Phase 2 study of danicopan in patients with paroxysmal nocturnal hemoglobinuria with an inadequate response to eculizumab.

Paroxysmal nocturnal hemoglobinuria (PNH) is characterized by uncontrolled terminal complement activation and subsequent intravascular hemolysis (IVH). C5 inhibitors prevent membrane attack complex formation, but patients may experience extravascular hemolysis (EVH) and continue to require blood transfusions. Danicopan, an oral proximal complement inhibitor of alternative pathway factor D (FD), is designed to control IVH and EVH. In a phase 2 dose-finding trial, eculizumab-treated transfusion-dependent patients with PNH (n = 12) received danicopan, 100 to 200 mg thrice daily, in addition to their eculizumab regimen for 24 weeks. End points included hemoglobin (Hgb) change vs baseline at week 24 (primary), reduction in blood transfusions, and patient-reported outcomes. Safety, tolerability, and pharmacokinetics/pharmacodynamics were measured. Twelve patients received ≥1 danicopan dose; 1 patients discontinued from a serious adverse event deemed unlikely related to danicopan. Eleven patients completed the 24-week treatment period. Addition of danicopan resulted in a mean Hgb increase of 2.4 g/dL at week 24. In the 24 weeks prior to danicopan, 10 patients received 31 transfusions (50 units) compared with 1 transfusion (2 units) in 1 patient during the 24-week treatment period. Mean Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue score increased by 11 points from baseline to week 24. The most common adverse events were headache, cough, and nasopharyngitis. Addition of danicopan, a first-in-class FD inhibitor, led to a meaningful improvement in Hgb and reduced transfusion requirements in patients with PNH who were transfusion-dependent on eculizumab. These benefits were associated with improvement of FACIT-Fatigue. This trial was registered at www.clinicaltrials.gov as #NCT03472885.

Danicopan: an oral complement factor D inhibitor for paroxysmal nocturnal hemoglobinuria

Paroxysmal nocturnal hemoglobinuria (PNH) is characterised by complement-mediated intravascular hemolysis (IVH) due to absence of complement regulators CD55 and CD59 on affected erythrocytes. Danicopan is a first-in-class oral proximal, complement alternative pathway factor D (FD) inhibitor. Therapeutic FD inhibition was designed to control IVH and prevent C3-mediated extravascular hemolysis (EVH). In this open-label, phase 2, dose-finding trial, 10 untreated hemolytic PNH patients received danicopan monotherapy (100-200 mg thrice daily). Endpoints included change in lactate dehydrogenase (LDH) at day 28 (primary) and day 84 and hemoglobin. Safety, pharmacokinetics/pharmacodynamics, and patient-reported outcomes were measured. Ten patients reached the primary endpoint; two later discontinued: one for a serious adverse event (elevated aspartate aminotransferase/alanine aminotransferase coincident with breakthrough hemolysis, resolving without sequelae) and one for personal reasons unrelated to safety. Eight patients completed treatment. IVH was inhibited, demonstrated by mean decreased LDH (5.7 times upper limit of normal [ULN] at baseline vs 1.8 times ULN [day 28] and 2.2 times ULN [day 84]; both p.

Australasian Trends in Allogeneic Stem Cell Transplantation for Myelofibrosis in the Molecular Era: A Retrospective Analysis from the Australasian Bone Marrow Transplant Recipient Registry.

To review the updated trends of national practice and outcomes in transplantation to treat myelofibrosis (MF), we retrospectively evaluated 142 patients who underwent allogeneic hematopoietic stem cell transplantation (allo-HSCT) for primary (n = 94) or secondary (n = 48) MF at an Australian/New Zealand transplantation center between 2006 and 2017. The median duration of follow-up was 51.8 months (range, 3.1 to 148 months). The median age at allo-HSCT was 56 years (range, 26 to 69 years). Fifty-two percent of the patients had HLA-identical sibling donors, and 45% had matched unrelated donors (UD). Conditioning regimens were predominantly reduced intensity (83%). Before transplantation, 16% of the patients had undergone splenectomy or splenic irradiation, and 38% (n = 54) received JAK inhibitor therapy. JAK2 mutation testing was performed in 66.9% of the patients, whereas other mutations (CALR, MPL, ASXL1, SRSF2, U2AF1Q57, EZH2, and IDH1/2) were rarely tested (1.4% to 8.4%). Only 4.2% of patients had next-generation sequencing mutation analysis. The median time to neutrophil engraftment was 19 days (range, 10 to 43 days), and the median time to platelet engraftment was 27 days (range, 13 to 230 days). The cumulative incidence of grade II-IV acute graft-versus-host disease (aGVHD) was 21.4% at 100 days, and that of extensive chronic GVHD (cGVHD) at 5 years was 18.1%. Overall survival (OS) was 67% at 1 year and 57% at 5 years. GVHD-free, relapse-free survival was 54% at 1 year and 42% at 5 years. The cumulative incidence of nonrelapse mortality (NRM) was 16% at 100 days and 25% at 1 year. In multivariate analysis, age ≥65 years and use of an UD were identified as significant unfavorable risk factors for OS and NRM. Use of an UD increased the incidence of aGVHD, whereas administration of antithymocyte globulin/alemtuzumab lowered the risk of both aGVHD and cGVHD. Pretransplantation splenectomy/splenic irradiation had a positive influence on time to engraftment. There have been no improvements in the outcomes of allo-HSCT for MF in Australasia over the last decade, with a low uptake of molecular genomic technology due to limited access to funding.

Haploinsufficiency of the NF-κB1 Subunit p50 in Common Variable Immunodeficiency.

Common variable immunodeficiency (CVID), characterized by recurrent infections, is the most prevalent symptomatic antibody deficiency. In ∼90% of CVID-affected individuals, no genetic cause of the disease has been identified. In a Dutch-Australian CVID-affected family, we identified a NFKB1 heterozygous splice-donor-site mutation (c.730+4A>G), causing in-frame skipping of exon 8. NFKB1 encodes the transcription-factor precursor p105, which is processed to p50 (canonical NF-κB pathway). The altered protein bearing an internal deletion (p.Asp191_Lys244delinsGlu; p105ΔEx8) is degraded, but is not processed to p50ΔEx8. Altered NF-κB1 proteins were also undetectable in a German CVID-affected family with a heterozygous in-frame exon 9 skipping mutation (c.835+2T>G) and in a CVID-affected family from New Zealand with a heterozygous frameshift mutation (c.465dupA) in exon 7. Given that residual p105 and p50­translated from the non-mutated alleles­were normal, and altered p50 proteins were absent, we conclude that the CVID phenotype in these families is caused by NF-κB1 p50 haploinsufficiency.

Novel α-Globin Splice Site Mutation (HBA2: c.96-5C>A) in Combination with Three-Gene Deletion Hb H Disease.

The choice of acceptor splice site during exon-exon splicing by the spliceosome is determined by a variety of factors. We report here a family with a novel acceptor splice site variant within intron 1 of the α-globin gene that provides some in vivo insight into the rules governing RNA splicing in homo sapiens. A 2-year-old female with Hb H disease, was found to have not only three α-globin genes deleted (- -FIL/-α3.7) but also a HBA2: c.96-5C>A variant on her remaining α-globin gene. The HBA2: c.96-5C>A variant was in cis with -α3.7 and mRNA studies indicate that this variant creates a new acceptor splice site which is used in approximately 35.0% of α-globin mRNA transcripts. The reduced levels of normal mRNA transcript predicts a more severe Hb H disease than expected for the three-gene deletion Hb H disease with a phenotype similar to nondeletional Hb H disease. We propose that this variant be called Hb Beach Haven (HBA2: c.96-5C>A).

Upfront lower dose lenalidomide is less toxic and does not compromise efficacy for vulnerable patients with relapsed refractory multiple myeloma: final analysis of the phase II RevLite study.

The combination of lenalidomide and dexamethasone is an established treatment for patients with multiple myeloma (MM). Increasingly, treatment attenuation is advocated for frail/elderly patients to minimize toxicity even though there have been no prospective studies to demonstrate whether lenalidomide dose attenuation impacts on response and survival outcome. This prospective multicentre phase II study assessed the efficacy and tolerability of lower dose lenalidomide (15 mg) and dexamethasone (20 mg) in 149 eligible patients with relapsed/refractory MM aged over 59 years and/or with renal impairment. The overall response rate was 71% (complete response 15%). Median (range) progression-free survival (PFS) and overall survival (OS) were 8·9 (6·9-11·5) and 30·5 (20·0-36·2) months, respectively. Upon formal statistical comparison of these endpoints to that of a matched cohort of patients from the pivotal phase III MM009/MM010 studies who received standard-dose lenalidomide (25 mg) and high-dose dexamethasone (40 mg) no difference was seen in PFS (P = 0·34) and OS (P = 0·21). Importantly, grade 3-4 toxicities were reduced with low-dose lenalidomide, mainly lower neutropenia (29% vs. 41%), infections (23% vs. 31%) and venous thromboembolism (3% vs. 13%). This study supports a strategy of lenalidomide dose reduction at the outset for at-risk patients, and prospectively confirms that such an approach reduces adverse events while not compromising patient response or survival outcomes.

Massive parallel sequencing of solid tumours - challenges and opportunities for pathologists.

The role of pathologists is to provide diagnostic, prognostic and predictive data to enable clinical colleagues to manage patients optimally. Current histo/anatomical pathology is predominantly morphology-based, with the addition of biomarkers, applied largely through immunohistochemistry, fluorescence in-situ hybridization (FISH) and a limited range of polymerase chain reaction (PCR)-based molecular tests. The desire to apply genomics to the clinical care of patients has been facilitated by the human genome project and subsequently by high-throughput technologies known collectively as massive parallel sequencing (MPS, also referred to as next-generation sequencing, NGS). The use of MPS to identify mutations/variants and tissue RNA expression profiles for diagnosis, prognostication and targeted therapy stratification is now a reality in many clinical specialities. If histopathologists are considered experts in solid tumour pathology, MPS potentially falls within their scope; however, it challenges our predominant morphology-based paradigm. This review summarizes and comments on the current and future state of play of MPS for the practising histopathologist. It will focus on somatic mutations in solid tumours and will challenge histopathologists to take further leadership roles in this area.

Medical specialists' attitudes to prescribing biosimilars.

PURPOSE: Biosimilars are a cost-effective alternative to biologics that could improve patients' access to expensive biological medicines. Currently, there are little data on doctors' perceptions of biosimilars and in what situations they are comfortable prescribing biosimilars. In this study, we investigated medical specialists' perceptions of biosimilars and the factors associated with the acceptance of biosimilars. METHODS: A national sample of 110 of 327 medical specialists working in the areas of rheumatology, dermatology, gastroenterology, oncology and haematology completed an online questionnaire examining attitudes towards prescribing biosimilars, indication extrapolation and switching patients to a biosimilar. RESULTS: Most specialists held positive views of biosimilars, with between 54 and 74% confident in the safety, efficacy, manufacturing and pharmacovigilance of biosimilars. Seventy-one percent of specialists agreed that they would prescribe biosimilars for all or some conditions meeting relevant clinical criteria. Specialists were less confident about indication extrapolation and switching patients from an existing biologic. Acceptance of biosimilars was significantly associated with a lower perceived time to explain a biosimilar to a patient and lower number of weekly patient appointments. The most common situations that they would not prescribe a biosimilar was where there was a lack of clinical data supporting efficacy (32%), or evidence of adverse effects (17%). CONCLUSIONS: Medical specialists held generally positive attitudes towards biosimilars but were less confident in indication extrapolation and switching patients from a biologic. Providing clinicians with guidance on how to explain biosimilars to patients and written patient material may help overcome some of the barriers to the use of biosimilars. Copyright © 2017 John Wiley & Sons, Ltd.

Hb Feilding [ß12(A9)Thr → Pro; HBB: c.37A>C]: a novel unstable ß-globin chain variant.

We report here a patient heterozygous for a previously unreported ß chain variant. A 72-year-old Caucasian female was found to have an abnormal hemoglobin (Hb) as an incidental finding following Hb A1C analysis. There was no family history of anemia or hemoglobinopathy. Her full blood count revealed a mild normochromic anemia with Hb 11.1 g/dL (range 11.5-15.0), mean corpuscular volume (MCV) 93.0 fL (range 80.0-100.0) and mean corpuscular Hb (MCH) 30.0 pg (range 27.0-32.0). Isopropanol stability tests and a variant Hb on high performance liquid chromatography (HPLC) comprizing 37.0% of the total Hb suggested an unstable Hb variant. Sanger sequencing of the ß-globin gene revealed a single base substitution, HBB: c.37A>C, causing the missense mutation ß12(A9)Thr → Pro in exon 1 of the HBB gene. This mutation changes the threonine residue at position 12(A9) to a proline in the ß-globin chain. We propose that this variant be called Hb Feilding after the town where the proband lived. Three dimensional modeling suggested that the disruption of the Hb structure was due to the introduction of a proline at helix A9 which caused distortion of the helical structure and resulted in reduced solubility.

All-trans-retinoic acid, idarubicin, and IV arsenic trioxide as initial therapy in acute promyelocytic leukemia (APML4).

The treatment of acute promyelocytic leukemia has improved considerably after recognition of the effectiveness of all-trans-retinoic acid (ATRA), anthracycline-based chemotherapy, and arsenic trioxide (ATO). Here we report the use of all 3 agents in combination in an APML4 phase 2 protocol. For induction, ATO was superimposed on an ATRA and idarubicin backbone, with scheduling designed to exploit antileukemic synergy while minimizing cardiotoxicity and the severity of differentiation syndrome. Consolidation comprised 2 cycles of ATRA and ATO without chemotherapy, followed by 2 years of maintenance with ATRA, oral methotrexate, and 6-mercaptopurine. Of 124 evaluable patients, there were 4 (3.2%) early deaths, 118 (95%) hematologic complete remissions, and all 112 patients who commenced consolidation attained molecular complete remission. The 2-year rate for freedom from relapse is 97.5%, failure-free survival 88.1%, and overall survival 93.2%. These outcomes were not influenced by FLT3 mutation status, whereas failure-free survival was correlated with Sanz risk stratification (P[trend] = .03). Compared with our previously reported ATRA/idarubicin-based protocol (APML3), APML4 patients had statistically significantly improved freedom from relapse (P = .006) and failure-free survival (P = .01). In conclusion, the use of ATO in both induction and consolidation achieved excellent outcomes despite a substantial reduction in anthracycline exposure. This trial was registered at the Australian New Zealand Clinical Trials Registry (www.anzctr.org.au) as ACTRN12605000070639.

A phase III randomized trial of high-dose CEOP + filgrastim versus standard-dose CEOP in patients with non-Hodgkin lymphoma: 10-year follow-up data: Australasian Leukaemia and Lymphoma Group (ALLG) NHL07 trial.

Increasing dose intensity (DI) of chemotherapy for patients with aggressive non-Hodgkin lymphoma (NHL) may improve outcomes at the cost of increased toxicity. This issue was addressed in a randomized trial aiming to double the DI of myelosuppressive drugs. Between 1994 and 1999, 250 patients with previously untreated aggressive NHL were randomized to treatment with six cycles of 3-weekly standard (s) or intensive (i) chemotherapy: s-CEOP-cyclophosphamide 750, epirubicin 75, vincristine 1.4 mg/m(2) all on day 1, and prednisolone 100 mg days 1-5; i-CEOP-cyclophosphamide 1,500, epirubicin 150, vincristine 1.4 mg/m(2) all on day 1, and prednisolone 100 mg days 1-5. Primary endpoint was 5-year overall survival (OS). Relative to s-CEOP patients, i-CEOP patients achieved a 78% increase in the DI of cyclophosphamide and epirubicin. Despite this, there was no significant difference in any outcome: 5-year OS (56.7% i-CEOP; 55.1% s-CEOP; P = 0.80), 5-year progression free survival (PFS; 41% i-CEOP; 43% s-CEOP; P = 0.73), 5-year time to progression (TTP; 44% i-CEOP; 47% s-CEOP; P = 0.72), or complete remission (CR) + unconfirmed CR (CRu) rates (53% i-CEOP; 59% s-CEOP; P = 0.64). Long-term follow up at 10 years also showed no significant differences in OS, PFS, or TTP. The i-CEOP arm had higher rates of febrile neutropenia (70 vs. 26%), hospitalisations, blood product utilisation, haematological and gastrointestinal toxicities, and lower quality of life scores during treatment, although without significant differences 6-month later. In the treatment of aggressive NHL in the prerituximab era, increasing DI did not result in improved outcomes, while at the same time lead to increased toxicity.

Clinical variability of family members with the C104R mutation in transmembrane activator and calcium modulator and cyclophilin ligand interactor (TACI).

PURPOSE: Common Variable Immunodeficiency Disorder (CVID) is a complex disorder that predisposes patients to recurrent and severe infections. The C104R mutation in the transmembrane activator and calcium modulator and cyclophilin ligand interactor (TACI) is the most frequent mutation identified in patients with CVID. We carried out a detailed immunological and molecular study in a family with a C104R mutation. METHODS: We have undertaken segregation analysis of a kindred with C104R mutations of the TACI gene. Detailed immunological and molecular investigations were carried out for this kindred and the clinical phenotype was compared to the genotype. RESULTS: Segregation analysis of our kindred showed that inheriting single or double copy of the C104R mutation does not consign an individual to CVID. All heterozygotes in the family were phenotypically different, ranging from asymptomatic to ill-health. A family member with a wild type TACI variant had CVID-related phenotype including IgA deficiency and type 1 diabetes. Interestingly, a family member with the homozygous C104R/C104R variant did not meet the criteria for CVID because he had excellent, albeit unsustained, vaccine responses to T cell dependent and T cell independent vaccine antigens despite profound hypogammaglobulinemia. CONCLUSION: The C104R mutation does not correlate with the clinical phenotypes in this family.

Safety and efficacy of zanubrutinib in relapsed/refractory marginal zone lymphoma: final analysis of the MAGNOLIA study.

The primary analysis of MAGNOLIA, an open-label, single-arm, multicenter, phase 2 study, demonstrated that the next-generation Bruton tyrosine kinase (BTK) inhibitor zanubrutinib provided a high overall response rate (ORR) in patients with relapsed/refractory marginal zone lymphoma (R/R MZL), with a favorable safety/tolerability profile. Presented here, is the final analysis of MAGNOLIA, performed to characterize the durability of response and longer-term safety and tolerability. Zanubrutinib (160 mg twice daily) was evaluated in 68 patients with R/R MZL who had received at least 1 anti-CD20-directed regimen. The primary end point was independent review committee (IRC)-assessed ORR. Secondary end points included investigator-assessed ORR, duration of response (DOR), progression-free survival (PFS), overall survival (OS), health-related quality of life, safety, and tolerability. With a median follow-up of 27.4 months, the IRC-assessed ORR was 68.2% (95% confidence interval [CI], 55.6-79.1), with a 24-month DOR event-free rate of 72.9% (95% CI, 54.4-84.9). PFS and OS at 24 months were 70.9% (95% CI, 57.2-81.0) and 85.9% (95% CI, 74.7-92.4), respectively. The zanubrutinib safety profile was consistent with the primary analysis, with no new safety signals observed. Atrial fibrillation/flutter (n = 2 [2.9%]) and hypertension (n = 3 [4.4%]) were uncommon. Neutropenia (n = 8 [11.8%]) was the most common grade ≥3 adverse event. In this final analysis of MAGNOLIA, zanubrutinib demonstrated sustained clinical responses beyond 2 years, with 73% of responders alive and progression free. Zanubrutinib continued to demonstrate a favorable safety/tolerability profile with the additional time on treatment. This trial was registered at www.clinicaltrials.gov as #NCT03846427.

Results of the APML3 trial incorporating all-trans-retinoic acid and idarubicin in both induction and consolidation as initial therapy for patients with acute promyelocytic leukemia.

BACKGROUND: Initial therapy for patients with acute promyelocytic leukemia most often involves the combination of all-trans-retinoic acid with anthracycline-based chemotherapy. The role of non-anthracycline drugs in induction and consolidation is less well-established and varies widely between different cooperative group protocols. DESIGN AND METHODS: In an attempt to minimize relapse and maximize survival for patients with newly diagnosed acute promyelocytic leukemia, the Australasian Leukaemia and Lymphoma Group utilized all-trans-retinoic acid and idarubicin as anti-leukemic therapy for both induction and consolidation. The protocol (known as APML3) was subsequently amended to incorporate maintenance with all-trans-retinoic acid, methotrexate and 6-mercaptopurine. RESULTS: Eight (8%) of 101 patients died within 30 days, and 91 (90%) achieved complete remission. With a median estimated potential follow-up of 4.6 years, 4-year overall survival was 84%, and 71% of the patients remained in remission at 4 years. The cumulative incidence of all relapses was 28.1%, with 15 of the 25 relapses initially identified as an isolated molecular relapse. Both FLT3 mutations (internal tandem duplications and codon 835/836 kinase domain mutations) and increased white cell count at diagnosis were associated with inferior overall survival, but in multivariate analyses only FLT3 mutations remained significant (hazard ratio 6.647, P=0.005). Maintenance therapy was significantly associated with improved remission duration (hazard ratio 0.281, P<0.001) and disease-free survival (hazard ratio 0.290, P<0.001). CONCLUSIONS: The combination of all-trans-retinoic acid and just two cycles of idarubicin followed by triple maintenance produced durable remissions in most patients, but patients with high-risk disease, especially those with FLT3 mutations, require additional agents or alternative treatment approaches. The significant reduction in relapse seen after the addition of maintenance to the protocol supports a role for maintenance in the context of relatively low chemotherapy exposure during consolidation. (actr.org.au identifier: ACTRN12607000410459).

Imatinib mesylate does not increase bone volume in vivo.

Imatinib mesylate is a tyrosine kinase inhibitor used in the management of disorders in which activation of c-Abl, PDGFR, or c-Kit signaling plays a critical role. In vitro, imatinib stimulates osteoblast differentiation, inhibits osteoblast proliferation and survival, and decreases osteoclast development. Patients treated with imatinib exhibit altered bone and mineral metabolism, with stable or increased bone mass. However, recovery from the underlying disease and/or weight gain might contribute to these effects. We therefore investigated the skeletal effects of imatinib in healthy rats. We evaluated the effects of imatinib on bone volume, markers of bone turnover, and bone histomorphometry in mature female rats treated for 5 weeks with either vehicle, imatinib 40 mg/kg daily, or imatinib 70 mg/kg daily. Compared to vehicle, imatinib reduced trabecular bone volume/tissue volume (mean [SD]: vehicle 26.4% [5.4%], low-dose imatinib 24.8% [4.9%] [P = 0.5], high-dose imatinib 21.1% [5.7%] [P = 0.05]), reduced osteoblast surface (mean [SD]: vehicle 12.8% [5.8%], low-dose 6.8% [1.9%] [P < 0.01], high-dose 7.8 [3.1%] [P < 0.05]), and reduced serum osteocalcin (mean change from baseline [95% CI]: vehicle -8.2 [-26.6 to 10.2] ng/ml, low dose -79.7 [-97.5 to -61.9] ng/ml [P < 0.01 vs. vehicle], high-dose -66.0 [-82.0 to -50.0] ng/ml [P < 0.05 vs. vehicle]). Imatinib did not affect biochemical or histomorphometric indices of bone resorption. These results suggest that, in healthy animals, treatment with imatinib does not increase bone mass and that the improvements in bone density reported in patients receiving imatinib may not be a direct effect of the drug.

The MAGNOLIA Trial: Zanubrutinib, a Next-Generation Bruton Tyrosine Kinase Inhibitor, Demonstrates Safety and Efficacy in Relapsed/Refractory Marginal Zone Lymphoma.

PURPOSE: Marginal zone lymphoma (MZL) is an uncommon non-Hodgkin lymphoma with malignant cells that exhibit a consistent dependency on B-cell receptor signaling. We evaluated the efficacy and safety of zanubrutinib, a next-generation selective Bruton tyrosine kinase inhibitor, in patients with relapsed/refractory (R/R) MZL. PATIENTS AND METHODS: Patients with R/R MZL were enrolled in the phase II MAGNOLIA (BGB-3111-214) study. The primary endpoint was overall response rate (ORR) as determined by an independent review committee (IRC) based on the Lugano 2014 classification. RESULTS: Sixty-eight patients were enrolled. After a median follow-up of 15.7 months (range, 1.6 to 21.9 months), the IRC-assessed ORR was 68.2% and complete response (CR) was 25.8%. The ORR by investigator assessment was 74.2%, and the CR rate was 25.8%. The median duration of response (DOR) and median progression-free survival (PFS) by independent review was not reached. The IRC-assessed DOR rate at 12 months was 93.0%, and IRC-assessed PFS rate was 82.5% at both 12 and 15 months. Treatment was well tolerated with the majority of adverse events (AE) being grade 1 or 2. The most common AEs were diarrhea (22.1%), contusion (20.6%), and constipation (14.7%). Atrial fibrillation/flutter was reported in 2 patients; 1 patient had grade 3 hypertension. No patient experienced major hemorrhage. In total, 4 patients discontinued treatment due to AEs, none of which were considered treatment-related by the investigators. CONCLUSIONS: Zanubrutinib demonstrated high ORR and CR rate with durable disease control and a favorable safety profile in patients with R/R MZL.

Final analysis of the UKLG LY02 trial comparing 6-8 cycles of CHOP with 3 cycles of CHOP followed by a BEAM autograft in patients <65 years with poor prognosis histologically aggressive NHL.

This trial involved 457 patients and sought to assess the value of early intensification with autologous transplantation in patients with poor prognosis histologically aggressive non-Hodgkin lymphoma (NHL) showing a response to initial CHOP (cyclophosphamide, doxorubicin, vincristine, prednisolone) chemotherapy. Randomization was made at the time of diagnosis with 223 assigned to continuing CHOP and 234 to 3 cycles of CHOP followed by a BEAM (carmustine, etoposide, cytarabine, melphalan) autograft. Analysis was on an intention to treat basis. After the initial three cycles of CHOP 19% of the whole group were in complete response (CR) and 53% in partial remission (PR). At the end of treatment 86% of patients in the CHOP arm had responded with 58% in CR. In the high-dose therapy arm the overall response rate was 83% with 64% in CR (difference between arms not significant). The progression-free survival (PFS) and overall survival at 5 years for the continuing CHOP arm were 38% and 50% respectively, and for the autograft arm were 44% and 50% (differences not significant). Of the patients who attained CR and subsequently relapsed, there were no long-term survivors in the autograft recipients compared to 46% of the continuing CHOP recipients (P = 0.0008). In conclusion, no survival benefit was demonstrated for an early autograft in first response.

Human gastrointestinal neoplasia-associated myofibroblasts can develop from bone marrow-derived cells following allogeneic stem cell transplantation.

This study characterized the contribution of bone marrow-derived cells to human neoplasia and the perineoplastic stroma. The Australasian Bone Marrow Transplant Recipient Registry was used to identify solid organ neoplasia that developed in female recipients of male allogeneic stem cell transplants. Eighteen suitable cases were identified including several skin cancers, two gastric cancers, and one rectal adenoma. Light microscopy, fluorescence and chromogenic in situ hybridization, and immunohistochemistry were performed to determine the nature and origin of the neoplastic and stromal cells. In contrast to recent reports, donor-derived neoplastic cells were not detected. Bone marrow-derived neoplasia-associated myofibroblasts, however, were identified in the rectal adenoma and in a gastric cancer. Bone marrow-derived cells can generate myofibroblasts in the setting of human gastrointestinal neoplasia.

Paternalism in practice: informing patients about expensive unsubsidised drugs.

Recent research conducted in Australia shows that many oncologists withhold information about expensive unfunded drugs in what the authors of the study suggest is unacceptable medical paternalism. Surprised by the Australian results, we ran a version of the study in New Zealand and received very different results. While the percentages of clinicians who would prescribe the drugs described in the scenarios were very similar (73-99% in New Zealand and 72-94% in Australia depending on the scenario) the percentage who would not discuss expensive unfunded drugs was substantially lower in New Zealand (6.4-11.1%) than it was in Australia (28-41%). This seems surprising given the substantial similarities between the two countries, and the extensive interaction between their medical professions. We use the contrast between the two studies to examine the generalisability of the Australian results, to identify influences on clinicians' decisions about what treatment information to give patients, and so the tendency towards medical paternalism and, more pragmatically, about how such decisions might be influenced.

Treatment outcomes of patients with acute promyelocytic leukaemia between 2000 and 2017, a retrospective, single centre experience.

All-trans retinoic acid (ATRA) and arsenic trioxide (ATO) are effective induction therapy for acute promyelocytic leukaemia (APL). However, early thrombo-haemorrhagic complications and mortality remain high. We aimed to investigate how the timing of ATRA initiation and the inclusion of ATO influence patient outcomes. Clinical records were retrospectively reviewed for all patients treated for APL in a single, tertiary centre during 2000-2017. Among 70 patients with APL, 36 (51.4%) presented with thrombo-haemorrhagic complications, and four (5.8%) died within 30 days. The median time to ATRA initiation was 11.2 (range 0-104) h from the time of admission. Patients requiring more transfusions started on ATRA sooner (P = 0.04). Patients with adverse early events did not start ATRA later (P = 0.99). Nevertheless, patients that required additional tests for diagnosis (PML immunofluorescence or molecular) started on ATRA later (28.5 versus 5.3 h; P < 0.0001), and had more thrombo-haemorrhagic complications (P = 0.04). Long-term survival was actually better in patients who started ATRA later (P = 0.03), which is likely explained by higher proportion of low risk patients in this group. Patients treated with ATO (n = 23) maintained higher fibrinogen levels and required less transfusions during induction (P < 0.05), with no disease-related deaths in this group over a median follow-up time of 37.8 months (interquartile range 44.9 months). In summary, fast ATRA initiation reduces early but not late adverse events in APL patients, and the inclusion of ATO helps further improve both early and late outcomes in APL.