Chronic lymphocytic leukaemia Australasian consensus practice statement.

Chronic lymphocytic leukaemia (CLL) is the most common haematological malignancy in Australia and New Zealand (ANZ). Considerable changes to diagnostic and management algorithms have occurred within the last decade. The availability of next-generation sequencing and measurable residual disease assessment by flow cytometry allow for advanced prognostication and response assessments. Novel therapies, including inhibitors of Bruton's tyrosine kinase (BTKi) and B-cell lymphoma 2 (BCL2) inhibitors, have transformed the treatment landscape for both treatment-naïve and relapsed/refractory disease, particularly for patients with high-risk genetic aberrations. Recommendations regarding appropriate supportive management continue to evolve, and special considerations are required for patients with CLL with respect to the global SARS-CoV-2 pandemic. The unique funding and treatment environments in Australasia highlight the need for specific local guidance with respect to the investigation and management of CLL. This consensus practice statement was developed by a broadly representative group of ANZ experts in CLL with endorsement by peak haematology bodies, with a view to providing this standardised guidance.

Allogeneic stem cell transplantation achieves long-term remissions in mantle cell lymphoma, including in TP53-mutated disease.

Cytarabine-containing chemoimmunotherapy followed by autologous transplantation and rituximab maintenance achieves durable remissions for most patients with mantle cell lymphoma (MCL). However, patients with TP53-mutated disease have poor outcomes with standard approaches. We previously reported that allogeneic stem cell transplantation (alloSCT) achieved durable remissions in MCL, however follow-up among patients with TP53-mutated disease was limited. Here we report extended follow-up of the overall cohort (n = 36) and TP53-mutated subset (n = 13) (median follow-up 10.8 and 4.2 years, respectively). Estimated overall survival was 56% at 10 years for the overall cohort and 59% at 4 years for the TP53-mutated subset. Among patients with TP53-mutated disease, no relapses occurred beyond 6 months post-transplant. Survival after post-alloSCT disease relapse was poor (median 2.1 years). These data confirm that alloSCT can be curative in MCL, including patients with TP53-mutated disease, and should be considered for earlier utilization in this subgroup for whom conventional chemoimmunotherapy is ineffective.

Treatment approaches for patients with TP53-mutated mantle cell lymphoma.

Mantle cell lymphoma is an uncommon subtype of lymphoma characterised by clinical and biological heterogeneity. Although most patients with mantle cell lymphoma have durable responses after chemoimmunotherapy, there is a need to prospectively identify high-risk subsets of patients for whom disease control with standard chemotherapy will be short lived. Among the available prognostic factors, TP53 mutations are uniquely informative owing to their strong association with early disease progression and death among patients receiving conventional chemoimmunotherapy, with the highest negative prognostic value compared with other established risk indicators, including the mantle cell lymphoma international prognostic index, histological features, elevated Ki-67, and other genetic lesions. The poor outcomes for patients with TP53-mutated mantle cell lymphoma receiving chemoimmunotherapy and second-line Bruton tyrosine kinase inhibitors represent an urgent need for alternative approaches. In this Review, we synthesise the available data to inform the management of this high-risk subset of patients and present a treatment strategy prioritising clinical trials and early use of cellular therapies.

Medico-legal dispute resolution: Experience of a tertiary-care hospital in Singapore.

INTRODUCTION: The resource burden of healthcare disputes and medico-legal claims has been rising. A dispute resolution system operating at the hospital level could ameliorate this disturbing trend. METHODS: This is a retrospective observational study on patient complaints and medico-legal cases received by the dispute resolution unit of an acute tertiary hospital from 2011 to 2015. We described the characteristics and analysed the resolution methodology and outcomes of all closed medico-legal cases. RESULTS: Patient complaints significantly increased at a compound annual growth rate (CAGR) of 4.2% (p<0.01), while medico-legal cases and ex-gratia payments for case settlements decreased at CAGRs of 4.8% (p<0.05) and 15.9% (p = 0.19), respectively. Out of 237 closed medico-legal cases, 88.6% were resolved without legal action, of which 78.1% were closed without any ex-gratia payments or waivers. Of the 11.4% of medico-legal cases that involved legal action, 66.7% were settled without ex-gratia payments or waivers. The primary resolution modes were the Patient Relations Service (PRS)'s engagement of the complainants and facilitation of written replies. No cases were brought to court. Cases were more likely resolved without legal action when there was engagement by the PRS (p = 0.009). These cases incurred a lower median settlement value than those with legal action. CONCLUSION: Our hospital-based dispute resolution system which addressed patients' core dissatisfactions and providers' perspectives, through a process of early engagement, open disclosure, and fair negotiations, was able to promote claims resolution before legal action was taken. This early dispute resolution strategy contained costs and maintained provider-patient relationships and complements system-level mediation and arbitration to reduce medico-legal litigation.

Enrichment of BTK Leu528Trp mutations in patients with CLL on zanubrutinib: potential for pirtobrutinib cross-resistance.

The covalent Bruton's tyrosine kinase inhibitors (BTKis) are highly effective for the treatment of chronic lymphocytic leukemia (CLL). The dominant resistance mechanism observed with the BTKi ibrutinib is the development of BTK Cys481 codon mutations. Whether a similar resistance mutation profile exists for the newer-generation, more selective BTKi zanubrutinib is unknown. In samples referred for diagnostic next-generation sequencing in patients with progressive CLL, we observed an enrichment in the kinase-dead BTK Leu528Trp mutation in patients treated with zanubrutinib compared with ibrutinib (54%; 7 of 13 vs 4%; 1 of 24, P = .001). We describe 2 patients with BTK Leu528Trp mutations who showed clinical cross-resistance and progressive enrichment of the BTK Leu528Trp mutation over time when treated with the noncovalent BTKi pirtobrutinib. Both patients subsequently responded to venetoclax-based treatment. In summary, we have identified an enrichment of the BTK Leu528Trp mutation arising in patients treated with zanubrutinib that may impart cross-resistance to the noncovalent inhibitor pirtobrutinib and therefore may have implications for sequencing of these treatments in CLL.

Clinical experiences with venetoclax and other pro-apoptotic agents in lymphoid malignancies: lessons from monotherapy and chemotherapy combination.

BH3-mimetics are a novel drug class of small molecule inhibitors of BCL2 family proteins which restore apoptosis in malignant cells. The only currently approved BH3-mimetic, the selective BCL2 inhibitor venetoclax, is highly efficacious in chronic lymphocytic leukemia and has rapidly advanced to an approved standard of care in frontline and relapsed disease in combination with anti-CD20 monoclonal antibodies. In this context, tumour lysis syndrome and myelosuppression are the most commonly encountered toxicities and are readily manageable with established protocols. Venetoclax is active in other lymphoid malignancies including several B cell non-Hodgkin lymphomas, acute lymphoblastic leukemia and multiple myeloma, with the highest intrinsic sensitivity observed in mantle cell lymphoma and Waldenstrom macroglobulinemia. Venetoclax combination with standard regimens in follicular lymphoma, multiple myeloma and aggressive B cell neoplasms has shown some promise, but further studies are required to optimize dose and scheduling to mitigate increased myelosuppression and infection risk, and to find validated biomarkers of venetoclax sensitivity. Future research will focus on overcoming venetoclax resistance, targeting other BCL2 family members and the rational design of synergistic combinations.

Single-cell multiomics reveal the scale of multilayered adaptations enabling CLL relapse during venetoclax therapy.

Venetoclax (VEN) inhibits the prosurvival protein BCL2 to induce apoptosis and is a standard therapy for chronic lymphocytic leukemia (CLL), delivering high complete remission rates and prolonged progression-free survival in relapsed CLL but with eventual loss of efficacy. A spectrum of subclonal genetic changes associated with VEN resistance has now been described. To fully understand clinical resistance to VEN, we combined single-cell short- and long-read RNA-sequencing to reveal the previously unappreciated scale of genetic and epigenetic changes underpinning acquired VEN resistance. These appear to be multilayered. One layer comprises changes in the BCL2 family of apoptosis regulators, especially the prosurvival family members. This includes previously described mutations in BCL2 and amplification of the MCL1 gene but is heterogeneous across and within individual patient leukemias. Changes in the proapoptotic genes are notably uncommon, except for single cases with subclonal losses of BAX or NOXA. Much more prominent was universal MCL1 gene upregulation. This was driven by an overlying layer of emergent NF-κB (nuclear factor kappa B) activation, which persisted in circulating cells during VEN therapy. We discovered that MCL1 could be a direct transcriptional target of NF-κB. Both the switch to alternative prosurvival factors and NF-κB activation largely dissipate following VEN discontinuation. Our studies reveal the extent of plasticity of CLL cells in their ability to evade VEN-induced apoptosis. Importantly, these findings pinpoint new approaches to circumvent VEN resistance and provide a specific biological justification for the strategy of VEN discontinuation once a maximal response is achieved rather than maintaining long-term selective pressure with the drug.

Clonal hematopoiesis, myeloid disorders and BAX-mutated myelopoiesis in patients receiving venetoclax for CLL.

The BCL2 inhibitor venetoclax has established therapeutic roles in chronic lymphocytic leukemia (CLL) and acute myeloid leukemia (AML). As BCL2 is an important determinant of survival of both myeloid progenitor and B cells, we investigated whether clinical and molecular abnormalities arise in the myeloid compartment during long-term continuous venetoclax treatment of CLL in 89 patients (87 with relapsed/refractory CLL). Over a median follow-up of 75 (range 21-98) months, persistent cytopenias (≥1 of neutropenia, thrombocytopenia, anemia) lasting ≥4 months and unrelated to CLL occurred in 25 patients (28%). Of these patients, 20 (80%) displayed clonal hematopoiesis, including 10 with therapy-related myeloid neoplasms (t-MNs). t-MNs occurred exclusively in patients previously exposed to fludarabine-alkylator combination therapy with a cumulative 5-year incidence of 10.4% after venetoclax initiation, consistent with rates reported for patients exposed to fludarabine-alkylator combination therapy without venetoclax. To determine whether the altered myelopoiesis reflected the acquisition of mutations, we analyzed samples from patients with no or minimal bone marrow CLL burden (n = 41). Mutations in the apoptosis effector BAX were identified in 32% (13/41). In cellular assays, C-terminal BAX mutants abrogated outer mitochondrial membrane localization of BAX and engendered resistance to venetoclax killing. BAX-mutated clonal hematopoiesis occurred independently of prior fludarabine-alkylator combination therapy exposure and was not associated with t-MNs. Single-cell sequencing revealed clonal co-occurrence of mutations in BAX with DNMT3A or ASXL1. We also observed simultaneous BCL2 mutations within CLL cells and BAX mutations in the myeloid compartment of the same patients, indicating lineage-specific adaptation to venetoclax therapy.

Point-of-Care Ultrasound Predicts Clinical Outcomes in Patients With COVID-19.

OBJECTIVES: Point-of-care ultrasound (POCUS) detects the pulmonary manifestations of COVID-19 and may predict patient outcomes. METHODS: We conducted a prospective cohort study at four hospitals from March 2020 to January 2021 to evaluate lung POCUS and clinical outcomes of COVID-19. Inclusion criteria included adult patients hospitalized for COVID-19 who received lung POCUS with a 12-zone protocol. Each image was interpreted by two reviewers blinded to clinical outcomes. Our primary outcome was the need for intensive care unit (ICU) admission versus no ICU admission. Secondary outcomes included intubation and supplemental oxygen usage. RESULTS: N = 160 patients were included. Among critically ill patients, B-lines (94 vs 76%; P < .01) and consolidations (70 vs 46%; P < .01) were more common. For scans collected within 24 hours of admission (N = 101 patients), early B-lines (odds ratio [OR] 4.41 [95% confidence interval, CI: 1.71-14.30]; P < .01) or consolidations (OR 2.49 [95% CI: 1.35-4.86]; P < .01) were predictive of ICU admission. Early consolidations were associated with oxygen usage after discharge (OR 2.16 [95% CI: 1.01-4.70]; P = .047). Patients with a normal scan within 24 hours of admission were less likely to require ICU admission (OR 0.28 [95% CI: 0.09-0.75]; P < .01) or supplemental oxygen (OR 0.26 [95% CI: 0.11-0.61]; P < .01). Ultrasound findings did not dynamically change over a 28-day scanning window after symptom onset. CONCLUSIONS: Lung POCUS findings detected within 24 hours of admission may provide expedient risk stratification for important COVID-19 clinical outcomes, including future ICU admission or need for supplemental oxygen. Conversely, a normal scan within 24 hours of admission appears protective. POCUS findings appeared stable over a 28-day scanning window, suggesting that these findings, regardless of their timing, may have clinical implications.

Outcomes of patients with CLL sequentially resistant to both BCL2 and BTK inhibition.

Covalent Bruton tyrosine kinase inhibitors (BTKi's) and the B-cell lymphoma 2 (BCL2) inhibitor venetoclax have significantly improved outcomes for patients with chronic lymphocytic leukemia (CLL), especially those with biologically adverse disease. Patients with CLL resistant to their first targeted agent (TA) can be effectively treated with the alternative class. However, relapses are expected with second-line TA therapy, and the clinical challenge of double class-resistant disease is now emerging with increasing frequency. To define the characteristics and outcomes of patients with double class-resistant disease, we retrospectively analyzed 17 patients who developed progressive disease (PD) on both TA classes for CLL (venetoclax, then BTKi, n=12; BTKi, then venetoclax, n = 5). The cohort was heavily pretreated (median lines of prior therapy, 4) and enriched for adverse disease genetics (complex karyotype, 12 of 12 tested [100%]; del(17p)/TP53 mutations, 15 of 17 [88%]). The median time to progression on prior venetoclax was 24 months (range, 6-94 months) and was 25 months (range, 1-55 months) on prior BTKi. Progression on second-line TA was manifest as progressive CLL in 11 patients and as Richter transformation in 6. The median overall survival after progression on second-line TA was 3.6 months (95% confidence interval, 2-11 months). Patients with double class-resistant CLL have a dismal prognosis, representing a group of high unmet need.

How I treat chronic lymphocytic leukemia after venetoclax.

Venetoclax-based regimens have expanded the therapeutic options for patients with chronic lymphocytic leukemia (CLL), frequently achieving remissions with undetectable measurable residual disease and facilitating time-limited treatment without chemotherapy. Although response rates are high and durable disease control is common, longer-term follow-up of patients with relapsed and refractory disease, especially in the presence of TP53 aberrations, demonstrates frequent disease resistance and progression. Although the understanding of venetoclax resistance remains incomplete, progressive disease is typified by oligoclonal leukemic populations with distinct resistance mechanisms, including BCL2 mutations, upregulation of alternative BCL2 family proteins, and genomic instability. Although most commonly observed in heavily pretreated patients with disease refractory to fludarabine and harboring complex karyotype, Richter transformation presents a distinct and challenging manifestation of venetoclax resistance. For patients with progressive CLL after venetoclax, treatment options include B-cell receptor pathway inhibitors, allogeneic stem cell transplantation, chimeric antigen receptor T cells, and venetoclax retreatment for those with disease relapsing after time-limited therapy. However, data to inform clinical decisions for these patients are limited. We review the biology of venetoclax resistance and outline an approach to the common clinical scenarios encountered after venetoclax-based therapy that will increasingly confront practicing clinicians.

Rehabilitation in patients with lymphoma: An overview of Systematic Reviews.

OBJECTIVE: To evaluate existing evidence from published systematic reviews for the effectiveness of rehabilitation interventions in patients with lymphoma. DATA SOURCES: A comprehensive literature search was conducted using medical/health science databases up to 1 October 2020. Bibliographies of pertinent articles, journals and grey literature were searched. DATA EXTRACTION AND SYNTHESIS: Two reviewers independently selected and reviewed potential reviews for methodological quality and graded the quality of evidence for outcomes using validated tools. Any discrepancies were resolved by final group consensus. RESULTS: Twelve systematic reviews (n = 101 studies, 87,132 patients with lymphoma) evaluated 3 broad categories of rehabilitation interventions (physical modalities, nutrition and complementary medicine). Most reviews were of moderate-to-low methodological quality. The findings suggest: moderate-quality evidence for exercise programmes for improved fatigue and sleep disturbance; low-quality evidence for exercise therapy alone and qigong/tai chi for improved symptoms and overall quality of life, and an inverse association between sunlight/ultraviolet radiation exposure and incidence of non-Hodgkin's lymphoma; and very low-quality evidence for beneficial effects of yoga for sleep disturbances. Association between physical activity and lymphoma risk is indistinct. CONCLUSION: Despite a range of rehabilitation modalities used for patients with lymphoma, high-quality evidence for many is sparse. Beneficial effects of exercise programmes were noted for fatigue, psychological symptoms and quality of life. More research with robust study design is required to determine the effective rehabilitation approaches.

Recurrent Multifocal Mycoplasma orale Infection in an Immunocompromised Patient: A Case Report and Review.

A young woman with mixed connective tissue disease complicated by erosive arthritis, secondary hypogammaglobulinemia due to rituximab, and a history of many infectious complications developed multiple nonhealing wounds, polyarticular joint pain, and leukocytosis. Radiographic studies demonstrated multiple scattered areas of osteomyelitis and complex abscesses. Purulent fluid drained from multiple sites did not yield a microbiologic diagnosis by standard culture technique, but Mycoplasma orale was ultimately identified using 16 S ribosomal RNA gene amplification and sequencing. We describe this unique case and review the literature.

Effective Antimicrobial StewaRdship StrategIES (ARIES): Cluster Randomized Trial of Computerized Decision Support System and Prospective Review and Feedback.

BACKGROUND: Prospective review and feedback (PRF) of antibiotic prescriptions and compulsory computerized decision support system (CDSS) are 2 strategies of antimicrobial stewardship. There are limited studies investigating their combined effects. We hypothesized that the use of on-demand (voluntary) CDSS would achieve similar patient outcomes compared with automatically triggered (compulsory) CDSS whenever broad-spectrum antibiotics are ordered. METHODS: A parallel-group, 1:1 block cluster randomized crossover study was conducted in 32 medical and surgical wards from March to August 2017. CDSS use for piperacillin-tazobactam or carbapenem in the intervention clusters was at the demand of the doctor, while in the control clusters CDSS use was compulsory. PRF was continued for both arms. The primary outcome was 30-day mortality. RESULTS: Six hundred forty-one and 616 patients were randomized to voluntary and compulsory CDSS, respectively. There were no differences in 30-day mortality (hazard ratio [HR], 0.87; 95% CI, 0.67-1.12), re-infection and re-admission rates, antibiotic duration, length of stay, or hospitalization cost. The proportion of patients receiving PRF recommendations was not significantly lower in the voluntary CDSS arm (62 [10%] vs 81 [13%]; P = .05). Appropriate indication of antibiotics was high in both arms (351/448 [78%] vs 330/433 [74%]; P = .18). However, in geriatric medicine patients where antibiotic appropriateness was <50%, prescription via compulsory CDSS resulted in a shorter length of stay and lower hospitalization cost. CONCLUSIONS: Voluntary broad-spectrum antibiotics with PRF via CDSS did not result in differing clinical outcomes, antibiotic duration, or length of stay. However, in the setting of low antibiotic appropriateness, compulsory CDSS may be beneficial.

BTK inhibitor therapy is effective in patients with CLL resistant to venetoclax.

Highly active BTK inhibitors (BTKis) and the BCL2 inhibitor venetoclax have transformed the therapeutic landscape for chronic lymphocytic leukemia (CLL). Results of prospective clinical trials demonstrate the efficacy of venetoclax to salvage patients with disease progression on BTKis, but data on BTKi therapy after disease progression on venetoclax are limited, especially regarding durability of benefit. We retrospectively evaluated the records of 23 consecutive patients with relapsed/refractory CLL who received a BTKi (ibrutinib, n = 21; zanubrutinib, n = 2) after stopping venetoclax because of progressive disease. Median progression-free survival (PFS) and median overall survival after BTKi initiation were 34 months (range, <1 to 49) and 42 months (range, 2-49), respectively. Prior remission duration ≥24 months and attainment of complete remission or undetectable measurable residual disease on venetoclax were associated with longer PFS after BTKi salvage (P = .044 and P = .029, respectively). BTKi therapy achieved durable benefit for patients with the BCL2 Gly101Val venetoclax resistance mutation (estimated 24-month PFS, 69%). At a median survivor follow-up of 33 months (range, 2-53), 11 patients remained on BTKi and 12 had stopped therapy because of disease progression (n = 8) or toxicity (n = 4). Our findings indicate that BTKi therapy can provide durable CLL control after disease progression on venetoclax.