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The prevalence of donor-derived leukemia is estimated to be 80.5 per 100 000 transplants, with a mean duration of transplant to incidence of donor-derived leukemia of 44 months (ranging from 2 to 2...

Introduction Bronchiolitis obliterans syndrome (BOS) after allogeneic haemopoietic stem cell transplant (HSCT) is an under-recognised and difficult to treat disease. This occurs in the context of limited clinical research and inconsistent diagnostic criteria. Method Retrospective data was collected on 275 patients who underwent allogeneic HSCT at an Australian tertiary hospital between 2007 and 2017. The prevalence of BOS, defined by 2014 National Institute of Health criteria, as well as predictors for BOS and mortality were determined. Treatment outcomes, using serial spirometry, were compared between patients who received early versus late immunosuppression for BOS. Results The prevalence of BOS was 9.1%. Myeloablative conditioning (OR: 2.7, 95%CI: 1.13–6.50, p = 0.03) and extra-pulmonary chronic graft-versus-host disease (OR 2.62, 95% CI: 1.04–6.60, p = 0.04) were associated with BOS. There was reduced median survival in the BOS group compared with the non-BOS group, but this was not statistically significant (4.1years (IQR: 2.8, 6.8) versus 4.6years (IQR: 2.4, 7.8), respectively, p = 0.33). The vast majority (87.5%) of BOS patients failed to attain improvement in FEV1 at 12 months, regardless of treatment strategy. Patients who underwent a late immunosuppression strategy had worse mean FEV1 decline compared to those who received early immunosuppression (−36.3% versus −1.6%, respectively, p = 0.03). Conclusion BOS is a common and progressive disease following HSCT and is largely refractory to current treatment strategies. Compared to late immunosuppression, early augmentation of immunosuppression may slow lung function deterioration in the short term. However, further research is urgently needed to identify effective prevention and treatment strategies for BOS.

Background Persons living with human immunodeficiency virus (HIV) are at elevated risk of developing the malignant diseases that require allogeneic stem cell transplantation (ASCT). Recent data suggest that these individuals are also at an elevated risk of certain complications post-ASCT. This risk may result from preexisting HIV-related factors affecting dynamics of immune reconstitution post-ASCT. However, to date, there has been little work describing the dynamics of immune reconstitution post-ASCT in persons with HIV and none comparing these data to controls without HIV. Methods We assessed T-cell reconstitution in 6 ASCT with HIV recipients (HIV+ASCT) compared to a control population of 21 ASCT without HIV recipients. In a subset of HIV+ASCT recipients we performed additional flow cytometry profiling of CD8+ T-cell subsets and antigen specificity of reconstituting CD4+ and CD8+ T cells. Results We observe no difference in post-ASCT CD4+ T cells between HIV+ASCT and HIV-negative ASCT recipients, despite much lower pre-ASCT CD4+ T-cell counts in the HIV+ASCT group. In contrast, we observed significantly higher CD8+ T-cell numbers in the HIV+ASCT group post-ASCT. The reconstituting CD8+ T-cells were predominantly CD45RO+, whereas homing markers and antigen specificity of these cells varied between participants. Conclusion This study represents the most extensive characterization of immune-reconstitution post-ASCT in persons with HIV, and the first to our knowledge to compare these data to ASCT controls without HIV. The results indicate that immune reconstitution in this group can be affected by preexisting HIV infection and post-ASCT antigen exposure.

Hematological cancer survivors are highly vulnerable to cardiometabolic complications impacting long-term health status, quality of life and survival. Elevated risk of diabetes and cardiovascular disease arises not only from the effects of the cancers themselves, but also from the toxic effects of cancer therapies, and deconditioning arising from reduced physical activity levels. Regular physical activity can circumvent or reverse adverse effects on the heart, skeletal muscle, vasculature and blood cells, through a combination of systemic and molecular mechanisms. We review the link between hematological cancers and cardiometabolic risk with a focus on adult survivors, including the contributing mechanisms and discuss the potential for physical activity interventions, which may act to oppose the negative effects of both physical deconditioning and therapies (conventional and targeted) on metabolic and growth signaling (kinase) pathways in the heart and beyond. In this context, we focus particularly on strategies targeting reducing and breaking up sedentary time and provide recommendations for future research.

High-risk (HR) multiple myeloma (MM) has poor outcomes with conventional therapy. Tandem autologous-non-myeloablative (NMA) allogeneic stem cell transplantation (autologous stem cell transplantation (ASCT)-NMA allogeneic SCT) is potentially curative secondary to graft-versus-myeloma effect. We retrospectively analysed ASCT-NMA allogeneic SCT outcomes of 59 HR and relapsed MM patients. At a median follow-up of 35.8 months, the outcomes for HR-MM upfront tandem ASCT-NMA allogeneic SCT and standard-risk (SR) MM upfront ASCT alone were comparable (median PFS 1166 days versus 1465 days, P=0.36; median overall survival (OS) not reached in both cohorts, P=0.31). The 5-year PFS and OS of patients who had ASCT-NMA allogeneic SCT after relapsing from previous ASCT were 30% and 48% respectively. High CD3+ cell dose (>3 × 108/kg) infusion was associated with more acute GvHD (grade 2-4) (47% vs 17.5%; P=0.03), extensive chronic GvHD (80% vs 50%; P=0.04), increased transplant-related mortality (26.3% vs 5%; P=0.009) and inferior OS (median OS 752 days vs not reached; P=0.002). On multivariate analysis, response achieved with tandem transplant (

// Peter Tan 1 , Ing Soo Tiong 1, 2 , Shaun Fleming 1 , Giovanna Pomilio 2 , Nik Cummings 3 , Mark Droogleever 4 , Julie McManus 3 , Anthony Schwarer 5 , John Catalano 6 , Sushrut Patil 1 , Sharon Avery 1 , Andrew Spencer 1, 2 and Andrew Wei 1, 2 1 Malignant Haematology and Stem Cell Transplantation Service, Alfred Hospital, Melbourne, Australia 2 Australian Centre for Blood Diseases, Monash University, Melbourne, Australia 3 Department of Pathology, Alfred Hospital, Melbourne, Australia 4 Faculty of Medicine, University of Amsterdam, Amsterdam, The Netherlands 5 Eastern Health Clinical School, Monash University, Box Hill, Australia 6 Clinical Haematology, Frankston Hospital, Frankston, Australia Correspondence to: Andrew Wei, email: andrew.wei@monash.edu Keywords: acute myeloid leukemia, everolimus, azacitidine, mTOR, clinical trial Received: October 21, 2016 Accepted: November 20, 2016 Published: November 29, 2016 ABSTRACT Therapeutic options are limited in relapsed/refractory acute myeloid leukemia (AML). We evaluated the maximum tolerated dose (MTD) and preliminary efficacy of mammalian target of rapamycin (mTOR) inhibitor, everolimus (days 5–21) in combination with azacitidine 75 mg/m 2 subcutaneously (days 1–5 and 8–9 every 28 days) in 40 patients with relapsed ( n = 27), primary refractory ( n = 11) or elderly patients unfit for intensive chemotherapy ( n = 2). MTD was not reached following everolimus dose escalation (2.5, 5 or 10 mg; n = 19) to the 10 mg dose level which was expanded ( n = 21). Major adverse events (grade > 2) were mostly disease-related: neutropenia (73%), thrombocytopenia (67%), mucositis (24%) and febrile neutropenia (19%). Overall survival (OS) of the entire cohort was 8.5 months, and overall response rate (ORR; including CR/CRi/PR/MLFS) was 22.5%. Furthermore, a landmark analysis beyond cycle 1 revealed superior OS and ORR in patients receiving 2.5 mg everolimus with azoles, compared to those without azoles (median OS 12.8 vs. 6.0 months, P = 0.049, and ORR 50% vs. 16%, P = 0.056), potentially due to achievement of higher everolimus blood levels. This study demonstrates that everolimus in combination with azacitidine is tolerable, with promising clinical activity in advanced AML.

Objectives Infections are a major cause of mortality after allogeneic haemopoietic stem cell transplantation (alloHSCT), and immune recovery is necessary for prevention. Novel transplant procedures have changed the epidemiology of infections but contemporary data on functional immune recovery are limited. In this pilot study, we aimed to measure immune recovery in the current era of alloHSCT. Methods Twenty, 13, 11, 9 and 9 alloHSCT recipients had blood collected at baseline (time of conditioning) and 3‐, 6‐, 9‐, and 12‐months post‐alloHSCT, respectively. Clinical data were collected, and immune recovery was measured using immunophenotyping, lymphocyte proliferation, cytokine analysis and antibody isotyping. Results Median absolute T‐ and B‐cell counts were below normal from baseline until 9‐ to 12‐months post‐alloHSCT. Median absolute CD4+ T‐cell counts recovered at 12‐months post‐alloHSCT. Positive proliferative responses to Aspergillus, cytomegalovirus (CMV), Epstein‐Barr virus (EBV), influenza and tetanus antigens were detected from 9 months. IL‐6 was the most abundant cytokine in cell cultures. In cultures stimulated with CMV, EBV, influenza and tetanus peptides, the CD4+ T‐cell count correlated with IL‐1β (P = 0.045) and CD8+ T‐cell count with IFNγ (P = 0.013) and IL‐1β (P = 0.012). The NK‐cell count correlated with IL‐1β (P = 0.02) and IL‐17a (P = 0.03). Median serum levels of IgG1, IgG2 and IgG3 were normal while IgG4 and IgA were below normal range throughout follow‐up. Conclusions This pilot study demonstrates that immune recovery can be measured using CD4+ T‐cell counts, in vitro antigen stimulation and selected cytokines (IFNγ, IL‐1β, IL‐4, IL‐6, IL‐17, IL‐21, IL‐31) in alloHSCT recipients. While larger studies are required, monitoring immune recovery may have utility in predicting infection risk post‐alloHSCT.

Data from the Australasian Bone Marrow Transplant Recipient Registry show a steady increase in the number of allogeneic haemopoietic stem cell transplantations (HSCT) performed annually in Australia and New Zealand. In 2012, 629 allogeneic HSCT were performed. Allogeneic HSCT is associated with numerous potential complications, including chronic graft-versus-host disease (cGVHD). The oral cavity is one of the most frequent sites affected by cGvHD, often leading to significant disability and reduced quality of life. Management strategies are often complex, of variable efficacy and influenced by the availability of various therapeutic agents, access to compounding pharmacies and associated costs. This paper summarises the current status of allogeneic HSCT in Australia and New Zealand with a focus on oral cGvHD and the associated challenges in its management.

Background: Allogeneic hematopoietic stem cell transplantation (HSCT) can lead to significant changes to the HIV reservoir and HIV immune responses, indicating that further characterization of HIV-infected patients undergoing HSCT is warranted. Methods: We studied 3 patients who underwent HSCT after either reduced intensity conditioning or myeloablative conditioning regimen. We measured HIV antigens and antibodies (Ag/Ab), HIV-specific CD4+ T-cell responses, HIV RNA, and DNA in plasma, peripheral blood mononuclear cells, isolated CD4+ T cells from peripheral blood, and lymph node cells. The patients remained on antiretroviral therapy throughout the follow-up period. Results: All patients have been in continued remission for 4–6 years post-HSCT. Analyses of HIV RNA and DNA levels showed substantial reductions in HIV reservoir–related measurements in all 3 patients, changes in immune response varied with pronounced reductions in 2 patients and a less dramatic reduction in 1 patient. One patient experienced unexpected viral rebound 4 years after HSCT. Conclusions: These 3 cases highlight the substantial changes to the HIV reservoir and the HIV immune response in patients undergoing allogeneic HSCT. The viral rebound observed in 1 patient indicates that replication competent HIV can re-emerge several years after HSCT despite these marked changes.

Adolescents and adults with acute lymphoblastic leukemia/lymphoma (ALL) have better outcomes when treated using pediatric protocols compared with treatment using adult protocols. We reviewed the progress and outcomes of 40 adolescents and adults up to 45 years of age, from three Australian centers, treated on the intensive French group for childhood ALL (FRALLE)-93 pediatric protocol. All except one patient achieved a morphologic complete remission following induction chemotherapy. Three-year overall survival for all-risk and standard-risk disease was 70% and 75%, respectively. The treatment protocol was generally well tolerated with no treatment related mortality. The FRALLE-93 pediatric protocol showed excellent overall survival for patients with standard-risk disease, without the need for allogeneic hematopoietic stem cell transplant in first remission.

Cardiovascular disease is a major cause of late morbidity and increased mortality in long-term survivors of haematological malignancy treated with stem cell transplantation (SCT).1, 2 The metabolic syndrome (MetS), a clustering of risk factors for cardiovascular disease, occurs frequently after SCT.3, 4 Lifestyle intervention is effective in reducing the occurrence of MetS and its components in both general population cohorts5 and survivors of non-haematological cancers,6 however, effectiveness following SCT is not established. This prospective pilot study aimed to assess the effectiveness of a 12-month lifestyle intervention program on reducing the number and/or severity of MetS risk factors in long-term survivors of SCT.

Factors associated with post-traumatic stress symptoms experienced in the acute phase following haemopoietic stem cell transplant

Tumour lysis syndrome (TLS) is a life-threatening oncological emergency characterized by hyperuricaemia, hyperkalaemia, hyperphosphataemia, and hypocalcaemia [1, 2] due to the rapid lysis of malignant cells, following the initiation of anticancer therapies [3]. Traditionally, therapy for TLS involved intensive hydration, urinary alkalinization and administration of allopurinol [4–6]. Newer guidelines now include rasburicase, with monitoring of electrolytes, white blood cell counts (WCC) and lactate dehydrogenase (LDH) concentrations [1, 7, 8]. Rasburicase, a recombinant urate oxidase enzyme, effectively decreases existing serum uric acid (UA) by oxidizing it to allantoin which is readily soluble and excretable [3]. Although the recommended dose is 0.2 mg kg−1 day−1 for 5–7 days [9], studies have shown the efficacious use of reduced doses for shorter periods of time and subsequent cost savings [5, 6, 10–17]. Expert guidelines by Coieffer et al. [7] in 2008 and Cairo et al. in 2010 [1] on the management of TLS recommend a rasburicase dose of 0.1–0.2 mg kg−1 on the first day, then repeated for up to 7 days [1] or as necessary [7]. We present an analysis of a fixed 3 mg dose of rasburicase administered to adult patients, treated at a tertiary referral centre. The study was approved by the Alfred Health Human Research Ethics Committee and the Monash University Human Research Ethics Committee. Demographic data were collected. Biochemical parameters (serum creatinine, serum UA, phosphate and LDH concentrations), at baseline, 24 h and 72 h after initial administration of rasburicase were recorded and compared. The institution guideline indicates rasburicase to be given before the first dose of chemotherapy in patients considered high risk for TLS. This includes a diagnosis of Burkitt's lymphoma, acute lymhoblastic leukaemia, bulky non-Hodgkin's lymphoma, lymphoblastic lymphoma or acute myeloid leukaemia with one or more of the following: serum UA>0.46 mmol l−1, white cell count (WCC) >50 × 109 l−1 or LDH >two times normal. Patients who were at an ongoing risk of TLS (i.e. elevated UA or LDH or multiple days of aggressive cytoreductive chemotherapy) were allowed a repeat dose of rasburicase 3 mg. Adherence to the guideline was measured. Forty-one patients received 42 courses of rasburicase over a 40 month period (Figure 1A). Diagnosis, demographic and baseline biochemical data are presented in Table 1. Figure 1 Summaryof rasburicase courses and uric acid concentrations. A) Summary of rasburicase courses administered. B) Median uric acid concentrations over time stratified by presentation a baseline. ♦, normal; ▪, hyperuricaemic; ▴, all ... Table 1 Patientcharacteristics Rasburicase was administered as per institution guidelines in 40 (95%) of the patients. Median serum UA concentrations were within normal range at 72 h in all groups; in those who presented with hyperuricaemia, in those who presented with normal baseline serum UA concentrations and overall (Figure 1B). The majority of patients received one dose of rasburicase 3 mg (Figure 1A). In 34 patient episodes requiring one dose only, there was a decline in the median (range) UA concentration from 0.44 mmol l−1 (0.13–1.15) at baseline to 0.22 mmol l−1 (0.02–0.66) at 24 h. This decrease was maintained at 72 h (P < 0.0001) with a median of 0.21 mmol l−1 (0.02–0.52). Serum creatinine concentrations were within normal range (60–105 μmol l−1) at baseline in 74% of patients, with 82% having a normal creatinine at 72 h. Hyperphosphataemia was present in 29% of patients at baseline and increased to 44% at 72 h. Eight patient episodes required more than one dose due to the ongoing risk of TLS. In these patients the median (range) baseline UA was 0.50 mmol l−1 (0.02–2.0), 0.33 mmol l−1 (0.02−1.10) at 24 h and 0.24 mmol l−1 (0.02−1.10) at 72 h (P < 0.0001). Of these patients only 52% had a normal creatinine at baseline, increasing to 83% at 72 h. Mean phosphate concentrations decreased over time but all patients remained hyperphosphataemic at 72 h. No hypersensitivity reactions were noted, no patients required haemodialysis and no deaths were related to the administration of rasburicase. Our results demonstrate that a single fixed dose of rasburicase 3 mg, repeated if required, should be the standard regimen in the management of TLS. Recent studies and published guidelines have shown cumulative support for the safe and efficacious use of off-label dosing regimens of rasburicase [1, 5–8, 10, 11, 16, 17]. A quarter of our patients presented with a baseline WCC>100 × 109 l−1 (Table 1), which is considered a high risk for developing TLS [1, 7]. The Product Information recommends rasburicase 0.1–0.2 mg kg−1 day−1 for 1–7 days [9]. We successfully used a fixed 3 mg dose for these patients. Our data support that presented by Trifilio et al. [11] in a recent study of 287 episodes, the largest published series at this time, of raised UA concentrations successfully treated with a single 3 mg dose of rasburicase, repeated if required. In our cohort, which was smaller in size, a single 3 mg dose was equally effective in both patients who had a normal baseline UA and those with hyperuracaemia. This differed from that published by Trifilio et al., where the single dose was more successful in patients with a lower baseline UA concentration. Our patient cohort also had a higher median LDH. Suboptimal management of hyperphosphatemia was identified in our cohort. More stringent monitoring of patient phosphate concentrations may be warranted in the future to minimize the risk of renal impairment. Serum creatinine, showing a gradual decrease with time, was used as a surrogate maker to indicate an improvement in renal function. Rasburicase was used in conjunction with allopurinol, urinary alkalinazation and intravenous hydration. This strategy is also supported by recent studies and recommendations [1, 11, 16], although the benefit of administering alkalinization with rasburicase needs further investigation [1, 7]. A single fixed 3 mg dose of rasburicase, in the setting of an institution guideline, was efficacious in the management of TLS.

Defibrotide is an agent used to treat sinusoidal obstruction syndrome (SOS/VOD) in patients undergoing haemopoietic stem cell transplantation. The aim of this study was to evaluate the effectiveness of defibrotide used within institutional guidelines for the treatment of SOS/VOD in patients undergoing haemopoietic stem cell transplantation (HSCT). Data for 23 patients was retrospectively reviewed to evaluate the effectiveness of defibrotide and the utility of response criteria to direct therapy as specified within institution guidelines. Patients met institutional criteria for a diagnosis of SOS/VOD based on predominantly Baltimore criteria and received defibrotide. Stabilisation or improvement in symptoms and biochemical markers was required for continuation of therapy with defibrotide. Overall, 14 patients responded to therapy. Survival at day 100 post HSCT was 70%. Median serum (total) bilirubin concentrations in all evaluable patients had decreased at days 5 and 10 (p

The long-term outcome of patients with haematological malignancies treated with reduced-intensity conditioned allogeneic peripheral blood stem cell transplantation is not known. We report the outcome of 79 patients with poor-risk myeloid and lymphoid malignancies transplanted with reduced-intensity conditioning (RIC) regimens. The diagnoses include AML/myelodysplastic syndrome (n=43), non Hodgkin's lymphoma (n=30), Hodgkin's lymphoma (n=3), ALL (n=2) and CML (n=1). For the entire cohort, the disease-free survival (DFS) and OS were 61.2 and 35.7%, respectively. Twenty patients relapsed, 18 within the first three years, and 14 patients succumbed to progressive disease. Overall, 31 patients died from transplant-related complications within the first three years. Day 100 non-relapse mortality correlated with a higher total nucleated cell dose in the graft (odds ratio: 3.9). For those in CR at 3 years, the DFS and OS were 84.2 and 81.1%, respectively. Furthermore, of 43 patients with active disease at the time of transplantation, 16 remained in CR after 3 years. The majority of the long-term survivors were functioning independently. One patient died from a second malignancy. No post-transplant lymphoproliferative disorder was seen. In conclusion, durable disease control was achieved after RIC allogeneic stem cell transplantation for patients with advanced myeloid and lymphoid malignancies.

Phosphoinositide signaling regulates diverse cellular functions. Phosphoinositide-3 kinase (PI3K) generates PtdIns(3,4,5)P3 and PtdIns(3,4)P2, leading to the activation of proliferative and anti-apoptotic signaling pathways. Termination of phosphoinositide signaling requires hydrolysis of inositol ring phosphate groups through the actions of PtdIns(3,4,5)P3 3-phosphatase (PTEN), PtdIns(3,4,5)P3 5-phosphatases (eg, SHIP), and PtdIns(3,4)P2 4-phosphatases (eg, INPP4B). The biological relevance of most of these phosphoinositide phosphatases in acute myeloid leukemia (AML) remains poorly understood. Mass spectrometry-based gene expression profiling of 3-, 4- and 5-phosphatases in human AML revealed significant overexpression of INPP4B. Analysis of an expanded panel of 205 AML cases at diagnosis revealed INPP4B overexpression in association with reduced responses to chemotherapy, early relapse, and poor overall survival, independent of other risk factors. Ectopic overexpression of INPP4B conferred leukemic resistance to cytosine arabinoside (ara-C), daunorubicin, and etoposide. Expression of a phosphatase inert variant (INPP4B C842A) failed to abrogate resistance of AML cells to chemotherapy in vitro or in vivo. In contrast, targeted suppression of endogenously overexpressed INPP4B by RNA interference sensitized AML cell lines and primary AML to chemotherapy. These findings demonstrate a previously unsuspected and clinically relevant role for INPP4B gain of function as a mediator of chemoresistance and poor survival outcome in AML independent of its phosphoinositide phosphatase function.

Presented in part at the 53rd Annual Meeting of the American Society of Hematology, San Diego, CA, December 10-13, 2011, and the 17th Congress of the European Haematology Association, Amsterdam, June 14-17, 2012. Therapeutic options are limited for elderly patients with acute myeloid leukemia (AML). A phase Ib/II study was undertaken to evaluate the maximum-tolerated dose (MTD) and preliminary efficacy of the pan-histone deacetylase inhibitor panobinostat (LBH589) in combination with azacitidine in patients with AML or high-risk myelodysplastic syndrome (MDS) naïve to intensive chemotherapy. Thirty-nine patients (AML=29, MDS=10) received azacitidine 75 mg/m2 subcutaneously (days 1-5) and oral panobinostat (starting on day 5, thrice weekly for seven doses) in 28-day cycles until toxicity or disease progression. Dose-limiting toxicities during the phase Ib stage were observed in 0/4 patients receiving 10 mg panobinostat, in 1/7 patients (fatigue) receiving 20 mg, in 1/6 patients (fatigue) receiving 30 mg and in 4/5 patients (fatigue, syncope, hyponatremia and somnolence) receiving 40 mg. In phase II, an additional 17 patients received panobinostat at a MTD of 30 mg. The overall response rate (ORR=CR+CRi+PR) in patients with AML was 31% (9/29) and that in patients with MDS was 50% (5/10). After a median follow-up of 13 months, the median overall survival was 8 and 16 months in patients with AML and MDS, respectively. Increased histone H3 and H4 acetylation was a useful early biomarker of clinical response. Combining panobinostat with azacitidine was tolerable and clinically active in high-risk MDS/AML patients, warranting further exploration. Refereed/Peer-reviewed

Improved therapeutic options for relapsing patients with acute myeloid leukemia (AML) are urgently needed. Poor outcomes following salvage therapy have been reported in those with short initial remission duration, adverse risk karyotype, prior allograft, older age, FLT3-internal tandem duplication (ITD) AML and prior high-dose cytarabine (HiDAC) induction therapy. We present a cohort of 58 patients (aged 18-70) treated with fludarabine, cytarabine, granulocyte-colony stimulating factor (G-CSF) and amsacrine (FLAG-amsacrine) as salvage chemotherapy for AML at first relapse. 83% had received prior HiDAC-based therapy. The overall complete remission (CR/CR with incomplete blood count recovery [CRi]) rate was 59%, with median event-free survival (EFS) and overall survival (OS) of 6.9 and 10.6 months, respectively. FLAG-amsacrine was an effective bridge to allogeneic transplant with 38% successfully transplanted with excellent outcomes (median OS not reached). FLAG-amsacrine was also effective in elderly patients (≥ 60 years), with 61% achieving second remission. The regimen was well tolerated, with 30- and 42-day treatment-related mortality of 3.4% and 13.8%, respectively. Outcomes remained poor in those with short initial remission duration (

Neurologic relapse of systemic diffuse large B-cell lymphoma (DLBCL) is associated with poor outcome. The existing literature about this specific entity is very limited. We present a retrospective analysis of patients with neurological relapse of DLBCL and correlate the outcome according to the disease stage at autologous stem cell transplantation (ASCT) and the cell of origin phenotype. Totally, 11 patients with neurologic relapse of DLBCL underwent ASCT, seven in complete remission (CR) and four with active disease. The conditioning regimens included LACE (six), BEAM (two), and Bu/Mel (three). Ten patients relapsed after ASCT. All patients with CNS relapse died of progressive disease. Patients with systemic relapse were salvaged by further treatment. The median disease free survival (DFS) and overall survival (OS) for patients in CR at ASCT is far superior than those with active disease at ASCT (24 and 33 months versus 3 and 5 months, respectively). For patients undergoing ASCT in CR, the germinal centre (GC) phenotype is associated with a superior DFS and OS as compared to non GC phenotype (36 and 40 months versus 3.5 months and 5 months, respectively). Patients with neurological relapse of DLBCL have a poor outcome after ASCT; the outcome is worse for patients with non-GC phenotype irrespective of the disease stage at ASCT.

Disease relapse is a major cause of treatment failure after reduced-intensity allografts and while donor lymphocyte infusions (DLIs) can be effective salvage therapy they are associated with severe graft-versus-host disease (GVHD) when administered early after transplantation. We have therefore examined whether imatinib mesylate can delay relapse and postpone the requirement for DLI in 22 patients with chronic myeloid leukemia (CML) allografted using a reduced-intensity regimen. Imatinib was commenced on day + 35 and continued until 1 year after transplantation. Posttransplantation imatinib was well tolerated and abolished the risk of relapse during this period. Twenty-one patients completed 11 months of imatinib therapy, 15 of whom subsequently relapsed and received DLI. Ten patients to date have achieved molecular remission after DLI. Adjunctive targeted therapy allows the kinetics of disease relapse after a reduced-intensity allograft to be manipulated and represents a novel strategy by which outcome may be improved in patients who undergo transplantation for CML and other leukemias.

Background/Aim: Despite recent advances in the management of ALL, alloHSCT remains standard of care for younger adults with high-risk features. The optimum conditioning regimen for adults is not yet established. There is evidence for usage of Etoposide or higher-dose TBI in advanced disease transplants for ALL in a mixture of adult and paediatric patients (Marks et al, Biol BMT, 2006) We undertook a retrospective analysis of adult ALL patients who underwent allogeneic stem cell transplantation at our centre to find out factors influencing outcome and early treatment related complications. We also compared between Cyclophosphosphamide and Total Body Irradiation (Cy/TBI) and Etoposide and Total Body Irradiation (Etop/TBI). Method: Patients were identified from a transplant database search from January 2000 to May 2015 at the Alfred Hospital Melbourne, Australia. Decision to transplant the patients were based on high risk factors such as adverse cytogenetics (Ph+, MLL, complex karyotype), high presenting WBC count, delayed blast clearance with induction treatment and relapsed and refractory disease. Patients were compared based on transplant conditioning, disease factors and analysed for disease outcomes and complications. We also stratified the patients based on EBMT risk score and investigated the applicability of the score to predict outcome. High EBMT score was defined as >3. Results: 69 patients identified (34 Cy/TBI, 35 Etop/TBI) with median age of 33 years (range 17 - 59 years). Age was comparable for each group (Cy/TBI 35 years, Etop/TBI 31 years, p=0.84). 52 patients were males. The diagnoses were B ALL(49),T ALL(15), Bilineage Leukemia(1) and ambiguous lineage leukemia(1). 27 sibling and 42 non-sibling transplants, similar proportion for each conditioning (p=0.14). T-cell depletion with antithymocytic globulin used in 43 cases (all non-sibling and 1 sibling). High EBMT scores seen in 22 patients, with significantly higher numbers in Cy/TBI group (47% vs. 17%, p=0.01). 43 transplants done in CR1, 8 in CR2 and 18 in active-disease. There were significantly higher non-CR transplants in the Cy/TBI group (55% vs. 20%,p=0.003). Stem cell source was bone marrow in 10 patients (6 in CyTBI, 4 in Etop/TBI, p=0.5). 18 patients developed grade 3-4 acute GVHD and 13 of them were from Etop/TBI group (p=0.09). 28 patients developed extensive chronic GVHD and 20 of them received Etop/TBI conditioning(p=0.006). TRM was similar in both groups (38% vs. 31%, p=0.62). TRM was lower in patients transplanted in CR1 versus non-CR1 (25% vs. 50%, p=0.04). Median overall survival (OS) was 263 days in the Cy/TBI group versus not reached in the Etop/TBI group (p=0.08). In patients transplanted in CR1, OS was similar (NR, p=0.59) with a predicted 3-year OS of 77% and 62% in Cy/TBI and Etop/TBI groups respectively. OS was superior in CR1 transplants compared to the rest (NR vs 174 days, p Discussion: Outcomes for allogeneic stem cell transplant are similar for Cy/TBI and Etop/TBI for transplants performed in first remission, with equivalent outcomes for sibling and unrelated donor transplants. The rates of chronic graft vs. host disease are higher in Etop/TBI conditioned transplants. The EBMT score was highly predictive of outcome in ALL transplants, with high transplant related and disease related mortality. While long-term survivors are seen with Etop/TBI conditioning in non-CR1 transplants, the outcome in this patient group are very poor, highlighting the need for better prediction of relapse risk to aid appropriate patient selection for allografts in CR1. Figure 1. Figure 1. Figure 2. Figure 2. Figure 3. Figure 3. Disclosures Wei: Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: 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; Abbvie: Membership on an entity's Board of Directors or advisory committees, Research Funding; Agios: Membership on an entity's Board of Directors or advisory committees; Astra Zeneca: Membership on an entity's Board of Directors or advisory committees; Bayer: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees.

Persistent aplasia is a rarely reported complication after intensive chemotherapy for AML and is associated with high morbidity and mortality. A small number of reports have treated persistent aplasia after chemotherapy for AML with allogeneic haematopoietic SCT (HSCT).1 In the current report, we describe a case of invasive fungal infection (IFI) necessitating simultaneous pneumonectomy and allogeneic HSCT as a result of severe iatrogenic aplasia.

Acute myeloid leukaemia (AML) is an aggressive blood cancer that is usually fatal within weeks without effective therapy. Treatment currently involves standard chemotherapy agents such as cytarabine (Ara-C) and anthracyclines but these drugs fail to elicit complete clinical responses in 20-30% of cases. An understanding of the mechanisms in AML mediating resistance to chemotherapy may uncover new oncoproteins amenable to medicinal targeting. Activation of the phosphoinositide 3-kinase (PI3-K)/AKT pathway is prevalent in AML and linked to chemotherapy failure and poor outcomes. Homeostatic regulation of PI3K activity is orchestrated by a triad of lipid phosphatases, categorized functionally as 3-, 4-, or 5-phosphoinositide phosphatases (PIPs). We screened for pathological expression of 3-, 4-, or 5-PIPs in AML using a quantitative multiplexed MassArray platform (Sequenom®) and found marked overexpression of inositol polyphosphate 4-phosphatase II (INPP4B) in a subset of primary AMLs compared to normal bone marrow. Immunohistochemical staining of 120 primary AML bone marrow samples showed INPP4B was overexpressed (>20% blasts positive) in 16% of cases. INPP4B overexpression was associated with an inferior complete response rate to intensive chemotherapy (33%), compared to AMLs low (5-20%; CR 66%) or negative ( Citation Format: Sewa Rijal, Nhu-Y Nugyen, Tse-Chieh Teh, Natalie K. Rynkiewicz, Nik Cummings, Lisa Ooms, Sharon Avery, Julie Mcmanus, Mark A. Guthridge, Catriona Mclean, Christina A. Mitchell*, Andrew Wei*. Elucidating a novel role for inositol polyphosphate 4-phosphatase type II (INPP4B) in mediating chemoresistance in acute myeloid leukemia. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5283. doi:10.1158/1538-7445.AM2014-5283

Multiple myeloma (MM) remains incurable despite widespread deployment of novel agents and high-dose melphalan/autologous stem cell transplantation (ASCT) earlier in the disease course.1 Recently, non-myeloablative (NMA) allogeneic stem cell transplantation (allo SCT) has been introduced in an attempt to exploit the well-documented graft-versus-myeloma effect (GVM), while at the same time reducing the prohibitively high transplant-related-mortality (TRM) associated with myeloablative allografting in the past.2 This approach, however, still results in significant rates of acute and chronic graft-versus-host disease (GVHD) and has limited cytoreductive capability. The sequential use of a cytoreductive and immunosuppressive ASCT followed by a NMA allo SCT (auto-allo SCT), with the aim of reducing TRM and optimizing tumur control through a GVM effect, has been explored by a number of groups and compared prospectively with tandem ASCT. Although this represents a promising approach, a recent meta-analysis of six biological assignment trials of almost 1200 patients found outcome data to be inconsistent because of the various conditioning regimens used, and any improvements in progression-free survival (PFS) and overall survival (OS) are frequently offset by the high allo SCT-associated TRM.3 We report our single-institution experience of delivering auto-allo SCT for MM in the ambulatory setting, associated with limited toxicity, a low TRM and minimal resource utilization. From May 2008 to December 2012, 33 patients with a diagnosis of MM underwent an auto-allo SCT at the Alfred Hospital. Patients were considered for auto-allo SCT if they were VGPR 83% versus 46% P=0.03) and PFS (median not reached versus 1.2 years; P=0.03) compared with those patients undergoing the procedure at first progression or relapse. Relapse and progressive disease continue to be the principle cause of treatment failure and death in patients receiving tandem auto-allo SCT for MM. In line with previous reports, we observed significant disease responses to immunotherapy post allograft; 5 of our 12 relapsing patients responded to escalating doses of donor lymphocytes either alone or in combination with other agents. Novel agents, in particular bortezomib and lenalidomide, have well documented potent synergistic activity with alloreactive T cells post allograft and may provide a platform for enhancing tumor control post allograft, particularly in those patients with high-risk disease in CR or with minimal residual disease on flow cytometry or PCR.7, 8 The feasibility of this approach in post allo SCT relapse patients has been explored recently by two groups, where the introduction of lenalidomide following NMA allo SCT resulted in responses in over a third of patients, often however at the expense of acute GVHD.9, 10 Balancing the potential to achieve disease control with lenalidomide in this setting against the risk of inducing or exacerbating acute GVHD remains a challenge. In conclusion, our single-centre experience with tandem auto-allo SCT, using outpatient Flu/TBI conditioning, yields durable disease control in over 60% of patients with a highly acceptable TRM when compared with a salvage ASCT.11 The low toxicity of the procedure enabled the majority of patients to be managed as outpatients and to benefit from the curative potential of allo SCT with minimal inconvenience. Given the low morbidity, mortality and ambulatory nature of auto-allo SCT in our hands, one may argue that there should be less reluctance to offer this procedure as part of initial therapy in young patients with MM or patients with high-risk disease in whom long-term disease control is unlikely to be achieved with available or emerging pharmacotherapeutic approaches.

Aim/Background Reduced intensity/non-myeloablative allogeneic haemopoietic stem cell transplantation (allo HSCT) for myeloma following a myeloablative autologous stem cell transplant (ASCT), is associated with lower TRM rates than myeloablative allografting and has the potential to induce long term disease control through the well documented graft-versus-myeloma effect. Continuing attempts to reduce the procedure-related toxicity as well as resource utilisation are likely to result in the use of curative tandem auto-allo earlier in the disease course. We retrospectively reviewed the outcomes of 33 outpatient tandem autologous/non-myeloblative (NMA) conditioning allo HSCT referred to our institution. Methods Between May 2008 and December 2012, 33 patients were referred for tandem auto-allo procedures. Patients were transplanted either upfront (n=18) as part of their initial management or as a deferred procedure (n=15), usually as salvage following an initial autograft followed by maintenance/consolidation. Patients were transplanted upfront if they had one or more of the following high risk features: t(4;14) or t(14;16) translocations, 1q amplification, 1p and 17p deletion on cytogenetics/FISH; elevated LDH; stage III ISS disease or less than a PR with a novel agent-containing induction regimen. Patients were eligible for tandem auto-allo if they had achieved at least a PR to the latest therapy, had no significant co-morbidity and were less than 70 years of age. All autografts were conditioned with melphalan 200mg/m2 and an outpatient NMA allo HSCT timed to occur 3 months later using oral fludarabine 48mg/m2 on days -4 to -2 and 2Gy TBI on day 0 as conditioning. A target cell dose of 2 x 106/kg CD34+ donor stem cells were infused on day 0. Graft versus host disease prophylaxis consisted of cyclosporine and mycophenolate mofetil. Results The median age for the entire cohort was 52 (range 39-65), 19 males and 15 females and the median follow up was 719 days (50-1733). The overall response rate post-allo HSCT was 26/33 (79%) with a significantly higher proportion of CR/VGPRs seen in those transplanted upfront rather than deferred (15/18 v 7/15; p=0.03). The majority of patients were transplanted as outpatients (29/33) and only 4 were admitted for social reasons. Transplant complications requiring admission in the first 30 days occurred in 15/33 (45%) of patients, with a median length of stay of 1.5 days, and only 4 patients were hospitalised for more than 7 days. Median nadir neutrophil and platelet counts were 0.5 x 109/L (range 0.1-1.1) and 94 x 109/L ( range 23-143) respectively across the entire cohort and no patient experienced graft failure. Acute GVHD occurred in 14 (44%) of patients, was mild in the majority of cases and only 3 (9%) developing severe GII-IV aGVHD. Manageable chronic GVHD occurred in 19/31 (61%) evaluable patients, there were no transplant-related deaths by day 100 and 2 patients died of infection (microbiologically-unconfirmed sepsis at day 240 and disseminated nocardia infection at day 1025), resulting in a TRM of 6%. At the time of analysis, 26 (79%) patients were alive including 15 (45%) in ongoing CR. The median OS for the entire cohort has not been reached and the median PFS for all patients is 2.8years. Patients allografted upfront had significantly longer PFS compared to those recipients of a deferred transplant procedure (median NR versus 1.2 years respectively; p=0.03) but there was no significant difference in OS at 2 years follow up. Conclusion Tandem autologous/NMA allo HSCT for myeloma, when performed in the ambulatory setting, is feasible, well tolerated and associated with minimal toxicity and low TRM. Our results with outpatient tandem auto-allo compare favourably with ASCT and suggests allo HSCT may benefit selected patients earlier in their disease course. Disclosures: Spencer: Celgene: Honoraria, Membership on an entity’s Board of Directors or advisory committees.

Background Chimerism analysis is routinely performed following allogeneic haemopoietic stem cell transplantation (allo HSCT) as a means of monitoring donor engraftment and relapse risk, although its role in the management of allografted myeloma patients is controversial. Multiparameter flow cytometry (MFC) assessment of minimal residual disease has been demonstrated to predict outcome following myeloblative autologous stem cell transplantation (ASCT) in multiple myeloma (MM). Relapse and disease progression is the principle cause of allograft failure and the detection of minimal residual disease (MRD) following tandem autologous/non-myeloablative(NMA) allo HSCT may potentially identify patients at risk of early relapse and provide a platform for early post-allograft therapy designed to further cytoreduce or enhance alloreactive T cell function and graft versus myeloma effect. Aim To evaluate the impact of MRD assessment performed at 3 months post-allo HSCT on PFS and OS and document the incidence and kinetics of full donor chimerism (FDC) in a cohort of myeloma patients undergoing tandem ASCT/outpatient non-myeloablative (NMA) allogeneic HSCT for MM. Methods Retrospective analysis of 33 MM patients referred to our centre for tandem ASCT/outpatient NMA HSCT between May 2008 and December 2012. Patients were transplanted as part of their front line management (upfront) (n=18) if they had one or more high risk disease features (poor prognosis cytogenetics/FISH abnormalities, elevated LDH, stage III disease or less than a PR following a novel agent-containing induction regimen) or as a ‘deferred’ procedure (n=15), if relapsing/progressing after an initial ASCT and maintenance/consolidation. Allo HSCT was undertaken as an ambulatory procedure and conditioned with oral fludarabine 48mg/m2 on days -4 to -2 and 2Gy TBI on day 0 followed by donor stem cell infusion, with a target CD34 dose of 2 x 106/kg and T cell dose of 3 x 108/kg. Sequential peripheral blood monitoring of CD3+ and CD33+ donor-specific chimerism was performed on days 30, 60, 90, 180 and 365 following allo HSCT. Bone marrow samples were collected for MRD analysis using MFC incorporating a CD56/CD19/CD45 panel following CD38/CD138 gating on plasma cells. MRD assessment was performed every 3 months during the first 12 months, 6 monthly during the second year and annually thereafter. Results The median age for the entire cohort (M 19, F 14) was 52 years (range 39-65) and the analysis performed after a median follow up of 719 days (50-1733). All patients were transplanted using matched sibling (20/33) or unrelated donors (13/33). Non-relapse mortality was 0% at 1 year and 6% overall. At the time of analysis, 26 (79%) patients were alive including 15 (45%) in CR. The median PFS for all patients was 2.8 years and although the median OS for the entire cohort has not been reached, the estimated probability of overall survival at 4 years is 67% (95% CI: 38-85%). 29/33 (88%) patients had MRD assessments performed at least once post-allo HSCT and 4 patients progressed within 3 months prior to MRD evaluation. At the first 3 month assessment, 11/29 (38%) were MRD +, 12/29 (41%) were MRD – , results were unavailable in 3/29 (10.5%) and 3 (10.5%) patients had morphological evidence of disease. Patients achieving MRD negativity at 3 months had superior PFS in comparison to those who remained MRD positive (median 2.81 years v 1.02 years; p=0.01) but this has yet to translate into an OS advantage. The MRD + patients transplanted as a deferred procedure (n=6) had a median PFS of less than 6 months (0.47 years), suggesting this subset of patients have a particularly poor outcome, although overall numbers are insufficient to directly compare outcome according to MRD status and transplant timing. 30 (91%) patients achieved FDC (16 and 14 in the upfront and deferred groups respectively) with 2 patients not assessed. The median time to FDC for the entire cohort was 180 days (range 30-730) and there was no significant difference according to transplant timing or relationship between FDC and MRD status, GVHD, PFS or PS. Conclusion The majority of patients undergoing outpatient-based tandem ASCT/NMA allo HSCT for myeloma achieve FDC. MRD status as assessed by MFC at 3 months post-allo HSCT appears to predict PFS and may be a useful early trigger for additional post-allograft therapy, particularly in patients with high risk disease or those transplanted later in their disease course. Disclosures: Spencer: Celgene: Honoraria, Membership on an entity’s Board of Directors or advisory committees.

Abstract 3625 Background: Despite achieving remission after intensive chemotherapy for AML, the majority of patients will relapse. Maintenance therapy is an attractive option, with the goal of eradicating residual disease and prolonging disease remission. The hypomethylating agent azacitidine and the immunomodulatory drug lenalidomide have been shown to be active in high risk MDS, especially in combination (Sekeres et al, Journal of Clinical Oncology 2010; 2253). Azacitidine maintenance therapy has been examined after intensive induction chemotherapy for high risk MDS and MDS progressing to AML (Grövdal et al, British Journ of Haem 2010; 293). In this study, an azacitidine dose of 75 mg/m2 resulted in excessive neutropenic toxicity. An amended dose of azacitidine 60 mg/m2 for 5 days each cycle was found to be deliverable, with acceptable hematopoietic toxicity. The goal of this study was to determine the optimal maintenance dosing schedule of azacitidine in combination with lenalidomide after intensive chemotherapy for AML in complete remission (CR) and a high risk of relapse. Methods: A phase Ib/II open label dose escalation study enrolled patients with high risk AML in CR/CRi and high risk features (age > 60, adverse risk karyotype, FLT3-ITD+ or CR2). Patients were treated with azacitidine subcutaneously on days 1–5 of each 28-day cycle combined with lenalidomide orally on days 5–25 for a maximum of 12 cycles. A 3×3 dose escalation schema to identify the maximum tolerated dose was conducted. Cohort A (Table 1) assessed the safety of azacitidine 50 mg/m2 alone. Cohorts B-H planned to investigate azacitidine 50–75 mg/m2 in combination with lenalidomide 5–25mg. Results: We report herein the analysis of the first 16 patients (M 8, F 8), median age 65 years (43–73) recruited to the study. Patients were at high-risk for relapse, based on age >60 years (n=11), CR2 (n=3), adverse risk karyotype (n=1) or FLT3-ITD+ (n=1). Neutrophil (Figure 1) and platelet (Figure 2) toxicity was modest during cycle 1. A summary of outcomes is shown in table 1. After a median follow-up of 301 days, 6/16 patients have relapsed with a median relapse-free survival (RFS) of 219 days (17–546) and median overall survival (OS) of 443 days (86–546). Dose-escalation is ongoing. Conclusion: The combination of azacitidine with lenalidomide as maintenance therapy after intensive chemotherapy for high-risk AML is well tolerated. The clinical efficacy of this regimen and the maximum tolerated dose remains to be determined. Disclosures: Wei: Celgene: Honoraria, Research Funding. Schwarer:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen-Cilag: Honoraria; Hospira: Membership on an entity's Board of Directors or advisory committees. Harrison:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Tam:Celgene: Honoraria.

Abstract 3301 Background Although the demethylating agent azacitidine has an established role in myelodysplastic syndromes and encouraging activity in oligoblastic acute myeloid leukemia (AML), information regarding its role in relapsed and refractory AML is still emerging. The French ATU reported an overall response rate (ORR; CR/CRi+PR) in relapsed and refractory AML of 11% (Itzykson et al. ASH 2009 #1054). In a similar population, azacitidine salvage therapy produced a CR/CRi rate of 19% (Ayari S, et al. ASH 2009 #2044). Rapamycin, an inhibitor of the AKT downstream target mammalian Target Of Rapamycin (mTOR), is reported to specifically target leukemic stem cells and orally bioavailable rapamycin derivatives, such as everolimus (RAD001), are in active clinical development. Clinical responses with single agent everolimus in relapsed, refractory AML, however, have been modest (Yee et al, Clin Cancer Research 2006 and Boehm et al, European Journal of Internal Medicine 2009). Aim Building on our experience combining everolimus with low dose cytarabine (submitted to ASH, 2010), we have sought to investigate the feasibility and preliminary efficacy of combining everolimus with azacitidine in relapsed and refractory AML. Methods Phase Ib/II open label dose escalation study. Patients were treated with azacitidine 75 mg/m2 s.c. daily on days 1–5 and 8–9 of each 28-day cycle with either 2.5, 5 or 10 mg everolimus orally on days 5–21 for a maximum of 12 cycles. Results This preliminary analysis includes 20 patients (M 14, F 6), median age 64 years (range 17–76) receiving 2.5 mg (n=6), 5 mg (n=12) or 10 mg (n=2) everolimus. 9 (45%) had chemotherapy refractory and 11 (55%) relapsed AML after 1 (n=8), 2 (n=10) or 3 (n=2) previous lines of therapy. 7/17 (41%) had poor risk and 10/17 (59%) intermediate risk cytogenetics. 6/19 (32%) had secondary AML. The overall response rate (ORR) in 14 evaluable patients was 36% (2 CR, 3 PR). Stable disease (SD) was observed in 7 (50%) patients and 2 (14%) had progressive disease. Absolute bone marrow blast reductions from baseline in the 5 responders ranged from 9 to 88% (Figure 1). Grade 3/4 non-hematologic toxicities are summarized as follows: 2.5 mg everolimus cohort- septicemia (n=1) and mucositis (n=1, dose limiting toxicity; DLT), 5 mg everolimus cohort- septic arthritis (n=1, DLT). Febrile neutropenia during the first cycle of therapy was reported in 5/20 (25%). Safety analysis in the 10 mg everolimus cohort is ongoing. With a median follow up of 82 days, 30 day mortality was 0%. Enrolment continues to a planned 40 patients. Of interest, 2 out of 3 patients with FLT3-ITD+ AML refractory to high-dose cytarabine and antracyclines, had a striking reduction in bone marrow blasts after commencing azacitidine + everolimus (2.5 mg) therapy, with the absolute blast count falling from 95% to 16% and 92% to 5%, respectively, and lasting for at least 5 months in both. One of these patients has so far proceeded to allogeneic stem cell transplant (allo-SCT). Another patient with 3rd relapse of AML after failing allo-SCT, achieved CR after 3 cycles of treatment with azacitidine + everolimus (2.5 mg) and remains in CR after 157 days. Conclusion In relapsed and refractory AML, azacitidine in combination with the mTOR inhibitor everolimus was well tolerated and demonstrates substantial clinical activity in this advanced AML population. Further evaluation of this promising combination is ongoing. Disclosures: Wei: Novartis: Advisory board, Research Funding; Celgene: Research Funding. Off Label Use: AML therapy. Catalano:Celgene: Research Funding; Roche: Honoraria, Research Funding, Travel Grants.

Abstract 3299 Background Pre-clinical studies suggest that mammalian target of rapamycin (mTOR) is important for leukemic stem cell proliferation and self-renewal. Rapamycin produces short-lived leukocyte reductions in advanced AML (Boehm et al, Euro J. of Int. Med 2009). Everolimus (RAD001) is an orally available ester derivative of the macrolide antifungal antibiotic sirolimus (rapamycin). As a single agent, everolimus is tolerated at a daily dose of 10 mg daily and demonstrates modest clinical activity in myelodysplastic syndrome (Yee et al, Clin Cancer Res 2006). Rapamycin synergistically kills AML cells when combined with cytarabine in vitro (Janus et al, Anti-Cancer Drugs 2009). Aim To determine the safety and preliminary efficacy of everolimus in combination with low dose cytarabine (LDAC) in untreated, elderly AML unfit for intensive chemotherapy. Methods Phase Ib open label dose escalation study. Patients were treated with LDAC 20 mg s.c. twice daily on days 1–10 of each 28-day cycle for a maximum of 4 cycles and either 2.5, 5 or 10 mg everolimus per orally daily on days 1–28 for a maximum of 12 cycles. 8 patients were treated at each everolimus dose level. Results 24 patients (M 14, F 10), median age 74 years (range 62–86), were included in the study. 71% had at least one poor risk factor defined by age >75 (33%), ECOG>2 (13%), secondary AML (38%) or adverse risk cytogenetics (25%). During cycle 1, grade 4 thrombocytopenia occurred in 58% and grade 4 neutropenia in 67%. Grade 3/4 non-hematologic toxicity occurred in 6 (25%) patients; 2.5 mg everolimus (n=1; flare leucocytosis), 5 mg everolimus (n=1; peripheral edema) and 10 mg everolimus (n=4; cough, mouth ulcers and septicemia-2). The maximum tolerated dose of everolimus was 5 mg in combination with LDAC. The most frequently delivered dose of everolimus was 2.5 mg (46 cycles), compared to 5 mg (31 cycles) and 10 mg (17 cycles). After 2 cycles, the overall response rate (ORR) was 34% (CR 13%, CRi 4% and PR 17%). Stable disease was observed in 50%, while 4% had progressive disease. ORR was 50%, 13% and 38%, respectively in the 2.5, 5 and 10 mg everolimus cohorts. 30 and 60-day mortality was 8 and 25%, respectively. Median overall survival for the entire cohort was 179 days. One and two-year survival was 29% and 18%, respectively. Median overall survival was superior in responders (not reached) compared to non-responders (142.5 days; p=0.005). There was no significant difference in overall survival between the 3 everolimus dosing cohorts (p=0.9). The median progression free survival was 76 days (range 13–475). Two patients in CR relapsed within 2 to 4 months after ceasing everolimus at 12 months. A stratified analysis was performed comparing elderly unfit AML treated with LDAC on the UK Leukemia Research Fund AML14 study (Burnett et al, Cancer 2007) adjusting for possible imbalances in risk factors. The Wheatley index is a validated score used to define good, standard and poor risk elderly AML groups (Wheatley et al, Brit. J. Haematol. 2009). Patient groups were similar in demographics, with no significant differences by Wheatley risk group (LDAC+everolimus vs LDAC: good 21 vs 10%; standard 25 vs 28%; poor 54 vs 61%; p=0.3). In analyses stratified for Wheatley risk, LDAC + everolimus gave non-significantly better outcomes (HR 0.74, 95% CI 0.46 to 1.19, p=0.2). In poor risk patients, median survival was superior with LDAC + everolimus vs LDAC alone (175 days vs 44 days), and interestingly, survival was not significantly different to poor risk patients treated with intensive chemotherapy (median survival 175 days, p=0.3, Figures 1). Conclusion: In an unfit elderly AML population, everolimus in combination with LDAC followed by everolimus maintenance therapy was tolerable and active, with extended survival observed in those achieving hematologic response. Further evaluation is warranted in randomised trials. Disclosures: Wei: Novartis: Advisory board, Research Funding. Off Label Use: AML. Catalano:Celgene: Research Funding; Roche: Honoraria, Research Funding, Travel Grants.

Optimal management of intercurrent hematological malignancy in patients with HIV, in particular the feasibility of allogeneic peripheral blood stem cell transplantation (PSCT), remains to be defined. We present our experience with allogeneic transplantation in a series of three patients with HIV. The first patient is a 38 yo man with secondary myelodysplasia in transformation to acute myeloid leukemia. He had had no AIDS-defining illnesses, and was maintained on second-line anti-retroviral therapy of Stavudine, Lamivudine and Tenofovir with an undetectable HIV viral load and CD4 count 58 cells/μL. He received a HLA-identical PSCT, conditioned with cyclophosphamide 60 mg/m2 and total body irradiation (TBI) 13.2 Gy in 6 fractions with standard graft-versus host disease (GVHD) and infective prophylaxis. Transplantation was complicated by severe BK-virus associated hemorrhagic cystitis and prolonged neutropenia with sepsis necessitating temporary withdrawal of anti-retrovirals. Engraftment occurred at day 48, and bone marrow aspirate (BMA) confirmed remission. Anti-retroviral therapy was re-introduced 12 months post-transplantation in response to a rising HIV viral load. He subsequently developed progressive renal impairment due to post-transplant glomerulopathy, but had no late infective complications and is otherwise well and in remission 21 months post-transplantation with HIV viral load 150 copies/mL and CD4 count 181 cells/μL. The second patient was a 41 yo man with multiply-relapsed acute myeloid leukemia in third complete remission. He had no AIDS-defining illnesses and was maintained on fifth-line anti-retroviral regimen of Emtricitabine, Tenofovir, and Fosamprenavir with an undetectable viral load and CD4 count 275 cells/μL. He received an HLA-Identical sibling PSCT, conditioned as above, with additional anti-microbial prophylaxis with Entecavir for HBV; Azithromycin for MAC and Ciprofloxacin for a previous Rhodococcal pulmonary infection. Transplantation was complicated by neutropenic sepsis, pericarditis, and grade 2 cutaneous GVHD. Engraftment occurred day 21; BMA confirmed remission. He remained well with no further infective complications until day 67, when he presented with drug resistant Pseudomonal sepsis, multi-organ failure and succumbed day 78. The third patient was a 24 yo man with multiply-relapsed T-cell acute lymphoblastic leukaemia in second complete remission without prior AIDS-defining illnesses, maintained on second-line anti-retroviral regimen of Tenofovir, Ritonavir, and Fosamprenavir, with an undetectable HIV viral load and CD4 count 204 cells/μL. He received an HLA-identical sibling PSCT conditioned with etoposide 60 mg/m2 and TBI 13.2 Gy in 6 fractions, with extended anti-microbial prophylaxis. This was complicated by neutropenic dental infection and grade 2 cutaneous GVHD, treated with steroid therapy. Engraftment occurred day 25; BMA confirmed remission. There were no late complications and he maintained an undetectable HIV viral load and CD4 counts >200 copies/mL. At day 101 he relapsed, was treated with palliative intent, and died day 105. This series illustrates that allogeneic transplantation is a feasible therapeutic modality for high-grade hematological malignancies in carefully selected patients. Careful optimization of HIV control, and preventive management of infective complications and drug toxicity are critical to successful outcomes.

Although essential in the management of AML, there is little information quantitating transfusion requirements for these patients. We evaluated 111 consecutive adults treated for AML, showing that approximately 150 blood donors are required to adequately cater for a single patient's complete therapy with little variation for age, prognostic group or intensity of treatment.