Pediatric regimens improve outcomes in adolescent and young adult (AYA) acute lymphoblastic leukemia (ALL) patients. End-consolidation (time point 2 [TP2]) minimal residual disease negativity (MRDneg) is associated with improved survival. In this study, standard consolidation chemotherapy was replaced with blinatumomab to improve TP2 MRDneg-a key survival surrogate in B-lineage ALL. From 2019 to 2022, 55 patients constituted the intention-to-treat (ITT) cohort, median age 25 (range, 16-39) years. Using a Simon's 2-stage design, blinatumomab replaced standard consolidation chemotherapy cycles with TP2 MRDneg as the primary endpoint. Blinatumomab was associated with an improved TP2 MRDneg rate of 70.8% (95% CI, 55.9%-83.0%) versus the null hypothesis of 60% (P = 0.037). When compared to our previous ALL06 study, median time from protocol I commencement to next treatment phase was 84 versus 97 days (P = 0.0001), with 82.7% versus 45.1% (P < 0.0001), commencing protocol M or high-risk block therapy by day 94. Induction mortality was 1.8%. Blinatumomab was well tolerated. Median follow-up was 42.9 (range, 1.9-54.7) months, with 3-year disease-free survival (DFS) 88.6% (95% CI, 76.3%-94.7%) and 3-year overall survival (OS) 90.5% (95% CI, 78.6%-95.9%) in the ITT cohort. Higher than medium-risk patients had poorer DFS but not OS. Standard genomic risk patients had 100% 3-year DFS and OS. Adverse genomic risk stratified by TP2 MRDpos predicted poorer DFS but not OS. Blinatumomab consolidation for de novo B-lineage AYA ALL was associated with high MRDneg rates and excellent survival, particularly in standard-risk disease. Genomics may assist in predicting response to blinatumomab in de novo ALL (ACTRN12618001734257).

Introduction The impact of blinatumomab on the health-related quality of life (HRQoL) of adolescents and young adults (AYA) in the treatment of de novo acute lymphoblastic leukemia (ALL) has not previously been reported. The phase II ALL09 “SuBliME” study showed the substitution of chemotherapy by blinatumomab in the consolidation phase of a BFM based protocol improved day 79 minimal residual disease (MRD) negativity rates and resulted in excellent 2-year disease free and overall survival. We present the patient-reported HRQoL in participants from ALL09. Methods Study participants were treated with a conventional 4-drug induction, followed by a 28-day infusional blinatumomab consolidation (together with intrathecal methotrexate) planned to commence at day (d) 36, and be completed by d64. HRQoL was assessed at screening and at the end of each treatment phase, sequentially for the duration of the study, with study participants following protocol-driven treatment pathways. The timepoints presented here (screening, d36, d64), are most representative of the impact of blinatumomab on HRQoL without dilution from subsequent treatments in the study protocol. Change in HRQoL scores at d36 (end of induction) or d64 (end of blinatumomab consolidation) are presented relative to corresponding mean scores at screening (baseline). Overall HRQoL was assessed using the Functional Assessment of Cancer Therapy-Leukemia (FACT-Leu) trial outcome index (TOI); this is a composite of the FACT-Leu (Leukemia specific score) + FACT-G Physical + Functional scales. FACT-G Physical and Emotional scores, and the FACT-GOG NTX, the neurotoxicity specific scale, are also presented. The mean change in HRQoL score from screening to d36 and d64 was tested for equality to zero with the paired t-test. Results Fifty-five participants with a median age of 25 years (range 16 to 39) were enrolled from April 2019 to April 2022 and followed for a median of 61.5 months (range 53-78 months). 54.5% (30/55) were male; performance status ECOG 0/1 96% (53/55). Questionnaire completion rates were high: 98% (54/55) at screening, 89% (49/55) at d36, and 87% (48/55) at d64. FACT-LEU TOI [Mean 76.77, SD 16.93] did not change significantly from baseline to d36 (p=.54), but at d64 had improved significantly to +9.82 [SD 17.45] above baseline (p<.001). The constituents of this score were as follows: the FACT-LEU score which includes Leukemia-specific items addressing systemic symptoms, fatigue, infection, and uncertainty regarding the future, was 42.36 [SD 10.31] at baseline, +1.30 [SD 9.22] at d36 (p=.33), but at d64 had improved significantly above baseline [+6.84, SD 9.18] (p<.001); FACT-G Physical wellbeing significantly deteriorated by -2.14 [SD 5.38] (p=.008) at d36 from a mean of 20.43 [SD 5.57] at baseline, and significantly improved +2.31 (SD 6.33) above baseline by d64 (p=.015); and FACT-G-Functional wellbeing which relates to work, sleep and general enjoyment, did not significantly change at d36 (p=.54) or d64 (p=.46). FACT-G Emotional wellbeing score (relating to coping with illness, worsening condition, and dying) improved by +1.69 [SD 4.27] (p=.008) by d36, and +2.17 (SD 3.69; p<.001) by d64. FACT-G Social wellbeing (family, friend support, family acceptance of illness, sexuality) score at d36 did not change significantly from baseline [-0.66, SD 3.95] (p=.25), but significantly deteriorated -2.00 [SD 3.54] below baseline (p<.001) at d64. FACT-GOG NTX, encompassing neurotoxicity-related questions, deteriorated significantly at d36 by -5.10 [SD 8.32] from screening (p<.001), but at d64 had returned to baseline levels [-0.90, SD 8.72] (p=.47). Conclusions This is the first study to report the effect of blinatumomab on the HRQoL of AYA patients treated as part of induction/consolidation for de novo CD19+ Ph negative ALL. Blinatumomab consolidation was associated with an improved FACT-Leu TOI at d64 versus screening or end of induction at d36, but reduced FACT-G Social. These findings support the use of blinatumomab in the de novo setting but suggest the need to investigate psychosocial interventions that may improve the social wellbeing of patients during consolidation. Future studies will explore whether targeted changes in protocol design can improve HRQoL measures in adolescent and adult patients with de novo ALL.

Introduction: Despite the benefits conferred by pediatric treatment protocols, outcomes in adolescent and young adult (AYA) acute lymphoblastic leukemia (ALL) remain inferior to children. Poor outcomes in AYA ALL have been associated with reduced tolerability of intensive cytotoxics and higher incidence of adverse risk disease. Our earlier ALLG ALL06 study demonstrated intensive pediatric induction/consolidation could be delivered in a similar time frame as in children suggesting tolerability was not a major contributor to poor outcome in AYA ALL. ALL06 established post consolidation (TP2=d79) minimal residual disease (MRD) positivity (MRD+) and high BMI was predictive of inferior disease free- and overall survival (OS). In order to improve TP2 MRD negativity (MRD-) in B-cell disease, the ALLG ALL09 study substituted standard consolidation for blinatumomab (blin) in phase I and II of a BFM-style protocol . We present the impact of blin on outcomes in genomic cohorts from ALL09 and compare these to similar cohorts from ALL06 treated with standard chemotherapy. Methods: Between Sep 2020 and Apr 2022, 55 patientswere enrolled to ALL09. Of these, 45 had appropriate samples for genomic analyses and 39/45 had an MRD marker identified. These 39 patients formed the genomic cohort presented below. Genomic subtyping was performed using whole transcriptome sequencing, MLPA, karyotype and FISH analyses, and disease was classified into genomic adverse (AR) vs standard (SR) risk based on contemporary literature classifiers. Bone marrow MRD was assessed using ASO-PCR for IGH and TCR rearrangements, at d33 post induction (TP1), and TP2 post blin consolidation. Differences in TP2 MRD were assessed, with estimated 3 yr relapse free survival (RFS) and OS calculated using the Kaplan-Meier method. Results: In the ALL09 cohort, median follow up was 629 days with 3 yr RFS 84.5% and OS 87.1%. In the genomic cohort, median follow up was 602 days with 3 yr RFS 88.8% and OS 93.2%, respectively. These compared favorably to 3 yr RFS and OS (both 67.5%) in the B-cell genomic cohort from ALL06. Between ALL09 and ALL06 there were similar proportions of AR patients (73% and 62.5%, respectively). In ALL09, the most frequent subtypes were PAX5alt (18%) and PAX5 p.P80R (11%) versus KMT2Ar and DUX4r (both 17.5%) in ALL06. In ALL09, Ph-like disease represented 13% vs 12.5% in ALL06. In the ALL09 genomic cohort, the MRD+ rate reduced between TP1 and TP2 (p< 0.001), with the reduction in the rate of positivity being more pronounced in the AR cohort (AR MRD+ TP1=85% vs AR TP2=39%; p< 0.001). In contrast, in ALL06 MRD+ in the AR cohort reduced by only 28% between TP1 and TP2 (p >0.05). This suggests a positive impact of blin consolidation in AR patients in ALL09. Despite improved AR MRD+ rates overall, not all genomic subtypes in ALL09 followed this trend (Table 1). To date, there are 5 relapses in the ALL09 cohort, 4 from the genomic cohort. Of these, 1 was hypodiploid and strikingly the remaining 3 patients harbored a TCF3 rearrangement ( TCF3r). All 4 relapses were significantly associated with MRD+ at TP2 (RFS: MRD-, 100% (n=14) vs MRD+, 71% (n=25); p= 0.013), and all were observed in the AR genomic group. Of interest, the fifth case, outside of the genomic cohort, was classified as PAX5alt. In ALL09, high-risk (HR) patients proceeded to intensive HR block chemotherapy with the aim of eliminating MRD prior to allogeneic transplant (SCT). In the genomics cohort 15 patients proceeded to HR therapy, n=12 were considered AR. Sustained MRD+ through HR blocks 1 and 2 was noted in patients harboring PAX5 p.P80R (3/3), KMT2Ar (2/2) and TCF3r (2/3). Of the 9 patients who proceeded to SCT, 3 had PAX5 p.P80R 1 had PAX5alt, 2 were KMT2Ar and there was 1 each of DUX4r, hypodiploid and TCF3r. The 3 patients who remained MRD+ in the SR cohort had PAX5 p.P80R and all 3 proceeded to SCT. Conclusion: This is the first report of the impact of blin consolidation on genomic subsets of de novo AYA ALL. Our study suggests blin sensitivity as assessed by TP2 MRD response may be genomic subtype dependent, with TCF3r associated with sustained MRD+, leading to eventual relapse (3/3 patients). In addition, the PAX5 p.P80R subset was also associated with sustained high levels of TP2 MRD+ (3/4 with an MRD marker) and SCT (3/5 patients). These results may assist with identification of AYA ALL subsets that could benefit from alternative approaches as blin becomes increasingly incorporated into front-line protocols.

Background Paediatric inspired regimens have improved outcomes in AYA ALL but results remain inferior compared to children. Historically, this has been associated with the poor tolerance of paediatric regimens as well as the unique biology of AYA ALL. Our previous AYA ALL trial, ALLG ALL06 demonstrated that a BFM based protocol could be administered to pts 15-40 years in a similar timeframe to children with estimated 3 yr DFS 72.8% and 3 yr OS 74.9%. In ALL06, only day 79 (end consolidation) MRD negativity was associated with improved DFS and OS while BMI ≥30kg/m2 was associated with inferior OS. The anti-CD19 bispecific T cell engager, blinatumomab has been associated with improved outcomes in both relapsed/refractory and MRD-positive CD19+ pre-B ALL. The primary objective of the ALLG ALL09 "SuBliME” trial was to assess whether the substitution of standard multi-agent cytotoxics with blinatumomab in protocol I phase 2 (consolidation) of a BFM based protocol in de novo AYA CD19+ ALL would be associated with improved day 79 MRD negativity rates and subsequent improvements in DFS and OS when compared to the ALL06 trial. Methods Previously untreated pts with CD19+ Ph-negative ALL were eligible for enrolment. ALL09 differed from ALL06 by replacing standard cyclophosphamide, cytarabine and 6MP chemotherapy with 28 days of infusional blinatumomab in protocol I and II phase 2 therapy but was similar to ALL06 in all other phases including protocol I phase I, protocol M, protocol II phase I and maintenance to a total of 2 yrs of therapy. MRD was assessed centrally using RQ-PCR assays with a sensitivity of 10-4 or greater at day 33 and day 79 of protocol I and reported according to EuroMRD criteria. Stratification to high risk (HR) therapy was based on diagnostic and treatment response criteria with the aim of eliminating MRD prior to allogeneic transplantation (SCT) if a suitable donor was available or further intensive chemotherapy. ALL09 utilised a Simon 2-stage design, with every patient enrolled to receive blinatumomab. The comparator arm was the ALL06 study. The primary endpoint (percentage of pts who achieved MRD negativity by day 79) was assessed on a modified intention to treat (mITT) population consisting of all ITT patients who 1. commenced blinatumomab at day 36 and 2. had informative MRD at day 79. Results 55 pts were enrolled on ALL09 from 04/19 to 04/22. Median age was 25 (16-39) years. 54.5% were male. Presenting WCC was <100 x 109/L in 91%. Extramedullary disease was present in 7.3% (CNS disease in 5.5%). Most (75.5%) pts had B lymphoblastic leukaemia / lymphoma NOS by WHO criteria; n=2 had t4:11. Of 55 eligible pts, n=4 had no MRD marker, n=1 treatment related death in protocol I phase 1, n=1 had progressive disease, and n=1 withdrew consent leaving n=48 in the mITT cohort. Morphological CR was achieved in 68% at day 15, 94.9% by day 33 and 100% of evaluable pts by day 79. There have been 2 relapses and 2 deaths to date (n=1 relapse death). N=25 pts experienced 53 AE's in protocol I phase II including thromboembolic event (n=3), peripheral neuropathy (n=3), cytokine release syndrome (n=2), febrile neutropenia (n=2) and seizure (n=1). MRD results were available in 47 pts at day 33 and 48 pts at day 79. Day 33 and day 79 MRD results were as follows: MRDneg 16/47 (34.0%) and 34/48 (70.8%), MRDlowpos (<5 x 10-4) 18/47 (38.2%) and 10/48 (20.8%) and MRDpos (≥5 x 10-4) 13/47 (27.8%) and 4/48 (8.4%). 20% of pts to date have proceeded to HR therapy with n=6 proceeding to SCT as of last follow up. For the Simon's 2-stage primary endpoint there was a significant improvement in the rate of day 79 MRD negativity from an estimated 60% in ALL06 to 70.8% in the mITT population in ALL09 (p=0.037). Conclusion Substituting standard cytotoxic therapy with the novel bispecific T cell engaging antibody blinatumomab in protocol I phase 2 of a BFM based protocol appeared tolerable and was associated with a significantly higher rate of end-consolidation MRD negative remission than our previous ALL06 protocol. While these results should be confirmed in larger studies, using a Simon's 2-stage design has allowed us to demonstrate the preliminary efficacy of this approach using an MRD endpoint with demonstrated prognostic significance in ALL06 and other trial cohorts. We plan to take this protocol forward in a larger cohort while introducing novel therapies in HR blocks to improve MRD negativity rates in those already exposed to blinatumomab prior to SCT.

Abstract Background Survival rates for lymphoma are highest amongst hematological malignancies. In 2019, it was estimated that over 6400 Australians were diagnosed with lymphoma, a group of hematological malignancies with a high 5-year survival rate of ~ 76%. There is an increased focus on the promotion of wellness in survivorship and active approaches to reducing morbidity related to treatment; however, current models of follow-up care heavily rely on hospital-based specialist-led care. Maximizing the potential of general practitioners (GPs) in the ongoing management of cancer is consistent with the national health reform principles and the Cancer Council Australia’s Optimal Care Pathways. GPs are well positioned to provide guideline-based follow-up care and are more likely to address comorbidities and psychosocial issues and promote healthy lifestyle behaviors. This study aims to test the feasibility of the GOSPEL I intervention for implementing an integrated, shared care model in which cancer center specialists and community-based GPs collaborate to provide survivorship care for patients with lymphoma. Methods We describe a protocol for a phase II, randomized controlled trial with two parallel arms and a 1:1 allocation. Sixty patients with Hodgkin’s and non-Hodgkin’s lymphoma will be randomized to usual specialist-led follow-up care (as determined by the treating hematologists) or a shared follow-up care intervention (i.e., GOSPEL I). GOSPEL I is a nurse-enabled, pre-specified shared care pathway with follow-up responsibilities shared between cancer center specialists (i.e., hematologists and specialist cancer nurses) and GPs. Outcome measures assess feasibility as well as a range of patient-reported outcomes including health-related quality of life as measured by the Functional Assessment of Cancer Therapy—Lymphoma, patient experience of care, symptom distress, comorbidity burden, dietary intake, physical activity behaviors, financial distress/interference, and satisfaction of care. Safety indicators including hospital admission and unscheduled lymphoma clinic visits as well as process outcomes such as intervention fidelity and economic indicators will be analyzed. Discussion This trial is designed to explore the feasibility and acceptability of a new model of shared care for lymphoma survivors. Patient-reported outcomes as well as potential barriers to implementation will be analyzed to inform a larger definitive clinical trial testing the effects and implementation of a shared care model on health-related quality of life of lymphoma survivors. Trial registration Australia and New Zealand Clinical Trials Registry ACTRN12620000594921 . Registered on 22 May 2020.

Background: BCR signaling mediated through Bruton's tyrosine kinase (BTK) plays a critical role in the development and maintenance of marginal zone lymphoma (MZL). BTK inhibitors have established activity in relapsed/refractory (R/R) MZL with the phase 2 study of ibrutinib demonstrating an objective response rate (ORR) of 48% (Noy et al. Blood. 2017;129:2224-2232). Zanubrutinib is a potent and highly specific next-generation BTK inhibitor designed with greater selectivity for BTK vs TEC- and EGFRfamily kinases, which are thought to be related to off-target toxicities. Therapeutic activity of zanubrutinib was established in an early-phase study (BGB-3111-AU-003) of 20 patients (pts) with R/R MZL demonstrating an ORR of 80%, with a complete response (CR) rate of 15%, and partial response (PR) rate of 65% (Tedeschi et al. EHA 2020, abstract 2804). Aims: To present initial efficacy and safety results in pts with R/R MZL enrolled in MAGNOLIA (BGB-3111-214). Methods: MAGNOLIA is a phase 2, multicenter, single-arm study of adults with R/R MZL who had received ≥1 line of therapy including ≥1 CD20-directed regimen. All were treated with zanubrutinib 160 mg twice daily until disease progression or unacceptable toxicity. Use of long-term antiplatelet and anticoagulation agents was permitted. The primary end point was ORR determined by an independent review committee in accordance with the Lugano classification. Secondary end points include ORR by investigator assessment, duration of response (DOR), progression-free survival (PFS), and safety. Results: As of January 11, 2021, 68 pts were enrolled and treated. Median age was 70 years (range, 37-95), with 28% aged ≥75 years. Subtypes included extranodal (mucosa-associated lymphoid tissue;38%), nodal (38%), splenic (18%), and indeterminate (6%) MZL. Median number of prior therapies was 2 (range, 1-6) and 32% of pts had disease that was refractory to last therapy. Median duration of drug exposure was 59.1 weeks (range, 3.7-84.1). Sixty-six pts were evaluable for efficacy. At a median study follow-up of 15.5 months (range, 1.6-21.7), investigator-assessed ORR (CR + PR) was 74% (CR 24%, PR 50%, stable disease 17%). Responses were observed in all subtypes, with an ORR of 68%, 84%, 75%, and 50% in extranodal, nodal, splenic, and indeterminate subtypes, respectively. CR rate was 36% for extranodal MZL, 20% for nodal, 8% for splenic, and 25% for indeterminate subtype. Median DOR and PFS were not reached;15-month PFS was 68% and 12-month DOR was 81%. IRC review is ongoing. Twenty-eight (41%) pts discontinued treatment: 20 due to disease progression, 1 withdrew consent, 3 required prohibited medications, 4 due to adverse events (AEs;2 due to COVID-19 pneumonia, 1 due to pyrexia attributed to disease transformation, and 1 due to myocardial infarction [MI]). The most common (≥10%) treatment-emergent AEs reported were diarrhea (22%), bruising (21%), constipation (15%), pyrexia (13%), abdominal pain (12%), upper respiratory tract infection (12%), back pain (10%), and nausea (10%). Most AEs were grade 1 or 2. Neutropenia was the most common grade ≥3 AE (10%). Two pts died from COVID-19 pneumonia and 1 pt with pre-existing coronary artery disease died from MI. No fatal AEs were considered related to zanubrutinib. All-grade AEs of interest included neutropenia (13%), thrombocytopenia (13%), atrial fibrillation/flutter (3%), and hypertension (3%). No major/serious hemorrhage was reported. No AEs led to dose reductions. Summary/Conclusion: Zanubrutinib demonstrated high response rates and durable disease control with a favorable safety profile in pts with R/R MZL.

Targeted antibody therapies improve outcomes for chronic lymphocytic leukemia (CLL) patients. However, resistance often develops. We have previously shown that resistance to therapeutic antibodies, by monocyte derived macrophages (referred to as nurse like cells, NLCs), from CLL patients is characterized by suppression of antibody dependent phagocytosis (ADP). The mechanism(s) contributing to the muted ADP responses remain unresolved. In this regard, an innate immune checkpoint was recently described that uses the CD47:SIRPα axis to suppress phagocytic responses by macrophages. In this study we examine whether the SIRPα axis regulates ADP responses to the anti-CD20 antibody, obinutuzumab, by NLCs. Using siRNA depletion strategies we show that SIRPα is a suppressor of ADP responses. Moreover, we show that this innate immune checkpoint contributes to the resistance phenotype in NLCs derived from CLL patients. Finally, we show that SIRPα suppression is mediated via the phosphatase, Shp1, which in turn suppresses SYK-dependent activation of ADP. Thus, we identify a druggable pathway that could be exploited to enhance sensitivity to existing therapeutic antibodies used in CLL. This is the first study to show that activation of the CD47:SIRPα innate immune checkpoint contributes to ADP resistance in NLCs from CLL patients.

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.

First reported in 1999, germline runt-related transcription factor 1 (RUNX1) mutations are a well-established cause of familial platelet disorder with predisposition to myeloid malignancy (FPD-MM). We present the clinical phenotypes and genetic mutations detected in 10 novel RUNX1-mutated FPD-MM families. Genomic analyses on these families detected 2 partial gene deletions, 3 novel mutations, and 5 recurrent mutations as the germline RUNX1 alterations leading to FPD-MM. Combining genomic data from the families reported herein with aggregated published data sets resulted in 130 germline RUNX1 families, which allowed us to investigate whether specific germline mutation characteristics (type, location) could explain the large phenotypic heterogeneity between patients with familial platelet disorder and different HMs. Comparing the somatic mutational signatures between the available familial (n = 35) and published sporadic (n = 137) RUNX1-mutated AML patients showed enrichment for somatic mutations affecting the second RUNX1 allele and GATA2. Conversely, we observed a decreased number of somatic mutations affecting NRAS, SRSF2, and DNMT3A and the collective genes associated with CHIP and epigenetic regulation. This is the largest aggregation and analysis of germline RUNX1 mutations performed to date, providing a unique opportunity to examine the factors underlying phenotypic differences and disease progression from FPD to MM.

Primary cutaneous lymphomas represent a heterogeneous group of T‐ and B‐cell lymphomas with distinct clinical presentations, histopathologic features, treatment approaches and outcomes. The cutaneous T‐cell lymphomas, which include mycosis fungoides and Sézary syndrome, account for the majority of the cutaneous lymphomas. This Clinical Practice Statement is reflective of the current clinical practice in Australia. An expanded form of the Clinical Practice Statement (and updates), along with helpful patient resources and access to support groups, can be found at the following ( http://www.australasianlymphomaalliance.org.au ).

The British Journal of Haematology publishes original research papers in clinical, laboratory and experimental haematology. The Journal also features annotations, reviews, short reports, images in haematology and Letters to the Editor.

Antibody therapies are important treatment options for Chronic lymphocytic leukemia (CLL). Monocyte-derived-macrophages (MDMs) are thought to be a major immune effector that clears leukaemic cells ...

Fcγ receptor (FcγR) signalling in monocyte derived macrophages from chronic lymphocytic leukaemia (CLL) patients is poorly understood. This signalling pathway is the key determinant of the ability of the macrophages to respond to therapeutic antibodies in current clinical use for CLL. Muted FcγR signalling activity accompanies disease progression and results in resistance to therapeutic antibodies. The molecular mechanisms controlling FcγR signalling and resistance are unknown. Here, we demonstrate that the class I phosphoinositide 3-kinase (PI3K) catalytic subunit p110δ is essential for CLL-derived macrophages to respond to therapeutic antibodies. Inhibition of p110δ in the macrophages reduces FcγR-mediated antibody immune responses. Surprisingly, our studies indicated that FcγR downstream signalling is independent of SYK and BTK activity. Thus, we show that FcγR antibody responses occur via a previously unidentified p110δ-dependent pathway, which is independent of the previously described SYK/BTK activation pathway. These data provide novel insights into the effectors of antibody responses. Our data also provide mechanistic insights into therapy resistance in CLL.

There is a continued reliance on antibody therapies for treating chronic lymphocytic leukaemia (CLL). Whilst the inclusion of antibody therapies in many standard treatment regimes results in good outcomes, acquired resistance remains a significant clinical challenge for many CLL patients resulting in insensitivity to the antibody treatment. Thus, understanding the mechanisms driving treatment resistance is likely to lead to therapies to reverse resistance and improve patient outcomes. Earlier studies from our laboratory have shown that resistance to therapeutic antibodies, in CLL, is due to a reduced ability of monocyte derived macrophages (MDMs) to participate in FcγR-dependent antitumour responses (e.g. ADCC and antibody-dependent phagocytosis (ADP). In this regard, we recently showed that SYK and BTK activation are downstream of the FcγRs (Oncogene, 36(17):2366-2376, 2017). Moreover, we showed that signalling through the FcγR pathway was reduced in antibody-resistant MDMs and could be reversed using inhibitors of SHIP1. These studies indicated that knowledge of FcγR signalling could exploited to reverse resistance. Unfortunately, knowledge of the exact signalling events controlling FcγR activity in MDMs from CLL patients is unclear.

Immune checkpoint inhibitors (ICI's) have revolutionized the management of patients with advanced melanoma (AM). However, the data on the effectiveness of ICI's has been largely restricted to patients on clinical trials, thus excluding patients with second malignancies. Chronic Lymphocytic Leukemia (CLL) is the most prevalent adult leukemia and is associated immune dysregulation and a 3.8 fold increase in melanoma incidence. We report a multi-center, retrospective case-control study examining differences between patients who received checkpoint therapy in the context of the dual diagnoses of CLL and advanced melanoma (n = 20) compared to those with advanced melanoma alone (n = 154).

High dose chemotherapy for acute hematological malignancies is usually prescribed with curative intent. However, treatment-related toxicities such as infection, prolonged myelosuppression, neurotoxicity, renal impairment, gastrointestinal toxicity and cardiovascular complications cause significant morbidity and in some instances mortality. Balancing efficacy and toxicity is a constant challenge. Between 1980–2013, the worldwide prevalence of overweight or obese adults rose by 28% [1]. Body mass index (BMI), defined as weight in kilograms divided by square of height in meters, is used to define overweight as a BMI 25 kg/m and obese as a BMI 30 kg/m [2]. Weight-based chemotherapy doses have been commonly reduced in overweight and obese hematology and oncology patients [3]. This is due to concerns regarding altered chemotherapy pharmacokinetics and an excess of toxicity in this population. Whilst there are numerous publications reviewing treatment outcomes in patients of increased weight, most do not capture information regarding weightbased dose modifications. Consequently, results cannot be adequately interpreted to guide future patient dosing. This systematic review of the literature was performed to collate treatment-related toxicities and outcomes in overweight and obese adult patients compared to normal weight patients with acute leukemia or aggressive lymphoma. The aim was to determine the appropriateness of dosing chemotherapy according to actual body weight (ABW) in this population. Dosing of novel targeted therapies was not addressed in this review. A literature search of four databases (PubMed, EMBASE, Web of Science and Cochrane Central Register of Controlled Trials) was conducted for English language articles published between 1995 and the end of 2014. The PubMed search terms were (obes* AND acute myel* leukemia) OR (overweight AND acute myel* leukemia) OR (obes* AND acute lymph* leukemia) OR (overweight AND acute lymph* leukemia) OR (obes* AND lymphoma) OR (overweight AND lymphoma). The EMBASE search used combinations of the Emtree terms ‘‘obesity’’, ‘‘lymphoma’’, ‘‘acute lymphoblastic leukemia’’ and ‘‘acute granulocytic leukemia’’, the latter being the database’s search term for acute myeloid leukemia. For the Web of Science and Cochrane Central Register of Controlled Trials searches we used the same search terms and combinations as for the PubMed search. Two authors (SM, GS) independently screened titles, collated potentially relevant articles and then read them in full in order to determine their eligibility for this review. Discrepancies were resolved by consensus. Published articles were only included in this review if treatment outcomes were detailed (including toxicities, disease response and/or survival), currently accepted chemotherapy regimens were used and a comment was made that doses were weight-based with no, or specified, modification of doses in a minority of patients of increased weight (except vincristine). Studies in stem cell transplantation were excluded because doses in conditioning chemotherapy regimens are often intentionally myeloablative and treatment-related toxicities could be confounded by total body irradiation, immunosuppression and stem cell dose. Furthermore, a comprehensive literature review in this population had been published recently [4]. Pediatric (defined as below 16 years of age) studies, literature reviews, small case series and case reports, abstracts and editorials were similarly excluded. A total of 861 acute leukemia studies and 1098 lymphoma studies were identified using this search strategy [Fig. 1]. Upon screening titles and evaluating the articles for potential relevance, only five articles for acute myeloid leukemia and four for lymphoma fulfilled

Background: This year, germline predisposition to haematological malignancy (HM) debuts in the World Health Organization classification of myeloid neoplasms and acute leukemia (Blood, 2016;127:2391). It has been 17 years since germline mutations in RUNX1 were found to lead to familial platelet disorder (FPD) with predisposition to myelodysplastic syndrome and acute myeloid leukaemia (MDS/AML) (Nat Genet. 1999;23:166). Now, nearly 80 families have been reported with damaging germline mutations or deletions affecting RUNX1 function, associated with FPD, making it an increasingly significant clinical presence. Although thrombocytopenia and platelet dysfunction are present in almost all RUNX1 mutant carriers, we and others have observed that the predisposition to HM varies between family members, with respect to age at diagnosis and the type of malignancy, and in some cases RUNX1 mutation carriers have no apparent HM development over their lifespan. The reasons for this heterogeneity are currently unknown. Aims: We are conducting an international collaborative study examining RUNX1 mutated families. The aim of the research project is to classify the range of phenotypes correlated with RUNX1 mutations comprehensively (including non-malignant phenotypes such as skin disorders) and to determine if the type of RUNX1 mutation and the presence of other germline and acquired mutations in relevant HM genes correlate with the likelihood of HM development, or the type of HM that develops. Across all of our data we aim to analyse clinically relevant information that will be used to inform prognosis and clinical management in germline RUNX1 mutation carriers. Results:From a review of the literature for previously characterised RUNX1 mutant families most mutations are predicted to be loss-of-function, with the combination of frameshift, stopgain, splicing and deletion accounting for the majority of alterations (57, 70%) compared to missense mutations (22, Figure 1). The most common sites of mutation are R201 and R204, affected by both missense and stopgain (10 total), which lie within the nuclear localisation signal at the end of the RUNT domain (Figure 1). We also surveyed in detail 12 RUNX1 pedigrees with both novel and previously described missense, frameshift, stopgain and deletion mutations and found that, while all families developed myeloid malignancies, 6 families also had individuals who developed lymphoid malignancy (most often Acute lymphoblastic leukemia (ALL)) which was heritable in sub-families, and subject to anticipation (e.g see IV-5 and V-5 in Figure 2). Consistent with population genome wide association studies identifying RUNX1 as a susceptibility locus for psoriasis (J Autoimmun. 2015;64:66), we find that skin conditions (psoriasis, eczema) are common, and present in germline RUNX1 carriers in 50% of our families; most commonly observed in families with stopgain and frameshift mutations. Genomic analysis of selected samples confirms that mutation of the other RUNX1 allele is the most commonly acquired mutation in germline RUNX1 mutation carriers developing HM. Alterations of chromosomes 21 and 7 are also common. DNMT3A and PHF6 acquired mutations were the next most frequently observed in tumors and mutations in U2AF1 and ASXL1 in the blood of RUNX1 carriers without HM were observed, suggestive of pre-HM clonal expansion. Finally, in a family with a novel R169I RUNX1 mutation, a rare germline ASXL1 variant (E1102D, 1.0% in ExAC) was found in two RUNX1 carriers who developed early onset AML. This variant is also significantly enriched in an MDS cohort unselected for family history compared to the general population (HR 1.3, p=0.02), as well as ASXL1 N986S (0.1% in ExAC, HR 3.3, p=0.0002) suggesting they operate as germline HM risk modifiers. Interestingly RUNX1 and ASXL1 acquired mutations often co-occur in sporadic MDS/AML and our data suggests this collaboration may also occur at the germline level. Conclusions:Annotation of skin phenotypes co-existent with a family history of haematological malignancy may assist in identifying RUNX1 mutant families. Both acquired and germline mutations in known HM genes may modify germline RUNX1 driven HM penetrance and phenotype. Our data suggest that screening of RUNX1 germline mutation carriers for germline and acquired variants in other HM genes could provide an important tool for defining risk and requires further investigation. Disclosures Owen:Pharmacyclics: Research Funding; Janssen: Honoraria; Roche: Honoraria, Research Funding; Novartis: Honoraria; Gilead: Honoraria, Research Funding; Lundbeck: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Abbvie: Honoraria. Godley:UpToDate: Honoraria; Onconova, Inc.: Research Funding.

Multiple trials now demonstrate the potential for treatment-free remission (TFR) in patients with sustained deep molecular response to tyrosine kinase inhibitors (TKIs). We describe two patients who remain in treatment-free remission after achieving undetectable BCR-ABL with ponatinib on the phase II PACE trial, despite being multiply resistant/intolerant to other agents or carrying the T315I mutation. Patient 1 previously had a suboptimal response to imatinib (BCRABL >10% at 15mo) and then was intolerant of nilotinib and dasatinib due to grade 3 liver enzyme abnormalities. He achieved undetectable BCR-ABL (Molecular MD laboratories) by six months on ponatinib. His ponatinib dose was gradually reduced from 45mg/d to 15mg/d due to vascular events (myocardial infarction requiring stenting, carotid stenosis requiring endarterectomy, recurrent ischaemic colitis). At the time of his last episode of colitis, his BCR-ABL had been undetectable for 47 months and hence a decision to attempt TFR was made. He remains in TFR 11 months post-cessation. Patient 2 progressed on imatinib and was found to carry the T315I mutation. He achieved undetectable BCR-ABL by nine months on ponatinib. His ponatinib dose was also gradually reduced from 45mg/d to 15mg/d due to vascular events (popliteal stenosis requiring stenting, embolic stroke, coronary artery disease requiring stenting). At the time of his last event, his BCR-ABL had been undetectable for 30 months and hence a decision to attempt TFR was made. He remains in TFR 17 months post-cessation. This series adds to the one prior case report of ponatinib facilitating treatment-free remission (Engel NW et al. J Oncol Pract 2016. 12(6);592-4) and these remissions are notable because they occur in patients not considered for other TFR studies because of refractoriness to other agents or known T315I mutations. This is an alternative avenue to dose reduction to reduce the risk of vascular events in ponatinib-treated patients. Disclosures Mills: Ariad: Other: This clinical study funded by Ariad.