Treatment Strategies for Patients with Diffuse Large B-Cell Lymphoma: Past, Present, and Future.

Apr 2012

Sinha R, Nastoupil L, Flowers CR.

Source

Department of Hematology/Medical Oncology, Winship Cancer Institute, 1365 C Clifton Road, Ste 4005, Atlanta, GA 30322, Office: 404-778-1827.

Keywords:Diffuse Large B-Cell Lymphoma, Lymphoma, Non-Hodgkin Lymphoma, chemoimmunotherapy, rituximab, treatment

Abstract

Diffuse large B-cell lymphoma (DLBCL) is the most commonly occurring lymphoma in the Western world. DLBCL is a clinically, biologically, and pathologically heterogeneous entity with biologically distinct subtypes that have different expected treatment outcomes. The addition of rituximab to combination chemotherapy has improved outcomes for all patients with DLBCL and can produce cure for many individuals. Relapsed DLBCL is generally managed with salvage chemo-immunotherapy followed by high dose therapy and autologous stem cell transplantation which can cure additional patients. 

However, outcomes for patients who relapse early after upfront rituximab and chemotherapy have a poorer prognosis. Novel therapies and strategies are desperately needed for these patients and several emerging treatments hold promise for improving DLBCL treatment outcomes in the future.

PubMed

R-CHOP therapy alone in limited stage diffuse large B-cell lymphoma.

Feb 2013

Tomita N, Takasaki H, Miyashita K, Fujisawa S, Ogusa E, Matsuura S, Kishimoto K, Numata A, Fujita A, Ohshima R,Kuwabara H, Hagihara M, Hashimoto C, Takemura S, Koharazawa H, Yamazaki E, Fujimaki K, Taguchi J, Sakai R,Ishigatsubo Y.

Source

Department of Internal Medicine and Clinical Immunology, Yokohama City University Graduate School of Medicine, Yokohama, Japan.

Abstract

Long-term observation has identified a pattern of continuing relapse in limited stage diffuse large B-cell lymphoma (DLBCL) treated by three cycles of R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) plus involved-field irradiation. We retrospectively analysed 190 untreated patients with limited stage DLBCL treated by R-CHOP alone. All the patients were scheduled to undergo primary therapy with six cycles of full-dose R-CHOP. Cases with a dose reduction of more than 20% were excluded from the study. Additional local irradiation was allowed in patients with partial response (PR). Five patients received additional local irradiation after PR at the end of the R-CHOP therapy. The median observation period was 52 months. Median age at diagnosis was 63 years. The responses to therapy were 180 complete responses, eight PR, and two progression of disease (PD). The 5-year progression-free survival and 5-year overall survival rates were 84% and 90%, respectively, both in plateau. During the observation period, 29 patients experienced PD. The progression sites were the primary sites in 15 patients, outside the primary sites in 10, and undetermined in four patients. These results suggest that the 'standard' strategy of three cycles of R-CHOP followed by involved-field radiotherapy for limited stage DLBCL could be effectively replaced by six cycles of R-CHOP alone.

PubMed

Treatment of diffuse large B cell lymphoma.

Dec 2012

Kwak JY.

Source

Department of Internal Medicine, Chonbuk National University Medical School, Jeonju, Korea.

Abstract

Diffuse large B cell lymphoma (DLBCL) is the most common subtype of non-Hodgkin lymphoma in all countries and all age groups. DLBCL is potentially curable, and the outcome of patients with DLBCL has completely changed with the introduction of therapy involving the monoclonal antibody rituximab in combination with chemotherapy. Nonetheless, relapse is detected after treatment with rituximab, cyclophosphamide, hydroxydaunorubicin, vincristine, and prednisolone in approximately 30% of patients. It has recently become clear that DLBCL represents a heterogeneous admixture of quite different entities. Gene expression profiling has uncovered DLBCL subtypes that have distinct clinical behaviors and prognoses; however, incorporation of this information into treatment algorithms awaits further investigation. Future approaches to DLBCL treatment will use this new genetic information to identify potential biomarkers for prognosis and targets for treatment.

Full text article:

KJIM

Is there any role for transplantation in the rituximab era for diffuse large B-cell lymphoma?

2012

Gisselbrecht C.

Source

1Hospital Saint Louis, Paris Diderot University, Paris, France.

Abstract

Salvage chemotherapy followed by high-dose therapy and autologous stem cell transplantation is the standard of treatment for chemosensitive relapses in diffuse large B-cell lymphoma. The addition of rituximab to chemotherapy has improved the response rate and failure-free survival after first-line treatment and relapses. Fewer relapses are expected, although there is no consensus on the best salvage regimen. The intergroup Collaborative Trial in Relapsed Aggressive Lymphoma (CORAL) set the limits for this standard of treatment after first comparing 2 salvage regimens: rituximab, ifosfamide, etoposide, and carboplatin (R-ICE) and rituximab, dexamethasone, aracytine, and cisplatin (R-DHAP). There was no difference in response rates or survivals between these salvage regimens. Several factors affected survival: prior treatment with rituximab, early relapse (< 12 months), and a secondary International Prognostic Index score of 2-3. For patients with 2 factors, the response rate to salvage was only 46%, which identified easily a group with poor outcome. Moreover, patients with an ABC subtype or c-MYC translocation responded poorly to treatment. More than 70% of patients will not benefit from standard salvage therapy, and continued progress is needed. Studies evaluating immunotherapy after transplantation, including allotransplantation, new conditioning regimens with radioimmunotherapy and other combinations of chemotherapy based on diffuse large B-cell lymphoma subtype, are discussed herein. Early relapses and/or patients refractory to upfront rituximab-based chemotherapy have a poor response rate and prognosis. A better biological understanding of these patients and new approaches are warranted.

Hematology

Prognostic significance of rituximab and radiotherapy for patients with primary mediastinal large B-cell lymphoma receiving doxorubicin-containing chemotherapy.

Nov 2012

Xu LM, Fang H, Wang WH, Jin J, Wang SL, Liu YP, Song YW, Ren H, Zhou LQ, Li YX.

Abstract

The aim of this study was to evaluate the prognostic importance of rituximab and radiotherapy in patients with primary mediastinal large B-cell lymphoma (PMBCL) receiving doxorubicin-containing chemotherapy. Seventy-nine patients with PMBCL received CHOP chemotherapy with (n = 39) or without rituximab (n = 40), and 60 patients received additional radiotherapy. Patients treated with R-CHOP had significantly superior survival rates. The 5-year overall survival (OS) and progression-free (PFS) rates were 83.7% and 76.7% for R-CHOP, compared with 48.3% (P=0.011) and 44.2% (P=0.012) for CHOP, respectively. Similarly, the 5-year OS and PFS rates for early stage patients were 93.8% and 84.6% with R-CHOP, and 52.0% (P=0.002) and 46.6% (P=0.003) with CHOP, respectively. Patients treated with chemotherapy and radiotherapy had better survival and local control (LC) rates compared with chemotherapy alone. The 5-year OS, PFS and LC rates for early stage patients were 73.6%, 69.9% and 92.6% for chemotherapy and radiotherapy, and 50.8% (P = 0.076), 36.9% (P = 0.008) and 56.4% (P<0.001) for chemotherapy alone, respectively. Early stage patients treated with R-CHOP and radiotherapy had 5-year OS, PFS and LC rates of 96.4%, 85.9% and 93.1%. R-CHOP plus consolidation radiotherapy was associated with excellent survival and LC rates.

PubMed

The Absolute Monocyte and Lymphocyte Prognostic Index for Patients With Diffuse Large B-Cell Lymphoma Who Receive R-CHOP.

Nov 2012

Batty N, Ghonimi E, Feng L, Fayad L, Younes A, Rodriguez MA, Romaguera JE, McLaughlin P, Samaniego F, Kwak LW,Hagemeister FB Jr.

Source

Department of Medicine, Roswell Park Cancer Institute, Buffalo, NY.

Abstract

BACKGROUND:

The baseline absolute monocyte count and absolute lymphocyte count were used to generate a prognostic index (the AMLPI) for survival in diffuse large B-cell lymphoma (DLBCL).

METHODS:

Data from 245 patients with DLBCL who were treated with standard R-CHOP (rituximab, cyclophosphamide, doxorubicin hydrochloride, vincristine sulfate, prednisone) were reviewed. By using the values previously reported for the AMLPI, its prognostic value was examined in our population.

RESULTS:

After a median follow-up of 22 months for censored observations, the 3-year progression-free survival (PFS) rates for the international prognostic index (IPI) 0-2 and 3-5 risk groups were 73% and 58%, respectively (P = .0004); comparable overall survival (OS) rates were 88% and 68%, respectively (P < .0001). For patients with IPI scores of 0-2, 1-year PFS rates for AMLPI low-, intermediate-, and high-risk groups were 92%, 89%, and 80%, respectively (P = .022); comparable 1-year OS rates were 96%, 95%, and 80%, respectively (P = .049). By multivariate analysis, with the adjustment of IPI in the model, AMLPI effects (low- vs. high-risk groups) on PFS and OS rates were significant, with P = .046 (hazard ratio [HR] 0.402 [95% CI, 0.164-0.986] and P = .052 (HR 0.325 [95% CI, 0.104-1.011]), respectively.

CONCLUSIONS:

The absolute monocyte and lymphocyte counts prognostic index (the AMLPI) may add prognostic value beyond that of the IPI for patients with DLBCL who receive R-CHOP.

PubMed

Long-term remission of primary bone marrow diffuse large B-cell lymphoma treated with high-dose chemotherapy rescued by in vivo rituximab-purged autologous stem cells.

2012

Kazama H, Teramura M, Yoshinaga K, Masuda A, Motoji T.

Source

Department of Hematology, Tokyo Women's Medical University, 8-1, Kawada-cho, Shinjuku-ku, Tokyo 162-8666, Japan.

Abstract

Primary bone marrow diffuse large B-cell lymphoma (DLBCL) is a rare type of extranodal lymphoma with poor prognosis. Here, we report a case of primary bone marrow DLBCL successfully treated with high-dose chemotherapy and rescued by in vivo rituximab-purged autologous stem cells. A 39-year-old woman visited our hospital because of anemia. Bone marrow examination revealed a large B-cell lymphoma invasion. An (18)F-fluorodeoxyglucose positron emission tomography scan revealed disseminated bone marrow uptake without evidence of dissemination at other sites. These findings led to a diagnosis of primary bone marrow DLBCL. Our patient underwent R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone) chemotherapy and achieved complete remission. Subsequently, she received high-dose chemotherapy with an in vivo rituximab-purged autologous stem cell transplant. Seven years have passed since the transplantation, and she remains in remission. This suggests that transplantation of an in vivo rituximab-purged autograft is a promising strategy for primary bone marrow DLBCL.

Case Reports in Medicine

Bone marrow involvement is predictive of infusion-related reaction during rituximab administration in patients with B cell lymphoma.

Oct 2012

Hong J, Kim JY, Ahn HK, Lee SM, Sym SJ, Park J, Cho EK, Ahn JY, Park S, Lee SP, Shin DB, Lee JH.

Source

Division of Hematology & Medical Oncology, Department of Internal Medicine, Gachon University School of Medicine, Gachon University Gil Hospital, Incheon, Republic of Korea.

Abstract

PURPOSE:

The purpose of this study is to evaluate risk factors for infusion-related reaction (IRR) following rituximab administration in patients with B cell non-Hodgkin lymphoma.

METHODS:

A retrospective analysis was conducted of patients with newly diagnosed B cell lymphoma who have received rituximab-included immunochemotherapy with appropriate premedication and commonly used schedule of infusion rate. IRRs were graded by review of the patients' electronic medical record according to the Common Terminology Criteria for Adverse Events version 4.0.

RESULTS:

One hundred and sixty-nine patients were included in the analysis and most of the patients (150; 88.8 %) had diffuse large B cell lymphoma (DLBCL). Thirty-six patients (21.3 %) had any grade of IRRs: 23 patients were grade (G) 1 (13.6 %), 13 had ≥G2 IRRs (7.7 %), and only 4 had ≥G3 IRRs (2.4 %). All except one patient had IRR during the first cycle and only two had repetitive IRR thereafter. Bone marrow (BM) involvement was the strongest risk factor for IRR in multivariable analysis (odds ratio 4.06, 95 % confidence interval 1.67-9.89; p = 0.002). A subgroup analysis confined to patients with DLBCL showed very similar results when compared with the entire population, and patients with DLBCL who had ≥G2 IRR showed shorter event-free and overall survival when compared to those who did not.

CONCLUSIONS:

BM involvement is predictive of occurrence of IRR during rituximab administration in patients with B cell lymphoma. More intensive premedication and careful observation for IRR during rituximab administration are required for patients with B cell lymphoma who have BM involvement.

PubMed

The Hans algorithm failed to predict outcome in patients with diffuse large B-cell lymphoma treated with rituximab.

Oct 2012

Benesova K, Forsterova K, Votavova H, Campr V, Stritesky J, Velenska Z, Prochazka B, Pytlik R, Trneny M.

Abstract

Diffuse large B-cell lymphoma (DLBCL) consists of at least two biologically and pathogenetically different subtypes, the germinal centre B-cell (GCB) and the activated B cell type (ABC). It has been suggested that immunohistochemistry can discriminate these subtypes as well. The aim of this study was to verify the validity of the most commonly used Hans algorithm in patients with DLBCL treated with anthracycline- based chemotherapy with rituximab. Immunohistochemical staining using standard protocols was performed on formalin fixed paraffin-embedded tissues. CD20, CD5, CD23, BCL2, CD10, BCL6, MUM1 and Ki67 antibodies were applied. Out of 120 examined cases 52 patients were evaluated as GCB type and 68 patients as having non-GCB, out of a set of 99 patients treated with immunochemotherapy 45 patients with GCB and 54 patients with non-GCB DLBCL were identified. In this set of patients, there was no statistically significant difference neither in overall survival (OS) (HR 1.47 95% CI 0.51-2.63; p=0.45) nor in progression free survival (PFS) (HR 1.57, 95 % CI 0.76-3.22; p=0.731) between both groups. Keywords: DLBCL, Hans, rituximab, GC, nonGC.

DOI System

PubMed

Double-hit Lymphomas Constitute a Highly Aggressive Subgroup in Diffuse Large B-cell Lymphomas in the Era of Rituximab.

Sept 2012

Kobayashi T, Tsutsumi Y, Sakamoto N, Nagoshi H, Yamamoto-Sugitani M, Shimura Y, Mizutani S, Matsumoto Y, Nishida K,Horiike S, Asano N, Nakamura S, Kuroda J, Taniwaki M.

Source

1Division of Hematology and Oncology, Department of Medicine, Kyoto Prefectural University of Medicine, Kyoto.

Abstract

OBJECTIVE:

The incorporation of rituximab in immunochemotherapy has improved treatment outcomes for diffuse large B-cell lymphoma, but the prognosis for some diffuse large B-cell lymphomas remains dismal. Identification of adverse prognostic subgroups is essential for the choice of appropriate therapeutic strategy.

METHODS:

We retrospectively investigated the impact of so-called 'double-hit' cytogenetic abnormalities, i.e. cytogenetic abnormalities involving c-MYC co-existing with other poor prognostic cytogenetic abnormalities involving BCL2, BCL6 or BACH2, on treatment outcomes for 93 consecutive diffuse large B-cell lymphoma patients.

RESULTS:

According to the revised international prognostic index, no patients were cytogenetically diagnosed with double-hit lymphomas in the 'very good' risk group or in the 'good' risk group, while 5 of 33 patients had double-hit lymphomas in the 'poor' risk group. All the double-hit lymphoma patients possessed both nodal and extranodal involvement. The overall complete response rate was 89.3%, overall survival 87.1% and progression-free survival 75.8% over 2 years (median observation period: 644 days). The complete response rates were 93.2% for the non-double-hit lymphoma patients and 40.0% for the double-hit lymphoma patients. Significantly longer progression-free survival and overall survival were observed for the 'very good' and the 'good' risk patients than for the 'poor' risk patients. Moreover, the progression-free survival of double-hitlymphoma was significantly shorter than that of the non-double-hit lymphoma 'poor' risk patients (P = 0.016). In addition, the overall survival of the double-hit lymphoma patients also tended to be shorter than that of the non-double-hit lymphoma 'poor' risk group.

CONCLUSIONS:

The diagnosis of double-hit lymphoma can help discriminate a subgroup of highly aggressive diffuse large B-cell lymphomas and indicate the need for the development of novel therapeutic strategies for double-hit lymphoma.

Oxford - Japanese Journal of Clinical Oncology

Aurora A inhibitor (MLN8237) plus Vincristine synergizes with Rituximab as a potential curative therapy in aggressive B-cell non-Hodgkin lymphoma.

Feb 2012

Mahadevan D, Stejskal A, Cooke LS, Manziello A, Morales C, Persky DO, Fisher RI, Miller TP, Qi W.

Source

Hematology/Oncology, The University of Arizona Cancer Center.

Abstract

PURPOSE:

Aurora A and B are oncogenic serine/threonine kinases that regulate mitosis. Over-expression of Auroras promotes resistance to microtubule targeted agents. We investigated mechanistic synergy by inhibiting the mitotic spindle apparatus in the presence of MLN8237 [M], an Aurora A inhibitor with either vincristine [MV] or docetaxel [MD] in aggressive B-NHL. The addition of rituximab [R] to MV or MD was evaluated for synthetic lethality.

EXPERIMENTAL DESIGN:

Aggressive B-NHL cell subtypes were evaluated in vitro and in vivo for target modulation and anti-NHL activity with single agents, doublets and triplets by analyzing cell proliferation, apoptosis, tumor growth, survival and mechanisms of response/relapse by gene expression profiling with protein validation.

RESULTS:

MV is synergistic while MD is additive for cell proliferation inhibition in B-NHL cell culture models. Addition of R to MV is superior to MD but both significantly induce apoptosis compared to doublet therapy. Mouse xenograft models of mantle cell lymphoma showed modest single agent activity for M, R, D and V with tumor growth inhibition (TGI) of ~10-15%. Of the doublets, MV caused tumor regression, while TGI was observed with MD (~55-60%) and MR (~25-50%) respectively. Although MV caused tumor regression, mice relapsed 20 days after stopping therapy. In contrast, MVR was curative, while MDR led to TGI of ~85%. PCNA, Aurora B, cyclin B1, cyclin D1 and Bcl-2 proteins of harvested tumors confirmed response and resistance to therapy.

Clinical Cancer Research