Ibrutinib as part of risk-stratified treatment for post-transplant lymphoproliferative disorder: The phase 2 TIDaL trial.

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.

The efficacy and safety of venetoclax therapy in elderly patients with relapsed, refractory chronic lymphocytic leukaemia.

Elderly chronic lymphocytic leukaemia (CLL) patients treated outside of trials have notably greater toxicity with the Bruton's tyrosine kinase inhibitor ibrutinib compared to younger patients. It is not known whether the same holds true for the B-cell lymphoma 2 inhibitor venetoclax. We provide a comprehensive analysis of key safety measures and efficacy in 342 patients comparing age categories ≥75 and <75 years treated in the relapsed, refractory non-trial setting. We demonstrate that venetoclax has equivalent efficacy and safety in relapsed/refractory CLL patients who are elderly, the majority of whom are previous ibrutinib-exposed and therefore may otherwise have few clear therapeutic options.

Efficacy of venetoclax monotherapy in patients with relapsed chronic lymphocytic leukaemia in the post-BCR inhibitor setting: a UK wide analysis.

Venetoclax is a BCL2 inhibitor with activity in relapsed/refractory (R/R) chronic lymphocytic leukaemia (CLL). We conducted a multi-centre retrospective analysis of 105 R/R CLL patients who received venetoclax pre-National Health Service commissioning. The median age was 67 years and median prior lines was 3 (range: 1-15). 48% had TP53 disruption. At ≥2 lines, 60% received a Bruton Tyrosine Kinase inhibitor (BTKi) and no prior phosphoinositide 3-kinase inhibitor (Pi3Ki), 25% received a Pi3Ki and no prior BTKi, and 10% received both. Patients discontinued B cell receptor inhibitor (BCRi) because of toxicity in 44% and progression in 54%. Tumour lysis syndrome risk was low, intermediate or high in 27%, 25%, and 48% respectively. Overall response was 88% (30% complete response [CR]). The overall response rate was 85% (CR 23%) in BTKi-exposed patients, 92% (CR 38%) in Pi3Ki-exposed patients and 80% (CR 20%) in both (P = 0·59). With a median follow-up of 15·6 months, 1-year progression-free survival was 65·0% and 1-year overall survival was 75·1%. Dose reduction or temporary interruption did not result in an inferior progression-free or discontinuation-free survival. Risk of progression or death after stopping a prior BCRi for progression was double compared to those stopping for other reasons (predominantly toxicity) (Hazard Ratio 2·01 P = 0·05). Venetoclax is active and well tolerated in R/R CLL post ≥1 BCRi. Reason(s) for stopping BCRi influences venetoclax outcomes.

Results of a multicentre UK-wide retrospective study evaluating the efficacy of brentuximab vedotin in relapsed, refractory classical Hodgkin lymphoma in the transplant naive setting.

Relapsed or refractory classical Hodgkin lymphoma (cHL) is associated with a poor outcome when standard chemotherapy fails. Brentuximab vedotin (BV) is an anti-CD30 monoclonal antibody-drug conjugate licensed for use at relapse after autologous stem cell transplant (ASCT) or following two prior therapies in those unsuitable for ASCT. There are limited data assessing the ability of BV to enable curative SCT. We performed a UK-wide retrospective study of 99 SCT-naïve relapsed/refractory cHL. All had received 2 prior lines and were deemed fit for transplant but had an insufficient remission to proceed. The median age was 32 years. Most had nodular sclerosis subtype, Eastern Cooperative Oncology Group performance status 0-1 and advanced stage disease. The median progression-free survival (PFS) was 5·6 months and median overall survival (OS) was 37·2 months. The overall response rate was 56% (29% complete response; 27% partial response). 61% reached SCT: 34% immediately post-BV and 27% following an inadequate BV response but were salvaged and underwent deferred SCT. Patients consolidated with SCT had a superior PFS and OS to those not receiving SCT (P < 0·001). BV is an effective, non-toxic bridge to immediate SCT in 34% and deferred SCT in 27%. 39% never reached SCT with a PFS of 3·0 months, demonstrating the unmet need to improve outcomes in those unsuitable for SCT post-BV.

Lenalidomide can be highly effective in chronic lymphocytic leukaemia despite T-cell depletion and deletion of chromosome 17p.

Lenalidomide is an immunomodulatory agent with activity in a range of haematological cancers including chronic lymphocytic leukaemia (CLL). However, major questions remain concerning its effectiveness in patients with T-cell depletion or deletion of TP53 on chromosome 17p. This case report provides insight into these questions by showing that lenalidomide/dexamethasone in combination can be highly effective as induction therapy for refractory 17p-CLL, that remission quality can be improved by subsequent maintenance with lenalidomide alone and that the anti-leukaemic effects of lenalidomide and its stimulatory effects on non-malignant B cells are preserved despite prolonged T-cell depletion resulting from prior alemtuzumab/methylprednisolone.

Allogeneic stem cell transplantation for chronic lymphocytic leukemia in the era of novel agents.

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.