RESUMEN
Post-transplant lymphoproliferative disorder (PTLD) is a rare complication of solid organ transplantation, and cytotoxic chemotherapy is associated with treatment-related morbidity and mortality. Current treatment takes a sequential, risk-stratified approach, patients with low-risk disease following initial immunotherapy can avoid escalation to immunochemotherapy. TIDaL is a prospective, single-arm phase 2 trial investigating the activity and tolerability of ibrutinib combined with risk-stratified therapy for first-line treatment of PTLD. Eligible patients were adults with newly-diagnosed CD20-positive B-cell PTLD after solid organ transplant and performance status 0 to 2. Initial treatment comprised 49 days of ibrutinib 560mg once daily, with 4 doses of weekly rituximab. Treatment response on interim scan and baseline international prognostic index were used to allocate patients to either a low-risk arm (who continued ibrutinib, alongside 4 further doses of 3-weekly rituximab) or high-risk (escalation to R-CHOP immunochemotherapy, ibrutinib continuing in patients aged <65 years). The primary outcome was complete response on interim scan, achieved by 11/38 patients (29%, 95% confidence interval (CI) 15% - 46%). This did not reach the pre-specified threshold for clinically significant activity. Secondary outcomes included allocation to the low-risk arm (41% of patients), 2-year progression-free survival (58%, 95% CI 44% - 76%), and 2-year overall survival (76%, 95% CI 63% - 91%). Adverse events were mostly haematological, gastrointestinal and infective. Whilst TIDaL does not support adding ibrutinib into first-line treatment of PTLD, increasing the proportion of patients who can be treated without cytotoxic chemotherapy remains an important aim of future research. This trial was registered as ISRCTN32667607.
RESUMEN
Acute myeloid leukaemia is prevalent in older patients that are often ineligible for intensive chemotherapy and treatment options remain limited with azacitidine being at the forefront. Azacitidine has been used in the clinic for decades, however, we still lack a complete understanding of the mechanisms by which the drug exerts its anti-tumour effect. To gain insight into the mechanism of action, we defined the mutational profile of sequential samples of patients treated with azacitidine. We did not identify any mutations that could predict response and observed lack of a uniform pattern of clonal evolution. Focusing on responders, at remission, we observed three types of response: (1) an almost complete elimination of mutations (33%), (2) no change (17%), and (3) change with no discernible pattern (50%). Heterogeneous patterns were also observed at relapse, with no clonal evolution between remission and relapse in some patients. Lack of clonal evolution suggests that non-genetic mechanisms might be involved. Towards understanding such mechanisms, we investigated the immune microenvironment in a number of patients and we observed lack of a uniform response following therapy. We identified a higher frequency of cytotoxic T cells in responders and higher frequency of naïve helper T cells in non-responders.
RESUMEN
Relapsed or refractory primary central nervous system lymphoma (rrPCNSL) confers a poor prognosis with no accepted standard of care. Very few prospective studies have been conducted in this patient group. This study was a multicenter phase 1/2 study that investigated thiotepa in combination with ifosfamide, etoposide, and rituximab (TIER) for the treatment of PCNSL relapsed or refractory to high-dose methotrexate-based chemotherapy. A 3 + 3 design investigated the recommended phase 2 dose of thiotepa for a single-stage phase 2 cohort by assessing the activity of 2 cycles of TIER against rrPCNSL. The primary outcome was overall response rate. The dose-finding study demonstrated that 50 mg/m2 of thiotepa could be safely delivered within the TIER regimen. No dose-limiting toxicities were encountered in phase 1, and TIER was well-tolerated by the 27 patients treated in phase 2. The most common grade 3 to 4 toxicities were neutropenia (56% of patients) and thrombocytopenia (39%). An overall response was confirmed in 14 patients (52%), which met the prespecified threshold for clinically relevant activity. The median progression-free survival was 3 months (95% confidence interval [CI], 2 to 6 months) and overall survival 5 months (95% CI, 3 to 9 months). Exploratory analyses suggest a greater benefit for thiotepa-naïve patients. Six patients successfully completed autologous stem cell transplantation (ASCT) consolidation, with 4 experiencing durable remissions after a median follow-up of 50 months. The TIER regimen can be delivered safely and is active against rrPCNSL. When it is followed by ASCT, it can provide durable remission and long-term survival. However, for the majority of patients, prognosis remains poor, and novel treatment strategies are urgently needed. This trial was registered at https://www.clinicaltrialsregister.eu/ctr-search/search as EudraCT 2014-000227-24 and ISRCTN 12857473.
