Management and Outcomes of Diffuse Large B Cell Lymphoma Post-Transplant Lymphoproliferative Disorder in the PET/CT Era: A Multicentre Study from the Australasian Lymphoma Alliance
Authors: Boyle Stephen , Tobin Joshua W.D. , Perram Jacinta , Hamad Nada , Barraclough Allison , Singaraveloo Lydia , Han Min-Hi , Blennerhassett Richard , Nelson Niles Elizabeth , Johnston Anna , Talaulikar Dipti , Karpe Krishna , Bhattacharyya Abir , Cheah Chan Yoon , Subramoniapillai Elango , Bokhari Waqas , Lee Cindy , Hawkes Eliza A , Gullapalli Veena , Jabbour Andrew , Strasser Simone , Chadban Steve , Brown Christina , Mollee Peter , Hapgood Greg 
Published: February 2021

Introduction
Post-transplant lymphoproliferative disorders (PTLD) are aggressive lymphomas which occur in solid organ transplant recipients and cause significant mortality. In the era of positron emission tomography (PET) staging and rituximab (R), there is limited real-world data on treatment outcomes and the incidence of graft rejection after reduction in immunosuppression (RIS) has not been well defined. We report real-world outcomes of monomorphic diffuse large B cell lymphoma (DLBCL), the commonest histological subtype of PTLD in which treatment is most likely to be standardised.
Methods
We conducted a multicentre retrospective study across 11 Australian tertiary referral centres. Inclusion criteria were: (1) age ≥ 18 years with history of solid organ transplant; (2) a diagnosis of monomorphic DLBCL PTLD between January 2004 and December 2017; (3) staging with PET. We examined responses based on treatment: (1) 'R-primary' was defined as patients receiving initial rituximab monotherapy followed by further rituximab monotherapy for patients in remission or R-CHOP chemotherapy for patients with persistent or progressive disease; (2) 'R-chemotherapy' was defined as patients who received rituximab-based chemotherapy at diagnosis. Response assessment was defined according to current international lymphoma criteria (complete metabolic remission (CMR) = Deauville score 1-3). We examined the incidence of clinical and biopsy-proven graft rejection during and after PTLD diagnosis (early &lt;1 year; late ≥1 year). Survival was analysed using the Kaplan-Meier method with the log rank test used to compare groups.
Results
91 DLBCL patients were identified. The median follow-up of living patients was 4.7 years (range 0.5-14.5 years). Baseline characteristics for all patients are shown in Table 1.
Management approaches:
Reduction in immunosuppression (RIS) was used in 88% of patients and rituximab (R) +/- chemotherapy in almost all patients (98%, n=89). Rituximab monotherapy (R-primary) was the first treatment in 24 patients (35%). Of these, 20 had PET restaging after rituximab and 9 patients (45%) achieved CMR and did not require chemotherapy. CMR rate rose to 71% with the subsequent addition of R-CHOP in R-primary non-responders. For patients initially treated with R-CHOP, the CMR rate was 76%. The incidence of graft rejection was 9% for the entire duration of follow up (n=4 biopsy-proven; n=4 clinically suspected) with 3 cases occurring within one year of PTLD diagnosis (Table 2).
Survival and Prognostic Factors
For the entire cohort, 3-y OS and PFS were 72% and 69%, respectively. There was no significant difference in OS between patients treated with an R-primary vs R-chemotherapy approach (P=0.13). Treatment-related mortality (TRM) was 7% with no significant difference between R-primary and R-chemotherapy approach (p=0.97). Outcomes for patients without CNS involvement (n=68) were comparable to patients with CNS involvement (n=23): 3-y OS 72.5% non-CNS vs 73.1% CNS; (P=0.78) - Figure 1. In multivariate analysis, elevated LDH (HR=3.58, P=0.025 [95% CI 1.17-10.8]) and ECOG ≥2 (HR=3.46, P=0.006 [95% CI 1.43-8.33]) were identified as predictors of worse OS.
End of Treatment (EoT) PET imaging
A total of 60 patients (66%) had EoT PET. Reasons for not performing an EoT PET (n=31) were: 7 MRI scans for CNS disease, 2 CT scans without PET, 10 patients without imaging (6 PD, 4 TRM), 12 missing data. Achieving CMR at EoT PET was predictive of OS (3-year OS PET negative 92.9% vs PET positive 51.4%; P=0.035) and only 5% of these patients relapsed (Figure 2).
Conclusions
In one of the largest real-world assessments of monomorphic DLBCL PTLD in the modern era of rituximab and PET imaging our data demonstrate: (1) similar response rate, OS and TRM compared to the PTLD-1 trial (Trappe et al, 2017); (2) the safety and efficacy of an R-primary approach; (3) similar OS for patients with CNS involvement compared to those with systemic lymphoma; (4) lower incidence of graft rejection than previously reported; and (5) achieving CMR at EOT PET is predictive of OS. This demonstrates that RIS and rituximab-based treatment is safe with a low likelihood of graft rejection and effective with a high cure rate for patients achieving CMR.

Disclosures
Tobin: Gilead: Research Funding. Hamad:Novartis: Honoraria; Abbvie: Honoraria. Talaulikar:Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Cheah:Celgene, F. Hoffmann-La Roche, Abbvie, MSD: Research Funding; Celgene, F. Hoffmann-La Roche, MSD, Janssen, Gilead, Ascentage Pharma, Acerta, Loxo Oncology, TG therapeutics: Honoraria. Lee:Celgene/BMS: Consultancy; Amgen: Consultancy; Janssen: Consultancy. Strasser:Gilead Sciences: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bayer Healthcare: Honoraria, Membership on an entity's Board of Directors or advisory committees; Ispen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Eisai: Honoraria, Membership on an entity's Board of Directors or advisory committees; MSD: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees; CSL Behring: Honoraria, Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Astellas: Honoraria, Membership on an entity's Board of Directors or advisory committees. Mollee:Pfizer: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS/Celgene: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Caelum: Membership on an entity's Board of Directors or advisory committees.