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Double-hit lymphoma (DHL) is an aggressive subtype of high-grade B-cell lymphoma with inferior prognosis using standard dose chemotherapy. Controversy remains whether more intensive chemotherapy regimens such as dose-adjusted etoposide, prednisolone, vincristine, cyclophosphamide, doxorubicin and rituximab (DA-EPOCH-R) provide better outcomes in this cohort.To review consecutive cases of DHL treated with DA-EPOCH-R at our institution in comparison to available literature.We conducted a retrospective study of 13 consecutive patients with DHL treated with DA-EPOCH-R at our institution. Primary endpoints included complete response (CR), event-free survival (EFS) and overall survival (OS).CR rate with DA-EPOCH-R in DHL was 69% in our cohort. Median EFS and OS duration was 61 months (95% CI: 41-86 months) and 64 months (95% CI: 42-86 months) respectively. One patient discontinued DA-EPOCH-R due to recurrent febrile neutropenia and there were no treatment or infection-related deaths during the study.This study suggests that DA-EPOCH-R is a well tolerated outpatient regimen for DHL and should be considered for initial treatment in medically fit patients. Further prospective studies are warranted to confirm these findings.

Introduction Midostaurin is the only approved FLT3 inhibitor for combination with intensive induction and consolidation chemotherapy in newly diagnosed patients with FLT3 mutant AML. The FLT3 inhibitor, sorafenib, was investigated in the randomized SORAML trial (Röllig, Lancet Onc 2015), in combination with intensive chemotherapy (IC) for newly diagnosed adults with AML Methods The Australasian Leukaemia and Lymphoma Group (ALLG) conducted a randomized phase 2 study [ACTRN12611001112954] in 99 adults aged 18-65 years with newly diagnosed FLT3-ITD positive (allelic ratio (AR) ≥0.05) AML to determine whether addition of SOR to IC would improve event-free survival (EFS). The study was powered to identify a 25% increase in 2-year EFS with SOR. Patients 18-55 yrs received induction with IDAC-3 (idarubicin [IDA] 12 mg/m2 D1-3 and ara-C 1.5 g/m2 BD D1,3,5,7); patients 56-65 received 7+3 (IDA 12 mg/m2 D1-3 and ara-C 100 mg/m2 D1-7 IVI). Patients were randomized 2:1 to SOR or PBO 400 mg BD on days 4-10 of induction and each consolidation cycle. Due to the pharmacokinetic interaction between SOR and azoles, antifungal prophylaxis during induction was with AmBisome 5 mg/kg IV twice weekly. For consolidation, patients 18-55 yrs received 2 cycles of IcE (IDA 9 mg/m2 D1-2, ara-C 100 mg/m2 D1-5 IVI and etoposide 75 mg/m2 D1-5), those 56-65 yrs received 2 cycles of IDAC-2 (IDA 12 mg/m2 D1-2 and ara-C 1g/m2 BD D1,3,5). Maintenance was with SOR/PBO 400 mg bd days 1-28 for 12 cycles. Allogeneic HCT (allo-HCT) was at investigator discretion. SOR/PBO was not continued post allo-HCT. The primary endpoint was EFS without censoring for allo-HCT with events defined as failure to achieve complete remission (CR) or CR with incomplete hematologic recovery (CRi), relapse or death. Pre-specified secondary endpoints included overall response rate (ORR) defined as CR and CRi, tolerability, EFS according to FLT3-ITD AR < or ≥ 0.7 and impact of randomization on allograft outcome. Results Between Jan 2013-May 2018, 18 centers randomized 99 patients to induction with either SOR (n=65) or PBO (n=33); one patient later found to be FLT3-ITD negative was excluded. Patient characteristics are shown in Table 1. Treatment arms were balanced apart from fewer patients in the SOR arm with NPM1 mutant AML. Deliverability of therapy was comparable, with commencement of consolidation in 78% and 79% and maintenance therapy in 32% and 27% in the SOR and PBO arms, respectively. The overall response rate (ORR) was high in both arms; 91% in the SOR (CR 80%, CRi 11%) and 94% in the PBO (CR 70%, CRi 24%) arm. In the SOR arm, 5% achieved partial remission, went off study and were deemed treatment failures. With a median overall follow-up of 25 mo, there was no significant difference in EFS (HR 0.87 95% CI 0.50-1.49; P=0.61)(Fig A) or OS (HR 0.70 95% CI 0.38-1.29; P=0.26)(Fig. B), nor in a sensitivity analysis with censoring at HCT. 2 yr EFS was 47.9% (SOR) vs 45.4% (PBO) and 2-year OS 66.8% (SOR) vs 56.4% (PBO). Hematopoietic cell transplant (HCT) in CR1 was performed in 62% and 58% in the SOR and PBO arms, respectively. For patients in CR1, 2 yr OS post-HCT was 78.5% (SOR) vs 54.2% (PBO)(Fig C). Suggestive of an on-target effect against FLT3-ITD, the impact of SOR on OS appeared greater for patients with higher FLT3-ITD AR ≥0.7 (Fig. D) (Table 2). Only one early death (within 30 days) was recorded in each treatment arm. The frequency of grade 3-4 adverse events (AEs) were similar between the two arms, apart from palmar-plantar rash, reported as drug-related in 15.4% and 6.1% pts in the SOR and PBO arms, respectively. Correlative studies will be reported in a companion abstract. Conclusions SOR did not improve EFS when combined with intensive chemotherapy in adults with newly diagnosed FLT3-ITD AML. Although not powered for significance, SOR showed a trend for improved OS among patients with higher FLT3-ITD AR or receiving HCT in CR1. Further exploration of more potent FLT3 inhibitors in the pre- and post-allograft setting are warranted for patients with newly diagnosed FLT3 mutant AML. Acknowledgements: The ALLG AMLM16 trial was funded through an Australian Government NHMRC grant and a research grant from the Leukaemia Foundation of Australia. Bayer supplied sorafenib and Gilead AmBisome. Disclosures Wei: Roche: Honoraria; Servier: Consultancy, Honoraria, Research Funding; Novartis: Honoraria, Research Funding, Speakers Bureau; Amgen: Honoraria, Research Funding; Abbvie: Honoraria, Research Funding, Speakers Bureau; Pfizer: Honoraria; Bristol Myers Squibb: Honoraria, Research Funding, Speakers Bureau; Walter and Eliza Hall Institute of Medical Research: Patents & Royalties: AW is eligible for royalty payments related to venetoclax; Astra Zeneca: Honoraria, Research Funding; Janssen: Honoraria; Macrogenics: Honoraria. Enjeti:Novartis: Membership on an entity's Board of Directors or advisory committees; Alexion: Speakers Bureau; Bayer: Speakers Bureau; Sanofi: Speakers Bureau; AbbVie: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees. D'Rozario:Abbvie: Membership on an entity's Board of Directors or advisory committees; BMS/ Celgene: Membership on an entity's Board of Directors or advisory committees. Marlton:Celgene: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees; F. Hoffmann-La Roche Ltd: Membership on an entity's Board of Directors or advisory committees; Astra-Zeneca: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees. Verner:Janssen Cilag Pty Ltd.: Research Funding. Hahn:Roche: Honoraria; Astra Zeneca: Honoraria. Hiwase:Novartis Australia: Research Funding. Anstee:Walter and Eliza Hall Institute: Patents & Royalties: milestone and royalty payments related to venetoclax.. Levis:FujiFilm: Honoraria, Research Funding; Amgen: Honoraria; Daiichi-Sankyo: Honoraria; Menarini: Honoraria; Astellas: Honoraria, Research Funding. Bajel:Abbvie: Honoraria; Astellas: Honoraria; Pfizer: Honoraria; Amgen: Honoraria, Speakers Bureau; Novartis: Honoraria. Roberts:Genentech: Patents & Royalties: for venetoclax to one of my employers (Walter & Eliza Hall Institute); I receive a share of these royalties; Janssen: Research Funding; Servier: Research Funding; AbbVie: Research Funding. OffLabel Disclosure: Sorafenib for FLT3-ITD AML

Management practices in early-stage (I/II) follicular lymphoma (FL) are variable and include radiation (RT), systemic therapy, or combined modality therapy (CMT). There is a paucity of data regarding maintenance rituximab in this cohort. We conducted an international retrospective study of patients with newly diagnosed early-stage FL staged with positron emission tomography (PET)–computed tomography and bone marrow biopsy. Three hundred sixty-five patients (stage I, n = 221), median age 63 years, treated from 2005-2017 were included, with a median follow-up of 45 months. Management included watchful waiting (WW; n = 85) and active treatment (n = 280). The latter consisted of RT alone (n = 171) or systemic therapy (immunochemotherapy [n = 63] or CMT [n = 46]). Forty-nine systemically treated patients received maintenance rituximab; 72.7% of stage I patients received RT alone, compared to 42.6% with stage II (P < .001). Active therapies yielded comparable overall response rates (P = .87). RT alone and systemic therapy without maintenance rituximab yielded similar progression-free survival (PFS) (hazard ratio [HR], 1.32; 95% confidence interval [CI], 0.77-2.34; P = .96). Maintenance rituximab improved PFS (HR, 0.24; 95% CI, 0.095-0.64; P = .017). The incidence of transformation was lower with systemic therapy compared to RT or WW (HR, 0.20; 95% CI, 0.070-0.61; P = .034). Overall survival was similar among all practices, including WW (P = .40). In the largest comparative assessment of management practices in the modern era, variable practices each resulted in similar excellent outcomes. Randomized studies are required to determine the optimal treatment in early-stage FL.

Summary A 34-year-old woman presented 18 months post-partum with blurred vision, polyuria, amenorrhoea, headache and general malaise. Comprehensive clinical examination showed left superior temporal visual loss only. Initial investigations revealed panhypopituitarism and MRI demonstrated a sellar mass involving the infundibulum and hypothalamus. Lymphocytic hypophysitis was suspected and high dose glucocorticoids were commenced along with desmopressin and thyroxine. However, her vision rapidly deteriorated. At surgical biopsy, an irresectable grey amorphous mass involving the optic chiasm was identified. Histopathology was initially reported as granulomatous hypophysitis. Despite the ongoing treatment with glucocorticoids, her vision worsened to light detection only. Histopathological review revised the diagnosis to partially treated lymphoma. A PET scan demonstrated avid uptake in the pituitary gland in addition to splenic involvement, lymphadenopathy above and below the diaphragm, and a bone lesion. Excisional node biopsy of an impalpable infraclavicular lymph node confirmed nodular lymphocyte-predominant Hodgkin lymphoma. Hyper-CVAD chemotherapy was commenced, along with rituximab; fluid-balance management during chemotherapy (with its requisite large fluid volumes) was extremely complex given her diabetes insipidus. The patient is now in clinical remission. Panhypopituitarism persists; however, her vision has recovered sufficiently for reading large print and driving. To the best of our knowledge, this is the first reported case of Hodgkin lymphoma presenting initially as hypopituitarism. Learning points Lymphoma involving the pituitary is exceedingly rare and, to the best of our knowledge, this is the first reported case of nodular lymphocyte-predominant Hodgkin lymphoma presenting as hypopituitarism. There are myriad causes of a sellar mass and this case highlights the importance of reconsidering the diagnosis when patients fail to respond as expected to appropriate therapeutic intervention. This case highlights the difficulties associated with managing panhypopituitary patients receiving chemotherapy, particularly when this involves large volumes of i.v. hydration fluid.

Introduction Lymphoma complicates approximately 1/6000 pregnancies (Pereg, Haematologica 2007), and presents challenges for the patient, her family, and medical professionals. This rare event raises unique therapeutic, social and ethical issues, with the welfare of both mother and unborn child to consider. There are challenges regarding symptom obfuscation, diagnosis delays and treatment delivery. In this retrospective study, we aimed to describe the experience, treatment patterns and outcomes of lymphoma in pregnancy in Australia and New Zealand. Methods We identified patients aged ≥18 diagnosed with lymphoma in pregnancy between 1 January 2009 and 31 December 2020 , across 11 institutions in Australia and New Zealand. We defined "lymphoma in pregnancy" as diagnoses occurring during pregnancy (antenatal cases) or the first 12 months after delivery (postpartum cases). Postpartum cases were included to account for the phenomenon of diagnostic delay during gestation due to deferral of diagnostic investigations and symptom obfuscation (de Haan, Lancet Oncol 2018). Overall survival was calculated by Kaplan-Meier methods from the date of diagnosis to death, with patients alive and lost to follow-up censored on the last day of follow-up. Results We identified 63 patients, 34 diagnosed antepartum and 29 diagnosed postpartum (Table 1). The most common diagnoses were classical Hodgkin lymphoma (HL) (35), followed by diffuse large B cell lymphoma (11) and primary mediastinal B cell lymphoma (6). The median age was 32 (range 23-42) years. Women diagnosed antepartum were more likely to be nulliparous (p=0.004). Of the postpartum cases, symptoms of malignancy first appeared during pregnancy in 24%. At diagnosis, 44% had advanced stage disease. 60% of women had PET as part of baseline staging, however only 8% underwent PET whilst pregnant, all during the second or third trimester. 83% of HL patients had adverse risk factors (mediastinal bulk >1/3 diameter, ESR>50mm/hr, >2 sites). ESR alone, which may be elevated physiologically in pregnancy, was the sole adverse risk factor for 9% of HL patients. Median days between diagnosis and treatment initiation were 14 (IQR 8-30) for antenatal patients and 21 (IQR 7-40) for postnatal. 19% of the antenatal cohort with aggressive lymphoma had treatment deferred/delayed explicitly due to pregnancy. The majority (89%) of antenatal patients were treated with ABVD (HL) or (R)CHOP/(R)EPOCH (NHL) whilst pregnant. 3 patients received first-line treatment divergent from standard (vinblastine for HL, interferon for indolent B-NHL and surgery for primary cutaneous ALCL). 37% received radiotherapy, although only 1 patient received it antenatally. Median follow up was 34 months. 5 year OS for HL was 83% (95%CI 54%-95%) and for DLBCL 74% (95%CI 30%-93%)(Figure 1). Seven patients died (4 from lymphoma, 2 treatment-related infection, 1 unknown). Discussion of elective termination of pregnancy was documented in 24 of 34 antenatal diagnoses, advised in 3 and performed in 2, both in the first trimester. Only 31 (49%) of 63 women had documented evidence of counselling regarding future fertility strategies. Of the 48 patients with available data, there were 45 live births, 2 elective terminations and 1 spontaneous abortion in the first trimester. The mean gestation at birth was significantly earlier and marginally preterm for antenatal diagnoses (mean 35.6wk v 38.2wk, p=0.002). 6 neonates (11%) were small for gestational age, 5 of whom were born to mothers diagnosed antenatally. 29% of neonates were admitted to neonatal intensive care or special care units. There were no cases of neonatal neutropenia, one case of sepsis of prematurity and one case of PJP infection in a term baby. Conclusion Lymphoma in pregnancy is rare and lacks a harmonised approach. We present a large multicentre cohort reflecting contemporary practice. Although standard therapy could be provided to most patients, delays in treatment and diagnosis were common, and most antenatally-diagnosed women did not receive optimal staging. Neonates in the antenatally-diagnosed group were more likely to be premature, however there are likely a number of confounders and causality cannot be presumed. There were no neonatal deaths. It is imperative to continue to report on data regarding lymphoma in pregnancy to inform optimal care in this setting. Figure 1 Figure 1. Disclosures Greenwood: Amgen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees; Servier: Membership on an entity's Board of Directors or advisory committees, Research Funding; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees. Gregory: Janssen: Consultancy; Novartis: Consultancy; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel fees, Speakers Bureau. Hamad: Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

Background The role of brentuximab peri-allogeneic transplantation in patients with relapsed and/or refractory CD30 positive lymphomas remains poorly defined. Aim To assess the outcome of use of brentuximab as a bridge to allogeneic stem cell transplantation (SCT) in patient with relapsed/refractory CD30+ classic Hodgkin lymphoma cHL and anaplastic large cell lymphoma (ALCL). Methods Outcomes of consecutive patients with relapsed/refractory cHL/ALCL treated with brentuximab as a bridge to SCT were determined by retrospective review of individual medical records. Survival analysis was measured from start of brentuximab treatment. Results A total of 12 patients (10 cHL, 2 ALCL) had received brentuximab as a planned bridge to allogeneic SCT. Median age was 27 years (range 20-54 years); median prior lines of therapy was 4 (range 3-6) and all except one patient had undergone prior autologous SCT (92%). Patients received at median of 3 brentuximab doses pre-allogeneic SCT (range 1-4), with an overall response rate of 66.7%. At a median follow up of 30 months (range 6-52 months), 2 years progression free survival and overall survival post-allogeneic SCT is 58 and 92% respectively. Incidence of non-relapse mortality, grade 3-4 acute graft versus host disease and extensive stage chronic graft versus host disease is 8, 17 and 18% respectively. Of five patients who subsequently relapsed post-SCT, four remain alive with disease control post manipulation of immune-suppression. Conclusion Our experience suggests that brentuximab use pre-allogeneic SCT is not associated with any significant post-transplant toxicity, and is associated with a rapid response in a majority of patients with relapsed/refractory CD30 positive lymphomas. Brentuximab may thus provide a non-toxic bridge to allogeneic SCT for patients with relapsed/refractory CD30 positive cHL or ALCL.

Background Aplastic anaemia (AA) is a rare acquired bone marrow failure syndrome resulting from the immune-mediated destruction of haemopoietic stem cells. For adults in whom first-line haemopoietic progenitor cell transplantation is not feasible, combination anti-thymocyte globulin (ATGAM) plus cyclosporine A is standard therapy; however, there are minimal data available regarding the optimal ATGAM dosage in terms of efficacy and survival. Aims Our institutions have historically used different dosing protocols of ATGAM in the treatment of AA. We aimed to review the outcome of AA patients treated with these protocols and compare them to the published literature. Methods We conducted a retrospective study of 31 adults who received first-line ATGAM for AA and compared response rates and survival between cohorts who received standard (40 mg/kg/day D1-4) versus lower-dose (15 mg/kg/day D1-5) ATGAM schedules. Results There were similar rates of response (64 vs 71%, P = 1.0), relapse (33 vs 33%, P = 1.0), transformation (14 vs 24%, P = 0.66) or infection (43 vs 47%, P = 1.0), respectively, between standard and lower-dose cohorts. At a median follow up of 24 months, there was no statistical difference between standard and lower-dose cohorts in either event-free (42.2 vs 64.7%, P = 0.91) or overall survival (73.1 vs 88.2%, P = 0.75). Conclusion Our experience suggests that lower-dose ATGAM at 15 mg/kg/day D1-5 as treatment of AA produces similar responses and outcomes as per standard-dose ATGAM schedules. Prospective trials comparing ATGAM dose schedules in AA are warranted.

Pomalidomide and low-dose dexamethasone prolongs progression-free and overall survival in patients with relapsed/refractory multiple myeloma following lenalidomide and bortezomib. As with other IMI...

The proportion of patients with acute myeloid leukemia (AML) cured is increased by administering high-dose cytarabine (HiDAC). It remains uncertain whether to administer HiDAC as induction or consolidation, and whether ≥1 cycle of HiDAC is required. Our retrospective study of 416 adult AML patients, excluding good risk cytogenetics, compared a single cycle of HiDAC-based therapy followed by 2 cycles of standard-dose cytarabine (SDAC) (HiDAC induction cohort) with SDAC-based chemotherapy followed by 2 cycles of HiDAC-based chemotherapy (HiDAC consolidation cohort). Complete remission (CR) rate was greater in the HiDAC induction cohort (90% vs 78%, P

The prognosis for patients with respiratory syncytial virus (RSV) or parainfluenza virus type 3 (PIV3) respiratory tract infection post allogeneic haematopoietic progenitor cell transplant (HPCT) is historically poor. The use of oral ribavirin (RBV) has not been widely studied in this patient population. We examined the outcomes of 15 consecutive patients (RSV, n=13 and PIV3, n=2) treated with oral RBV post HPCT. Oral RBV was commenced at a starting dose of 10 mg/kg/day, increasing to a maximum dose of 60 mg/kg/day depending on response and tolerance. At diagnosis, seven patients had upper respiratory tract infection (URTI) and eight had lower respiratory tract infection (LRTI). The starting RBV dose of 10 mg/kg/day did not prevent the progression of URTI to LRTI in any patient. However, with dose escalation, six of the seven patients responded to RBV therapy and survived their infective episode. Of the eight patients presenting with LRTI, six patients survived their infection, again after dose escalation of RBV. There was no dose-limiting toxicity seen in any patient. Our results indicate that oral RBV has clinical efficacy in the treatment of RSV/PIV3 infection post HPCT. However, a starting dose of 10 mg/kg/day appears ineffective; we recommend a starting dose of 20 mg/kg/day in this patient group.

The optimal initial therapy for treatment of adult acute lymphoblastic leukemia is yet to be defined. Hyper-CVAD has become a widely used treatment for adult acute lymphoblastic leukemia, although publication of outcomes is largely limited to single-center experience. We performed a retrospective analysis of 63 patients treated with Hyper-CVAD at two Australian institutions between 1995 and 2007. Complete remission was obtained in 86% of patients, with an induction mortality of 8%. Treatment-related toxicity was high, resulting in premature cessation of planned treatment in 29% of patients achieving CR. Survival estimates were comparable to previously published experience, with estimated 5-year overall and progression-free survival of 48% and 42%, respectively. Allogeneic stem cell transplant was performed in 22% of patients in first complete remission, with encouraging survival outcomes (estimated 5-year overall survival 75%, progression free survival 82%). Hyper-CVAD is an effective and tolerable induction strategy for adult ALL, and is suitable for use prior to allogeneic stem cell transplant in first complete remission.

Background Stage I/II or early-stage follicular lymphoma (ESFL) is considered potentially curable with radiotherapy (XRT). While XRT does achieve local disease control in >90% of cases, more than half the patients (pts) relapse by 10 years (yr), generally outside of the radiation field. A recent randomized controlled trial (TROG 99.03) demonstrated that combined modality therapy (CMT), with sequential XRT and systemic therapy, significantly improved PFS but not overall survival (OS) compared to XRT alone in ESFL. However, only half the pts were staged with 18F‐FDG positron emission tomography and computed tomography (PET) and 58% of CMT pts did not receive rituximab.Compared with CT staging, 20-60% of cases are upstaged by PET. Consequentially, there are limitations in applying this trial to modern populations. Despite the support of current guidelines, only one third of pts in clinical practice are treated with XRT. This suggests a need to better understand the role of other treatments, including watchful waiting (WW), in the PETera. Our aim was to compare outcomes with real-world treatment approaches in rigorously staged ESFL patients. Methods We conducted an international, multicenterretrospective study of stage I and II FL pts rigorously staged with bone marrow biopsy and PET. Eligible pts were >18yr with newly-diagnosed grade 1-3A FL and ≥3 months follow up. Primary outcome measures were overall response rate (ORR), progression free survival (PFS), OS and risk of transformation. Survival curves were estimated with the Kaplan-Meier method and uni- and multi-variate analysis was performed using Cox regression model. Results A total of 387 pts treated at 13 Australian and 3 Canadian centres between 2005-2017 were studied. Median follow-up was 45 months (range 3.1 - 164.0).5-yrPFS and OS rates were 73.5% (95% CI 66.0-78.5) and 94.4% (95% CI 89.4-93.6) respectively. 22 patients had stage IE duodenal FL with 5-yr PFS and OS rates of 100% and 100% respectively. Considering the unique biology and favorable prognosis of duodenal FL, these cases were excluded from subsequent analyses. Treatment approaches 365 pts included WW (defined as absence of treatment within 6 months from diagnosis) (23.2%), XRT (46.8%), immunochemotherapy (17.2%) and CMT (12.6%). Treatment regimens were: R-CHOP (48.1%), R-CVP (24.4%), BR (9.9%), other (17.6%). First-line therapies for actively treated pts yielded comparable ORRs of 95.6%, 96.7% and 95.9% for XRT, immunochemotherapy and CMT, respectively (P=0.94). Overall, 18.2% of pts relapsed at distant sites, 88.2% of all relapses. Treatment cohorts differed in baseline clinical characteristics. WW pts were significantly older (P=0.007) but otherwise comparable to those treated actively. Compared to chemotherapy or CMT pts, those treated with XRT had more favorable features including fewer B symptoms (4.2% vs 11.2% p=0.029), bulk (≥7cm) (6.8% vs 25.3%, p Outcomes differed among treatment approaches. Active treatment was associated with superior PFS compared with WW pts (HR 0.54 p=0.004) however, 49.4% of WW pts remained untreated at 5-yrs (Fig 1a). Considering actively treated pts, systemic therapy (immunochemotherapy or CMT) was associated with superior PFS compared to XRT by univariate analysis (HR 0.49, p=0.009) (Fig 1b). This association remained after multivariate adjustment for bulk, B symptoms, nodal sites and stage (HR 0.41 p=0.002). Treatment with immunochemotherapy and CMT demonstrated a comparable PFS (p=0.2). Maintenance rituximab (n=45) was associated with superior PFS compared with observation after systemic therapy (HR 0.24, p=0.017). There were no differences in OS among treatment approaches (P=0.734). There was a higher incidence of transformation in XRT pts compared to systemic therapy pts (6.4% vs 1.6% p=0.046). Conclusion In the largest assessment of rigorously-staged ESFL pts in the PETera, pts treated with systemic therapy (chemotherapy or CMT) had a superior PFS and a lower rate of transformation compared to pts treated with XRT, although treatments were not randomized. These findings are similar to the TROG 99.03 trial and challenge the paradigm that ESFL should be uniformly treated with XRT alone. Half the pts observed from diagnosis remained treatment-free at 5-yrs, suggesting that WW may be appropriate in selected pts. Disclosures Tobin: Celgene: Research Funding; Amgen: Other: Educational Travel. Tam:Roche: Honoraria; Roche: Honoraria; Pharmacyclics: Honoraria, Travel funding; Pharmacyclics: Honoraria; Beigene: Honoraria, Other: Travel funding; Beigene: Honoraria, Other: Travel funding; AbbVie: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Gilead: Honoraria; Gilead: Honoraria; AbbVie: Honoraria, Research Funding. Abro:Amgen: Other: education support congress attendance; Celgene: Other: education support congress attendance; Bristol-Myers Squibb: Speakers Bureau; Janssen: Other: education support congress attendance; Novartis: Consultancy. Hawkes:Bristol Myers Squibb: Other: Speaker fee, Research Funding; Takeda: Other: Speaker fee; Astra Zeneca: Research Funding; Merck Sharpe Dohme: Research Funding; Merck KGA: Research Funding; Celgene: Other: Advisory board, Research Funding; Merck: Other: Advisory board; Roche: Other: Speaker fee; advisory board. Talaulikar:Amgen: Consultancy, Honoraria; Roche: Honoraria, Speakers Bureau; Janssen: Honoraria, Speakers Bureau; Takeda: Research Funding; Novartis: Honoraria, Speakers Bureau. Gandhi:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Merck: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria; Takeda: Honoraria; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Membership on an entity's Board of Directors or advisory committees, Research Funding.

Organ dysfunction in AL amyloidosis is related to the production and deposition of amyloidogenic monoclonal light chains. These pathological light chains can now be quantified using the recently developed serum free light chain assay.Methods: We retrospectively reviewed 31 patients with AL amyloidosis to determine the frequency of abnormal free light chain assay results at diagnosis and whether changes in the serum free light chain assay predict outcome after therapy.Results: An abnormal free light chain assay was found in 30 of 31 patients (97%) at the time of diagnosis. In the subset of our patients who received treatment for AL amyloidosis, a >50% reduction of the pathological free light chain following treatment was shown to predict improved overall survival. In our series of analyses, achievement of greater magnitudes of reduction of the free light chain result did not appear to provide additional prognostic information, nor did the baseline free light chain result predict outcome.Conclusion: Our findings support the use of the free light chain assay in the diagnostic work-up of patients with suspected AL amyloidosis, and also as a sensitive biomarker of response to therapy.

Primary familial and congenital polycythaemia (PFCP) is a rare form of inherited erythrocytosis caused by heterozygous mutations in the erythropoietin receptor gene (EPOR). We present a novel mutation in the EPOR in a 15-year-old male who was referred to our clinic for investigation of a persistently elevated haemoglobin level. A significant family history of unexplained erythrocytosis spanning four generations of the patient's family was established. The family history was also significant for an apparent increased rate of cerebrovascular disease in individuals with erythrocytosis. The mutation detected in our patient resides in exon 8 of EPOR, similar to all other EPOR mutations responsible for PFCP. These mutations result in truncation of the cytoplasmic domain of the receptor and impair down-regulation of signalling via the erythropoietin receptor (EPOR). Clinical manifestations in published cases have varied widely and there is a paucity of firm recommendations regarding the management of affected patients. Given the strong family history of complications attributable to erythrocytosis we have recommended venesection with a haematocrit target of ≤0.45 for our patient.

Introduction: The optimal treatment approach for newly diagnosed patients with AML remains uncertain. HiDAC is widely considered to increase the proportion of patients cured compared to standard-dose cytarabine. However, it remains uncertain whether HiDAC is best given during induction or consolidation, and how many cycles of HiDAC are optimal. Many centres in Australia treat younger patients (age ≤60 yrs) with newly diagnosed AML with one of two approaches: either 7+3 induction followed by HiDAC-2 consolidation for 2 cycles; or a single course of HiDAC-3±7 induction followed by 2 cycles of lower dose cytarabine-based therapy (eg 5+2±5). Our retrospective study compared the outcomes of these 2 approaches in a large cohort of Australian patients treated at 5 centres. Methods: Consecutive patients aged ≤60 yrs with a new diagnosis of AML (de novo or secondary) were included in the study if they were planned for treatment with either: 1) cytarabine 100 mg/m2 for 7 days plus idarubicin 12 mg/m2 for 3 days (7+3) induction followed by 2 cycles of HiDAC 3 g/m2 days 1,3,5,7 plus idarubicin 12 mg/m2 for 2 days (HiDAC consolidation cohort); or 2) HiDAC 3 g/m2 days 1,3,5,7 plus idarubicin 9-12 mg/m2 for 3 days ± etoposide 75-100 mg/m2 for 7 days as induction followed mostly by cytarabine 100 mg/m2 for 5 days plus idarubicin 9-12 mg/m2 for 2 days ± etoposide 75-100 mg/m2 for 5 days as consolidation (HiDAC induction cohort). Patients were diagnosed from 1999 to June 2013, and were followed for at least 12 months with data cut off June 2014. Results: 486 patients were included: HiDAC consolidation cohort n=251; HiDAC induction cohort n=235. The HiDAC consolidation cohort had a greater median age (49 vs 47 yrs, p=0.02) and more patients with good risk cytogenetics (16% vs 8%, p= Conclusions: OS and PFS using HiDAC as induction or consolidation therapy were similar, and compared favourably to published data. Interestingly, the better CR rate and a greater use of alloHSCT in CR1 in the HiDAC induction cohort did not lead to a better PFS or OS - because of a greater relapse rate in this cohort - primarily seen in those patients not undergoing alloHSCT in CR1. In the absence of mutational prognostic information, these data may suggest that HiDAC as induction therapy can achieve CR in patients with biologically higher risk disease who have a higher relapse rate, and that including 2 cycles of HiDAC in consolidation in the absence of alloHSCT in CR1 is a more effective therapy than a single cycle of HiDAC administered during induction therapy. Disclosures Mollee: Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Nilelse: Research Funding.

This prospective randomized phase II study aimed to determine the safety and efficacy of deferasirox in preventing iatrogenic iron overload in patients receiving induction/consolidation chemotherapy for acute myeloid leukaemia (AML) ize. Serum ferritin, transferrin saturation and CRP were measured pre-, mid- and post- each chemotherapy cycle. Patients were randomized to receive either therapy with deferasirox vs. no deferasirox therapy once serum ferritin increased to >500 μg/l. The trial was stopped prematurely due to excess gastrointestinal (GI) and infectious toxicity demonstrable in the deferasirox arm, after 10 patients had been randomized to deferasirox and 6 patients to the control arm. Overall, deferasirox was poorly tolerated, with median maximum tolerated dose only 13·8 mg/kg/d and no patient able to tolerate doses >20 mg/kg/d. Median duration of deferasirox therapy was only 72 d (range 19-130 d), with 9/10 patients requiring unplanned dose interruptions and 4/10 patients unable to continue the drug predominantly due to GI effects. Although all 3 treatment-related deaths occurred in the deferasirox arm (P = 0·25), median overall survival was similar between treatment arms. Use of deferasirox to prevent iatrogenic iron overload in AML patients undertaking induction/consolidation is poorly tolerated and appears to be associated with excess GI and infectious toxicity.

Invasive fungal disease (IFD) is a common complication of therapy for acute leukemia. Whilst the efficacy and safety of prophylactic strategies to prevent IFD during induction chemotherapy for acute myeloid leukemia are relatively well defined, very few data are available with respect to IFD incidence in adult acute lymphoblastic leukemia (ALL). Over the last decade the intensity of induction protocols in adult ALL have increased significantly, resulting in increased corticosteroid exposure and prolonged neutropenic episodes, both well-defined risk factors for the development of IFD. Consequently, the adequacy of fluconazole-based prophylactic strategies to prevent IFD during therapy of ALL is increasingly debatable. However, due to the potential for interactions between various chemotherapy agents used in ALL induction and the extended-spectrum azoles, fluconazole continues to be used for standard IFD prophylaxis, despite its lack of anti-mold activity. More data with respect to the actual incidence and/or burden of IFD within adult ALL is needed to better define the risks and benefits of implementing anti-mold prophylaxis in this setting.We reviewed the outcome of consecutive adult patients diagnosed with ALL and treated with hyperfractionated cyclophosphamide, vincristine, doxorubicin and dexamethasone (Hyper-CVAD) at our institution between May 2005 and December 2010...

Background / Aims Although combination anti-thymocyte globulin (ATGAM®, Pfizer Inc, NY USA) plus cyclosporine (CsA) is standard therapy for aplastic anaemia (AA), there is minimal data available with respect to optimal ATGAM dose in this disorder. Our institutions have used differing protocols incorporating equine ATGAM at either 40mg/kg/day D1-4 (160mg/kg; standard dose) or 15mg/kg/day D1-5 (75mg/kg; lower dose), in combination with identical CsA and methylprednisolone schedules as treatment of AA where first-line sibling allograft was unavailable. We aimed to review the outcome of AA patients treated with these different ATGAM dose schedules at our institutions. Methods All patients >16yrs who received ATGAM for AA between January 2002 and December 2013 were identified from institutional data bases. Diagnostic details and clinical outcomes were determined by retrospective review of individual medical records. Aplastic anaemia severity and response to ATGAM / CsA were defined as per EBMT criteria (Blood 2003; 101: 1236). The primary outcomes were overall response (CR / PR), relapse rate (RR), transformation into AML / MDS and overall survival (OS). Results A total of 31 patients were identified, including 14 (45%) treated with standard dose ATGAM and 17 (55%) treated with the low dose schedule. Overall 7% (1), 86% (12) and 7% (1) were classified as non-severe, severe and very severe AA in the standard dose group, and 17% (3), 71% (12) and 12% (3) in the low dose group respectively (p=?NS). Median age at diagnosis was similar between groups; 36yrs (range 23-63ys) for standard vs 44yrs (range 17-80yrs) for low dose ATGAM respectively. At a median time to treatment of 17 (range 5-2084 days) vs 11 days (range 5-1877 days) respectively, overall response was similar between groups: 64% (CR=1; PR=8) for standard vs 76% (CR=5, PR=8) for low dose ATGAM schedules (p=0.69). Median time to best response was also no different between ATGAM treatments: 81days (range 50-164 days) for standard vs 91days (range 48-2133 days) for low dose ATGAM respectively. Although RR was identical between groups (33% vs 30%; p=1.0), median time to relapse was significantly shorter post the lower dose schedule (median 11nths vs 5mths for standard vs low dose ATGAM respectively. Post-ATGAM transformation into AML / MDS occurred in 3 patients in the standard dose group (21%) at a median of 23 mths post therapy (range 19-71 mths) vs 18% (n=3) in the low dose group at a median of 59mths (range 3-81 mths). Response to 2nd line treatment (rabbit ATG / alloSCT) for non-response or relapse was also similar; 40% vs 50% for standard vs low dose ATGAM respectively (p=1.0). At a median follow up of 25mths (range 6-122 mths) vs 22mths (range 7-99 mths) respectively, OS is identical between groups (71% vs 71% for standard vs low dose ATGAM respectively, p=1.0) Conclusion Our experience suggests that low dose ATGAM at 15mg/kg/day D1-5 as treatment of AA produces similar responses and outcomes as per standard dose ATGAM scheduling. Prospective trials comparing ATGAM dose schedules in AA are warranted. Disclosures Off Label Use: Off-label: Horse ATG (ATGAM), rabbit ATG (Thymoglobuline), Cyclosporin, Alemtuzumab and Eltrombopag are all used off-label for treatment of Aplastic Anaemia in Australia..

Introduction Platelet transfusion refractoriness (PTR) is relatively common in patients undergoing treatment for haematological malignancies. Alloimmunisation to either human leucocyte antigens (HLA) or human platelet specific antigens (HPA) can be demonstrated in up to 20% of cases. Recent data suggests that PTR may be associated with increased risk of non-engraftment following allogeneic haematopoietic progenitor cell transplantation (HPCT). We aimed to review the outcome of patients with PTR undertaking HPCT at our institution. Methods: All adults undertaking allogeneic HPCT for haematological malignancy at our institution between January 2008 and December 2013 were identified from an institutional database. This list was then correlated with records for special platelet support provided by the ARCBS for patients with PTR. Incidence of platelet engraftment, defined as the first of five consecutive days of transfusion-independent platelet counts >20 x109/L, time to platelet engraftment and graft failure or rejection was then compared between those patients undertaking HPCT without prior PTR versus those patients with prior PTR. All grafts were T-cell replete; syngeneic and umbilical cord blood transplants were excluded. Results In total 480 patients underwent HPCT for haematological malignancy during the time period under review; 28 (6%) had PTR prior to HPCT and 452 did not. Of patients with PTR, 20/28 (71%) had demonstrable alloimmunisation due to anti HLA antibodies (n=20) or both anti-HLA and anti-HPA (n=1).Median age was identical for both the non-PTR vs PTR group respectively (50yrs; p=NS). Compared to the non-PTR group, the PTR group included a significantly greater proportion of AML diagnoses (75% vs 43%; p=.001), a non-significant increase in use of myeloablative conditioning (57% vs 40%; p=0.08) and increased use of unrelated donors (79% vs 59%; p=0.05). Although platelet engraftment occurred significantly less frequently in PTR patients (n=23, 82% vs n=431, 95%; p=0.01), time to platelet engraftment was similar between groups (median 20days, range 13-46 vs 18days, range 1-165 for PTR vs non-PTR groups respectively; p=0.24). Interestingly, of the 26 patients who failed to engraft platelets, 92% suffered early severe complications post-HPCT (multi-organ failure; severe sepsis; acute GVHD; diffuse alveolar haemorrhage), with only 2 patients (8%) suffering graft rejection; both of these patients were previously PTR. Risk of graft rejection was significantly associated with prior PTR (7% vs 0% respectively; p=0.003). Conclusion: PTR pre-HPCT is associated with significantly greater risk of graft rejection and non-platelet engraftment compared to patients without PTR. Early complications post-HPCT also appears to be associated with risk of platelet non-engraftment, irrespective of prior PTR or not. Disclosures No relevant conflicts of interest to declare.

Background / Aims Increasing bed pressure in health care systems is driving delivery of chemotherapy for acute leukaemia into ambulatory care settings. In our institution patients with acute lymphoblastic leukaemia/ lymphoma (ALL) are admitted to hospital for initial induction but based on social circumstance and medical co-morbidities, subsequently receive consolidation cycles on an outpatient basis whenever possible. We aimed to examine the safety of outpatient delivery of Hyper-CVAD based chemotherapy in adult ALL patients treated at our institution. Methods All patients >14yrs diagnosed with B- and T- ALL between 1999 and 2011 and treated with Hyper-CVAD based induction were identified from an institutional database. During this period Hyper-CVAD was the standard chemotherapy used to treat ALL at our institution. Chemotherapy outcomes including ≥ grade 3 hepatic, renal, neurological and infectious toxicity as well as hospital length of stay for chemotherapy cycles delivered as inpatient vs. outpatient were then retrospectively determined by review of individual medical records. As the initial cycle of Hyper-CVAD (cycle 1A) was delivered on an inpatient basis in all patients, analysis of inpatient vs. outpatient chemotherapy toxicity was restricted from the 2nd Hyper-CVAD cycle and beyond. Toxicity was graded according to standard CTCAE v4.0. Results In total 44 patients had been treated with > 1 cycle of Hyper-CVAD for newly diagnosed ALL during the time period under review. Median age was 36 (range 14-73 yrs); 28 (64%) were male. In total 270 individual cycles of Hyper-CVAD were administered in these 44 patients, with a median of 6 cycles per patient (range 2-8). Excluding cycle 1, a total of 98 A cycles and 128 B cycles were administered, with 78 cycles (35%) delivered on an inpatient basis and 148 (65%) on an outpatient basis. A significantly greater proportion of B cycles were delivered in an inpatient setting compared to A cycles (43% vs 23%; p=0.003). Overall incidence of ≥ grade 3 toxicity was similar for inpatient vs. outpatient delivery for both A (21% vs. 21%; p=1.0) and B cycles (78% vs. 75%; p=0.8). For hepatic toxicity incidence was similar for inpatient vs. outpatient treatment for A cycles (5% vs. 5%; p=1.0), but of borderline difference for B cycles (31% vs. 15%; p=0.051), likely reflecting appropriate selection of patients with co-morbidity for inpatient treatment. Overall incidence of ≥ grade 3 renal and neurological toxicity was low ( Conclusion Our experience of delivery of Hyper-CVAD chemotherapy in an outpatient setting in adult ALL suggests that ambulatory-based chemotherapy is both safe and not associated with increased toxicity compared to inpatient delivery. The associated reduction in requirement for inpatient hospitalisation is likely to result in meaningful reductions in cost and resource utilisation. Disclosures: No relevant conflicts of interest to declare.

Abstract 4341 Aim Acute myeloid leukemia (AML) incidence increases with age, yet treatment of elderly patients has reduced efficacy compared with younger patients and is often poorly tolerated. We aimed to determine the outcome of elderly patients with de novo AML treated with intensive chemotherapy with or without allogeneic stem cell transplantation. Methods All patients with de novo AML (excluding APML) aged ≥ 60 years treated with induction chemotherapy at our institutions between February 1999 and July 2011 were retrospectively identified from institutional databases. Information on cytogenetic risk, chemotherapy protocols, response to therapy, disease-free survival (DFS), and overall survival (OS) were then determined retrospectively by review of individual medical records. Survival analyses were calculated by the Kaplan-Meier method and compared using the log-rank test. Results Intensive induction chemotherapy was received by 128 patients (57.7% of elderly patients diagnosed with de novo AML), including 105 patients (82.0%) treated with standard-dose cytarabine (SDAC) (100mg/m2 days 1–7) and 14 patients (10.9%) treated with high-dose cytarabine (HiDAC) (≥ 2000mg/m2/day for at least 4 days). The median age of this cohort was 67 years (range 60–83 years). Based on cytogenetic profile, 3.1% of patients had favourable, 54.7% had intermediate, and 27.3% had adverse-risk disease. Responses to 1–2 cycles of induction chemotherapy were complete remission (CR1) in 73.4% of patients, refractory disease in 14.8%, and induction death in 11.7%. 83.0% of patients who achieved CR1 received consolidation chemotherapy, incorporating SDAC in 74.4% and HiDAC in 23.1%. At a median follow-up of 22 months for survivors, intensive induction chemotherapy resulted in a median DFS of 11 months, and median OS of 13 months (Figure 1); 3 year OS for the entire cohort was 27.9%, with favourable, intermediate, and adverse risk groups having 50.0%, 31.6%, and 12.6% 3 year OS, respectively. Thirteen patients (10.2%) proceeded to allogeneic transplantation in CR1; median age was 63 years (range 60–66 years). These patients did not reach median DFS or OS; 11 (84.6%) remain alive and disease-free at a median follow-up of 27 months post-transplant (Figure 2). The elderly patients were compared to the cohort of younger patients (15–59 years) with de novo AML treated over the same time period. This analysis found that the older patients had a higher rate of adverse-risk cytogenetics (27.3% vs 16.1%, respectively; P = 0.02), refractory disease (14.8% vs 3.3%, respectively; P = 0.0002) and induction death (11.7% vs 4.7%, respectively; P = 0.03), and lower CR1 rate (73.4% vs 91.9%, respectively; P < 0.0001), DFS (median DFS 11 months vs 25 months, respectively; P = 0.0009) and OS (median OS 13 months vs 78 months, respectively; P < 0.0001). Conclusions Despite intensive chemotherapy, the majority of patients ≥ 60 years with AML have poor outcomes, with high rates of induction death, refractory disease, and relapsed AML. However, a proportion of these patients experience long-term survival. While patients selected for allogeneic transplantation in CR1 have high DFS and OS, only a minority of patients receive this therapy. Disclosures: No relevant conflicts of interest to declare.

Abstract 3577 Background: Iron overload, as measured by raised serum ferritin, is recognised as a significant risk factor for excess transplant related mortality (TRM) in allogeneic stem cell transplantation (SCT). Due to blood transfusions received during initial induction/consolidation chemotherapy, almost all patients undertaking SCT with AML have significantly raised ferritin pre-SCT. Aims: To determine the efficacy of deferasirox (Exjade®) in preventing iatrogenic iron overload in patients receiving induction/consolidation chemotherapy for AML. Methods: Prospective randomised phase II study in AML patients planned to receive induction and/or consolidation chemotherapy. Iron studies and CRP were measured pre, mid and post each chemotherapy cycle. Patients were randomised to receive either therapy with deferasirox (starting at 5–10mg/kg/day PO and increasing to maximum 40mg/kg/day PO as tolerated) vs. no deferasirox therapy. Desferasirox was commenced once ferritin increased to >500μg/L and continued until transfusion independence after completion of all chemotherapy. The primary endpoint was ferritin concentration at completion of chemotherapy. Based on historical controls, to detect a difference of >1000μg/L in ferritin between groups a sample size of 14 per arm was required. Results: The study was terminated prematurely after 16 patients were enrolled (deferasirox arm n=10; control arm n=6) due to excess grade 2–4 GIT (frequency 1.26 vs. 0.75 events/chemotherapy cycle for deferasirox vs. control arm respectively; p=0.04) and infectious toxicity (frequency 2.22 vs. 1.38 events/chemotherapy cycle for deferasirox vs. control arm respectively; p=0.05) experienced in the deferasirox arm. Overall desferasirox was poorly tolerated, with mean maximum tolerated dose only 13.2mg/kg/day (range 5–20mg/kg/day) and 4/10 patients unable to continue the drug predominantly due to GIT toxicity. Post-treatment ferritin, % change in ferritin and number of transfusions received were no different between arms. Post-chemotherapy CR rate was lower in the desferasirox arm (60% vs. 100%; p=0.234), and all treatment-related deaths (n=3; all infectious-related) occurred in the desferasirox arm (p=0.25). Median OS was similar in both arms (median 450 vs. 476 days for deferasirox vs. control arm respectively; p=0.72). Conclusions: Use of desferasirox to prevent iatrogenic iron overload in AML patients undertaking induction/consolidation is ineffective, poorly tolerated, and associated with excess GIT and infectious toxicity. Disclosures: No relevant conflicts of interest to declare.