ALBERT

Description: Background: Lower total CD34+ cell dose and increased HLA-mismatch are known predictors of engraftment failure and higher transplant related mortality (TRM) in cord blood (CB) recipients. To compensate for cell dose, double unit grafts (DUCBT) are commonly used in adult. However, in the majority of patients (pts), only one of the two CB units engrafts. Identification of the factors that predict which unit will engraft remains elusive, although increased recipient-donor HLA-matching and larger CD3+ cell dose have been associated with the predominating unit in a single center retrospective analysis (Ramirez et al, 2012). Historically, CB units are selected by maximizing matching at the HLA-A and -B antigen and -DRB1 allelic level. Evidence supports that matching at HLA-C appears to decrease TRM, and many clinicians incorporate HLA-C antigen matching into unit selection. It is unclear, however, if HLA-C matching predicts the engrafting unit in DUCBT. This study retrospective study evaluates whether HLA-C matching is associated with the winning CB unit. Design: Clinical data was reviewed from all pts with a hematologic malignancy receiving a DUCBT at Moffitt Cancer Center between November 13, 2009 and August 29, 2013. Chimerism studies identified the predominating unit (〉 65% single unit) between day 21 and day 28. Subsequent chimerism analyses performed at a median of day 100 confirmed unit predominance. Unit selection required intermediate resolution antigen match at HLA-A, -B, -C, and high resolution allele match at -DRB1. Units were a minimum of 4/8 matched to the patient and each other with a minimum cell dose of 1.5 x 107 total nucleated cell dose (TNC) /kg. Serology for donor specific antibodies against both units was negative. Results: Excluding 6 pts who were missing HLA-C typing on one or both CB units, 54 pts with hematologic malignancies (ALL=6, MDS/AML=29, Other=19) received chemotherapy and total body irradiation as part of a myeloablative conditioning (MAC) or reduced intensity conditioning (RIC) with or without thymoglobulin (ATG) followed by a DUCBT (MAC=14, RIC=23, RIC+ATG=17). Median age was 52 (range 22-69) years. Seven pts demonstrated persistent mixed chimerism in the myeloid and/or lymphoid cell lines beyond day 100. A total of 20 pts with available chimerism data received at least one CB unit matched to the recipient at HLA-C, with one patient excluded due to persistent mixed chimerism. Six pts received both CB units matched at HLA-C, but of the 13 pts receiving one matched and one mismatched unit, the HLA-C matched unit was the engrafting unit 69% (9/13) of the time. Comparing similar HLA mispairings, a matched unit engrafted over a mis-matched unit at HLA-A 50% (5/10) of the time, at HLA-B 38% (5/13) of the time, and at HLA-DRB1 50% (3/6) of the time. TNC dose (larger vs smaller with a required difference of at least 0.03 x 107 TNC/kg), order of infusion (first vs second unit), and overall CB unit HLA matching (4/8-8/8), were assessed as potential predictors for engraftment. Of evaluable patients, the CB unit with the larger TNC engrafted 44% (16/36) of the time, and the first unit infused was the engrafting unit 54% (21/39) of the time. In patients with an unequal overall match grade between the CB units, the better HLA-matched CB unit engrafted 64% (14/22) of the time. Survival analysis of all pts revealed that those who received at least one CB unit antigen matched at HLA-C (n=20) had a 100 day and 1 year overall survival (OS) of 85% (95% Confidence Interval(CI): 67–97%) and 55% (95% CI: 33–75), respectively, whereas pts receiving two HLA-C mismatched CB units (n=34), 100 day OS was 62% (95% CI: 45–77) with 1 year OS 44% (95% CI: 28–61) (Fig 1). Conclusion: HLA-C antigen matching appears to help predict the winning unit in settings of HLA-match disparity and DUCBT. Confirmation in a larger population of DUCBT recipients is necessary. To date, the effects of HLA matching and other variables influencing engraftment have been predominately evaluated in recipients of single unit transplants and studies in DUCBT have been limited. Further investigation assessing HLA matching as well as donor-donor interactions is best served through a multicenter data resource. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

Description: Background Twenty four-hour urine collection remains one of the most crucial tools for the diagnosis and monitoring of proteinuria and quantification of urinary monoclonal protein in patients with plasma cell dyscrasias (PCD) even though it is cumbersome. Nephrology guidelines recommend replacement of 24-hour urine collection with a spot urine protein/creatinine (Pr/Cr) ratio for the measurement of proteinuria. However, only limited data exist regarding accuracy of spot urine Pr/Cr ratio in patients with PCD and utility of this measure to estimate urinary paraprotein remains uncertain. We conducted a prospective study evaluating the role of spot urine Pr/Cr ratio in patients with PCD. Methods From 04/2012 to 05/2013, a total of 120 PCD patients were prospectively enrolled at Moffitt Cancer Center. Oliguric patients or those requiring dialysis were ineligible. Spot urine was collected on the same day as 24-hour urine collection. Spot urine Pr/Cr ratios were compared to 24-hour urine collections with regard to the amount of (1) total protein and (2) monoclonal protein (M-spike). Results Eighty four out of 120 patients (70%) were evaluable (17 did not provide spot urine samples; no Pr/Cr ratios available in 11; protein below the level of detection in 7; and one without 24-hour urine collection). Evaluable patients had a median age of 68 (range, 36 - 90) years, 63% were male, and 85% were Caucasian. Primary diagnoses were myeloma (n=74; 88%), amyloidosis (n=4), multiple plasmacytomas (n=2), solitary plasmactyoma (n=1) and MGUS (n=3). Prior therapies included chemotherapy in 95% and autologous transplant in 45%. Comorbidities included hypertension (48%), chronic kidney disease (30%), diabetes (15%), coronary artery disease (8%), atrial fibrillation (7%) and congestive heart failure (2%). The median serum creatinine was 0.9 mg/dL (range, 0.5 - 5.1). The median spot urine Pr/Cr ratio was 137 mg/g creatinine (range, 26 - 21,447). The median 24-hour urine protein was 120 mg/24h (range, 27 - 15,092), and the median urine M-spike was 1.2 mg (range, 0 - 8,099). More than half of spot urine samples were collected in the morning (59%). There were strong correlations between (1) spot urine Pr/Cr ratio and 24-hour total urine protein (Spearman correlation coefficient=0.91, p 〈 0.0001), and (2) spot urine Pr/Cr ratio and 24-hour urine M-spike (Spearman correlation coefficient=0.91, p 〈 0.0001). The timing of spot urine sample collection had no significant effects on the correlations (p = 0.46 and 0.95 by Wilcoxon rank-sum test). Conclusions Spot urine Pr/Cr ratio strongly correlates with degrees of proteinuria measured in 24-hour urine collection and may also predict the quantity of urine M-spike in non-oliguric PCD population. Spot urine Pr/Cr ratio is a potentially useful marker as a screening tool or an alternative semi-quantitative measure for rapid estimation of proteinuria which may be used for longitudinal patient follow-up in lieu of cumbersome repeated 24-hour collections. Disclosures: No relevant conflicts of interest to declare.

Description: Introduction: Gastro-intestinal GVHD (GI GVHD) is a common and severe complication of allogeneic hematopoietic cell transplantation (HCT). Systemic glucocorticoids remain the standard of care for GI GVHD, despite their incomplete efficacy and toxicity. Steroid-sparing activity and improved survival were reported with oral administration of poorly absorbed beclomethasone dipropionate (BDP) in combination with systemic glucocorticoids for upper GI GVHD, and promising results were described with the adjunct of budesonide (BUD) for lower GI GVHD. No data have been reported on BDP or BUD without systemic glucocorticoids. Our team has adopted the practice of administering BDP/BUD without systemic glucocorticoids as fist-line therapy. Here we assess safety and efficacy of our practice in the treatment of isolated GI GVHD. Methods: We analyzed retrospective data from 297 consecutive patients (pts) with isolated GI GVHD after hematopoietic peripheral blood stem cell transplantation performed at the Moffitt Cancer Center between July 2004 and June 2013. At discretion of the treating physician, patients with upper with or without lower GI GVHD were treated with BDP (5 mg BID or TID orally), BDP plus prednisone (PRED 0.5-2 mg/kg or equivalent glucocorticoid dose), BDP+BUD (3 mg BID or TID orally) or BDP+BUD+PRED. The primary study endpoint was response of GI GVHD after 28 days, defined as complete resolution of all GI symptoms without addition of other immune suppressive (IS) agent(s) or partial reduction of GI symptoms, without resolution and without addition of other IS agent(s). Secondary endpoints were response to treatment after 200 days, chronic GVHD (CGVHD), CMV infection, relapse free survival (RFS), and overall survival (OS). All endpoints were analyzed according to treatment arm (Figure 1). A multivariable model was used to test the association between response after 28 days and treatment arm, after adjusting for primary diagnosis, conditioning regimen, disease status at HCT, pts/donor characteristics, GI GVHD overall grade, GI GVHD site, and albumin level. Results: BDP vs. BDP+PRED. Baseline characteristics were well balanced among the BDP (n=90) and BDP+PRED (n=24) groups, including treatment for isolated upper GI GVHD (84% vs. 67%, p=0.08), with the remainder affected by both upper and lower GI GVHD. BDP+PRED showed a significantly higher response of GI GVHD after 28 days compared to BDP (88% vs. 56%, multivariate OR 23, 95% CI 3-161, p=0.002); however there was no significant difference in response after 200 days (50% vs. 33%, univariate p=0.5). There were no significant differences in terms of treatment duration, requirement of additional IS agents, CMV reactivation, CGVHD development, RFS and OS between the two treatment cohorts. BDP+BUD vs. BDP+BUD+PRED. BDP+BUD+PRED pts (n=53) had more rapid onset of GI GVHD (median 20 vs. 26 days after HCT, p=0.001), higher incidence of lower GI involvement (61% vs. 38%, p=0.008) and higher incidence lower GI stage II-III GVHD (p=0.0004) compared to BDP+BUD pts (n=130). Despite adjusting for these higher risk features by multivariable analyses, BDP+BUD+PRED was associated with a significantly higher response after 28 (90% vs. 75%, multivariate OR 15, 95% CI 3-62, p=0.0003) and 200 days (70% vs. 45%, univariate p=0.0003). There were no significant differences in treatment duration, CMV reactivation, CGVHD development, RFS and OS between the two treatment cohorts. Conclusions: This retrospective analysis suggests that the addition of systemic PRED to topical BDP/BUD therapy for isolated GI GVHD was associated with a better response after 28 days of treatment. Despite the inferiority in GI GVHD response, there were no differences in secondary endpoints including treatment duration, CMV reactivation, RFS and OS. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

Description: TLK199 is a novel glutathione analog that is a selective inhibitor of the enzyme glutathione S-transferase (GST) P1-1. TLK199 treatment induces hematopoietic cell proliferation and differentiation through activation of the MAP kinase signaling pathway leading to activation of JNK and ERK2. In rodent models of chemotherapy induced neutropenia, treatment with TLK199 accelerated recovery of white cell counts at rates comparable to treatment with G-CSF. We now report TLK199 treatment of myeloid progenitor cells isolated from normal human blood resulted in the increased formation of CFU-GM (46%) CFU-MK (47%) and BFU-E (142%) lineages over baseline. A corresponding increase in the percentage of cells expressing CD11b, a granulocyte and monocyte marker, was observed in the CFU-GM cells. Since TLK199 is currently being evaluated in a Phase 2a trial in patients with refractory MDS, we examined the effect of treatment on formation of BFU-E, CFU-GM and CFU-GEMM before and after TLK199 treatment at doses of 50 to 400 mg/m2. A significant increase in the number of hematopoietic progenitor cell colonies measured from patient peripheral blood and bone marrow was observed as early as Day 4 of Cycle 1 as compared to pretreatment baseline. Ten of 12 patients showed an increase in at least one colony forming type (BFU-E, CFU-GM and CFU-GEMM) and 7 of 12 had an increase in all three colony forming types following TLK199 administration. These results correlate with clinical improvement in hematological parameters in peripheral blood and bone marrow observed in MDS patients treated with TLK199. Studies are underway to define the mechanism of bone marrow and peripheral blood count recovery observed following treatment of MDS patients with TLK199 and the role of GST P1-1 as a regulatory element in myeloid proliferation and differentiation.

Description: Abstract 4162 Background: Plasmablastic lymphoma (PBL) is a distinctive B-cell lymphoma that shows diffuse proliferation of large neoplastic cells resembling B-immunoblasts and having an immunophenotype of plasma cells. It was originally described as a rare variant of diffuse large B cell lymphoma involving the oral cavity and occurring in the clinical setting of HIV and latent EBV infection (Delecluse et al. 1997). However, the natural history of this disease in HIV-negative (HIV-) patients is poorly understood due to its rarity. Methods: Patients with a histologic diagnosis of PBL from January 1999 to June 2010 at Moffitt Cancer Center were identified and their charts were reviewed. Relevant clinical, pathologic, laboratory data and treatment variables were recorded and analyzed. Results: A total of 16 patients with PBL were evaluated including 9 HIV- cases, 5 HIV positive (HIV+) cases and 2 cases with unknown HIV status. The mean age at diagnosis was 39.8 and 58.4 years for HIV+ and HIV- patients (p=0.01) respectively. Flow cytometry and/or immunohistochemical staining analyses showed all cases phenotypically expressed at least one plasma cell marker (CD138 12/14; bright CD38 8/8; MUM1 8/8) and were negative for B-cell markers tested (CD20 16/16; PAX-5 3/3). All 5 HIV+ patients had CD4 count less than 100 (range 5–82). All 4 patients that had documented EBV status were positive. They all presented with advanced stages ranging from IIIB to IVB. Two patients received treatment, but did not have any response. All the HIV+ patients died within 6 months from diagnosis. HIV- cases (9) were more heterogeneous (summarized in Table 1). The stage at diagnosis varied from IE to IV. The list of common disease sites in the order of the frequency was following: oral-facial structures (5), lymph nodes (LN) (4), bone marrow (BM) (2), bone (1), GI tract (1). EBV was associated with 4 out of 7 cases while in 2 patients, the EBV status was unknown. Patient #5 developed PBL secondary to EBV reactivation 5 months post umbilical cord blood allogeneic stem cell transplant (HSCT) for MDS. Seven out of 9 patients received CHOP as a front-line therapy and 2 were treated with hyper-CVAD. Six out of 8 patients with assessed responses achieved complete response (CR), while one had very good partial response adequate for HSCT consolidation and the other one required salvage therapy. Four patients underwent autologous HSCT after achieving CR1. Three of them were stage IV at diagnosis and 1 was stage IIB. Two of these 4 patients were alive and disease-free (A-NED) at the end of the follow-up. The remaining 2 patients (#2 and #3) had disease recurrence at 2 and 14 months post HSCT, respectively. Interestingly, the patient #3 was treated with bortezomib/dexamethasone and achieved CR2. Despite consolidation with allogeneic HSCT, this patient recurred in 5 months post HSCT and died. The mean overall survival for our HIV- patients was 46.6 months with median survival not reached. Conclusion: Our study suggests that HIV- PBL is a heterogeneous disorder in terms of etiology and clinical course. A limited understanding of pathobiology and a lack of active biological agents for this subtype of B-cell lymphoma due to absence of cell surface CD20 expression might result in unfavorable prognosis in patients with advanced stages. Currently, more aggressive induction chemotherapy and consolidation with HSCT in CR1 have been offered to this group of patients at our center. A role of bortezomib in the front-line or relapse treatment settings needs to be tested on a larger cohort of patients. Disclosures: Off Label Use: Bortezomib use in this type of disease is considered off-label. Similarly, rituximab use is also off-label since CD20 is negative in this disease.

Description: Background: Multiple myeloma remains incurable despite impressive array of available novel agents and therapeutic strategies. Allogeneic hematopoietic cell transplantation (HCT) remains the only potentially curative option for patients with multiple myeloma but it is limited by its toxicities. We previously reported initial result of a phase 2 study of upfront allogeneic HCT in myeloma patients achieving at least very good partial response (VGPR) after initial therapy (Nishihori, et al. ASH 2013 abstract 3390) and here we report more mature results after a median follow up of 3 years. Methods: Twenty seven myeloma patients received allogeneic HCT between 01/2010 and 02/2015 at Moffitt Cancer Center (NCT 00948922). Eligible patients were age ≤ 60, achieving first ≥ VGPR or complete response (CR), and have 8/8 HLA-matched related or unrelated donors. Conditioning regimen consisted of fludarabine 30 mg/m2 for 4 days (days -6, -5, -4, and -3) and melphalan 70 mg/m2 for 2 days (days -4 and -3) followed by a single dose of bortezomib 1.3 mg/m2 on day -3 (Flu/Mel/Vel regimen). GVHD prophylaxis was initially left to the discretion of physicians but later modified to only tacrolimus/methotrexate. No maintenance therapy was prescribed after allogeneic HCT. Results: The median age at transplant was 50 (range, 25-58) years. Disease status at the time of allogeneic HCT was VGPR (n=17: 63%) and CR/stringent CR (n=10: 37%). All patients received unmanipulated peripheral blood stem cell grafts from HLA-matched related donors (n=14) or HLA-matched unrelated donors (n=13). Graft-versus-host disease (GVHD) prophylaxis was tacrolimus plus either methotrexate (n=19: 70%), or mycophenolate mofetil (n=4), or sirolimus (n=4). All patients achieved neutrophil engraftment with a median of 15 (range, 11-19) days. Platelet engraftment was achieved with a median of 17 (range, 13 - 35) days and 2 patients did not recover platelets. The cumulative incidences of grades II-IV and grades III-IV acute GVHD at day 100 were 63.6% (95% confidence interval (CI): 43.1-81.1) and 19.6% (95%CI: 5.4-39.9), respectively. The cumulative incidence of moderate to severe chronic GVHD was 56.4% (95%CI: 36.3-75.5) at 1-year. The cumulative incidences of transplant-related mortality at day 100, 1 year and 2 years were 7.4% (95%CI: 0.8-20.0), 11.1% (95%CI: 2.7-25.4), and 11.1% (95%CI: 2.7-25.4), respectively. Progression-free survival estimates at 1, 2, and 3 years were 74.1% (95%CI: 53.2-86.7), 65.1% (95%CI: 43.3-80.2), and 65.1% (95%CI: 49.9-87.5), respectively. With a median follow up of 39 months for surviving patients, overall survival estimates at 1, 2 and 3 years were 85% (95%CI: 64.9-94.1), 75.4% (95%CI: 52.6-88.3), and 69.1% (95%CI: 53.8-93.5), respectively. Conclusions: The results of the this phase 2 trial of upfront allogeneic HCT with fludarabine/melphalan/bortezomib (Flu/Mel/Vel) conditioning are promising and provide the rationale for reasonable potentially curative option to younger and fit patients who are eligible for upfront intensive consolidation strategy. This approach may be potentially valuable for those with high-risk myeloma and a multicenter study is currently being conducted (BMT CTN protocol 1302:NCT02440464). Disclosures Nishihori: Novartis: Research Funding; Signal Genetics: Research Funding. Baz:Takeda/Millennium: Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Research Funding; Novartis: Research Funding; Karyopharm: Research Funding; Bristol-Myers Squibb: Research Funding; Signal Genetics: Research Funding. Shain:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Amgen/Onyx: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Signal Genetics: Research Funding; Takeda/Millennium: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Speakers Bureau. Alsina:Signal Genetics: Consultancy; Novartis: Research Funding; Takeda/Millennium: Research Funding; Amgen/Onyx: Consultancy, Speakers Bureau.

Description: Abstract 4581 Allogeneic hematopoietic cell transplantation (HCT) from HLA-identical siblings has been shown to prolong survival of patients with multiple myeloma in some studies. However, all published clinical trials of up front allogenic transplant for myeloma were conducted before thalidomide, lenalidomide and bortezomib became available; as such, less than 10% of the patients were in complete remission (CR) at time of transplantation. With contemporary therapy incorporating novel agents, more than 50% of patients achieve very good partial response (VGPR) or better (VGPR or CR). We summarize our experience with the safety and efficacy of allogeneic transplantation for patients achieving VGPR or better following induction therapy containing novel agent(s). Thirteen myeloma patients with first VGPR or CR received allogeneic HCT between July 2007 and January 2011. Median age at transplant was 45 years (range, 25 – 59), median time from initial therapy to transplant was 236 days (range, 122 – 410). Six patients (46%) have high-risk cytogenetics/FISH. Five patients received bortezomib plus lenalidomide induction therapy and eight patients received bortezomib-induction. Three patients (23%) underwent autologous HCT with melphalan plus bortezomib conditioning (melphalan 100 mg/m2 for 2 days followed by bortezomib 1.3 mg/m2) subsequent to induction therapies to achieve further cytoreduction prior to allogeneic HCT. Median number of prior therapies was 2 (range, 1–2). Disease status at the time of allogeneic HCT was stringent CR (n=5), CR (n=3), and VGPR (n=5). All patients received unmanipulated peripheral blood stem cell grafts from HLA-matched sibling donors (n=5) and HLA-matched unrelated donors (n=8). Six patients received fludarabine 30 mg/m2 for 4 days and melphalan 70 mg/m2 for 2 days followed by a single dose of bortezomib 1.3 mg/m2 (Flu/Mel/Vel). Seven patients received fludarabine 40 mg/m2 for 4 days and melphalan 70 mg/m2 for 2 days (Flu/Mel). Graft-versus-host disease (GVHD) prophylaxis constitutes tacrolimus/methotrexate (n=5), tacrolimus/mycophenolate mofetil (n=4), and tacrolimus/sirolimus (n=4). All patients achieved neutrophil engraftment after a median of 17 days (range, 11 – 19), and all patients achieved platelet engraftment after a median of 17 days (range, 12 – 21). All patients established stable donor cell chimerism. Best responses after allogeneic HCT were sCR (n=10), CR (n=2) and VGPR (n=1). The cumulative incidence of grades 2–4 acute GVHD at day 100 was 57% (95% CI 0.30 – 1.00) with Flu/Mel conditioning and 33% (95% CI 0.11 – 1.00) for Flu/Mel/Vel conditioning, respectively (p=0.24). This observation suggests that a single dose of bortezomib 48 hours before HCT may prevent GVHD. One patient died of GVHD complications, 1 had disease progression and 11 remain alive, progression free with a median follow-up of one year (range 4 months to 4 years). The one year progression-free survival estimate is 90% (95%CI 0.71 – 1.00). These initial data indicate that allogenic transplant for myeloma in VGPR or CR is well tolerated. Longer follow-up is required to assess the efficacy of allogeneic HCT in the era of novel agents in preventing progression of the disease. Disclosures: Baz: Millenium: Research Funding, Speakers Bureau; Celgene: Research Funding. Alsina:Millennium: Consultancy, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Membership on an entity’s Board of Directors or advisory committees; Allergan: Research Funding.

Description: Background The use of allogeneic hematopoietic cell transplantation (HCT) in multiple myeloma (MM) remains controversial but the role of allogeneic HCT for consolidation of initial response in the era of novel agents has not been defined. Therefore, we conducted a phase 2 study of allogeneic HCT in MM patients achieving at least very good partial response (VGPR) after initial therapy. Methods Seventeen MM patients with first VGPR or complete remission (CR) received allogeneic HCT between 01/2010 and 04/2013 at Moffitt Cancer Center (NCT 00948922). Eligible patients were age ≤ 60, achieving ≥ VGPR, and have suitable HLA-matched donors. Six patients received bortezomib plus lenalidomide induction, 7 received bortezomib-based, and 4 received lenalidomide-based induction. Three patients (18%) underwent autologous HCT with melphalan plus bortezomib conditioning (melphalan 100 mg/m2 for 2 days followed by bortezomib 1.3 mg/m2) following induction therapies in order to achieve further cytoreduction. Conditioning regimen before allogeneic HCT consisted of fludarabine 30 mg/m2 for 4 days and melphalan 70 mg/m2 for 2 days followed by a single dose of bortezomib 1.3 mg/m2 (Flu/Mel/Vel). GVHD prophylaxis was tacrolimus plus either methotrexate (n=9), or mycophenolate mofetil (n=4), or sirolimus (n=4). No maintenance therapy was prescribed after allogeneic HCT. Results The median age at transplant was 51 (25 – 57) years and the median time from initial therapy to transplant was 236 (126 – 418) days. Seven patients (41%) have high-risk cytogenetics/FISH. The median number of prior therapy was 1. Disease status at the time of allogeneic HCT was VGPR (n=8), CR (n=3), or stringent CR (n=6). All patients received unmanipulated peripheral blood stem cell grafts from HLA-matched sibling donors (n=7) or 8/8 HLA-matched unrelated donors (n=10). All patients achieved neutrophil engraftment with a median of 14 (11 - 18) days and platelet engraftment with a median of 17 (13 - 21) days. All patients established stable donor cell chimerism. Best responses after allogeneic HCT were CR (n=2), sCR (n=13), and disease progression (n=2). The 2-year progression-free survival estimate is 80% (95%CI: 51 – 98) for standard-risk group and 51% (95%CI: 15 – 87) for high-risk, respectively. With a median follow up of 18 (3 - 43) months for surviving patients, the 2-year overall survival estimate is 88% (95%CI: 68 – 99). The cumulative incidence of non-relapse mortality was 6% (95%CI: 0.0 – 22) at 100 days and 13% (95%CI: 1 – 34) at 1 year, respectively. The cumulative incidence of grades 2-4 acute GVHD at day 100 was 41% (95% CI: 20 – 65) and the cumulative incidence of moderate to severe chronic GVHD at 1 year was 8.0% (95% CI: 0.0 – 29). Conclusions These results indicate that allogeneic HCT for MM in VGPR or CR as consolidation achieves favorable disease control. The study is ongoing to assess long-term safety of this modality. A multicenter trial is planned to evaluate the utility of allogeneic HCT in high-risk MM. Overall Survival Months Disclosures: Off Label Use: bortezomib - transplant conditioning. Alsina:Millennium: Membership on an entity’s Board of Directors or advisory committees, Research Funding.

Description: Introduction: TLK199 is a novel glutathione analog inhibitor of the enzyme GST P1-1. Exposure of cells to TLK199 results in the activation of the MAP kinase signaling pathway leading to JNK and ERK2 activation. TLK199 treatment induces hematopoietic progenitor cell growth, maturation and differentiation. TLK199 has demonstrated in vitro myelostimulant activity in human bone marrow cultures and accelerated neutrophil recovery in the chemotherapy induced neutropenia rodent model. Methods: The objectives of this ongoing multicenter study in MDS are to determine the safety, efficacy and phamacokinetics. Blood levels of TLK199 and metabolites are measured by LC-MS-MS. TLK199 is administered as an i.v. infusion over 60 minutes daily x 5 days every two weeks in the dose ranging stage, and at 600 mg/m2 x 5 days every 3 weeks in Phase 2a for up to 8 cycles or until lack of response, blast count progression, or unacceptable toxicity. Results: At interim analysis, twenty-five patients (pts) with MDS (13 RA, 1 RARS, 7 RAEB, 3 RAEB-t and 1 CMML), median age 73 years (range 22-89), received 98+ cycles (500+ treatments) with a median of 3 cycles per pt (range 1–8). Seventeen pts (70%) were transfusion-dependent for red blood cells and 8 (30%) for platelets prior to enrollment. Pts failed a median of 1 prior therapy (range 0–4) including: erythropoietin (13), G-CSF (3), thalidomide (4), IL-11 (3), azacitidine (3), and other therapies (7). Five dose levels were studied from 50–600 mg/m2. No dose-limiting toxicities were observed and 600 mg/m2 was chosen for Phase 2a based on clinical and biologic activity. Twenty pts were evaluable for efficacy, 9 (45%) experienced improvement in one or more blood cell lineages. Six pts (30%) showed Hematologic Improvement by MDS IWG response criteria. Four of 6 experienced improvement in all 3 blood cell lineages and two pts in 2 blood cell lineages. A decrease in the marrow blast count was observed in 1 pt with RAEB. The longest duration of therapy was 8 cycles. Clinical responses were accompanied by clinical symptom improvement with decrease in transfusion requirements or transfusion independence. Bone marrow examination showed improvements in maturation, differentiation, M/E ratios, and decreased dysplastic morphology. Most common adverse events were mild (grade 1 – 2): flushing (6), rigors (4), nausea (3), headache (3), vomiting (2), pain in extremity (3), back pain (2). Grade 4 back pain occurred in one pt. Conclusions: TLK199 is well tolerated. Nine pts (45%) experienced improvement in one or more blood lineages and six (30%) showed Hematologic Improvement by MDS IWG response criteria. Enrollment in Phase 2a continues. These data support further clinical development of TLK199 in myelodysplastic syndrome as well as in other hematologic disorders characterized by cytopenias.

Description: Current pharmacologic strategies employed in allogeneic hematopoietic cell transplantation (HCT) largely fail to prevent chronic graft vs. host disease and do not effectively induce donor-recipient immune tolerance. We report a long-term follow-up (LTFU) analysis of a randomized phase II trial comparing sirolimus/tacrolimus (SIR/TAC, n=37) vs. methotrexate/tacrolimus (MTX/TAC, n=37). The primary endpoint of the trial was grade II-IV acute GVHD within 100 days. Per protocol, SIR/TAC patients were treated with at least 1 year of SIR post-HCT. In the present LTFU analysis, we studied the following: Compliance with SIR; incidence, severity, classification, and organ manifestations of chronic and late acute GVHD; glucocorticoid exposure; discontinuation of immune suppression (IS); and current estimation of relapse, non-relapse mortality (NRM) and overall survival. A subset analysis examined chronic GVHD therapeutic outcomes. The study groups had no significant differences in recipient/donor age or gender, diagnosis and remission status, CIBMTR risk category, donor type, or conditioning regimen (p=NS). The cumulative incidence of grade II-IV acute GVHD through day 100 post-HCT differed (SIR/TAC: 43% vs. MTX/TAC: 89%, p 〈 0.001). Median follow up time for surviving patients was 41 months (range 27-60) for SIR/TAC and 49 months (range 29 – 63) for MTX/TAC. One patient discontinued SIR at 161 days post-HCT due to TMA (grade 1). Otherwise, SIR was not discontinued for toxicity, and the median duration of SIR therapy among patients (n=27) surviving ≥ 1 year was 33 months (range 5.29 – 60 months). NIH Consensus moderate-severe chronic GVHD was significantly lower in SIR/TAC vs. MTX/TAC (34% vs. 65%, p=0.004). NIH global (0-3) severity score was significantly lower in SIR/TAC vs. MTX/TAC (p=0.003). While not significantly different, lung, liver, and GI involvement and severity were decreased in the SIR/TAC group, and fewer cases had overlap subtype of chronic GVHD (7 vs. 14, p=0.15). Late acute GVHD was also significantly lower among SIR/TAC vs. MTX/TAC (20% vs. 43%, p=0.04). While SIR/TAC patients had lower prednisone exposure and earlier discontinuation of tacrolimus (median time to TAC discontinuation SIR/TAC 368 days vs. MTX/TAC 821 days, p=0.002), there was no difference in complete IS discontinuation (at 60 months post-HCT: SIR/TAC 43% vs. MTX/TAC 31%, p=0.78). Malignancy relapse was lower among SIR/TAC vs. MTX/TAC (19% vs. 39%, p=0.06), and overall survival was not different. Co-administration of escalated dose IV busulfan (7500µM/L*min/day) together with fludarabine resulted in excess NRM among SIR/TAC (NRM: 3/5) patients, but not MTX/TAC (NRM: 1/11). When restricted to standard dose conditioning, no difference in NRM was observed (at 48 months: SIR/TAC 10% vs. MTX/TAC 16%, p=0.98). Subgroup analysis of those with chronic GVHD did not demonstrate differences (second-line systemic IS therapy, treatment success, or failure-free survival) to suggest that ongoing SIR treatment modified the natural history and therapeutic responsiveness of chronic GVHD. In summary, prolonged sirolimus administration is associated with reduced moderate-severe chronic and late acute GHVD, decreased total prednisone exposure, and earlier TAC discontinuation post-HCT. Investigation of determinants of immune suppression discontinuation and development of tools to assess immune tolerance are needed to advance the field. Figure: Cumulative incidence of NIH Consensus moderate-severe chronic GVHD Figure:. Cumulative incidence of NIH Consensus moderate-severe chronic GVHD Disclosures No relevant conflicts of interest to declare.