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

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 &amp;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. </jats:sec

Management and Outcomes of Diffuse Large B-cell Lymphoma Post-transplant Lymphoproliferative Disorder in the Era of PET and Rituximab: A Multicenter Study From the Australasian Lymphoma Alliance

There are limited data on post-transplant lymphoproliferative disorder (PTLD) in the era of positron emission tomography (PET) and rituximab (R). Furthermore, there is limited data on the risk of graft rejection with modern practices in reduction in immunosuppression (RIS). We studied 91 patients with monomorphic diffuse large B-cell lymphoma PTLD at 11 Australian centers: median age 52 years, diagnosed between 2004 and 2017, median follow-up 4.7 years (range, 0.5–14.5 y). RIS occurred in 88% of patients. For patients initially treated with R-monotherapy, 45% achieved complete remission, rising to 71% with the addition of rituximab, cyclophosphamide, doxorubicin, vincristine, prednisolone (R-CHOP) for those not in complete remission. For patients initially treated with R-CHOP, the complete remission rate was 76%. There was no difference in overall survival (OS) between R-monotherapy and R-chemotherapy patients. There was no difference in OS for patients with systemic lymphoma (n = 68) versus central nervous system (CNS) involvement (n = 23) (3-y OS 72% versus 73%; P = 0.78). Treatment-related mortality was 7%. End of treatment PET was prognostic for patients with systemic lymphoma with longer OS in the PET negative group (3-y OS 91% versus 57%; P = 0.01). Graft rejection occurred in 9% (n = 4 biopsy-proven; n = 4 suspected) during the entire follow-up period with no cases of graft loss. RIS and R-based treatments are safe and effective with a low likelihood of graft rejection and high cure rate for patients achieving complete remission with CNS or systemic PTLD

Tranexamic acid versus placebo to prevent bleeding in patients with haematological malignancies and severe thrombocytopenia (TREATT): a randomised, double-blind, parallel, phase 3 superiority trial

Background: Bleeding is common in patients with haematological malignancies undergoing intensive therapy. We aimed to assess the effect of tranexamic acid on preventing bleeding and the need for platelet transfusions. Methods: TREATT was an international, randomised, double-blind, parallel, phase 3 superiority trial conducted at 27 haematology centres in Australia and the UK. We enrolled adults (aged ≥18 years) receiving intensive chemotherapy or haematopoietic stem-cell transplantation for a haematological malignancy, with a platelet count of 10 × 109 platelets per L or less for 5 days or longer. Patients were randomly assigned (1:1) using block randomisation, stratified by site, to tranexamic acid (1 g every 8 h intravenously or 1·5g every 8 h orally) or placebo when their platelet count was less than 30 × 109 platelets per L. Treatment was continued until platelet recovery or day 30. Prophylactic platelet transfusions were maintained as standard of care. The primary endpoint was the proportion of patients who died or had WHO grade 2 or higher bleeding up to day 30. A modified intention-to-treat population including randomly assigned patients whose platelet count decreased to 30 × 109 platelets per L or less was used for analysis. This trial is registered with ClinicalTrials.gov (NCT03136445), ISRCTN (ISRCTN73545489), and the European Clinical Trials Register (EudraCT 2014-001513-35). Findings: Between June 23, 2015, and Feb 17, 2022, 1736 patients were screened for eligibility, 616 of whom were enrolled and randomly assigned (310 to tranexamic acid and 306 to placebo). 19 participants were excluded from the modified intention-to-treat analysis, leaving 300 participants in the tranexamic acid group and 297 in the placebo group. Participant median age was 58 years (IQR 49–65), 380 (62%) of 616 participants were male, and 235 (38%) were female. The proportion of participants who died or had WHO grade 2 or higher bleeding was 31·7% (90/298 [95% CI 26·6–37·4]) in the tranexamic acid group and 34·2% (98/295 [29·0–40·0]) in the placebo group (hazard ratio 0·92 [95% CI 0·67–1·27]; p=0·62). There were no differences in thrombotic events or veno-occlusive disease. 94 serious adverse events in 77 participants were reported up to day 60 in the tranexamic acid group and 103 events in 82 participants in the placebo group. Interpretation: There is insufficient evidence to support routine use of tranexamic acid to reduce bleeding in patients with haematological malignancies undergoing intensive chemotherapy. Funding: UK National Health Service Blood and Transplant and Australian National Health and Medical Research Council