Concurrent Follicular Lymphoma At Diagnosis Has a Negative Impact On The Outcome Of Patients With Diffuse Large B Cell Lymphoma
Authors: Wrench David , Rizvi Hasan , Wilson Andrew , O'Riain Ciaran , Clear Andrew , Matthews Janet , Laszlo Daniele , Lister T. Andrew , Gribben John G. , Calaminici Maria , Montoto Silvia 
Published: October 2019

Abstract
In contrast to either de novo diffuse large B cell lymphoma (dnDLBCL) or follicular lymphoma (FL) that transforms to DLBCL, the clinical course of DLBCL and FL presenting simultaneously (DLBCL/FL) is not well characterised.
From 1 October 1975 to 31 December 2010, 819 patients were diagnosed with DLBCL at St Bartholomew’s Hospital. Twenty-seven patients with bone marrow (BM) involvement were excluded because of histologies other than FL or DLBCL in the BM (n=2) or unavailable BM samples (n=25). The remaining patients comprised the study population (n=792) which consisted of 45 histologically confirmed DLBCL/FL and 747 dnDLBCL. A pathological review was performed of all DLBCL/FL and all the positive BM samples. Remission duration (RD), progression-free survival (PFS), overall survival (OS) and lymphoma-specific survival (LSS) were compared in DLBCL/FL and dnDLBCL.
DLBCL/FL comprised composite (both histologies in the same tissue sample; n=24) and discordant (both histologies in separate tissue samples; n=21) lymphoma. The majority (n=18, 75%) of composite DLBCL/FL were diagnosed on lymph node (LN) sampling with the remainder identified in tonsil (n=3) with single cases in testis, salivary gland and BM. Discordant DLBCL/FL, presented as DLBCL and FL involving LN and BM respectively in 16 cases (76%). Other combinations included DLBCL and FL in separate LNs (n=2) and one each of kidney + BM, mesentery + LN, bone biopsy + BM.
At presentation, DLBCL/FL had more advanced stage (p<0.01), higher IPI (p=0.02) and lower Hb (p=0.02) than dnDLBCL in keeping with BM involvement rates of 19/45 (42%) and 32/747 (4%), respectively. Most DLBCL/FL (n=42; 93%) received anthracycline based combination chemotherapy (a single case received HD-MTX and 2 cases palliative / no treatment both of whom died within 3.5 months) and, since 2003, addition of rituximab (24% of cases) to CHOP (n=10) or CODOX-M/IVAC (n=1); with similar rates of anthracycline (82%) and rituximab (29%) use in dnDLBCL. The 44 documented responses in DLCBL/FL included complete response (CR, n=26; 59% similar to 66% in 696 patients with dnDLBCL and assessable responses), partial response (n=7) and stable disease/progression (n=11) with a shorter RD for DLBCL/FL (median 8.7 yrs) compared to dnDLBCL (median not reached), although this was not statistically different (p=0.09). PFS was significantly shorter for DLBCL/FL in comparison with dnDLBCL (2.0 versus 4.6 yrs, respectively; p=0.02) and DLBCL/FL not achieving CR had inferior OS (0.4 yrs) than those achieving CR (11.5 yrs; p<0.01). Relapse after CR occurred in 12/26 (46%) patients with DLBCL/FL and in 142/456 (31%; p=0.13) of those with dnDLBCL; 83% and 87% relapsed cases have died, respectively.
With a median follow-up of 10 yrs, 71% patients with DLBCL/FL have died as compared to 65% patients with dnDLBCL, and no differences in median OS were observed (4.0 yrs for DLCBL/FL versus 5.5 yrs for dnDLBCL; p=0.28). Death was most commonly due to lymphoma, the rate being similar in patients with DLBCL/FL (56%) and dnDLBCL (52%). However, LSS was shorter for DLBCL/FL (6.3 yrs) than dnDLBCL (13.8 yrs; p<0.01) and, with the long follow-up, we found no differences in OS between DLBCL with concordant (DLBCL, n=32) or discordant (FL, n=18) BM involvement (p=0.38).
This study, to the authors’ knowledge the largest series of concurrent FL and DLBCL, confirms the relative frequency of DLBCL/FL to DLBCL (45:747, 6%) and demonstrates that the simultaneous presence of FL negatively influences the outcome of patients with DLBCL, by shortening PFS and LSS. This data emphasizes the importance of thorough staging at diagnosis, including BM biopsies, and highlights the need for better management of this population, which has a worse prognosis than dnDLBCL and is frequently excluded from clinical trials.

Disclosures:
No relevant conflicts of interest to declare.