Modified risk-stratified sequential treatment (subcutaneous rituximab with or without chemotherapy) in B-cell Post-transplant lymphoproliferative disorder (PTLD) after Solid organ transplantation (SOT): the prospective multicentre phase II PTLD-2 trial

Abstract

The prospective multicentre Phase II PTLD-2 trial (NCT02042391) tested modified risk-stratification in adult SOT recipients with CD20-positive PTLD based on principles established in the PTLD-1 trials: sequential treatment and risk-stratification. After rituximab monotherapy induction, patients in complete remission as well as those in partial remission with IPI < 3 at diagnosis (low-risk) continued with rituximab monotherapy and thus chemotherapy free. Most others (high-risk) received R-CHOP-21. Thoracic SOT recipients who progressed (very-high-risk) received alternating R-CHOP-21 and modified R-DHAOx. The primary endpoint was event-free survival (EFS) in the low-risk group. The PTLD-1 trials provided historical controls. Rituximab was applied subcutaneously. Of 60 patients enrolled, 21 were low-risk, 28 high-risk and 9 very-high-risk. Overall response was 45/48 (94%, 95% CI 83-98). 2-year Kaplan-Meier estimates of time to progression and overall survival were 78% (95% CI 65-90) and 68% (95% CI 55-80) - similar to the PTLD-1 trials. Treatment-related mortality was 4/59 (7%, 95% CI 2-17). In the low-risk group, 2-year EFS was 66% (95% CI 45-86) versus 52% in the historical comparator that received CHOP (p = 0.432). 2-year OS in the low-risk group was 100%. Results with R-CHOP-21 in high-risk patients confirmed previous results. Immunochemotherapy intensification in very-high-risk patients was disappointing.

Conflict of interest statement

HZ received grant support from ATARA, and other non-financial support from ATARA and Janssen, all outside the submitted work. MHD received grant support and personal fees from Roche, all outside the submitted work. UD received grant support from Celgene and personal fees from Amgen and Celltex Patient Treatment, all outside the submitted work. DH received grants from Abbvie, Astellas, Bayer, BerGenBio, BMS, Daiichi Sankyo, Jazz Pharmaceuticals, Novartis, Pfizer and Roche, personal fees from Abbvie, Eurocept, Jannsen, Jazz Pharmaceuticals, Novartis and Takeda, and other non-financial support from Abbvie, Agios, BMS, Daiichi Sankyo, Jazz Pharmaceuticals, Kura Oncology, Pfizer, PinotBio, Roche and Tolremo, all outside the submitted work. IAH received personal fees from Astellas, Biotest, CareDx Inc., MSD, Novartis, Takeda and Teva, all outside the submitted work. CS received personal fees from BMS, Gliead, Janssen and Novartis and non-financial support from BMS, Gliead, Jannsen, Novartis and Roche, all outside the submitted work. PS received grants from the German research foundation and the German Ministry for Education and Research, all outside the submitted work. MR received personal fees from Abbvie, AstraZeneca, Jannsen, MSD and Roche, all outside the submitted work. NM received non-financial support from GlaxoSmithKline, PharmaMar and Jannsen, all outside the submitted work. RS received grant support from the German Cancer Aid, the German Research Foundation, KKI Buchholz/Holm Seppensen, the BW Foundation and the German Ministry for Education and Research, and personal fees from AstraZeneca, all outside the submitted work. RUT received grant support from Roche during the conduct of the study; grant support from Roche and ATARA, personal fees from Abbvie and ATARA, and other non-financial support from Abbvie, ATARA, Celgene, Janssen and Roche, all outside the submitted work. All other authors declared no conflicts of interest.

© 2022. The Author(s).

Figures

Fig. 1. Modified risk-stratified sequential treatment schedule.

RituximabIV denotes rituximab 375 mg/m2 IV and RituximabSC denotes rituximab 1400 mg SC. PD denotes progressive disease, SD stable disease, PR partial remission and CR complete remission. IPI ≥ 3/<3 denotes three or more/less than three international prognostic index risk factors at diagnosis (age > 60 years, Ann Arbor stage ≥III, ECOG performance status ≥2, elevated LDH, and more than one extranodal disease manifestation). RSC-CHOP-21: rituximab 1400 mg SC day (d) 1, cyclophosphamide 750 mg/m2 IV d1, doxorubicin 50 mg/m2 IV d1, vincristine 1.4 mg/m2 (max. 2 mg, 1 mg if over 70 years) IV d1, and prednisone 50 mg/m2 PO d1-5, every 21 days). RSC-DHAOx is modified R-DHAOx: rituximab 1400 mg SC day d1, oxaliplatin 130 mg/m2 IV d1, cytarabine 2 × 1000 mg/m2 IV d2, dexamethasone 40 mg PO d1. In case of progressive disease from d1 to d50, patients proceeded to R-CHOP-21 immediately. Thoracic SOT recipients are all patients after heart, lung or any other solid organ combined with a heart or a lung transplant. *Dose reduction of 50% in cycle 1 was recommended for patients with ECOG > 2.

Fig. 2. CONSORT diagram illustrating numbers of patients enrolled, treated and evaluated for response in the PTLD-2 trial.

RSC denotes rituximab 1400 mg SC. PD denotes progressive disease, SD stable disease, PR partial remission and CR complete remission. IPI refers to the number of international prognostic factor risk factors. These as well as the RSC-CHOP and RSC-DHAOx regimes are detailed in the Methods section. TRM denotes treatment-related mortality.

Fig. 3. Time-to event outcomes in the intention-to treat population of the PTLD-2 trial (n = 60, except Fig. 3A).

Median time of follow-up was 2.8 years. Numbers at risk are indicated at the bottom of each graph. A Response duration (patients in CR or PR, n = 45). B Time to progression. C Overall survival. D Progression-free survival.

Fig. 4. Event-free survival, overall survival and progression-free survival in the PTLD-2 low-risk group (n = 21, solid line).

The comparator group (n = 25, broken line) are patients in CR (or PR with <3 initial IPI risk factors) after rituximab IV induction who were treated with CHOP consolidation in the PTLD-1 ST trial [13]. Events were infections grade 3/4 from day 50 to day 143, treatment discontinuation for any reason, disease progression and death. Numbers at risk for both populations (PTLD-2 and comparator) are indicated at the bottom of each graph. A Event-free survival (p = 0.432). The 2-year Kaplan–Meier EFS estimate in the low-risk group was 66% (95% CI 45–86); comparator group 52% (95% CI 32–72). B Overall survival (p = 0.324). The 2-year Kaplan–Meier OS estimate in the low risk group was 100%; comparator 88% (95% CI 75–100). C Progression-free survival (p = 0.597). The 2-year Kaplan–Meier PFS estimate in the low-risk group was 85% (95% CI 69–100); comparator group 76% (95% CI 59–93).

Fig. 5. Overall and progression-free survival of 58 patients treated with rituximab monotherapy consolidation in the respective low-risk groups of the PTLD-1 RSST and PTLD-2 trials by complete or partial remission after rituximab induction.

42 patients in CR after rituximab induction in the PTLD-1 RSST (37 patients) and the PTLD-2 trials (5 patients) are denoted by a broken line. 16 patients in PR after rituximab induction with A Overall survival (p = 0.762). B Progression-free survival (p = 0.833).