Evidence Of Minimal Residual Disease Research Articles

A Systematic Literature Review (SLR) of Clinical Outcomes after Stem Cell Transplantation (SCT) in Adult Acute Lymphoblastic Leukemia (ALL) Patients with or without Minimal Residual Disease (MRD)

▪Background: Most adult patients with ALL will achieve a complete hematologic remission following frontline therapy, but approximately 40% of patients will subsequently have evidence of MRD. This status describes the presence of leukemia cells in the bone marrow, which cannot be detected by conventional methods and is recognized as an independent negative prognostic factor for disease relapse and survival. An SLR was conducted to evaluate evidence comparing clinical outcomes following SCT among patients who are MRD+ vs. MRD- prior to transplant.Methods: Medline, Embase, and Central databases were systematically searched with keywords for ALL and MRD to identify relevant literature on adults undergoing transplants according to MRD status published through 5/8/2018. Oncology conferences were also searched for relevant data presented between 2014─2018.Results: 30 primary studies were identified that reported outcomes following SCT in ALL patients with MRD results available prior to transplant. Clinical outcome comparisons between MRD+ and MRD- patients were most commonly reported (27/30 studies). Comparisons between MRD+ and MRD- patients universally suggested that those with MRD+ status prior to SCT had lower survival rates at all time points reported relative to patients who were MRD- with an exception of one study, evaluating patients treated with salvage therapy, which favored MRD+ in survival gains with a non-significant difference between MRD+ and MRD- groups (Table 1).The available hazard ratio (HR) on overall survival consistently indicated that patients with MRD+ status before transplant were more likely to die after SCT as patients who are MRD- (HRs for OS: 1.51-2.646) (Figure 1). MRD+ status was also associated with higher likelihood of disease progression, (HRs for PFS: 2.15 to 2.8).Six studies reported data on mean or median survival; median OS after SCT ranged from 1.98 months to 17 months among MRD+ patients compared with 17 months to 67 months among those with MRD- status. This translated to median OS difference ranging from -8 to -50 months for the MRD+ vs. MRD- patients. Data indicated that patients who are MRD- at time of transplant also experienced longer median event-free survival (EFS) (median EFS difference was -8 months for MRD+ vs. MRD- in two studies) and longer median relapse-free survival (RFS) (median RFS MRD+ vs. MRD- of -40.5 months in one study).While 12 studies reported data on the proportion of patients who relapsed after SCT, timepoints were not consistently reported and population sizes varied widely. Among all studies reporting this data, 16% to 100% of MRD+ patients relapsed after SCT, while 0% to 50% of MRD- patients experienced a relapse after SCT. Only four studies reported complete remission (CR); 35.6% to 86%of MRD+ patients achieved CR after SCT, while 100% of MRD- patients maintained CR after SCT based on one study.Conclusion: This systematic literature review found consistent evidence of markedly worse transplant outcomes among patients with MRD+ vs. MRD-, including shorter median survival (OS, RFS and EFS), higher risks of death and relapse events and lower likelihood to achieve hematologic remission. Therapies that can eradicate MRD among adult ALL patients can potentially improve the outcomes of SCT in these critically ill patients. DisclosuresTurner:Evidera: Employment. Shah:Amgen, Inc.: Employment, Equity Ownership. Martin:Evidera: Employment. Cong:Amgen, Inc.: Employment, Equity Ownership. Stein:Amgen Inc.: Speakers Bureau; Celgene: Speakers Bureau.

Long Term Follow-up after SCRI-CAR19v1 Reveals Late Recurrences As Well As a Survival Advantage to Consolidation with HCT after CAR T Cell Induced Remission

Background: CD19 chimeric antigen receptor (CAR) T cell therapy has demonstrated robust responses in refractory/relapsed subjects with CD19+ acute lymphoblastic leukemia (ALL). Our Phase 1 clinical trial demonstrated a minimal residual disease (MRD) negative complete remission (CR) rate of 93% at 21 days following SCRI-CAR19v1 (a CD19 specific CAR T cell product) infusion (PMID: 29171004). Though remission is frequently attained, approximately half of patients recur. Controversy exists regarding the benefit of hematopoietic cell transplant (HCT) following CD19 CAR T cell therapy. Although not mandated by the study, our current institutional recommendation for relapsed/refractory patients without a history of allogeneic HCT is to undergo a HCT once in remission following SCRI-CAR19v1. Additionally, we have recommended HCT to those who have a short duration of persistence of SCRI-CAR19v1 in vivo regardless of prior HCT status. We report here the leukemia free survival (LFS) of subjects who proceeded to HCT following remission after SCRI-CAR19v1 infusion.Methods/Results: We analyzed the first 64 subjects on our Phase 1/2 trial, PLAT-02 (NCT02028455), with follow-up of ≥1 year to evaluate the potential benefit of consolidative HCT. We excluded subjects that did not respond (n=5) or relapsed prior to day 63 (n=9). Thirty-two of the evaluated subjects were treated on the Phase I dose finding portion of the study and 18 were treated on the Phase 2 portion at dose level of 1x106cells/kg. Of the 50 evaluable subjects, 33 had a history of at least one prior HCT, whereas 17 had no history of HCT. Figure A demonstrates the LFS for patients that did and did not undergo HCT following SCRI-CAR19v1.There is a trend towards improved LFS (p-value 0.057; Figure B) in patients who underwent first HCT following SCRI-CAR19v1. Of the 17 patients without a history of HCT, 3 did not pursue HCT following CAR therapy. Of those 3 subjects, only 1 remains in remission at 28 months. The other 2 subjects relapsed at 6 and 7 months with CD19+ and CD19- disease, respectively. Of the 14 patients that underwent first HCT after SCRI-CAR19v1, 2 relapsed following HCT. One had evidence of MRD by flow at the time of HCT and the other subject relapsed with CD19- disease. The role of second HCT following CAR therapy remains unclear. Of the 33 subjects with a history of HCT, 10 underwent a second HCT following SCRI-CAR19v1 infusion, and 5 are alive and remain in remission. The recurrences included 2 lineage switches and 2 CD19+ (1 was MRD positive by deep sequence prior to HCT), and one transplant related mortality (TRM). Of the 23 subjects that did not undergo a second HCT, 8 remain in remission (p-value not significant (NS); Figure C).We previously reported that subjects with a short duration of B cell aplasia (BCA) ≤63 days following SCRI-CAR19v1 have an increased risk of relapse. Here we show that subjects with short BCA who attained a CR and did not relapse prior to day 63 demonstrate a clear benefit of consolidative HCT (p-value 0.007; Figure D). Of the 15 subjects with short BCA (regardless of HCT history), 6 did not pursue HCT and all recurred (5 CD19+, 1 CD19-). Of the short BCA subjects that underwent HCT, 1 subject died of TRM (2ndHCT for this subject) and 2 subjects relapsed following HCT (1 was MRD positive prior to HCT).All events in the consolidative HCT group have occurred by 20 months following SCRI-CAR19v1. However, we continue to see late relapses following CAR T cell therapy in the group who did not proceed with HCT. Three subjects have relapsed beyond 2 years: 1 with CD19+ disease at 27months, 1 with CD19- disease at 41 months, and 1 patient with lineage switch AML at 38 months. Further analysis is needed to understand the continued long-term risk of relapse following CD19 CAR T cell therapy and the potential role and timing for consolidative HCT in patients with a previous HCT.Conclusions: We demonstrate a trend towards improved LFS for subjects without a history of HCT who undergo a consolidative HCT following CD19 CAR T cell therapy on PLAT-02. In addition, HCT appears to benefit subjects who attain a CR but are at increased risk of relapse with short-term BCA. Currently, the benefit of second HCT following CD19 CAR T cell therapy is unclear and may be restricted to those that have short functional persistence of SCRI-CAR19v1. Late relapses after SCRI-CAR19v1 have only occurred in those without consolidative HCT, but longer follow up is needed to confirm these findings. DisclosuresJensen:Juno Therapeutics, Inc.: Consultancy, Patents & Royalties, Research Funding.

Genomics Reveal Potential Biomarkers of Response to Pembrolizumab after High Dose Cytarabine in an Ongoing Phase II Trial in Relapsed/Refractory AML

Background: Outcomes remain dismal for patients (pts) with relapsed/refractory (R/R) AML. Programmed Death-1 (PD-1), an inhibitory receptor on T and B cells, suppresses immune activation. We hypothesized that administration of pembrolizumab, a monoclonal antibody targeting PD-1, after high dose cytarabine (HiDAC) salvage chemotherapy would stimulate a T-cell mediated anti-leukemic immune response leading to improved efficacy in R/R AML.Methods: We are conducting a multicenter phase II study of HiDAC (<60 years: 2 gm/m2 IV Q12hours days 1-5; ≥60 years: 1.5 gm/m2 IV Q12hours days 1-5) followed by pembrolizumab 200 mg IV on day 14 in R/R AML pts 18-70 years. The primary objective of this study is to estimate the overall complete remission (CR + CRi) rate. Overall responders can receive maintenance phase pembrolizumab 200 mg IV Q3weeks for up to 2 years until progression. Allogeneic stem cell transplant (SCT) is permissible before or after maintenance phase.Results: To date, 26 pts are evaluable for safety and response (Table 1). Grade ≥3 immune-related adverse events have been rare and self-limiting. The overall CR rate is 35%. Of the 9 CR pts, 5 (56%) had no evidence of minimal residual disease (MRD) by standard monitoring. Notably, 2/3 primary refractory pts with inv(3) cytogenetics achieved CR and underwent SCT. Additionally, 1 pt with relapsed AML with most recent treatment refractory to HiDAC salvage achieved CR with no evidence of MRD. Five pts received maintenance pembrolizumab: 3 relapsed (median duration of CR = 2.8 months; range: 2-5.7 months), 1 proceeded to SCT after 2 cycles, and 1 initially achieved a partial remission (PR) and had stable disease for 12 cycles of maintenance pembrolizumab before progressing. Four pts received a SCT in CR (n=3) and morphologic leukemia free state (MLFS) (n=1). Grade II acute graft-versus host disease (GVHD) and moderate chronic GVHD was seen in 2/4 (50%) pts, respectively. With a median follow up of 10.8 months to date, median overall survival is 10.5 months (range: 1.8-20.8 months).We performed B cell receptor amplicon sequencing, T cell receptor (TCR) amplicon sequencing from CD8+ T cells, and RNA-seq from enriched blasts and non-blast fractions in bone marrow (BM) from 3 CR and 3 non-responders (NR) prior to HiDAC. From the BM blast enriched fraction, expression of innate immune genes such as NLRP12, C3, S100A9, S100A12 and CD14 correlated with response. Gene Set Enrichment Analysis (GSEA) demonstrated that CR correlated with expression of genes in the Toll Pathway, Lysosome pathway, and adaptive immune system while NRs were associated with expression of the PAR1 and GATA3 pathways. From the non-blast BM population, CR correlated with expression of cell-cycle genes such as CCNE1, CCNB2, E2F2, KIF18B and CDKN3. Not surprisingly, GSEA revealed that expression of cell cycle pathways correlated with response. CR correlated with increased expression of B cell metagenes and the inverse IPRES signature in the non-blast BM fraction. As previously reported, there was a significant increase in peripheral blood (PB) TCR diversity in CR pts. CR was also significantly associated with the abundance and richness of the non-blast BM fraction of the B cell heavy and both light chains suggesting that a broader immune response at baseline may be critical for response to HiDAC and pembrolizumab. Finally, CR correlated with increased expression of CD300E, CCR7, CCR4, CCR8 and CCL7 in PB CD8+ T cells suggesting that migration of monocytes, T and B cells is associated with response.Conclusions: Our findings demonstrate that pembrolizumab is well tolerated after HiDAC in an ongoing study in R/R AML. An encouraging response rate has been seen in a high-risk patient population without apparent additive toxicity post-SCT. Our RNA-seq and amplicon sequencing data indicate that biomarkers of response are present prior to therapy. Increased expression of innate immune genes expressed by leukemic blasts and cell cycle genes by the non-blast fraction correlated with response to therapy. Additionally, CR was associated with increased measures of B and T cell diversity and immune cell migration. Further immunogenomic biomarker correlates are ongoing to determine predictors of response to pembrolizumab after HiDAC in R/R AML. [Display omitted] DisclosuresZeidner:Tolero: Honoraria, Other: Travel Fees, Research Funding; Asystbio Laboratories: Consultancy; Merck: Research Funding; Takeda: Other: Travel fees, Research Funding; Rafael Pharmaceuticals: Other: Travel Fees; Celgene: Honoraria. Vincent:Merck: Research Funding. Foster:Celgene: Research Funding; Macrogenics: Research Funding; Pfizer: Research Funding; Shire: Honoraria. Coombs:Incyte: Other: Travel fees; AROG: Other: Travel fees; DAVA Oncology: Honoraria; Abbvie: Consultancy; H3 Biomedicine: Honoraria. Luznik:WIndMIL Therapeutics: Equity Ownership, Patents & Royalties. Gojo:Merck inc: Research Funding; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Amgen: Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees. Serody:Merck: Research Funding.

Minimal residual disease by either flow cytometry or cytogenetics prior to an allogeneic hematopoietic stem cell transplant is associated with poor outcome in acute myeloid leukemia

Relapsed acute myeloid leukemia (AML) is a significant challenge after allogeneic hematopoietic cell transplant (HCT). Multiparameter flow cytometry (MFC), conventional cytogenetics (CG), and fluorescence in situ hybridization (FISH) are routinely performed on bone marrow specimens prior to HCT to assess disease status. We questioned the extent by which pre-HCT evidence of minimal residual disease (MRD) detected by these standard assays, corresponded with post-HCT relapse. We conducted a single center, retrospective study of 166 AML patients who underwent HCT. Thirty-eight of one hundred sixty-six (23%) patients in complete remission (CR) or CR with incomplete count recovery (CRi) had MRD detectable by MFC, CG, or FISH. MRD was more frequently seen in patients with poor risk karyotype at diagnosis (P = 0.011). MRD-negative patients (MRDneg) had significantly longer overall survival (OS) and relapse-free survival than patients who were MRD positive (MRDpos) (P = 0.002 and 0.013, respectively). In patients with MRDpos prior to HCT, the presence of acute graft vs. host disease (GVHD) (grade ≥ 2) or chronic GVHD significantly improved progression free survival (PFS) (hazard ratio (HR) = 0.053 (95% confidence interval (CI): 0.01–0.279), P = 0.0005) and OS (HR = 0.211 (95% CI: 0.081–0.547), P = 0.0014).

Persistently low lymphocyte counts after FCR therapy for chronic lymphocytic leukemia are associated with longer overall survival.

Decreased absolute lymphocyte counts (ALCs) following frontline therapy for chronic lymphocytic leukemia may be associated with disease control, even in patients without evidence of minimal residual disease. We studied the prognostic significance of ALCs during the first year following treatment with fludarabine, cyclophosphamide, and rituximab (FCR). We evaluated 99 patients who achieved a partial response without lymphocytosis (<4.0×103 cells/μL) or better after FCR. Absolute lymphocyte counts were recorded at 3-, 6-, 9-, and 12-month posttreatment and correlated with overall survival (OS) and event-free survival (EFS). For each time point, analyses were limited to patients without lymphocytosis, so as to avoid possible biases from undocumented disease progressions. Lymphopenia (ALC<1.0×103 cells/μL) at 3m after FCR (69% of patients n=68), was associated with a longer OS (5y OS 91% vs 64%, P=.001), as were ALC≤2×103 cells/μL at 6m (5y OS 85% vs 48%, P=.004) and ALC≤1.8×103 cells/μL at 9m (5y OS 93% vs 54%, P=.009). A normal-range ALC (≤4×103 cells/μL) at 12m was also associated with a 91% 5y OS. Higher ALCs (but without lymphocytosis) were associated with shorter EFS (median EFS 27months for ALC>1.8 vs not reached for ALC≤0.7 at 9months, P<.0001). In conclusion, lower ALC levels in the first few months following frontline FCR therapy were associated with longer OS and EFS. Possible explanations may be that lower ALCs reflect deeper clonal suppression or protracted Treg depletion. Absolute lymphocyte count levels may be a cheap and widely available prognostic marker, though the added value for clinical practice is the minimal residual disease era needs to be explored.

Efficacy and Safety of CTL019 in the First US Phase II Multicenter Trial in Pediatric Relapsed/Refractory Acute Lymphoblastic Leukemia: Results of an Interim Analysis

Background: CTL019 is an investigational therapy derived from autologous T-cells expressing a CD19-specific chimeric antigen receptor (CAR). A single center, phase I/IIa trial of CTL019 showed complete and durable remissions in pediatric/young adult patients (pts) with relapsed/refractory (R/R) B-cell acute lymphoblastic leukemia (B-ALL) (Maude et al NEJM 2014); these results have yet to be reproduced in a multicenter setting. Here, we report results from a 6-month interim analysis of the first multicenter phase II trial of an engineered cell therapy in leukemia. Methods: 9 US sites participated in this single-arm phase II study in pediatric/young adult pts with R/R B-ALL. Leukapheresis products were shipped for centralized manufacturing according to the University of Pennsylvania (Penn) process in an academic-industry collaboration. T cells were transduced with a lentiviral vector encoding a CAR composed of anti-CD19 scFv, CD3ζ and 4-1BB domains. Following lymphodepletion with fludarabine and cyclophosphamide, a single dose of CTL019 cells was administered (target dose 2.0-5.0×10 6 cells/kg for ≤50 kg and 1.0-2.5×10 8 cells for >50 kg). The primary endpoint was overall remission rate (ORR = CR + CRi [CRi, complete remission with incomplete blood count recovery] maintained at 2 evaluations ≥28 days apart) as determined by an Independent Review Committee. Secondary objectives included minimal residual disease (MRD), relapse-free survival (RFS), overall survival (OS) and safety. All analyses were performed on infused patient set. Results: 29/35 pts enrolled (82.9%) were infused with CTL019; 6 withdrew prior to infusion (2 manufacturing failures [1 lack of growth, 1 contamination]; 4 deaths [median, 48 days from enrollment; 2 progressive disease, 1 multi-organ failure, 1 pneumonia]). Mean bone marrow involvement at enrollment was 68.2% (SD, 27.3%; Table 1). 2 pts did not receive lymphodepleting chemotherapy due to leukopenia. Collection, manufacturing and infusion were feasible in a multicenter setting with a median time from enrollment to infusion of 37 days. Target cell dose was met in 24/33 (72.7%) manufactured products. ORR in all infused pts was 69.0% (20/29 pts; 98.95% CI 43.6, 88.1). Of the 5 pts who received CTL019 below the target dose, 2 achieved CR/CRi. Of note, deep remission with no evidence of MRD ( Conclusions: In this first multicenter trial of CAR-modified T cell therapy, CTL019 therapy was feasible and efficacious, showing a high ORR with durable remissions in pediatric/young adult pts with R/R B-ALL. Despite the high rate of toxicity with CTL019 in the R/R setting, the rate of grade 3 or 4 CRS was comparable to the single center study, and standardized management of CRS was successful in a multicenter trial with no deaths attributable to CRS. In this highly refractory population, a vast majority of eligible pts can be successfully infused in a timely fashion and outcomes appear reproducible in a multicenter setting despite a more heterogeneous population than the single center study. The trial is continuing under Novartis manufacturing. Disclosures Maude: Novartis: Consultancy. Pulsipher: Medac: Other: Travel support for a study group; Chimerix: Consultancy, Other: Advisory Board ; Jazz Pharmaceutical: Consultancy, Other: Advisory Board; Novartis: Consultancy, Other: Advisory Board, Steering Committee for Phase II Study. Grupp: Pfizer: Consultancy; Novartis: Consultancy, Research Funding. Davies: Novartis: Honoraria. Verneris: Bimogen: Other: Advisory Board. Schlis: Novartis: Honoraria. Driscoll: Novartis: Consultancy. June: Immune Design: Consultancy, Equity Ownership; Pfizer: Honoraria; Celldex: Consultancy, Equity Ownership; Novartis: Honoraria, Patents & Royalties, Research Funding; Johnson & Johnson: Honoraria; Novartis: Honoraria, Patents & Royalties, Research Funding; Tmunity Therapeutics: Equity Ownership. Levine: GE Healthcare Bio-Sciences: Consultancy; Novartis: Patents & Royalties, Research Funding. Wood: Novartis Pharmaceuticals: Employment, Other: Stock. Yi: Novartis: Employment.

Phase 1 Study of Pomalidomide Given at the Time of Early Lymphocyte Recovery after Induction Timed Sequential Chemotherapy in Newly Diagnosed Acute Myeloid Leukemia (AML) and High-Risk Myelodysplastic Syndrome (HR-MDS)

Introduction: AML pts have a poor prognosis with conventional chemotherapy regimens. Early lymphocyte recovery (ELR) following intensive timed sequential therapy (TST) induction is characterized by a dysfunctional immunosuppressive state. Pomalidomide (Pom), a small molecule immunomodulatory agent (IMiD), has direct effects on T cell co-stimulation by promoting the ubiquitination of Aiolos, an IL-2 transcriptional repressor. We hypothesized that the administration of Pom at the time of ELR after induction TST may influence T cell differentiation and enhance an anti-leukemia immune effect.Methods: A multicenter phase 1 dose escalation study was conducted to determine the safety and tolerability of Pom after intensive induction TST in newly diagnosed AML and HR-MDS pts 18-65 years. Core-binding factor AML was excluded. All pts received induction chemotherapy with AcDVP16: cytarabine 667 mg/m2/day IV continuous infusion days 1-3, daunorubicin 45 mg/m2/day IV days 1-3, etoposide 400 mg/m2/day IV days 8-10. Pom was administered at the assigned dose and schedule after day 14 and within 3 days of the total white blood cell count (WBC) reaching >0.2x109/L above nadir, defined as ELR. Three dose levels were planned (2 mg, 4 mg and 8 mg) within 2 cohorts: 10 days of Pom and 21 days of Pom, in a traditional 3+3 dose escalation design.Results: 25 pts were enrolled on this study January 2014-June 2016 across 3 institutions (Table 1). Pom administration occurred at a median of 21 days after AcDVP16 induction. There were no dose-limiting toxicities (DLTs) in the first cohort of Pom x 10 days within each dose level- 2 mg (n=3), 4 mg (n=3) and 8 mg (n=7). There were no DLTs seen at 4 mg x 21 days (n=7). Two DLTs were seen at Pom 8 mg x 21 days (Grade 3 ALT increase and Grade 3 hypoxia, respectively). Thus, Pom 4 mg x 21 days will be further expanded.Nine (36%) pts discontinued Pom early (median duration = 5 days) due to: grade 3 rash (n=3), physician discretion (decreased WBC: n=1, fever and increased creatinine: n=1), grade 3 ALT increase (n=1), grade 3 hypoxia (n=1), disease progression (n=1), and pt preference (n=1). Adverse events (AEs) possibly associated with Pom that were seen in >1 pt included fever (n=8), rash (n=7), AST/ALT increase (grade 1: n=4, grade 3: n=1), mucositis (n=2), and fatigue (n=2). All of these AEs were self-limiting with supportive care and/or discontinuation of Pom.60-day mortality was 0%. A complete remission (CR) was achieved in 18 pts and 1 achieved CR with incomplete platelet recovery (CRp) with a combined CR + CRp = 19/25 (76%). Among pts with adverse-risk AML, 5/6 (83%) achieved CR. One pt achieved a partial remission and 5 pts were refractory to treatment. Of the 19 CRs, 15 had no evidence of minimal residual disease by cytogenetics, FISH, or flow cytometry. Among pts who completed a course of Pom (10 days or 21 days), 14/16 (88%) achieved CR. As previously reported, a dramatic decrease of Aiolos expression via flow cytometry in T cell subsets was observed in vivo for the duration of POM treatment with doses > 2 mg, but the effect was lost after Pom was stopped. Figure 1 displays the pattern of cytokine production of CD4+ T cells visualized with pie charts, and shows a significantly different subset composition at ELR in Pom-treated pts compared to the same pts at full recovery (p=0.02), and compared to control AML pts at the same time point (p=0.004). Furthermore, there was a significant increase in TNF-α production (p=0.009) and the combination of TNF-α and IL-2 production (p=0.03) in stimulated CD4+ T cells during Pom treatment, which was reduced to baseline values after Pom was discontinued at full recovery (Figure 1: data analysis performed with the SPICE software).Conclusions: Pom can be safely administered at the time of ELR after intensive induction TST. Fever and rash are the most common AEs seen after Pom administration. Inhibition of Aiolos and consequent increase in both IL-2 and TNF-α expression, as measured by flow cytometry, appear to be reliable markers of Pom-induced T cell modulation in vivo. Planned expansion of the cohort of 4 mgx 21 days will allow further evaluation of safety and activity of Pom in AML. [Display omitted] [Display omitted] DisclosuresZeidner:Takeda: Research Funding; Merck: Research Funding; Agios: Honoraria; Otsuka: Consultancy; Tolero: Research Funding. Zeidan:Celgene: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Ariad: Consultancy, Honoraria; Incyte: Consultancy, Honoraria. Smith:Celgene: Consultancy, Other: member of DSMB. Levis:Millennium: Consultancy, Research Funding; Daiichi-Sankyo: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; Astellas: Consultancy, Honoraria, Research Funding. Foster:Celgene: Research Funding.

A Phase 1b Study of Vadastuximab Talirine in Combination with 7+3 Induction Therapy for Patients with Newly Diagnosed Acute Myeloid Leukemia (AML)

A Phase 1b Study of Vadastuximab Talirine in Combination with 7+3 Induction Therapy for Patients with Newly Diagnosed Acute Myeloid Leukemia (AML)

Life after transplant: are we becoming high maintenance in AML?

Allogeneic hematopoietic cell transplantation (allo-HCT) for patients with AML is increasingly able to impact the historically poor outcomes in this disease. Nonetheless, even with transplant, the rates of post-HCT relapse are unacceptably high, and remain a great challenge in the treatment of patients with AML. Maintenance therapies after allo-HCT, given to patients at high risk of relapse or with evidence of minimal residual disease (MRD), may provide a way to reduce relapse rates and improve survival. New therapies may offer acceptable toxicity profiles in the post-HCT setting, and investigations are ongoing using hypomethylating agents, histone deacetylase inhibitors, immunomodulatory drugs, targeted tyrosine kinase inhibitors, drug-antibody conjugates and cellular therapies. Future directions in the field of post-HCT therapies may include better risk stratification with MRD, as well as the exploitation of novel mechanisms such as immune checkpoint inhibition and modified chimeric antigen receptor (CAR) T cells. In this mini review, we discuss the current landscape of clinical research in post-HCT maintenance therapies, as well as future therapeutic strategies of interest. Although there is great potential for post-HCT agents to improve AML outcomes, these will need to be evaluated prospectively through well-designed randomized clinical trials.

Minimal Residual Disease (MRD) By Either Flow Cytometry or Cytogenetics Prior to an Allogeneic Hematopoietic Cell Transplant (allo-HCT) Predicts Poor Acute Myeloid Leukemia (AML) Outcomes

Introduction: Persistent AML is a known risk factor for poor outcomes after allo-HCT. The impact of MRD in patients who achieve complete remission (CR) or CR with incomplete count recovery (CRi) has been less well studied.Methods: We retrospectively reviewed the records of AML patients who underwent allo-HCT in morphological remission (<5% myeloblasts and normal marrow cellularity) with or without blood count recovery between January, 2000 and January, 2014. Data was collected for variables known to impact the prognosis of AML patients (Table 1). MRD was defined as evidence of abnormalities associated with AML by either flow cytometry, cytogenetics or Fluorescence in situ hybridization (FISH). The impact of MRD identified at the time of allo-HCT on cumulative incidence of relapse (CIR), progression free survival (PFS), and overall survival (OS) was assessed in MRD+ and MRD- patients.Results: A total of 166 eligible patients were identified. The median follow-up among living patients is 46 months (range, 13-103).Thirty seven (22%) patients had evidence of MRD (13 by flow cytometry only, 17 by cytogenetics/FISH only and 7 by both). MRD was more common in patients with poor risk karyotype at diagnosis and CRi at the time of allo-HCT (Table 1). PFS (P= 0.0016), OS (P=0.002), and CIR (P=0.02) were all significantly worse in MRD+ patients (Figures 1& 2). In univariate analysis, MRD+ patients, assessed by flow cytometry had worse PFS (P=0.0216) and OS (P=0.0314) compared to MRD- patients. Similarly patients with evidence of MRD+ by cytogenetics/FISH had worse PFS (P=0.007) and OS (P=0.0031). In a multivariate cox proportional hazards model 1) any MRD positivity prior to allo-HCT, 2) poor-risk karyotype at diagnosis, and 3) CRi at allo-HCT independently predicted significantly poor PFS and OS. Only poor-risk karyotype was associated with a significant increase in CIR, while MRD positivity showed a trend towards higher CIR.Conclusion: MRD positivity prior to HCT by either flow cytometry or by cytogenetics/FISH independently predicts adverse AML outcomes.Table 1Comparison of pre-transplant variablesCovariateLabelMRD + (N=37)MRD - (N=129)P-ValueAge(years)< 408 (21%)20 (16%)0.70840 - 5920 (53%)69 (54%)≥ 6010 (26%)39 (30%)Karyotype riskFavorable/ Intermediate19 (53%)95 (74%)0.011Poor18 (47%)33 (26%)Timing of Allo-HCT1st remission (CR1)28 (74%)97 (76%)0.792> CR110 (26%)31 (24%)Allo-HCT after1st relapse(>CR1): duration of CR1> 12 mo31 (82%)113 (88%)0.285≤ 12 mo7 (18%)15 (12%)Secondary AMLNo23 (60%)78 (61%)0.964Yes15 (40%)50 (39%)Complete remission vs CRiCR28 (74%)110 (86%)0.077CRi10 (26%)18 (14%)Conditioning RegimenAblative24 (63%)72 (56%)0.449Other14 (37%)56 (44%)Donor TypeMatched sibling donor12 (32%)42 (33%)0.887Other26 (68%)86 (67%)Female donor: male recipient (FDMR)Other28 (80%)91 (78%)0.844FDMR7 (20%)25 (22%) [Display omitted] [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Exploring Relationships of Exposure, Pharmacodynamic Changes and Gene Expression to Clinical Outcome in Adults with Acute Lymphoblastic Leukemia Receiving Inotuzumab Ozogamicin

▪BackgroundInotuzumab ozogamicin (InO) is a targeted antibody-drug conjugate (ADC) under development for treatment of patients with relapsed or refractory CD22-positive acute lymphoblastic leukemia (ALL) and non-Hodgkin's Lymphoma. Correlative analyses from an open-label, Phase 1/2 study (B1931010) included exploring the relationship between InO pharmacokinetic exposure, hematologic measures, and gene expression to treatment response.MethodsPatients received 2 to 3 weekly intravenous doses of InO by 1 hour infusion over a 28-day cycle for ≤ 6 cycles (table).Blood samples were drawn during Days 1 and 15 of Cycles 1 and 2 (at 0, 1 and 3 h), and Day 1 of Cycle 4 (at 0 and 1 h) for concentration determination of InO and unconjugated calicheamicin in serum. Samples were analyzed using a validated LC/MS/MS procedure. InO levels were correlated to CD22 protein expression on CD19+ B-lymphocytes in blood and bone marrow, and to minimum residual disease. Lymphocyte regeneration was described using a linear mixed-effects model. To explore the relationship between clinical outcome and expression of genes such as those involved in DNA damage response and apoptosis, optional blood samples for gene expression analysis were collected on Cycle 1 Day 1 and Cycle 1 Day 15 [each at pre- and post-dose time-points]. These samples were assessed for baseline gene expression and gene expression changes using 96-gene TaqMan Low Density Array cards.ResultsUnconjugated calicheamicin levels were below the limit of quantitation (50 pg/mL) for most patients and time points. Treatment-related decreases in CD22 antigen expression on lymphocytes were rapid but unrelated to InO concentration. Lymphocyte depletion in blood was also rapid, consistently observed regardless of InO dose, and followed by slow regeneration with substantial inter-patient differences in regeneration rate. Percentage of bone marrow blasts was directly related to InO elimination rate. With treatment, as blast percentage decreased, InO elimination rate decreased by approximately 50% by Cycle 4 (ie, after 10 dosing events) compared to the first dose. In bone marrow, lower disease burden at baseline tended to be associated with faster regeneration of lymphocytes during the follow-up period. Patients achieving minimal residual disease (MRD)-negativity tended to have higher peak and trough serum concentrations of InO throughout each cycle compared to patients not achieving MRD-negativity. There was no observed correlation between percentage of blasts at baseline and MRD-negativity. CD22 mRNA levels in blood decreased approximately 10-fold by Day 15 relative to baseline, consistent with selective killing of CD22-positive leukemic blasts by InO. This decrease was more pronounced in subjects who exhibited complete response with/without incomplete platelet count recovery with no evidence of MRD than in subjects who did not exhibit clinical response (p=0.001 using Wilcoxon Rank Sum Test). In addition, multiple other transcripts exhibited decreases following InO administration, including mRNAs encoded by genes regulating proliferation (cyclin-dependent kinase 2), DNA repair (XRCC2), and cell death (death-associated protein kinase 1).ConclusionIn patients with ALL receiving InO, CD22 protein expression and lymphocyte count decreased rapidly, followed by slow and variable regeneration, as patients with low disease blast counts at baseline exhibited faster recovery of their counts than those with higher levels. While CD22 expression is not a significant determinant of InO concentration, the number of doses administered did influence drug elimination rate; an effect thought to be associated with target-mediated drug clearance. In related fashion, patients achieving MRD-negativity tended to have higher InO concentrations following InO treatment. Changes in mRNA profiles in blood consistent with the mechanism of action of InO were evident. The extent of reduction in CD22 mRNA was associated with clinical outcome. Study is ongoing for long term follow up. [Display omitted] DisclosuresFostvedt:Pfizer Inc: Employment, Other: stock ownership. Laird:Pfizer Inc: Employment, Other: Stock ownership. Marshall:Pfizer Inc: Employment, Other: Stock ownership. Li:Pfizer Inc: Employment, Other: Stock ownership. Boni:Pfizer Inc: Employment, Other: Stock ownership.

Fludarabine, Cyclophosphamide, Ofatumumab (FC-O2) As Front-Line Treatment for Young and Fit Patients with Chronic Lymphocytic Leukemia (CLL): Preliminary Results of the Prospective Phase 2 LLC0911 Gimema Study

Introduction. The fludarabine, cyclophosphamide, rituximab (FCR) regimen is associated with high complete response (CR) rates and a negative residual disease status in a significant proportion of cases and is considered the optimal front-line treatment for fit patients with chronic lymphocytic leukemia (CLL). In addition, long-term follow-up of patients treated with FCR at the MD Anderson Cancer Center, in the multicenter German CLL8 study and at Italian institutions indicate that a sizable fraction of patients characterized by a favorable biologic profile remains free from progression in excess of 10 years. FC combined with ofatumumab (FC-O), a human monoclonal antibody which targets an epitope of the CD20 molecule, has also been associated with a high CR rate. The aim of this study was to evaluate whether a double dose of ofatumumab (O2) combined with FC could improve the CR rate in young (≤65 yrs) and fit patients with CLL.Methods. Sixty-one fit CLL patients from 15 Italian institutions were enrolled in this front-line study and treated with the FC-O2 regimen based on the FC schedule (F 25 mg/sqm i.v. d1-3, C 250 mg/sqm i.v. d1-3) combined with 13 doses of O (300 mg i.v. d14; 1000 mg d21 at the first cycle; 1000 mg d1 and d15 at cycles 2-6 and d28 at cycle 6). As infection prophylaxis, patients received bactrim and peg-filgrastim in order to prevent granulocytopenia. CLL diagnosis, treatment requirement and response were assessed according to the 2008 iwCLL guidelines. Minimal residual disease (MRD) was evaluated by flow cytometry in the peripheral blood (PB) and bone marrow (BM), and also by RQ-PCR in flow negative cases. CT scan evaluation was included in the response assessment. Adverse events (AEs) were graded according to the NCI-CTCAE.Results. The median age of patients was 60 years (range 36-65), Binet stages B and C were recorded in 86% of cases, B-symptoms in 21%, increased β2M values in 74% and bulky nodes (≥5 cm) in 10%. An IGVH unmutated status was recorded in 60% of cases, deletion 13q in 37%, no aberrations in 33%, deletion 11q in 14%, trisomy 12 in 12%, 17p deletion and/or TP53 mutation were found in 10% of cases. At present, the median follow-up of patients is 7 months (range 1-20). Response to treatment has been assessed in 29 patients after a median number of 6 courses of treatment (range 2-6). The overall response rate is 90%, with a CR rate of 69% (20 patients). No evidence of MRD was observed by flow cytometry in both PB and BM in 15/20 CR patients (75%). To date, 11 patients with cytometric MRD negative CR have been evaluated by RQ-PCR and no residual disease was detected in 3. Grade 3-4 granulocytopenia was recorded in 4 patients (7%), a severe infection in 4 (7%) and 5 patients (8%) experienced a severe infusion-related reaction during ofatumumab administration. Treatment was discontinued in 8 patients as a result of toxicity (infection, 2 cases; FUO, 1; infusion-related toxicity, 1; autoimmune hemolytic anemia, 1; recurrent granulocytopenia, 1; tachyarrhythmia, 1; non-specified toxicity,1). A non-treatment-related death (traumatic aortic transaction due to a dislocated aortic endoprostheses) has been recorded in a patient after 2 months from treatment discontinuation and 1 showed a disease progression after 4 courses of FC-O2.Conclusions. Taken together, the first analysis of this ongoing front-line study suggests that the combination of FC with an increased dose of ofatumumab is well tolerated with acceptable and no unexpected toxicity. Our preliminary results show that the FC-O2 treatment is associated with a high rate of cytometric MRD-negative CR in young and fit patients with previously untreated CLL. DisclosuresCarella:Seattle Genetics Inc.: Research Funding. Foà:Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

Preliminary Evidence That ODSH (2-O, 3-O Desulfated Heparin) Is Safe and Enhances Count Recovery in Patients Treated with Intensive Therapy for Acute Myeloid Leukemia – Results of a Pilot Study

IntroductionIntensive treatment of acute myeloid leukemia (AML) is associated with severe pancytopenia. Thrombopoietic agents have so far failed to mitigate treatment-associated thrombocytopenia. Platelet factor 4 (PF4) is a potent negative regulator of megakaryopoeisis and its levels correlate with platelet transfusion requirements in children treated for acute lymphoblastic leukemia. Anti-PF4 antibodies diminish chemotherapy-induced thrombocytopenia in mice. ODSH (2-O, 3-O Desulfated Heparin), a heparin derivative with low anticoagulant activity, is a potent inhibitor of PF4, mitigates heparin-induced thrombocytopenia and, like other heparins, may inhibit the CXCL12/CXCR4 axis. The purpose of this pilot study was to obtain preliminary data on the effect of ODSH when combined with intensive AML treatment.MethodsAdult patients with newly diagnosed untreated AML (excluding acute promyelocytic and acute megakaryoblastic leukemia) were enrolled. Induction therapy consisted of cytarabine (100 mg/m2 as a continuous 24-hour infusion on days 1 – 7) and idarubicin (12 mg/m2 by intravenous bolus on days 1 – 3). During induction cycles, ODSH was given as a bolus of 4 mg/kg on day 1 followed by a continuous infusion of 6 mg/kg/day on days 1 – 7. Patients 60 or older received further post-induction therapy off study. Patients younger than 60 received consolidation therapy with high dose cytarabine (3 g/m2 every 12 hours on days 1, 3, and 5) along with ODSH given as a bolus of 4 mg/kg on day 1 followed by a continuous infusion of 6 mg/kg/day on days 1 – 5. Patients received transfusion and antibiotic support per standard guidelines. Patients did not receive growth factor support during induction cycles.Primary endpoints were to determine the safety and tolerability of ODSH combined with intensive AML therapy, and to obtain preliminary data on the effect of ODSH on platelet count recovery. Secondary endpoints included obtaining preliminary data on the effect of ODSH on complete remission rate and tolerability of chemotherapy. Data presented here are for induction cycles. Data for consolidation cycles will be presented at the meeting.ResultsTen patients were enrolled. Two patients did not complete the full induction cycle due to complications unrelated to ODSH therapy and are not included in the analysis. The median age of the 8 patients (3 women) who completed the full induction cycle and were analyzed was 55 (range: 22 – 74). There were no ODSH-associated adverse events. Based on cytogenetic, molecular, or antecedent hematologic disorder, 1, 5, and 2 patients fell into the better, intermediate, and poor risk categories, respectively. Day 14 bone marrow biopsies were obtained on all 8 patients and were aplastic without detectable leukemia in all. Seven out of 8 patients who completed induction had evidence of a morphologic complete remission upon count recovery using IWG criteria. One of the 7 patients in morphologic remission had evidence of minimal residual disease by flow cytometry and cytogenetics. It is noteworthy that the 2 patients who did not receive a full course of induction therapy (treatment discontinued on Day 3 and Day 5 of the induction cycle, respectively) achieved a complete remission upon count recovery using IWG criteria with evidence of minimal residual disease by molecular testing.All 8 patients who received a full course of induction therapy were evaluable for platelet count recovery. Among those patients, the median day to obtain a sustained platelet count above 20,000/ml without transfusion was day 20 (range: 16 – 22). Five of the 8 patients who received a full course of induction therapy were evaluable for neutrophil count recovery. Among those patients, the median day to a neutrophil count above 1,000/mL was day 23 (range: 21 – 27).ConclusionWe conclude that ODSH is well tolerated when combined with aggressive therapy for the treatment of AML. Results from this pilot study show that ODSH may enhance count recovery and treatment efficacy. These results justify further study of this strategy in a randomized trial. DisclosuresKennedy:Cantex Pharmaceuticals: Equity Ownership. Bavisotto:Cantex Pharmaceuticals: Consultancy. Marcus:Cantex Pharmaceuticals: Employment, Equity Ownership. Shami:JSK Therapeutics: Equity Ownership, Membership on an entity’s Board of Directors or advisory committees; Lone Star Thiotherapies: Equity Ownership; Cantex Pharmaceuticals: Research Funding.

Minimal Residual Disease Assessment By Flow Cytometry in AML Is an Independant Prognostic Factor Even after Adjusting for Cytogenetic/Molecular Abnormalities

Minimal residual disease (MRD) assessment provides early evaluation of the efficacy of anti-leukemic therapy. Previous studies suggested that MRD status serves as a prognostic tool in AML. By contrast to pediatric ALL, where assessment of MRD routinely informs prognosis and guides therapeutic decisions, MRD in adult AML is not routinely used in the clinical context. Moreover, the relationship of MRD status to state-of-the-art molecular prognostic algorithms has not been investigated; it is unknown whether integrating MRD data with molecular profiling allows investigators to better identify patients at increased risk of relapse. In order to investigate the clinical relevance of MRD and its relationship with molecular-based prognostic schema, we performed flow cytometric MRD profiling on AML patients enrolled in the ECOG-led intergroup phase 3 trial, E1900, which randomized patients to induction with cytarabine plus 45 or 90mg/m2 daunorubicin.189 patients (29.3% of the original cohort) had MRD analyzed at morphologic and hematologic complete remission (CR). MRD was evaluated by 4-color flow cytometry (FC) and positivity defined as 0.1% of leukemic cells in bone marrow. There was no association between MRD status and daunorubicin dose (p=1.0), suggesting that dose-intensification, which significantly improving overall survival (OS) (Fernandez et al, NEJM 2010), did not reduce the frequency of MRD positivity. We found a highly significant relationship between MRD positivity and OS (p=0.0002). Of note, the relevance of MRD status to OS was significant in univariate (p=0.0002) and multivariate analyses, after adjusting for age, gender, Hb, WBC/platelet count and cytogenetic risk profile, with a hazard ratio (HR) of MRD positivity vs. MRD negativity of 2.12 (95% CI, 1.31 to 3.41; p=0.0022). The impact of MRD status after consolidation on disease-free survival (DFS) and OS was assessed in 140 patients with evaluable samples at completion of consolidation. Both univariate and multivariate analyses showed strong association between MRD positivity and DFS (p<0.0001 in both analyses) and OS (p<0.0001 in both analyses); the HR for multivariate analysis was 4.16. Notably, using different cut-off thresholds for defining MRD positivity (0.01% and 0.05%) did not change the results of these analyses, confirming that the clinically relevant MRD level in adult AML is 10-times higher than in pediatric ALL.We next investigated whether MRD status provided prognostic information independent of integrated molecular profiling. We assessed the prognostic relevance of MRD status in each of our previously reported molecularly defined risk categories (Patel et al, NEJM 2012). The frequency of MRD positivity increased with increasing risk of relapse as assessed by integrated molecular profiling (p=0.017), with 51% of favorable patients, 76% of intermediate patients, and 73% of unfavorable risk patients having evidence of MRD at the time of CR. Multivariate analysis demonstrated that MRD status had a powerful impact on OS independent of molecularly defined risk (p=0.003), demonstrating that molecular analysis of pre-therapy leukemic cells and post-induction analysis of MRD status independently predict outcome in AML. Notably, the impact of MRD status on outcome was most dramatic in favorable and intermediate risk patients; in each of these subgroups MRD positive patients had an absolute reduction in survival by 28-30% compared to MRD negative patients. By contrast, MRD positive patients with molecularly defined adverse risk did not fare worse than MRD negative patients of this risk class, suggesting that patients with high risk genetic lesions have poor OS regardless of MRD status post induction therapy.The presence of MRD, assessed by flow cytometry, was an independent prognostic factor in newly diagnosed AML patients, both at time of CR and following consolidation. MRD had a strong association with OS even after adjusting for cytogenetic and molecular abnormalities with a most powerful impact on outcome in patients with molecularly defined favorable and intermediate risk disease. Subsequent studies are waranted to delineate the molecular basis for MRD in different AML subsets, and to investigate if MRD-directed therapies can improve outcomes by reducing disease relapse. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Idarubicin, Cytarabine and Pravastatin As Induction Therapy for Untreated Acute Myeloid Leukemia and High-Risk Myelodysplastic Syndrome

Background: AML patients who achieve a “good CR” meaning CR with count recovery (ANC > 1000/ μL, platelets > 100,000/ μL) by day 35 of induction therapy without evidence of minimal residual disease (MRD) on flow cytometry or cytogenetics are less likely to relapse than patients who enter CR with MRD or have slower count recovery. At our institution approximately 75% of CRs are “good CRs” and the good CR rate has been 50%. To improve the latter we combined idarubicin + Cytarabine with the HMG-CoA reductase inhibitor pravastatin (IAP) in newly-diagnosed AML because (a) high intracellular cholesterol levels in AML cells may be an adaptive mechanism of chemoresistance and (b) IAP resulted in higher than expected CR rates in relapsed/refractory AML (Advani et al, ASCO, 2013).Methods: Patients age 18 to 74 with untreated AML (except APL) or MDS/MPN with ≥10% blasts and an anticipated <10% treatment-related mortality rate (Walter et al. 2001) were eligible. Patients received pravastatin (1,280 mg po daily days 1-8), cytarabine (1.5 g/m(2) IV daily, days 4-7) and idarubicin (12 mg/m(2) IV daily, days 4-6). Patients were taken off study if the bone marrow examination between days 17-20 revealed more than 60% myeloid blasts, or if MRD were present between days 31-38. Up to 3 cycles of consolidation with a shortened course of the same regimen was permitted (2 days of IA). Maximum sample size was 50 pts. The study was to stop early if after evaluation of each cohort of 5 patients either (a) the Bayesian posterior probability was < 5% that the true good CR rate was ≥ 70% or (b) the posterior probability was >25% that the TRM rate by day 28 was≥ the historical 5%. Thus parameterized the probability that early stopping would occur if the true good CR rate was 70% and the true TRM rate 5% was 17% after entry of 25 patients, 23% after entry of 30 patients, and 30% after entry of 40 patients.Results: Between May 2013 and April 2014, 24 patients [AML=21 (87%), MDS=2 (9%), CMML=1 (4%)] were treated per protocol. Median age was 57 (range, 35-72) and per ELN classification, 4 (19%), 4 (19%), 6 (29%) and 7 (33%) AML patients had favorable, intermediate-1, intermediate-2 and adverse risk cytogenetics, respectively. Twenty-three (96%) patients completed induction and 9 (37.5%) received consolidation per protocol. Conventional CR was achieved in 17 (71%) patients but only 12 (50%) achieved “good CR”. Two (8.3%) patients died within 28 days after induction (from typhlitis and septic shock (day and five (21%) patients had persistent disease. Given the above noted stopping rules accrual ceased after entry of these 24 patients. 6 patients relapsed after initial CR (3 before HCT and 3 after HCT). Median time to relapse was 112 days (range, 49-164). and 3 patients died between days 175 and 285 after induction therapy from multi-organ system failure and sepsis. The most common grade 3-4 adverse effects were infections (including febrile episodes), gastrointestinal and dermatologic and were observed in 100%, 80% and 50% of patients, respectively. Nineteen (79%) patients were alive after median follow-up of 7.2 months (range, 0.4-11.9).Conclusion: IAP did not meet the pre-defined criteria for success: good CR rate ≥ 70%, TRM rate < 5% leading to early stopping with only a 17% chance that such stopping would have occurred if these were the true rates with this therapy. While it remains possible that our 24 patients were “more unfavorable” than the historical population, stressing the need for development of observed/expected ratios applicable to individual patients in a trial, the demographics of the IAP population suggest this was not the case. DisclosuresOff Label Use: Pravastatin is not FDA approved for treatment of AML.

High-Dose Cyclophosphamide for the Treatment of Refractory T-Cell Acute Lymphoblastic Leukemia in Children

Despite an almost 80% overall survival rate in pediatric T-cell acute lymphoblastic leukemia (T-ALL), there is a subset of patients who are refractory to standard chemotherapy regimens and could benefit from novel treatment approaches. Over a 2-year period, we treated 5 pediatric patients with refractory T-ALL, aged 3 to 15 years, with high-dose cyclophosphamide (CY) at a dose of 2100 mg/m for 2 consecutive days either alone (n=1) or in combination with other chemotherapy agents (n=4). Four of these 5 patients had a 1.5 log decrease in disease burden. Three of the 5 patients had no evidence of minimal residual disease (MRD) after high-dose CY. One patient developed transient grade 4 transaminitis and 1 patient developed grade 3 typhlitis. All 5 patients ultimately proceeded to hematopoietic stem cell transplant when MRD levels were <0.01%. Pediatric T-ALL patients with persistent MRD after treatment with conventional chemotherapy may respond to CY at escalated dosing.

Indications for allogeneic hematopoietic cell transplantation for acute myeloid leukemia in the genomic era.

Few choices in medical oncology are as stark as the decision of whether or not to proceed with allogeneic hematopoietic cell transplantation (HCT) in the treatment of acute myeloid leukemia (AML). Recent advances provide more information to inform the decision, including molecular studies of leukemia that predict tumor responsiveness, assays of minimal residual disease that measure early treatment outcome, and comorbidity indices that predict nonrelapse mortality. Although large prospective studies incorporating all of these factors are lacking, literature reviews and consensus statements exist that can help the clinician in this difficult choice. Allogeneic HCT should be considered for all patients younger than age 65, with an available donor, an acceptable comorbidity index, and whose had initial induction therapy has failed. Similarly, allogeneic HCT is appropriate therapy for all patients with AML in second remission younger than age 75, with an appropriate donor, and a comorbidity index of 5 or less. For patients younger than age 60 with AML in first complete remission (CR), there is little evidence that HCT benefits those with favorable-risk disease who achieve CR with one cycle of induction and have no evidence of minimal residual disease. Allogeneic HCT is indicated for essentially all other categories of patients. For those age 60 and older, few prospective studies are available on which to base recommendations, but, as in younger patients, the benefit of allogeneic HCT is questionable for patients with favorable-risk AML. For patients with higher-risk disease, allogeneic HCT is a reasonable option with the caution that the risk of HCT increases dramatically in those with a comorbidity index of 3 or higher.

Post-Transplantation Cyclophosphamide Following Busulfan and Fludarabine Myeloablative Conditioning Prevents Severe Acute and Chronic Graft-Versus-Host Disease and Minimizes Duration Of Immunosuppression: Results Of a Multi-Institutional Trial In Patients With High-Risk Hematologic Malignancies

IntroductionAllogeneic blood or marrow transplantation (alloBMT) involves a multi-faceted platform with each component having significant implications for the overall success of the transplant. However, the optimal transplantation platform is unknown. We combined two promising approaches, intravenous (IV) busulfan (Bu)/fludarabine (Flu) myeloablative conditioning and high-dose, post-transplantation cyclophosphamide (PTCy) graft-versus-host disease (GVHD) prophylaxis, in a multi-institutional trial for patients receiving HLA-matched related or unrelated bone marrow allografts. We hypothesized that this transplantation platform could prevent severe acute and chronic GVHD, while shortening the duration of post-grafting immunosuppression, having low treatment-related toxicity, and providing effective disease control. MethodsBusulfan was given in daily IV doses which were adjusted based on measured pharmacokinetics. Fludarabine was given at 40 mg/m2/day. PTCy (50 mg/kg/day in IV daily dosing) was administered as sole GVHD prophylaxis on days +3 and +4 after infusion of unmanipulated bone marrow. Forty-five (49%) patients received HLA-matched related allografts, while 47 (51%) received HLA-matched unrelated allografts. Seventy-three (79%) patients were transplanted for myeloid diseases, including 53 (58%) with acute myelogenous leukemia and 13 (14%) with myelodysplastic syndrome. Fifteen (16%) patients had acute lymphocytic leukemia. Sixty-seven (73%) patients were in morphologic complete remission (CR) at the time of alloBMT, and the remaining twenty-five (27%) patients had active disease. Eighteen (20%) patients had evidence of minimal residual disease. Twenty-five (27%) patients were males who received allografts from females. The primary endpoint of the study was the cumulative incidence of grade III-IV acute GVHD. Pre-defined secondary endpoints included chronic GVHD, non-relapse mortality, event-free and overall survival, and use and duration of systemic immunosuppressants beyond the originally planned two days of PTCy. GVHD was scored centrally by an independent reviewer. ResultsThe median follow-up was 595 days (1.6 years) for all patients and 794 days (2.2 years) for patients who were alive at last follow-up. The cumulative incidence (CI) of grade II-IV and III-IV acute GVHD were 51% and 15%, respectively, at two years. The CI of chronic GVHD was 14% at two years. Thirty-five percent of all patients and 39% of patients alive at last follow-up never required immunosuppression for any reason beyond day +4 post-transplant. Corticosteroid use occurred in 61% of all patients and 60% of patients alive at last follow-up. A median 98 days (range 10-1221) elapsed from first initiation to final cessation of corticosteroids. Immunosuppression beyond corticosteroids was used for 50% of all patients and 52% of patients alive at last follow-up. A median 167.5 days (range 1-1156) elapsed from first initiation to final cessation of secondary immunosuppression. A calcineurin inhibitor was required for any reason in 45% of patients. Only 16% of patients required additional immunosuppression beyond corticosteroids and/or a second systemic immunosuppressant. Seventy-two percent of patients alive at last follow-up were off all immunosuppression at one year.Non-relapse mortality was 9% and 16% at 100 days and one year, respectively. Event-free survival and overall survival were 62% and 67% at two years and were 80% and 79% at two years for patients in CR without MRD at the time of alloBMT. Multivariate Bayesian analysis showed that having an unrelated donor, being in CR without MRD, and having a higher nucleated cell count all had beneficial effects on EFS. ConclusionMyeloablative IV Bu/Flu conditioning followed by single-agent GVHD prophylaxis with PTCy results in low rates of severe acute and chronic GVHD and effective disease control for patients with high-risk hematologic malignancies undergoing HLA-matched alloBMT even from unrelated donors. Moreover, the use of post-grafting immunosuppression beyond day +4 was not required in a significant subset of patients and was rapidly tapered in others. This study confirms the efficacy of PTCy after myeloablative conditioning and provides further support for future randomized studies comparing PTCy against other GVHD prophylactic approaches. Disclosures:Off Label Use: post-transplantation cyclophosphamide as graft-versus-host disease prophylaxis. Luznik:Otsuka Pharmaceutical: Research Funding.

Phase I Study of Oral Clofarabine Consolidation in Adults Aged 60 and Older With Acute Myeloid Leukemia

Abstract 3633 Background: Less than 16% of adults aged 60 and older diagnosed with acute myeloid leukemia (AML) will remain disease free after cytarabine consolidation. Clofarabine (clo) is a next generation nucleoside analogue whose IV formulation has shown considerable activity in older patients with AML considered unlikely to benefit from conventional therapy. This phase I trial is the first study of an oral formulation of clo for consolidation in patients >= 60 with AML who achieve a remission with cytotoxic induction regimens. Methods: The primary objective was to determine the maximum tolerated dose (MTD) and dose limiting toxicities (DLT) of oral clo on a 21 day dosing schedule for consolidation therapy. For safety reasons, the initial cohort was tested on a 14 day schedule. Tolerability of the regimen was a secondary objective. Six cohorts were tested (1 mg × 14 days, and 1 mg, 2 mg, 3 mg, 4 mg, and 6 mg × 21 days) with oral clo administered once daily for 14 or 21 days of a 28 day cycle, for up to 5 cycles. DLT were assessed during cycle 1 and defined as Grade 4 neutropenia lasting >=14 days or Grade 3–4 neutropenia with infection; Grade 4 thrombocytopenia >= 7 days or Grade 3–4 thrombocytopenia with bleeding; or Grade 3 or 4 non-hematologic toxicities with the exception of drug-related fever, alopecia, anorexia, or adequately treated nausea, vomiting and/or diarrhea. Results: Twenty patients were enrolled on the dose escalation phase of the study. Seventeen patients completed at least 1 cycle and were thus evaluable for response, while 3 patients were taken off study prior to completion of cycle 1 due to relapse. No DLTs were observed in any cohort. At the 1 mg dose, 3 patients completed all 5 cycles of therapy (2 on the 21 day schedule), 2 patients relapsed after 2 or 3 cycles, (21 day and 14 day schedule, respectively), and 1 patient withdrew after completion of cycle 1 (14 day schedule). At the 2 mg dose, 2 patients completed all 5 cycles and 1 patient relapsed after cycle 1. The 1 mg dose on both dosing schedules and the 2 mg dose were well-tolerated and did not require dose reductions. Of the 3 patients enrolled at the 3 mg dose, one completed 5 cycles with a dose reduction to 2 mg after the first cycle for intermittent grade 4 neutropenia, 1 patient completed 3 cycles with no evidence of disease, then received allogeneic transplant at the discretion of the treating physician, and the final patient completed 3 cycles with persistent grade 2–3 neutropenia and thrombocytopenia and was taken off study for evidence of minimal residual disease. In the 4 mg cohort, 2 patients completed 3 cycles and were subsequently taken off study, one to proceed to allogeneic transplant at the discretion of the treating physician and one for recurrent disease. A third patient completed 2 cycles and has proceeded to allogeneic transplant for recurrent disease. The fourth patient was dose reduced to 3 mg after the first cycle for grade 3 thrombocytopenia, completed a total of 3 cycles, and was subsequently taken off study for persistent cytopenias. One patient received the 6 mg dose and required 2 dose reductions (to 4mg and then 3 mg) for grade 3–4 neutropenia and thrombocytopenia. Therefore, enrollment at the 6 mg dose level was halted. Grade 1–2 non-hematologic toxicities occurring in >=30% of patients were fatigue, diarrhea, nausea, hyperbilirubinemia, elevated AST or ALT, infection, hyperglycemia, electrolyte abnormalities, hypoalbuminemia, dizziness, cough, SOB, and anxiety. Grade 3 non-hematologic toxicities included: fatigue (1), AST elevation (1), hyperglycemia (3), hyperbilirubinemia (1) and anxiety (1). These Grade 3 toxicities were transient and did not require dose reductions. No Grade 4 toxicities occurred. Conclusions: Oral clo consolidation is a well-tolerated regimen in adults aged 60 or older with acute myeloid leukemia in remission. Although the MTD is undefined as no DLTs occurred in any cohort, Grade 3–4 cytopenias halted enrollment at the 6 mg dose and patients in both the 3 and 4 mg cohorts required dose reductions subsequent to cycle 1 for cytopenias. Future studies investigating clo as a maintenance strategy appear feasible at 3 mg with an option to dose reduce in the setting of prolonged cytopenias. Disclosures: Off Label Use: Clofarabine is a purine nucleoside inhibitor indicated for the treatment of pediatric patients aged 1 to 21 with relapsed or refractory ALL. Cashen: Genzyme: Membership on an entity9s Board of Directors or advisory committees. Uy: Genzyme: Consultancy. Abboud: Genzyme: Membership on an entity9s Board of Directors or advisory committees, Research Funding.

Feasibility of Allografting in Patients with Advanced Acute Lymphoblastic Leukemia After Salvage Therapy With Inotuzumab Ozogamicin

No highly effective salvage therapy exists for patients with relapsed acute lymphoblastic leukemia (ALL). Inotuzumab ozogamicin (IO) is a CD22 monoclonal antibody attached to calicheamycin that targets B lymphocytes in early stages of development, successfully inducing remission in patients with multiply relapsed ALL. We describe our findings in 26 patients who received allogeneic hematopoietic stem cell transplantation (SCT) after treatment with IO between September 2010 and October 2011. Patients with a median age of 33 years (range, 5-70 years) received an allogeneic matched sibling donor (n = 9), matched- or 1-antigen mismatched unrelated donor (n = 16), or cord blood donor SCT (n = 1) while in complete remission (n = 23) or with active disease (n = 3). At the time of SCT, 15 patients were in complete remission without evidence of minimal residual disease (MRD) measured by multiparameter flow cytometry. Patients were heavily pretreated, including 5 patients who had received previous allogeneic SCT. Patients received a median of 3 courses of IO (range, 1-5 courses) before SCT. Seven patients are alive at a median follow-up of 13 months (range, 5-16 months), with 1-year event-free and overall survival (OS) of 22% and 20%, respectively. Patients without MRD at time of SCT had a markedly better 1-year OS of 42%. The cumulative incidence of nonrelapse mortality (NRM) at 6 months and 1 year were 40% and 60%, respectively, with 5 deaths attributed to venoocclusive disease (VOD). Treatment with IO allows more patients to undergo transplantation while in remission, with favorable overall survival in patients without MRD who undergo transplantation. Reduction in hepatic toxicity is needed to improve overall results.