ALBERT

Description: Background Measurable residual disease (MRD) is associated with inferior outcomes in patients with acute myeloid leukemia (AML). MRD monitoring enhances risk stratification and may guide therapeutic intervention. Post-induction MRD is frequently cleared with further therapy and the clearance may lead to better outcomes. In contrast, persistent MRD is associated with poor outcomes. At present it is not possible to predict which patients are likely to clear MRD with further therapy. Here we report a simple, objective, widely applicable and quantitative MFC approach using the ratio of blast/PDC to predict persistent MRD and poor outcomes in AML. Patients and Methods A cohort of 136 adult patients with a confirmed diagnosis of AML by WHO criteria who underwent standard induction therapy at a single center between 4/2014 and 9/2017 was initially included. 69 patients achieved complete morphologic remission (36 MRD-neg. and 33 MRD-pos.). MRD status was assessed by MFC using a different from normal (DfN) approach. PDC were quantified as the percent of total WBC by flow cytometry based on low side scatter, moderate CD45, CD303, bright CD123 and HLA-DR expression. Results The proportion of PDC was markedly decreased in patients with AML (≥20% blasts) (N=136) with a median of 0.016% (interquartile range IQR: 0.0019%-0.071%, Figure 1A), more than 10-fold lower than observed in normal controls (median 0.23%, IQR 0.17%-0.34%) (N=20). While there was no difference between MRD-neg. and normal control groups (median 0.31%, IQR: 0.17%-0.49%; vs. 0.28%, IQR: 0.17%-0.34%), MRD-pos. group had significantly reduced PDC proportion compared to the control (median 0.074%, IQR: 0.022%-0.33%, Wilcoxon rank sum, p=0.019). In an attempt to achieve better separation and to eliminate possible effects of hemodilution, the ratio of blast/PDC was calculated by using the proportions of blasts and PDCs out of total WBCs as quantitated by flow cytometry. A cut-off threshold of the blast/PDC ratio of 10 was chosen to separate each group (Figure 1B). Importantly, a ratio cut-off of 10 had a corresponding specificity of 97.4% for predicting MRD positivity status. MRD positivity was significantly associated with inferior overall survival (OS) and relapse-free survival (RFS) in our study cohort (OS HR 4.11 (95% CI: 1.30-13.03), p=0.016; RFS HR 4.20 (95% CI: 1.49-11.82), p=0.007, Figure 1C and D). The 2-year cumulative incidence of relapse in the MRD-neg. group compared to MRD-pos. group was 10% (95% CI: 2-24%) vs. 37% (95% CI: 18-56%, p=0.014). Importantly, blast/PDC ratio ≥10 was also strongly associated with inferior OS and RFS (OS HR 3.12 (95% CI: 1.13-8.60), p= 0.028; RFS HR 4.05 (95% CI: 1.63-10.11), p=0.003, Figure 1E and F), which is similar in magnitude to MRD positivity. Furthermore, MRD-pos. patients with blast/PDC ratio

Description: Increased expression levels of miR-181 family members have been shown to be associated with favorable outcome in patients with cytogenetically normal acute myeloid leukemia. Here we show that increased expression of miR-181a and miR-181b is also significantly (P 〈 .05; Cox regression) associated with favorable overall survival in cytogenetically abnormal AML (CA-AML) patients. We further show that up-regulation of a gene signature composed of 4 potential miR-181 targets (including HOXA7, HOXA9, HOXA11, and PBX3), associated with down-regulation of miR-181 family members, is an independent predictor of adverse overall survival on multivariable testing in analysis of 183 CA-AML patients. The independent prognostic impact of this 4-homeobox-gene signature was confirmed in a validation set of 271 CA-AML patients. Furthermore, our in vitro and in vivo studies indicated that ectopic expression of miR-181b significantly promoted apoptosis and inhibited viability/proliferation of leukemic cells and delayed leukemogenesis; such effects could be reversed by forced expression of PBX3. Thus, the up-regulation of the 4 homeobox genes resulting from the down-regulation of miR-181 family members probably contribute to the poor prognosis of patients with nonfavorable CA-AML. Restoring expression of miR-181b and/or targeting the HOXA/PBX3 pathways may provide new strategies to improve survival substantially.

Description: Recruitment of histone deacetylases and DNA hypermethylation of promoter regions of specific genes are two mechanisms of transcriptional repression and gene silencing which have been linked, and are implicated in differentiation block in AML. We hypothesized that the histone deacetylase inhibitor (HDI) depsipeptide could result in transcriptional de-repression, upregulation of specific target genes and differentiation of the leukemic clone in AML. Eighteen patients (pts), median age 60 years (range 25–77) with relapsed or refractory AML were enrolled on a multicenter Phase II study of depsipeptide in AML. Patients were stratified into 2 groups on study entry: Group A (n=14) included patients without specific chromosomal abnormalities known to recruit histone deacetylases. Group B (n=4) included patients with chromosomal aberrations such as the t(8;21), inv 16 and t(15;17) known to recruit histone deacetylases. Depsipeptide was administered intravenously at a dose of 18mg/m2/d on days 1, 8 and 15 of a 28 day cycle. Peripheral blood mononuclear cells were obtained prior to (hour 0), and after 4 (hr 4) and 24 hrs (hr 24), on days 1 and 8 of the first cycle of therapy for evaluation of histone acetylation by flow cytometry, and gene re-expression by REAL-time RT-PCR. Target genes of interest include MDR1, a target of HDI mediated upregulation, and p15INK4B (p15), a target of DNA hypermethylation in AML. MDR1 and p15 copy numbers are expressed as a normalized quotient of MDR1 and p15, respectively, to the housekeeping gene ABL. The drug has been well tolerated. The most common adverse effects noted included grade 1/2 nausea, vomiting and fatigue. No objective evidence of response (CR or PR) or other evidence of antileukemic activity has been seen in group A. In contrast, 2 of 4 pts (50%) in Group B, have had a disappearance of bone marrow blasts (blast percentage 〈 5%) in the setting of a normocellular marrow, with concomitant recovery of near-normal hematopoiesis following 1 and 2 cycles of therapy respectively. This anti-leukemic effect was short-lived, with both pts developing an increase in bone marrow blasts within 30 days of the initial response. Both of these patients also had translocations involving the AML1 gene {1 had t(8;21) and the other had a novel translocation t(4;21)}. Interestingly both of these responding pts and one other pt (75%) in cohort B demonstrated an increase in H3 acetylation at 4 and/or 24 hrs, in contrast to 4 of 14 pts (28%) in cohort A. There was an overall mean increase of 41% in MDR1 expression at hr 4 on days 1 and 8 (p=0.04). p15 expression was also upregulated at hr 4 on days 1 and 8 (91% mean increase, p=0.01). We conclude that the HDI, depsipeptide, may have anti-leukemic activity in specific cytogenetic subsets of AML known to recruit histone deacetylases, and this is associated with a concomitant increase in histone acetylation. In addition, upregulation of specific target genes occurred in patient derived mononuclear cells, following depsipeptide treatment. The study remains open to accrual for pts with specific chromosomal abnormalities known to recruit histone deacetylases.

Description: Abstract 3978 It has been demonstrated that MEK/MAPK and PI3K/Akt are constitutively activated in the majority of AML cases and that their aberrant expression is associated with a poor prognosis. Targeted inhibition of either the MEK/MAPK or the PI3K/Akt pathway alone has only demonstrated mild to modest clinical activity, possibly due to feedback activation of compensatory pathways. Thus, preclinical studies have recently turned to targeted inhibition of both of these pathways simultaneously. In the current study, the efficacy of the combination of two orally available inhibitors to MEK (AZD6244, Astra Zeneca) and PI3K/mTOR (NVP-BEZ235, Novartis) was evaluated in AML cell lines and in primary AML patient samples. In MV 4;11 AML cells (harboring both the MLL re-arrangement and FLT3 internal tandem mutation), AZD6244 or BEZ235 alone moderately decreased viable cell numbers by 30–40% as measured by the MTS assay, a colorimetric assay for cellular growth and survival, but the combination of these two had a dramatic additive effect with a decrease of viable cell numbers by 70–80%. Similar effects were observed in AML cell lines with different cytogenetic and molecular abnormalities including THP-1 [t (6;11)], HL-60, KG-1 [del(5q)], and Kasumi-1 [t(8;21)]. Similar results were also obtained in leukemia cells from 3 patients with AML with different recurring cytogenetic abnormalities. Apoptotic cell death was determined by detection of

Description: Abstract 3395 Poster Board III-283 Therapy-related myeloid neoplasms (t-MN) are associated with unfavorable cytogenetics, drug resistance, and poor outcomes. For appropriate candidates, allogeneic HCT is the most likely curative therapy. We, and others, have shown that outcomes from HCT using RIC regimens are comparable to standard myeloablative conditioning regimens for high-risk patients with myeloid neoplasms. Few studies have focused on transplant outcomes for pts with t-MN. Therefore, we reviewed outcomes of 46 pts (median age 51; range, 25-71) with t-MN who underwent HCT at the University of Chicago between 3/89 and 1/09. Eleven had presented with 〈 20% marrow blasts, and 35 had 〉 20% blasts. Prior malignancies included Hodgkin lymphoma (n = 9), NHL (n = 9), CLL (n = 2), ALL (n = 2), APL (n = 1), and solid tumors (n = 19). Four pts had non-malignant prior diseases (SLE, Crohns disease, heart transplant, kidney transplant), but had received cytotoxic therapy. Since 2001, 37 pts received RIC transplants, whereas 9 earlier pts received myeloablative conditioning. Overall survival (OS) at day 100, 1 yr, and 2 yrs was 63% (95%CI, 49-77%), 40% (95%CI, 25-55%), and 34% (95%CI, 19-49%), respectively. Disease status at transplant was highly predictive of outcome (p = 0.03), with those pts in CR (n = 12) at the time of transplant exhibiting a 2 yr OS of 69% (95% CI, 38-100%) versus those with persistent disease (n = 34) exhibiting a 2 yr OS of 24% (95% CI, 8-40) (see figure below). ECOG performance status (PS) of 0 and 1 (n = 32) had similar outcomes, while no pts with a PS of 2 (n= 4) were alive at 2 years. Neither patient age (〉50) nor donor source (related [n = 28] vs unrelated [n = 18]) had a significant impact on outcome (p= 0.73 and 0.07, respectively). Interestingly, cytogenetic subset did not affect outcome; 2 yr OS was 35% (95%CI, 9-61%) for those with intermediate (n = 15) and 31% (95%CI, 12-50%) for those with poor-risk (n = 30) cytogenetics. Only one patient in the group had a good-risk cytogenetic pattern. RIC was associated with a 2 yr OS of 38% (95%CI, 18-58%), while ablative regimens resulted in a 2 yr OS of 21% (95% CI, 0-43%) (p = 0.04). Since RIC transplants were performed more recently, improvements in supportive care may have affected outcomes. These data represent one of the largest series reported on transplant outcome for t-MN. We conclude that RIC followed by related or unrelated donor HCT should be considered for pts with t-MN, regardless of cytogenetic abnormalities. The results for pts transplanted in remission are encouraging with 2 yr OS of 69%. Disclosures: No relevant conflicts of interest to declare.

Description: Abstract 1030 Poster Board I-52 Few clinical protocols have focused exclusively on the care of patients with therapy-related myeloid neoplasms (t-MN), and typically the disease confers a poor prognosis. We conducted a clinical trial exclusively for these patients. Between February 2003 and February 2009, we enrolled 32 adult patients with untreated t-MN. The median age was 56 years old (range, 23-83), and 38% were 〉60 years old. Eight patients (25%) had a total combined Charlson comorbidity index of 〉4, indicating that they were at high-risk for toxicity from the treatment, either due to older age or medical co-morbidities. T-MN developed following cytotoxic therapy for a malignant disease in 28 patients (88%), following cytotoxic therapy for rheumatologic disease in 2 patients (6%), and with immunosuppressive therapy after solid organ transplants in 2 patients (6%). The latency interval was highly variable, but the greatest fraction of patients (28%) experienced a latency of 4 - 9 years between their primary cytotoxic treatment and development of t-MN (median latency, 3.6 years; range 0.9-23 years). In 8 patients (25%), the latency was 2 years or less. 84% of patients had clonal cytogenetic abnormalities; 35% had a complex karyotype; 45% had abnormalities of chromosomes 5 or 7 or both.; 5 patients had t(9;11). All patients received induction chemotherapy with high-dose cytarabine (3,000mg/m2 over 4 hours) followed immediately by mitoxantrone (30mg/m2 over 1 hour), both given once on days 1 and 5 in a timed-sequential schedule. The complete remission (CR) rate after a single course was 66% and the partial remission (PR) rate was 16%, for an overall response rate of 82%. Grade 4 cardiac dysfunction occurred in 4 patients, resulting in the early death of one. Three of these patients had normal ejection fractions prior to beginning induction chemotherapy (including the patient who died), and one began therapy with an ejection fraction of 43%. Among the 21 patients who achieved a CR, 13 (62%) received consolidation therapy with allogeneic HCT, 4 (19%) received an autologous HCT, and 3 (14%) received only further chemotherapy. Three of the 5 patients who achieved a PR received an allogeneic HCT. Long-term disease-free survival (DFS) was observed in patients with each of the 3 modalities of consolidation therapy. The median overall survival (OS) was 399 days (range, 15-1972+), and OS at 1 year was 51%. Survival was significantly better among those patients who achieved a CR (median, 673 days) compared to those who had a PR (median, 126 days) to induction chemotherapy (P=0.003). OS at 1 year was 74% for patients who had achieved a CR compared with 20% for patients who had achieved a PR to induction. Median DFS was 415 days, with 59% of patients remaining disease-free at 1 year. OS was significantly longer in patients who underwent HCT compared to those who did not. The median survival for patients who received an allogeneic HCT was 673 days (range, 74-1798+) compared to 399 days for patients who received an autologous HCT (range, 353-917+), and 93 days for patients who received no transplant (range, 15-1972+) (P=0.002). OS at 1 year was 72% for patients who had undergone an allogeneic HCT, 75% for patients who had an autologous HCT, and 17% for patients who had not received a transplant. The DFS at 1 year was 67% for patients who underwent either an allogeneic or autologous stem cell transplant compared to 25% for those who did not have a transplant. To date, 9 patients (28%) remain alive and disease-free: 7 (22%) after allogeneic HCT; 1 after autologous HCT; and 1 after consolidation with only chemotherapy. Overall, remission induction therapy with high-dose cytarabine and mitoxantrone is an effective and tolerable regimen for patients with t-MN, allowing aggressive consolidation regimens, HCT, and long-term disease-free survival. Disclosures: Stock: Genzyme: Research Funding.

Description: We treated 86 patients with SAA, 31 patients who failed to respond to previous therapy underwent haploidentical hematopoietic SCT (haplo-HSCT, n=26) or mismatched unrelated donor HSCT (MMUD-HSCT, n=5). The other 55 patients were treated with immunosuppressive therapy (IST). At 6 months post-treatment, the treatment failure rates of HSCT and IST groups were 19.35% and 29.09% (P=0.320). Hematopoietic recovery time was shorter in the HSCT group than IST group (P 〉 0.05). The estimated OS at 3 years was 79.2% ± 7.7% in HSCT group and 89.7% ± 4.4% in the IST group (P=0.058). The estimated failure-free survival (FFS) at 3 years was 79.2% ± 7.7% in the HSCT group and 62.9% ± 8.0% in the IST group (P=0.391). The estimated FFS at 3 years in SAA that had progressed from non-SAA (NSAA) of HSCT was 71.6% ± 14.0% and 16.7% ± 13.6% of IST (P=0.021). Within the HSCT group, 38.71% of the patients developed grade II-IV acute GVHD, and 18.52% of the patients experienced moderate-severe chronic GVHD. These results suggest that haplo-HSCT/MMUD-HSCT and IST have similar treatment failure rate, OS and FFS. haplo-HSCT/MMUD-HSCT might provide a better chance of FFS than IST for SAA that had progressed from NSAA. Disclosures No relevant conflicts of interest to declare.

Description: Introduction While patients (pts) with diffuse large B cell lymphoma (DLBCL) and B cell lymphoma unclassifiable with features intermediate between DLBCL and Burkitt lymphoma (BCLU) harboring rearrangement of MYC (MYC-R) face a poor prognosis as compared to DLBCL/BCLU pts without MYC-R, the prognosis of DLBCL/BLCU pts with MYC-R in the absence of rearrangements of BCL2 (BCL2-R) and BCL6 (BCL6-R) has not clearly been reported in the literature. Additionally, it is not well known whether amplification of MYC in the absence of MYC-R portends a poor prognosis for DLBCL/BCLU pts. Here, we analyze outcomes for these pts in comparison to DLBCL/BCLU pts without MYC-R or MYC amplification. Methods Pts diagnosed with DLBCL or BCLU treated at the University of Pennsylvania and Northwestern University from 3/2002-3/2015 whose diagnostic specimens underwent fluorescence in situ hybridization for MYC-R with8q24 breakapart and/or t(8;14)(q24;q32) fusion probes were included in this analysis. Pts with primary CNS and HIV-associated lymphoma were excluded. Cases with MYC-R but not BCL2-R and BCL6- R were defined as single hit (SH), cases with MYC-R as well as BCL2 -Rand/or BCL6-R as double hit (DH), cases with 〉4 copies of MYC as amplified (MYC amp) and cases without MYC-R and ≤4 copies of MYC as normal (MYC normal). Therapy was given at the discretion of the treating clinician. Progression free survival (PFS) was defined as time from diagnosis to radiographic progression, regimen change, death or last follow-up. Overall survival (OS) was defined as time from diagnosis to death or last follow-up. Data were censored on 7/1/15. Results 224 pts were included in the full analysis: 190 MYC normal, 19 SH and 15 MYC amp. An additional 46 DH pts were analyzed for PFS and OS only. No pts were both SH and MYC amp. Pts baseline characteristics were reported as follows: 52% female, 47% age 〉60 years (yrs), 66% LDH 〉normal, 62% stage ≥3, 15% lymphomatous involvement of bone marrow, 11% ECOG performance status (PS) 〉2, 66% extranodal disease, 29% B symptoms, 42% International Prognostic Index (IPI) score ≥3, 4% BCLU histology and 18% low-grade transformation. Only the presence of BCLU histology differed significantly between SH and MYC normal pts (26% vs. 1%, p=0.001) and between MYC amp and MYC normal pts (13% vs. 1%, p=0.028). PFS and OS are depicted in Figure 1. For all pts, the median length of follow-up was 15.4 months (mos) (range 0.1-156.1 mos), median PFS not yet reached and median OS not yet reached. Rates of PFS and OS at 2 yrs for MYC normal, SH and MYC amp pts were 72%, 52%, 62% and 81%, 65%, 74%, respectively. When compared to MYC normal pts, SH pts experienced significantly shorter rates of PFS (p=0.043) and OS (p=0.038) at 2 yrs; however, rates of PFS and OS at 2 yrs did not differ significantly between MYC amp and MYC normal pts (p=0.29 and p=0.67, respectively). For comparison, rates of PFS and OS at 2 yrs for DH pts were 32% and 37%, and did not differ significantly from those of SH pts (p=0.26 and p=0.18, respectively). For SH patients, rates of PFS and OS at 2 yrs for those receiving induction therapy with R-CHOP vs. intensive induction (II), defined as either R-EPOCH, R-hyperCVAD or R-CODOX-M/IVAC, were 25% vs. 76% (p=0.13) and 75% vs. 73% (p=0.94), respectively. Baseline characteristics significantly associated with progression on univariate analysis (UVA) were LDH 〉 normal (HR 2.50, 95% CI 1.20-5.17, p=0.014), ECOG PS 〉2 (HR 2.17, 95% CI 1.05-4.70, p=0.036) and B symptoms (HR 2.49, 95% CI 1.48-4.19, p=0.001); however, only B symptoms remained statistically significant on multivariate analysis (MVA) (HR 2.66, 95% CI 1.41-5.01, p=0.003). Baseline characteristics significantly associated with death on UVA were LDH 〉 normal (HR 3.99, 95% CI 1.19-13.4, p=0.025), ECOG PS 〉2 (HR 3.19, 95% CI 1.29-7.90, p=0.012), B symptoms (HR 2.70, 95% CI 1.31-5.57, p=0.007) and SH vs. MYC normal (HR 2.59, 95% CI 1.06-6.31, p=0.037); however, no factor remained statistically significant on MVA. Conclusions This analysis of the largest reported series of SH and MYC amp pts suggests inferior rates of PFS and OS at 2 yrs for SH pts, but not MYC amp pts, as compared to MYC normal pts. SH pts receiving II experienced similar rates of PFS and OS at 2 yrs as compared to MYC normal pts. Much like DH pts, SH pts should be considered a poor prognosis subgroup of non-Burkitt high-grade B cell non-Hodgkin lymphomas and identified as candidates for risk-adapted and/or targeted therapies. Figure 1. Figure 1. Disclosures Dwivedy Nasta: Millenium Takeda: Research Funding; BMS: Research Funding. Svoboda:Immunomedics: Research Funding; Celldex: Research Funding; Celgene: Research Funding; Seattle Genetics: Research Funding. Schuster:Genentech: Consultancy; Pharmacyclics: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Hoffman-LaRoche: Research Funding; Janssen: Research Funding; Gilead: Research Funding; Novartis: Research Funding; Nordic Nanovector: Membership on an entity's Board of Directors or advisory committees. Mato:Gilead: Consultancy, Research Funding; Celgene Corporation: Consultancy, Research Funding; Genentech: Consultancy; Pharmacyclics: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; Pronai Pharmaceuticals: Research Funding; TG Therapeutics: Research Funding. Petrich:Seattle Genetics: Consultancy, Honoraria, Research Funding.

Description: Chromosome translocations are among the most common genetic abnormalities in human leukemia. Their abnormally expressed genes identify specific markers for their clinical diagnosis. Important biological properties are often conserved across species. However, although genetically engineered mouse leukemia models are well-established, few systematic studies have validated the genes that exhibit similar abnormal expression patterns in both human and mouse leukemia models. MLL-ELL and MLL-ENL fusion genes resulting from t(11;19)(q23;p13.1) and t(11;19)(q23;p13.3), respectively, are frequently involved in human acute leukemia, and in retrovirus-mediated mouse leukemia models. We used the SAGE technique to compare gene expression profiles between MLL-ELL or MLL-ENL myeloid leukemia progenitor cells and normal myeloid progenitor cells in both human and mouse. We analyzed four patient samples (two with each fusion) and two retrovirally-induced mouse leukemias containing either MLL-ELL or MLL-ENL fusions, and a leukemia cell line with an MLL-ELL fusion. 484,303 SAGE tags were identified from the nine samples, yielding 103,899 unique tags in human and 60,993 in mouse samples. We identified 40 candidate genes that appear to be abnormally expressed in both human and murine MLL-ELL leukemias (2 up- and 38 down-regulated), and 72 in both human and murine MLL-ENL leukemias (23 up and 49 down). 25 candidate genes are down-regulated in both types of leukemias, and many of them can bind with and/or regulate other candidate genes in the candidate list. For example, LCN2 can bind directly with and positively regulate MMP9; MMP9 and TMSB4X may positively regulate FOS; FOS and JUNB can bind directly and positively regulate each other. JUNB may inhibit proliferation and promote apoptosis, and it was reported that inactivation of JunB in LT-HSC leads to MPD while its inactivation in committed myeloid progenitors also predisposes to leukemia evolution. LCN2 may also positively regulate apoptosis. Meanwhile, some important candidate genes are observed only in one type of leukemia. For example, both PXN and ARHGEF1 are down-regulated only in MLL-ELL leukemias. PXN can bind directly with ARHGEF1, and the latter may inhibit proliferation. Similarly, MYB is significantly upregulated only in MLL-ENL leukemias, which was reported to play a role in MLL-ENL-mediated transformation. Taken together, some common pathways may exist in the development of both types of leukemias, whereas each may also have their own pathway. The deregulation of the important candidate genes may contribute to leukemogenesis through inhibiting apoptosis while promoting proliferation of hematopoietic cells. We have validated the expression patterns of the candidate genes, and are studying the functions and pathways of the validated candidate genes. Our studies will provide important insights into the complex functional pathways related to MLL rearrangements in the development of acute myeloid leukemia, which may lead to more effective therapy for these leukemias.

Description: There are limited data regarding the incidence or prognostic value of cytogenetic abnormalities in pts with leukemic relapse after allogeneic hematopoietic cell transplantation (HCT). Between 2002 and 2005, 70 consecutive pts with high risk AML or MDS were transplanted with a reduced intensity preparative regimen of fludarabine 30 mg/m2/day IV (150 mg/m2 total), alemtuzumab SC 20 mg/day IV (100 mg total) D-7 to D-3, and melphalan 140 mg/m2 IV D-2, with tacrolimus given for post-transplantation immunosuppression. Twenty-five pts relapsed or progressed; 21 had AML, 3 had MDS and 1 had mast cell leukemia. Twenty-two pts had cytogenetic analysis available prior to HCT and at relapse. Cytogenetic abnormalities were present in 12/22 (55%) pts prior to HCT. The median OS was 184 days (95% CI: 81 – 300) after relapse. Four pts with cytogenetic abnormalities prior to HCT reverted to a normal karyotype at relapse. Ten pts had no changes in their cytogenetics from HCT to relapse; they either remained normal or retained the same abnormality. Eight pts developed a new clonal abnormality at relapse, and had a median OS of 106 days (95% CI: 30 – 322). There was a non-significant trend toward inferior OS among pts with new abnormalities compared to the other groups (HR = 1.74, 95% CI 0.69 – 4.44, P = 0.24). The higher than previously reported rate of clonal evolution (8/22, 36%) may be due to the high prevalence of refractory disease at HCT in this cohort, more refined cytogenetic analysis, or regimen related factors (e.g. reduced intensity conditioning). The same clonal abnormality with or without new changes occurred in 7/22 pts. Thus, minimal residual disease monitoring in the subset of pts harboring pre-HCT karyotypic derangements may be a viable strategy for early detection and intervention. Our data suggest that clonal evolution at relapse of AML and MDS after HCT is relatively frequent, and in this small series, a trend toward worse outcomes exists for pts who develop new cytogenetic abnormalities. Larger studies are warranted to more completely characterize the prognostic value of cytogenetics and karyotypic evolution at relapse after HCT. Cytogenetic abnormalities for AML/MDS relapsing after HCT (N = 22) Pre HCT* Relapse *History of cytogenetic abnormality any time before HCT **Clonal evolution in 8/22 (36%) No 10 (45%) No 7 (32%) Yes (New)** 3 (14%) Yes 12 (55%) No 4 (18%) Yes (Same) 3 (14%) Yes (New)** 5 (27%)