Clinical Investigation
Patterns of Failure in Patients With Double Hit or Double Expressor Lymphomas: Implications for Radiation Therapy

https://doi.org/10.1016/j.ijrobp.2018.01.041Get rights and content

Purpose

Lymphomas with MYC and either BLC2 or BCL6 rearrangements or MYC and BCL-2 protein overexpression, classified as double-hit (DHL) or double-expressor (DEL) lymphomas, respectively, are associated with poorer response to standard immunochemotherapy. Optimal therapy is not clear, and little information exists on the contribution of consolidative radiation therapy in these patients. This study describes the patterns of failure of DHL/DEL in relation to initial sites of disease and indications for radiation therapy in unselected diffuse large B-cell lymphoma (DLBCL).

Methods and Materials

A retrospective single-institution study of all patients with diagnoses of non-Hodgkin lymphoma between 2011 and 2015 was performed. DHL status was determined by fluorescence in-situ hybridization, and DEL status was determined by immunohistochemistry. Progression-free survival (PFS) was calculated from the end of chemotherapy using the Kaplan-Meier method. Cox modeling was used for multivariable analysis.

Results

Screening of 275 DLBCL patients yielded a 53-patient cohort, including 32 patients with DHL, 10 with DEL, 9 with a triple rearrangement, and 2 triple expressors. Of the 26 patients whose disease progressed, 15 had primary refractory disease. The remaining 11 failures were relapses after complete response to initial chemotherapy. Of those failures, 6 (55%) occurred at initially involved site(s), and 4 (36%) were isolated initial site relapses. Consolidative radiation therapy was associated significantly with improved PFS on multivariable analysis (hazard ratio 0.17, 95% confidence interval 0.02-0.94, P = .04).

Conclusions

DHL/DEL are associated with high relapse rates, which preferentially occur at initially involved sites. Among patients achieving complete response to chemotherapy, consolidative radiation therapy was associated with improved PFS. This provides a rationale for the continued role of radiation therapy in the treatment of DHL and DEL and requires validation in a larger cohort.

Introduction

Standard immunochemotherapy of rituxan, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) for diffuse large B-cell lymphoma (DLBCL) in unselected patients produces 6-year progression-free survival (PFS) in excess of 80% 1, 2. However, up to one-fourth of DLBCL harbor MYC and BLC2 or BCL6 gene rearrangements or protein overexpression, known as double-hit lymphomas (DHL) or double-expressor lymphomas (DEL), respectively, and are associated with significantly worse prognosis and response to traditional immunochemotherapy 3, 4, 5, 6. Although alternative intensified regimens have been associated with improved outcomes in nonrandomized experiences, the optimal therapy for DHL/DEL remains unclear 7, 8.

Similarly, whereas the role of consolidative radiation therapy is well delineated for limited stage disease and for bulky, partially responding, or special extranodal sites such as skeletal involvement 9, 10, 11, 12, 13, its effect in DHL/DEL specifically remains undefined. Descriptive studies have associated DHL/DEL with a predilection for extranodal and advanced stage presentation, and also with a poor response to immunochemotherapy and dismal salvage outcomes upon relapse 14, 15. This set of features thus may be suspected to alter or even obviate the traditional benefit of consolidative radiation therapy because of the competing risk of relapse at nonirradiated sites.

This study sought to detail the patterns of failure of DHL/DEL after immunochemotherapy and to analyze the implications for the role of radiation therapy for traditional indications in DLBCL.

Section snippets

Patient cohort

After institutional review board approval, a retrospective review was conducted on 275 cases of DLBCL diagnosed from 2011 to 2015 at 2 hospital systems within the same institution. DHL status was determined by fluorescence in-situ hybridization (FISH) for classic rearrangements in MYC and BCL-2 or BCL-6. DEL status was determined by immunohistochemistry (IHC) showing protein overexpression of MYC (≥40%) and BCL-2 (≥50%), in concordance with most prior analyses on DEL 16, 17 and the most recent

Analyses

Primary refractory disease was defined as progression or Lugano 4 to 5 (19) response on 18F-FDG positron emission tomography (PET) within 90 days of the completion of systemic or radiation therapy, if delivered. Complete response to chemotherapy was defined as achievement of a Lugano 1 to 3 response at end of therapy PET. Pattern of recurrence was delineated as at initially involved sites or at other (distant) sites, based on clinical or radiographic progression. Estimates of rates of local

Patient characteristics and treatments

Our inclusion criteria yielded 53 patients with DHL/DEL, including 32 with DHL, 10 with DEL, 2 triple expressors, and 9 triple rearranged patients. Corresponding to a change from on-request to reflexive testing for DHL status by FISH in 2014, the yield for DHL/DEL among DLBCL diagnoses increased from 15% (24/161 cases) to 25% (29/114) (Fisher's exact test P = .04) during the study period. The median follow-up time was 10 months. A total of 6 (11%) patients were stage I, 8 (15%) were stage II, 7

Patterns of Failure

Among those patients with complete response to chemotherapy, 11/38 (crude rate 29%) subsequently experienced relapse, as detailed in Table 2. Nine of these relapses were in patients with advanced disease at presentation: 6 with extranodal involvement, 2 with pulmonary involvement, 2 with more than 1 extranodal site, and 1 with only bone marrow involvement. The pattern of failure was at initially involved site(s) of disease in 6/11 (55%) of patients, of which 4 (36%) were isolated initial site

Prognostic Factor Analysis

Given the strong contribution of initially involved sites to relapse pattern and the potential implication on decision making for radiation therapy, we assessed for factors associated with recurrence, specifically recurrence at initially involved sites, in those patients achieving complete response to chemotherapy. We excluded primary refractory patients from this analysis because they had already experienced progression and did not inform decision making regarding consolidative radiation

Discussion

DHL/DEL are separate entities from traditional DLBCL, with significantly worse response to traditional immunochemotherapy and higher rates of presentation with advanced and extranodal disease 3, 4, 5, 6. Owing to the presumed competing risk of relapse at multifocal sites and increasing use of intensified immunochemotherapy, the role of consolidative radiation therapy in DHL/DEL remains unclear. In this single-institution retrospective study, we sought to determine the patterns of failure of DHL

References (21)

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Conflict of interest: none.

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