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.
Background: Ibrutinib (IBR) inhibits CLL proliferation and effects prolonged remission without eradicating disease. Obinutuzumab (OBI) is an anti-CD20 monoclonal antibody that can effect depletion of measurable residual disease (MRD) below 0.01%. In the IcICLLe study (ISRCTN12695354), 20 treatment-naïve (TN) CLL patients & 20 with relapsed/refractory (R/R) CLL received IBR until complete remission with <0.01% MRD in the bone marrow (BM) or disease progression. The IcICLLe Extension Study examined the efficacy/safety of combining IBR & OBI in 40 patients with R/R CLL and was open to the IcICLLe R/R cohort. Initial results after 1 month of combination treatment indicated that adding OBI to IBR improved CLL depletion, and 3-5 year follow-up data is now available. Aim: To assess the long-term MRD response status for patients treated with IBR as a sole agent or in combination with OBI. Patients: Patients received continuous IBR (420mg OD) with the addition of 6 cycles of OBI given over 6 months in the extension study. 20 TN patients received IBR monotherapy; 20 R/R patients (median 2 prior treatments, range 1-7) initiated IBR monotherapy of which 10/20 enrolled in the Extension study receiving OBI after >1year of IBR monotherapy; and 30 IBR-naïve R/R (median 1 prior treatment, range 1-3) started OBI 24 hours after first IBR dose. MRD assessment was performed according to ERIC guidelines with a maximum detection limit of 0.001%/10-5. Results: IBR monotherapy in TN patients was well tolerated with 18/20 patients alive and 13/20 remaining on IBR after median 4.9 years follow-up (range 0-5.9). IBR was stopped due to toxicity (3), progression/relapse (2) or other causes (2). IBR-monotherapy resulted in median 0.65 log depletion per year in years 1-2, followed by relatively stable disease levels (median 0.2 log depletion per year) in the subsequent 3 years in 13/20 evaluable patients. Only 1 patient showed >0.3log increase in PB MRD level and this preceded clinical progression. No patients achieved an IWCLL CR/CRi and MRD was >0.01% in PB/BM in all patients at all time points. In the R/R group initially receiving IBR-monotherapy, 11/20 patients remain alive and 3/20 remain on IBR after a median 3.9 years follow-up (range 0.3-5.3). In this heavily pre-treated group, 10 did not enrol on the OBI Extension study (1 died, 1 progression/relapse, 4 ineligible/other causes, 4 patient preference) with 10/20 receiving OBI at median 16.2 months (range 13-19) after starting IBR-monotherapy of which 7/10 had resolved any lymphadenopathy pre-OBI. 2/10 achieved MRD-negative remission and stopped treatment, while 6/10 have since stopped IBR due to death (2), progression/relapse (3) or other causes (1). 30 R/R patients with no prior IBR exposure (most in first relapse) started IBR & OBI at the same time: 26/30 remain alive and 18/30 remain on IBR after median 3.0 years follow-up (range 0.8-4.2). IBR was stopped in 2/30 patients achieving MRD-negative remission while 10 stopped IBR due to death (2), disease progression/transformation (3), toxicity (4), or patient decision (1). There were no Grade 5 adverse events related to OBI. 3 months post-OBI, patients with >1 year prior IBR-monotherapy achieved a higher response rate (CR/CRi 50% vs. 30%), MRD response (<0.01% BM MRD in 50% vs. 6%) and a greater depth of remission (3.1 vs. 1.5 log reduction) compared to IBR-naive patients despite greater number of prior treatment lines. The deepest PB MRD responses were observed 6-12 months after the last OBI infusion. MRD levels showed little change in the following year to month 24 (median 0 log depletion, range 1.3 log depletion to 2.5 log increase). After 2 years of IBR exposure, the MRD levels shows a similar pattern to TN patients on IBR monotherapy, being generally very stable (<0.3log increase) except in 7 patients showing >0.3log increase at two sequential timepoints of which 4/7 have shown clinical disease progression and 3/7 still have low (<1%) but rising MRD levels. Conclusions: The addition of OBI to IBR may substantially improve depletion of CLL cells from the PB and BM. A greater impact in MRD response rate and depth was seen when OBI was introduced after >1 year of IBR treatment and tumour bulk was low. One fifth of patients maintain <0.01% MRD up to 3 years after combined IBR+OBI, demonstrating that response improvements associated with OBI are sustainable in some cases. Figure 1 Disclosures Rawstron: Abbvie: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Pharmacyclics: Consultancy, Honoraria, Research Funding; Roche: Honoraria, Research Funding. Hillmen:AbbVie: Speakers Bureau; Janssen: Speakers Bureau; Gilead: Speakers Bureau; Pharmacyclics: Other: Financial or Material spport; Morphosys: Other: Consulting fees; Sunesis: Other: Consulting fees. Brock:AstraZeneca: Current equity holder in publicly-traded company; GlaxoSmithKline: Current equity holder in publicly-traded company; Eli Lilly: Other: Consulting and speaker fees; Invex: Other: Consulting and speaker fees; Merck: Other: Reimbursement of costs. Patten:Roche: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astra Zeneca: Honoraria; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Pettitt:Chugai: Research Funding; Gilead: Honoraria, Other: Hospitality, Research Funding; Kite: Honoraria, Other: Hospitality, Research Funding; Celgene: Other: Hospitality, Research Funding; GSK: Research Funding; Novartis: Research Funding; Napp: Research Funding; Roche: Honoraria, Other: Hospitality, Research Funding. Fox:Abbvie: Honoraria, Research Funding; Adienne: Honoraria, Research Funding; AstraZeneca: Research Funding; Celgene: Research Funding; Sunesis: Research Funding; Atarabio: Research Funding; Roche: Honoraria, Research Funding; Takeda: Honoraria, Research Funding; Gilead: Honoraria, Research Funding. Bloor:Abbvie: Consultancy, Honoraria, Other: Conference Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Other: Conference Funding , Speakers Bureau. Hillmen:Apellis: Consultancy, Research Funding, Speakers Bureau; Gilead: Other: Financial or material support, Research Funding; AstraZeneca: Consultancy, Speakers Bureau; Acerta: Other: Financial or material support; Roche: Consultancy, Other: Financial or material support, Research Funding, Speakers Bureau; AbbVie: Consultancy, Other: Financial or material support, Research Funding, Speakers Bureau; Pharmacyclics: Other: Financial or material support, Research Funding; Janssen: Consultancy, Other: Financial or material support, Research Funding, Speakers Bureau; Alexion: Consultancy, Research Funding, Speakers Bureau.
Background For patients with acute myeloid leukaemia (AML), the only potentially curative treatment is intensive chemotherapy (IC). This is highly toxic, particularly for patients > 60 years, potentially leading to prolonged hospitalisations requiring intensive supportive care, and sometimes treatment-related death. This also results in extensive healthcare costs and negatively impacts quality of life (QoL). Venetoclax with low-dose cytarabine (VEN + LDAC) is a novel, low-intensity treatment for AML patients who cannot receive IC. VEN + LDAC is given as an outpatient and toxicity appears significantly lower than with IC. Analysis of clinical trials performed to date are promising for patients with the genotype NPM1mutFLT3 ITDneg, where remission and survival rates appear comparable to those achieved with IC. Methods VICTOR is an international, two-arm, open-label, multi-centre, non-inferiority, randomised-controlled phase II trial to assess VEN + LDAC compared to standard of care (IC) as first-line treatment in older patients (initially aged ≥ 60 years) with newly diagnosed AML. The trial will recruit patients with a NPM1mutFLT3 ITDneg genotype; those with a favourable risk in relation to the experimental treatment. University of Birmingham is the UK co-ordinating centre, with national hubs in Aarhus University Hospital, Denmark, and Auckland District Health Board, New Zealand. The primary outcome is molecular event-free survival time where an event is defined as failure to achieve morphological complete response (CR) or CR with incomplete blood count recovery after two cycles of therapy; molecular persistence, progression or relapse requiring treatment change; morphological relapse, or; death. Secondary outcomes include cumulative resource use at 12- and 24-months, and QoL as assessed by EORTCQLQ-C30 and EQ-5D-3L at 3-, 6-, 12-, 18- and 24-months. The trial employs an innovative Bayesian design with target sample size of 156 patients aged > 60 years. Discussion The principle underpinning the VICTOR trial is that the chance of cure for patients in the experimental arm should not be compromised, therefore, an adaptive design with regular checks on accumulating data has been employed, which will allow for a staged expansion of the trial population to include younger patients if, and when, there is sufficient evidence of non-inferiority in older patients. Trial registration EudraCT: 2020–000,273-24; 21-Aug-2020. ISRCTN: 15,567,173; 08-Dec-2020.
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