Safety of bendamustine for the treatment of indolent non-Hodgkin lymphoma: a UK real-world experience.

ABSTRACT: Bendamustine is among the most effective chemotherapeutics for indolent B-cell non-Hodgkin lymphomas (iNHL), but trial reports of significant toxicity, including opportunistic infections and excess deaths, led to prescriber warnings. We conducted a multicenter observational study evaluating bendamustine toxicity in real-world practice. Patients receiving at least 1 dose of bendamustine with/without rituximab (R) for iNHL were included. Demographics, lymphoma and treatment details, and grade 3 to 5 adverse events (AEs) were analyzed and correlated. In total, 323 patients were enrolled from 9 National Health Service hospitals. Most patients (96%) received bendamustine-R, and 46%, R maintenance. Overall, 21.7% experienced serious AEs (SAE) related to treatment, including infections in 12%, with absolute risk highest during induction (63%), maintenance (20%), and follow-up (17%) and the relative risk highest during maintenance (54%), induction (34%), and follow-up (28%). Toxicity led to permanent treatment discontinuation for 13% of patients, and 2.8% died of bendamustine-related infections (n = 5), myelodysplastic syndrome (n = 3), and cardiac disease (n = 1). More SAEs per patient were reported in patients with mantle cell lymphoma, poor preinduction performance status (PS), poor premaintenance PS, and abnormal preinduction total globulins and in those receiving growth factors. Use of antimicrobial prophylaxis was variable, and 3 of 10 opportunistic infections occurred despite prophylaxis. In this real-world analysis, bendamustine-related deaths and treatment discontinuation were similar to those of trial populations of younger, fitter patients. Poor PS, mantle cell histology, and maintenance R were potential risk factors. Infections, including late onset events, were the most common treatment-related SAE and cause of death, warranting extended antimicrobial prophylaxis and infectious surveillance, especially for maintenance-treated patients.

Humoral and cellular responses to SARS-CoV-2 in patients with B-cell haematological malignancies improve with successive vaccination.

Patients with haematological malignancies are more likely to have poor responses to vaccination. Here we provide detailed analysis of the humoral and cellular responses to COVID-19 vaccination in 69 patients with B-cell malignancies. Measurement of anti-spike IgG in serum demonstrated a low seroconversion rate with 27.1% and 46.8% of patients seroconverting after the first and second doses of vaccine, respectively. In vitro pseudoneutralisation assays demonstrated a poor neutralising response, with 12.5% and 29.5% of patients producing a measurable neutralising titre after the first and second doses, respectively. A third dose increased seropositivity to 54.3% and neutralisation to 51.5%, while a fourth dose further increased both seropositivity and neutralisation to 87.9%. Neutralisation titres post-fourth dose showed a positive correlation with the size of the B-cell population measured by flow cytometry, suggesting an improved response correlating with recovery of the B-cell compartment after B-cell depletion treatments. In contrast, interferon gamma ELISpot analysis showed a largely intact T-cell response, with the percentage of patients producing a measurable response boosted by the second dose to 75.5%. This response was maintained thereafter, with only a small increase following the third and fourth doses, irrespective of the serological response at these timepoints.

Anti-CCR9 chimeric antigen receptor T cells for T-cell acute lymphoblastic leukemia.

T cell acute lymphoblastic leukemia (T-ALL) is an aggressive malignancy of immature T lymphocytes, associated with higher rates of induction failure compared with those in B cell acute lymphoblastic leukemia. The potent immunotherapeutic approaches applied in B cell acute lymphoblastic leukemia, which have revolutionized the treatment paradigm, have proven more challenging in T-ALL, largely due to a lack of target antigens expressed on malignant but not healthy T cells. Unlike B cell depletion, T-cell aplasia is highly toxic. Here, we show that the chemokine receptor CCR9 is expressed in >70% of cases of T-ALL, including >85% of relapsed/refractory disease, and only on a small fraction (<5%) of normal T cells. Using cell line models and patient-derived xenografts, we found that chimeric antigen receptor (CAR) T-cells targeting CCR9 are resistant to fratricide and have potent antileukemic activity both in vitro and in vivo, even at low target antigen density. We propose that anti-CCR9 CAR-T cells could be a highly effective treatment strategy for T-ALL, avoiding T cell aplasia and the need for genome engineering that complicate other approaches.

Treatment patterns and outcomes of unfit and elderly patients with Mantle cell lymphoma unfit for standard immunochemotherapy: A UK and Ireland analysis.

Mantle cell lymphoma (MCL) presenting in elderly, unfit patients represents a clinical challenge. Front-line 'attenuated' or low-intensity immunochemotherapy is often employed, although outcomes are relatively unexplored. We report outcomes of attenuated immunochemotherapy in 95 patients with MCL across 19 centres in the UK and Ireland considered unfit for full-dose rituximab-bendamustine or rituximab-cyclophosphamide, doxorubicin, vincristine, prednisolone (R-CHOP). Regimens examined were rituximab-cyclophosphamide, vincristine, prednisolone (R-CVP) (n = 19), dose-attenuated R-CHOP (n = 22), dose attenuated rituximab-bendamustine (n = 24) and rituximab-chlorambucil (n = 30). The primary outcome was progression-free survival (PFS). The secondary outcomes included overall response, overall survival (OS) and toxicity. The median (range) age was 79 (58-89) years and 50% were aged ≥80 years. The median (range) Cumulative Illness Rating Scale-Geriatric score was 6 (0-24). The median PFS for all patients was 15 months [95% confidence interval (CI) 8·7-21·2) and median OS was 31·4 months (95% CI 19·7-43·2). By multivariable analysis (MVA), the only clinical factor associated with an inferior PFS was blastoid morphology [hazard ratio (HR) 2·90, P = 0·01). Notably, higher treatment intensity (R-CHOP/R-bendamustine composite) provided an independently superior PFS compared with R-CVP/R-chlorambucil (MVA HR 0·49, P = 0·02). Factors associated with inferior OS by MVA were Eastern Cooperative Oncology Group Performance Status (HR 2·14, P = 0·04), blastoid morphology (HR 4·08, P = 0·001) and progression of disease at <24 months status (HR 5·68, P < 0·001). Overall, survival after front-line dose-attenuated immunochemotherapy is unsatisfactory. Clinical trials investigating novel agents such as Bruton tyrosine kinase and B-cell lymphoma 2 inhibitors in this specific clinical setting are warranted.

Current and emerging therapeutic approaches for T-cell acute lymphoblastic leukaemia.

T-cell ALL (T-ALL) is an aggressive malignancy of T-cell progenitors. Although survival outcomes in T-ALL have greatly improved over the past 50 years, relapsed and refractory cases remain extremely challenging to treat and those who cannot tolerate intensive treatment continue to have poor outcomes. Furthermore, T-ALL has proven a more challenging immunotherapeutic target than B-ALL. In this review we explore our expanding knowledge of the basic biology of T-ALL and how this is paving the way for repurposing established treatments and the development of novel therapeutic approaches.

PEACE in the midst of an emergency: a rash not to miss.

We present the case of a 29-year-old woman who initially presented to her GP with a short history of non-pruritic annular skin lesions with central clearing. A month later, she developed signs and symptoms of bone marrow failure with bruising, epistaxis and fatigue. After urgent review of a blood film, she was diagnosed with acute promyelocytic leukaemia (APML), which is a haematological emergency. Treatment with all-trans retinoic acid (ATRA) was commenced immediately and she was subsequently treated with arsenic trioxide (ATO). The annular rash was subsequently diagnosed as paraneoplastic erythema annulare centrifugum (PEACE), which resolved with treatment. This case demonstrates the importance of the urgent diagnosis of APML and highlights PEACE as a rash that clinicians should be aware of, as it can be the initial manifestation of a number of both haematological and non-haematological malignancies.

Assessment of the Efficacy of Therapies Following Venetoclax Discontinuation in CLL Reveals BTK Inhibition as an Effective Strategy.

PURPOSE: Venetoclax-based therapy is a standard-of-care option in first-line and relapsed/refractory chronic lymphocytic leukemia (CLL). Patient management following venetoclax discontinuation remains nonstandard and poorly understood. EXPERIMENTAL DESIGN: To address this, we conducted a large international study to identify a cohort of 326 patients who discontinued venetoclax and have been subsequently treated. Coprimary endpoints were overall response rate (ORR) and progression-free survival for the post-venetoclax treatments stratified by treatment type [Bruton's tyrosine kinase inhibitor (BTKi), PI3K inhibitor (PI3Ki), and cellular therapies]. RESULTS: We identified patients with CLL who discontinued venetoclax in the first-line (4%) and relapsed/refractory settings (96%). Patients received a median of three therapies prior to venetoclax; 40% were BTKi naïve (n = 130), and 81% were idelalisib naïve (n = 263). ORR to BTKi was 84% (n = 44) in BTKi-naïve patients versus 54% (n = 30) in BTKi-exposed patients. We demonstrate therapy selection following venetoclax requires prior novel agent exposure consideration and discontinuation reasons. CONCLUSIONS: For BTKi-naïve patients, selection of covalently binding BTKis results in high ORR and durable remissions. For BTKi-exposed patients, covalent BTK inhibition is not effective in the setting of BTKi resistance. PI3Kis following venetoclax do not appear to result in durable remissions. We conclude that BTKi in naïve or previously responsive patients and cellular therapies following venetoclax may be the most effective strategies.See related commentary by Rogers, p. 3501.

Biological applications of quantum dots.

Quantum dots (QDs) are a novel class of inorganic fluorophore which are gaining widespread recognition as a result of their exceptional photophysical properties. They are rapidly being applied to existing and emerging technologies, and could have an important role in many areas. Significant challenges remain, however, which must be understood and more fully defined before they can be widely validated. This review provides on overview of QD technology, covering QD characteristics, synthesis methods, and the applications in which they have been put to use. The influence of synthesis methods on QD characteristics and their subsequent suitability to different applications is discussed, and a broad outline of the technologies into which they have been incorporated is presented, and the relative merits and weaknesses of their incorporation are evaluated. The potential for further development, and inclusion in other technologies is also discussed, and barriers restricting further progress specified, particularly with regard to the poorly understood surface chemistry of QDs, the potential for alteration of function of biological molecules when complexed with QDs, and on a larger scale the significant potential for cytotoxicity both in vitro and in vivo.