Combination Therapy with Vorinostat and Bortezomib in Patients with High Risk Acute Myeloid Leukemia and Myelodysplastic Syndromes

Abstract Abstract 4277 Introduction: Patients with acute myeloid leukemia (AML) or myelodysplastic syndromes (MDS) refractory to or progressive on standard therapies present a challenging population of patients to treat and warrant novel therapy. Investigational combination therapy with vorinostat and bortezomib may synergistically target additive aberrant cellular processes and may modulate NK cell mediated killing. Patients and Methods: Patients with refractory/relapsed AML (non-M3) and high risk MDS progressive on hypomethylating agents or lenalidomide were eligible. Karnofsky Performance Status (KPS) of &gt; 60, creatinine &lt; 2, ALT/AST &lt; 3X ULN, and bilirubin &lt; 2, ejection fraction &gt; 40%, absence of central nervous system disease, and &lt; grade 2 peripheral neuropathy were required for enrollment. Cycles consisted of vorinostat 400 mg/day Day 1–14 and bortezomib 1.3 mg/m2 IV Days 1,4,8, and 11 of a 21 day cycle. Pre therapy bone marrow biopsy and transfusion requirements were documented. Disease response was planned after 3 cycles. Clinical responses were defined as complete morphologic remission (CR), partial remission (PR), hematologic improvement (HI), stable disease (SD), or progressive disease (PD) as defined by IWG criteria. (Cheson et al 2003 and 2006) Completion of 1 full cycle was required for analysis of clinical response. All patients were included in toxicity assessment. Patients achieving a CR, PR, or HI after 3 cycles of therapy could proceed with an additional 3 cycles of therapy in the absence of dose limiting toxicity. Twelve patients (AML=9, MDS-3), median age of 66 (range 48–88), median KPS of 80, and predominantly male (n=7) have been treated. AML patients were primary induction failures (n=1), an untreated elderly unfit for standard induction (n=1), relapsed/refractory (n=3), and with progressive disease after response to azacitidine (n=1). Cytogenetics were complex (n=4), 7q- (n=1), normal with FLT3+ (n=1) or miscellaneous abnormalities (n=3). Median blast burden at the time of therapy was 66%. All MDS patients had progressive disease after prior hypomethylating agents and were RAEB-2 with complex cytogenetics (n=2). Comorbidites for the entire group included vascular disease (predominantly cardiac n=4), COPD (n=1), prior GI bleed (n=1), prior fungal infection (n=1) Results: A total of 9 patients were evaluable for clinical response. The remaining three patients failed to complete the first full round of chemotherapy due to transition to hospice (n=2) and unrelated fall/hip fracture (n=1). Five patients completed all 3 cycles with the majority requiring dose reduction, 2 patients completed therapy through cycle 2, and 2 patients completed cycle 1 before disease progression. The overall clinical response (CR, PR, HI, and SD) was 56% (n=1 morphologic CR, n=4 SD). The remaining 4 patients had PD. All of responding patients had AML, and none of the patients requiring initial hydroxyurea control of WBC responded to therapy. Toxicity was common with fatigue, anorexia, dehydration, nausea, and neuropathy the most common side effects. Severe adverse effects included fevers, pulmonary infection, QT prolongation that lead to syncope, and infection with or without neutropenia. Two deaths occurred during or soon after completion of therapy. One patient with extensive prior cardiac disease status post numerous cardiac stents died after cardiac arrest when admitted for neutropenic fever. Another patient hospitalized for high fevers related to possible pulmonary fungal infection was found unresponsive and died. While these events were felt to have causes unrelated to drug therapy, they were classified as toxicity that was possibly treatment related. The overall toxicity rate was 50%. Conclusion: The combination of vorinostat and bortezomib produced disease stability in a subset of patients and a complete morphologic remission in one suggesting clinical activity in myeloid diseases. Toxicity limited additional cycles of therapy in some responding patients and protocol therapy dose adjustments have been made to address this issue so that extended therapy is feasible. While toxicity was frequent, the majority of therapy was tolerated in the outpatient setting. The combination of vorinostat and bortezomib may be a clinically promising therapy with the potential for disease stabilization if toxicity issues can be improved by our current plan for tailoring dose based on patient tolerance. Disclosures: No relevant conflicts of interest to declare. </jats:sec

Allogeneic Stem Cell Transplantation for Adults with Myelodysplastic Syndromes: Importance of Pretransplant Disease Burden

AbstractAllogeneic stem cell transplantation is the only known curative therapy for myelodsyplastic syndromes (MDS). We present the transplant outcomes for 84 adult MDS patients, median age 50 (18-69 years), undergoing allogeneic hematopoietic stem cell transplantation (HSCT) at the University of Minnesota between 1995 and 2007. By WHO criteria 35 (42%) had refractory anemia with excess blasts (RAEB-1 or 2), 23 (27%) had refractory cytopenia with multilineage dysplasia (RCMD) or RCMD and ringed sideroblasts (RCMD-RS), and the remaining 26 (31%) had refractory anemia (RA), myelodysplastic syndrome-unclassifiable (MDS-U), chronic myelomonocytic leukemia (CMML), myelodysplastic/myeloproliferative disease (MDS/MPD), or myelodysplastic syndrome-not otherwise specified (MDS-NOS). Graft source was related in 47 (56%), unrelated donor (URD) marrow in 11 (13%), and unrelated cord blood (UCB) in 26 (31%). The conditioning regimen included total body irradiation (TBI) in 94% of transplantations; 52 (62%) myeloablative (MA) and 32 (38%) nonmyeloablative (NMA) regimens. Cumulative incidence of neutrophil engraftment by day +42, acute graft-versus-host disease (aGVHD) by day +100, and chronic GVHD (cGVHD) by 1 year were 88% (80%-96%, 95% confidence interval [CI]), 43% (36%-50%, 95% CI), and 15% (10%-20%, 95% CI), respectively. One-year treatment-related mortality (TRM), relapse, disease-free survival (DFS), and overall survival (OS) were 39% (28%-50%, 95% CI), 23% (12%-32%, 95% CI), 38% (28%-48%, 95% CI), and 48% (38%-58%, 95% CI) respectively. Cumulative incidence of relapse at 1 year in patients with pre-HCT complete remission (CR) or <5% blasts was improved at 18% (8%-28%, 95% CI) compared to 35% (16%-54%, 95% CI) in patients with 5%-20% blasts (P = .07). Additionally, with MA conditioning, the incidence of relapse at 1 year trended lower at 16% (6%-26%, 95% CI) versus 35% (18%-52%, 95% CI) in NMA (P = .06), and a statistically significant decrease in relapse was noted in patients entering HCT with CR or <5% blasts with an incidence of 9% (0%-18%, 95% CI) (MA) versus 31% (11%-51%, 95% CI) (NMA) (P = 0.04). For those patients with ≥5% blasts, MA conditioning did not significantly decrease relapse rates. One-year TRM was similar between MA and NMA conditioning. For patients entering transplant in CR or with <5% blasts, prior treatment to reach this level did not impact rates of relapse or transplant-related mortality when all patients were analyzed; however, when broken down by conditioning intensity, there was a trend toward improved DFS in those NMA patients who were pretreated. Finally, 1-year DFS was similar using related donor peripheral blood stem cell (PBSC)/marrow, URD marrow, or UCB grafts. These data suggest that (1) blast percentage <5% at HSCT is the major predictor of improved DFS and relapse and prior treatment to reach this disease status may have value in leading to improved DFS; (2) MA conditioning is associated with lower relapse risk, particularly in patients with CR or <5% blasts, but is not able to overcome increased disease burden; (3) NMA conditioning yields equivalent TRM, DFS, and OS, and is reasonable in patients unsuited for MA conditioning; (4) the donor sources tested (PBSC, bone marrow [BM], or UCB) yielded similar outcomes

Induction Of In Vivo Oligoclonal T Cell Expansion and Specific In Vitro T Cell Responses Following K562/GM-CSF Vaccination Of MDS Patients

Abstract Background Myelodysplatic syndromes (MDS) are a heterogeneous group of clonal hematopoietic stem cell malignancies, characterized by the ineffective hematopoiesis, and risk of progression to acute myeloid leukemia. Allogeneic stem cell transplant (SCT) remains the only potentially curative therapy, but toxicities limit its application in older adults. Vaccination strategies have been developed to modulate the immune system, ideally with less toxicity. We present results from a pilot study of single agent K562/GM-CSF whole cell vaccination in MDS patients (pts). Methods Poor-risk or transfusion-dependent MDS pts (n=5) were enrolled and received K562/GM-CSF whole cell vaccine (1 X 108 cells) every 3 weeks for 4 cycles followed by a booster vaccination 8 weeks later. Eligible pts could receive supportive care only for the 2 months preceding study entry, have no history of SCT, and not be on immunosuppressants. Blood, bone marrow, and skin biopsies were taken prior to vaccination, day 4 following first vaccine, and at 4 weeks after the booster vaccination. Diversity of the T cell compartment was assessed in the blood, marrow and skin using the TCRExpress Quantitative Analysis Kit (Biomed Immunotech, Tampa FL). Fragment length analysis was performed by the DNA Analysis Facility. In vitro stimulation studies for proliferation and cytokine production were performed using peripheral blood monocytes (PBMCs) for the pt with the best clinical response (&gt;4 years). Proliferation of banked PBMCs, collected prior to every vaccination and stimulated with the vaccine, was assessed using 3H-Thymidine. The cytokines generated were measured using a multiplexed bead based immunoassay (Human 17-plex bioplex pro-panel) (Biorad, Hercules CA). Results All pts tolerated the vaccinations well with localized skin reactions being common. Clinically, 2 pts normalized their blood counts and became transfusion independent following the immunotherapy. One responding pt (CMML) remained stable without need for medical intervention for 4 yrs and only recently showed progression. T cell spectratyping indicated oligocolonal populations of T cells in post-vaccination skin, blood and marrow samples. T cells infiltrating the skin were tracked to the marrow. Interestingly, the best clinical responder demonstrated the most restricted skewed repertoire with a significant number of oligoclonal T cells tracking from skin to marrow (n=5). The marrow also had infiltrates of oligoclonal T cells not detected in the post-vaccination skin. Further, this skewed repertoire was absent when the pt relapsed. Proliferation assays measuring this pt’s T cell cytokine production in response to the vaccine cells in vitro, showed increased levels of IL-2, IL-13 and IL-5 that were suppressed or not produced by the time of the 4th vaccination. Inversely, IL-6, IL-10, IL-17, IL-1beta, MIP-1beta and TNF alpha levels increased throughout. The expected proliferative “boost” was seen with the initiation of the booster vaccine series at the time of progression, and co-culture of the pt’s lymphocytes with the vaccine cells suppressed the ability of the vaccine cells to produce GM-CSF in vitro. The ability to suppress GM-CSF production decreased during therapy and the pt’s lymphocytes had no effect on GM-CSF production by the vaccine at the end of the immunotherapy. Conclusions All pts showed T cell skewing by spectratyping analysis, suggesting that each had a change in T cell proliferation patterns in response to the vaccine. One pt had a significant clinical response and the most specific T cell response by spectratyping to the original vaccine, followed by the absence of these cells in the marrow at the time of progression. This suggests that an immune response may have stabilized his disease and progression was associated with loss of this T cell population. Proliferation studies suggest that the lymphocytes recognized the vaccine. Lastly, GM-CSF levels produced by the vaccine were decreased during the vaccination cycles suggesting that the pt’s lymphocytes and/or tumor had a suppressive effect on the vaccine cells. It is unclear if the GM-CSF suppression was essential, detrimental, or unrelated to the pt’s clinical response. Further study of the T cells patterns in these pts may elucidate details of the immune response that are integral to clinical responses. Disclosures: No relevant conflicts of interest to declare. </jats:sec

Validation of a Modified Comorbidity Index for Allogeneic Hematopoietic Cell Transplant

Abstract INTRODUCTION Among adult allogeneic hematopoietic cell transplant (HCT) recipients, the HCT-specific comorbidity index (HCT-CI) is a standard measure of baseline comorbidity. This measure incorporates 17 different comorbidities into a combined, categorically weighted score of standard, intermediate and high risk. Using the specific weights for each comorbidity from the single center analysis, the HCT-CI has been validated in other studies, most notably in a recent analysis including 8115 HCT recipients from the United States. The HCT-CI has been useful in controlling for confounding of comorbidities among patients. We previously reported that the efficiency and predictive power could be improved by removing the conversion of adjusted hazard ratios (HR) for non-relapse mortality (NRM) to three possible weights (1-3) for each comorbidity. METHODS Because some comorbidities show effects on a continuous scale and others show no effect, we proposed a weighting scheme in which each comorbidity is assigned the natural weight based on Fine and Gray regression analysis on NRM. The final modified comorbidity index (MCI) is based on a multiplicative model controlling for age, disease risk index, donor type and stratified by conditioning intensity. In this current study, we tested validation of calculations for the MCI by randomizing 2/3 of 1114 adult allogeneic patients with prospectively collected (2000-2015) comorbidities to a training set and 1/3 of patients to a test set. Using weights from the training set, we compared the MCI to the HCT-CI for the endpoints of NRM and overall survival (OS) in the test set. We did this using regression analysis and bootstrapping the difference in C-statistics for each method. RESULTS The median patient age was 51 (IQR: 39-59), 59% were male, donors included 41% HLA-matched sibling donors, 7% matched unrelated donors (URD) and 52% umbilical cord blood (UCB). Patients had malignant diagnoses with a disease risk index (DRI) of 19% low, 62% intermediate and 19% high or very high. Conditioning intensity included 65% reduced intensity (RIC) regimens. Using the HCT-CI, 19% were classified as low, 31% as intermediate and 39% as high risk. Based on the MCI, 34% were classified as low, 54% as intermediate and 12% as high risk. After adjusting for other factors, the independent weights for each comorbidity were calculated in our training set. We calculated the MCI by exponentiating the sum of all parameter coefficients from the regression analysis. The revised index score is: MCI = exponent [0.40*(binary indicator for cardiac disorders) + 0.85*(heart valve disease) + 0.05*(inflammatory bowel disease) + 0.48*(peptic ulcer) + 0.46* (diabetes) + 0.03*(psychiatric disturbance) + 0.20*(mild hepatic function) + 0.93*(moderate/severe hepatic function) + 0.19*(infection) + 2.00*(renal insufficiency) + 0.17*(moderate pulmonary abnormalities) + 0.39*(severe pulmonary abnormalities) + 0.16*(prior solid tumor)]. Comorbidities including obesity, cerebrovascular disease and rheumatologic disorders had no influence on NRM. This on-line calculator facilitates scoring of the modified index--MCI: http://bmt.ahc.umn.edu:8082/hct. In the test set (N=372), MCI was more predictive of NRM (table, fig 1a and 1b) and showed a trend toward increased sensitivity for OS compared to the original HCT-CI. The HR for intermediate and high risk categories increased (≥60% for NRM and &gt;30% for OS). The adjusted likelihood ratio (showing model fit) increased from 20.3 to 22.5 for NRM and from 38.9 to 40.7 for OS when substituting MCI for HCT-CI. An increase shows better prediction of the endpoint. The C-statistic reflecting more NRM with a higher score and worse survival increased from 0.540 to 0.562 for NRM (P=0.02) and increased from 0.567 to 0.594 for OS (P=0.08). DISCUSSION This new MCI showed higher discriminating and predictive power for post-HCT NRM and a trend towards more predictive power for OS. As many HCT recipients have pre-existing comorbidities, the greater discrimination in assigning patient comorbidity will better inform decision-making for HCT recipients and HCT studies by better adjustment of these important risk factors. This MCI methodology should be used to create more efficient and predictive assessments in a larger multi-center study. Disclosures No relevant conflicts of interest to declare. </jats:sec