ALBERT

Description: Alfa Interferon, commonly used in chronic phase chronic myeloid leukemia (CML-CP) in the pre-imatinib era, was able to induce a cytogenetic response in a minority of patients (pts). Pegylated interferon (Peg-IFN) is better tolerated than IFN, and increases molecular response rates when used in combination with imatinib (IM) compared with IM monotherapy (Preudhomme NEJM 2010). The phase II Pinnacle (ALLG CML 11) study evaluated the tolerability and molecular response rate of nilotinib (NIL) with Peg-IFN alfa-2B (PegIntron, MSD) in de novo CML-CP. Pts were screened for cardiac / vascular disease and associated risk factors at baseline (EKG, left ventricular ejection fraction, arterial duplex of carotids and lower limbs, blood HbA1c and lipid profiles). Those with uncontrolled vascular risk factors (diabetes, hypertension, dyslipidemia) or a history of vascular events were excluded. Eligible pts received NIL 300mg BID alone for the first 3 months (mths). PegIntron was then added at 30mcg/week in pts without persistent hematological toxicities, increasing to 50mcg/week as tolerated over the following mth. Combination therapy continued until 24 mths, when pts reverted to TKI monotherapy. Switching to IM 400-600mg QD was allowed for pts with persistent grade II or any grade III/IV toxicity from NIL.. Sixty pts were enrolled from 12 Australian centres. Median age was 48.5 years (range 19-72); 45% were female. Sokal risk was low in 43% and high in 18%. Median follow up (FU) was 28 mths (16-51). Data is presented on an intention to treat basis. Figure 1a shows BCR-ABL1 transcript levels over time. The co-primary end points are MMR (BCR-ABL1 ≤0.1% IS) AT 12 mths and MR4.5 (BCR-ABL1 ≤0.0032% IS) at 24 mths. At 12 mths, MMR and MR4.5 rates were 76.7% (95% CI 63.4-87%). and 43.4% (95% CI 30.1-57.3%), respectively. In 40 evaluable pts at 24 mths, MR4.5 was 50% (95% CI 29.9-70.1%). The median time to MMR and MR4.5 was 5.8 mths and 18 mths respectively for pts achieving these responses (Figs 1B & C). Six pts (10%) had BCR-ABL1 ≥10% at 3 mths - 2 of whom had multiple dose interruptions due to toxicity; 3/6 have since achieved MMR, 1 has BCR-ABL 90% of their assigned dose, 13 (22%) received between 50-90% and 25 pts (41%) received

Description: Background Patients with HGL achieving complete remission (CR) after first-line combination chemotherapy undergo regular surveillance to detect early signs of relapse. As follow-up imaging is associated with increased radiation-related risk and minimal benefit in asymptomatic (aSx) patients, imaging as surveillance is no longer routine. (Eichenauer Ann Oncol 2014, Tilly Ann Oncol 2015) Regular laboratory testing (Labs) still feature in internationally-recognised surveillance guidelines (eg NCCN), despite limited evidence in the modern era for their use in relapse detection. Studies conducted prior to modern imaging (PET/CT) and use of rituximab suggested LDH and ESR may be useful, and more recently the absolute lymphocyte count (ALC) and lymphocyte-monocyte ratio (LMR) have shown promise in small series (Weeks JCO 1991, Henry-Amar Ann Int Med 1991,Wei Leuk Lymph 2015, Porrata Leukemia 2010). However large scale data are lacking hence there is no consensus on the value and optimum frequency of specific laboratory parameters for use in routine surveillance of HGL. Methods We conducted a retrospective analysis of patients with histologically-proven cHL, DLBCL, T-cell lymphoma or Burkitt lymphoma receiving curative-intent treatment over a 15-year period. Eligible patients were aged≥16years, in CR for ≥3 months & had 〉12months follow-up. Primary CNS lymphoma, HIV-associated lymphomas and transformation from indolent subtypes were excluded. Data were collated from patient records. Laboratory results were considered abnormal if a) FBE, ALC, neutrophil count, absolute monocyte count (AMC), ESR or LDH fell outside local laboratory normal limits b) the derangement was not present previously and c) could not be explained by a concurrent medical condition. Abnormal Lab results were investigated at clinician discretion. Labs were evaluated based on their independent ability to detect relapse within 3 months of confirmation. Kaplan-Meier method was used for survival analysis and compared by the log-rank test between groups. Results Between 2000-2015, 346 eligible patients underwent 3048 outpatient visits. Median follow-up was 30 months (range 3-184). Labs were performed at 90% of appointments: FBE in 99.7%, LDH in 78% (of NHL), ESR in 38% (of HL) with abnormalities in 26%, 12% and 16% respectively. Fifty-five patients relapsed (16%). Routine Labs detected aSx relapse in 3/55 (5%); routine imaging detected 9/55 relapses (16%) and clinical symptoms/signs lead to diagnosis of relapse in 43/55 (78%; 19/43 were unscheduled visits). Unscheduled appointments due to patient-reported symptoms (3% of all visits) showed a significantly stronger association with relapse than scheduled visits (OR 50.4, p

Description: Obinutuzumab (GA101; G) is an anti-CD20 monoclonal antibody with activity in relapsed/refractory follicular lymphoma (FL) as a single agent and in combination with chemotherapy. G-chemotherapy induction followed by G-maintenance has not been evaluated for untreated FL. The open-label, randomized, phase Ib GAUDI study (NCT00825149) investigated safety and efficacy of G + CHOP (G-CHOP) or bendamustine (G-B) as first-line treatment for FL. We report data from patients (pts) who received G-maintenance after responding to G-chemotherapy induction. Pts with treatment-naïve CD20+ B-cell FL and ≥1 bi-dimensionally measurable lesion (CT scan; largest dimension 〉1.5cm) were allocated on a per-center basis to receive induction G IV 1000mg + standard CHOP (3-weekly, 6–8 cycles) or B IV 90mg/m2(4-weekly, 4–6 cycles). Induction responders received G-maintenance every 3 months for 2 years or until disease progression (PD). Pts completing maintenance were followed for a further 2 years, until PD or start of new anti-lymphoma therapy. Anti-infective prophylaxis was used at investigator discretion. The primary objective was safety. Secondary objectives included progression-free survival (PFS) and response rates. The overall safety population comprised 81 pts (G-B: n=41; G-CHOP: n=40). Baseline characteristics (age, sex, FLIPI status, bone marrow involvement, bulky disease [lesion ≥7cm], time from diagnosis) were balanced between arms. Median observation time from study start was 31 months (G-B) and 33 months (G-CHOP). The maintenance safety population comprised 72 pts (n=36 from each induction therapy arm). Most pts completed maintenance (G-B: 81%; G-CHOP: 72%). There were 17 discontinuations (24%; G-B: n=7; G-CHOP: n=10), due to an adverse event (AE)/intercurrent illness (n=9), insufficient therapeutic response (n=5), administrative/other (n=2) and death (n=1). During 2 years’ maintenance most pts had AEs: G-B, 100% (44% grade ≥3); G-CHOP, 78% (31% grade ≥3). The most common AE (all grades) was cough (G-B: 17%; G-CHOP: 11%). The grade ≥3 AEs mainly reflected infections and cytopenia. Six G-B pts (17%) experienced 7 grade ≥3 infections; 4 were considered treatment related (genital infection, oral herpes, pneumonia klebsiella, neutropenic infection). Five G-CHOP pts (14%) had one grade ≥3 infection each; 4 were considered treatment related (viral meningitis, respiratory tract infection [RTI], bacterial pneumonia [2 events]). Six G-B pts (17%) experienced 10 grade ≥3 cytopenia AEs; 7 were considered treatment related (anemia, febrile neutropenia, pancytopenia, neutropenia [2 events], thrombocytopenia [2 events]). No G-CHOP pt experienced a grade ≥3 cytopenia AE. AEs led to dose delays in 17% (G-B) and 6% (G-CHOP) of pts. Three pts (G-B: n=1; G-CHOP: n=2) had treatment-related AEs during, or within 24 hours of, an infusion (all grade 1–2). Two deaths (both G-CHOP) occurred during maintenance or maintenance follow-up; 1 due to PD and 1 due to a G-related AE (RTI leading to fatal lactic acidosis). At the end of maintenance, all pts with data available (G-B: n=41; G-CHOP: n=39) had experienced B-cell depletion (0.07x109cells/L). Median IgG levels remained within normal range during maintenance. In the overall safety population, complete response (CR) rate (based on CT scan rather than PET) as best overall response increased from end of induction (G-B: 37%; G-CHOP: 35%) to end of maintenance (G-B: 61%; G-CHOP: 70%). PFS rate at 32 months after first study drug was 92% (G-B) and 84% (G-CHOP). Median PFS was not reached; 10 pts (G-B: n=4; G-CHOP: n=6) had PD, including one transformation to diffuse large B-cell lymphoma. G-maintenance after G-chemotherapy induction was associated with a high CR rate in pts with previously untreated FL. Opportunistic infections occurred infrequently. Clinically relevant neutropenia was experienced by 14% of pts who received G-B induction but was not observed in G-CHOP pts. A phase III trial (GALLIUM) is investigating G versus rituximab in chemoimmunotherapy induction followed by immunotherapy maintenance in pts with untreated indolent non-Hodgkin lymphoma. Disclosures Off Label Use: Obinutuzumab is a type II CD20 monoclonal antibody which is licensed for use in combination with chlorambucil in untreated patients with CLL but is not currently approved for use in follicular lymphoma.. Grigg:Roche: Consultancy. Dreyling:Roche: Honoraria, Research Funding. Rule:Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees. Lei:Roche Products Ltd.: Employment. Wassner-Fritsch:Roche: Employment. Fingerle-Rowson:F. Hoffmann–La Roche: Employment. Marlton:Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees.

Description: Introduction: Hodgkin lymphoma (HL) is a rare disease that commonly occurs in AYAs, defined in the United States as patients 15 to 39 years of age. Brentuximab vedotin (Adcetris®; A) is an anti-CD30 antibody-drug conjugate approved for adult patients with previously untreated stage III or IV classical HL (cHL) in combination with doxorubicin, vinblastine and dacarbazine (AVD) chemotherapy based on results from the phase 3 ECHELON-1 trial which demonstrated a significantly improved modified progression-free survival (mPFS) compared with doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) (HR, 0.77; 95% CI, 0.60-0.98; P=0.04) (Connors JM, et al. N Engl J Med. 2018;378:331-344). Here we describe key efficacy and safety results for 18-to-39-year-old AYA patients enrolled in ECHELON-1. Methods: ECHELON-1 is a global, open-label, multicenter, randomized trial of patients with previously untreated stage III or IV cHL. Patients ≥18 years of age enrolled from both academic and community sites were randomized to receive A+AVD (n=664) or ABVD (n=670). The primary endpoint was mPFS, defined as progression, death, or receipt of additional anticancer therapy for patients who were not in complete response after completion of frontline therapy, as adjudicated by an independent review facility (IRF). Safety and tolerability was also assessed. To account for regional differences in the age ranges that define AYA patients, this exploratory subgroup analysis compares efficacy and key safety outcomes for AYA patients

Description: Introduction Cyclosporin (CSA) is commonly used as graft vs host disease (GvHD) prophylaxis in allogeneic haematopoietic stem cell transplant (alloHSCT) recipients. The usual IV dose is 3mg/kg and the recommended oral dose at switching is 3mg/kg BD in the pre-posaconazole era (Inoue et al. 2014). Posaconazole is now commonly used as antifungal prophylaxis in this context; it increases CSA levels through inhibition of the cytochrome involved in CSA metabolism (Sánchez-Ortega et al. 2012). We evaluated CSA-related toxicity after switch from IV to oral CSA in alloHSCT recipients receiving posaconazole with the aim of defining the optimal weight based oral dose. Methods A retrospective audit was performed of adult alloHSCT patients between October 2015 and October 2017 who received IV and then oral CSA together with posaconazole prophylaxis. Posaconazole was commenced during conditioning and continued at 300mg IV or oral daily according to gastrointestinal tolerance; patients with levels below 0.5mg/L received 200mg orally BD. Despite being protocolised, in practice the starting oral CSA dose in mg/kg, based on actual body weight, was at consultant discretion based on comorbidities at the time, predominantly renal dysfunction. Two groups were analysed: those with starting oral CSA doses ≥ 2.8mg/kg BD ('higher dose') and 〈 2.8mg/kg BD ('lower dose'). Exclusion criteria included continuation of IV CSA beyond day 30 or CSA taper before day 40 due to relapsed or persistent disease. Data collected included CSA doses in mg/kg at 3 time points: transition from IV to oral CSA, day 40 and day 60, and CSA dose reductions due to the following toxicities: renal impairment (fall in eGFR 〉15 ml/min/1.73m2 from transition eGFR), new/worsening hypertension, hypomagnesaemia (

Description: Aim: To evaluate the safety and efficacy of nivolumab for the treatment of relapsed or residual haematological malignancies after allogeneic stem cell transplantation (alloSCT). Background: Relapse of haematological malignancies following alloSCT is a major cause of post-transplant mortality. Interaction between programmed cell death protein-1 (PD-1) and its ligand (PD-L1) inhibits T-cell alloreactivity and contributes to immune escape. Nivolumab inhibits PD-1 signalling and augments T-cell cytotoxicity. The safety and efficacy of nivolumab post-alloSCT has not been evaluated in a clinical trial. Method: In this investigator-initiated phase IIa clinical trial, patients with relapsed or persistent haematological malignancies following alloSCT receive nivolumab 3mg/kg for up to 48 weeks. Patients with current graft-versus-host disease (GVHD) or prior grade ≥2 acute GVHD or chronic GVHD are excluded. Results: Six participants have received at least one dose of nivolumab at this interim assessment. Primary haematological malignancies relapsing post-alloSCT included Hodgkin lymphoma (HL, 2 patients), acute myeloid leukaemia (AML, 2), transformed chronic lymphocytic leukaemia (tCLL, 1) and mantle cell lymphoma (MCL, 1). The median time from alloSCT to first dose of nivolumab was 25.5 months. Two participants developed grade 3 acute GVHD at 6 days and 13 days following the first dose of nivolumab. Complete or partial responses were observed in 3 participants (50%). Two participants with HL achieved complete responses. One participant with MCL had a complete nodal response with small volume persistent bone marrow disease. One participant with monosomal karyotype AML achieved initial blast reduction (23% to 13%) however subsequently developed progressive AML. T-cell phenotyping at first AML relapse (prior to nivolumab) demonstrated a high proportion of CD8+ T cells that expressed PD-1 and T-cell immunoglobulin and mucin domain 3 (TIM-3) consistent with T-cell exhaustion. Following treatment with nivolumab there was an increase in TNFα production by CD8+ T-cells at day 7 post nivolumab, demonstrating augmentation of T-cell activity. Despite continued nivolumab treatment TNFα production subsequently declined and correlated with loss of clinical response. TIM-3 expression was further upregulated at post-nivolumab progression suggesting this inhibitory checkpoint receptor may have contributed to nivolumab resistance. Conclusion: Nivolumab treatment after alloSCT results in potent immune stimulation with a high rate of clinical responses, albeit with a risk of GVHD. Acquired resistance to nivolumab may develop via upregulation of alternative inhibitory checkpoints. Disclosures Szer: Alexion Pharmaceuticals, Inc.: Consultancy, Honoraria, Other: Travel Support , Research Funding. Grigg:BMS: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees.

Description: Background Survival rates for older pts with advanced HL (aged ≥60 yrs) were historically poor with doxorubicin, bleomycin, vinblastine and dacarbazine (ABVD). Reasons may include decreased tolerance of therapy, increased toxicity (particularly with bleomycin), comorbidities, and disease biology. The pivotal phase 3 ECHELON-1 study demonstrated superior 2-yr modified progression-free survival (mPFS) with frontline brentuximab vedotin + doxorubicin, vinblastine and dacarbazine (A+AVD) vs ABVD in pts with stage III/IV cHL (Connors JM et al, NEJM 2018). The study allowed entry of older pts, with no upper age limit. Alternative dosing schedules of the A+AVD regimen have been studied (e.g., sequential brentuximab vedotin before and after AVD; NCT01476410, Evens AM et al, J Clin Oncol 2018). We report efficacy and safety results from ECHELON-1 for older pts with cHL and compare these with those for pts aged

Description: Toxoplasma gondii is a ubiquitous protozoan parasite which infects approximately one third to one half of the world's population. In the immunocompetent host it typically causes a self limiting and asymptomatic infection before entering a lifelong latent phase. Reactivation and disseminated toxoplasmosis occur in the setting of impaired cellular immunity as described in patients with acquired immunodeficiency syndrome (AIDS) secondary to human immunodeficiency virus (HIV) infection and those receiving prolonged immunosuppression post solid organ or allogeneic haematopoietic stem cell transplantation. Toxoplasmosis post autograft has been rarely described. We present a case of toxoplasma encephalitis in a patient with persistent CD4 lymphopenia post autograft for peripheral T-cell lymphoma (PTCL). A 64y HIV negative female was diagnosed with autoimmune haemolytic anaemia (AIHA) and idiopathic thrombocytopenic purpura (ITP) in 2012 and 2013, treated with intravenous immunoglobulin (IVIg), 4 months in total of prednisolone (two separate courses, average dose 30mg/day), a single dose of 375mg/m2 rituximab and 6 months of azathioprine 100mg/day. The lymphocyte count prior to AIHA was normal (2.9 x 109/L; normal range 1-4 x109/L). The subsequent course was complicated by persistent lymphopenia in the absence of immunosuppression (0.3-0.7x109/L,) and cutaneous mycobacterium kansasii infection. PTCL was diagnosed in February 2015 and treated with 6 cycles of high dose chemotherapy (CHEOP) followed by an autograft in July 2015 with BEAM conditioning. Lymphocyte counts at 3, 7, 9 and 12 months post transplant were 0.4, 0.5 ,0.8 and 0.3 x 109/L respectively. Dapsone for pneumocystis jirovecii pneumonia (PJP) prophylaxis was given; cotrimoxazole was contraindicated due to a rash. Twelve months post autograft she developed left leg weakness and intermittent headache. A MRI brain showed 4 enhancing cerebral lesions, of which histology demonstrated toxoplasma tachyzoites in neutrophils confirmed by PCR. Toxoplasma serology was IgG positive but IgM negative. The CD4 count was severely reduced 0.09 x 109/L (normal 0.65-2.0 x 109/L) as were other lymphocyte subsets (CD8 0.04 x 109/L (0.33-1.3), NK 0.03 x 109/L (0.13-0.54) and B cells 0.13 x 109/L (0.19-0.55). Immunoglobulin levels were normal. Treatment with pyrimethamine and sulfadiazine was commenced with some improvement in neurology prior to discharge for rehabilitation. Toxoplasmosis occurring more than 2 months post autograft is very rare, with to our knowledge only 9 cases previously reported. Of these, 6 of the 8 evaluable documented an additional risk factor for reactivation including persistent lymphopenia (one case attributable to CD34 selection), etanercept and high dose steroids. In our case the main risk factor appeared to be pre-existing (historically most likely auto-immune mediated (Regent, Medicine 2014)) and persistent post-autograft lymphopenia with particularly low CD4 levels. After an autograft, CD3 counts can be expected to return to baseline by three months but CD4 counts recover more slowly and incompletely by 12 months (meanat 1, 3, 6 and 12 months: 0.22, 0.27, 0.38 and 0.46 x 109/L respectively (Damiani, Ann Oncol 2003) Post autograft, no prophylaxis or screening for toxoplasmosis infection is recommended (Tomblyn, Biol Blood Marrow Transplant 2009). However, when warranted, the drug of choice is cotrimoxazole, often concurrently administered for PJP prophylaxis. In practice due to myelosuppression or rash, cotrimoxazole is frequently replaced by dapsone or pentamadine, neither of which is proven to be effective against toxoplasma. This case highlights a need to review current guidelines and consider prophylaxis for toxoplasmosis in patients at high risk of reactivation post autograft, such as those with persistent lymphopenia and high dose steroids. Disclosures No relevant conflicts of interest to declare.

Description: Key Points Approximately 40% of patients with undetectable minimal residual disease on imatinib can stop treatment without loss of molecular response. Patients in treatment-free remission still have detectable BCR-ABL DNA several years after stopping imatinib.

Description: Aim Venous thromboembolism (VTE) is a major cause of morbidity and mortality and is estimated to cost approximately AUD$117 000 per person (Access Economics 2008). Despite advances in thrombosis management, recurrence rates remain high and management strategies are often heterogenous even within a single institution. While most studies have analysed specific aspects of VTE management, we aim to provide a holistic evaluation of real-world VTE management in the warfarin era including identifiying potential causal effects and complications. Method Retrospective evaluation of VTE over an 18-month period, from July 2011 to December 2012, at two major hospitals in Northeast Melbourne, Australia, including demographics, provoking factors, management, complications and mortality. Comparisons were made between cancer and non-cancer populations. Result 1003 patients, with median age of 63 (range 19-97) years, were identified including 26 recurrences (total 1029 episodes) - 577 (56%) pulmonary embolism (PE), 428 (42%) deep venous thrombosis (DVT). There was an overall male predominance (52%), particularly affecting the DVT subgroup (57% vs 48%, p=0.003) with no gender differences detected in the PE subgroup. 20% reported prior VTE and left limb DVT was more common (49% vs 43%, p=0.0008). The median follow up was 20 (range 10-32) months. NON-CANCER PATIENTS In this cohort, 63% had provoked VTE and thrombophilia screen was performed in 41%. The median duration of anticoagulation was 6 and 7 months for DVT and PE respectively. The majority (90%) was on warfarin for long-term anticoagulation. 5% required further interventions – IVC filter (n=28) and thrombolysis (n=15). 38% had end-of-treatment repeat imaging and residual clot was observed in 40%. Clot persistence was associated with increased recurrence risk, with an odds ratio of 2.64 (1.15 – 6.04, p=0.02). 8% had recurrent thrombosis with no difference between provoked versus unprovoked VTE (7.5% vs 9.0%, p=0.45). 5% reported grade III/IV bleeding, independent of duration of anticoagulation. Patients on enoxaparin had higher risk of bleeding (28% vs 10%, p