Abstract: Introduction Post-transplant lymphoproliferative disease (PTLD) is a rare and life-threatening complication of solid organ transplantation (SOT). Most are of B-cell origin and treated with rituximab with or without chemotherapy. Patients achieving a complete response (CR) to rituximab have good outcomes and can avoid the excess toxicity of chemotherapy. The prospective PTLD-1 trial reported a CR rate of 25% with rituximab. We postulated adding ibrutinib to rituximab may increase CR rates, avoid chemotherapy for more patients and improve outcomes overall. Methods TIDaL is a prospective, single-arm, phase II trial evaluating the activity of ibrutinib in combination with rituximab (IR), with chemotherapy added using a risk-stratified sequential treatment strategy. Eligible patients had treatment naïve, CD20-positive PTLD of any histologic subtype arising after SOT. Patients required measurable disease and adequate organ function. All patients received ibrutinib 560 mg daily with 4 doses of rituximab 375 mg/m 2 on days 1, 8, 15 and 22. Interim response to IR was assessed by CT scan between days 42-49. Risk stratification for subsequent therapy was based on baseline and interim CT response. Patients were assigned to the low risk arm if they achieved a CR on interim CT (irrespective of IPI) or a partial response (PR) with an IPI of 0-1. They continued with IR receiving 4 further 3-weekly doses of rituximab, ibrutinib continued until 3 weeks after the last dose of rituximab. All other patients were assigned to the high risk arm and received 4 cycles of R-CHOP-21 (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisolone in 21-day cycles). Ibrutinib continued until 3 weeks after the last cycle of R-CHOP for all , . Prophylaxis against Pneumocystis pneumonia was mandated, as was granulocyte colony stimulating factor for all high risk patients. The primary outcome was CR assessed by interim CT. A CR rate of ≥40% was considered to be of interest, with an unacceptable CR rate set at ≤25%. Following a Simon's 2 stage design, 38 evaluable patients would need to be recruited, with at least 12 achieving CR to indicate further investigation is warranted. Secondary outcomes included allocation to the low risk arm, progression free survival (PFS), post-IR PFS (excluding disease progression events during initial IR treatment), overall survival (OS), and treatment tolerability. Results Between January 2017 and March 2020, 39 patients were recruited from 17 sites; 22 male, median age 59 years (range 23 to 76), 28% with IPI 3-5. Transplanted organs were kidney (n=20), liver (n=13), heart (n=4) and lung (n=2). Primary outcome analysis was based on the first 38 patients recruited. After initial IR treatment, 11 patients (29%, 95% confidence interval 15% to 46%) achieved a CR, not reaching the pre-specified threshold. All other analyses were based on the full set of 39 evaluable patients. An overall response (OR) by 7 weeks was seen in 25 patients , comprising 12 CR and 13 PR. Sixteen patients (41%) were subsequently allocated to the low risk arm, 23 (59%) to high risk. , 26 patients (67%, 50% to 81%) achieved an OR (22 CR, 4 PR). After a median follow up of 24 months, 1 year and 2 year outcomes are: PFS 63% (50% to 81%) and 56% (42% to 75%); post-IR PFS 72% (59% to 89%) and 65% (51% to 84%); OS 83% (72% to 96%) and 75% (62% to 92%). Serious adverse events were most commonly infective (38%), and during IR-CHOP therapy (56%). Other common SAEs were gastrointestinal (31%) and haematological (9%). Two patient deaths due to sepsis and Pneumocystis pneumonia were related to treatment, 6 of the 7 further deaths were due to lymphoma. Conclusions Adding ibrutinib to rituximab for the initial treatment of PTLD did not result in a sufficiently high CR rate to warrant further investigation. Survival outcomes (PFS and OS) in our study are similar to those reported previously for rituximab with or without CHOP chemotherapy using a sequential risk stratified treatment approach. Of interest, in comparison to previous reports, a greater proportion of patients (41%) were allocated to low risk and continued IR therapy, thus avoiding cytotoxic chemotherapy. Therefore, the incorporation of novel agents in PTLD management merits further investigation to reduce treatment-related toxicity and improve survival. Figure 1 Figure 1. Disclosures Chaganti: Novartis: Consultancy, Honoraria, Other: Travel support, Research Funding, Speakers Bureau; Takeda: Consultancy, Honoraria, Other: travel support, Research Funding, Speakers Bureau; Celgene-BMS: Consultancy, Honoraria, Other: Travel support; Atara Bio: Consultancy, Honoraria, Research Funding, Speakers Bureau; Kite, a Gilead Company: Consultancy, Honoraria, Other: Travel support, Research Funding, Speakers Bureau; Janssen: Research Funding; Incyte: Honoraria, Speakers Bureau. Cwynarski: Gilead: Consultancy, Speakers Bureau; Incyte: Consultancy, Speakers Bureau; Atara: Consultancy; Celgene: Consultancy; Takeda: Consultancy, Other: travel to scientific conferences, Speakers Bureau; Kite, a Gilead Company: Consultancy, Other: travel to scientific conferences, Speakers Bureau; Janssen: Consultancy, Other: travel to scientific conferences; Roche: Consultancy, Other: travel to scientific conferences, Speakers Bureau; BMS/Celgene: Other: travel to scientific conferences. Fox: Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Other: speaker fees. McKay: Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria, Other: Travel to scientific conferences; KITE: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel to scientific conferences; Janssen: Honoraria, Other: Travel to scientific conferences; Beigene: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS/Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees. Paneesha: Janssen: Honoraria; Gilead: Honoraria; Bristol Myers Squibb: Honoraria; AbbVie: Honoraria; Roche: Honoraria; Celgene: Honoraria. Collins: Beigene: Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Speakers Bureau; Pfizer: Honoraria; Celgene: Research Funding; Amgen: Research Funding; AstraZeneca: Honoraria, Research Funding; ADC Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celleron: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck Sharp & Dohme: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel expenses, Speakers Bureau. Davies: Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel to scientific conferences, Research Funding; Kite: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Honoraria, Research Funding; Karyopharm Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Acerta Pharma/AstraZeneca: Honoraria, Research Funding; ADC Therapeutics: Honoraria, Research Funding; BioInvent: Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel to scientific conferences, Research Funding; Incyte: Membership on an entity's Board of Directors or advisory committees. Menne: Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Kite/Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel grant, Research Funding, Speakers Bureau; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel grants; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel grants; Astra Zeneca: Research Funding; Jazz: Other: Travel grants; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel grants; Bayer: Other: Travel grants; Kyowa Kirin: Other: Travel grants; Daiichi Sankyo: Honoraria, Membership on an entity's Board of Directors or advisory committees; Atara: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Other: Honoraria for Lectures; Roche: Other: Honoraria for Lectures. OffLabel Disclosure: Ibrutinib for PTLD.

Abstract: Although novel agents (NAs) have improved outcomes for patients with chronic lymphocytic leukemia (CLL), a subset will progress through all available NAs. Understanding outcomes for potentially curative modalities including allogeneic hematopoietic stem cell transplantation (alloHCT) following NA therapy is critical while devising treatment sequences aimed at long-term disease control. In this multicenter, retrospective cohort study, we examined 65 patients with CLL who underwent alloHCT following exposure to ≥1 NA, including baseline disease and transplant characteristics, treatment preceding alloHCT, transplant outcomes, treatment following alloHCT, and survival outcomes. Univariable and multivariable analyses evaluated associations between pre-alloHCT factors and progression-free survival (PFS). Twenty-four-month PFS, overall survival (OS), nonrelapse mortality, and relapse incidence were 63%, 81%, 13%, and 27% among patients transplanted for CLL. Day +100 cumulative incidence of grade III-IV acute graft-vs-host disease (GVHD) was 24%; moderate-severe GVHD developed in 27%. Poor-risk disease characteristics, prior NA exposure, complete vs partial remission, and transplant characteristics were not independently associated with PFS. Hematopoietic cell transplantation–specific comorbidity index independently predicts PFS. PFS and OS were not impacted by having received NAs vs both NAs and chemoimmunotherapy, 1 vs ≥2 NAs, or ibrutinib vs venetoclax as the line of therapy immediately pre-alloHCT. AlloHCT remains a viable long-term disease control strategy that overcomes adverse CLL characteristics. Prior NAs do not appear to impact the safety of alloHCT, and survival outcomes are similar regardless of number of NAs received, prior chemoimmunotherapy exposure, or NA immediately preceding alloHCT. Decisions about proceeding to alloHCT should consider comorbidities and anticipated response to remaining therapeutic options.

Abstract: Introduction: Prior to effective novel agent (NA) approval for CLL, alloHSCT was recommended for CLL patients (pts) with early relapse/refractory disease after purine-analogs or deletion 17p (del17p) or TP53 mutation (TP53mut) based on expert consensus and retrospectively demonstrated overall survival (OS) advantage. Since 2014, approvals of ibrutinib (ibr), venetoclax (ven), and PI3K inhibitors (PI3Ki) have led to fewer alloHSCT for CLL. While NAs are indisputably effective, many pts will eventually progress through all available NAs. In the absence of data-driven consensus regarding role of alloHSCT for CLL, decision about proceeding to transplant is currently based on disease and transplant risk, response to NAs, and pt preference. This study of CLL pts who underwent alloHSCT following NA therapy (tx) aimed to help define the role of this potentially curative modality in the era of NAs. Methods: This multicenter, retrospective cohort study examined CLL pts who underwent alloHSCT following treatment with ≥ 1 NA, including baseline clinical, prognostic, and transplant characteristics, tx preceding alloHSCT, transplant outcomes, and tx following alloHSCT. Complex karyotype (CK) and CLL status [complete remission (CR), partial remission (PR), stable disease (SD), and progression of disease (POD)] were defined per iwCLL criteria (Hallek, et al. Blood 2018) . Univariate analyses utilizing COX regression evaluated association between pre-alloHSCT factors and progression free survival (PFS). PFS, OS, and non-relapse mortality (NRM) were estimated using Kaplan Meier and life table methods. Other statistics were descriptive. Results: 69 pts with CLL underwent alloHSCT following ≥ 1 NA across 14 US and EU centers, including 6 pts with Richter's transformation (RT) prior to alloHSCT. Table 1 describes baseline characteristics. Prior to alloHSCT, 78% received ibr (n=53), 39% ven (n=25), 20% PI3Ki (n=13), and 36% ≥ 2 NAs. 90% (n=62) received a NA immediately preceding alloHSCT [n=32 ibr (16% CR, 75% PR, 9% SD/POD), n=25 ven (52% CR, 40% PR, 8% SD/POD), 4 PI3Ki (75% PR, 25% SD/POD), 1 IMiD]. With a median (med) follow up 28 months (mo; range 1.2 -85), med PFS and OS from alloHSCT for the entire cohort were not reached (Figure 1A, B). PFS and OS for pts with CLL (excluding RT pts) from alloHSCT were 60% and 82% at 24 mo respectively. Poor risk disease characteristics (TP53mut, del17p, CK), prior NA exposure (ibr, ven, PI3Ki, ≥2 NAs), and transplant characteristics (matched (8/8) vs. mismatched ( 〈 8/8) donor, positive CMV serology) were not associated with inferior PFS (Table 2). NRM was 3.4% at D+100, 8.9% at 12 mo, 10.4% at 24 mo. Acute graft-vs-host disease (GHVD) was observed in 52% (med onset = D+49); moderate-severe chronic GVHD occurred in 26%. Fifteen deaths (22%) were observed due to POD (n=6), infection (n=7), GVHD (n=2). 21 pts relapsed following alloHSCT; post HSCT pts were treated with ibr (n=6), ven (n=6), rituximab (n=3), R-CHOP (n=2), R-HyperCVAD (n=1), second alloHSCT (n=1). To guide decision making about timing of alloHSCT, we examined pts who received 1 (n=44) vs. ≥2 (n=25) NAs. These groups were similar in terms of poor risk features (del 17p 48% vs. 38%, TP53mut 44% vs. 40%, del11q 21% vs. 36%, CK 41% vs. 54%), transplant risk (med age 60 for both groups, med HSCT-CI 0 vs. 1, matched donor 86% vs. 71%), and disease status prior to alloHSCT (CR 25% vs. 40%, PR 66% vs. 48%, SD/POD 9% vs. 12%). PFS was similar for those exposed to 1 vs. ≥ 2 NAs (Figure 1C). Disease status at time of alloHSCT and hematopoietic cell transplantation-specific comorbidity index (HCT-CI) significantly impacted PFS (Figure 1D, E). Conclusions: In the largest series of alloHSCT following NAs, data demonstrate that alloHSCT remains a viable curative strategy that can overcome adverse CLL characteristics including TP53 disruption and CK. As many pts treated with ibr and/or ven will progress or be intolerant, alloHSCT should be included in treatment algorithms for appropriate candidates. These data suggest that exposure to 1 vs. ≥2 prior NAs did not impact outcomes, though disease status at time of alloHSCT and HCT-CI are important predictors of PFS. Therefore, decision about proceeding to alloHSCT should consider comorbidities and current depth of response, as well as anticipated depth of response with the therapeutic options remaining. These data may significantly add to development of evidence-based guidelines for alloHSCT in the era of NAs. Figure 1 Disclosures Roeker: AbbVie: Equity Ownership; Abbott Laboratories: Equity Ownership. Brown:TG Therapeutics: Consultancy; Verastem: Consultancy, Research Funding; Sun Pharmaceuticals: Research Funding; Janssen: Honoraria; Teva: Honoraria; Morphosys: Other: Data safety monitoring board; Invectys: Other: Data safety monitoring board; Octapharma: Consultancy; Dynamo Therapeutics: Consultancy; Sunesis: Consultancy; Juno/Celgene: Consultancy; Genentech/Roche: Consultancy; Gilead: Consultancy, Research Funding; Catapult Therapeutics: Consultancy; AbbVie: Consultancy; Acerta Pharma: Consultancy; AstraZeneca: Consultancy; BeiGene: Consultancy; Novartis: Consultancy; Pfizer: Consultancy; Loxo: Consultancy, Research Funding; Kite, a Gilead Company: Consultancy, Research Funding; Pharmacyclics: Consultancy. Dreger:AbbVie, AstraZeneca, Gilead, Janssen, Novartis, Riemser, Roche: Consultancy; AbbVie, Gilead, Novartis, Riemser, Roche: Speakers Bureau; MSD: Membership on an entity's Board of Directors or advisory committees, Other: Sponsoring of Symposia; Neovii, Riemser: Research Funding. Eyre:Roche: Honoraria; Abbvie: Honoraria, Other: Travel to Conferences; Takeda: Other: Travel to Conferences ; Gilead: Consultancy, Other: Research support, Speakers Bureau; Janssen: Honoraria, Other: Travel to Conferences . Brander:AbbVie: Consultancy, Honoraria, Research Funding; Genentech: Consultancy, Honoraria, Research Funding; Teva: Consultancy, Honoraria; Tolero: Research Funding; Acerta: Research Funding; TG Therapeutics: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy, Research Funding; Novartis: Consultancy; Pharmacyclics LLC, an AbbVie Company: Consultancy; BeiGene: Research Funding; DTRM Biopharma: Research Funding; MEI: Research Funding. Skarbnik:Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pharmacyclics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Verastem Oncology: Honoraria, Research Funding, Speakers Bureau; Kite Pharma: Honoraria, Speakers Bureau; Gilead Sciences: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Consultancy, Honoraria, Speakers Bureau; Acerta: Research Funding; Seattle Genetics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Genentech: Honoraria, Speakers Bureau; CLL Society: Consultancy, Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Speakers Bureau; Novartis: Speakers Bureau. Coombs:H3 Biomedicine: Research Funding. Orchard:Pfizer: Membership on an entity's Board of Directors or advisory committees; Jazz Pharma: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees, Other: Unrestricted educational award for regional meetings ; Incyte: Other: Unrestricted educational award for regional meetings ; Adienne: Other: Unrestricted educational award for regional meetings . Sauter:Juno Therapeutics: Consultancy, Research Funding; Sanofi-Genzyme: Consultancy, Research Funding; Spectrum Pharmaceuticals: Consultancy; Novartis: Consultancy; Celgene: Consultancy; Kite/Gilead: Consultancy; Precision Biosciences: Consultancy; Genmab: Consultancy; GSK: Consultancy. Giralt:Johnson & Johnson: Consultancy, Research Funding; Jazz Pharmaceuticals: Consultancy; Kite: Consultancy; Amgen: Consultancy, Research Funding; Actinium: Consultancy, Research Funding; Novartis: Consultancy; Miltenyi: Research Funding; Takeda: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Spectrum Pharmaceuticals: Consultancy. Perales:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Meyers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Omeros: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Merck: Consultancy, Honoraria; Medigene: Membership on an entity's Board of Directors or advisory committees; Servier: Membership on an entity's Board of Directors or advisory committees; Kyte/Gilead: Research Funding; Nektar Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bellicum: 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; Miltenyi: Research Funding; NexImmune: Membership on an entity's Board of Directors or advisory committees; MolMed: Membership on an entity's Board of Directors or advisory committees. Mato:Celgene: Consultancy; AbbVie: Consultancy, Research Funding; TG Therapeutics: Consultancy, Other: DSMB member , Research Funding; LOXO: Consultancy, Research Funding; DTRM Biopharma: Research Funding; Genentech: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding; Gilead: Research Funding; Acerta: Consultancy; Janssen: Consultancy; AstraZeneca: Consultancy, Research Funding; Sunesis: Consultancy, Research Funding; Johnson & Johnson: Consultancy, Research Funding.