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Haplo-identical donors have been increasingly used as an alternative source of stem cells in patients with severe aplastic anemia in need of an allogeneic transplantation but lack a matched donor. Single cord blood (CB) transplant also offers a curative option for this disease, but few adult patients have been reported due to low number of progenitor cells leading to prolonged cytopenias and a high risk of infections. CB stem cell expansion may theoretically solve these pitfalls but has not been used previously in non-malignant diseases, likely due to fear of graft rejection and lack of availability of expanded CBs outside clinical trials. We report the first case of an adult patient with severe aplastic anemia who was successfully transplanted with a UM171-expanded CB graft. After a conditioning of rabbit antithymocyte globulin, fludarabine, cyclophosphamide, and total body irradiation, a UM171 expanded graft of 3.29 × 106 CD34 + cells/kg (a 51-fold increase) was infused. Full donor chimerism was observed on day + 14, with neutrophil and platelet engraftment on days + 23 and + 27. There was no severe infection or graft-vs-host disease. UM171-expanded grafts offer a valuable option for patients with aplastic anemia in need of transplantation but have no suitable donor.

Summary Background Benefits of cord blood transplantation include low rates of relapse and chronic graft-versus-host disease (GVHD). However, the use of cord blood is rapidly declining because of the high incidence of infections, severe acute GVHD, and transplant-related mortality. UM171, a haematopoietic stem cell self-renewal agonist, has been shown to expand cord blood stem cells and enhance multilineage blood cell reconstitution in mice. We aimed to investigate the safety and feasibility of single UM171-expanded cord blood transplantation in patients with haematological malignancies who do not have a suitable HLA-matched donor. Methods This single-arm, open-label, phase 1–2 safety and feasibility study was done at two hospitals in Canada. The study had two parts. In part 1, patients received two cord blood units (one expanded with UM171 and one unmanipulated cord blood) until UM171-expanded cord blood demonstrated engraftment. Once engraftment was documented we initiated part 2, reported here, in which patients received a single UM171-expanded cord blood unit with a dose de-escalation design to determine the minimal cord blood unit cell dose that achieved prompt engraftment. Eligible patients were aged 3–64 years, weighed 12 kg or more, had a haematological malignancy with an indication for allogeneic hematopoietic stem cell transplant and did not have a suitable HLA-matched donor, and a had a Karnofsky performance status score of 70% or more. Five clinical sites were planned to participate in the study; however, only two study sites opened, both of which only treated adult patients, thus no paediatric patients (aged ClinicalTrials.gov , NCT02668315 . Findings Between Feb 17, 2016, and Nov 11, 2018, we enrolled 27 patients, four of whom received two cord blood units for safety purposes in part 1 of the study. 23 patients were subsequently enrolled in part 2 to receive a single UM171-expanded cord blood transplant and 22 patients received a single UM171-expanded cord blood transplantation. At data cutoff (Dec 31, 2018), median follow-up was 18 months (IQR 12–22). The minimal cord blood unit cell dose at thaw that achieved prompt engraftment as a single cord transplant after UM171 expansion was 0·52 × 105 CD34-positive cells. We successfully expanded 26 (96%) of 27 cord blood units with UM171. Among the 22 patients who received single UM171-expanded cord blood transplantation, median time to engraftment of 100 neutrophils per μL was 9·5 days (IQR 8–12), median time to engraftment of 500 neutrophils per μL was 18 days (12·5–20·0), and no graft failure occurred. Median time to platelet recovery was 42 days (IQR 35–47). The most common non-haematological adverse events were grade 3 febrile neutropenia (16 [73%] of 22 patients) and bacteraemia (nine [41%]). No unexpected adverse events were observed. One (5%) of 22 patients died due to treatment-related diffuse alveolar haemorrhage. Interpretation Our preliminary findings suggest that UM171 cord blood stem cell expansion is feasible, safe, and allows for the use of small single cords without compromising engraftment. UM171-expanded cord blood might have the potential to overcome the disadvantages of other cord blood transplants while maintaining the benefits of low risk of chronic GVHD and relapse, and warrants further investigation in randomised trials. Funding Canadian Institutes of Health Research, Canadian Cancer Society and Stem Cell Network.

Background Benefits of cord blood (CB) transplantation include low rates of relapse and chronic graft-versus-host disease (GVHD). However, CB use has rapidly declined because of the high rates of infections, severe acute GVHD, and transplant-related mortality (TRM) as well as prolonged hospitalization. We therefore initiated a clinical trial with UM171, a potent agonist of hematopoietic stem cell (HSC) self-renewal, to attempt to solve these limitations and permit transplantation of smaller, better HLA-matched CBs. Methods Expansion culture lasted 7 days and patients received a myeloablative conditioning regimen followed by a single CB transplant including both the expanded CD34+ cells and the lymphocyte-containing CD34- fraction. Results Between 9/16-11/18, 22 adults with mostly high- to very high-risk hematologic malignancies were transplanted. Median transplant co-morbidity index was 2 (0-5). Five patients had already failed an allogeneic transplant, 3 patients had acute leukemia not in remission, and 2 patients had relapsed/refractory aggressive lymphoma. UM171 treatment profoundly changed the cellular composition of the graft, including a 600 and 8000-fold increase in dendritic and mast cell progenitors, respectively. Neutrophil engraftment was prompt with median time to 100 and 500 neutrophils/μL of 9.5 and 18 days, respectively. Patients seemed to derive clinical benefit from achieving 100 neutrophils rapidly translating into early resolution of febrile neutropenia (median day 7) contributing to shorter hospitalization when compared to conventional CB transplants at same institution with larger cell doses and similar time to 500 neutrophil engraftment. Median CD4 counts at 3 and 12 months were 218 and 413/μL, respectively. Incidence of grade 3-4 acute GVHD was low (9%) and there was no steroid refractory GVHD or moderate-severe chronic GVHD. More than 90% of patients were off immunosuppressive therapy by 12 months. One patient died of TRM ( Conclusions A 7-day UM171 expansion CB protocol is feasible and provides clinical benefits beyond engraftment, such as very low TRM. If confirmed, UM171 expansion may overcome the shortcomings of CB transplants while maintaining its benefits of low risk of chronic GVHD and relapse. We have now embarked on a phase 2 trial to confirm if a UM171 modified graft, enriched in dendritic cells, will have a potent antileukemia effect in extremely high-risk patients such as refractory leukemias and high risk mutations (e.g.: p53, EVI-1).

Background A better survival in patients with multiple myeloma (MM) progressing after tandem autologous (auto)/allogeneic (allo) hematopoietic stem cell transplantation (HSCT) has been previously reported (Htut M. et al. BBMT 2018), suggesting a persistent graft-versus-multiple myeloma (GvMM) effect even after relapse. We sought to confirm this observation in a homogeneous cohort of MM patients who relapsed after upfront tandem auto/allo HSCT in our institution. Methods 92 consecutive, newly diagnosed MM patients who received tandem auto/allo HSCT were paired with 81 patients who received auto HSCT only between 2001 and 2010. Patients pairing criteria were age ≤ 65 years at diagnosis, Durie-Salmon 1B, 2 or 3, a glomerular filtration rate ≥ 60 mL/min, only one line of induction treatment, absence of progression within 4 months of auto HSCT and cytogenetics (if available). After their 1st auto HSCT with high dose melphalan, all allo transplant recipients received an outpatient nonmyeloablative conditioning of fludarabine 30 mg/m2 and cyclophosphamide 300 mg/m2 × 5 days followed by G-CSF mobilized stem cells from a matched sibling donor. Results Median age in the auto/allo group was 53 years, compared to 57 years in the auto group (p Conclusion Tandem auto/allotransplant enables long-term survival and offers a potentially curative option in selected newly diagnosed MM patients. At time of 1st relapse, tandem auto/allo transplant does not confer a significant outcome advantage compared to auto HSCT only.

Cerebral adenovirus endotheliitis presenting as posterior reversible encephalopathy syndrome after allogeneic stem cell transplantation

Graft-versus-host disease (GVHD) is a major cause of transplant-related mortality (TRM) after allogeneic haematopoietic stem cell transplantation (HSCT) and presents a challenge in haploidentical HSCT. GVHD may be prevented by ex vivo graft T-cell depletion or in vivo depletion of proliferating lymphocytes. However, both approaches pose significant risks, particularly infections and relapse, compromising survival. A photodepletion strategy to eliminate alloreactive T cells from mismatched donor lymphocyte infusions (enabling administration without immunosuppression), was used to develop ATIR101, an adjunctive therapy for use after haploidentical HSCT. In this phase I dose-finding study, 19 adults (median age: 54 years) with high-risk haematological malignancies were treated with T-cell-depleted human leucocyte antigen-haploidentical myeloablative HSCT followed by ATIR101 at doses of 1 x 10(4)-5 x 10(6) CD3(+) cells/kg (median 31 days post-transplant). No patient received post-transplant immunosuppression or developed grade III/IV acute GVHD, demonstrating the feasibility of ATIR101 infusion for evaluation in two subsequent phase 2 studies. Additionally, we report long-term follow -up of patients treated with ATIR101 in this study. At 1 year, all 9 patients receiving doses of 0 center dot 3-2 x 10(6) CD3(+) cells/kg ATIR101 remained free of serious infections and after more than 8 years, TRM was 0%, relapse-related mortality was 33% and overall survival was 67% in these patients.

Background Autologous hematopoietic stem cell transplantation (AHSCT) in the older population is associated with an increased risk of morbidity and mortality. Determination of the hematopoietic cell transplant comorbidity index (HCT-CI) has contributed to improve patient selection while allowing prediction of their non-relapse mortality (NRM). The goal of this study was to identify factors influencing both safety and efficacy of AHSCT in an older non-Hodgkin lymphoma (NHL) population to better select those who will benefit from this intervention in the Canadian context of a single-payer government healthcare program. Methods This single center, retrospective study, examined clinical outcomes in 90 consecutive older patients (≥60 years old) with B-cell NHL treated with AHSCT between 2008 and 2014. Findings Median age was 63 (60–69) at time of transplantation. The HCT-CI risk score was low, intermediate and high in 34%, 40% and 26% of patients, respectively. NRM was 1% at 100 days and one-year post transplant and not influenced by age. At a median follow-up of 52 months, median progression-free survival (PFS) was 56 months while median overall survival (OS) was still not reached. Stable and progressive disease status at time of transplantation were associated with a lower PFS (HR 2.94) and OS (HR 3.91). BEAC conditioning and a graft cell dose 5 × 106 CD34+/kg led to faster recovery, decreased toxicity and resource consumption. Interpretation In the older population, AHSCT is safe and optimal when restricted to fit chemosensitive patients.

Background Benefits of cord blood (CB) transplantation include low rates of relapse and chronic graft-versus-host disease (cGVHD). However, CB use is rapidly declining because of delayed neutrophil recovery, high rates of infections and severe acute GVHD leading to high transplant-related mortality (TRM) and prolonged hospitalization. Several of these complications are related to the low cell number of CB grafts, compromising early engraftment and optimal HLA matching. In order to improve these limitations, we initiated a phase II clinical trial exploiting UM171 expanded CB. This molecule has previously been shown to efficiently expand stem and progenitor cells in 7-day ex vivo cultures. More recent studies have also documented the dominant expanding effect of UM171 on several immuno-modulatory cells, thus profoundly changing graft composition and possibly further reducing relapse and GVHD. Methods Patients (pts) received a myeloablative conditioning regimen. On day (D)-7 of transplant, CB was thawed and CD34+ selected. The CD34- lymphocyte containing fraction was cryopreserved and infused on D+1. The CD34+ component was placed in a closed culture system with UM171 and media was injected once a day until D0, when cells were washed and infused. This fed-batch culture system allowed for small culture volumes, saving cost and labor. Moreover, the short duration of expansion made the process practical and clinically viable. Findings Between 9/16-11/18, 22 adults with a median age of 44 years and high- to very high-risk hematologic malignancies were transplanted with a single UM171 CB. Five pts (23%) had already failed a prior allogeneic transplant and 5 (23%) had refractory/relapsed acute leukemia or aggressive lymphoma. Median co-morbidity index was 2 and 36% of pts had an index ≥3. Because minimal cell dose requirements were lower, we had access to 47% of the CBs in the banks instead of 5% for a 70 kg pt. Consequently, >80% of pts received a ≥6/8 HLA matched CB. UM171 profoundly changed graft composition, including a 600 and 8000-fold increase in dendritic and mast cells, respectively. Median 1st day of 100 and 500 neutrophils were D+10 and D+18, respectively. Achieving 100 neutrophils was 5 days faster than seen with pts receiving peripheral blood (PB) or marrow (BM) at same institution and appeared cell dose independent, suggesting that clinically meaningful expansion of an early repopulating myeloid progenitor is at saturation even with smaller CBs. In contrast, attaining 500 neutrophils was accelerated but dependent on cell dose and similar to our BM-PB pts. More importantly, pts appeared to derive clinical benefit beyond neutrophil engraftment as median last day of fever was D+8, much earlier than engraftment and 4 days earlier than seen with our PB-BM pts, translating into a shorter duration of admission, similar to that with BM-PB. Median CD4 count was 218/μL and 413/μL at 3 and 12 months, respectively. Cumulative incidences (CI) of grade 2-4 and 3-4 acute GVHD were 60% and 9%, respectively. We observed no steroid refractory acute GVHD, no moderate/severe cGVHD and 91% of patients were off immunosuppressive therapy by 12 months. One patient died of TRM ( Interpretation A 7-day UM171 expansion CB protocol is feasible and provides clinical benefits beyond engraftment, such as very low TRM and severe GVHD with prompt withdrawal of immunosuppression resulting in excellent GRFS. Hypotheses to explain this could be earlier achievement of 100 neutrophils, protective effect of the immuno-modulatory dendritic cells on mucosal integrity and relapse, and mast cells on gut GVHD, as well as better HLA matching. If confirmed, UM171 expansion may overcome the shortcomings of CB transplants while maintaining its benefits of low risk of cGVHD and relapse. Encouraged by our observation that several pts with very high-risk disease (e.g. refractory leukemia) remain in CR, we have now embarked on a Canadian and US trial to ascertain if indeed UM171 modified grafts will have a potent antileukemia effect in extremely high-risk disease pts such as those with refractory acute leukemias and high-risk molecular anomalies like p53 mutation and EVI-1 rearrangement. Figure Disclosures Cohen: ExCellThera: Consultancy, Equity Ownership, Patents & Royalties: Royalities from sales of UM171, Research Funding. Roy:Celgene: Consultancy, Honoraria, Research Funding; ExCellThera: Patents & Royalties: Royalties from sales of UM171, Research Funding; Amgen Canada: Honoraria; Janssen Canada: Honoraria; Sanofi Canada: Research Funding. Delisle:ExCellThera: Patents & Royalties, Research Funding. Bambace:ExCellThera: Patents & Royalties: royalities. Ahmad:ExCellThera: Patents & Royalties. Lachance:ExCellThera: Patents & Royalties. Bernard:ExCellThera: Patents & Royalties. Kiss:ExCellThera: Patents & Royalties. Busque:Paladin: Consultancy; Pfizer: Consultancy; Novartis: Consultancy; ExCellThera: Patents & Royalties; BMS: Consultancy. Roy:Kiadis Pharma: Other: Travel support; University of Montreal: Patents & Royalties: Author on patent; Hopital Maisonneuve-Rosemont: Patents & Royalties: Author on patent. Milano:ExCellThera: Research Funding; Amgen: Research Funding. Sauvageau:ExCellThera: Consultancy, Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties. OffLabel Disclosure: None of the medications listed are approved for this indication.

High-dose chemotherapy with autologous stem cell transplantation (ASCT) remains the standard of care for patients with multiple myeloma. Outpatient ASCT can be an attractive option given wait times and costs associated with inpatient procedures. We initiated an outpatient transplantation protocol in 2006. Patients were treated at a university hospital outpatient clinic that was open 5 days a week. The present study investigated safety and cost-effectiveness of the outpatient program. Ninety-one patients underwent ASCT between 2006 and 2010. The majority of patients (77%) had Durie-Salmon stage III disease; 38% had 1 or more comorbidities. Seventy-six patients (84%) were hospitalized during the first 100 days, mainly for febrile neutropenia (n = 71). Overall survival at day 100 was 100%. No patient was admitted to an intensive care unit. Risk factors for prolonged hospitalization (longer than 7 days) were disease stage IIB or higher and age >60 years. The cost savings was $19,522 (Canadian dollars) per patient compared with inpatient ASCT, for an annual savings of approximately $740,000. In summary, outpatient ASCT performed in a weekday clinic for patients with multiple myeloma appears to be safe and cost-effective, but is associated with a relatively high hospitalization rate.

Introduction: Multiple myeloma (MM) remains incurable with standard therapies. Allogeneic stem cell transplantation (alloSCT) is the only curative treatment for these patients. We hypothesized that bortezomib (BTZ) consolidation after tandem autologous stem cell transplantation (ASCT) and nonmyeloablative (NMA) alloSCT could improve quality of response while decreasing relapse and cGVHD. We also sought to determine prospectively the predictive value of bone marrow minimal residual disease (MRD) evaluation using a highly sensitive flow cytometry assay. Methods: Newly diagnosed myeloma (NDMM) patients ≤65 years with high-risk (HR) features (based on cytogenetics, ISS 3 or plasma cell leukemia) or ≤50 year regardless of risk status with an 8/8 HLA matched donor are eligible to participate in this prospective trial. After a BTZ-based induction and ASCT, outpatient NMA alloSCT is performed with either fludarabine and cyclophosphamide (sibling donor) or fludarabine and TBI 2 Gy (unrelated donor) followed by peripheral blood stem cells. GVHD prophylaxis consists of tacrolimus and MMF. BTZ is initiated on day +120 post-alloSCT at 1.3 mg/m2 every 2 weeks for 1 year. Response evaluation is based on IMWG criteria. Bone marrow MRD evaluation is performed on 10x106 nucleated cells with highly sensitive (≥10-5) next-generation flow cytometry using the 8-color EuroFlow protocol (CD45, CD38, CD138, CD56, CD19, CD27, CD81, CD117, CyIgκ and CyIgλ) before alloSCT, before BTZ and every 3 months for 2 years. Immunophenotypic complete response (iCR) is defined as stringent CR in addition to 2 consecutive negative MRD results. aGVHD and cGVHD are evaluated prospectively. Results: As of June 29th 2018, 37 patients have been enrolled with a median age of 53 (range: 35-64) years. ISS 3 is found in 43% and HR cytogenetics in 54% (5% del17p, 14% t(4;14), 22% gain 1q21 and 14% >1 HR cytogenetics). Induction consisted of CyBorD (81%) or VTD (19%) for a median of 4 (range: 4-7) cycles. Median times from induction to ASCT and from ASCT to alloSCT were 5.8 and 4.4 months, respectively. Sibling and unrelated donor transplants were performed in 43% and 57%, respectively. KPS and HCT-CI were 90 (range 80-100) and 1 (range 0-3), respectively. Median follow-up is 21 (range 0-39) months after alloSCT. Of enrolled patients, 34 have started BTZ and received 92.5% of planned doses, with no dose reduction needed for toxicity. Observed grade ≥3 non-hematologic toxicities possibly/related to BTZ included diarrhea (n=1), viral hemorrhagic cystitis (2 adenovirus, 1 BK) and nocardial brain abscesses (n=1). Cumulative incidences of grade II-IV and III-IV aGVHD were 26% and 11%. Incidences of all grade, moderate/severe and severe cGVHD at 24 months were 61%, 47% and 10%, respectively, with mostly mouth, skin and liver involvement. Compared to 27 historical controls who did not receive BTZ after tandem transplant, the incidence of moderate/severe cGVHD was much lower in BTZ recipients (47 vs 78%; p=0.002). After reviewing each target organ involvement, mouth and eye cGVHD were significantly less severe with BTZ. Three patients died, one from myeloma progression and 2 from grade III aGVHD, with a 24-month non-relapse mortality of only 8%. BTZ consolidation improved depth of response, increasing ≥CR rate from 64% to 85% and iCR rate from 25% to 59%, regardless of cytogenetic abnormalities (Table 1). Probability of progression-free survival (PFS) at 24 months was 65% (CI 95%: 42-81) while overall survival (OS) was 90% (CI 95%: 70-97; Fig. 1A). The cumulative incidence of progression at 24 months was 28%. Importantly, the presence of ≤50 myeloma cells in the bone marrow 10 months post-alloSCT (after 6 months of BTZ) was associated with a significantly lower probability of progression (15% versus 80%; p=0.03; Fig. 1B). Conclusion: Tandem ASCT-NMA alloSCT followed by BTZ consolidation results in a remarkably high rate of ≥CR, including iCR. For the first time in allogeneic transplant recipients, MRD evaluation using the EuroFlow protocol demonstrates that identification of ≤50 myeloma cells in the bone marrow 10 months after alloSCT/6 months after BTZ seems predictive of a better outcome. If confirmed, this landmark could be used to design future therapeutic interventions in order to decrease the risk of relapse after tandem transplant. Finally, BTZ following alloSCT is safe and may contribute to decrease both incidence and severity of cGVHD. Disclosures Leblanc: Amgen Canada: Membership on an entity's Board of Directors or advisory committees; Janssen Inc.: Membership on an entity's Board of Directors or advisory committees; Celgene Canada: Membership on an entity's Board of Directors or advisory committees; Takeda Canada: Membership on an entity's Board of Directors or advisory committees. Sebag:Amgen Canada: Membership on an entity's Board of Directors or advisory committees; Takeda Canada: Membership on an entity's Board of Directors or advisory committees; Janssen Inc.: Membership on an entity's Board of Directors or advisory committees; Celgene Canada: Membership on an entity's Board of Directors or advisory committees. Cohen:ExCellThera: Patents & Royalties: Royalities from sales of UM171. Kiss:Alexion: Membership on an entity's Board of Directors or advisory committees, Research Funding; Otsuka: Membership on an entity's Board of Directors or advisory committees, Research Funding. Lachance:ExCellThera: Patents & Royalties: Royalities from sales of UM171. Roy:Kiadis Pharma: Other: Travel support; University of Montreal: Patents & Royalties: Author on patent; Hopital Maisonneuve Rosemont: Patents & Royalties: Author on patent. Sauvageau:ExCellThera: Employment, Equity Ownership. Roy:Janssen Inc.: Membership on an entity's Board of Directors or advisory committees; Takeda Canada: Membership on an entity's Board of Directors or advisory committees; Celgene Canada: Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding.

Cord blood (CB) transplants have fallen into disfavor in large part due to low cell dose leading to prolonged hospitalizations and high transplant related mortality (TRM). UM171, a novel and potent agonist of hematopoietic stem cell (HSC) self-renewal could solve this major limitation, allowing for CB's important qualities of lower risk of chronic GVHD and relapse to prevail. In addition, UM171 could permit transplantation of smaller, better HLA matched cords, associated with lower TRM. Hence, we initiated a clinical trial to test the safety and efficacy of UM171 expanded CB (eCB). Our goal was to design a clinically viable eCB transplant with a TRM as low or lower than other HSC sources all the while maintaining CB's low relapse rate. Patients (pts) received a myeloablative conditioning regimen. On day (D)-7 of transplant, CB was thawed and CD34+ selected. The CD34- lymphocyte containing fraction was cryopreserved and infused on D+1. The CD34+ component was placed in a closed culture system with UM171 and media was injected once a day until D0, when cells were washed and infused. This fed-batch culture system allowed for small culture volumes, saving cost and labor. Between 7/16-6/18, 21 adult pts (median age 44 years) were transplanted with an eCB. Median final culture volume and net viable CD34 fold expansion were 670 mL and 35, respectively. Median 1st day of 100 and 500 neutrophils were D+10 and D+18, respectively. Achieving 100 neutrophils was 5 days faster than seen with our pts receiving peripheral blood (PB) or marrow (BM) and appeared cell dose independent, suggesting that clinically meaningful expansion of an early repopulating myeloid progenitor is at saturation even with smaller CBs. In contrast, attaining 500 neutrophils was accelerated but dependent on cell dose. More importantly, pts appeared to derive clinical benefit beyond neutrophil engraftment (defined as 500 neutrophils). Pts' median last day of fever prior to 500 neutrophils was D+8, much earlier than engraftment and 4 days earlier than seen with our PB-BM pts. We offer 2 hypotheses as explanation: i) 100 neutrophils, which are attained early, provide significant defense against infection, ii) the graft contains a significant proportion of dendritic cell precursors (30-40%) which offer mucosal protection during severe neutropenia. Duration of hospitalization was shorter by 12 days and longer by 2 days compared to our non eCB and PB-BM transplants, respectively. In addition, because cell dose requirements were lower, 12/21 pts received a better HLA matched CB, thus >80% of patients were transplanted with a ≥6/8 HLA matched eCB. As a result of lower minimal cell dose criteria, we can now use ∼half the CBs in the banks instead of only 5% for a 70 kg patient. Platelet engraftment occurred at a median of 42 days. With a median follow up of 14 months, there has been no CMV disease, no PTLD, 2 adenovirus cystitis, 2 (10%) grade 3-4 acute GVHD, no moderate/severe chronic GVHD and 1 TRM (5%) despite a median comorbidity index of 2 (0-5). Full donor chimerism was achieved in all cell subsets. Immune recovery was faster than seen in our unrelated donor transplants who routinely receive ATG prophylaxis with 196, 300 and 413 CD4+/µL at 3, 6 and 12 months, respectively. Interestingly, transcriptome analysis of UM171-eCB cells shows an enhanced lymphoid progenitor-associated gene signature when compared to DMSO exposed cells. Animals transplanted with UM171-eCB cells showed a 20 to 35-fold increase in thymic cellularity at 8 weeks post-transplant. Despite some very high risk pts in our trial, only 3 relapsed. Overall, progression free, and GVHD/relapse free survival (GRFS) are excellent at 95, 77 and 67%, respectively, at 12 months. A 7 day UM171 single eCB protocol is feasible and provides clinical benefits beyond faster engraftment with fewer infectious complications, better HLA matching and very low TRM, all the while saving production and hospitalization costs. Nevertheless, longer follow up will be required to better assess relapse howbeit encouraging preliminary results. Furthermore, patients' quality of life is paramount and best evaluated by GRFS which is excellent thanks to a very low rate of significant chronic GVHD all the while maintaining a low risk of relapse. In conclusion, this 1st trial documents the potency of UM171 and positions UM171-eCB as a promising HSC source which could compete with the current standard of care. Figure. Figure. Disclosures Cohen: ExCellThera: Patents & Royalties: Royalities from sales of UM171. Roy:ExCellThera: Patents & Royalties: Royalities from sales of UM171. Lachance:ExCellThera: Patents & Royalties: Royalities from sales of UM171. Roy:Hopital Maisonneuve Rosemont: Patents & Royalties: Author on patent; Kiadis Pharma: Other: Travel support; University of Montreal: Patents & Royalties: Author on patent. Busque:BMS: Consultancy; Novartis: Consultancy; Pfizer: Consultancy; Paladin: Consultancy. Kiss:Alexion: Membership on an entity's Board of Directors or advisory committees, Research Funding; Otsuka: Membership on an entity's Board of Directors or advisory committees, Research Funding. Caudrelier:ExCellThera: Employment. Zandstra:ExCellThera: Equity Ownership. Sauvageau:ExCellThera: Employment, Equity Ownership.

Despite survival improvement with novel agents and use of autologous hematopoietic stem cell transplantation (HSCT), cure of patients with multiple myeloma (MM) remains anecdotal. Initial observations suggested that chronic GvHD was accompanied by an anti-myeloma effect after myeloablative HSCT, but unfortunately this procedure was hampered by high non-relapse mortality (NRM). To maximize the anti-myeloma effect and minimize NRM, we developed a non-myeloablative (NMA) regimen associated with a high incidence of chronic GvHD and tested its efficacy on patient survival and disease eradication. From 2001 to 2010, 92 patients aged ⩽ 65 years with a compatible sibling donor received autologous HSCT followed by an outpatient NMA allogeneic HSCT using a conditioning of fludarabine and cyclophosphamide. Patient median age was 52 years and 97% presented Durie-Salmon stages II-III disease. After a median follow-up of 8.8 years, probability of 10-year progression free and overall survival were 41% and 62%, respectively. Although the cumulative incidence of extensive chronic GvHD was high (at 79%), the majority of long-term survivors were off immunosuppressive drugs by year 5 and NRM was low (at 10%). Together, our results suggest that potential MM cure can be achieved with NMA transplantation regimens that maximize graft-versus-myeloma effect and minimize NRM.

Cord blood (CB) transplants are hampered by low cell dose and high transplant related mortality (TRM). UM171, a novel and potent agonist of hematopoietic stem cell (HSC) self-renewal could solve this major limitation, allowing for CB's important qualities as lower risk of chronic GVHD and relapse to prevail. Hence, we initiated a clinical trial to test the safety and efficacy of UM171 expanded CB (eCB). The procedure was designed to be non-labor intensive and of short duration for it to be clinically viable. Patients (pts) received a myeloablative conditioning regimen. On day(D)-7 of transplant, CB was thawed and CD34+ selected. The CD34- lymphocyte containing fraction was cryopreserved and infused on day of transplant. The CD34+ component was placed in a closed culture system with UM171 and media was injected once a day until D0, when cells were washed and infused. The first 3 pts also received a 2nd nonmanipulated CB (neCB) to permit documentation of eCB engraftment. This fed-batch culture system allowed for small culture volumes, saving cost and labor. Between 6/16-7/17, 16 adults with a median weight and age of 77 kg and 44 years, respectively, were transplanted with a single eCB (13 pts) or with an eCB and a neCB (3 pts). Median final culture volume was 609 mL. The median net viable (v)CD34 fold expansion was 36. Median 1st day of 100 and 500 neutrophils were D+10 and D+19, respectively. Achieving 100 neutrophils was faster than expected and cell dose independent, suggesting that clinically meaningful expansion of an early repopulating myeloid progenitor is at saturation even with smaller CBs. In contrast, attaining 500 neutrophils was accelerated but dependent on infused vCD34+ cell dose. More importantly, patients appeared to derive clinical benefit beyond neutrophil engraftment defined as the 1st of 3 consecutive days of 500 neutrophils. Patients' last day of fever prior to neutrophil engraftment was Day +7, which occurred much earlier than D+19 of engraftment. We offer 2 hypotheses as explanation: i) 100 neutrophils, which are attained much earlier at D+10, provide significant defence against infection, ii) the graft contains a significant proportion of dendritic cell precursors (>25%) which offer protection during severe neutropenia. When compared to our pts who have received the same conditioning regimen with peripheral blood or marrow, eCB pts were free of fever much earlier (D+7 vs D+15 p Despite preliminary data, it appears that a 7 day UM171 single eCB protocol is feasible and provides clinical benefit beyond faster engraftment with fewer infectious complications, better HLA matching and low TRM, all the while saving production and hospitalization costs. In conclusion, this 1st trial documents the potency of UM171 and positions UM171-expanded CB as a viable HSC source. Disclosures Cohen: University of Montreal: Patents & Royalties: royalties. Marinier: ExCellThera: Equity Ownership. Busque: Novartis Canada Inc.: Honoraria; Bristol Myer Squibb: Honoraria; Pfizer: Honoraria; Paladin: Honoraria. Caudrelier: ExCellThera: Employment. Kiss: Otsuka: Membership on an entity's Board of Directors or advisory committees, Other: meeting attendance support, Research Funding; Alexion: Membership on an entity's Board of Directors or advisory committees, Research Funding. Zandstra: ExCellThera: Equity Ownership. Sauvageau: ExCellThera: Equity Ownership, Patents & Royalties: royalties.

Anaplastic lymphoma kinase (ALK)-positive lymphomas respond to chemotherapy, but relapses, which bear a poor prognosis, occur. Crizotinib inhibits ALK in vitro and in vivo and was administered as monotherapy to 11 ALK+ lymphoma patients who were resistant/refractory to cytotoxic therapy. The overall response rate was 10 of 11 (90.9%; 95% confidence interval [CI] = 58.7% to 99.8%). Disease status at the latest follow-up is as follows: four patients are in complete response (CR) (months >21, >30, >35, >40) under continuous crizotinib administration; 4 patients had progression of disease (months 1, 2, 2, 2); 1 patient obtained CR on crizotinib, received an allogeneic bone marrow transplant, and is in CR; 2 patients (treated before and/or after allogeneic bone marrow transplant) obtained and are still in CR but they have stopped crizotinib. Overall and progression-free survival rates at 2 years are 72.7% (95% CI = 39.1% to 94.0%) and 63.7% (95% CI = 30.8% to 89.1%), respectively. ALK mutations conferring resistance to crizotinib in vitro could be identified in relapsed patients. Crizotinib exerted a potent antitumor activity with durable responses in advanced, heavily pretreated ALK+ lymphoma patients, with a benign safety profile.

Many new therapeutic agents have been approved for follicular lymphoma (FL) but none appear to be curative. Despite novel agents, some patients (pts) experience early relapse, become chemorefractory or suffer transformation into more aggressive lymphomas. Options for these pts are limited. High dose chemotherapy with autologous stem transplant (ASCT) prolongs progression free survival (PFS) and overall survival (OS) in FL pts in first relapse and registry data shows favorable outcome with ASCT in cases of histologic transformation. However, ASCT is usually not curative. Myeloablative allogeneic transplant (MT) has produced long term PFS but is hampered by significant non relapse mortality (NRM) while nonmyeloablative transplant (NMT) has a higher relapse rate compared to MT especially in high risk pts. Finally, many transplant studies have excluded these high risk pts such as those with chemorefractory or transformed disease. We hypothesized that a tandem transplant consisting of an ASCT followed by a NMT would confer the same benefit as a MT without the associated high NRM by separating the high dose chemotherapy from graft versus host disease (GVHD) while preserving the graft versus lymphoma effect. The goal of our study was to improve long term PFS in high risk FL pts. We therefore initiated a prospective protocol in April 2003, for pts with high risk relapsed FL as defined by chemorefractory disease, early 1st relapse, >1st relapse or transformation into aggressive histology. At least one therapy was attempted to document chemosensitivity prior to ASCT. However, regardless of disease status prior to transplant, pts underwent ASCT followed 3 months later by an outpatient NMT from an HLA-identical sibling. NMT comprised 5 days of fludarabine 30 mg/m2/day and cyclophosphamide 300mg/m2/day followed by an infusion of >2x106CD34+ cells/kg. GVHD prophylaxis, chosen to take advantage of the low incidence of acute (a) GVHD and the putative protective effect of chronic (c) GVHD, consisted of tacrolimus starting on day (D) - 8 to achieve levels of 8-12 nmol/L then tapered off by D+100 or D+180 depending on disease risk and of mycophenolate mofetil 1g bid from D+2 to D+50. We previously reported on 27 pts with a follow-up (f/u) of 3 years (yrs). We now report a larger cohort of 40 pts with a median f/u of 8 yrs. Up until July 2015, 40 pts were enrolled with a median age of 50 yrs (34-65). Pts had previously been treated with a median of 3 lines of therapy (2-6). Median time from diagnosis to ASCT was 33 months. Disease status at ASCT was: 14 CR, 16 PR and 10 refractory. Conditioning for ASCT included BEAM/BEAC (n=39), and Cy-TBI (n=1). In addition, 4 pts received radiotherapy after ASCT to sites of previously bulky disease. Median time between ASCT and NMT was 138 days (75-238). Pre NMT disease status was: 25 CR, 12 PR and 3 refractory. Engraftment was prompt in all pts after ASCT and median neutrophil and platelet recovery were respectively 13 days (0-19) and 0 day (0-18) post NMT. Seven pts (18%) developed aGVHD: 2 grade II and 5 grade III. Overall, 29 pts (73%) developed cGVHD: 1 mild, 13 moderate and 15 severe according to NIH revised criteria. Median time to discontinuation of immunosuppression was 22 months. To date, 2 pts have progressed at 11 and 59 months post NMT (one died from relapse and one is now in CR after chemotherapy and DLI) and 5 pts died from either GVHD related complications (n=4) or unknown cause (n=1). All pts alive at last f/u were in CR. With a median f/u of 8 yrs in surviving pts (1-12), OS is 95% at 3 and 5 yrs and 82% at 8 yrs. PFS is 92% at 3yrs, 89% at 5 yrs and 80% at 8 yrs. NRM and relapse rate at 8 yrs are 18% and 6% respectively. Based on our current results in 40 pts, we conclude that ASCT followed by sibling NMT for high risk relapsed FL is associated with excellent disease response and PFS. Furthermore, this tandem strategy appears to be safe and well tolerated. The incidence of cGVHD remains high but could in part explain the impressive PFS in this high risk cohort. This approach should now be further explored in a multi institution setting, include matched unrelated donors and consider the addition of rituximab post-transplant to reduce the incidence and severity of cGVHD with the hope that relapse will not be increased. Figure 1 Figure 1. Disclosures Busque: Pfizer: Honoraria, Speakers Bureau; BMS: Honoraria, Speakers Bureau; Novartis: Honoraria, Research Funding, Speakers Bureau.

Introduction: Over the last decade transplant programs have seen a significant increase in the median age of autologous hematopoietic stem cell transplant (AHSCT) recipients (McCarthy et al. 2013).We recently demonstrated thathigh-dose chemotherapy (HDT) followed by AHSCT was safe and well tolerated in elderly patients withchemosensitivenon-Hodgkin lymphoma (NHL) regardless of their age. Furthermore, we wanted to assess if the survival benefits conveyed by transplantation were equally associated with the maintenance of a good quality of life (QoL). Method: This single-center, research and ethic committee approved retrospective study, examined QoL of survivors following AHSCT for the treatment of NHL in the elderly. Inclusion criteria were defined as patient aged of 60 years and older who had received an AHSCT for a NHL at our hospital between January 1st, 2008 and January 1st, 2015 and survived. 59 patients from the original cohort of 90 patients met the inclusion criteria. Forty-seven of them (79.7%) participated by completing a survey. Patients were required to sign an informed consent.EQ-5D (Rabin et al. 2001) instrument was usedto assessmobility, self-care, usual activities, pain/discomfort and anxiety/depression.In addition, FACT-BMT (McQuellonet al. 1997)questionnaire was also used to assessfive different areas: physical well-being (PWB), social/family well-being (SWB), emotional well-being (EWB), functional well-being (FWB) and BMT specific concerns. The different scores were correlated to the type ofconditioning regimen, gender, age sub-groups ( Results: The median time from AHSCT was 50 months (ranges 17-96). A total of 7 (15%) patients were in relapse when surveyed. Results from theEQ-5Dquestionnaire (table 1) showed that 28 patients (60%) were fit with no or one domain of impairment.Only 4 patients (9%) reported impairments in 4 or 5 domains. 46 patients (98%) were having no or slight problem walking. Almost all patients (98%) reported being able to take care of themselves. Experiencing pain was the most frequently reported issue with 19% of patients being affected by moderate to severe pain. Interestingly, 96% of patients reported having no or slight problem related to anxiety or depression. LowerKarnofskyindex at diagnostic was associated with impaired mobility (p = 0,03) and self-care (p = 0,03). Anxiety was worse for patients in relapsed after transplant (p=0,001). Other comparators did not impact on any of these outcomes. FACT-BMT questionnaire results (Table 2) showed that PWB, SWB and EWB were good while FWB was more variable. Relapse was associated with impaired EWB (p=0,05) as well as BMT specific concerns (p=0,18) and lower FACT-BMT results (p=0,035). Other comparators did not impact on any of these outcomes. Conclusion: This study demonstrates that physical, social and functional well-being are maintained and very good for elderly patients following AHSCT. LowKarnofskyscore prior transplant is a predictor of disability following AHSCT. Relapse following AHSCT represents the most significant challenge and impediment to maintain a good QoL. Elderly patients are, once more, no different from younger ones in their capacity to regain their QoL following transplantation. For this reason, elderly patients should not be denied from transplantation solely based on their age. Disclosures No relevant conflicts of interest to declare.

Introduction: Allogeneicstem cell transplantation (alloSCT) is the only curative modality for newly diagnosed multiple myeloma (NDMM) patients (pts). However, we have previously shown in a large cohort of 92 pts that relapse remains common (49%) and the incidence/severity of chronic GVHD is significant (79%) after tandem auto-allo SCT in NDMM pts (Ahmad et al. BMT 2016;51:529). We hypothesized that a tandem auto-nonmyeloablative (NMA) alloSCT followed by bortezomib (btz) consolidation might be safe, while decreasing both the severity/incidence of chronic GVHD and the risk of relapse in young and/or high-risk NDMM pts. In addition, we hypothesized that btz might further increase depth of responses after alloSCT. Methods: NDMM pts with either ISS stage III, plasma cell leukemia, abnormal cytogenetics defined as t(4;14) with ISS II or III, t(14;16), t(14;20), 17p-, 1p-, or 1q+ in ≥ 10% of purified plasma cells or age ≤ 50 years with a 6/6 sibling or 8/8 unrelated donor were prospectively enrolled in this phase II trial. After a btz-based induction with ≥ partial response and autologous (A) SCT, outpatient NMA alloSCT was performed with either a conditioning of fludarabine 30 mg/m2 x 5 days and cyclophosphamide 300 mg/m2 x 5 days (sibling donor) or fludarabine 30 mg/m2 x 3 days and TBI 2Gy (unrelated donor), followed by G-CSF mobilized stem cells infusion. Acute GVHD prophylaxis consisted of tacrolimus and mycophenolate mofetil. Btz 1.3 mg/m2 SC every 2 weeks was started on day +120 after alloSCT for 1 year. Bone marrow aspirates before alloSCT, before starting btz and every 3 months thereafter were prospectively collected for 2 years in order to assess the impact of btz on minimal residual disease (MRD) by a highly sensitive (≥10-5) multiparametric flow cytometry using the 8-color Euroflow protocol evaluating ≥ 10 x 106 cells/specimen. MRD negativity was defined as the detection of < 30 clonal aberrant plasma cells. Response evaluation is based on IMWG criteria including immunophenotypic complete response (iCR) defined as a stringent CR (sCR) plus a negative MRD. Immunophenotypic remission (iR) is defined as MRD negativity regardless of other disease status. Results: As of 06/30/2016, 20 MM pts have been enrolled and 18 allotransplanted (8 siblings; 10 unrelated); median age is 54.5 (range 35-63) years. Of these pts we report: age ≤ 50 (n=6), ISS stage III (n=10) or poor risk cytogenetics (n=7; 5 with 1q+, 2 with t(4;14)). Pts received initial induction with VTD (n=7) or CyBorD (n=11), followed by ASCT (melphalan 200 mg/m2; median CD34+/kg infused: 7.2 x 106). Median times from diagnosis to ASCT and from ASCT to alloSCT were 7.0 (range: 5.3-11) and 4.8 (range: 3.0-7.0) months, respectively. All pts allotransplanted (median CD34+/kg infused: 7.4 x 106) engrafted. With a median follow-up of 282 (range: 22-562) days after alloSCT, 15 pts have received 221 of 239 (92%) planned doses of btz. Observed grade ≥3 non-hematologic adverse events include btz-induced diarrhea (n=1), herpes mucositis despite adequate prophylaxis (n=1), viral hemorrhagic cystitis (n=3) and asymptomatic EBV reactivation (n=4) requiring rituximab. In contrast, CMV reactivation was infrequent. None of the pts developed or exacerbated pre-existing peripheral neuropathies. Fifteen pts were followed ≥ 7 months after alloSCT; acute GVHD occurred in 3 pts (1 grade II; 2 grade III) and chronic in 10 (67%; 3 mild; 7 moderate). Two pts died from grade III acute GVHD. Nine pts (60%) required hospitalization for a median of 13 days (8-184). Response rates after induction, ASCT, alloSCT and btz are shown in Table 1. Most notably, depth of response improved after btz, with 6 pts (40%; 2 with 1q21, 1 with t(4;14), 2 normal and 1 unknown) in iCR and 4 pts (27%; 1 with 1q21, 2 normal and 1 unknown) in sCR. An additional 20% of pts not in iCR or sCR were in iR with negative MRD. No patient developed extramedullary disease. Conclusions: Our major finding is a high sCR + iCR of 67% in young and/or high-risk NDMM pts following tandem auto-alloSCT and btz consolidation. Although our follow-up is still short, our results are encouraging for an eventual low relapse rate. Additionally, administration of btz 1.3 mg/m2 SC every 2 weeks starting on day +120 after alloSCT is safe and well tolerated. Finally, close monitoring of EBV should be performed prospectively in alloSCT recipients who receive a proteasome inhibitor in order to better assess the risk of viral reactivation. Disclosures Sebag: Celgene: Honoraria; Novartis: Honoraria; Janssen: Honoraria.

Introduction: High dose chemotherapy (HDT) and autologous hematopoietic cell transplantation (AHCT) are considered standard of care as first line therapy in mantle cell lymphoma (Dreyling et al., 2005; Geisler et al., 2012) and in first line refractory and chemosensitive relapse Non-Hodgkin Lymphoma (NHL) (Philip et al., 1995) . The development of hematopoietic cell transplant comorbidity index (HCT-CI) (Sorror et al., 2009) for recipient selection and transplant risk evaluation have impacted on patient selection. Over the last decade, most transplant program have seen an increase in the median age of AHCT recipients(McCarthy et al., 2013). Limited data are available to optimise elderly patients selection for transplantation while minimising the risk of treatment related toxicity and mortality (TRM). The goal of this study was to identify factors impacting the safety and efficacy of AHCT in the elderly NHL patients in order to better select those who will benefit from this intervention. Method: This is a single center, retrospective study examining outcomes of AHCT in elderly patients (≥60 years old) with NHL. Between January 1st, 2008 and January 1st, 2015, 90 patients met the inclusion criteria and were included in the study. Patients signed an informed consent and the ethics committee of our institution approved the study. Progression-free-survival (PFS) and overall survival (OS) were analyzed according to age at time of transplantation, HCT-CI, lymphoma histology and disease status at time of transplant. Toxicities were analyzed according to age and HCT-CI. Results: Median age at time of NHL diagnostic was 60 years (range 42 to 68) and 63 years at time of transplant (range 60 to 69). One third (33%) of our cohort was ≥65 years old. Histologic sub-type was mainly composed of follicular (36%), mantle cell (20%) and large B-cell lymphoma (38%). 50% of patients had high-risk disease and 31% had low risk disease. HCT-CI was low-risk in 34%, intermediate risk in 40% and high-risk disease in 26%. BEAM/BEAC conditioning regimen was used in 94%. The median graft CD34+/kg cell dose infused was 4.87. The median time to neutrophil engraftment was 10 days (range 8 to 14 days) and platelet recovery was 16 days (range 11 to 43 days). The incidence of febrile neutropenia was 92% with 2% admission to the intensive care unit (ICU) with no difference between patients younger or ≥65 years old. Our cohort received a median of 8 days of antibiotics (range 0 to 41 days). Absolute lymphocyte count < 0,3 X 103 cells/uL at 14 days after transplant was associated with higher incidence of septic choc (p=0,024) and ICU admission (p=0,034). Age ≥65 year was not associated with an increase TRM and was surprisingly associated with less total parenteral nutrition (p=0,046) and narcotics uses (P=0,011). The median length of stay was 26 days. The median follow-up was 27 months (range, 1 to 87), median PFS of 46 months (Confidence Interval (CI); 95%, 24,4-67,6) (graph 1) and OS not reached (graph 2). The estimated 5 years OS is 62% and PFS is 40%. Transplant related mortality (TRM) was only 1% at 100 days and 2% at 1year after transplant. The only 2 patients who died from TRM died from cardiac arrest (1 month) and from an unknown cause (3 months). The 1-year progression rate was 30% (graph 3) and mortality rate only 12%. Progressive disease status following first line therapy was associated with a worse PFS compared to the achievement of a complete remission (Hazard Ratio (HR) 2,77; CI 95%, 1,18; 6,49). Progressive disease status at time of transplant was also associated with a lower PFS (HR 9,30: CI 95% 2,55 to 33,92) and OS (HR 13,44: CI 95% 2,68 to 67,48). HCT-CI score did not correlate with OS. International Prognostic Index (IPI), age and treatment type did not influence PFS or OS. Surprisingly, HCT-CI score did not correlate with toxicities, morbidity or mortality. Conclusion: In this single center retrospective study of elderly patients with NHL, AHCT was proven to be safe and effective. Progressive disease at the time of transplant was associated with worse PFS and OS. HCT-CI did not allow the categorization of patients in different prognostics group. Lymphocyte count at day 14 could identify patients at significant risk of complications. Our data suggest that age alone should not exclude patients from transplantation. However, HDT and AHCT should be reserved to chemosensitive patients and avoided in the elderly patient with progressive disease. Figure 1. Figure 1. Figure 2. Figure 2. Figure 3. Figure 3. Disclosures No relevant conflicts of interest to declare.

In hematological disorders ALK expression is present in >50% of Anaplastic Large Cell Lymphomas (ALCL) as a result of a t(2;5)(p23;q35) translocation that causes the ALK gene on chromosome 2 to fuse with the NPM gene on chromosome 5. ALK + ALCL respond to cytotoxic drugs, but relapses occur and bear a poor prognosis(Stein, Foss et al. Blood 96 3681-95 2000; Ferreri, Govi et al. Crit Rev Oncol Hematol 83 293-302 2012). ALK-positive large B-cell lymphoma (ALK+ LBCL) is a rare lymphoma with a most frequent t(2;17)(p23;q23) translocation responsible for Clathrin-ALK fusion protein(Swerdlow, Campo et al. 2 2008). Crizotinib is the first ALK inhibitor which entered clinical practice: it is an orally bioavailable small-molecule inhibitor active on the ALK and MET receptor tyrosine kinases. While the activity of crizotinib in ALK+ lung cancer is documented (Kwak, Bang et al. N Engl J Med 363 1693-703 2010)no report on long term effects of crizotinib in ALK+ lymphomas exists; impressive short-term therapeutic activity was reported in two patients (Gambacorti-Passerini, Messa et al. N Engl J Med 364 775-6 2011), but no long-term data are available. In the present study, crizotinib was administered (250 mg BID) as monotherapy to 11 ALK+ lymphoma patients, diagnosed with ALK+ Non-Hodgkin lymphoma (NHL) by immunohistochemistry and FISH. Nine patients had a ALCL histology while the remaining 2 were DLBCL Patients had a refractory or relapsed disease after at least one prior chemotherapy regimen and measurable disease. All had involvement at multiple sites (nodal and extranodal) as well as B symptoms and an ECOG performance score of 1-4. Response to therapy was assessed according to RECIST criteria (Therasse, Arbuck et al. J Natl Cancer Inst 92 205-16 2000) The Overall Response Rate (ORR) was 10/11 (91%, 95% CI: 60-99%) and included 9 CR (82%, 95% CI: 51-96%) and 1 PR. Evidence of response by PET/CAT scan was present as early as 12 days. B symptoms disappeared promptly and LDH levels normalized within 30 days after the start of crizotinib. Disease status at the latest follow-up (June 2013) is as follows: 4 patients are in CR under continuous crizotinib treatment; they also test negative by RT-PCR for NPM/ALK (Mussolin, Damm-Welk et al. Leukemia 27 416-22 2012). Three patients (2 with LBCL and 1 with ALCL) died due to disease progression; 1 patient obtained CR, relapsed after 2 months of treatment and is now in CR on continued brentuximab treatment (month 29); 1 patient obtained CR on crizotinib and after 2 months stopped treatment, received an alloBMT and is still in CR; 2 patients treated for relapses post alloBMT obtained CR and are still in CR but they stopped crizotinib after 8-10 months. The two patients with ALK+ LBCL died within 3 months; in those with ALCL the CR rate was 9/9 (100%, 95% CI, 74-100%) with a median duration of 10 months (range 2-37). The 3 years PFS and OS rates are 62% (95% CI, 35-85%) and 73% (95% CI, 40-93%) respectively, with a plateau in the curve after the initial 6 months. In two relapsed patients the kinase domain of NPM-ALK could be amplified from peripheral blood samples obtained at the time of relapse (month 5 and 2). Deep sequencing of these products revealed the presence of different mutations: Q1064R at high prevalence (95%,) in patient (pt) #2 and I1171N (33%) plus M1328I (14%) in pt #6. All these mutations were not present in samples obtained before crizotinib treatment. I1171N was already discovered in an in-vitro screening (Ceccon, Mologni et al. Mol Cancer Res 11 122-32 2012): it commands an intermediate level of resistance to crizotinib (RI: 5.8) which however is cross resistant with other anti-ALK TKI such as AP26113 and NVP-TAE684. The other two mutations were not previously described: they present a RI to crizotinib of 2.4 (M1328I) and 8.5 (Q1064R). Since these residues do not form direct contacts with crizotinib, they probably interact with different structures within the catalytic domain such as the hydrophobic R-spine (I1171N) (Ceccon, Mologni et al. Mol Cancer Res 11 122-32 2012), the activation loop (M1328I), or yet unidentified regions (Q1064R). In conclusion, these positive results extend our initial observation on two patients (Gambacorti-Passerini, Messa et al. N Engl J Med 364 775-6 2011) and provide long-term follow up data. Crizotinib exerted a potent antitumor activity in advanced ALK+ lymphoma and produced durable responses in this population of heavily pre-treated patients, with a benign safety profile. Disclosures: Gambacorti-Passerini: Pfizer: Consultancy, Research Funding; BMS: Consultancy.