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Despite widespread vaccination rates, we are living with high transmission rates of SARS-CoV-2. Although overall hospitalisation rates are falling, the risk of serious infection remains high for patients who are immunocompromised because of haematological malignancies. In light of the ongoing pandemic and the development of multiple agents for treatment, representatives from the Haematology Society of Australia and New Zealand and infectious diseases specialists have collaborated on this consensus position statement regarding COVID-19 management in patients with haematological disorders. It is our recommendation that both patients with haematological malignancies and treating specialists be educated regarding the preventive and treatment options available and that patients continue to receive adequate vaccinations, keeping in mind the suboptimal vaccine responses that occur in haematology patients, in particular, those with B-cell malignancies and on B-cell-targeting or depleting therapy. Patients with haematological malignancies should receive treatment for COVID-19 in accordance with the severity of their symptoms, but even mild infections should prompt early treatment with antiviral agents. The issue of de-isolation following COVID-19 infection and optimal time to treatment for haematological malignancies is discussed but remains an area with evolving data. This position statement is to be used in conjunction with advice from infectious disease, respiratory and intensive care specialists, and current guidelines from the National COVID-19 Clinical Evidence Taskforce and the New Zealand Ministry of Health and Cancer Agency Te Aho o Te Kahu COVID-19 Guidelines.

Acquired hypogammaglobulinemia is common in chronic lymphocytic leukemia (CLL), non-Hodgkin lymphoma (NHL) and multiple myeloma (MM). No previous systematic reviews (SR) have compared different approaches to infection prevention. We aimed to assess the efficacy and safety of prophylactic immunoglobulin (Ig), antibiotics and vaccinations in these patients. We performed a SR and meta-analysis of randomized controlled trials (RCTs) evaluating the efficacy and safety of prophylactic Ig, antibiotics and vaccinations in adult patients with hematological malignancies commonly associated with acquired hypogammaglobulinemia, specifically CLL, NHL and MM. We searched Pubmed (MEDLINE), EMBASE and Cochrane Registry to 01/09/2021. Results for dichotomous data were expressed as relative risks (RR) with 95% confidence intervals (CI) and pooled using a random effects model. This review was registered with PROSPERO CRD42017070825. From 10,576 studies screened, there were 21 completed and one ongoing RCT. Of these, eight evaluated prophylactic Ig (n=370, seven published before 2000); five evaluated prophylactic antibiotics (n=1587), seven evaluated vaccinations (n=3996) and one compared Ig to antibiotics (n=60). Prophylactic Ig reduced the risk of clinically documented infections (CDIs) by 28%, (n=2 trials; RR 0.72 [95% CI 0.54-0.96]) and vaccinations reduced risk of CDIs by 63%, RR 0.37 (95% CI 0.30-0.45). Prophylactic antibiotics did not reduce the risk of CDIs. No interventions reduced all-cause mortality. Prophylactic Ig and antibiotics increased risk of adverse events. Findings should be interpreted with caution given high risk of bias in many studies. There is a clear need for high-quality contemporary trials to establish the effectiveness of different approaches to prevent infections.Copyright © 2022 American Society of Hematology.

Venetoclax, a potent B-cell lymphoma-2 (BCL-2) inhibitor, has demonstrated clinical efficacy in chronic lymphocytic leukemia (CLL). VENICE II is an open-label, single-arm, phase 3b study (NCT02980731) evaluating the impact of venetoclax monotherapy (400 mg once daily) for ≤2 years on health-related quality of life (HRQoL) of patients with relapsed/refractory CLL. The primary endpoint was mean change in the global health status (GHS)/quality of life (QoL) subscale of the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) from baseline to Week 48. Overall, 210 patients received ≥1 dose of venetoclax; median treatment duration was 67.4 weeks. The primary endpoint was met with mean improvement of +9.3 points (n = 156, 95% confidence interval 6.1-12.5; p=.004) in GHS/QoL. At Week 48, clinically meaningful improvements were observed for role functioning, fatigue, and insomnia domains of EORTC QLQ-C30, suggesting venetoclax monotherapy has a positive impact on HRQoL. No new safety signals were reported.

Patients with invasive fungal disease (IFD) are at significant risk of morbidity and mortality. A productive partnership between patients, their carers/families, and the multidisciplinary team managing the infection and any underlying conditions, is essential. Sharing information and addressing knowledge gaps are required to ensure those at risk of IFD avoid infection, while those with suspected or confirmed infection optimise their therapy and avoid toxicities. This new addition to the Australian and New Zealand consensus guidelines for the management of IFD and antifungal use in the haematology/oncology setting outlines the key information needs of patients and their carers/families. It specifically addresses risk factor reduction, antifungal agents and adherence, and the risks and benefits of complementary and alternative therapies. Knowledge gaps are also identified to help inform the future research agenda.Copyright © 2021 Royal Australasian College of Physicians.

Myelodysplastic syndromes (MDS) have a major impact on quality of life (QoL). We performed a post hoc analysis of two multicenter trials of azacitidine-based disease-modifying therapy for patients with MDS and low blast count acute myeloid leukemia (AML), to identify factors associated with QoL. 231 patients were included (median age 70 years). At baseline, higher initial hemoglobin, but not neutrophil or platelet count, was associated with better global QoL and physical function (p < 0.001 and p = 0.001, respectively). During therapy, increase in hemoglobin was associated with improvement in QoL and physical function (p = 0.005 and p < 0.001, respectively). Lower initial hemoglobin was associated with higher dyspnea and fatigue scores (p < 0.001 and p = 0.001, respectively), and hemoglobin response was associated with improvement in dyspnea and fatigue (p < 0.001 for each). In patients with MDS and low blast count AML, hemoglobin level was strongly correlated with global QoL, physical functioning, dyspnea and fatigue, both before and during azacitidine-based therapy.Copyright © 2021 Informa UK Limited, trading as Taylor & Francis Group.

Background: Prophylactic immunoglobulin (Ig) replacement and prophylactic oral antibiotics (PA) are used to prevent infections in patients with haematological malignancies and acquired hypogammaglobulinemia. Ig has been shown to reduce infection risk, but is costly and in limited supply. PA have been shown to reduce infection risk in other patient populations and are less expensive, but have side-effects and can increase antimicrobial resistance rates. Guidelines and clinical practice vary internationally, with some recommending a trial of PA prior to commencing Ig replacement, and others omitting PA. The efficacy, safety and cost-effectiveness of Ig and PA have not been directly compared in a randomised controlled trial (RCT) in patients with acquired hypogammaglobulinemia secondary to haematological malignancies. Aim(s): To determine the feasibility of delivering PA as an alternative to Ig replacement in patients with haematological malignancies and acquired hypogammaglobulinemia. Method(s): Phase II, multicentre, feasibility RCT (ACTRN12616001723471). Eligible patients had acquired hypogammaglobulinemia due to a haematological malignancy, a history of recurrent or severe bacterial infections or an IgG level <4g/L (excluding paraprotein), and had a life expectancy more than 12 months. Exclusion criteria included prior allogeneic haematopoietic stem cell transplant and prior Ig replacement in the preceding 3 months. Patients were randomised to receive Ig (0.4g/kg IV every 4 weeks, modified to achieve an IgG trough level >= lower limit of reference range; or 0.1g/kg/week SC, modified to achieve an IgG trough level of >= lower limit of reference rage) or daily oral prophylactic antibiotics (trimethoprim-sulfamethoxazole 160mg/800mg, with 100mg doxycycline as an alternative for hypersensitivity) for 12 months at a 1:2 ratio. Randomisation was stratified by site. Patients allocated to PA were allowed to cross over to Ig if they experienced a CTCAE >= Grade 3 infection.

Australia and New Zealand have achieved excellent community control of COVID-19 infection. In light of the imminent COVID-19 vaccination roll out in both countries, representatives from the Haematology Society of Australia and New Zealand and infectious diseases specialists have collaborated on this consensus position statement regarding COVID-19 vaccination in patients with haematological disorders. It is our recommendation that patients with haematological malignancies, and some benign haematological disorders, should have expedited access to high-efficacy COVID-19 vaccines, given that these patients are at high risk of morbidity and mortality from COVID-19 infection. Vaccination should not replace other public health measures in these patients, given that the effectiveness of COVID-19 vaccination, specifically in patients with haematological malignancies, is not known. Given the limited available data, prospective collection of safety and efficacy data of COVID-19 vaccination in this patient group is a priority.Copyright © 2021 Royal Australasian College of Physicians

Patients with invasive fungal disease (IFD) are at significant risk of morbidity and mortality. A productive partnership between patients, their carers/families, and the multidisciplinary team managing the infection and any underlying conditions, is essential. Sharing information and addressing knowledge gaps are required to ensure those at risk of IFD avoid infection, while those with suspected or confirmed infection optimise their therapy and avoid toxicities. This new addition to the Australian and New Zealand consensus guidelines for the management of IFD and antifungal use in the haematology/oncology setting outlines the key information needs of patients and their carers/families. It specifically addresses risk factor reduction, antifungal agents and adherence, and the risks and benefits of complementary and alternative therapies. Knowledge gaps are also identified to help inform the future research agenda.

Australia and New Zealand have achieved excellent community control of COVID-19 infection. In light of the imminent COVID-19 vaccination roll out in both countries, representatives from the Haematology Society of Australia and New Zealand and infectious diseases specialists have collaborated on this consensus position statement regarding COVID-19 vaccination in patients with haematological disorders. It is our recommendation that patients with haematological malignancies, and some benign haematological disorders, should have expedited access to high-efficacy COVID-19 vaccines, given that these patients are at high risk of morbidity and mortality from COVID-19 infection. Vaccination should not replace other public health measures in these patients, given that the effectiveness of COVID-19 vaccination, specifically in patients with haematological malignancies, is not known. Given the limited available data, prospective collection of safety and efficacy data of COVID-19 vaccination in this patient group is a priority.

The COVID-19 pandemic poses a unique challenge to the care of patients with haematological malignancies. Viral pneumonia is known to cause disproportionately severe disease in patients with cancer, and patients with lymphoma, myeloma and chronic lymphocytic leukaemia are likely to be at particular risk of severe disease related to COVID-19. This statement has been developed by consensus among authors from Australia and New Zealand. We aim to provide supportive guidance to clinicians making individual patient decisions during the COVID-19 pandemic, in particular during periods that access to healthcare resources may be limited. General recommendations include those to minimise patient exposure to COVID-19, including the use of telehealth, avoidance of non-essential visits and minimisation of time spent by patients in infusion suites and other clinical areas. This statement also provides recommendations where appropriate in assessing indications for therapy, reducing therapy-associated immunosuppression and reducing healthcare utilisation in patients with specific haematological malignancies during the COVID-19 pandemic. Specific decisions regarding therapy of haematological malignancies will need to be individualised, based on disease risk, risks of immunosuppression, rates of community transmission of COVID-19 and available local healthcare resources.Copyright © 2020 Royal Australasian College of Physicians

Background: Venetoclax plus obinutuzumab has been established as a fixed-duration treatment regimen for patients with chronic lymphocytic leukaemia. We compared the long-term efficacy after treatment cessation of the combination of venetoclax plus obinutuzumab with chlorambucil plus obinutuzumab in patients with previously untreated chronic lymphocytic leukaemia. Method(s): CLL14 is a multicentre, randomised, open-label, phase 3 trial done at 196 sites in 21 countries. Eligible patients were aged 18 years or older, had untreated chronic lymphocytic leukaemia, and coexisting conditions with a cumulative illness rating scale greater than 6, a creatinine clearance of 30-69 mL/min, or both. Patients were randomly assigned (1:1) via a web and voicemail system with allocation concealment and based on a computer-generated randomisation schedule with a block size of six and stratified by Binet stage and geographical region. Patients received either venetoclax plus obinutuzumab (oral venetoclax initiated on day 22 of cycle 1 [28-day cycles], with a 5-week dose ramp-up [20 mg, 50 mg, 100 mg, and 200 mg, then 400 mg daily for 1 week], thereafter continuing at 400 mg daily until completion of cycle 12; combined with intravenous obinutuzumab for six cycles starting with 100 mg on day 1 and 900 mg on day 2 [or 1000 mg on day 1], 1000 mg on days 8 and day 15 of cycle 1, and subsequently 1000 mg on day 1 of cycles 2 through 6) or chlorambucil plus obinutuzumab (oral chlorambucil at 0.5 mg/kg bodyweight on days 1 and 15 of each cycle for 12 cycles combined with the same obinutuzumab regimen). The primary endpoint was investigator-assessed progression-free survival in the intention-to-treat population. Safety was assessed in all patients who received at least one dose of study treatment. Patient enrolment is complete, and the study is registered with ClinicalTrails.gov, NCT02242942. Finding(s): Between Aug 7, 2015, and Aug 4, 2016, 432 patients were enrolled and randomly assigned to

Background: The CLL14 trial demonstrated significant improvement of progression-free survival (PFS) with fixed-duration venetoclax-obinutuzumab (VenG) as compared to chlorambucil-obinutuzumab (ClbG) in patients with previously untreated CLL and coexisting conditions. Aim(s): The aim of this report is to provide efficacy and safety data from follow-up of the CLL14 trial with now all patients being off treatment for at least 2 years. Method(s): Patients with previously untreated chronic lymphocytic leukaemia and coexisting conditions were randomized 1:1 to receive 12 cycles of venetoclax with 6 cycles of obinutuzumab or 12 cycles of chlorambucil with 6 cycles of obinutuzumab. Primary endpoint was investigator- assessed PFS. Key secondary endpoints were response rates, rates of minimal residual disease (measured every 6 months up to 5 years after last patient enrolment) and overall survival. Follow-up is ongoing but all patients are off study treatment. This trial was registered with ClinicalTrials.gov, number NCT02242942. Result(s): Of the 432 enrolled patients, 216 were randomly assigned to receive VenG and 216 to receive ClbG. After a median follow-up of 39.6 months (interquartile range 36.8 - 43.0), progression-free survival continued to be superior for VenG as compared to ClbG (median not reached vs 35.6 months; hazard ratio [HR] 0.31 [0.22-0.44], p<0.001)(Figure A). At 3 years, the estimated PFS rate was 81.9% in the VenG arm and 49.5% in the ClbG arm. This benefit was consistently observed across all clinical and biological risk groups, including patients with TP53 mutation/deletion and unmutated IGHV status. Of note, PFS was also significantly longer for VenG treated patients with mutated IGHV status compared to ClbG (HR 0.33 [0.16-0.70] p = 0.004). Overall, 21 disease progressions after VenG treatment have been observed. Assessment of minimal residual disease in peripheral blood 18 months after the end of treatment showed that 47.2% of patients in the VenG arm

Introduction: A pandemic coronavirus, SARS-CoV-2, causes COVID-19, a potentially life-threatening respiratory disease. Patients with cancer may have compromised immunity due to their malignancy and/or treatment, and may be at elevated risk of severe COVID-19. Community transmission of COVID-19 could overwhelm health care services, compromising delivery of cancer care. This interim consensus guidance provides advice for clinicians managing patients with cancer during the pandemic. Main recommendations: During the COVID-19 pandemic:. In patients with cancer with fever and/or respiratory symptoms, consider causes in addition to COVID-19, including other infections and therapy-related pneumonitis. For suspected or confirmed COVID-19, discuss temporary cessation of cancer therapy with a relevant specialist. Provide information on COVID-19 for patients and carers. Adopt measures within cancer centres to reduce risk of nosocomial SARS-CoV-2 acquisition; support population-wide social distancing; reduce demand on acute services; ensure adequate staffing; and provide culturally safe care. Measures should be equitable, transparent and proportionate to the COVID-19 threat. Consider the risks and benefits of modifying cancer therapies due to COVID-19. Communicate treatment modifications, and review once health service capacity allows. Consider potential impacts of COVID-19 on the blood supply and availability of stem cell donors. Discuss and document goals of care, and involve palliative care services in contingency planning. Changes in management as a result of this statement: This interim consensus guidance provides a framework for clinicians managing patients with cancer during the COVID-19 pandemic. In view of the rapidly changing situation, clinicians must also monitor national, state, local and institutional policies, which will take precedence. Endorsed by: Australasian Leukaemia and Lymphoma Group; Australasian Lung Cancer Trials Group; Australian and New Zealand Childr

INTRODUCTION: Autologous T-cells transduced to express a chimeric antigen receptor (CAR) directed against CD19 elicit high response rates in relapsed or refractory (r/r) B-cell non-Hodgkin lymphoma (B-NHL). However, r/r B-NHL remissions are durable in fewer than half of recipients of second-generation CAR T-cells. Third-generation (3G) CARs employ two costimulatory domains, resulting in improved CAR T-cell efficacy in vitro and in animal models in vivo. This investigator-initiated, phase I dose escalation trial, termed ENABLE, will investigate the safety and preliminary efficacy of WZTL-002, comprising autologous T-cells expressing a 3G anti-CD19 CAR incorporating the intracellular signalling domains of CD28 and Toll-like receptor 2 (TLR2) for the treatment of r/r B-NHL. METHODS AND ANALYSIS: Eligible participants will be adults with r/r B-NHL including diffuse large B-cell lymphoma and its variants, follicular lymphoma, transformed follicular lymphoma and mantle cell lymphoma. Participants must have satisfactory organ function, and lack other curative options. Autologous T-cells will be obtained by leukapheresis. Following WZTL-002 manufacture and product release, participants will receive lymphodepleting chemotherapy comprising intravenous fludarabine and cyclophosphamide. A single dose of WZTL-002 will be administered intravenously 2 days later. Targeted assessments for cytokine release syndrome and immune cell effector-associated neurotoxicity syndrome, graded by the American Society Transplantation and Cellular Therapy criteria, will be made. A modified 3+3 dose escalation scheme is planned starting at 5×104 CAR T-cells/kg with a maximum dose of 1×106 CAR T-cells/kg. The primary outcome of this trial is safety of WZTL-002. Secondary outcomes include feasibility of WZTL-002 manufacture and preliminary measures of efficacy. ETHICS AND DISSEMINATION: Ethical approval for the study was granted by the New Zealand Health and Disability Ethics Committee (reference 19

The COVID-19 pandemic poses a unique challenge to the care of patients with haematological malignancies. Viral pneumonia is known to cause disproportionately severe disease in patients with cancer, and patients with lymphoma, myeloma and chronic lymphocytic leukaemia are likely to be at particular risk of severe disease related to COVID-19. This statement has been developed by consensus among authors from Australia and New Zealand. We aim to provide supportive guidance to clinicians making individual patient decisions during the COVID-19 pandemic, in particular during periods that access to healthcare resources may be limited. General recommendations include those to minimise patient exposure to COVID-19, including the use of telehealth, avoidance of non-essential visits and minimisation of time spent by patients in infusion suites and other clinical areas. This statement also provides recommendations where appropriate in assessing indications for therapy, reducing therapy-associated immunosuppression and reducing healthcare utilisation in patients with specific haematological malignancies during the COVID-19 pandemic. Specific decisions regarding therapy of haematological malignancies will need to be individualised, based on disease risk, risks of immunosuppression, rates of community transmission of COVID-19 and available local healthcare resources.

INTRODUCTION: A pandemic coronavirus, SARS-CoV-2, causes COVID-19, a potentially life-threatening respiratory disease. Patients with cancer may have compromised immunity due to their malignancy and/or treatment, and may be at elevated risk of severe COVID-19. Community transmission of COVID-19 could overwhelm health care services, compromising delivery of cancer care. This interim consensus guidance provides advice for clinicians managing patients with cancer during the pandemic. MAIN RECOMMENDATIONS: During the COVID-19 pandemic: In patients with cancer with fever and/or respiratory symptoms, consider causes in addition to COVID-19, including other infections and therapy-related pneumonitis. For suspected or confirmed COVID-19, discuss temporary cessation of cancer therapy with a relevant specialist. Provide information on COVID-19 for patients and carers. Adopt measures within cancer centres to reduce risk of nosocomial SARS-CoV-2 acquisition; support population-wide social distancing; reduce demand on acute services; ensure adequate staffing; and provide culturally safe care. Measures should be equitable, transparent and proportionate to the COVID-19 threat. Consider the risks and benefits of modifying cancer therapies due to COVID-19. Communicate treatment modifications, and review once health service capacity allows. Consider potential impacts of COVID-19 on the blood supply and availability of stem cell donors. Discuss and document goals of care, and involve palliative care services in contingency planning. CHANGES IN MANAGEMENT AS A RESULT OF THIS STATEMENT: This interim consensus guidance provides a framework for clinicians managing patients with cancer during the COVID-19 pandemic. In view of the rapidly changing situation, clinicians must also monitor national, state, local and institutional policies, which will take precedence. ENDORSED BY: Australasian Leukaemia and Lymphoma Group; Australasian Lung Cancer Trials Group; Australian and New Zealand Childre

Introduction: The multinational, open-label, phase 3 CLL14 trial (NCT02242942) compared fixed-duration targeted venetoclax plus obinutuzumab (VenG) treatment with chlorambucil-obinutuzumab (ClbG) treatment in previously untreated patients (pts) with chronic lymphocytic leukemia (CLL) and comorbidities. We present endpoint analyses with particular emphasis on progression-free survival (PFS) and minimal residual disease (MRD)-negativity. Method(s): Pts with a CIRS score >6 and/or an estimated creatinine clearance <70 mL/min were randomized 1:1 to receive equal duration treatment with 12 cycles of standard Clb or Ven 400 mg daily in combination with G for the first 6 cycles. The primary endpoint was PFS. MRD-negativity in peripheral blood (PB) or bone marrow (BM) 3 months after treatment completion was a key secondary endpoint. MRD was analyzed serially from Cycle 4 every 3 months by an allele-specific oligonucleotide polymerase chain reaction assay (ASOABSTRACT PCR; cut-off, 10-4) and by next generation sequencing (NGS; cut-offs, 10-4, 10-5, 10-6). Result(s): 432 pts were enrolled (216 in each treatment group; intentto- treat population). Median age, total CIRS score, and CrCl at baseline were 72 years, 8, and 66.4 mL/min respectively. After 29 months' median follow-up, superior PFS was observed with VenG vs ClbG (Figure 1a). Median PFS was not reached in either group: at Month 24, PFS rates were 88% with VenG and 64% with ClbG (hazard ratio [HR] 0.35; 95% confidence interval [CI] 0.23-0.53; P<0.0001). MRD-negativity by ASO-PCR was significantly higher with VenG vs ClbG in both PB (76% vs 35% [P<0.0001]) and BM (57% vs 17% [P<0.0001]) 3 months after treatment completion. Overall, 75% of VenG MRD-negative pts in PB were also MRDnegative in BM vs 49% in the ClbG group. Landmark analysis for this timepoint by PB MRD status showed that MRD-negativity was associated with longer PFS. MRD-negativity rates were more sustainable with VenG: 81% (VenG) vs 27% (ClbG) of pts were

Background: Acquired hypogammaglobulinaemia secondary to haematological malignancies is associated with increased infection risk. Immunoglobulin (Ig) replacement reduces major infections but not mortality, and is costly. No prospective randomised trials have compared Ig replacement with prophylactic antibiotics. Aim(s): To identify variation in current practice regarding management of secondary hypogammaglobulinaemia in Australia and New Zealand, to identify barriers to best practice, and to inform the development of a clinical trial assessing antibiotic prophylaxis in secondary hypogammaglobulinaemia. Method(s): We conducted an online survey of current clinical practice regarding management of secondary hypogammaglobulinaemia among haematologists in Australia and New Zealand. Result(s): Seventy-two haematologists responded; 89% of whom reported commencing Ig replacement for secondary hypogammaglobulinaemia in the setting of recurrent or severe infection. Most monitored trough immunoglobulin G levels, most often 3 monthly. Criteria for stopping Ig replacement varied. Most respondents recommended influenza and pneumococcal vaccination, while only 21% reported using antibiotic prophylaxis. Few respondents (3%) reported prescribing prophylactic antibiotics before commencing Ig replacement. Most reported an interest in recruiting patients to a clinical trial comparing Ig replacement with prophylactic antibiotics. Conclusion(s): In comparison to limited international data, this survey finds variation in practice, which may be due to differences in local policies governing access to Ig. These findings highlight the need for research into the indications for Ig commencement and cessation, and will inform design of prospective trials of infection prevention in secondary hypogammaglobulinaemia.Copyright © 2018 Royal Australasian College of Physicians

Background: The BCL2 inhibitor venetoclax has shown activity in patients with chronic lymphocytic leukemia (CLL), but its efficacy in combination with other agents in patients with CLL and coexisting conditions is not known. Method(s): In this open-label, phase 3 trial, we investigated fixed-duration treatment with venetoclax and obinutuzumab in patients with previously untreated CLL and coexisting conditions. Patients with a score of greater than 6 on the Cumulative Illness Rating Scale (scores range from 0 to 56, with higher scores indicating more impaired function of organ systems) or a calculated creatinine clearance of less than 70 ml per minute were randomly assigned to receive venetoclax-obinutuzumab or chlorambucil- obinutuzumab. The primary end point was investigator-assessed progression- free survival. The safety of each regimen was also evaluated. Result(s): In total, 432 patients (median age, 72 years; median Cumulative Illness Rating Scale score, 8; median creatinine clearance, 66.4 ml per minute) underwent randomization, with 216 assigned to each group. After a median follow-up of 28.1 months, 30 primary end-point events (disease progression or death) had occurred in the venetoclax-obinutuzumab group and 77 had occurred in the chlorambucil-obinutuzumab group (hazard ratio, 0.35; 95% confidence interval [CI], 0.23 to 0.53; P<0.001). The Kaplan-Meier estimate of the percentage of patients with progression- free survival at 24 months was significantly higher in the venetoclax-obinutuzumab group than in the chlorambucil-obinutuzumab group: 88.2% (95% CI, 83.7 to 92.6) as compared with 64.1% (95% CI, 57.4 to 70.8). This benefit was also observed in patients with TP53 deletion, mutation, or both and in patients with unmutated immunoglobulin heavy-chain genes. Grade 3 or 4 neutropenia occurred in 52.8% of patients in the venetoclax-obinutuzumab group and in 48.1% of patients in the chlorambucil-obinutuzumab group, and grade 3 or 4 infections occurred in 17.5%

Background The BCL2 inhibitor venetoclax has shown activity in patients with chronic lymphocytic leukemia (CLL), but its efficacy in combination with other agents in patients with CLL and coexisting conditions is not known. Methods In this open-label, phase 3 trial, we investigated fixed-duration treatment with venetoclax and obinutuzumab in patients with previously untreated CLL and coexisting conditions. Patients with a score of greater than 6 on the Cumulative Illness Rating Scale (scores range from 0 to 56, with higher scores indicating more impaired function of organ systems) or a calculated creatinine clearance of less than 70 ml per minute were randomly assigned to receive venetoclax-obinutuzumab or chlorambucil-obinutuzumab. The primary end point was investigator-assessed progression-free survival. The safety of each regimen was also evaluated. Results In total, 432 patients (median age, 72 years; median Cumulative Illness Rating Scale score, 8; median creatinine clearance, 66.4 ml per minute) underwent randomization, with 216 assigned to each group. After a median follow-up of 28.1 months, 30 primary end-point events (disease progression or death) had occurred in the venetoclax-obinutuzumab group and 77 had occurred in the chlorambucil-obinutuzumab group (hazard ratio, 0.35; 95% confidence interval [CI], 0.23 to 0.53; P<0.001). The Kaplan-Meier estimate of the percentage of patients with progression-free survival at 24 months was significantly higher in the venetoclax-obinutuzumab group than in the chlorambucil-obinutuzumab group: 88.2% (95% CI, 83.7 to 92.6) as compared with 64.1% (95% CI, 57.4 to 70.8). This benefit was also observed in patients with TP53 deletion, mutation, or both and in patients with unmutated immunoglobulin heavy-chain genes. Grade 3 or 4 neutropenia occurred in 52.8% of patients in the venetoclax-obinutuzumab group and in 48.1% of patients in the chlorambucil-obinutuzumab group, and grade 3 or 4 infections occurred in 17.5% and 15.0%

Deep molecular response in chronic phase chronic myeloid leukaemia (CP-CML) is associated with superior event free survival, provides a platform for treatment free remission and is increasingly being adopted as a goal of therapy. Interferon was a commonly used CML therapy in the pre-imatinib era, exerting direct anti-leukemic activity and immune-stimulatory properties. Combining interferon and tyrosine kinase inhibitors (TKI) may lead to synergistic anti-leukemic effects. We report the interim analysis of the Pinnacle phase II study, combining nilotinib with pegylated interferon alfa-2B (Peg-IFN) in CP-CML, evaluating tolerability of the combination and efficacy as measured by molecular responses. All patients received nilotinib 300mg BID for the first 3 months (mths). Peg-IFN (PegIntron, MSD) was added at 30mcg/week in the 4 mth in patients without persistent haematological toxicities, increasing to 50mcg/week as tolerated over the following mth. Combination therapy continued until 24 mths, when patients reverted to TKI monotherapy. Switching to imatinib 400-600mg QD was allowed for patients with persistent grade II or any grade III/IV toxicity from nilotinib. The co-primary end points are MR4.5 (BCR-ABL1 <=0.0032% IS) at 24 mths and MMR (BCR-ABL1 <=0.1% IS) at 12 mths. Patients were screened for cardiac / vascular disease and associated risk factors at baseline (EKG, ejection fraction via ultrasound or nuclear med, arterial duplex of carotids and lower limbs, blood HbA1c and lipid profiles). Patients with uncontrolled vascular risk factors (diabetes, hypertension, dyslipidemia) or a history of vascular events were excluded. Sixty patients were recruited from 12 Australian centres. Median age was 48.5 years (range 19-72), and 45% were female. Sokal risk was low in 43% and high in 18%. Median follow up was 14 mths (2.4-37). Figure 1 shows BCR-ABL1 transcript levels over time. Of the 59 patients followed up for >=3 mths, 5 had BCR-ABL1 >10% at 3 mths (8.5%). Two pati

Optimal red cell transfusion thresholds in myelodysplastic syndrome are not established. In this survey of 110 Australasian haematologists' practice in myelodysplastic syndrome-related anaemia, 92% of respondents set transfusion thresholds, and would typically transfuse at a haemoglobin <80 g/L aiming for a post-transfusion haemoglobin 90-100 g/L, reflecting a restrictive transfusion strategy. Higher thresholds were typically used for patients with cardiovascular disease or anaemia symptoms. These results will inform the design of clinical trials comparing transfusion thresholds.Copyright © 2017 Royal Australasian College of Physicians

There is a strong argument for the use of antifungal prophylaxis in high-risk patients given the significant mortality associated with invasive fungal disease, the late identification of these infections, and the availability of safe and well-tolerated prophylactic medications. Clinical decisions about which patients should receive prophylaxis and choice of antifungal agent should be guided by risk stratification, knowledge of local fungal epidemiology, the efficacy and tolerability profile of available agents, and estimates such as number needed to treat and number needed to harm. There have been substantial changes in practice since the 2008 guidelines were published. These include the availability of new medications and/or formulations, and a focus on refining and simplifying patient risk stratification. Used in context, these guidelines aim to assist clinicians in providing optimal preventive care to this vulnerable patient demographic.Copyright © 2014 The Authors; Internal Medicine Journal © 2014 Royal Australasian College of Physicians.