated relapsed/refractory DLBCL. Two groups of investigators have shown improved response rates by adding rituximab to salvage regimens such as ifosfamide, carboplatin, and etoposide (ICE) or dexamethasone, high-dose cytarabine, and cisplatin (DHAP) compared with historical controls. [115, 116] However, the majority of the patients included in those clinical trials had not been previously exposed to rituximab in the frontline setting.

Groupe d'Etude des Lymphomes de l'Adulte (GELA) reported a subset analysis with long-term follow up of the 202 DLBCL patients who relapsed/progressed following frontline R-CHOP or CHOP chemotherapy in the context of the landmark study. All 202 patients underwent salvage chemotherapy, of which 31 received a rituximab-containing salvage regimen (22 and 9 previously treated with CHOP or R-CHOP, respectively). Patients treated with rituximab-containing salvage chemotherapy had a 2 years OS rate of 58%, as opposed to 24% for those treated with salvage chemotherapy alone (P =.00067). Of interest and while the numbers are small, the benefit of adding rituximab to the salvage regimen was statistically significant only for those DLBCL patients treated with CHOP chemotherapy in the frontline setting. [97]

While this observation is of interest, the sample size of those R-CHOP patients previously treated for relapsed/refractory DLBCL receiving rituximab-containing salvage chemotherapy was extremely small (9 patients), which should limit the significance of the conclusions derived from this study.

Salvage chemotherapy regimens for DLBCL

There are a vast number of regimens used in the treatment of patients with relapsed/refractory DLBCL, and they are primarily based on non–cross-resistant chemotherapy agents to those used in the frontline setting plus/minus rituximab. The goal of salvage regimens is to achieve maximum tumor-burden cytoreduction in preparation for HDC-ASCS. The current salvage regimens available for refractory/relapsed DLBCL have been evaluated in phase II studies. Investigators have also tested the efficacy of adding rituximab to established salvage regimens and compared them with pre-rituximab historical controls. Several chemotherapy regimens have been used in case of disease relapse, as follows:

  • DHAP (dexamethasone, high-dose cytarabine, and cisplatin)
  • ESHAP (etoposide, methylprednisolone, high-dose cytarabine, and cisplatin)
  • MIME (mesna, ifosfamide, methotrexate, and etoposide)
  • IMVP-16 (ifosfamide, methotrexate, and etoposide)

The only randomized phase III trial that compared established salvage regimens in combination with rituximab (R-ICE vs R-DHAP) was the ongoing CORAL study. [117] Recently, the investigators reported an interim analysis of 200 patients enrolled that demonstrated factors affecting EFS include second-line age-adjusted IPI (aaIPI) of 0-1 (39% vs 56% P =.0084), relapse less than 12 months after completion of first-line therapy (36% vs 68%, P < .001), and prior rituximab exposure in the frontline setting (34% vs 66%, P < 0.001). [117] The preliminary results of the CORAL study validate the predictive factor of the aaIPI at the time of relapse, as previously described, and stress again that rituximab chemotherapy in the frontline is selective for forms of DLBCL more difficult to control in the salvage setting.

Final results of this study are eagerly awaited to further define the optimal salvage regimen and the role of rituximab maintenance following HDC-ASCS in relapsed/refractory DLBCL.

In general, when selecting the optimal salvage regimen, consider regimens with higher response rates, especially higher complete response (CR rates), low hematological and nonhematological toxicity, and a lesser degree of stem cell damage to secure effective peripheral blood stem-cell collection (PBSC).

Types of salvage chemotherapy

Depending on the agents used, and outside of a clinical trial, salvage chemotherapy can be divided into the following 2 groups:

  • Platinum-based chemotherapy: Platinum-based chemotherapy yields higher response rates at the price of hematological and/or nonhematological toxicity than non–platinum-based regimens. Therefore, they are preferred in those patients who are candidates for HDC-ASCS.
  • Non–platinum-based chemotherapy: Non–platinum-based regimens are the treatment of choice for patients with poor bone marrow reserve (ie, relapsed after HDC-ASCS) or elderly patients who are not eligible for HDC-ASCS owing to age or previous comorbid conditions.

Platinum-based regimens in relapsed DLBCL

The antitumor effects of cisplatin, carboplatin, and, most recently, oxaliplatin, against B-cell lymphomas have been demonstrated in preclinical and clinical studies. Cisplatin has been extensively studied in combination with high-dose cytarabine- or gemcitabine-based regimens such as, rituximab plus/minus DHAP, ESHAP, or GDP, in patients with refractory/relapsed DLBCL. [118, 110, 114, 116, 117, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128] In addition, carboplatin has been combined with ifosfamide and etoposide (ICE) with or without rituximab.

In general, platinum-based regimens have response rates ranging from 43-82% and CR rates of 16-61%. Successful PBSC mobilization has been documented in the majority of patients eligible for bone marrow transplantation (BMT) treated with such regimens. On the other hand, significant grade 3 and 4 hematological and, to a lesser degree nonhematological, toxicity (grade 1-2) has been observed. Grade 3-4 neutropenia occurs in 50-70% of cases; grade 3-4 thrombocytopenia is observed in 30-90%. From 40-70% of the cases require at least 1 unit of red blood cell transfusion. Hospitalization for febrile neutropenia has been reported in 10-20% of the relapsed/refractory DLBCL patients receiving platinum-based salvage regimens. [118, 110, 114, 115, 116, 117, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128]

In addition nonhematological toxicity seen with these regimens includes renal dysfunction, cardiac toxicity (for ifosfamide-containing regimens only), neurotoxicity in the form of confusion (ifosfamide-containing regimens), and cerebellar toxicity (high-dose cytarabine-containing regimens) (< 5% of the cases). Recently several investigators had evaluated the possibility of replacing cisplatin/carboplatin with oxaliplatin given its favorable toxicity profile. However, no significant changes in the antitumor activity or toxicity profile of current available salvage regimens has been demonstrated by this strategy. [125]

Non–platinum-containing salvage regimens

In the past, 4 non–platinum-containing regimens were used in the salvage regimen in preparation for HDC-ASCS. The antitumor activity of regimens such as methylprednisolone, ifosfamide, mitoxantrone, and etoposide (MINE); ifosfamide, etoposide, cytarabine, and dexamethasone (IVAD); ifosfamide, epirubicin, and etoposide (IEV), or busulphan, etoposide, cytarabine, and melphalan (Mini-BEAM) is comparable to that observed with platinum-based regimen. [129, 130, 131, 132] Response rates to any of these 3 regimens in relapsed/refractory DLBCL (never exposed to rituximab) vary from 64-75%, and the safety profile is similar to platinum-containing regimens. [129, 130, 131, 132]

On the other hand, the use of these regimens has declined overtime for several reasons, such as (1) the restriction of anthracyclines in salvage regimens across previously CHOP/R-CHOP–treated patients to avoid cumulative cardiotoxicity, (2) the protection of stem cells by restricting the use of melphalan or busulphan in the salvage regimen prior to stem cell collection, and (3) the need to decrease nonhematological and hematological toxicity from high-dose ifosfamide-containing regimens by combining this agent with a platinum compound.

The most commonly used non–platinum-containing regimens are primarily gemcitabine based. These particular regimens are well tolerated in elderly patients, in patients with limited bone marrow reserve (ie, relapsed/refractory after HDC-ASCT), or those patients with multiple comorbid conditions. The hematological toxicity observed in clinical trials evaluating the efficacy and toxicity of nonplatinum gemcitabine-based regimens is significantly lower than in platinum-containing regimens. Grade 3-4 neutropenia and thrombocytopenia has been reported in only 20% and 10-25% of the patients, respectively. [133, 134]

Another strategy used by other investigators is to modify the schedule of administration of previously used agents. A good example of this approach is the development of the infusional regimen of dose-adjusted etoposide, vincristine, doxorubicin, cyclophosphamide, and prednisone (EPOCH), with or without rituximab. Wilson et al demonstrated that EPOCH was highly effective (74% overall response rate, with 24% CR) in relapsed/refractory aggressive non-Hodgkin lymphoma, with acceptable hematological and nonhematological toxicity. [135] The incident of cardiac toxicity was extremely low (3%), despite the fact that 94% of the patients enrolled had prior anthracycline exposure. [135, 136] Similar antitumor activity was reported by Jermann et al in patients with refractory/relapsed B-cell non-Hodgkin lymphoma treated with rituximab-EPOCH. [137]

The emergence of rituximab resistance is starting to be observed in patients with relapsed/refractory DLBCL. The evaluation of other biologically active monoclonal antibodies targeting CD20 (eg, ofatumumab), monoclonal antibodies directed against other key regulatory surface receptors (ie, CD40, CD22), or small-molecule inhibitors (eg, lenalidomide, proteasome inhibitors, mammalian target of rapamycin [mTOR] inhibitors) in combination with systemic chemotherapy is necessary to broaden the therapeutic armamentarium against relapsed/refractory DLBCL.

In summary, the incorporation of rituximab to standard doses of CHOP has resulted in improved clinical outcomes when compared with standard chemotherapy in patients with DLBCL and has raised the bar with respect to which new therapies are being evaluated in patients with aggressive lymphomas. While the clinical benefit of adding rituximab to CHOP or CHOP-like chemotherapy as frontline treatment of DLBCL is beyond dispute, previously accepted biomarkers of response (eg, Bcl-2 expression, IPI) also need reevaluation to raise new challenges in the therapeutic treatment of those patients in whom chemoimmunotherapy fails or who have relapse after chemoimmunotherapy.

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CNS Prophylaxis in DLBCL

CNS relapse is a rare but significant complication in the management of patients with diffuse large B-cell lymphoma (DLBCL). It has been estimated that the probability of CNS relapse after 1 year of diagnosis is 2.3-4.5%. [138, 139] The risk of CNS relapse appears to be higher in subsets of DLBCL (4- to 15-fold increase in risk), and identification of such patients is imperative in an attempt to implement prophylactic therapy (ie, intrathecal chemotherapy).

Boehme et al retrospectively evaluated the incidence and risk factors of CNS recurrence in 1693 patients with aggressive lymphomas. [140] In a multivariate analysis, only an elevated lactate dehydrogenase (LDH) level at diagnosis and lymphoma involvement of 2 or more extranodal sites were identified as predictor factors for CNS relapse. Similar findings had been observed in patients receiving chemoimmunotherapy.

Boehme et al studied the factors associated with CNS relapse in patients treated with rituximab and the 14-day cyclophosphamide, vincristine, doxorubicin, and prednisone (CHOP) (R-CHOP-14) regimen. In this retrospective study, the estimated 2-year incidence of CNS relapse was 6.9%. Using a Cox regression analysis, the investigators found that involvement of more than one extranodal site or the presence of B-symptoms was a predictor factor for CNS relapse. [140]

Recommendations for intrathecal chemotherapy

Routine intrathecal chemotherapy is strongly recommended in patients with DLBCL with the following characteristics:

  • Two or more extranodal sites of disease
  • Testicular or breast involvement, regardless stage
  • Lymphoblastic variants
  • Oropharyngeal or paraspinal sites of involvement
  • Bone marrow involvement
  • Concomitant infection with the human immunodeficiency virus (HIV)
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Investigative Treatment Regimens

A German trial explored the safety and feasibility of dose-escalated cyclophosphamide, Adriamycin, vincristine, and prednisone (CHOP)–etoposide with 3 autologous stem cell transplantations (ASCTs) as aggressive up-front therapy in young patients with high lactate dehydrogenase (LDH) levels. [141] The investigators found the therapy to be safe and feasible, but its role is unclear. Rituximab was not used, and whether these intensive regimens are better than less intense chemotherapy plus rituximab is currently under investigation.

Antisense therapy (Bcl-2 antisense therapy) has entered clinical trials with promising results. However, its role outside of these trials has not yet been established.

The addition of bortezomib, a protease inhibitor approved for the treatment of myeloma, to treatment using CHOP plus rituximab (R-CHOP), is also being investigated, in phase I and II trials. [142]

Multicenter trials of radioimmunotherapy with ibritumomab tiuxetan (yttrium-90 [90 Y] Zevalin) and iodine-131 (131 I) tositumomab (Bexxar), CD20-targeting radiolabeled antibodies approved for use in follicular lymphomas, are also ongoing.

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Supportive Care in Chemotherapy

Administer intravenous fluids and/or supportive care with analgesics and growth factors, as necessary. Patients often are started on allopurinol with the induction of chemotherapy to avoid acute renal failure from tumor lysis syndrome (TLS) and uric acid nephropathy.

Antiemetics

Antiemetics are always prescribed before and after the administration of chemotherapy, for the prevention of chemotherapy-induced nausea and vomiting. Antiemetics used include the following:

  • The 5-hydroxytryptamine 3 (5-HT3) antagonists such as granisetron (1 mg orally [PO] q12h) or ondansetron (8 mg PO q8h) for severe chemotherapy-induced nausea and vomiting
  • Lorazepam (1 mg PO/SL q4-6h)
  • Metoclopramide (0.5-2 mg/kg PO q3-4h)
  • Prochlorperazine (10 mg PO q4-6h)

Another antiemetic, palonosetron (Aloxi), is a selective 5-HT3 receptor antagonist with a long half-life (40 h). The adult dose is intravenous 0.25 mg once (30 min before chemotherapy). Administer this agent intravenously over 30 seconds, and do not repeat the dose within 7 days. Palonosetron may cause headache, constipation, diarrhea, or dizziness.

Growth factors

For patients with anemia, consider erythropoietin or epoetin alfa (Procrit) at 40,000-60,000 U, administered subcutaneously once weekly, or darbepoetin alfa 300 mcg, with weekly subcutaneous administration.

Growth factors stimulate blood cell production. Endogenous erythropoietin stimulates red blood cell hematopoiesis. Recombinant human erythropoietin (epoetin alfa) stimulates erythropoiesis in anemic conditions. Colony-stimulating factors act on hematopoietic cells to stimulate hematopoietic progenitor cell proliferation and differentiation. Interleukins stimulate stem cell proliferation.

Administer growth factor support (ie, granulocyte colony-stimulating factor [G-CSF], granulocyte-macrophage colony-stimulating factor [GM-CSF]) to patients with a previous episode of febrile neutropenia, during subsequent cycles. Patients who administer growth factors to themselves should be carefully advised on sterile techniques, and patients with fevers during periods of neutropenia should immediately seek the attention of the treating physician.

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Inpatient Care

Most patients are treated in an outpatient setting. However, hospitalization may be necessary for patients with disease- or therapy-associated complications, such as tumor lysis syndrome, neutropenic fever, and anemia and thrombocytopenia.

Tumor lysis syndrome

Patients with a high tumor burden may need to be admitted to the hospital to receive prophylaxis with allopurinol and alkaline hydration for prevention of this potentially life-threatening condition

Neutropenic fever

Patients are usually expected to be neutropenic approximately 10-14 days after a dose of chemotherapy, with individuals being most susceptible to infections at this point. If febrile, they should be admitted to the hospital and treated with intravenous antibiotics.

Anemia and thrombocytopenia

Transfusions (red blood cells or platelets) should be administered as clinically indicated for anemia and thrombocytopenia.

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Diet and Activity

Diet

No specific diet is recommended for patients with diffuse large cell lymphoma except a salt restriction when steroids are administered as part of the chemotherapy regimen.

Patients undergoing cytotoxic chemotherapy may develop severe neutropenia, as defined by an absolute neutrophil count of less than 500/µL. These patients should be advised to maintain a low microbial diet for the expected duration of neutropenia.

Activity

No specific limitation of activity is necessary unless the patient is thrombocytopenic, in which case activity restriction may be necessary to avoid traumatic bleeding or bruising. In addition, the patient may feel substantial fatigue due to the lymphoma, its treatment, or both.

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Consultations and Transfer

Consultations

A surgical oncologist may be consulted if an open biopsy is needed for the diagnosis or to treat a complication, such as perforated viscus.

A radiation oncologist may be consulted if the primary therapy involves a combination of chemotherapy and radiotherapy. In addition, an initial large lymphoma mass or a large residual mass following completion of chemotherapy may be considered for involved-field radiotherapy (IFRT).

Transfer

Patients whose condition relapses after multiple treatment regimens or who have poor performance status and who are therefore not candidates for further chemotherapy should be considered for palliative management and hospice care. The following services can be sought in appropriate clinical situations:

  • Pain management service
  • Nursing home
  • Terminal care facility (hospice)
  • Home care with specialized nursing support for pain management
  • Rehabilitative centers
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