Early-stage Diffuse Large B-cell Research Articles

Definition of bulky disease in early stage diffuse large B-cell lymphoma in computed tomography on coronal and transverse planes

BackgroundIn early stage diffuse large B-cell lymphoma (ESDLBL), tumor bulkiness is an important determinant of treatment and prognosis. Tumor bulk is usually measured on transverse computed tomography (CT) plane and variably defined from 5 to 10 cm.ObjectivesOur study aims to investigate the prognostic significance of bulky disease measured on CT coronal and transverse planes and to evaluate the outcome of patients with bulky disease.MethodsPatients with ESDLBL and treated with rituximab, cyclophosphamide, doxorubicin, and prednisolone (RCHOP) with or without radiotherapy were included. Receiver Operating Characteristic (ROC) analysis was used to identify the optimal tumor dimension that correlated with progression, relapse, or death. Correlation between different variables and progression-free survival (PFS) and overall survival (OS) were analyzed using log-rank (Mantel–Cox) test and Cox proportional hazard models.ResultsA total of 127 patients with a median age of 47 (range: 18–90) years were included. Eighty-two (64.6%) patients treated with combined modality treatment (CMT) [RCHOP + radiotherapy]. After a median follow-up of 40 (range: 2–114) months, 3-year PFS and OS were 83.9% (95% CI: 76.759%–89.981%), and 80.6% (95% CI: 72.499%–87.531%), respectively. Tumor dimension of >7.5 cm measured on either CT plane was the optimal cutoff point to define bulky disease. Three-year PFS and OS were inferior in the group of patients with no bulky disease on transvers plane (n = 84) but had bulky disease on coronal plane (n = 9,10.7%); (94.2% vs. 75%, p = 0.017 and 90.5% vs. 56.3%, p = 0.002), as well as in patients with no bulky disease on coronal plane (n = 89), but had bulky disease on transverse plane (n = 14, 15.7%); (94.1% vs. 62.3%, p < 0.001, and 90.4% vs. 63.5%, p = 0.002). Compared to RCHOP alone, 3-year PFS and OS were better in patients with bulky disease treated with CMT (78% vs. 52.5%, p = 0.018 and 81.8% vs. 38.7%, p = 0.003) but not in patients with non-bulky disease (96.2% vs. 93%, p = 0.691 and 87.6% vs. 91.5%, p = 0.477).ConclusionIn ESDLBL, measurement of tumor mass on transverse and coronal CT planes may help in better identification of patients with bulky disease. The use of CMT was associated with better survival outcomes in patients with bulky disease.

Patient Survival With and Without Radiation Therapy for Early-Stage Diffuse Large B-Cell Lymphoma in the Era of PET and Rituximab

PurposeThe benefit of radiation therapy (RT) becomes uncertain in the treatment of early stage diffuse large B-cell lymphoma (DLBCL) in the era of rituximab, positron emission topography (PET), and computed tomography (CT). We sought to retrospectively review modern patients with early stage I-II DLBCL treated with rituximab and staged by PET-CT to better define which patients benefit from consolidative RT. Methods and MaterialsPatients with early stage I-II DLBCL from 1998 to 2017 were reviewed coinciding with our institutional utilization of rituximab with the standard regimen of cyclophosphamide, doxorubicin, vincristine, and prednisone and PET-CT. Relevant clinical information was used to calculate National Comprehensive Cancer Network international prognostic index (IPI) scores. Kaplan-Meier survival analysis and a Cox proportional hazards model were used for overall survival (OS). ResultsSeventy-seven patients received chemoimmunotherapy alone, and 41 received chemoimmunotherapy plus RT. Median follow-up time was 9.5 years. On univariate analysis, extranodal disease (P = .04) and National Comprehensive Cancer Network IPI (P < .001) were significantly correlated with OS. Five-year OS was 87% versus 67%, and 10-year OS was 67% versus 58%, numerically higher favoring RT (P = .16). On multivariate Cox regression analysis of OS controlling for IPI and extranodal disease, the addition of RT was associated with improved OS (hazard ratio of 0.4, P = .01). ConclusionsThe current analysis supports the use of consolidative RT in early stage DLBCL given an OS benefit on multivariate analysis. Further prospective randomized data are needed to confirm these findings.

The impact of cell-of-origin, MYC/Bcl-2 dual expression and MYC rearrangement on disease relapse among early stage diffuse large B-cell lymphoma patients treated with combined modality therapy

We addressed the prognostic impact of cell-of-origin (COO), MYC and Bcl-2 overexpression as well as isolated MYC rearrangement among 111 patients with limited stage diffuse large B-cell lymphoma (DLBCL) treated with consolidative radiation therapy (RT) after a metabolic complete response to immunochemotherapy. With a median follow-up of 31.1 months (95% CI 27.4 − 34.8), 4 relapses occurred. The 3-year progression free survival (PFS), overall survival (OS), and loco-regional relapse free survival (LRFS) for the cohort were 95%, 96%, and 100%, respectively. There were no differences in OS, PFS, or LRFS based on COO or MYC/Bcl-2 dual expression (DE). Similarly, patients with MYC translocations without BCL2 or BCL6 rearrangements did not have worse outcomes. Consolidative RT produced excellent local control, regardless of DLBCL biology, with one late in-field failure.

Early Stage Diffuse Large B Cell Lymphoma in the Era of PET and Rituximab: Benefits from Radiotherapy in all NCCN International Prognostic Index Risk Groups

The use of radiotherapy (RT) remains controversial in the treatment of early stage diffuse large B-cell lymphoma (DLBCL) in the era of rituximab and PETCT, and it is unclear which subgroups of patients may benefit from RT. We sought to retrospectively review modern early stage I-II DLBCL patients treated with rituximab and staged by PETCT to better define which patients benefit from consolidative RT. An IRB approved retrospective review was performed of patients treated at our institution with early stage I-II DLBCL from 1998 to 2017 coinciding with our utilization of R-CHOP and PETCT. Inclusion criteria included AJCC 7th edition stage I-II DLBCL, treatment between the years of 1998-2017, chemotherapy as first line management, and age> = 18 years. Patients were excluded if they had prior RT or were diagnosed with multiple malignancies. Relevant clinical information including age, sex, ECOG performance status (PF), LDH values, tumor location (bulky, bony involvement, and extranodal), tumor size, and B symptoms was used to calculate NCCN IPI scores. Kaplan Meier survival analysis and Cox proportional hazards model were utilized for evaluation of prognostic factors of overall survival (OS). Between 1998 and 2017, 1040 adult patients were treated with lymphoma at our institution, with 144 patients with early stage DLBCL meeting inclusion criteria. Of these, 96 received chemotherapy alone while 48 received chemotherapy followed by RT. No prognostic factors examined were significantly correlated with receipt of RT. On univariate analysis, age(p<0.001), LDH (p = 0.005), ECOG PS (p<0.001), extranodal disease (p = 0.004), and NCCN IPI (p<0.001) were significantly correlated with OS. There was no correlation with either bony involvement (p = 0.67) or bulky disease (p = 0.58). Ten-year OS was 70.3% vs. 56.8% (p = 0.075) in favor of RT. When stratified by NCCN IPI risk group, RT trended towards benefit in all subgroups: 10-year OS for Low 100% vs. 80.1% (p = 0.14), Low-Int 73.6% vs. 62.0% (p = 0.095), and High-Int 35% vs. 16.5% (p = 0.096), with too few high-risk patients to analyze. Higher 10-year OS was noted among extranodal patients receiving RT 62.4% vs. 44.9% (p = 0.069) with no significant difference at 5-years following RT for patients with either bulky (79.1% vs. 54.8% (p = 0.37)) or bony (80% vs. 66.7% (p = 0.66)) involvement, respectively. On multivariate analysis, NCCN IPI (HR 2.56 (1.93-3.39), p<0.001) and RT (HR 0.44 (0.25-0.74), p = 0.002) were both significantly correlated with OS. The current analysis supports the use of consolidative RT in early stage DLBCL given an OS benefit noted on MVA that was maintained when controlling for NCCN IPI scores. There was no significant difference seen in bulky disease or bony involvement. Further prospective randomized data is needed to confirm these findings.

Patient Survival with and Without Radiotherapy for Early Stage Diffuse Large B-Cell Lymphoma in the Era of PET and Rituximab

Patient Survival with and Without Radiotherapy for Early Stage Diffuse Large B-Cell Lymphoma in the Era of PET and Rituximab

Outcomes Following Involved Node Radiation Therapy for Early Stage Diffuse Large B-Cell Lymphoma

Outcomes Following Involved Node Radiation Therapy for Early Stage Diffuse Large B-Cell Lymphoma

Genomic pattern of intratumor heterogeneity predicts the risk of progression in early stage diffuse large B-cell lymphoma.

Intratumor heterogeneity (ITH) plays an important role in tumor development, metastases, recurrence and has impact on clinical diagnosis, therapeutic responses. In this study, we used mutant-allele tumor heterogeneity (MATH) through whole-exome sequencing data to evaluate ITH in early stage diffuse large B-cell lymphoma (DLBCL). A discovery set of 22 patients and a validation set of 35 patients with primary DLBCL which staged I or II were chosen from The Cancer Genome Atlas database and The Gene Index Project database, respectively. Then patients were divided into low and high MATH score groups according to the median expression level. As a result, higher MATH score displayed an increasing risk of progression compared with lower MATH score both in the discovery set (P = 0.045) and the validation set (P = 0.025). Further, the genomic pattern according to MATH demonstrated that mutation rates of immunoglobulin lambda locus, B-cell translocation gene and membrane-associated guanylate kinase were the sites with the highest mutation rate. Moreover, Gene enrichment analysis showed that immunoglobulin lambda constant 2 (IGLC2) which belongs to immunoglobulin lambda locus was only enriched in high MATH group. Besides, BTG2 and Caspase recruitment domain-containing protein 11 were cancer driver genes which listed on the top three high rate of mutation. Our study revealed the prognostic value of MATH and relevant genomic pattern in early stage DLBCL. Potential mechanisms on genetic level of how genomic aberration influence the ITH of DLBCL are provided. MATH based on whole genome sequencing may be feasible for deciding clinical treatment of DLBCL patients in the future researches.

Radiotherapy for early stage diffuse large B-cell lymphoma with or without double or triple hit genetic alterations

We investigated whether adding radiation (RT) to systemic therapy improved outcomes in early stage diffuse large B-cell lymphoma (DLBCL) patients with or without double- or triple-hit lymphoma (DHL/THL) biology. This analysis included 183 patients profiled with fluorescent in situ hybridization (FISH) for alterations in MYC, BLC2, and/or BCL6. A total of 146 (80%) were non-DHL/THL, 27 (15%) were DHL, and 10 (6%) were THL. Systemic therapy without RT resulted in inferior freedom from relapse (FFR) (HR: 2.28; 95% CI, 1.10–4.77; p = .02). The median FFR for non-DHL/THL was not reached and was 33 and 22.3 months for DHL and THL, respectively; p < .001. Low-risk (R-IPI <2) DHL/THL patients treated with rituximab-based therapy had 3-year FFR rates of 11% and 71% for systemic therapy without and with RT, respectively; p = .04. No differences in overall survival were observed between the treatment groups. Treatment intensification with RT may improve early stage DHL/THL outcomes.Trial registration: ClinicalTrials.gov identifier: NCT02272686.Trial registration: ClinicalTrials.gov identifier: NCT02815397.

Management of Double/Triple Hit Early Stage Diffuse Large B-Cell Lymphoma With Radiation Therapy

The role of consolidative radiation therapy (RT) after R-CHOP in early stage Diffuse Large B-Cell Lymphoma (DLBCL) remains controversial. Further, recent research has identified double-hit (DHL) and triple-hit (THL) as aggressive subtypes of this disease, but the role of RT has not been well defined in these cases. We evaluated the outcome of patients treated with systemic therapy followed by consolidative RT vs. those treated with systemic therapy alone with a focus on DHL and THL. A total of 209 lesions treated in 188 patients with early stage DLBCL were identified for retrospective analysis. These patients were treated in a single institution, from February 1998 to December 2014. Details of clinical characteristics, treatments, outcomes, and molecular profiles were extracted from clinical chart review and radiologic examinations. A total of 141 lesions were treated with RT (67%). Outcomes including time to relapse (TTR) and overall survival (OS) were estimated with Kaplan-Meier rates. Univariate (UVA) and multivariate (MVA) Cox proportional hazard ratios (HR) were used to assess the effect of patient, tumor, and other predictive factors. The median age was 60 years (range: 20-90), the majority were male (n = 105; 56%) and white (n = 167; 89%). Stages of disease were 1A (n = 87; 46%), 1B (n = 5; 3%), 2A (n = 73; 39%), and 2B (n = 23; 12%). Seventy-five (40%) patients had germinal center B-cell subtype. 27 (14%) were identified as DHL (7 typical and 20 atypical), and 10 (5%) were identified as THL (3 typical and 7 atypical). In those treated with chemotherapy (CT) alone, the median number of CT cycles was 6 (range: 1-10), and in patients treated with CT and RT it was 4 (range: 0-8, P<0.001). Median follow-up from treatment completion was 33 months (0.3-204 months). Median RT dose was 36 Gy (20-54 Gy). A total of 40 patients (21%) were known to be dead at last analysis. The receipt of RT was significant on MVA for the TTR with a HR 0.38 (0.20 -0.71; P = 0.002) with a trend for OS on MVA (P = 0.08). TTR at 36 months was 46% and 83% in patients treated without and with RT (P<0.0001). MVA demonstrated significance for OS in THL vs. DHL with a HR 6.1 (1.6-22.8, P = 0.01), and THL vs. none with a HR 4.5 (1.4-12.9, P = 0.02). MVA demonstrated significance for TTR in THL vs. none HR 6.6 (1.4-30.7, P = 0.05). TTR and OS rates at 36 months were 80%/83%, 47%/72%, and 17%/44% in patients without analyzed genetic aberrations, DHL, and THL (P < 0.0001 and P = 0.0002), respectively. DHL and THL patients treated with R-CHOP benefited significantly from consolidative RT with a 36 month TTR rate of 64% and 11% in patients treated with and without RT, respectively (P = 0.04). The receipt of RT and DHL/THL status were the only factors that correlated with TTR on MVA. DHL and THL status correlated with worse OS, and consolidative RT may offer a significant benefit to this cohort of patients. Early identification of these patients for more aggressive treatment utilization may lead to improved outcomes.

352P The role of radiotherapy in early-stage primary diffuse large B-cell lymphoma of the Waldeyer's Ring: A retrospective cohort study

352P The role of radiotherapy in early-stage primary diffuse large B-cell lymphoma of the Waldeyer's Ring: A retrospective cohort study

Anti-Myelin Associated Glycoprotein Polyneuropathy in a Patient With Lymphoma and its Resolution After Chemotherapy

Anti-myelin associated glycoprotein (anti-MAG) antibody associated polyneuropathy is a chronic distal symmetric sensorimotor neuropathy. The rarity of this condition precludes establishment of a standard of care. It has been treated with steroids, intravenous immunoglobulin (IVIG) and Rituximab. We present a case of a 72 years old man presenting with 1 year history of neuropathic pain in lower extremities and hands bilaterally, right cervical lymphadenopathy on physical exam, and the anti-MAG antibody ELISA was positive. An excisional biopsy of the cervical lymph node showed diffuse large B cell lymphoma. The staging bone marrow examination did not show lymphoma involvement, the PET/CT did only demonstrated neck and mediastinal lymphadenopathy. The patient received four cycles of R-CHOP (Rituximab, Cyclophosphamide, Doxorubicin, Vincristine and Prednisone) for Stage IIA disease with complete response, and complete resolution of polyneuropathy after the first cycle of chemotherapy. The case report highlights the successful treatment of a rare presentation of anti-MAG polyneuropathy associated with early stage diffuse large B-cell lymphoma. J Med Cases. 2013;4(8):557-559 doi: https://doi.org/10.4021/jmc1399w

A Phase II Trial of R-CHOP Followed by Zevalin Radioimmunotherapy for Patients with Previously Untreated Stages I and II CD20+ Diffuse Large Cell Non-Hodgkin's Lymphoma: an Eastern Cooperative Oncology Group Study (E3402).

AbstractAbstract 2687 Background:Patients with early stage (Stages I, II) diffuse large B cell (DLBCL) have been traditionally treated with either CHOP x6 alone or with CHOP followed by involved field external beam radiotherapy (IFRT). With the demonstration of the superiority of rituximab CHOP (RCHOP) in advanced stage DLBCL, RCHOP has been adopted as the chemoimmunotherapy standard of care in early stage disease with or without IFRT. Radioimmunotherapy (RIT) has the advantage of delivering high-energy, short path length radiation in a targeted approach using an anti-CD20 antibody as the carrier. Thus, radiation is potentially targeted to microscopic sites outside of known disease. Goals:To evaluate the complete response (CR) rate and functional CR rate (CR or CRu/PR and PET negative) to a treatment regimen of RCHOP followed by 90Y-ibritumomab tiuxetan (Zevalin, Spectrum Pharmaceuticals) radioimmunotherapy (RIT); only patients not achieving PET negative status after RIT were to be given IFRT. The study goal was to achieve a functional CR rate of ≥75%. Patients and Methods:Eligible patients were those with new, untreated Stages I or II DLBCL as determined by standard CT scanning, adequate blood counts, creatinine and bilirubin <2.0 mg/dl, cardiac ejection fraction >45%, and a performance status 0–2. Stage I patients were required to have ≥1 adverse risk factor (≥60 years, bulky disease, elevated LDH or PS2). Patients received standard RCHOP21 × 2 cycles and then were restaged. Patients in CR received 2 additional cycles; those in PR or CRu received 4 additional cycles. At end of RCHOP a PET scan was repeated and centrally reviewed; those with a PR or functional CR proceeded to Zevalin RIT 0.4 mCi/kg (maximum 32 mCi) within 12 weeks of the last RCHOP. Patients were restaged 12 weeks post-RIT; PET negative patients were observed without maintenance; PET positive patients received 30Gy involved field radiation and then were restaged. Descriptive statistics were used to summarize the patient characteristics, treatment and response. The Kaplan-Meier method was used to estimate failure rates. Results:Between Dec 2004 and Nov 2008, 62 patients were enrolled; after pathology review 53 were considered eligible. 42% (22/53) patients were stage I/IE; 58% (31/53) were stage II/IIE. 57% (30/53) received 6 cycles of RCHOP; 40% (21/53) received 4 cycles; and 2 patients received 1 and 2 cycles, respectively. After immunochemotherapy, 79% (42/53) were in functional CR and 19% (10/53) PR; 1 was unevaluable. Of the 53 eligible patients who completed RCHOP therapy 91% (48/53) proceeded to RIT. After RIT, 87% (46/53; 95% CI: 75–95) were in CR/CRu and 89% (47/53; 95% CI:77–96%) were in functional CR. One patient proceeded to IFRT. The median follow-up is now 4.3 years. Seven (13%) of patients have had tumor progression but only 2 have died (1 of disease). At 4 years, 88% of patients remain progression free and 98% remain alive (Fig 1,2). The median has not been reached for either PFS or OS. There has been one case of myelodysplastic syndrome. Conclusions:Combination immunochemotherapy and RIT is an active regimen for patients with early stage DLBCL. Nearly all patients will achieve functional CR without the requirement of IFRT. The regimen of RCHOP and RIT for early stage DLBCL is worthy of further study. [Display omitted] [Display omitted] Disclosures:Witzig:Spectrum: Membership on an entity's Board of Directors or advisory committees, Research Funding, uncompensated Other. Off Label Use: Use of Zevalin in treating patients with Stage I-II DLBCL. Kahl:Roche: Consultancy; Genentech: Consultancy, Research Funding. Horning:Genentech: Employment; Roche: Equity Ownership.

H pylori-positive gastric diffuse large B-cell lymphomas are potentially curable by H pylori eradication therapy

8093 Background: We have recently demonstrated that early-stage gastric diffuse large B-cell lymphomas (DLBCLs) with MALToma, as well as their MALToma counterparts, may respond to H pylori eradication therapy (HPET). The present study was conducted to evaluate the effect of HPET in stage IE gastric DLBCLs without MALToma. Methods: Seven patients (4 men and 3 women; age range, 35 to 83 years) with H pylori infection and stage IE gastric DLBCL without MALToma received HPET as first-line treatment from June 2002 through May 2006. Additional immunohistochemical reaction with anticytokeratin was performed to exclude lymphoepithelial lesions (minimal MALToma components) in DLBCL. All patients received intensive endoscopic follow-up examinations with biopsy to evaluate tumor response. Patients with significant improvement of gross lesions that accompanied regression of tumor cells were followed up without additional treatment. Patients without significant improvement were immediately referred to systemic chemotherapy. Tumors that resolved to Wotherspoon grade 2 or less after successful HPET were considered as complete histologic remission. Results: Successful HPET was achieved in all patients. There were 5 patients with complete histologic remission. The complete remission rate was 71.4% (95% confidence interval, 45.1% to 97.7%). The median duration between HPET and complete histologic remission was 2.6 months (range, 1.1 to 5.7 months). At a median follow-up of 24.2 months (range, 5.7 to 56.8 months), all patients with complete histologic remission after HPET were alive and free of lymphoma. Conclusions: A substantial portion of early-stage gastric DLBCLs without MALToma remain H pylori-dependent and can potentially be cured by HPET. No significant financial relationships to disclose.

Therapeutic Comparison of Chemotherapy and Surgery for Early Stage Diffuse Large B-cell Gastric Lymphoma

PurposeThe use of surgery versus stomach-preserving treatment for primary gastric lymphoma has caused controversy among doctors. This retrospective, single center study aims to evaluate the efficacy and benefit of stomach-preserving treatment against surgery for early stage diffuse large B-cell lymphoma of stomach.Materials and MethodsFrom August 1991 to January 2006, 43 cases of early-stage diffuse large B-cell gastric lymphoma were reviewed.ResultsEleven cases were treated with chemotherapy or chemotherapy plus radiation (CT ± RT), 17 were treated with surgery alone (OP), and 15 were treated with surgery plus adjuvant chemotherapy (OP + CT). The complete remission and response rates were 63.6% and 90.9% in those treated with CT ± RT (7 complete responders, 3 partial responders, 1 non-responder), 100% and 100% in those treated with OP, and 100% and 100% in those treated with OP + CT, respectively. Five-year overall survival rates were 85.7%, 87.5%, and 100% in those treated by CT ± RT, OP, and OP + CT, respectively (p = 0.76). The five-year disease free survival rates were 100%, 87.5% and 100% in those treated by CT ± RT, OP, and OP + CT, respectively (p = 0.99). There was no significant difference in overall survival and disease free survival between modalities. Even though there are no definite differences in the number of complications between those treated by CT ± RT or OP, these facts reflect little concern on complications after surgery.ConclusionIn preventing morbidity arising from early or late complications from surgery and promoting quality of life, chemotherapy should be a primary consideration for early stage diffuse large B-cell lymphoma of the stomach.

Consolidation Radiotherapy following Brief Chemotherapy for Localized Diffuse Large B-cell Lymphoma: A Prospective Study

Many physicians administer involved field radiation therapy (RT) following brief chemotherapy for localized aggressive non-Hodgki n's lymphoma. Involved field irradiation usually implies treatment to the involved nodal regions with and without the contiguous lymphatic region, however, there is no agreements about its definition. Here we assess the appropriateness of RT irrespective of lymph node regions (localized field) following chemotherapy for patients with early stage diffuse large B-cell lymphoma. The localized field encompassed all original gross tumor volumes before chemotherapy with at least a 2- to 3-cm margin irrespective of lymphatic regions. We also evaluated the suitable radiation dose on the basis of response to chemotherapy. Twenty five eligible patients were treated with 3 cycles of chemotherapy (CHOP) followed by RT. All 25 patients had disease confined to Waldeye r's ring and/or cervical lymph nodes. Twenty two patients in complete response following chemotherapy received 30 Gy, and the remaining 3 in partial response received 40 Gy. With a median follow up of 42 months, both event free and overall survival rates at 2 years were 96.0%. There were no in-field recurrences, however, two patients experienced relapses. One developed central nervous system involvement and subsequently died of his disease. The other had mediastinal and submental lymph node relapse at 32 months, and is alive after salvage chemotherapy. Our study demonstrated that it should be possible to reduce treatment volume to less than the conventional involved field, and to limit the dose of RT in the range of 30–40 Gy.