Hogan, William J.

Background: Based on results from the phase 3 trials, maintenance therapy after autologous stem cell transplantation has become the standard of care. While lenalidomide is typically used as the maintenance agent, patients with high risk MM are often maintained on proteasome inhibitor-based maintenance treatment. We examined the trends in maintenance use and outcomes in a large group of patients transplanted at a single institution over two decades spanning the years when maintenance gradually became standard of care. Methods: We included patients who underwent their first autologous stem cell transplantation between 2000 and 2016 in the current study. Patients who received an allogeneic SCT or a planned tandem SCT were excluded. Clinical data was extracted from the medical records or from a prospectively maintained database. Early transplant was defined as SCT within 12 months of diagnosis. High risk (HR) myeloma was defined as per IMWG criteria, based on presence of high-risk FISH abnormalities. Progression free survival and overall survival were estimated from either diagnosis as well as from the date of SCT. Results: We included 1961 patients with MM who were transplanted between January 2000 and August 2016 in the current analysis. Majority (n=1496; 76%) had an early SCT while the remaining patients were transplanted beyond 12 mos from diagnosis. Maintenance was employed in 31% of the patients, 33% of the early SCT and 23% of the delayed SCT. Proportion of patients receiving maintenance increased over the years: <1% in 2000 to 85% in 2016. The most common maintenance approach was an IMiD (56%), followed by a PI (33%) and a PI+IMiD (8%). FISH risk was available in 875 patients, all assessed within 6 months of diagnosis, and 22% were HR. Overall, maintenance was more commonly used in HR patients (64% vs. 36%), and a PI containing maintenance was more commonly used in HR (42% vs. 12%). The PFS was superior for those receiving a maintenance therapy (70 vs. 23 mos, P<0.001); NR vs. 27 mos for early SCT and 25 vs. 16 mos for delayed SCT. The impact of maintenance therapy was more evident in the HR group HR vs SR risk ratio was 2.3 without maintenance, and 1.5 with maintenance. Among the HR patients, PI based maintenance had a trend towards better outcome, while the PFS was better with non-PI maintenance among the SR patients. OS from diagnosis was also better among the early SCT group who received maintenance (99 vs. 88 mos; p=0.01); however, the OS advantage appeared most evident among the HR patients. Conclusions: The experience with maintenance therapy post autologous SCT for myeloma in a non-clinical trial setting appear to confirm the findings from the phase 3 trials. Maintenance provided benefit in patients who had a delayed SCT in our experience. The benefit appear to be particularly relevant for high risk patients, who appear to benefit from PI based regimens. In contrast, SR patients appear to benefit primarily from IMiD based regimen. Disclosures Gertz: Spectrum: Consultancy, Research Funding; Johnson and Johnson: Speakers Bureau; Amgen: Consultancy; Ionis/Akcea: Consultancy; Research to Practice: Consultancy; Appellis: Consultancy; Celgene: Consultancy; Teva: Speakers Bureau; Alnylam: Consultancy; Janssen: Consultancy; Annexon: Consultancy; Abbvie: Other: personal fees for Data Safety Monitoring board; Medscape: Consultancy, Speakers Bureau; Prothena Biosciences Inc: Consultancy; Physicians Education Resource: Consultancy. Lacy:Celgene: Research Funding. Dispenzieri:Akcea: Consultancy; Intellia: Consultancy; Janssen: Consultancy; Pfizer: Research Funding; Takeda: Research Funding; Celgene: Research Funding; Alnylam: Research Funding. Dingli:Millenium: Consultancy; Rigel: Consultancy; Janssen: Consultancy; alexion: Consultancy; Karyopharm: Research Funding. Kapoor:Amgen: Research Funding; Takeda: Honoraria, Research Funding; Glaxo Smith Kline: Research Funding; Celgene: Honoraria; Janssen: Research Funding; Cellectar: Consultancy; Sanofi: Consultancy, Research Funding. Kumar:Takeda: Research Funding; Celgene: Consultancy, Research Funding; Janssen: Consultancy, Research Funding.

Abstract BACKGROUND Respiratory failure syndromes are common after allogeneic hematopoietic cell transplantation (allo-HCT), and are associated with substantial morbidity and mortality. These syndromes are incompletely understood, and may be associated with histopathologic evidence of acute lung injury (ALI). The role of biopsy in this setting is controversial, with uncertain benefits and considerable procedural risk. We report the clinical, radiologic and histopathologic features of patients with biopsy-proven ALI following allo-HCT in a large multi-site retrospective series. METHODS The medical records of 1,864 consecutive adults who underwent allo-HCT at Mayo Clinic, Minnesota (n = 916), Arizona (n = 694), and Florida (n = 254) (Jan 2005-Dec 2017) were reviewed. A total of 152 patients underwent a lung biopsy: 126 bronchoscopic, 22 surgical, and 4 CT-guided biopsies (Figure 1). Patients with a histopathologic diagnosis of ALI were included in the study, and were classified into clinicopathologic subgroups per published American Thoracic Society guidelines (Am J Resp Crit Care Med, 2011). Patients whose diagnosis remained uncertain after a detailed review of the medical records were included in a separate subgroup as undifferentiated ALI. Transplant characteristics, radiologic features, pulmonary function test (PFT) results, treatments, and outcomes were compared between groups. RESULTS Clinicopathologic diagnoses in 62 patients with biopsy-proven ALI consisted of an infectious etiology in 15 (24%), cryptogenic organizing pneumonia (COP) in 15 (24%), idiopathic pneumonia syndrome (IPS) in 9 (15%), bronchiolitis obliterans syndrome (BOS) in 9 (15%), diffuse alveolar hemorrhage in 3 (5%), periengraftment respiratory distress syndrome in 2 (3%), and undifferentiated ALI in 9 (15%) patients (Figure 2). Transplant characteristics were comparable between groups. Infectious pneumonia and IPS were the most common diagnoses during the first 100 days post HCT (50% and 36%, respectively). Between 100 and 365 days, a range of diagnoses were seen including infectious pneumonia (20%), COP (23%), IPS (14%), BOS (23%), and undifferentiated ALI (20%) (Table 1). In 14/15 (93%) infectious pneumonia cases, biopsy did not change management and diagnosis was concurrently established by bronchoalveolar lavage (BAL) or non-invasive testing. Patients with IPS, BOS, and undifferentiated ALI more commonly had a pleural effusion (66%, 44%, and 44%, respectively). Nodular infiltrates were most commonly seen in patients with infectious pneumonia (55%). Other radiographic findings were not clearly discriminative. BOS and infectious pneumonia were more commonly associated with an obstructive PFT (78% and 33%, respectively), whereas restrictive pattern was more frequently seen in COP and IPS (50% and 57%, respectively) (Table 2). Despite a histopathologic diagnosis of ALI, 9 (15%) patients had clear clinical and radiographic evidence of BOS. Steroids were used commonly in noninfectious syndromes: 93% of patients with COP and in 100% of IPS patients. Of 4 patients with IPS who received Etanercept, 2 (50%) showed complete recovery, whereas the remaining 5 patients who did not receive Etanercept died from fulminant respiratory failure. Most common treatment response was complete recovery in COP (73%), fulminant respiratory failure leading to death in IPS (78%), and chronic respiratory failure in BOS (78%). Estimated OS was shortest in the group with IPS and undifferentiated ALI (median 5 and 17 mons, respectively), whereas patients with COP had the best prognosis (mOS not reached) followed by the infectious pneumonia and the BOS groups (mOS of 59 and 55 mons, respectively). Pulmonary complications were the most common cause of death in patients with non-infectious ALI. Lung biopsy was associated with post-procedural pneumothorax in 17 (27%) patients; 12 of whom required a chest tube. CONCLUSIONS In this largest case series to date of histopathologic ALI after allo-HCT, biopsy does not appear to meaningfully change management in the majority of patients, and is associated with substantial procedural risk. Histopathologic findings do not clearly correlate with the clinical and radiographic picture in a sizeable proportion of the patients. PFT results, BAL findings, the timing of the onset of respiratory failure after HCT, and the response to steroids seem to be of greater diagnostic and/or prognostic value. Disclosures No relevant conflicts of interest to declare.

Abstract Introduction: Chronic myelomonocytic leukemia (CMML) is a chronic myeloid malignancy associated with monocytosis, autoimmunity (~30%) & an inherent risk for leukemic transformation. Bone marrow (BM) dendritic cell (DC) populations occur in ~30% of patients, with a poorly defined biological & prognostic role. The malignant immune microenvironment is regulated by indoleamine 2,3-dioxygenase-1 (IDO-1) expressing DCs, which modulate regulatory T (Treg) cells & block their conversion into proinflammatory T helper (Th17)-like cells. IDO-1 is a known immune checkpoint & functions by catabolizing tryptophan, an amino acid essential for T cell function. We hypothesized that distinct IDO-1 expressing DC populations in CMML modulate Tregs & contribute towards immune tolerance & aggressive disease biology. Methods: Primary diagnostic CMML peripheral blood mononuclear cells (PBMC) & BM biopsy specimens were obtained after Mayo Clinic IRB approval. A DC population was defined on H&E stained biopsy sections as focal collections (>10) of cells with characteristic elongated nuclei & cytoplasmic extensions. Transcriptomic & protein expression studies assessing IDO-1 expression were done by previously described methods. In addition, IHC expression of PD-1, PD-L1 & CTLA-4 was also done. IDO-1 promoter methylation studies with DIP-seq were performed. The impact on immune tolerance was assessed using mass cytometry (CyTOF). Results: Cohort: Twenty eight patients with CMML were included in the study, median age 70 (range: 51-80) years; 71% males. Eleven (39%) patients had coexisting autoimmune conditions. Of these, 8 (73%) had detectable DC populations either at diagnosis, or during the course of their disease. At a median follow-up of 46 (95% CI 27, 84) months, there were 14 (50%) deaths & 9 (32%) leukemic transformations.IHC results: Nine (32%) patients were identified to have a DC population at CMML diagnosis. CD123 & TCL1 staining was performed in 5 (56%) patients, with 3 being positive for both, & 2 positive for CD123 only (additional IHC studies ongoing). IDO1 expression by IHC was documented in all 9 (100%) cases (Fig 1A & 1B), while rare populations of PD-1, PD-L1 & CTLA-4 lymphocytes were also seen in all cases. Due to the low DC burdens (median cellularity ≤ 5%) & uniform staining intensity, IHC-based grading was not done. Samples at serial time-points, post-HMA therapy & at the time of blast transformation, were available in 5 & 3 patients respectively. Among the patients who did not have DC populations at diagnosis, 5 (42%) developed them post-HMA therapy, while 3 (50%) developed them at the time of LT. The development of DC populations was associated with loss of response to HMA (50%) & disease progression (50%).Transcriptomic analysis: RNA expression data was available on 7 (25%) patients, of whom only 1 (14%) had DC populations at diagnosis. The IDO-1 RPKM value in the former was higher than the mean pooled value in the latter group (330 versus 74, p=0.05).Methylation studies: DIP-seq was performed on 12 (43%) cases from the primary IHC cohort. Qualitative analysis of IDO-1 promoter hypomethylation was conducted & confirmed in all 9 (100%) cases with 5-mC & 5-hmC marks compared to input as displayed in figure 1C.Immune profiling: CyTOF was performed on 4 CMML samples (3 with IDO-1 expressing DC populations at diagnosis) from the primary IHC cohort & compared to a normal PBMC control. Results confirmed an increase in DC populations (fig 1D& 1E), & reduced % of Th17-like T cells in CMML samples compared to control (1.1 versus 5.07, p=0.05, fig 1F).Clinical correlates & survival analysis: With the exception that CMML patients with DC populations had a higher frequency of NRAS (P=0.007) mutations, the two groups were comparable for cytogenetic & molecular abnormalities. The median OS for the cohort was 45 (95% CI 29, 84) months. CMML patients with IDO-1 expressing DC populations at diagnosis had a shorter median OS, in comparison to those without (median OS 30 vs 45, p=0.03, Kaplan-Meier analysis in fig 1G). Conclusions: In conclusion, we demonstrate that DC populations are seen in ~30% of patients with CMML with a uniform expression of IDO-1 & limited expression of PD-1, PD-L1 & CTLA-4. CMML patients with BM DC populations have a higher frequency of NRAS mutations & DC IDO-1 expression is associated with tumor induced immune tolerance. Additional IHC, genomic & preclinical studies with IDO-1 inhibitors are ongoing. Figure 1. Figure 1. Disclosures Al-Kali: Novartis: Research Funding.

Abstract Introduction Autologous stem cell transplantation (ASCT) plays a central role in the treatment of multiple myeloma (MM), even in the era of novel therapies (Gonsalves et al, 2018). Given the efficacy of the latter, as well as for logistical reasons, many patients opt to store their stem cells and delay ASCT until the time of progression. Delayed transplant does not appear to affect overall survival (OS) (Attal et al, 2017). However, in the "salvage" setting, the impact of treatment with additional chemotherapy prior to ASCT is unknown. One study, albeit in the front-line, suggested that in patients achieving less than a partial response (PR), additional induction prior to ASCT did not improve survival (Vij et al, 2015). The present study investigates the role of induction therapy prior to salvage ASCT. Methods We identified 380 patients who underwent ASCT >12 months after being diagnosed with MM from January 1, 2006 to July 1, 2017 at Mayo Clinic Rochester. 121 had a delayed ASCT, but no International Myeloma Working Group (IMWG) progression prior to ASCT and were excluded. Another 17 patients achieved less than PR prior to ASCT, thus were deemed primary refractory and excluded. Finally, 8 patients were excluded because they received a planned tandem ASCT. Thus, 234 patients were included in the present study, which was approved by the Mayo Clinic Institutional Review Board, in accordance with the Declaration of Helsinki. We refer to the time of progression prior to ASCT, after which we examined the use of pre-ASCT therapy, as T0 to avoid confusion. Time to next therapy (TNT) was defined as the time from ASCT (stem cell infusion, Day +0) to the initiation of a new therapy, not including planned consolidation or maintenance. Patients who were alive and had not received any new therapies, or died before receiving another therapy were censored at the time of last follow up, as of May 15, 2018. OS was defined as the time from Day +0 to death from any cause, with living patients censored at the time of last follow-up. TNT and OS were estimated using the Kaplan-Meier method and compared using the log-rank test. A Cox proportional hazard model was used for univariate and multivariate analysis. High-risk cytogenetics were defined as del(17/17p), t(4;14), t(14;16), and t(14;20). The Mann-Whitney U test and Fisher's Exact test were used to compare continuous and categorical variables, respectively. Statistical analysis was completed using JMP 13.0 (SAS Institute Inc., Cary, NC, USA). Results Of the 234 patients who underwent salvage ASCT, 188 were treated with additional chemotherapy after T0 (hereafter referred to as "pre-ASCT induction"), whereas 46 patients went directly to ASCT. Baseline characteristics were comparable, however more patients in the pre-ASCT induction group had >1 progression prior to ASCT (28% vs. 9%, p= .0065) and had a trend towards a shorter duration of response (DOR) prior to T0 (14.7 vs. 18.5 months, p= .12). Intuitively, the pre-ASCT induction group had a longer time from T0 to ASCT (5.3 vs. 2.3 months, p< .0001). The median TNT for the entire cohort of 234 patients from Day +0 was 17.2 months (95% CI, 14.8-19.7); median OS was 50.4 months (95% CI, 43.3-60.7). TNT and OS were comparable between the two treatment groups (Figure 1). After adjusting for other significant prognostic factors, such as DOR prior to T0 and the presence of high risk cytogenetics, treatment with pre-ASCT induction did not significantly affect TNT or OS (Table 1). However, among the 188 patients treated with pre-ASCT induction, the subsequent depth of response prior to ASCT significantly affected TNT (Figure 2A) and OS (Figure 2B). TNT at 1-year post ASCT was 79.2% for patients achieving a ≥VGPR, 62.1% in those who achieved a PR or stable disease, and 45.7% for patients who had relapsed/refractory MM at the time of ASCT or received >2 lines of pre-ASCT therapy (p= .0003). Interestingly, the time from diagnosis to T0 was comparable between these 3 groups (27 vs. 28 vs. 26 months, respectively, p= .26). Conclusions Many patients with MM do not undergo ASCT until disease progression. In our cohort of 234 patients who underwent salvage ASCT, outcomes were similar whether patients received pre-ASCT induction or not. However, among the 188 patients treated with pre-ASCT induction, deeper responses correlated with significantly longer TNT and OS after ASCT. Further research into the role of chemotherapy prior to delayed ASCT in the era of novel agents is warranted. Disclosures Gertz: annexon: Consultancy; Apellis: Consultancy; Medscape: Consultancy; Teva: Consultancy; janssen: Consultancy; Amgen: Consultancy; Physicians Education Resource: Consultancy; Alnylam: Honoraria; Research to Practice: Consultancy; Ionis: Honoraria; spectrum: Consultancy, Honoraria; celgene: Consultancy; Prothena: Honoraria; Abbvie: Consultancy. Lacy:Celgene: Research Funding. Dispenzieri:Celgene, Takeda, Prothena, Jannsen, Pfizer, Alnylam, GSK: Research Funding. Dingli:Alexion Pharmaceuticals, Inc.: Other: Participates in the International PNH Registry (for Mayo Clinic, Rochester) for Alexion Pharmaceuticals, Inc.; Millennium Takeda: Research Funding; Millennium Takeda: Research Funding; Alexion Pharmaceuticals, Inc.: Other: Participates in the International PNH Registry (for Mayo Clinic, Rochester) for Alexion Pharmaceuticals, Inc.. Kapoor:Celgene: Research Funding; Takeda: Research Funding. Kumar:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding; KITE: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding.

Abstract Introduction: Primary refractory and early relapsed acute myeloid leukemia (RR-AML) continue to pose a therapeutic challenge. Salvage therapy treatment regimens for refractory and relapsed disease are not standardized but include the commonly-used mitoxantrone, etoposide, and cytarabine (MEC) and cladribine, cytarabine, filgrastim, and mitoxantrone (CLAG-M). Previous studies have suggested a potential benefit of CLAG-M, and therefore we performed an analysis of consecutive patients selected to receive either CLAG-M or MEC as salvage therapy for RR-AML. Methods: The study included 150 consecutive patients with RR-AML who received either CLAG-M or MEC between 09/01/2009 and 12/31/2017. Patients were identified through a pharmacy database based on use of mitoxantrone. Baseline disease and patient-related characteristics and clinical outcomes including allogeneic transplantation (ASCT) were obtained by systematic review of EMR. Overall survival (OS) and progression free survival (PFS) were estimated according to the Kaplan Meier method and log-rank test was used to compare outcomes between patients who received either of the two regimens. Results: There were 150 consecutive treated patients with RR-AML included in this analysis, 34 patients received CLAG-M and 116 patients received MEC. The median age was 57 years (18-76), and, and 52% were male. Forty-seven (31%) were treated for early relapsed disease (<6 months after successful induction), 17% (>6 months after induction), and the remainder had primary refractory disease (mean number of induction regimens was 1.8, range 1-6). AML risk was defined by cytogenetic criteria. There were a predominance of intermediate-risk subtypes at 47% (71/150) and followed by high-risk at 37% (55/150). Overall CR/CRi rates for CLAG-M and MEC were 74% (23/31) and 58% (63/108) in patients eligible for analysis (p=0.18). The median follow-up from relapse was 23.5 months (1-76). The median OS was 9.5 months for CLAG-M and 10.0 months for MEC (HR=0.88, 95%CI=0.54-1.41, p=0.59). In total, 76 patients (51%) were able to proceed to ASCT following salvage therapy with either CLAG-M or MEC. Among transplant recipients 56% (19/34) and 49% (57/116) were treated with CLAG-M and MEC, respectively. Median OS after ASCT was 13.0 months for CLAG-M and 31.0 months for MEC (HR=1.76, 95%CI=0.87-3.56, p=0.12). The median OS for refractory AML was 13.0 and 66.0 months for CLAG-M and MEC recipients, respectively (HR=0.92, 95%CI=0.46-1.84, p=0.24). Median OS for those with early relapse was 12.0 months for CLAG-M and 10.0 months for MEC (HR=0.69, 95%CI=0.22-2.11, p=0.51). Lastly, among those who had late relapse, median OS was 9.0 and 48.0 months for CLAG-M and MEC, respectively (HR=17.6, 95%CI=1.57-198, p<0.001). A univariate analysis was performed to investigate the impact of factors associated with OS, including treatment, age, gender, whether they proceeded to ASCT, cytogenetic risk type, and donor source. ASCT was associated with significant improvement in both PFS (HR=0.24, 95%CI=0.16- 0.37, p<0.001) and OS (HR=0.26, 95%CI=0.17-0.40, p<0.001) in this cohort. Age greater than 65 was associated with worse PFS (HR=1.02, 95%CI=1.00-1.03, p=0.04) but not OS (HR=1.01, 95%CI=1.00-1.03, p=0.06) after controlling for other variables including the impact of ASCT. Discussion: Despite a lower 30-day induction mortality we did not identify significant differences in outcomes among patients selected to receive CLAG-M vs. MEC. There was a statistically significant improvement in survival in patients who had late relapses and were treated with MEC, and a trend towards improvement in OS of those treated with MEC who proceeded to ASCT. As expected, ASCT was associated with significant improvement in OS in this cohort, and our results strongly support the use of ASCT as consolidation of remission after relapse for AML. Our data suggests that MEC may be a superior regimen, in particular including those with late relapse. Figure. Figure. Disclosures Foran: Agios: Research Funding; Xencor, Inc.: Research Funding. Al-Kali:Novartis: Research Funding. Palmer:Novartis: Research Funding.

Abstract Introduction: Our group (Porrata et al, BBMT 2016; 22: 1017-1023) previously published that the infusion of autograft natural killer (NK) cells correlates with survival post-autologous stem cell transplantation (ASCT) in non-Hodgkin's lymphoma (NHL) patients. A limitation of our previous study was the lack of killer-immunoglobulin-like receptor (KIR) analysis. Thus, we set up to investigate if the infusion of autograft activating and inhibitory KIR affects survival in NHL. Methods: From December 2007 to October 2010, 122 NHL patients participated in our Phase III clinical trial. A total of 111 patients finished the trail and samples were available for analysis. We analyzed the content of the autograft for inhibitory and activating KIR using flow cytometry analysis of each apheresis collection. Overall survival (OS) and progression-free survival (PFS) were analyzed from the date of transplant. Results: With a median follow-up of 82.8 months (range: 2.1-122.3 months), patients infused with an activating NKp30 (CD158b-CD337+) KIR ≥ 0.09 x 109 cells/kg experienced superior OS and PFS vs < 0.09 x 109 cells/kg: [OS: median was not reached vs 39.8 months, 5 years OS rates of 95% (95%CI, 56%-98%) vs 43% (95%CI, 22%-48%), p < 0.0001, respectively; and PFS: median was not reached vs 12.7 months, 5-years PFS rates of 77% (95%CI, 65%-86%) vs 13% (95%CI, 6%-24%), p < 0.0001, respectively]. Patients infused with the inhibitory KIR2DL2 (CD158b+CD337-) KIR < 0.066 x 109 cells/kg experienced superior OS and PFS vs ≥ 0.066 x 109 cells/kg : [OS: median was not reached vs 48.2 months, 5 years OS rates of 86% (95%CI, 75%-93%) vs 44% (95%CI, 31%-88%), p < 0.0001, respectively; and PFS: median was not reached vs 25.6 months, 5-years PFS rates of 62% (95%CI, 49%-74%) vs 31% (95%CI, 20%-44%), p < 0.0002, respectively]. We combined NKp30 and KIR2DL2 into NKp30/KIR2DL2 ratio. Patients infused with an NKp30/KIR2DL2 ratio ≥ 1.8 experienced superior OS (Figure 1) and PFS (Figure 2) vs < 1.8 : [OS: median was not reached vs 33.4 months, 5 years OS rates of 95% (95%CI, 86%-98%) vs 33% (95%CI, 21%-47%), p < 0.0001, respectively; and PFS: median was not reached vs 14.9 months, 5-years PFS rates of 76% (95%CI, 63%-85%) vs 14% (95%CI, 7%-27%), p < 0.0001, respectively]. Multivariate analysis revealed that the NKp30/KIR2DL2 ratio was an independent predictor for OS [HR = 0.03, 95%CI 0f 0.01-0.07, p < 0.0001] and PFS [HR = 0.17, 95%CI 0f 0.09-0.31, p < 0.0001]. Conclusion: The NKp30/KIR2DL2 ratio provides a platform to develop an immunocompetent autograft to improve clinical outcomes in NHL patients undergoing ASCT. Figure 1. Figure 1. Disclosures Ansell: LAM Therapeutics: Research Funding; Bristol-Myers Squibb: Research Funding; Trillium: Research Funding; Affimed: Research Funding; Celldex: Research Funding; Takeda: Research Funding; Merck & Co: Research Funding; Pfizer: Research Funding; Seattle Genetics: Research Funding; Regeneron: Research Funding.

Abstract Relapse of malignancy and lethal graft versus host disease (GVHD) are the principal causes of failure of allogeneic hematopoietic cell transplant (HCT). Recently we have shown that at seven days after HCT an algorithm using two serum biomarkers (ST2 and REG3α) can predict severe GVHD (Hartwell et al. JCI Insight 2017). We determined whether serial testing (in the first month following HCT) of patients with low probability biomarkers would improve the predictive accuracy of the algorithm and identify patients with different risks of relapse and lethal GVHD. Patients who received an HCT at 18 centers in the Mount Sinai Acute GVHD International Consortium (MAGIC) for hematologic malignancy and who supplied three blood samples were divided into a training set and validation set with equal numbers of lethal GVHD events, which was defined as death from GVHD or infection during treatment for GVHD. Patients in the training set (n=702) underwent HCT from January 1, 2006 until June 30, 2015, whereas patients in the validation set (n=906) underwent HCT from July 1, 2015 to May 1, 2017. Serum samples were analyzed using the previously published algorithm of two biomarkers up to three times (day 7, day 14, day 28 or GVHD onset, if onset occurred within the first 28 days). The algorithm generates a predicted probability of lethal GVHD between 0 and 1 for each patient. Patients were categorized as either low probability (LP) or high probability (HP) for lethal GVHD. HP thresholds of 0.20 and 0.16 were used to classify patients with and without GVHD symptoms, respectively (once categorized as HP, patients remained in that category and were not retested). All results were similar between training and validation sets, and we present here the validation set results. Serial testing identified 28% of patients as HP with a three-fold greater cumulative incidence of lethal GVHD at one year (13% vs 4%, p<0.001, Figure 1). Relapse rates were the same in both probability groups, and thus LP patients experienced significantly better relapse free survival (RFS) (69% vs 53%, p<0.001). As expected, significantly fewer LP patients experienced severe GVHD at onset (as measured by Minnesota risk), maximum grade III/IV GVHD, or steroid resistant GVHD by day 180 after HCT (Figure 2, p<0.001 for all three parameters). To measure the accuracy of prediction, at each timepoint we calculated the area under the curve (AUC) of receiver operating characteristic curves; the AUC increased significantly with each subsequent evaluation, from 0.59 at one timepoint (dotted line) to 0.74 at the third timepoint (solid line) (p<0.001), with a final sensitivity of 65% and specificity of 74% (Figure 3A). Early development of GVHD (by day 28) is a risk factor for lethal GVHD. Therefore, we next plotted RFS (dashed line), relapse (solid line), and lethal GVHD (dotted line) rates in patients who developed GVHD by day 28. 25% of patients with GVHD were categorized as HP and had a cumulative incidence of lethal GVHD more than four times higher (28%) than that of relapse (6%); however the risks were reversed for the 75% of patients who were LP, where relapse (15%) occurred twice as often as lethal GVHD (7%) (Figure 3B). In patients who did not develop GVHD in the first month, this reversal of risks was even more dramatic. Approximately half (53%) of the entire validation cohort did not develop GVHD by day 28 and was LP at all three evaluations. These patients had an exceptionally low risk of lethal GVHD and thus they relapsed (25%) much more often than they died from GVHD (3%). When malignancies were classified according to risk for relapse by the disease risk index (DRI) (Figure 3C), the probability of relapse was three fold higher than lethal GVHD in malignancies with a low DRI (12%), six fold higher for intermediate DRI (20%), and eleven fold higher for high/very high DRI (33%). We conclude that a serial monitoring strategy using GVHD biomarkers for one month after HCT is able to identify two groups of patients with very different risks of lethal GVHD and relapse. For these patients, the intensity of immunosuppression after day 28 could be tailored according to the probabilities of developing lethal GVHD and relapse in the context of clinical trials. Disclosures Aziz: Doris Duke Charitable Foundation: Research Funding. Ayuk:Therakos (Mallinckrodt): Honoraria; Novartis: Honoraria; Celgene: Consultancy; Gilead: Consultancy. Chen:REGiMMUNE: Consultancy; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees; Magenta Therapeutics: Consultancy; Takeda Pharmaceuticals: Consultancy. Merli:Neovii Biotech: Honoraria; AMGEN: Honoraria. Roesler:Sanofi: Other: Travel, Accommodations, Expenses; Amgen: Equity Ownership; Jazz Pharmaceuticals: Other: Travel, Accommodations, Expenses; Immunomedics: Equity Ownership; Biogen: Equity Ownership; Merck: Consultancy; Pfizer: Consultancy. Kitko:Novartis: Consultancy, Honoraria; Mallinckrodt: Honoraria, Other: Travel, Accommodations, Expenses. Qayed:Novartis: Consultancy. Wölfl:Bristol-myers Squibb: Equity Ownership; Novartis: Equity Ownership; Taheda: Equity Ownership; Juno: Equity Ownership; Neovii: Other: Travel, Accommodations, Expenses. Mielke:Celgene: Speakers Bureau; DGHO: Speakers Bureau; EHA: Speakers Bureau; Kiadis Pharma: Speakers Bureau; Miltenyi: Speakers Bureau. Wudhikarn:Takeda Oncology: Other: Travel, Accommodations, Expenses. Nakamura:Celgene: Honoraria; Molmed: Honoraria; Merck: Consultancy; Pharmacyclics: Consultancy; Atara: Consultancy; Jazz Pharmaceuticals: Consultancy. Pulsipher:CSL Behring: Consultancy; Novartis: Consultancy, Honoraria, Speakers Bureau; Adaptive Biotech: Consultancy, Research Funding; Amgen: Honoraria. Reshef:Pfizer: Consultancy; Atara Biotherapeutics: Consultancy; Kite Pharma: Consultancy; Takeda Pharmaceuticals: Consultancy; Bristol-Myers Squibb: Consultancy; Incyte: Consultancy. Levine:Therakos: Consultancy; Novartis: Consultancy; Bluebird: Consultancy; Incyte: Consultancy; Kamada: Research Funding; Viracor: Patents & Royalties. Ferrara:Incyte: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses; Xenikos: Consultancy, Other: Travel, Accommodations, Expenses; Kamada: Consultancy, Research Funding; Viracor: Consultancy, Patents & Royalties.

Abstract Introduction: The revised international prognostic scoring system (IPSS-R) for myelodysplastic syndrome (MDS) is widely accepted and has been validated in multiple studies. Patients with adverse cytogenetics do poorly and that is reflected in this scoring system by having the highest score for cytogenetics; 2 for intermediate, 3 for poor and 4 for very poor. Little is known about the effect of marrow blasts in adverse cytogenetic in the high-grade MDS defined by IPSS-R intermediate (>3), high (>4.5) and very high (>5). The goal is to examine the effect of marrow blast percentage on outcome in patients with adverse cytogenetics that is present in the high-grade MDS. Methods: We performed data collection from the Mayo clinic records for patients with confirmed MDS after obtaining appropriate IRB approval. Patients were divided based on their total IPSS-R score and we extracted high-grade MDS cases with intermediate, high and very-high IPSS-R only. Cytogenetics and baseline CBC were available for analysis. We calculated the survival difference in patients with blasts <5% and patient with blasts of 5% to 19% for every group. Survival estimates were calculated by Kaplan-Meier method and compared by log-rank testing using JMP v.13. Results: Our database had 1300 patients with confirmed MDS, 41% (N=536) are high-grade MDS. From those, the median age was 70 and 70% were males. Median bone marrow blast was 6% (0-19). Baseline hemoglobin is 9.2 g/dL, WBC 2.7, ANC 1.05, and platelets 69. Their cytogenetics were 1% very good, 31% good, 23% intermediate, 16% poor and 29% very poor. The total IPSS-R groups were 39%,31%, and 30% for the intermediate, high, and very-high groups respectively. The overall survival (OS) for the high-grade MDS with marrow blast <5% was 12.3 months and for patients with marrow blasts ≥5% 11.4 months (P=.4). At each high-grade MDS; intermediate, high and very high, there were no statistically significant differences for patients with marrow blasts below or above 5%. In term of risk of progression to AML, patients with blasts ≥5% were at higher risk of progression compared with <5% (25% vs 10% , P<.001), with no statistically significant difference in term of time-to-AML progression. Conclusion: The percentages of bone marrow blasts had no impact on overall survival among patients with high grade MDS. However, patients with ≥5% marrow blasts are at a higher risk for progression to AML. Disclosures Al-Kali: Novartis: Research Funding.

Abstract Background: Trabectedin is an FDA-approved DNA minor groove binder (MGB) that has activity against translocation-associated sarcomas. Lurbinectedin is a next-generation MGB with pre-clinical activity against myeloid leukemia cells. A dose-finding phase 1 clinical trial was performed in patients with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) with further assessment of safety and tolerability. Methods: Forty-two patients with relapsed/refractory AML/MDS received lurbinectedin administered as a 1-hour intravenous infusion in a 3+3 study design. Two dosing schedules were used: 3.5 mg, 5 mg, 7 mg, or 6 mg on days 1 and 8 or 2 mg, 3 mg, 1 mg, or 1.5 mg for 3 consecutive days on days 1 to 3. Patients 18 years or older with a diagnosis of advanced, relapsed/refractory AML (non-acute promyelocytic leukemia) and MDS were eligible and treated on study. Eligible patients had adequate hepatic, renal, and cardiac function and an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2. Patients with uncontrolled infection, human immunodeficiency virus, cardiac and neurological disorders, or those who were pregnant were ineligible. Clinical trial information: NCT01314599. Results: Three patients experienced dose-limiting toxicities of rhabdomyolysis (grade 4), hyperbilirubinemia (grade 3), and oral herpes (grade 3) with the days 1 and 8 schedule. Otherwise, adverse events mainly consisted of gastrointestinal manifestations (n=11), febrile neutropenia/infections (n=4), pulmonary toxicity (n=2), and renal failure (n=2). The most common laboratory abnormalities observed were an increase in creatinine (93%) and anemia, neutropenia, and thrombocytopenia (100%). Overall, 33 of 42 patients (79%) had reduction in blasts in peripheral blood or bone marrow. One patient achieved a partial response and two patients a morphologic leukemia-free state. Most (n=30, 71%) were discontinued due to progressive disease. Early deaths occurred from disease-related causes that were not attributable to lurbinectedin. Four patients with a chromosome 11q21-23 abnormality had significantly greater bone marrow blast reduction than those without such abnormality, with decrease of 31±14% (n=4) vs. 8±8% (n=16), respectively (P=0.04). Conclusions: Overall, lurbinectedin was safe and tolerated using the schedules and dose levels tested. While no sustained remissions were observed, single-agent lurbinectedin was transiently leukemia suppressive for some patients. Disclosures Rodríguez: PharmaMar: Employment. Ravandi:Bristol-Myers Squibb: Research Funding; Jazz: Honoraria; Abbvie: Research Funding; Seattle Genetics: Research Funding; Abbvie: Research Funding; Amgen: Honoraria, Research Funding, Speakers Bureau; Orsenix: Honoraria; Seattle Genetics: Research Funding; Astellas Pharmaceuticals: Consultancy, Honoraria; Sunesis: Honoraria; Orsenix: Honoraria; Macrogenix: Honoraria, Research Funding; Astellas Pharmaceuticals: Consultancy, Honoraria; Jazz: Honoraria; Xencor: Research Funding; Bristol-Myers Squibb: Research Funding; Amgen: Honoraria, Research Funding, Speakers Bureau; Macrogenix: Honoraria, Research Funding; Xencor: Research Funding; Sunesis: Honoraria. Daver:Sunesis: Consultancy; Alexion: Consultancy; Daiichi-Sankyo: Research Funding; BMS: Research Funding; ImmunoGen: Consultancy; Kiromic: Research Funding; Incyte: Research Funding; Pfizer: Consultancy; Incyte: Consultancy; ARIAD: Research Funding; Karyopharm: Consultancy; Pfizer: Research Funding; Karyopharm: Research Funding; Novartis: Consultancy; Sunesis: Research Funding; Novartis: Research Funding; Otsuka: Consultancy. Jain:Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; ADC Therapeutics: Research Funding; Infinity: Research Funding; Pfizer: Research Funding; Novimmune: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Research Funding; Servier: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Genentech: Research Funding; ADC Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologioes: Research Funding; Pharmacyclics: Research Funding; Incyte: Research Funding; Verastem: Research Funding; Seattle Genetics: Research Funding; Pharmacyclics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Astra Zeneca: Research Funding; Astra Zeneca: Research Funding; Servier: Research Funding; Celgene: Research Funding; Seattle Genetics: Research Funding; Verastem: Honoraria, Membership on an entity's Board of Directors or advisory committees; Astra Zeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees; Infinity: Research Funding; Adaptive Biotechnologies: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Research Funding; Cellectis: Research Funding; ADC Therapeutics: Research Funding; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologioes: Research Funding; Pharmacyclics: Research Funding; Cellectis: Research Funding; Verastem: Research Funding; Servier: Research Funding; Abbvie: Research Funding; Incyte: Research Funding; Genentech: Research Funding; Abbvie: Research Funding; BMS: Research Funding; Astra Zeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees; Verastem: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; ADC Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Servier: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novimmune: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees. Maiti:Celgene Corporation: Other: Research funding to the institution. Martinez:PharmaMar: Employment. Siguero:PharmaMar: Employment. Al-Kali:Novartis: Research Funding.

Abstract Background While unfavorable karyotype at referral is associated with significantly inferior overall and leukemia-free survival in myelofibrosis (MF) patients (Blood. 2011 Oct 27;118(17):4595), the incidence of clonal evolution during JAK inhibitor (JAKi) treatment and its clinical significance are not currently known. We conducted a sponsor-independent, single-center retrospective analysis examining the phenotypic correlates and prognostic impact of clonal evolution during JAKi treatment. Methods Clinical, cytogenetic and molecular data were collected on MF patients treated with one or more JAKi on a clinical trial at the Mayo Clinic, Rochester, MN. Baseline data pertained to the onset of treatment with first JAKi. Karyotype risk categories were as previously defined (Blood. 2011 Oct 27;118(17):4595). Serial bone marrow biopsies were obtained at varying frequencies based on individual JAKi protocol requirements. Mutation screening was performed as previously described (Leukemia. 2013 Apr 26. doi: 10.1038/leu.2013.119). Information on survival and leukemic transformation was updated in July 2013. Results A total of 157 MF patients were studied (60% male; median age 65 years, range 34-89 years). The DIPSS-plus distribution was: Low/Int-1 20 (13%), Int-2 66 (42%), and High 71 (45%). The first JAKi was momelotinib (CYT387) in 79 patients (50%), ruxolitinib in 51 (33%) and fedratinib (SAR302503) in 27 (17%). Median follow up from first JAKi treatment was 30 months (range 1-67 months); during this period, 72 deaths (46%) and 14 (9%) leukemic transformations were documented. Eighty nine patients (57%) had a median total 3 (range 2-8) bone marrow biopsies with karyotype analysis during JAKi treatment. Of these, 21 patients (24%) showed clonal evolution (ie, acquisition or loss of one or more chromosome abnormalities when comparing last observed karyotype during JAKi treatment to baseline). Overall, 13 patients (15%) had upstaging of karyotype risk category (eg, normal to unfavorable), 9 (10%) had downstaging (eg, favorable to normal) and 67 (75%) had no change. Acquisition of worse-than-baseline karyotype was significantly higher in DIPSS-plus high-risk patients (26%) versus non-high risk patients (6%) (p=0.03). There was no association between acquisition of a worse karyotype category and baseline karyotype risk category or ASXL1 or SRSF2 mutation status. There was borderline association with RBC transfusion-dependence and constitutional symptoms at baseline (p=0.06). There was no relationship between clonal evolution and achievement of spleen or anemia response during JAKi treatment (p>0.05). The median overall survival of the entire cohort was 41 months. On univariate analysis, overall survival was significantly worse in patients who acquired a worse-than-baseline karyotype risk category during JAKi treatment (n=13, 77% deaths, median survival=31 months) versus those who did not (n=76, 43% deaths, median survival=52 months) (p=0.01) (Figure). On multivariate analysis, the prognostic significance of acquiring a worse karyotype risk category was maintained against all individual DIPSS-plus prognostic variables, including baseline karyotype risk category, except age >65 years. On univariate analysis, leukemia-free survival was significantly worse in patients who acquired a worse-than-baseline karyotype risk category during JAKi treatment (n=13, 31% leukemic transformation, median leukemia-free survival=32 months) versus those who did not (n=76, 8% leukemic transformation, median leukemia-free survival not reached) (p=0.0006) (Figure). On multivariate analysis against known predictors of leukemic risk in PMF patients (ie, baseline unfavorable karyotype, SRSF1 mutated status and platelet count <100 x 109/L), only acquisition of a worse-than-baseline karyotype risk category maintained its prognostic value (HR 5.3, p=0.03) Conclusions This is the first study to examine the incidence of clonal evolution during JAKi treatment in MF patients. Approximately 25% of patients exhibited clonal evolution; acquisition of a worse-than-baseline karyotype risk category had a strong and independent association with inferior leukemia-free survival. A similar association was also observed for inferior overall survival, albeit not independent of older age. In contrast, there was no association with spleen or anemia response during JAKi treatment. Disclosures: Pardanani: Bristol Myers Squibb: Clinical trial support Other; Sanofi: Clinical trial support. Publication support service., Clinical trial support. Publication support service. Other; PharmaMar: Clinical trial support, Clinical trial support Other; JW Pharmaceutical Corp.: Clinical trial support, Clinical trial support Other.