Pre Autologous Stem Cell Transplantation Research Articles

Infectious Complications in the Outpatient and Inpatient Autologous Stem Cell Transplantation Setting for Patients with Multiple Myeloma. Princess Margaret Cancer Center Experience

Background: Autologous stem cell transplant (ASCT) for multiple myeloma (MM) can be feasible and safe in the outpatient setting and has become standard of care at many centers. Limited literature, however, exists on the types of infectious complications, including specific pathogenic isolates and resistance patterns in the outpatient (OP) setting and whether these differ from the inpatient (IP) setting. This creates uncertainty and variation among local treatment guidelines on antibiotic prophylaxis and treatment of infections in the outpatient population.Methods:In this retrospective study, at total of 240 patients who underwent ASCT at our institution from 2015 to 2016 were reviewed. Study objectives included: 1) to describe the types of infections and pathogenic isolates in MM patients during the acute transplant period and 2) compare isolate results between patients undergoing OP vs IP ASCT. We also aimed to assess 30-day post-ASCT all-cause mortality, readmission rates, and incidence of multidrug resistant bacterial infections in each cohort. As per standard transplant protocol at our institution, all patients received ciprofloxacin and fluconazole prophylaxis and standardized initial therapy for febrile neutropenia with piperacillin-tazocin. Daily GCSF support was routinely used starting day +7 for IPs, and on demand only for OPs.Results:Patient, disease and transplant characteristics:Baseline demographics of both OP and IP cohorts are shown in Table 1 (total n=240; 109 OP, 131 IP). As expected, IPs had poorer performance status (KPS<90), more comorbidities (HCT-CI ≥3), more advanced stage MM, had worse pre-transplant renal function, and were more likely to receive Melphalan dose reductions. Median time to engraftment was similar between groups - 12 days for IP and 13 days for OP (range 9-25), with duration of neutropenia <0.5x10^9/L exceeding 7 days in 46% of the cohort. Median length of stay in hospital was 17 days (12-55) for the inpatients. In the OP cohort, 63.9% of patients required readmission to hospital, with median 3-day hospital stay. In total, only 4 (1.7%) patients required ICU admission.Infections in total cohort (OP and IP):Overall, 121 of 240 patients (50.4%) developed febrile neutropenia, with most common causes including: blood stream infection (BSI) (n=35, 29%), pneumonia (n=18, 14.8%) and respiratory virus infections (n=16, 13.2%). Opportunistic infections were uncommon (n=6, 2.5%) with 1 case of invasive aspergillosis and 5 cases of CMV infection.Of the 43 cases of BSI, 33 (76%) were identified as central line associated blood stream infections (CLABSI), 20 (46.5%) due to gram positive and 20 (46.5%) due to gram negative organisms. Multi-drug resistant gram negative organism isolates were observed in 22 patients (51%), including 5 cases of extended spectrum beta lactamase producing bacteria (ESBL; 11.6%), 9 cases of gram negative bacteria carrying inducible AmpC gene (SPICE; 20.1%), and 10 (23%) cases of quinolone resistant gram negative BSI.Comparison of IP vs OP infections:Although the OP cohort were less frail with fewer comorbidities than the IP cohort, they had more episodes of febrile neutropenia (64% vs 51%; p=0.042), worse mucositis (22.0% vs 10.8%, p= 0.021), and more BSI (24.7% vs 12.9% p=0.019). In the multivariable analysis, only OP status (OR 2.4, p=0.03) and baseline ANC<1.5 pre ASCT (OR 6.3, p=0.003) predicted for BSI occurrence.At 18 months, OS was 98.5% and PFS was 68% for all patients, with no difference between IP and OP (p=0.772). PFS was worse in patients with BSI (p=0.0031, HR 8.7), with gram positive infections in particular (p=0.0264, HR 4.9)Conclusions:In our autotransplant experience, blood stream and lung infections are common, with multi-drug resistance a concern. We were surprised to report that patients undergoing outpatient-based transplant had more BSI, presumably central line-related, and that this may impact disease outcomes (PFS). We hypothesize that outpatients may undergo additional line manipulation or inferior line hygiene, suggesting that enhanced patient/staff education on infection control measures should be a focus. In general, though, outpatient ASCT patients had excellent outcomes, with similar engraftment rates, short readmission rates, low ICU usage, as the entire cohort. DisclosuresTiedemann:Novartis: Consultancy; Celgene: Consultancy; Bristol-Myers Squibb: Consultancy; Janssen: Consultancy; Amgen: Consultancy; Takeda: Consultancy; Merck: Consultancy; Roche: Consultancy. Chen:Amgen: Honoraria.

Preliminary Analysis of the Australasian Leukaemia and Lymphoma Group (ALLG) MM17 Trial: Response Adaptive Salvage Treatment with Carfilzomib-Thalidomide-Dexamethasone (KTd) for Newly Diagnosed Transplant Eligible Multiple Myeloma Patients Failing Front-Line Bortezomib-Based Induction Therapy

BackgroundData from the Australian and New Zealand (ANZ) Myeloma and Related Diseases Registry (MRDR) shows that 85% of newly diagnosed multiple myeloma (NDMM) patients (pts) in ANZ are induced with bortezomib(V)-containing therapies, predominantly triplets of V-cyclophosphamide-dexamethasone (VCD). Of these, 15% demonstrate treatment failure - either a sub-optimal response (<partial response [PR]) (SOR) or primary refractoriness (1REF). Published data demonstrate that the outcome for these pts remains poor with short progression free (PFS) and overall survival (OS), thus representing an area of ongoing unmet medical need. The ALLG MM17 trial was designed to evaluate the efficacy of early response adaption with a switch to an intensive salvage strategy built around the triplet of carfilzomib-thalidomide-dexamethasone (KTd) in transplant eligible (TE) NDMM patients failing V-based induction.MethodsMM17 was a multi-centre single arm study sponsored by the ALLG. Eligible pts were TE NDMM undergoing pre-autologous stem cell transplant (ASCT) induction with V-based therapy and demonstrating either SOR (defined as <minimal response [MR] after 2 inductions cycles or <PR after 4 induction cycles) or 1REF (defined as disease progression while on or within 60 days of completing induction therapy). KTd was K56mg/m2 on D1, 2, 8, 9, 15 and 16 of each 28-day cycle (27mg/m2 D1 and 2 of cycle 1); thalidomide 100mg D1-28; and, dexamethasone 40mg on D1, 8, 15, and 22 of each cycle. VTE and anti-viral prophylaxis was as per individual institutional practice. Pts were planned to receive KTd x 4 cycles then undergo disease re-evaluation. Those achieving a stringent complete response (sCR) (defined as a morphologically normal bone marrow [BM] and immunofixation negativity and normalisation of the involved light chain isotype) proceeded to a MEL200 conditioned ASCT. Those with <sCR received a further KTd x 2 cycles, then proceeded to ASCT. Commencing at day 100 post-ASCT pts received a further 2 cycles of KTd and then continued Td to complete a total of 12 months post-ASCT consolidation. Euroflow minimal residual disease (MRD) evaluation was undertaken pre-ASCT, at day 100 post-ASCT, after KTd x 2 consolidation post ASCT and after completion of Td. CD138 enrichment of BM at study entry was assessed for EMC-92 gene signature for disease stratification utilising the Affymetric DX2 platform. Liquid biopsies at study entry were obtained to isolate cell free (cf) DNA for high-sensitivity targeted amplicon sequencing (TAS) for mutational characterisation of the MM at both study entry and relapse. The primary endpoint of the study was the overall response rate (ORR) to pre-ASCT KTd.ResultsFifty pts were recruited from 6 Australian sites between September 2016 and April 2018. EMC92 stratification was successful in 21 pts with 10 (48%) being high-risk and with cfDNA successfully obtained from 49 pts and currently undergoing baseline TAS. Data cut-off date was July 18 2018 with 39 pts evaluable for the primary end-point with the reverse-Kaplan-Meier estimate of the median potential follow-up for survival being 10.9 months (95% CI: 6.0 - 13.1 months). Median age was 50 years (36-71) with 72% males. Disease status at study entry was SOR in 26 (66%) (< MR n = 13, < PR n = 13) and 1REF in 13 (33%). The median number of pre-ASCT KTd cycles was 6 (6 cycles, n = 27 [69%]; 5 cycles, n = 1 [3%], 4 cycles, n = 5 [13%]; ≤ 3 cycles, n = 6 [15%]). Two pts were withdrawn due to treatment related toxicity - pulmonary arterial hypertension (n=1) and acute renal failure (n=1). One pt died of sepsis on treatment and one was withdrawn and subsequently died due to a second primary malignancy. ORR was 72% (95% CI: 56-83%)* - sCR 13%, CR 5%, VGPR 36% and PR 18%. Euroflow confirmed MRD negativity in 36% (14 of 39) of pts pre-ASCT and in 43% (12 of 28) at day 100 post-ASCT. Eight pts have progressed, 7 with highly aggressive extra-medullary disease. Neither median PFS (left panel) nor OS (right panel) have been reached.ConclusionsThis preliminary analysis of the ALLG MM17 trial demonstrates that early response adaptive escalation to KTd results in high response rates, including MRD negativity, in patients failing V-based induction therapy.*95% Credible interval from the posterior distribution. Bayesian updating based on observed data and a minimally informative prior for ORR with a median of 35%. [Display omitted] DisclosuresSpencer:Celgene: Honoraria, Research Funding, Speakers Bureau; Janssen-Cilag: Honoraria, Research Funding, Speakers Bureau; Amgen: Honoraria, Research Funding; BMS: Research Funding; Takeda: Honoraria, Research Funding, Speakers Bureau; STA: Honoraria. Quach:Sanofi Genzyme: Research Funding; Janssen Cilag: Consultancy; Amgen: Consultancy, Research Funding; Celgene: Consultancy, Research Funding. Kalff:Janssen: Honoraria; Amgen: Other: travel to preceptorship; Celgene: Honoraria; Takeda: Honoraria. Bergin:AMGEN: Other: Travel to education meeting; Celgene: Consultancy. Reynolds:Novartis: Equity Ownership, Other: former employee of Novartis AG and holds stock in the company. .

APRIL Is Significantly Elevated at All Stages of Multiple Myeloma (MM) and Interferes with Anti-Bcma Monoclonal Antibody-Mediated Cytolysis, Supporting the Clinical Evaluation of Bion-1301 As a Novel Therapeutic Approach in MM

A proliferation inducing ligand (APRIL) is a natural ligand with higher affinity than BAFF for both B cell maturation antigen (BCMA) and transmembrane activator and CAML interactor (TACI), which are overexpressed on multiple myeloma (MM) cells. APRIL, which is abundantly secreted by myeloma-supporting osteoclasts and macrophages, promotes MM cell progression in vivo and further induces regulatory T cells (Treg) via TACI, but not BCMA, to promote an immunosuppressive MM bone marrow (BM) microenvironment (Blood 2017;130:3066). In preclinical studies, an antagonistic APRIL monoclonal antibody (mAb) significantly inhibited human MM cell growth in SCID-hu mice and abrogated APRIL-induced immunosuppression mediated by Tregs. Here we characterized the ability of BION-1301, a neutralizing APRIL mAb, currently under clinical development in MM (NCT03340883) to overcome protection conferred by APRIL against MM cell lysis induced by the anti-BCMA J6M0 mAb (Blood 2017 130:499).Our studies show that APRIL protects against MM cell lysis induced by J6M0 in the presence of FcR-expressing effector cells (PBMC, monocytes or NK), an effect which is blocked by neutralizing anti-APRIL mAb. APRIL also downregulates J6M0-induced cell membrane CD107a expression on NK cells co-cultured with BCMA-expressing MM cells, which is similarly abrogated by anti-APRIL mAb. Importantly, anti-APRIL mAb also significantly decreases protection conferred by osteoclasts against MM cell lysis induced by J6M0. These data indicate that blocking APRIL with anti-APRIL mAb may enhance BCMA mAb targeted (J6M0)-induced MM cell lysis. Next, using anti-human IgG1 to detect J6M0 binding to MM cell surface BCMA, we found that APRIL in a dose-dependent manner directly competes with J6M0 for binding to BCMA, which was confirmed by ELISA. In addition, APRIL effectively inhibits J6M0 binding to BCMA at 4°C, which argues against APRIL-induced BCMA receptor shedding and/or internalization. In contrast, BAFF affects J6M0 binding to BCMA only at higher concentrations (>1 µg/mL), consistent with > 2-log higher affinity of APRIL vs. BAFF for BCMA.We further assessed APRIL, BAFF, BCMA, and TACI levels in the serum of patients with MM at various stages of disease. Specifically, we used ELISA to measure free APRIL and the ELLA automated immunoassay platform to determine the levels of soluble BAFF, soluble BCMA, and soluble TACI in serum samples from patients with MM (n=193) as well as serum samples from healthy volunteers (HV, n=100). Patient samples included monoclonal gammopathy of undetermined significance (MGUS, n=12), smoldering MM (SMM, n=20), newly diagnosed MM (ND, n=39), post induction pre-autologous stem cell transplant (ASCT, n=55), post-ASCT (n=6), and relapsed refractory MM (RR, n=61). We found that free APRIL levels are significantly increased in serum samples from patients with MM at all stages of disease, when change from baseline levels were compared to those from HVs (post-ASCT: p=0.0003; other groups (MGUS, SMM, ND, pre-ASCT, and RR): p<0.0001). In contrast, average soluble BAFF levels gradually increase with progression of disease from 818.47 pg/mL at MGUS to 1685.50 pg/mL at RR MM. Both soluble BCMA and soluble TACI concentrations are highest in serum from a subset of patients with ND (593550 and 5999.63 pg/mL, respectively) and RR (1088897 and 5050.97 pg/mL, respectively) MM. A detailed analysis of clinical characteristics, treatment and response, as well as measurement of additional cytokines and chemokines is ongoing and will be reported when applicable.Our studies therefore indicate that therapies directed at the APRIL/BCMA and APRIL/TACI axes may simultaneously target MM cells and counteract APRIL-induced immunosuppression, and that combination strategies targeting APRIL with BCMA directed therapy may augment anti-MM activity. Moreover, elevated free APRIL serum levels in MGUS and all stages of MM suggest a role for APRIL in mediating immunosuppression during the development and in the pathogenesis of MM. DisclosuresDulos:Aduro Biotech: Employment. Guelen:Aduro Biotech Europe: Employment. van Zandvoort:Aduro Biotech Europe: Employment. van de Wiel:Aduro Biotech Europe: Employment. van de Crommert:Aduro Biotech Europe: Employment. Lejeune:Aduro Biotech Europe: Employment. Namini:Aduro Biotech: Employment. Eenennaam:Aduro Biotech Europe: Employment, Equity Ownership. van Elsas:Aduro Biotech Europe: Employment. Richardson:Oncopeptides: 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; Janssen: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm: Membership on an entity's Board of Directors or advisory committees; BMS: Research Funding; Jazz Pharmaceuticals: 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. Munshi:OncoPep: Other: Board of director. Anderson:Takeda Millennium: Consultancy; C4 Therapeutics: Equity Ownership; Bristol Myers Squibb: Consultancy; Gilead: Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy; Oncopep: Equity Ownership.

Efficacy and Safety of Melphalan 140mg/m2 Conditioned Autologous Stem Cell Transplantation in Elderly Pre-Dialysis and Dialysis Patients with Multiple Myeloma

Introduction:Information is currently available for the efficacy and safety of autologous stem cell transplantation (ASCT) conditioned with melphalan in multiple myeloma patients with mild to moderate chronic kidney disease. However, little information is available on ASCT in patients with severe renal impairment or those on dialysis with multiple myeloma. This population is usually not considered for ASCT due to a high risk of mortality. One retrospective study provides data on ASCT conditioned mainly with 200mg/m2 melphalan with high treatment related mortality (TRM) at 15%. Here we present safety and efficacy data on dose reduced melphalan (140/m2) conditioned ASCT in patients with severe renal impairment or haemodialysis at the time of transplant with a TRM of 0%.Patients and methods:We identified and report on 10 ASCT procedures carried out on 9 (7 males and 2 females) myeloma patients with a glomerular filtration rate (eGFR) of 35 ml/min/1.73m2 or less between 2006 and 2016. Median age was 58(51-74) years. Five patients were on haemodialysis at diagnosis and 4 went into ASCT while on haemodialysis. Six patients had light chain multiple myeloma. Initial therapy was bortezomib based in 6 patients, with 4 receiving thalidomide and 1 received both thalidomide and bortezomib pre ASCT. Most patients were mobilised with G-CSF alone and only 1 received cyclophosphamide and G-CSF. ASCT was conditioned in all cases with 140mg/m2of Melphalan. Patients on hemofiltration were supported during ASCT as per institutional guidelines. We collected data on response, stem cell collection, engraftment, progression free survival (PFS), overall survival (OS) and treatment related mortality (TRM).Results:Median follow up for the whole group was 24 (6-114) months. Pre ASCT 6 patients were in VGPR and 3 in PR. The median cell dose collected was 6.92×10 6 CD34 cells/kg (range 3.06-8.27). The median time to neutrophil engraftment (absolute neutrophil count>0.5×109/L) and platelet engraftment (>20×109/L) was at day 13 and 15 respectively. The TRM at day+100 was 0%. Post ASCT best responses were as follows-7 patients were in VGPR; 1 in PR and 1 progressed. The median PFS was 24months and median OS was 27 months. At the time of data collection only one person had died. The cause of death was disease progression with refractory disease. One patient became free of haemodialysis pre ASCT, one after ASCT and 1 more dropped frequency of dialysis sessions from 3 to 2 per week.Discussion:Autologous stem cell transplant using low dose Melphalan (140mg/m2) as consolidation post a bortezomib based induction therapy is an effective and safe treatment option for the pre-dialysis and dialysis patients with multiple myeloma. In our hands the TRM is extremely low suggesting the lower dose to be more appropriate than melphalan at 200mg/m2. It provides good PFS and in some cases freedom from haemodialysis. Further prospective trials are needed to confirm these findings. DisclosuresPaneesha:Abvie: Honoraria. Kishore:celgene: Other: travel grant.

Higher Hematopoietic Cell Transplant Comorbidity Index (HCT-CI) Is Associated with Poor Psychosocial Health Pre-Autologous Stem Cell Transplantation (ASCT) in Lymphoma Patients

The assessment of pre-transplant comorbidities is crucial for risk-stratification and is a tool to guide clinical decisions in hematological malignancy patients (pts) undergoing evaluation for stem cell transplantation (SCT). The HCT-CI scale is commonly used to identify high risk patients pre-transplant as it is highly predictive of non-relapse mortality (NRM), severity of graft versus host disease and survival after allogeneic SCT (Sorror et al, Blood 2005; Sorror et al, Blood 2014). However, its role in ASCT remains undefined. In a Center for International Blood and Marrow Transplant Research analysis, HCT-CI score of ≥3 was prognostic for higher NRM and overall mortality in ASCT patients (Sorror et al, Biol. Blood Marrow Transplant 2015), but other single institution studies have failed to confirm this observation in lymphoma patients (Jaglowski et al, Bone Marrow Transplant 2014; Dahi et al, Biol. Blood Marrow Transplant 2014; Hosing et al, Ann. Oncol. 2008). No study has correlated HCT-CI with psychosocial functioning in the setting of ASCT.We conducted a retrospective study of 350 patients with Hodgkin (N=70) and non-Hodgkin Lymphoma (N=280) who underwent ASCT at our institution from January 2009 to June 2015. Based on their HCT-CI score, patients were categorized into low risk (score 0, N=90), intermediate risk (score 1-2, N=123) and high risk (score ≥3, N=137). Psychosocial Assessment of Candidates for Transplantation (PACT) scale (0-4: 0 being poor candidate for procedure and 4 being excellent candidate) (Foster et al. BMT 2009) was used for pre-transplant psychosocial risk assessment and was available for 235 pts. We analyzed the impact of HCT-CI on transplant outcomes and its correlation with PACT scores.Our cohort was predominantly male (63%), and Caucasian (93%) with a median age of 55 years (range 20-78). The majority of the pts (96%) had good performance status with an ECOG of 0-1. The primary diagnosis was NHL in 80%, with mostly advanced stage disease (80%), and no B symptoms (93%). Median time from diagnosis to ASCT was 16 months with 75% of the pts having received ≤2 prior therapies. The median annual income based on zip code was $49406 (range $18753-127312). Disease status prior to transplant was CR/PR in 93% of the subjects. Patient and disease characteristics were comparable among the 3 HCT-CI risk groups. Higher HCT-CI risk category was associated with a lower median household income (p=0.012), higher LDH (p=0.004), more days of apheresis (p=0.026) and lower CD34+ dose x106/kg (0.046). In relation to PACT scores, higher HCT-CI was associated with poor mental health (p<0.001), decreased coping skills (p<0.001), unhealthy lifestyle habits/sedentary life (p<0.001), decreased compliance with medications/medical advice (p=0.014) and inadequate medical/transplant knowledge (p=0.017) and lower final PACT score (p<0.001). Median follow up was 35 months with 100 observed deaths, of which 72 were attributed to relapse. The 5 year estimated relapse rate, NRM, relapse free survival (RFS) and overall survival (OS) in our cohort were 42%, 11%, 49% and 62% respectively. On univariate analysis, there was no significant difference between high vs. low/intermediate HCT-CI scores on 30 day readmission rates (OR 1.24, p=0.61), 100 day mortality (OR 1.12, p=0.86), incidence of secondary malignancy (HR 0.41, p=0.17), relapse rate (HR 0.92, p=0.64), relapse mortality (HR 1.35, p=0.20), NRM (HR 0.86, p=0.71), OS (HR 1.2, p=0.37) or RFS (HR 0.98, p=0.92). Though not statistically significant, the intermediate risk group was noted to have higher 100 day mortality and NRM compared to the low and high risk groups.To our knowledge, this is first study to correlate pre-transplant HCT-CI with PACT scores in lymphoma pts who underwent ASCT. Higher HCT-CI was associated with lower socioeconomic status, poor mental health and coping skills, unhealthy lifestyle habits, decreased medical/transplant knowledge and compliance. HCT-CI did not predict survival in our cohort. Further studies are needed to investigate the association between psychosocial risk factors and HCT-CI and define their combined utility in pre-transplant risk assessment in ASCT patients. [Display omitted] [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Autologous Stem Cell Transplantation for Adult Acute Myelocytic Leukemia in First Remission: Better Outcome Following Busulfan and Melphalan Compared to Busulfan and Cyclophosphamide : A Retrospective Study from the Acute Leukemia Working Party of the EBMT

RationaleAutologous stem cell transplantation for adult acutemyelogenousleukemia (AML) is a therapeutic option for good and intermediate risk patients. New compounds and new formulations in conjunction with pre andpost transplant targeted therapy may improve outcome.A recent EBMT retrospective survey investigating on Busulfan administered IV (Nagler A et al:Haematologica. 2014 ) pre autologous stem cell transplantation (ASCT) suggested that the combination of Busulfan and High dose Melphalan (BUMEL) was associated with the best overall survival. To address this question, we compared this regimen with the historical Busulfanand Cyclophosphamide (BUCY) association.MethodsEligibilitycriteria consistedof all adult patients (age >18 years) with AMLautograftedin CR1, following a preparative regimen consisting of either BUCY or BUMEL, reported to the EBMT registry in the period from January 2005 to December 2013. The doses of Busulfan were either oral at 16 mg/kg over 4 days or IV at 12.8 mg/kg over 4 days. High dose Melphalan was 140mg/m². The data came from 231 centers 23 ofwhich usedboth regimens. The relationships between outcomes and patient, disease and transplant characteristics was evaluated in multivariate analyses using the Cox model.Results1120 patients received BUCY and 436 BUMEL prior to autografting in first remission. Patients receiving BUMEL were older (median 52 years versus 50 years, p=0.01) with less good risk diseases by cytogenetics (16% versus 28%, p=0.001). They were autografted with a longer interval from CR1 to autografting (120 days versus 104 days, p=0.001) and they were more frequently in a negative minimal residual disease (MRD) status by molecular biology (89% versus 82%, p= 0.03).The nature of the pretransplant regimen interacted with the interval from diagnosis to autografting on both relapse incidence (p=0.005) and leukemia free survival (p= 0.02): the outcome post BUMEL was superior to BUCY only in patients transplanted within less than six months post diagnosis. In these patients, following BUMEL and BUCY respectively, the RI was 35%versus 50.6% (p< 10-3), the LFS 61.1% versus 46.2% (p< 10-3) and the OS 79.4% versus 64.8% (p= 0.003). There was no difference for NRM.When considering only patients autografted at the time when MRD detection was negative, the LFS at two years was 75.8% for 134 patients receiving BUMEL and 58.6% in the 371 patients receiving BUCY, with no significant difference (p= 0.1). The major cause of death in the two groups was leukemia recurrence.ConclusionWe conclude that the BUMEL combination pre ASCT in AML CR1 is superior to BUCY when the transplant is performed less than 6 months after diagnosis. These registry data should be confirmed in a well designed two arm study assessing the role of ASCT in good risk and possibly intermediate -1 risk adult patients with AML.TablepHR95% CINRMBUMEL vs BUCY0.4501.3760.5993.16Age atTx/ 10years0.0011.0641.0251.10Time from diagnosis to Transplant.0.9000.9990.9841.01Cytogenetics :Intermediatevs good0.6100.7090.1912.63Poor versus good0.7100.7080.1124.46Missing0.4200.5910.1642.11centre (frailty)0.360RIBUMEL vs BUCY0.0010.6020.4450.816Age at Transplant / 10years0.0051.0121.0031.020Time from diagnosis to Transplant:0.7201.0000.9961.004Cytogenetics : Intermediatevs good0.5101.1450.7641.714Poor versus good0.0311.7991.0553.067Missingversus good0.4801.1500.7791.699centre (frailty)0.110OSBUMEL vs BUCY0.0020.6140.4490.841Age at Transplant / 10years<10-41.0251.0141.036Time from diagnosis toransplant0.940.9990.9951.004Intermediatevs good0.881.0360.6491.653Poor versus good0.111.6320.9012.956Missingversus good0.811.0580.6721.665centre (frailty)0.29LFSBUMEL vs BUCY0.0020.6490.4900.858Age at Transplant / 10years<10-41.0151.0061.023Time from diagnosis to Transplant0.7401.0000.9961.004Cytogenetics : Intermediatevs good0.5901.1100.7551.630Poor vs good0.0461.6791.0082.796Missingversus good0.5901.1060.7631.604centre (frailty)0.170Multivariate analyses of prognostic factors in patients autografted within 6 months [Display omitted] DisclosuresNemet:Celgene: Honoraria; Pliva: Honoraria; Amgen: Honoraria; Sanofi: Honoraria; Pfizer: Honoraria; Janssen: Honoraria. Mohty:Janssen: Honoraria; Celgene: Honoraria. Nagler:Biokine LTD: Consultancy.

A Comparison of the Outcomes of Early Versus Delayed Autologous Stem Cell Transplantation for Multiple Myeloma in the Era of Novel Therapies

Background:In phase 3 studies comparing high dose melphalan (mel) with autologous stem cell transplantation (ASCT) to conventional chemotherapy, ASCT improves progression free survival (PFS) and, in some studies, overall survival (OS). However, these studies were performed before the use of potent, novel induction therapies such as bortezomib (V), lenalidomide (R), and dexamethasone. The optimal timing and benefit of ASCT in the era of novel therapies is unknown.In our program, upon completion of stem cell harvest (SCH), some patients elect to delay ASCT after discussion of risks and benefits. The aim of this retrospective study is to compare the time to progression (TTP) and OS of patients who proceeded to ASCT early as consolidation of initial therapy, versus ASCT delayed until relapse. While data from prospective studies are eagerly awaited, this retrospective study has the advantage of a long follow up.Methods:In this IRB approved, retrospective case series, electronic medical records of all patients with symptomatic MM who had SCH at Saint Vincent's Medical Center or Mount Sinai Hospital between 1/1/2005 to 6/30/2014 were reviewed. Patients were divided into the following groups:Time to progression (TTP) is calculated using Kaplan-Meier analysis. OS is calculated using a landmark analysis at 2 and 3 years after diagnosis.Results:572 consecutive patients were identified. 18 were excluded for incomplete data. Baseline characteristics are shown in Table 1.The groups did not differ significantly in terms of stage (either Durie Salmon or International Staging System), disease isotype, or high risk disease features (defined by cytogenetics or FISH as amp 1q, t(14;16), t(14;20), del 17p13). The median follow-up for the entire group was 47.5 months.Not surprisingly, the median TTP after ASCT diminished with delay of ASCT, from 28.4 mo for early ASCT to 12.2 mo for delayed (p < 0.001). That said, when comparing groups 1 and 2, there was no difference in the median time from diagnosis to progression after mel 200 mg/m2 ASCT Ð 39.1 vs 43.6 mos (p = 0.945). Using landmark analysis starting at 2 years from diagnosis, the median OS was 61.3, 37.4, 18.9, and 116.7 for groups 1, 2, 3, and 4 respectively (p = 0.087 for group 1 vs 2; p < 0.001 for group 1 vs 3; Figure 1). Landmark analysis at 3 years from diagnosis showed median OS of 50.3, 56.5, 13.9, and not reached (p = 0.41 for group 1 vs 2; p < 0.001 for group 1 vs 3).Conclusions:There are three findings of interest. 1) TTP in those who underwent early ASCT was 15 months longer than those who underwent ASCT at relapse. 2) TTP after SCT was comparable in groups 1 and 2, which may be attributable to the preferential use of maintenance chemo either pre or post ASCT, respectively. 3) The rank ordering of median OS by landmark analysis suggests an interplay between therapy and disease biology Ð many patients may do very well without SCT, perhaps due to durable remissions with novel regimens. The remaining groups demonstrate a striking decrease in OS as the number of relapses in a given time period increases, indicating the need for novel approaches to MM that behaves in clinically aggressive manner. [Display omitted] [Display omitted] [Display omitted] DisclosuresBiran:Celgene: Speakers Bureau. Jagannath:Celgene: Honoraria; Merck: Honoraria; Novartis: Honoraria; Janssen: Honoraria; Bristol Myers Squibb: Honoraria. Chari:Onyx: Consultancy, Research Funding; Millennium/Takeda: Consultancy, Research Funding; Biotest: Other: Institutional Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Array Biopharma: Consultancy, Other: Institutional Research Funding, Research Funding; Novartis: Consultancy, Research Funding.

Thrombin Generation and Venous Thromboembolism Among Multiple Myeloma Patients Receiving Lenalidomide and Prednisolone Maintenance Following Autologous Stem Cell Transplantation (ASCT)

BackgroundLenalidomide is effective in the treatment of multiple myeloma (MM) but is associated with an increased risk of venous thromboembolism (VTE). The mechanism underlying this increase risk remains unclear. As routine coagulation tests do not reflect true in vivo coagulation, global coagulation assays such as thrombin generation might be a better surrogate marker of thrombosis risk.AimTo sequentially monitor thrombin generation in myeloma patients receiving lenalidomide and alternate day prednisolone (RAP) maintenance following ASCT and correlating it with objectively confirmed VTE.MethodsThe LEOPARD study was a phase II, open label, single arm, multi-centre study of RAP (lenalidomide 10mg/continuous daily increasing to 15mg after 8 weeks and alternate day prednisolone 50mg) maintenance therapy commencing 6-8 weeks after a single MEL200 ASCT as part of first-line therapy for patients with MM. RAP was continued until toxicity or relapse/progression.Enrolled patients were systematically observed for symptomatic objectively confirmed VTE. Plasma samples were collected and frozen pre-ASCT, post-ASCT prior to commencing RAP maintenance and at six months post ASCT. Thrombin generation (TG) was measured using calibrated automated thrombography (CAT™) following a single thaw, blinded to the clinical outcome following completion of the study.Results28 of 60 patients enrolled in the LEOPARD had available all three predetermined plasma samples for analysis and remained on RAP at 6m post ASCT. Female=14, male=14 with a median age of 61 years (range, 41-71). Of the 60 patients, 44 and 6 patients received low-dose Aspirin and Enoxaparin as thromboprophylaxis post ASCT respectively. Ten patients received no thromboprophylaxis. Overall, 3 out of 60 patients (5%) enrolled had objectively confirmed VTE. Two episodes of symptomatic proximal deep vein thrombosis occurred at 9, and 14 months post ASCT; both patients were in complete remission and remained on RAP. One patient developed symptomatic pulmonary embolism at 14 months post ASCT and was in partial remission.TG as measured by endogenous thrombin generation (ETP) did not differ significantly between pre-ASCT, post-ASCT (pre RAP maintenance) and 6months post ASCT. The mean ETP was 1682nM pre ASCT, 1645nM post ASCT (pre RAP maintenance) and 1537nM 6 months post ASCT. Similarly, there was no significant difference between peak thrombin (PTG) at each of the time points with mean PTG of 376nM pre ASCT, 388nM post ASCT (pre RAP maintenance) and 367nM 6 months post ASCT. Moreover, no apparent difference in TG between the 3 patients who experienced a VTE and the remainder of the cohort was evident (for the 3 VTE patients mean ETP, 1396.8nM pre RAP maintenance and 1385.8 nM 6 months post ASCT; mean peak thrombin is 216.5 pre RAP maintenance and 221.7 6 months post ASCT).ConclusionThe risk for VTE was low in this cohort of MM patients receiving maintenance RAP following ASCT most of whom were receiving pharmacological thromboprohylaxis. This is supported by the findings of no significant difference in TG (both ETP and PTG) at pre-ASCT, post-ASCT (pre RAP maintenance) and 6 months post ASCT. A late accumulative risk for VTE due to RAP cannot be excluded with 3 late episodes of VTE observed. A larger study is needed to confirm these findings. DisclosuresSpencer:Celgene: Consultancy, Honoraria.

Longterm Outcomes and Improved Renal Function with Autologous Stem Cell Transplantation (ASCT) in Light Chain Deposition Disease (LCDD)

Background: Light chain deposition disease (LCDD) is a systemic disorder characterized by monoclonal light chain deposition in organs, most often the kidney but also in the liver, heart and nervous system. Treatment aims to suppress the monoclonal plasma cell population producing the light chains to allow for improvement in or delay deterioration of organ function. Treatments are generally modeled on those for myeloma and light chain amyloidosis. The options are cyclical chemotherapy lately using a novel agent based conditioning regime and, in selected patients, high dose melphalan followed by autologous stem cell transplantation. Due to LCDD being an immunoglobulin disease, based on experience with systemic AL amyloidosis, there is a reluctance to consider ASCT due perceived risks of morbidity and transplant related mortality. There is limited data on the safety and outcomes after ASCT in LCDD. We report here the role of autologous stem cell transplantation to treat LCDD in the largest cohort of patients to date.Methods: This study included all patients between 2003 and 2013 with LCDD who had undergone ASCT from the database of the UK National Amyloidosis Centre (NAC). Data on disease status (clonal markers and organ involvement) at diagnosis, pre and post ASCT was collected from the respective transplant centres for patient progress during and immediately after ASCT. Organ function and clonal response data were serially collected for all patients including clinical course, renal, cardiac and neurological function.Results: A total of ten patients with LCDD were identified who underwent ASCT. This accounted for 23% of all LCDD patients seen at the NAC over this time period. The baseline characteristics were: median age 48 (range 36-60), eGFR 17 ml/min (<10-51), Alkaline phosphatise 92 (51-334), LV wall thickness 10 mm, NT-proBNP 1121 (range 318-4346). Serum monoclonal M protein was quantifiable in 2/10 patients. 9/10 patients had elevated kappa serum free light chains (SFLC) with median level of 1069 mg/dl (range 281-2962) with median κ/λ ratio of 21 (range 0.1-151, NR 0.26-1.65). Only 1/10 had elevated lambda LC. All patients had clonal plasma cells on marrow aspirate with 5/10 patients having >10% (median 15; range 12-50%) and 5/10 , </= 10% (range 2-10%). All patients received chemotherapy prior to ASCT. The median time from diagnosis to ASCT was 13.5 months (Range 4-27). Median follow up post ASCT was 4.8 years (range 6 months-11 years). Haematological responses were seen in all patients with 7/10 acheiving a complete clonal response, 1 patient achieving a VGPR and 2 patients achieving PR. All patients had renal impairment prior to ASCT and 5/10 were on renal dialysis. There was no transplant related mortality and all patients are still alive. After ASCT, 4 patients’ renal function improved, 4/5 remained unchanged on dialysis and 2 patients showed a deterioration in renal function. Of the patients whose renal function improved, one came off dialysis post ASCT, the other three were not on dialysis at any time point. Of the two patients whose renal function deteriorated post ASCT, one required dialysis 3 years after ASCT.Conclusion: This largest study of autologous stem cell transplantation in LCDD to date shows a very high clonal response rate post ASCT. 50% patients had improvement in renal function after transplant. ASCT in LCDD is safe with no transplant related mortality. None of the patients progressed to active myeloma after ASCT. This data supports the use of ASCT in patients with LCDD. Given the rarity of the condition, international registry data would be important to confirm these encouraging findings. DisclosuresNo relevant conflicts of interest to declare.

Induction Of Anti-Myeloma Cellular and Humoral Immunity By Pre-Targeting Clonogenic Myeloma Cells Prior To Stem Cell Transplant With T Cells Armed With Anti-CD3 x Anti-CD20 Bispecific Antibody Leads To Transfer Of Cellular and Humoral Anti-Myeloma Immunity

▪A phase Ib trial was conducted in standard and high risk multiple myeloma (MM) patients to determine whether infusions of anti-CD3 x anti-CD20 bispecific antibody (CD20Bi) armed activated T cells (aATC) prior to autologous stem cell transplant (ASCT) were safe and would induce anti-myeloma (anti-MM) immunity that could be detected after ASCT. We hypothesized that targeting CD20+/CD138- myeloma clonogenic cells with aATC would release “MM antigens” including anti-Sry-HMG-box 2 (SOX-2). Engagement of target cells by aATC also induces release of Th1 cytokines by aATC creating an environment conducive for in situ immunization against MM antigens. Twelve patients received two infusions of 1010 one week apart and within 4 weeks prior to ASCT. Four patients received a 10 x 109 aATC booster infusion between 6 and 18 months after ASCT. There were significant increases in the fraction of patients who developed IFN-g EliSpots directed at CD20+ Daudi lymphoma cells (p<0.06), CD20 negative RPMI 8226 multiple myeloma cells (p<0.02), and K562 natural killer cell targets (p<0.01) from 6 to 12 months after ASCT. Specific cytotoxicity directed at Daudi (p<0.03), K562 (p<0.009), and RPMI 8226 (p<0.02) targets increased significantly after aATC infusions and post ASCT compared to pre infusion baseline cytotoxicity. SOX-2 IgG antibody levels increased above baseline after aATC infusions (p<0.002) and post ASCT (p<0.02) (Fig. 1A). There was no significant difference observed between pre and 1 month post ASCT in anti-SOX-2 levels or between pre and 3 month post ASCT serum samples from control ASCT patients who did not receive IT (Fig. 1B). In order to determine whether there was an association between the level of anti-SOX-2 antibodies and clinical outcome, anti-SOX-2 antibody levels were plotted in patients who progressed and those who did not progress. The box plots show the clear separation between two groups. The median anti-SOX-2 antibody levels at 3 months after ASCT in patients who relapsed was 19.7 ng/ml (25-75%, 8.6 - 40.3) and in patients who remained in remission was 48.1 ng/ml (37.5 - 73.3), these data suggest that anti-SOX-2 levels may predict clinical outcomes (Fig. 1C). There were no dose-limiting toxicities. In summary, aATC infusions pre ASCT induced anti-myeloma IFN-g EliSpot and anti-SOX-2 IgG responses that could be detected at 6-12 months after ASCT and these responses were boosted in 4 of 4 patients after ASCT. Data suggest that infusions of targeted T cells given prior to ASCT could induce cellular and humoral anti-myeloma immunity that could be transferred, detected, and boosted after ASCT. These results have implications for the design of immunotherapy in combination with ASCT. [Display omitted] Disclosures:Lum:Transtarget Inc: Equity Ownership, In situ Immunization Patent, In situ Immunization Patent Patents & Royalties.

Implementing Cybord As First-Line Therapy For Transplant-Eligible Multiple Myeloma Patients : A Single-Center Preliminary Comparaison

IntroductionThe best induction regimen for first-line therapy in multiple myeloma patients who are eliglible for autologous stem cell transplant (ASCT) is still unknown. In 2009, we started to use CyBorD and gradually changed our first-line therapy from Vel-Dex to CyBorD based on published work from Princess Margaret Hospital in Toronto. Here, we describe the first 10 patients to have received CyBorD and compare them to an historical cohort from the same institution. MethodsWe conducted a retrospective review of patient's charts and transplant database from 2009/10/02 to 2013/04/19. We collected information on blood labs, cytogenetics, immunofixation, response rates, adverse events and graft collection. Patients not receiving the anticipated protocol or less than 3 cycles of treatment arm were excluded from this review. ResultsAll patients (100%) in both cohorts received an ASCT (CyBorD, n=10 and Vel-Dex, n=11). The 2 groups were comparable and there was 1 patient in each arm with unfavorable cytogenetics. The response rates pre ASCT were CR = 20%, >VGPR = 90% compared to CR = 0%, >VGPR = 81,8% in CyBorD and Vel-Dex patients respectively. Response rates at 100 days post-ASCT was CR = 60%, >VGPR = 100% compared to CR = 36.4%, >VGPR = 90.9% in CyBorD and Vel-Dex patients respectively. Patients in CyBorD had a median of 1 (1-2) day for graft collection and a median number of graft cells of 5,01 x 109(2,06-6,48) compared to 1 (1-2) and 4,46 x 109 (3-6,82) in the Vel-Dex group. The rate of grade 3/4 thrombocytopenia was 0%(n=0) vs 9%(n=1) in CyborD and Vel-Dex patients respectively. No case of neuropathy grade 3 or 4 was observed in the CyBorD arm. ConclusionCyBorD is an effective and safe induction regimen for first-line therapy in ASCT eligible multiple myeloma patients. It produces less neuropathy and has an easier schedule to administer. It is now our standard protocol for these patients but dexamethasone has been reduced to once weekly for every cycle since then. NBCyBorD (Cyclophosphamide 300 mg/m2 PO days 1,8,15,22; Bortezomib 1,5 mg/m2 SC days 1,8,15,22, Dexamethasone 20 mg PO bid days 1-4, 9-12, 17-20 for cycles 1-2, 20 mg PO bid once weekly for cycles 3-4.) Disclosures:Duquette:Janssen: Consultancy, Honoraria. Off Label Use: CyborD is a widely accepted regimen but has not been accepted by the FDA.

Normalization of pre-ASCT, FDG-PET imaging with second-line, non–cross-resistant, chemotherapy programs improves event-free survival in patients with Hodgkin lymphoma

AbstractWe previously reported that remission duration < 1 year, extranodal disease, and B symptoms before salvage chemotherapy (SLT) can stratify relapsed or refractory Hodgkin lymphoma (HL) patients into favorable and unfavorable cohorts. In addition, pre-autologous stem cell transplant (ASCT) 18FDG-PET response to SLT predicts outcome. This phase 2 study uses both pre-SLT prognostic factors and post-SLT FDG-PET response in a risk-adapted approach to improve PFS after high-dose radio-chemotherapy (HDT) and ASCT. The first SLT uses 2 cycles of ICE in a standard or augmented dose (ICE/aICE), followed by restaging FDG-PET scan. Patients with a negative scan received a transplant. If the FDG-PET scan remained positive, patients received 4 biweekly doses of gemcitabine, vinorelbine, and liposomal doxorubicin. Patients without evidence of disease progression proceeded to HDT/ASCT; those with progressive disease were study failures. At a median follow-up of 51 months, EFS analyzed by intent to treat as well as for transplanted patients is 70% and 79%, respectively. Patients transplanted with negative FDG-PET, pre-HDT/ASCT after 1 or 2 SLT programs, had an EFS of > 80%, versus 28.6% for patients with a positive scan (P < .001). This prospective study provides evidence that the goal of SLT in patients with Hodgkin lymphoma should be a negative FDG-PET scan before HDT/ASCT. The study was registered at www.clinicaltrials.gov as NCT00255723.

The Addition of Rituximab and/or Alpha-Interferon to High Dose Chemotherapy and Autologous Stem Cell Transplantation for Patients with Relapsed Follicular Lymphoma Produces Durable Progression Free Survival and Molecular Remissions

AbstractAbstract 1357 Introduction:High dose chemotherapy (HDT) with autologous stem cell transplantation (ASCT) is historically effective treatment for patients with relapsed follicular lymphoma (FL) but relapse is common possibly due to contaminated stem cell grafts or inadequate eradication of primary disease. The addition of immunotherapy to HDT/ASCT may augment “in vivo” graft purging and achieve more effective eradication of minimal residual disease (MRD) post ASCT. This may lead to improved PFS and OS. Methods:We conducted 3 sequential prospective phase 2 trials of HDT/ASCT combined with immunotherapy in patients with relapsed FL from 1997–2010. Protocol 1 (n=13) used a-interferon 3 MU/m2 SC TIW for 2 years post ASCT. Protocol 2 (n=23) used a single infusion of rituximab (R) 375 mg/m2 for ‘in vivo’ purging 3–5 days pre-stem cell collection and 2 sets of 4 weekly R at 2 and 6 months post ASCT respectively. Protocol 3 (n=32) used 3 infusions of R 375 mg/m2 pre stem cell collection, followed by a-interferon 3 MU/m2 SC TIW × 2 years + R 375mg/m2 × 6 weekly infusions post ASCT. Eligibility included adult patients age 18–65 with stage III or IV follicular lymphoma grades 1–3a in first or second relapse. Salvage chemotherapy was either CHOP or DHAP depending on prior anthracycline exposure. High dose therapy was cyclophosphamide, carmustine, and etoposide (CBV). Minimal residual disease (MRD) assessment of t(14; 18) by quantitative PCR was serially performed in blood, PBSC and marrow. Studies were REB approved and all patients gave informed consent. Results:Sixty-eight patients from the 3 trials are included. Median age at study enrolment was 47 (30-71) and patients were a median of 31 mo (9-197) from diagnosis. 54% were male. Median FLIPI score was 2. Median # of prior chemotherapies was 1. Median number of cycles of salvage chemotherapy was 4 (2 - 10). 63 patients proceeded to ASCT. 5 patients were not transplanted either do to disease progression (2), or failed stem cell mobilization (3). Baseline characteristics of the patients enrolled in the three trials were similar, with the exception of rituximab(R) exposure in 22% of the patients in Protocol 3. 4 (6%) patients were lost to follow up.Median time to death or last follow was 84.5 mo (7-166). 32 patients (47%) relapsed and 20 (29%) have died. Median follow up times for each trial were 116, 99 and 57 mo. Actuarial median OS for Protocol 1 was 136 mo from enrolment and has not yet been reached for Protocols 2 and 3. Actuarial median PFS for Protocols 1 and 3 are 49 and 78 mo respectively and has not yet been reached for Protocol 2.MRD assessment by PCR was collected on 48 patients. Compared with study 1, the increased use of R pre SC collection improved in vivo purging by 2 logs. In Protocols 1 and 2, most still had detectable disease in the graft to a sensitivity of 1 cell/100,000. In Protocol 3, 56% had MRD negative apheresis products. 91% of 46 evaluable patients achieved molecular remission post stem cell transplant.Thirteen patients (19%) developed secondary malignancies post ASCT with a median time to malignancy of 88.5 mo (39-144). 1 patient developed 2 distinct malignancies. Secondary malignancies present were: MDS (4), AML (1), ALL (1), basal cell carcinoma (2), squamous cell carcinoma (3), thyroid cancer (1), non small cell lung cancer (1) and adenocarcinoma of unknown origin (1). Five (7%) patients transformed to DLBCL, with a median time to transformation post ASCT of 43.5 mo (17-142).The majority of patients who received rituximab immunotherapy pre and post ASCT developed persistent hypogammaglobulinemia. 17 patients (26%) developed interstitial pneumonitis or >2 respiratory complications post rituximab. 4 patients (6%) require monthly IVIG to treat recurrent respiratory infections. 10 patients (15%) developed herpes zoster <90 days post ASCT.15% and 30% of patients in Protocols 1 and 3 did not complete the 2 years of alpha-IFN post ASCT secondary to one or more of depression, fatigue or cytopenias. Conclusion:HDT + ASCT combined with R +/− a-IFN produces durable PFS and molecular remissions but is associated with prolonged hypogammaglobulinemia and higher rates of interstitial pneumonitis. Three infusions of R pre SC collection achieve higher rates of molecular remission. Compliance with 2 years of a-IFN added to R post ASCT is poor and may not add clinical benefits to R alone. The additional role of HDT/ASCT in the era of R-chemotherapy for FL needs to be explored. [Display omitted] [Display omitted] Disclosures:No relevant conflicts of interest to declare.

Bortezomib, pegylated-lyposomal-doxorubicin and dexamethasone (PAD) as induction therapy prior to reduced intensity autologous stem cell transplant (ASCT) followed by lenalidomide and prednisone (LP) as consolidation and lenalidomide alone as maintenance

8518 Background: New agents have been introduced as induction treatment prior to ASCT and as consolidation or maintenance thereafter to improve complete response (CR) rates. In this study, we evaluate Bortezomib as induction preASCT, followed by consolidation/maintenance with Lenalidomide in elderly myeloma pts. Methods: Newly diagnosed MM pts aged 65–75 years were eligible. The induction included four 21-day PAD cycles (bortezomib1.3mg/m2 days 1,4,8,11, pegylated-liposomal-doxorubicin 30mg/m2 day 4 and dexamethasone 40mg days 1–4,8–11,15–18 for cycle 1 and days 1–4 for cycles 2–4). Cyclophosphamide (3g/m2) plus G-CSF was used to harvest stem-cells. Pts were then conditioned with tandem Melphalan 100mg/m2 and stem-cell support (MEL100). After ASCT pts received four 28-day LP cycles (Lenalidomide 25mg/day on days 1–21 plus Prednisone 50mg every other day) followed by Lenalidomide alone (10mg/day on days 1–21 every 28 days) as maintenance. Primary endpoints were safety (any Grade-3 non-hematologic toxicity<30%) and efficacy (near complete > response rate, nCR, >35%). According to Simon procedure, 100 pts were planned to be enrolled. Results: Ninety-four pts have been enrolled. After the 4 PAD cycles 95% of pts achieved at least partial response (PR), 60% at least very good partial response (VGPR), 23% at least nCR, and 13% CR. After tandem MEL100, 95% of pts showed PR, 80% at least VGPR, 60% at least nCR, and 33% CR. After LP consolidation regimen all patients achieved PR, 89% at least VGPR rate, 78% at least nCR, and 56% CR. During PAD, 25% of pts experienced grade3–4 hematologic toxicity, 17% grade3–4 peripheral neuropathy and 11% grade3–4 infections. During LP consolidation one DVT and one discontinuation due to prolonged anemia and thrombocytopenia were recorded. Conclusion: PAD as induction pre ASCT followed by LP as consolidation induced a high response rate with a 56% CR rate recorded at the end of a reduced intensity ASCT regimen for elderly patients. Updated results and molecular remission data will be presented at the meeting. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Celgene, Johnson & Johnson

Impact of Pre-Transplantation and Post-Transplantation Positron Emission Tomography (PET) Using 18-Fluorodeoxyglucose in Lymphoma Patients Treated with Autologous Stem Cell Transplantation.

Introduction : Assessment of therapeutic response using 18-Fluoro-deoxy-glucose (FDG) positron emission tomography (PET) is useful to determine prognosis in lymphoma. In poor prognosis lymphoma patients, it may have an important value in the pre-transplant evaluation and help to transplant-decision making. But the impact on patient outcome of post-transplant assessment is unknown.Patients and methods: In our department, between July 2004 and December 2005, 60 consecutive patients (M/F ratio= 37/23) who achieved tumor response and received high-dose chemotherapy plus autologous-stem-cell transplantation (ASCT) were prospectively explored with PET, prior to ASCT (after 3–4 chemotherapy cycles) and 100 days after ASCT. PET images were evaluated without knowledge of conventional imaging and clinical history. Presence (PET positive) or absence (PET negative) of abnormal FDG uptake was related to event-free survival (EFS) and overall survival (OS).Results :50 patients had non-Hodgkin lymphoma (20 diffuse-large-B-cell (DLBCL), 8 mantle-cell, 16 follicular, 4 T-large-cell, 2 Burkitt) and 10 Hodgkin's lymphoma. Median age was 52 ranging from 19 to 68 years. At diagnosis, 9 patients had 2–4 performance status, 40 elevated LDH, 30 extranodal involvement and 53 staged 3–4. Tumor bulk was above 10 cm in 14 patients. 22 patients received front-line ASCT mainly after ACVBP (n=14) or CHOP. Platinum-based salvage chemotherapy (DHAP, n= 26) was the most frequently used for 27 relapses and 11 refractory diseases. 40 patients received Rituximab with chemotherapy. Prior ASCT, there were 31 complete remission (CR), 23 uncertain CR and 6 partial remission. Conditioning regimen was BEAM in 39 patients; Zevalin BEAM in11, Total Body Irradiation was used in 10. 44 patients (75%) were pre-ASCT-PET negative and 48 (80%) post-ASCT-PET negative. 6 patients (10%) converted from pre-ASCT-PET positive to post-ASCT-PET negative (2 Hodgkin, 1 mantle, 2 follicular, 1 DLBC) and 2 patients (3%) converted from pre-ASCT-PET negative to post-ASCT-PET positive (1 pulmonary infection, 1 early relapse in DLBC). One year after ASCT, 10 patients died (OS 80%) and 17 relapsed (EFS 67%). OS was estimated to 90% in pre-ASCT-PET-negative patients vs. 51 % in PET-positive (p=0.0003), EFS was 75% vs. 43%, respectively (p=0.001). OS was estimated to 87% in post-ASCT-PET-negative patients vs. 48% in PET-positive (p<0.0001), EFS was 77% vs. 25%, respectively (p<0.0001). There was no difference within histological subtypes or front-line vs. relapse/refractory. The only adverse prognostic factors in multivariate analysis was PET positive either pre ASCT (relative risk=4) or post ASCT (relative risk=12).Conclusion: A positive PET after induction chemotherapy indicates a high risk of ASCT failure; in addition, this risk of failure is increased by a positive PET after ASCT. In pre-ASCT-PET-positive patients, more experimental approaches are needed. In pre-ASCT-PET-negative patients, post-ASCT-PET assessment may be omitted.

Positive positron emission tomography (PET) pre-autologous stem cell transplant (ASCT) in non-Hodgkin lymphoma (NHL) does not preclude successful outcome

Positive positron emission tomography (PET) pre-autologous stem cell transplant (ASCT) in non-Hodgkin lymphoma (NHL) does not preclude successful outcome

Pre-Autologous Stem Cell Transplantation (ASCT) Treatment with Rituximab Does Not Impair Stem Cell Harvest and Engraftment in Untreated Patients with Diffuse Large B-Cell Lymphoma (B-DLCL) at Poor Prognosis.

Introduction: Rituximab is a monoclonal antibody commonly used in B-DLCL both in salvage regimens and in combination with first-line chemotherapy. Some studies have reported delays in neutrophil or platelet engraftment after ASCT in patients treated with high dose chemotherapy and Rituximab prior to ASCT. We investigated the effect of adding Rituximab prior to ASCT on peripheral blood stem cell (PBSC) harvest, time to engraftment and short-term toxicity post ASCT.Patients and methods: We analyze stem cell mobilization, engraftment (median time to absolute neutrophil count > 500/mm3 for three consecutive days and platelets > 50.000) and short-term toxicity after ASCT (< 30 days) in two groups of patients affected by B-DLCL at diagnosis enrolled into two consecutive trials with or without Rituximab in combination with chemotherapy. All patients were < 61 years with B-DLCL at age-adjusted IPI Intermediate-High (IH) or High (H) risk and/or with bone marrow (BM) involvement.Group A: an intensified chemoimmunotherapy regimen R-MegaCEOP (Rituximab 375 mg/m2 day 1, CTX 1200 mg/m2 + EPI 110 mg/m2 + VCR 1.4 mg/m2 day 3 and PDN 40 mg/m2 days 3 to 7) every 14 days with G-CSF support for 4 courses; patients in complete response (CR) or partial response (PR) received two courses of intensified chemotherapy R-MAD (Mitoxantrone 8 mg/m2 + ARA-C 2000 mg/m2/12h + Dexamethasone 4 mg/m2/12h days 1 to 3 and Rituximab 375 mg/m2 day 4 and before PBSC harvest).Group B: MACOP-B 8 weeks + 2 courses of MAD (in patients in CR or PR) without Rituximab. Both groups were given ASCT with BEAM as conditioning regimen. Clinical characteristics at diagnosis were well balanced between the two groups.Results: 68 patients are evaluable: 35 pts in group A (with Rituximab) and 33 pts in group B (without Rituximab). All patients in both groups collected more than 2 x 106 CD34+ cell/kg. Median CD34+ cell/kg in group A was 13 x 106 (range 0-37) compared with 41 x 106 in group B (range 0–253) with no statistically significant difference. Median time to neutrophils engraftment after ASCT was similar in the two groups: 9 days in group A and 10 days in group B. No delay in the platelet recovery was observed in patients treated with chemoimmunotherapy: 15 days in group A vs 16 days in group B. Few severe early toxicities (WHO grade 3–4) were reported with no differences between group A vs B: severe mucositis in 11 pts vs 23 pts, gastrointestinal in 6 pts vs 4 pts. Severe infections occurred in 10 patients: group A 6 patients (2 Gram+ sepsis, 1 Gram- sepsis, 1 FUO, 2 bacterial pneumonia); group B 4 patients (2 FUO, 1 bacterial and 1 viral pneumonia). One patient in group A died of bacterial pneumonia after ASCT.Conclusions: Treatment with Rituximab may be safely included in a pre-ASCT high dose chemotherapy regimen with no delay in stem cell harvest, engraftment and without increased early toxicity after ASCT.