ALBERT

Description: Through an immune-mediated graft-versus-leukemia effect, allogeneic hematopoietic stem cell transplantation (HSCT) affords durable clinical benefits for many patients with hematologic malignancies. Nonetheless, subjects with high-risk acute myeloid leukemia or advanced myelodysplasia often relapse, underscoring the need to intensify tumor immunity within this cohort. In preclinical models, allogeneic HSCT followed by vaccination with irradiated tumor cells engineered to secrete GM-CSF generates a potent antitumor effect without exacerbating the toxicities of graft-versus-host disease (GVHD). To test whether this strategy might be similarly active in humans, we conducted a Phase I clinical trial in which high-risk acute myeloid leukemia or myelodysplasia patients were immunized with irradiated, autologous, GM-CSF-secreting tumor cells early after allogeneic, nonmyeloablative HSCT. Despite the administration of a calcineurin inhibitor as prophylaxis against GVHD, vaccination elicited local and systemic reactions that were qualitatively similar to those previously observed in nontransplanted, immunized solid-tumor patients. While the frequencies of acute and chronic GVHD were not increased, 9 of 10 subjects who completed vaccination achieved durable complete remissions, with a median follow-up of 26 months (range 12–43 months). Six long-term responders showed marked decreases in the levels of soluble NKG2D ligands, and 3 demonstrated normalization of cytotoxic lymphocyte NKG2D expression as a function of treatment. Together, these results establish the safety and immunogenicity of irradiated, autologous, GM-CSF-secreting leukemia cell vaccines early after allogeneic HSCT, and raise the possibility that this combinatorial immunotherapy might potentiate graft-versus-leukemia in patients.

Description: Key Points There is no difference in survival after BMT among children of different BMI.

Description: Non-myeloablative (NST) transplantation is increasingly used in the treatment of patients with AML and MDS who are not candidates for myeloblative transplant. Relapse of disease remains a major cause of treatment failure after NST. Predictive factors to identify patients at high risk of relapse are needed to identify patients who would benefit from additional interventions. Attainment of a high degree of donor engraftment achieved early after transplantation may indicate the presence of a more significant allo-immune effect. We have performed a retrospective analysis of 64 patients with AML and MDS receiving NST, assessing the impact of donor chimerism when measured early after transplantation on outcome. Overall survival (OS), progression free survival (PFS) and risk of graft versus host disease (GVHD) were compared for patients achieving ≥90 % or

Description: Abstract 4476 Chronic graft-versus-host disease (cGVHD) is a serious and frequent complication of allogeneic hematopoietic stem cell transplantation (HSCT). It is not known why some patients develop cGVHD and others do not, but identifying predictive biomarkers would facilitate the development of pre-emptive therapeutic strategies. Investigation into the pathophysiology of cGVHD has revealed different patterns of immune reconstitution in patients who develop cGVHD following HSCT. This suggests that the development of cGVHD occurs as a result of altered immune homeostasis and the inability to establish B and T cell tolerance. We prospectively examined 88 patients with hematologic malignancies following allogeneic HSCT at the Brigham and Woman's Hospital/Dana-Farber Cancer Institute between the years 2004 and 2008 and measured plasma cytokines known to modulate effector T cell, regulatory T cell, and B cell homeostasis and function. Seventy-six patients (86%) received reduced intensity conditioning; 84 (95%) received filgrastim-mobilized peripheral blood stem cells. Median follow-up for all patients was 5 years (range 2.9 to 7.3 years). Fifty-nine percent developed cGVHD. Plasma samples were collected at 1, 3, 6, and 12 months after HSCT and multiplex Luminex bead assays were used to measure levels of the following cytokines: Interferon-γ, IL-2, IL-7, IL-1β, IL-12, TNFα, IL-4, IL-5, IL-6, IL-10, and GM-CSF. Cytokine levels in patients who developed cGVHD were compared to patients who did not develop cGVHD. Results are shown in figure 1. Significantly higher levels of IL-4, IL-6, IL-12, and IL-1β were observed at 1 and/or 3 months after transplantation in patients who subsequently developed cGVHD. IL-4 and IL-6 are characteristic of T-helper-2 (TH2) cellular and humoral immune responses previously associated with cGVHD and fibrogenesis. IL-12 and IL-1β have heterogeneous functions including stimulating interferon-γ and TNFα production, enhancing cytotoxic and helper T cells, and promotion of autoimmunity. IL-1α also stimulates IL-6 production and activates fibroblasts. Finally, GM-CSF was significantly elevated in patients who do not develop cGVHD at 1 year following HSCT (2.5 v 1.46 pg/mL, p=0.017). As shown in figure 1, we observed a general pattern for many cytokines, including IFNγ, IL-2, IL-4, IL-5, IL-6, and IL-1β, in which these cytokines are initially similar in both groups, or lower in patients without cGVHD, but gradually increase over time in patients who do not develop cGVHD. In contrast, cytokine levels remain stable in patients with cGVHD and are generally lower 1 year after transplantation in these patients. These late differences may reflect immune suppressive therapies as well as persistent abnormalities of immune homeostasis. Taken together, these results support the hypothesis that alterations in immune homeostasis early after allogeneic HSCT are significantly associated with the subsequent development of cGVHD. Manipulation of the cytokine environment early after HSCT can modulate immune homeostasis and may be of potential prophylactic value. Administration of homeostatic cytokines late after HSCT may also have therapeutic benefit. Disclosures: No relevant conflicts of interest to declare.

Description: Background: Autologous stem cell transplantation (ASCT) can be curative for patients (pts) with relapsed/refractory Hodgkin lymphoma (HL) who are sensitive to salvage therapy, particularly for pts who achieve a complete metabolic response (CMR) before ASCT. Pts who fail multiple salvage regimens have inferior outcomes and are generally considered poor candidates for ASCT. Recent studies suggest that anti-PD-1 monoclonal antibodies (mAbs) may restore sensitivity to cytotoxic therapy in HL pts with previously chemorefractory disease. We hypothesized that PD-(L)1 mAb-based salvage therapy may therefore also improve ASCT outcomes for HL pts who had failed salvage therapy. Methods: Medical records were reviewed at 13 US transplant centers to identify pts with a diagnosis of classic HL who failed at least 2 systemic therapies, were treated with a PD-1 or PD-L1 mAb (either alone or in combination) as 3rd line or later therapy, and subsequently underwent ASCT. Results: 44 eligible pts were identified. The median age was 33 (range 19-68). Pts received ABVD (39), AVD (2), brentuximab vedotin (BV) + AVD (1), Stanford V (1), or eBEACOPP (1) as 1st line therapy. 26 pts (59%) were refractory to 1st line treatment and 8 additional pts (18%) relapsed within 12 months. High-risk clinical features were observed frequently at 1st relapse including extranodal involvement (47%), B symptoms (27%), and advanced stage (64%). Pts received PD-(L)1 based treatment after failing 2 lines (32%), 3 lines (57%), or ≥4 lines (11%) of therapy. 32 pts (73%) were refractory to the line of therapy before PD-(L)1, 25 pts (57%) to 2 consecutive lines before PD-(L)1, and 10 pts (22%) to 3 consecutive lines before PD-(L)1. 16 pts (36%) were refractory to ≥2 salvage therapies immediately before PD-(L)1 therapy and 17 (39%) were refractory to all prior treatments. 39 pts (89%) received BV or a BV-based combination before ASCT. 67% were BV-refractory, including 86% of those receiving BV monotherapy. Pts received a median of 6 doses of a PD-(L)1 mAb (range 2-26) either as monotherapy (75%) or as part of a PD-1 based combination (25%). The median time from last dose of PD-(L)1 mAb to ASCT was 54 days (range 12-386). Best response to PD-(L)1-based therapy was CR (53%), PR (33%), SD (12%), or PD (2%). The median number of systemic therapies (including PD-(L)1) before ASCT was 4 (range 3-7) and 12 pts (27%) received intervening salvage therapy between PD-(L)1 treatment and ASCT. Pre-ASCT PET status was CR in 31 pts (70%), PR in 9 (18%), SD in 4 (9%), and PD in 1 (2%). There were no ASCT-related deaths. 2 pts developed BCNU pneumonitis and 1 developed engraftment syndrome. All 3 pts responded to steroids. 14 pts (32%) have received maintenance therapy with BV (4), a PD-1 mAb (8), or BV + PD-1 mAb (2). 4 pts (9%) received consolidative radiation. With a median post-ASCT follow-up of 12.2 months, progression-free survival (PFS) at 1 yr was 91% [95CI 75-97]. Notably, resistance to chemotherapy before PD-(L)1 therapy did not predict worse post-ASCT outcomes (see Table). 1-yr PFS was 90% for pts who were refractory to the 3 lines of therapy before PD-(L)1, 93% for pts refractory to ≥2 salvage therapies immediately before PD-(L)1, and 90% for pts refractory to all prior treatments. Favorable 1-yr PFS was also seen among pts who received PD-(L)1 as 4th or later line therapy (88% vs 100% for pts receiving PD-[L]1 as 3rd line, p=0.17) and among pts who failed to achieve a CMR on pre-ASCT PET (1-yr PFS 81% vs 96% for CMR pts, p=0.34). Lack of response to PD-(L)1 therapy (1-yr PFS 67% vs 96%, p=0.04), receipt of intervening salvage therapy (1-yr PFS 72% vs 100%, p=0.026), and increasing age (HR 1.11, p=0.015) were all significant predictors of inferior PFS. 1-yr overall survival was 100%. Conclusions: This high-risk cohort is heterogenous in terms of number of prior therapies and degree of chemoresistance, but excellent post-ASCT outcomes were observed among even the most heavily pre-treated, chemorefractory subgroups. Outcomes for PD-(L)1 responders were particularly favorable with a 1-yr PFS of 96%, suggesting that response to PD-(L)1 rather than prior chemotherapy may be the more important predictor of post-ASCT outcomes in this pt population. While longer follow-up is required to confirm the durability of these remissions, ASCT can be considered for HL pts responding to PD-(L)1 based salvage therapy, even if they have previously demonstrated a high degree of chemoresistance. Table Disclosures Nieto: Novartis: Research Funding; Astra-Zeneca: Research Funding; Affimed: Research Funding; Affimed: Consultancy. Byrne:Karyopharm: Research Funding. Maddocks:BMS: Research Funding; Novartis: Research Funding; Teva: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Research Funding. Svoboda:BMS: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; Merck: Research Funding; Incyte: Research Funding; Pharmacyclics: Consultancy, Research Funding; AstraZeneca: Consultancy; Celgene: Research Funding; Kyowa: Consultancy; Kite: Consultancy. McGuirk:Juno Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; ArticulateScience LLC: Other: Assistance with manuscript preparation; Pluristem Ltd: Research Funding; Gamida Cell: Research Funding; Kite Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Research Funding; Fresenius Biotech: Research Funding; Astellas: Research Funding; Bellicum Pharmaceuticals: Research Funding. Advani:Kyowa Kirin Pharmaceutical Developments, Inc.: Consultancy; Millennium: Research Funding; Janssen: Research Funding; Cell Medica, Ltd: Consultancy; Regeneron: Research Funding; Autolus: Consultancy, Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees; Stanford University: Employment, Equity Ownership; Agensys: Research Funding; Kura: Research Funding; Pharmacyclics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche/Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Forty-Seven: Research Funding; Celmed: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Research Funding; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Merck: Research Funding; Seattle Genetics: Consultancy, Research Funding; Infinity Pharma: Research Funding; Gilead Sciences, Inc./Kite Pharma, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees. Cohen:Seattle Genetics, Inc.: Consultancy, Research Funding; Bristol-Meyers Squibb Company: Research Funding; Takeda Pharmaceuticals North America, Inc.: Research Funding; Gilead/Kite: Consultancy; LAM Therapeutics: Research Funding; UNUM: Research Funding; Hutchison: Research Funding; Astra Zeneca: Research Funding; ASH: Research Funding; Lymphoma Research Foundation: Research Funding; Genentech, Inc.: Consultancy, Research Funding; Janssen Pharmaceuticals: Consultancy. Frigault:Xenetic: Consultancy; Foundation Medicine: Consultancy; Novartis: Consultancy; Nkarta: Consultancy; Juno/Celgene: Consultancy; Kite/Gilead: Honoraria; Incyte: Consultancy. Chen:Magenta: Consultancy; Takeda: Consultancy; Incyte: Consultancy; Kiadis: Consultancy; Abbvie: Consultancy. Lynch:Johnson Graffe Keay Moniz & Wick LLP: Consultancy; Rhizen Pharmaceuticals S.A: Research Funding; Juno Therapeutics: Research Funding; Takeda Pharmaceuticals: Research Funding; Incyte Corporation: Research Funding; T.G. Therapeutics: Research Funding. Smith:Seattle Genetics: Research Funding; Denovo Biopharma: Research Funding; Ayala (spouse): Research Funding; Merck Sharp & Dohme Corp: Consultancy, Research Funding; Acerta Pharma BV: Research Funding; Incyte Corporation: Research Funding; Ignyta (spouse): Research Funding; Genentech: Research Funding; Bristol-Myers Squibb (spouse): Research Funding; Portola Pharmaceuticals: Research Funding; Pharmacyclics: Research Funding; AstraZeneca: Membership on an entity's Board of Directors or advisory committees, Research Funding. Ho:Jazz Pharmaceuticals: Research Funding; Jazz Pharmaceuticals: Consultancy; Omeros Corporation: Membership on an entity's Board of Directors or advisory committees. Armand:Affimed: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Sigma Tau: Research Funding; Infinity: Consultancy; Otsuka: Research Funding; Genentech: Research Funding; Pfizer: Consultancy; ADC Therapeutics: Consultancy; Tensha: Research Funding; Roche: Research Funding; Adaptive: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Herrera:Merck: Consultancy; BMS: Consultancy; Genentech: Research Funding; Adaptive Biotechnologies: Consultancy; Gilead Sciences: Research Funding; KiTE/Gilead: Consultancy; Genentech: Consultancy; Merck: Research Funding; Astra-Zeneca: Research Funding; Seattle Genetics: Consultancy; BMS: Research Funding; Seattle Genetics: Research Funding.

Description: Introduction Umbilical cord blood (UCB) transplantation yields survival comparable to adult stem cell transplantation, but there is significant variability among UCB products, in large part because of differences in processing conditions from collection to cryopreservation at cord banks. While impact of processing conditions on the actual UCB product has been reported, there is a little information regarding impact on patient-level outcomes. We report a retrospective exploratory analysis of processing performed at cord banks prior to freezing of UCB units and the impact on clinical outcomes such as engraftment, cord dominance, transplant-related mortality (TRM) and overall survival (OS) in 133 UCB recipients. Methods All adult recipients of unmanipulated double UCB transplantation (dUCBT) for hematologic malignancy from 2003 to 2011 at the 3 Harvard Cancer Center sites (Dana-Farber Cancer Institute, Massachusetts General Hospital, and Beth Israel Deaconess Medical Center) were included. All UCB units were thawed and washed prior to infusion. Multivariate analyses controlled for prognostic factors including age, malignancy, conditioning intensity, degree of HLA matching, presence of anti-HLA antibodies, order of cord infusion, TNC/kg, and CD34+/kg infused. Time to engraftment and treatment-related mortality were analyzed in the competing risks regression setting and survival was analyzed using proportional hazards models. Results 98 recipients underwent reduced-intensity conditioning, primarily fludarabine, melphalan and anti-thymocyte globulin. 35 underwent myeloablative conditioning, primarily cyclophosphamide and total body irradiation. Of the 48 banks contributing cords to this study, 42% employed simple cryopreservation and 23% employed plasma/volume reduction only, at some point during operation. These 2 methods were considered “RBC replete”. Of the 34 banks sharing their current practices, simple cryopreservation is no longer practiced by any; 12% practice plasma/volume reduction alone. 88% of the banks now employ RBC depletion, of which 67% use hydroxyethyl starch for RBC sedimentation and 67% use automated processing systems. Engraftment – Neutrophil and platelet engraftment were not impacted by RBC depletion, sedimentation with hydroxyethyl starch, automated processing, HLA matching or CD34+/kg dose in multivariate analyses. An anti-HLA antibody against one or more cords (p

Description: Investigation of the effects of rituximab (anti-CD20) on B-cell-activating factor of the tumor necrosis factor family (BAFF) and B cells would better define the significance of B-cell homeostasis in chronic graft-versus-host disease (cGVHD) pathophysiology. We studied 20 cGVHD patients at a median of 25 months after rituximab treatment when most patients had recovered total B-cell numbers. A total of 55% of patients had stable/improved cGVHD, and total B-cell numbers in these patients were significantly higher compared with rituximab-unresponsive patients. Although total B-cell number did not differ significantly between cGVHD groups before rituximab, there was a proportional increase in B-cell precursors in patients who later had stable/improved cGVHD. After rituximab, BAFF levels increased in all patients. Coincident with B-cell recovery in the stable/improved group, BAFF/B-cell ratios and CD27+ B-cell frequencies decreased significantly. The peripheral B-cell pool in stable/improved cGVHD patients was largely composed of naive IgD+ B cells. By contrast, rituximab-unresponsive cGVHD patients had persistent elevation of BAFF and a predominance of circulating B cells possessing an activated BAFF-RLoCD20Lo cell surface phenotype. Thus, naive B-cell reconstitution and decreased BAFF/B-cell ratios were associated with clinical response after rituximab in cGVHD. Our findings begin to delineate B-cell homeostatic mechanisms important for human immune tolerance.

Description: Sirolimus-based immunosuppressive regimens in organ transplantation have been associated with a lower than expected incidence of cytomegalovirus (CMV) disease. Whether sirolimus has a similar effect on CMV reactivation after allogeneic hematopoietic stem cell transplantation (HSCT) is not known. We evaluated 606 patients who underwent HSCT between April 2000 and June 2004 to identify risk factors for CMV reactivation 100 days after transplantation. The cohort included 252 patients who received sirolimus-tacrolimus for graft-versus-host disease (GVHD) prophylaxis; the rest received non–sirolimus-based regimens. An initial positive CMV DNA hybrid capture assay was observed in 225 patients (37.1%) at a median 39 days after HSCT for an incidence rate of 0.50 cases/100 patient-days (95% confidence interval [CI], 0.44-0.57). Multivariable Cox modeling adjusting for CMV donor-recipient serostatus pairs, incident acute GVHD, as well as other important covariates, confirmed a significant reduction in CMV reactivation associated with sirolimus-tacrolimus–based GVHD prophylaxis, with an adjusted HR of 0.46 (95% CI, 0.27-0.78; P = .004). The adjusted HR was 0.22 (95% CI, 0.09-0.55; P = .001) when persistent CMV viremia was modeled. Tacrolimus use without sirolimus was not significantly protective in either model (adjusted HR, 0.66; P = .14 and P = .35, respectively). The protective effect of sirolimus-containing GVHD prophylaxis regimens on CMV reactivation should be confirmed in randomized trials.

Description: Abstract 3029 Background: In patients with hematologic malignancies undergoing myeloablative hematopoietic stem cell transplantation (HSCT), an elevated serum ferritin prior to HSCT has been consistently associated with increased mortality. While serum ferritin is strongly correlated with liver iron content (LIC), to date no study has directly examined the effect of elevated LIC on HSCT outcomes. Furthermore, there are no studies of pre-transplantation chelation in this population. We conducted 2 prospective studies in patients with AML, ALL, or MDS undergoing HSCT. In the first, 45 patients were followed for 〉1 year with serial measurements of serum iron parameters and liver and cardiac iron (by MRI). In the second, we treated patients with severe iron overload (ferritin ≥ 1000 ng/ml and liver iron content (LIC) ≥ 5 mg/gdw) with deferoxamine 50 mg/kg/d starting in the weeks prior to transplantation and continuing until day -1, with the goal of controlling labile plasma iron (LPI) and especially the expected conditioning-induced rise in LPI. Results: The baseline characteristics of the patients on the observational study have been described in a prior publication (Armand et al., BBMT 2011). 5 patients (2 with AML in CR, 2 with AML and active disease, 1 with MDS) were enrolled on the chelation study; the median serum ferritin was 3, 746 ng/ml, and LIC 11.7 mg/gdw. They received deferoxamine for a median of 19 days before stem cell infusion. No significant drug-related toxicity occurred except for one episode of transient hypotension. There was no significant change in LIC after this short course of chelation. None of the 5 patients had a positive LPI assay before chelation or at the onset of conditioning; however, despite deferoxamine treatment, 2/5 had elevated LPI post-conditioning. Among those 5 patients, there was no disease relapse or death at a median follow-up of 20 months; only 1 patient developed grade II acute GVHD, and no patient developed VOD. Among the 50 patients in both studies combined, there was no significant change in serum ferritin, LIC or cardiac T2* in the first year after HSCT. After a median follow-up of 24 months, the estimated 2y overall survival (OS) and progression-free survival were 54% and 46%, respectively. When patients on the chelation study were excluded, there was a significant difference in OS for patients with pre-HSCT ferritin 〉 2, 500 ng/ml (2y OS 21% versus 62%, p =0.03) (Figure, panel A), similar to prior studies. However, there was no difference in OS, PFS, relapse or NRM for patients stratified by pre-HSCT LIC, regardless of the cutoff used and whether or not chelated patients were included (Figure, panel B). There was also no discernible impact of LIC on acute GVHD or VOD incidence. The difference in OS based on ferritin was apparent even among the patients with LIC