Cytarabine Regimen Research Articles

Homoharringtonine-based induction regimens for patients with de-novo acute myeloid leukaemia: a multicentre, open-label, randomised, controlled phase 3 trial

Homoharringtonine-based induction regimens have been widely used in China for patients with acute myeloid leukaemia. However, their efficacy has not been tested in a multicentre randomised controlled trial in a large population. We assessed the efficacy and safety of homoharringtonine-based induction treatment for management of newly diagnosed acute myeloid leukaemia. This open-label, randomised, controlled, phase 3 study was done in 17 institutions in China between September, 2007, and July, 2011. Untreated patients aged 14-59 years with acute myeloid leukaemia were randomly assigned (by a computer-generated allocation schedule without stratification) to receive one of three induction regimens in a 1:1:1 ratio: homoharringtonine 2 mg/m(2) per day on days 1-7, cytarabine 100 mg/m(2) per day on days 1-7, and aclarubicin 20 mg/day on days 1-7 (HAA); homoharringtonine 2 mg/m(2) per day on days 1-7, cytarabine 100 mg/m(2) per day on days 1-7, and daunorubicin 40 mg/m(2) per day on days 1-3 (HAD); or daunorubicin 40-45 mg/m(2) per day on days 1-3 and cytarabine 100 mg/m(2) per day on days 1-7 (DA). Patients in complete remission were offered two cycles of intermediate-dose cytarabine (2 g/m(2) every 12 h on days 1-3). The primary endpoints were the proportion of patients who achieved complete remission after two cycles of induction treatment and event-free survival in the intention-to-treat population. The trial is registered in the Chinese Clinical Trial Register, number ChiCTR-TRC-06000054. We enrolled 620 patients, of whom 609 were included in the intention-to-treat analysis. 150 of 206 patients (73%) in the HAA group achieved complete remission versus 125 of 205 (61%) in the DA group (p=0.0108); 3-year event-free survival was 35.4% (95% CI 28.6-42.2) versus 23.1% (95% CI 17.4-29.3; p=0.0023). 133 of 198 patients (67%) in the HAD group had complete remission (vs DA, p=0·20) and 3-year event-free survival was 32.7% (95% CI 26.1-39.5; vs DA, p=0.08). Adverse events were much the same in all groups, except that more patients in the HAA (12 of 206 [5.8%]) and HAD (13 of 198 [6.6%]) groups died within 30 days than in the DA group (two of 205 [1%]; p=0.0067 vs HAA; p=0.0030 vs HAD). A regimen of homoharringtonine, cytarabine, and aclarubicin is a treatment option for young, newly diagnosed patients with acute myeloid leukaemia. Chinese National High Tech Programme, Key Special Research Foundation of the Ministry of Science and Technology of China, National Nature Science Foundation of China, National Clinical Key Specialty Construction Project.

Cytarabine, aclarubicin and granulocyte colony-stimulating factor regimen represents an effective and safe salvage regimen for patients with acute myeloid leukemia refractory to first course of induction chemotherapy

There is no consensus regarding the optimal second induction course regimen for patients with acute myeloid leukemia (AML) refractory to an initial course of front-line induction. The CAG regimen (cytarabine, aclarubicin and granulocyte colony-stimulating factor) has shown promise for relapsed/refractory AML. We retrospectively compared the efficacy and toxicity of the CAG regimen (n = 44) with a non-CAG regimen (n = 31) in 75 patients with AML refractory to an initial induction chemotherapy. The complete remission (CR) rate was higher for the CAG than the non-CAG regimen (63.5% vs. 38.7%, p = 0.038), and this was more pronounced in the subgroup of patients with a lower white blood cell (WBC) count before first/second induction, better- and intermediate-risk patients, and non-AML-M4/5 (p = 0.019). Although the CAG group demonstrated a higher disease-free survival than the non-CAG group among the intermediate- and poor-risk patients (p = 0.019), no differences in overall survival were observed. The CAG regimen produced hematological and non-hematological side effects similar to those of the non-CAG regimen. The most frequent CAG regimen side effects were infection (45.5%), fever (50%) and elevated transaminase levels (31.8%). No patients died within 4 weeks after initiating the second induction course in the CAG regimen. Thus, CAG represents a highly effective and safe salvage regimen for patients with AML who are refractory to the first induction chemotherapy. This regimen may be of specific benefit for CR in patients with low WBC count, better- and intermediate-risk, and non-M4/5 disease.

Daunorubicin, Cytarabine, and Cladribine Regimen Plus Radiotherapy and Donor Lymphocyte Infusion for Extramedullary Relapse of Acute Myeloid Leukemia after Hematopoietic Stem Cell Transplantation

Myeloid sarcoma is a rare tumor consisting of myeloid blasts that involve anatomic sites outside the bone marrow. Fatal prognosis is inevitable in patients with extramedullary relapse after hematopoietic stem cell transplantation (HSCT), and no standard treatments are available yet. We report the first case of extramedullary relapse after HSCT treated with a combination of daunorubicin, cytarabine, and cladribine (DAC) regimen plus radiotherapy and donor lymphocyte infusion (DLI). This treatment induced a new and durable remission in our patient. The favorable toxicity profile and the reduced cost make this combination worthy of further investigations.

A Neutralizing Antibody (CSL362) Against the Interleukin-3 Receptor α-Chain Augments the Efficacy of a Cytarabine/Daunorubicin Induction-Type Therapy in Preclinical Xenograft Models of Acute Myelogenous Leukemia

AbstractAbstract 3599 Introduction:Despite the development of many new agents for the treatment of acute myelogenous leukemia (AML), the prognosis for most patients remains dismal. The interleukin-3 receptor α chain (IL-3Rα, CD123) is highly expressed on the surface of acute and chronic leukemias compared with normal hematopoietic stem cells, providing a rational therapeutic target. CSL362 is a fully humanized, second generation, neutralizing monoclonal antibody targeting CD123 that contains a modified Fc region to enhance human natural killer (huNK) cell-mediated antibody dependent cellular cytotoxicity (ADCC). The purpose of this study was to test the in vivo efficacy of CSL362 in combination with an induction-type chemotherapy regimen and adoptive transfer of huNK cells against xenograft models of human AML. Methods:Direct patient explants of 5 AML samples with defined genetic lesions were established as continuous xenografts in sub-lethally irradiated immune-deficient NOD/SCID or NSG mice. In order to complement the clinical development of CSL362 we optimized an induction-type regimen of cytarabine (AraC, 25 mg/kg IP daily × 4 × 2 weeks) combined with daunorubicin (DNR, 0.62 mg/kg IV weekly × 2 weeks) to simulate the complex biology of AML in a post-chemotherapy setting. For adoptive transplantation into AML engrafted mice, primary huNK cells were expanded 600- to 700-fold in vitro by culturing on feeder cells in the presence of IL-2 for 21 days. In efficacy experiments, an event was defined a priori to occur when the % human CD45 cells in the peripheral blood (%huCD45) reached 25%. Results:Human AML xenografts consistently and predictably produced progressive and disseminating disease in the peripheral blood, bone marrow, spleen, liver, kidneys, lungs and brain of mice between 42 and 200 days post-transplantation. Disease progression represented by increasing percentages of human CD45+ cells in the peripheral blood (%huCD45) inversely correlated with murine red blood cell and platelet counts, and mouse hematocrit and hemoglobin levels. The immunophenotype and gene expression profiles of each xenograft were comparable with the respective original patient samples, indicating that the xenografts provide a valid representation of the human disease. In vitro co-cultures of AML xenograft cells with CD56+/CD16+ huNK cells (5 h at a 1:10 ratio) resulted in an average AML cell death of 18% (range 7–38%). The addition of CSL362 (10 μg/ml) resulted in an average 26% (range 2–64%) increase in AML cell death compared with huNK alone. In vivo AraC/DNR treatment significantly extended the event-free survival (EFS) of mice engrafted with 3/3 AML xenografts by between 32 and 41 days compared with vehicle-treated control mice (P < 0.0001). The addition of CSL362 (300μg IP thrice weekly × 2) significantly extended the median EFS of AraC/DNR-treated mice by 5.9 days (P = 0.002). Moreover, while the adoptive transfer of huNK cells (20 million IV × 2) resulted in no significant survival advantage, huNK cells administered with CSL362 further prolonged mouse EFS by 15.2 days compared with chemotherapy alone (P = 0.0004), providing evidence of therapeutic enhancement. Conclusion:AML xenografts established in NOD/SCID or NSG mice from direct patient explants provide a clinically relevant experimental model for preclinical drug testing, and reflect the immunophenotype and gene expression profiles of the original biopsy specimen. CSL362 treatment of AML xenografted mice augments the efficacy of an induction-type therapy, with additional therapeutic enhancement achieved by the adoptive transfer of huNK cells. These data support the rationale for CSL362 treatment of AML patients post remission induction in an upcoming clinical trial. Disclosures:Lee:CSL Limited: Research Funding. Yee:CSL Limited: Research Funding. Busfield:CSL Limited: Employment. Vairo:CSL Limited: Employment. Lock:CSL Limited: Consultancy, Research Funding.

Histologic Transformation in Marginal Zone Lymphomas

Abstract 1571 Background.Information concerning histologic transformation (HT) of marginal zone lymphomas (MZL) into aggressive entities is scant. We retrospectively analyzed the clinical variables at diagnosis and outcome, with special reference to HT, in a population of consecutive patients (pts) with confirmed diagnosis of MZL, including extranodal MZL (MALT lymphoma), splenic MZL (SMZL) and nodal MZL (NMZL). Patients and methods.The database of the Oncology Institute of Southern Switzerland (IOSI, Bellinzona) and of the Hematology Division of the Amedeo Avogadro University of Eastern Piedmont (Novara) includes 373 cases of MZL diagnosed and treated since 1979 to 2012: 186 MALT lymphomas (50%), 88 SMZL (23%), 36 NMZL (10%). Sixty-three patients (17%) could not be properly classified (uMZL): they presented with bone marrow infiltration with or without detectable involvement of peripheral blood but without splenomegaly and with apparently no other extranodal or nodal involved site. Results.Incidence was not significantly different according to sex (male: 47; female: 53%), median age at diagnosis was 68 years (20–94 years); 244 pts (65%) had stage III-IV disease. LDH was elevated in 45/212 (21%) tested pts, beta2-microglobulin in 108/205 (53%) tested pts. B symptoms were reported in 27/368 pts (7%). Five percent of pts had an ECOG performance status higher than 1. Serologic evidence of hepatitis C virus (HCV) infection was reported in 45/243 (19%) pts for whom the data was available. Among the 186 MALT lymphomas, 91 pts (49%) had a gastric localization, and 54 (29%) had multiple extranodal sites of disease involvement.Median overall survival (OS) and progression-free survival of the whole population were 15 years and 8 years, respectively. After a median follow-up of 5 years, HT was observed in 14 cases (4%, 95%CI:2%-6%). A diagnosis of diffuse large B cell lymphoma was documented in 12 pts (85.7% of patients undergoing HT), while in two cases the diagnosis was of classical Hodgkin lymphoma and mantle cell lymphoma, respectively. HT occurred after a median interval of 3 years (range: 1–12 years) after diagnosis. With respect to MZL type, HT occurred in 6% SMZL, 4% MALT lymphomas, 3% NMZL, and 2% uMZL (P=0.635). Risk of HT was 4% (95%CI, 2–8%) at 5 years, 6% (95%CI:3%-11%) at 10 years and 9% (95%CI, 5–16%) at 15 years; the rate of transformation tended to plateau from that point onward. At the time of HT, most pts had high LDH serum levels (8/11, 73%) and presence of B symptoms (6/10, 60%). After transformation, nine pts received anthracycline-containing regimens, and four pts were treated with high dose cytarabine regimens; in a single patient only supportive measures were adopted. In four pts, autologous stem cell transplantation was performed after induction. At a median follow-up of 12 months after HT, five of 14 pts died, all for lymphoma-related causes, with a 2-year post-transformation survival rate of 38% (95%CI:5%-74%). There was no significant association between the risk of HT and any of the clinical variables at diagnosis or frontline treatment strategies. Conclusions.This large retrospective series documents that the risk of HT is low across all MZL types. The incidence of HT in MZL is apparently lower than that of other indolent B cell malignancies, namely follicular lymphoma (FL) and chronic lymphocytic leukemia (CLL). As also observed in FL and CLL, HT in MZL occurs relatively early during the clinical course, pointing to putative biological differences at diagnosis in MZL patients destined to transform. Disclosures:Off Label Use: Trial partially supported by a research grant by Celgene. Lenalidomide was provided free by Celgene. The use of Lenalidomide is off-label in untreated DLBCL. Bertoni:OncoEthix SA: Research Funding.

Dynamics of Molecular Response in Patients (pts) with Acute Myeloid Leukemia (AML) Withy Core Binding Factor (CBF) Abnormalities Treated with High-Dose Cytarabine Regimen

Abstract 3609 Background:AML associated with CBF abnormalities (CBF-AML) is the type of leukemia most responsive to cytarabine (ara-C) therapy and is of relative favorable prognosis. We have previously reported a complete remission (CR) rate of 93% (Borthakur et al. Cancer 2008). Aim:To investigate the molecular response to fludarabine, cytarabine, filgrastim, and GO (FLAG-GO) or idarubicin (FLAG-IDA) and the dynamic of this molecular response in newly diagnosed pts withCBF-AML. Methods:69 consecutive pts with newly diagnosed CBF-AML were assessed between 4/07 and 11/11. Of the 69 pts, 60 pts had regular monitoring testing and thus were eligible for this analysis. Quantitative reverse transcription PCR in peripheral blood/bone marrow samples was performed prior to therapy, at the documentation of the response and approximately every 3 months thereafter. Results:Median age was 48 yrs, range (19–78 yrs). 26 (43%) pts had inversion 16 and 34 (57%) t(8;21). 47 pts received FLAG-GO and 13 FLAG-IDA as induction/consolidation. The overall CR rate was 90% with median time to CR being 26 days, range 19–33 days. The CR rates for pts with inv 16 and t(8;21) were 88% and 91%, respectively. With a median follow-up of 32 months (range, 7 to 61), 51 pts remained alive; 6 (10%) pts relapsed with a median of 10.8 months (range, 7.8 to 20.5). The median overall and relapse-free survival was not reached. The 4-year OS and EFS rates were 79% and 77% respectively. All responders achieved a molecular response with the nadir being observed at a median of 7 months (range, 1 to 28) from the start of the therapy. 55 pts (92%) achieved a transcript level below 0.01% after a median of 4 months (range, 1 to 13) and 43 pts (72%) achieved a complete molecular response (CMR) or undetected level by PCR within 7 months (range, 1 to 28). Relapses were seen in 3/42 (7%) pts with CMR, 2/12 (17%) of pts with transcript level ≤0.01 and 1/5 (20%) of pts with transcript level >0.01 respectively (Fig. 1). The 4-year EFS and OS for pts achieving a CMR or not were 84% and 56% (p=0.015) and 88% and 51% (p=0.002), respectively. Figure 1 summarizes pt disposition. Of the 5 pts who never achieved a transcript level below 0.01%, one patient relapsed 5 months after achieving his nadir transcript value of6.08% and all remaining four pts have remained in CR for a median of 206 months (range, 7+ to 50+) despite persistent molecular disease. Of the 55 pts with a transcript level below 0.01%, 5 (9%) relapsed and 7 additional (13%, 3 of them with CMR) lost their molecular response to a level below 0.15% with no morphological relapse; 2 of the 3 with CMR regained a CMR after a median 15 months (range, 7 to 23 months). Conclusion:Front-line therapy of CBF-AML with FLAG-GO/IDA is highly efficacious and induces molecular responses in a significant number of pts. The achievement of CMR is associated with improvement of EFS and OS. Persistence of minimal disease and minor fluctuations in the transcript levels below 0.15% should be monitored and are not predictive of relapse. [Display omitted] Disclosures:Ravandi:Genzyme/Sanofi: Honoraria. Faderl:Genzyme: Advisory Board Other, Research Funding.

Disseminated Langerhans cell histiocytosis associated with acute myeloid leukaemia: complete remission with daunorubicin and cytarabine

Dear Editor, A 68-year-old man presented with cervical lymphadenopathy and bilateral tonsillar enlargement and ulcerations. Computed tomography (CT) showed an infiltrative disease (Fig. 1a, arrow). A blood count showed haemoglobin, 13.1 g/dL; leucocytes, 41.9 × 109/L (89 % blasts); and platelets, 48 × 109/L. Bone marrow examination confirmed acute myeloid leukaemia (AML) without maturation (Fig. 1b). Cytogenetic analysis showed 46,XY,t(7;14)(p13;q32), the significance of which was unknown. NPM1 and FLT3 genes were wild type. Unexpectedly, a biopsy of the tonsillar mass showed infiltration by medium-sized atypical cells with indistinct cytoplasmic borders (Fig. 1c) and irregular and grooved nuclei (insert). These atypical cells were positive for CD1a (Fig. 1d) and S100 (Fig. 1e). Myeloblasts were not evident. Pathological features were consistent with Langerhans cell histiocytosis (LCH). Marrow trephine biopsy showed myeloblasts intermixed with numerous atypical cells (Fig. 1f), which were also S100 positive (Fig. 1g). The overall diagnosis was therefore consistent with concomitant disseminated LCH and AML. As leukaemia treatment was more urgent, a standard AML regimen of daunorubicin (60 mg/m2/day × 3 days) and cytarabine (100 mg/m2/day × 7 days) was administered. Interestingly, the tonsillar masses and cervical lymphadenopathy subsided, and a day-22 marrow examination showed complete remission of AML and LCH. A positron emission tomography/CT (PET/CT) also confirmed complete response of the LCH. Two consolidation courses of high-dose cytarabine have since been given, with the patient remaining in CR 6 months after diagnosis. Fig. 1 Concomitant disseminated Langerhans cell histiocytosis and acute myeloid leukaemia. a Computed tomography showing bilaterally enlarged tonsils, more prominent on the left side (arrow). b Marrow aspirate showing predominance of myeloblasts. c Tonsillar ... LCH in association with leukaemia occurs mainly in two clinical patterns: LCH preceded by acute lymphoblastic leukaemia (pathogenesis undefined) and LCH treated by etoposide/vinblastine followed by therapy-related AML [1]. Concomitant LCH and AML have very rarely been reported [2,3]. Two explanations for this extraordinary phenomenon have been proposed: LCH and AML deriving from the same neoplastic precursors or LCH being reactive to the AML [1–3]. In our patient, the LCH was infiltrative with marrow metastasis, supporting that it was neoplastic. In addition to its diagnostic interest, this case had therapeutic implication. The optimal treatment of disseminated LCH remains undefined. The use of vinblastine, etoposide, 2-chlorodeoxyadenosine, cyclophosphamide and cytarabine has been described [4]. Anthracyclines have apparently not been studied before. Our case showed fortuitously that a standard daunorubicin/cytarabine regimen was highly effective in inducing a remission for disseminated LCH, an observation that requires further validation.

Favorable effect of priming with granulocyte colony-stimulating factor in remission induction of acute myeloid leukemia restricted to dose escalation of cytarabine

AbstractThe clinical value of chemotherapy sensitization of acute myeloid leukemia (AML) with G-CSF priming has remained controversial. Cytarabine is a key constituent of remission induction chemotherapy. The effect of G-CSF priming has not been investigated in relationship with variable dose levels of cytarabine. We randomized 917 AML patients to receive G-CSF (456 patients) or no G-CSF (461 patients) at the days of chemotherapy. In the initial part of the study, 406 patients were also randomized between 2 cytarabine regimens comparing conventional-dose (199 patients) versus escalated-dose (207 patients) cytarabine in cycles 1 and 2. We found that patients after induction chemotherapy plus G-CSF had similar overall survival (43% vs 40%, P = .88), event-free survival (37% vs 31%, P = .29), and relapse rates (34% vs 36%, P = .77) at 5 years as those not receiving G-CSF. However, patients treated with the escalated-dose cytarabine regimen benefited from G-CSF priming, with improved event-free survival (P = .01) and overall survival (P = .003), compared with patients without G-CSF undergoing escalated-dose cytarabine treatment. A significant survival advantage of sensitizing AML for chemotherapy with G-CSF was not apparent in the entire study group, but it was seen in patients treated with escalated-dose cytarabine during remission induction. The HOVON-42 study is registered under The Netherlands Trial Registry (www.trialregister.nl) as #NTR230.

VALOR, an adaptive design, pivotal phase III trial of vosaroxin or placebo in combination with cytarabine in first relapsed or refractory acute myeloid leukemia.

TPS6637 Background: The promising phase 2 activity/tolerability profile of vosaroxin with cytarabine in first relapsed or refractory AML (N=69) with median overall survival (OS) 7.1 mo, combined CR 28% (CR 25%), median LFS 25 mo and 30-day all‑cause mortality 3%, supported phase 3 trial. VALOR (NCT01191801), a phase 3, randomized, controlled, double-blind trial, evaluates vosaroxin and cytarabine versus placebo and cytarabine in patients with first relapsed or refractory AML and incorporates an adaptive design. Primary objective is OS; secondary/tertiary objectives include CR rates, safety, EFS, LFS, and transplantation rate. Key eligibility criteria: persistent AML or first relapsed AML after 1 or 2 induction cycles that include at least 1 regimen of cytarabine with an anthracycline/anthracenedione; adequate cardiac, hepatic, renal function; and adults with no upper age restriction. Methods: VALOR is recruiting patients at over 100 sites in 14 countries in North America, Europe, and Australia/NZ. Enrollment opened Dec 2010; 183 patients enrolled through Dec 2011. Adaptive design: Base case assumed 40% improvement in median OS (hazard ratio, HR=0.71), 90% power, 2-sided alpha of 0.05. At the interim analysis (50% events), DSMB may recommend a 50% sample size increase from 450 to 675 evaluable patients if results indicate a larger sample size is required to reduce the risk of failing to confirm a clinically meaningful OS benefit (Mehta, Pocock, Stat Med 2010). In consideration of FDA and EMA guidance on Data Monitoring Committees and adaptive design with respect to trial integrity, operational bias, firewalls, and data confidentiality and archival, VALOR uses the Access Control Execution System (ACES ) to store, share, and archive confidential DSMB reports in a secure environment with an audit trail, and to facilitate communication between the DSMB and trial sponsor. The DSMB periodically reviews a combination of blinded and unblinded analyses while the study team remains blinded as specified in the DSMB charter. The DSMB recommended VALOR continue as planned after reviewing safety data in Dec 2011.

Effect of fludarabine, cytarabine, filgrastim, and gemtuzumab ozogamicin (FLAG-GO) on relapse-free survival in patients with newly diagnosed core-binding factor acute myelogenous leukemia.

6528 Background: Prior modulation with fludarabine increases cytarabine-triphosphate (ara-CTP) accumulation and granulocyte-colony-stimulating factor (G-CSF) increases the fludarabine-triphosphate (F-ara-ATP) levels in leukemic blasts. Our front-line regimen of fludarabine, cytarabine and filgrastim (FLAG) based on this rationale showed improved event-free survival compared to anthracycline and cytarabine based regimens in patients (pts) with core-binding factor acute myelogenous leukemia (CBF-AML). Medical Research Council AML 15 trial reported survival benefit from addition of gemtuzumab ozogamicin (GO) to chemotherapy regimens in patients with favorable-risk cytogenetics AML. Methods: In a clinical trial combining GO (3 mg/m2 IV) with FLAG (FLAG-GO) in newly diagnosed CBF-AML, pts received GO on day 1 of induction and of post-remission cycles 2 or 3 and 5 or 6 in addition to FLAG. FLAG regimen was comprised of fludarabine 30 mg/m2 and cytarabine 2 gm/m2 IV daily (both for 5 days in induction and 3-4 days in post-remission cycles) with filgrastim started on day-1 and continued till neutrophil recovery. Pts who received one non-FLAG-GO induction could enroll irrespective of their remission status. Results: Fifty pts [30 with t(8;21) and 20 with Inv16] have been enrolled [5 of 50 (10%) were in remission at enrollment from prior induction]. Median age is 48 years (range, 19-76), median WBC count 12.3 x106/L (range, 1.3-97.2); 12 patients (24%) were &gt;60 years of age and frequency of kit mutation is 8%. Complete remission with or without platelet recovery (CR/CRp) was achieved in 43/45 (96%) pts with 2 deaths in induction. With 6 planned consolidations, the median number of consolidation treatments received is 5 (range, 0-6). Two-thirds of pts needed dose reduction during post-remission cycles. Seven (14%) pts [t(8;21)= 5, Inv 16=2] relapsed and with a median follow-up of 34 months (range, 15-54 months) the relapse-free survival rate is 83%. Conclusions: FLAG-GO is a highly effective regimen and has resulted in high rate of relapse-free survival in pts with newly diagnosed CBF AML.

Pregnancy outcomes in women with cancer.

6116 Background: Parenthood after cancer is a critical concern for many cancer patients (pts). Pregnancy (prg) during cancer is an emotional time for about 1/1000 pregnant women. No randomized controlled studies exist examining the impact of cancer treatment (tx) on the developing fetus nor on the woman with cancer. Methods: From 2002-2011, women presenting for cancer tx during prg were approached for this IRB-approved prospective database study. All pts provided written consent. Results: To date 143 pts are evaluable. The median age at diagnosis was 32.1 years and median gestational age (GA) at enrollment was 18.2 weeks. 95/143 (66.4%) are White, 19 (13.3%) are African American, 17 (11.9%) are Hispanic and 12 (8.4%) are Asian/Other. Primary cancers included breast (n=59, 41.3%), hematologic (n=29, 20.3%), melanoma (n=13, 9%), GYN (n=11, 8%), GI (n=8, 5.6%), head/neck (n=7, 6%) and other (n=16, 11%) (brain=4, GU=1, thyroid=3, head/neck=7, thoracic=1, sarcoma=6, unknown primary=1). 111/143 (77.6%) of prgs resulted in live births. Median birth weight was 6.5 lbs. Median follow-up time for pts was 32.3 months. To date, 3/19 pts who terminated prgs have died (1.6%). Most terminations occurred in the 1st trimester. To date, 79 pts (55.2%) are NED and 23 pts have died; of these 19 (1.7%) had live births. No major malformations were observed in the 74/143 (52%) of pts who received chemotherapy (CTx) during pregnancy. 57% received FAC/FEC; other regimens included ABVD (n=5), cytarabine (n=5), CHOP/R-CHOP, and platinum-based regimens. Median GA at the start of CTx was 19.7 wks. Median number of CTx cycles during prg was 4. Other pts underwent surgery (n=32), no tx (n=14), deferred tx until after delivery (n=17), radiation (2), transplant (3), other (1). Conclusions: Cancer diagnosis during prg is compatible with successful tx and prg outcome. Cancer tx during the 2nd and 3rd trimester can be safely given and in our pts did not result in adverse prg outcomes. Tx during the 1st trimester is usually not recommended. Thus cancer pts in their 1st trimester need to be extensively counseled about their disease as well as about the risks to the prg. In our pts continuation or termination of prg were not associated with an increased risk of death.

Inhibition of RNA Polymerase I Transcription by CX-5461 As a Therapeutic Strategy for the Cancer-Specific Activation of p53 in MLL-Rearranged Acute Myeloid Leukemias

Abstract 1548Increased transcription of the ribosomal genes (rDNA) by RNA Polymerase I (Pol I) is a common feature of human cancer1. Inhibition of Pol I transcription causes nucleolar stress that leads to the release of ribosomal proteins from the nucleolus into the nucleoplasm where they can sequester the p53 inhibitory protein MDM2, causing activation of p53 and induction of apoptosis2. We have developed a potent and selective small molecule inhibitor of Pol I transcription (CX-5461) that is non-genotoxic3. When evaluated for anti-proliferative activity against genetically diverse cancer cell lines, CX-5461 exhibited its greatest potency against wild-type (wt) p53 cells derived from hematological malignancies (median IC50 = 12 nM), while the median IC50s in cells derived from p53 mutated hematological, p53wt and p53 mutated solid tumors and normal cells were less sensitive to CX-5461 (median IC50s = 94 nM, 164 nM, 265 nM and 5 mM respectively), indicating CX-5461 selectively kills p53-wild type malignant hematopoietic cells. Consistent with the nucleolar stress model, p53 wt human leukemia cell lines exhibited robust activation of p53 signaling and apoptotic death in response to low nanomolar doses of CX-5461. To explore the therapeutic potential of Pol I transcription inhibition in vivo in hematological malignancies wt for p53 that are refractory to cytotoxic therapies we tested CX-5461 in mouse models of human acute myeloid leukemia (AML) expressing MLL fusion proteins4. Mice transplanted with 5×106 leukemia cells expressing MLL/ENL or MLL/AF9 together with oncogenic NRAS linked to GFP and luciferase biomarkers by virtue of bicistronic retroviral vectors, rapidly developed aggressive leukemia characterized by anemia, leukocytosis, hepatosplenomegaly and within 7–10 days (Mac1+, Gr-1) leukemic cell counts in peripheral blood. Treatment of recipient mice harboring MLL/ENL+NRAS leukemia with CX-5461 (40mg/kg Q3D) significantly increased median survival (17 days for vehicle vs 36 days for drug, P <0.0001), and reduced leukemic burden, as determined by leukemic cell luminescence imaging, peripheral white blood cell counts (20.77×103cells/ml±2.25 for vehicle vs 6.2×103cells/ml±0.68 for drug, P <0.0001) at sacrifice and FACS analysis of the peripheral blood (24.36% GFP leukemic cells±1.84 for vehicle vs 6.30% leukemic cells±0.5 for drug, P <0.0001) after 3 doses of treatment. The reduction in tumour burden was associated with in vivo activation of p53 signaling and apoptosis. In marked contrast, treatment of MLL/ENL+NRAS leukemic mice with a combination regimen of cytarabine (50 mg/kg 5XQD IP) and doxorubicin (1.5 mg/kg 3XQD IP) at the combined MTD dose failed to provide a significant survival advantage. Treatment of recipient mice harboring the highly aggressive MLL/AF9 + NRAS leukemia with CX-5461 (40mg/kg Q3D) was also able to increased overall survival (15 days for vehicle vs 23 days for drug, P 0.0009), with this delay accompanied by a significant decrease in leukemic burden as determined by peripheral white blood cell counts (114×103cells/ml±12.24 for vehicle vs 4.68×103cells/ml±0.7 for drug) and FACS analysis of the peripheral blood (65% GFP leukemic cells±4.9 for vehicle vs 0.26% leukemic cells±0.05 for drug) after 2 respectively 3 doses of treatment. Critically, in murine xenograft of human AML MV 4;11 that carries the MLL/AF4 fusion, treatment with CX-5461 (125 mg/kg Q7D IP) inhibited tumour growth by 93% and extended time to sacrifice from 21 to 36 days. Together this work demonstrates that CX-5461, which selectively inhibits Pol I transcription and non-genotoxically activates p53, may be used to therapeutically treat aggressive p53-wild type AMLs that are highly refractory to standard cytotoxic therapies. The fact that mutations or deletions of the p53 gene are relatively rare in AML, coupled with our data that p53-wt AML cancer cells are particularly sensitive to CX-5461, provides a compelling rationale for evaluating CX-5461 in this patient population. Disclosures:Drygin:Cylene Pharmaceuticals Inc: Employment. Huser:Cylene Pharmaceuticals Inc: Employment. Bliesath:Cylene Pharmaceuticals Inc: Employment. Ryckman:Cylene Pharmaceuticals Inc: Employment. Rice:Cylenen Pharmaceuticals Inc: Employment. Hannan:Cylene Pharmaceuticals Inc: Consultancy.

A meta-analysis of CAG (cytarabine, aclarubicin, G-CSF) regimen for the treatment of 1029 patients with acute myeloid leukemia and myelodysplastic syndrome

The regimen of cytarabine, aclarubicin and G-CSF (CAG) has been widely used in China and Japan for treatment of acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). We searched literature on CAG between 1995 and 2010 and performed a meta-analysis to determine its overall efficacy using a random-effects or fixed-effects model. Thirty five trials with a total of 1029 AML (n = 814) and MDS (n = 215) patients were included for analysis. The CR rate of AML (57.9%) was significantly higher than that of MDS (45.7%) (p < 0.01). No difference in CR was noted between the new (56.7%) and relapsed/refractory AML (60.1%) (p > 0.05). The CR rate was also significantly higher in patients with favorable (64.5%) and intermediate (69.6%) karyotypes than those with unfavorable one (29.5%) (p < 0.05). Remarkably, the CR rate of CAG was significantly higher than those of non-CAG regimens (odds ratio 2.43). CAG regimen was well tolerated, with cardiotoxicity in 2.3% and early death in 5.2% of the cases. In conclusion, CAG regimen was an effective and safe regimen for the treatment of AML, and may be more effective than non-CAG regimens. Randomized controlled trials are strongly recommended to evaluate its efficacy and safety in comparison with the current standard treatment.

**504 Detection of Cytogenetic Abnormalities Associated with Outcome Differences in Acute Myeloid Leukemia Using Array-Based Comparative Genomic Hybridization (aCGH) Analysis

Abstract 1633 Poster Board I-659 Background The presence of abnormal cytogenetic findings at diagnosis is an independent indicator of the outcome in patients with acute myeloid leukemias (AML). Recent availability of high-resolution analysis by aCGH technology has facilitated rapid detection of cytogenetic abnormalities previously undetected by the conventional G-banded karyotyping. Aim: To determine whether specific cytogenetic abnormalities, as detected by the aCGH analysis, are associated with differences in clinical outcomes in a group of patients with AML treated uniformly with the standard chemotherapy regimen of Idarubicin and Cytarabine. Methods A total of 111 patients with newly diagnosed AML (Median age: 55 years; range, 22 to 73 years) were enrolled in the study. All patients were treated with Idarubicin 12 mg/m 2 IV daily x 3 days and Cytarabine 1.5 g/m 2 by continuous IV infusion daily x 4 days (3 days in patients older than 60). The diagnostic bone marrow samples from 48 of these patients were analyzed by aCGH using a 44K CGH array with a spatial resolution of 50-75 kb (Agilent Inc). The aberrations detected by aCGH using CGH Analytics (Agilent Inc, Santa Clara, CA) and the Nexus Copy Number Software (Biodiscovery Inc, El Segundo, CA) were compared to conventional G-banded karyotyping results. Correlation of aCGH-detected aberrations with clinical outcome was performed by Kaplan-Meier analysis and log-rank test. Results Complete remission (CR) was achieved in 34/48 (71%) patients, out of which 16 (47%) patients relapsed in less than 1 year (Median: 18.5 weeks, range: 1-44 weeks) and the remaining 18 (53%) patients sustained CR beyond one year (Median: 89 weeks, range: 58-132 weeks). The comparison of aCGH findings between the patients achieving CR and the resistant patients showed significant association of loss of a 155 kilobase region on 5q33.3 with achievement of CR (p TP53 gene in 3/12 (25%) patients, although these three patients showed genetic instability and poor clinical outcome. Overall, the aCGH findings were in concordance with the conventional karyotyping results. The aCGH analysis was able to detect aberrations in samples containing blast count as low as 5%. In addition, aCGH identified previously undetected aberrations, as small as 5 kb, of currently unknown significance. Conclusion The aCGH analysis indicates that the loss of 5q33.3 is associated with achievement of complete remission and the loss of 17p11.2-q11.1 is associated with poor overall survival in AML patients treated with Idarubicin and Cytarabine. Array CGH analysis provides a useful and rapid diagnostic tool for identifying these high-risk patients. The biologic roles of EBF1 and RNF145 in therapy response warrant further investigation. Disclosures No relevant conflicts of interest to declare.

Use of Cytarabine for Mantle Cell Lymphoma Treatment: 10 Years of Experience of a French Haematology Department

AbstractAbstract 1755 Background:Mantle cell lymphoma (MCL) has been identified since 1994 in the Revised-European-American classification of Lymphoid neoplasm's. It's a rare and aggressive subtype representing 5% of all non-Hodgkin lymphomas (NHL) with a poor prognosis and a median overall survival (OS) of 30 to 43 months (m) due to refractory disease or frequently relapse. Chemotherapies including anthracyclines as CHOP regimen with or without rituximab are often used in first line treatment. Promising results have been obtained since 1998 with regimens including cytarabine and followed by intensive therapy with autologous stem-cell transplantation (ASCT) for younger patients. Since 1999 we adopted a policy of treating MCL with regimens including this molecule: younger and grafting patients received DHAP and rituximab (R-DHAP) regimen followed by intensive therapy with ASCT. Patients fit and aged over 65 years received 6 cycles of R-DHAP. Unfit patients over 65 years received R-COP-cytarabine regimen and older unfit and frail patients received cytarabine by subcutaneous (SC) weekly injections. We report a retrospective observational study of 10 years experience in our department. Methods:From 09/1999 to 09/2009, we collect all cases of patients with a MCL diagnosis and treated by cytarabine regimen in our haematology department. All diagnosis was reviewed by pathologist and cytologist. We collected clinical, biological, histological, cytological, prognosis, therapeutic monitoring and survey data from the database of the regional structure of reference of lymphoma in Limousin in France. A descriptive and survival analysis was performed using Statview software. Results:During this period, we followed 54 patients with MCL, median age 70,5 [45-87], sex ratio 2,6. Diagnosis was performed on associations of the following samples: biopsie in 72,2% (n=39), bone marrow cytological aspect and immunophenotyping in 48,1% (n=26), blood cytological aspect and immunophenotyping in 70,4% (n=38). Cyclin D1 overexpression in molecular analysis was detected in 79,6% (n=43). Ann Arbor stage I/II 7,4% (n=4), III/IV 92,6% (n=50). ECOG 0/1 83,3% (n=45), ECOG 2 16,7% (n=9). MIPI score was Lower Risk (LR) for 25,9% (n=14), Intermediate Risk (IR) for 27,8% (n=15) and Higher Risk (HR) for 46,3% (n=25). Median OS is significantly different among the MIPI score (p<0,0021) with 37,7 months for HR versus 72,6 months for IR and not reached for LR. First line treatment were distributed among SC weekly injections of cytarabine 13% (n=7), COP+/−R-cytarabine for 25,9% (n=14) and DHAP+/−R for 61,1% (n=33). ASCT was performed for 29,6% (n=16) followed induction treatment by DHAP+/−R. Median OS and PFS are respectively 59,4 and 46,3 months for the total population. Patients received SC cytarabine have a median OS of 37,7 months and median PFS 27,3 months. Patients received COP+/−R-cytarabine have a median OS of 29,4 months and PFS 17,7 months. And patients received DHAP+/−R have not reached median OS and PFS. For patients received ASCT, median OS and PFS are not reached versus respectively 46,3 and 33,5 months for ungrafted patients. Median follow-up is 35,4 months [1-124,7] for all patients, 37,7 months [1,1-59,3] for patients treated by SC cytarabine, 18,1 months [2,6-81,9] for patients treated by COP+/−R-cytarabine and 39,8 months [1-124,7] for patients treated by DHAP+/−R. Conclusion:The MIPI score was calculated a posteriori and validated in our series of patients distinguishing three different populations with significantly different survival (p<0,0021). Since 10 years, we usually used cytarabine in first-line treatment of MCL. Cytarabine regimen is associated with other molecule and adapted by age, comorbidities and renal function. In real life, the use of this molecule seems provide interesting results in term of survival and PFS particularly for younger receiving dose intensified regimens by R-DHAP followed by intensive therapy with ASCT. Several clinical trials include now cytarabine in their therapeutic schemes. Disclosures:No relevant conflicts of interest to declare.

Therapeutic and Mobilizing Activity of a Vinorelbine, Ifosfamide and Cytarabine Regimen (VIHA) as Salvage Regimen In Resistant/Relapse Non Hodgkin Lymphoma (NHL)

AbstractAbstract 1761 Background:The identification of active regimens sharing clinical and mobilizing activity are warranted NHL patients (pts) at high risk at onset or at relapse, as induction therapy before peripheral blood stem cell transplantation (PBSCT). Vinorelbine (VNR), ifosfamide (IFX), and cytarabine (ARA-C) are of proved efficacy in this setting. Methods:From November 1999 to September 2008, 115 pts underwent the VIHA regimen: VNR 25 mg/mq day 3, IFX 2500 mg/mq days 1–3, and ARA-C 2 gm/mq bid days 2–3. Pts older than 60 years, were given the same regimen at 75% of doses. A total of 4 cycles was repeated every 21 days with G-CSF support from day 7 to day 12 or up to the apheresis. Mobilization was performed from the 3rd cycle, in patients withat least partial remission (PR), achieved after cycle 2. All cases with at least stable disease (SD) at the end of VIHA induction and with a CD34+ cell collection of > 1.5 × 10<6/Kg were then candidated to PBSCT. Results:Main clinical characteristics: median age 47 (range 28–73) with 36 pts older 60 years, aggressive histology 73, indolent histology 42, primary refractory disease 44, relapsed disease 71, stage III or IV 42, bone marrow involvement 20, sIPI > 2 13. Seventy-seven pts had received at least two lines of chemotherapy before VIHA.Sixty-seven patients (59%) obtained an objective response (OR) with 48 (42%) of these obtained complete remission (CR) according to CT-scan criteria. Seventy-four patients entered PBSCT and 41 did not for the following reasons: 15 due to unplanned PBSCT, 13 pts failed mobilization, one for toxic deaths, and the others for disease progression. With a median follow-up of 47 months, 4-year progression free survival (PFS) and overall survival (OS) are 30% and 39%, respectively. In univariate analysis, only the histologic category (aggressive vs indolent) was a predictive factor of response (p.001) and survival (p<.0001). In multivariate analysis, only elevated IPI at relapsed (> 2) was a significant negative predictor. Interestingly, there was no difference in OR, PFS and OS between patients treated with full dose or reduced dose VIHA.As concerns stem cell mobilization, in 80 mobilized pts, median number of CD34+ cells collected was 7.1 × 106/Kg (range 1.5–45) after a median of 2 (1-3) apheretic procedures.Among more than 240 VIHA cycles analyzed for haematological toxicity 86% of full dose VIHA required platelet transfusions and 50% RBC transfusions, as compared to 46% (p<.0001), and 34% (p0.03), of reduced dose VIHA, respectively. Febrile neutropenia complicated 27% of all cycles and there were 19 documented infections. Thirty-five per cent required Hospitalization for documented infections or febrile neutropenia was necessary in 35% of full-dose VIHA cycles and in 16% of reduced VIHA cycles, (p.01). There was only one death-related therapy. Conclusions:VIHA shows clinical and mobilizing activity comparable to better known salvage chemotherapy regimens; otherwise our data suggest to use as well the reduced dose regimen, which shares clinical activity and lower toxicity profile. The high CD34 mobilizing activity is notheworthy. Disclosures:No relevant conflicts of interest to declare.

Patients with FLT3/ITD AML May Benefit From Allogeneic Transplant In First Remission: Outcomes From a Consecutive Series of Patients at a Single Institution

AbstractAbstract 2172AML patients with FLT3/ITD mutations have an inferior survival compared to AML patients with wild-type (WT) FLT3, primarily due to an increased relapse rate. Allogeneic transplant represents a post-remission therapy that is effective at reducing the risk of relapse for many cases of poor-risk AML. Whether or not allogeneic transplant in first complete remission (CR) can improve outcomes for patients with FLT3/ITD AML remains controversial. Our institution has adopted a policy of pursuing allogeneic transplant, including the use of alternate donors, for FLT3/ITD AML patients in remission.As part of an IRB-approved study, we performed a review of the clinical data from November 1, 2004 to October 31, 2008 on all adult patients under the age of 60 presenting in consecutive fashion to the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins with newly diagnosed non-M3 AML. We followed their outcomes through August 1, 2010.During the study period, 133 previously untreated AML patients between the ages of 20 and 59 were diagnosed and received induction and consolidation therapy at our institution. Of these 133 patients, 31 (23%) harbored a FLT3/ITD mutation at diagnosis. Fourteen of the total 133 patients were deemed unfit for intensive therapy, all WT patients. Of these, 6 (5%) received investigational agents on protocol while the other 8 (6%) were treated with combinations of supportive care and cytotoxic agents off protocol. Of the remaining patients, 119/133 (89%) received timed- sequential intensive induction therapy (TST) with infusional cytarabine, an anthracycline or anthracenedione, and a third drug. The majority, 95/133 (71%), received the three drug TST regimen of cytarabine, daunorubicin, and etoposide delivered in a timed sequential fashion, while 24/133 (18%) were treated with TST containing cytarabine, mitoxantrone, and the investigational agent flavopiridol on an institutional protocol. 72/119 (61%) achieved a CR with induction therapy (55 patients in AcDVP16 group and 17 patients in FLAM group). The OS (overall survival) from the time of diagnosis for the FLT3/ITD AML patients was compared to the OS of the entire cohort (n=133) (Figure 1). The median OS for the FLT3/ITD group was 19.3 (range 0.0–69.9) months and the median OS for the WT patients was 15.5 (range 0.7 to 64.6) months (p=0.56). Of the FLT3/ITD patients, 20/31 (65%) achieved a complete remission with intensive induction therapy. Of these 20 patients in CR1, 11 (55%) underwent an allogeneic transplant in first remission (4 HLA-matched myeloablative sibling, 5 HLA-matched myeloablative unrelated donor, and 2 nonmyeloablative haplo-identical related donor) compared to only 18/102 (17%) WT patients were transplanted in first CR, a statistically different proportion compared to the FLT3/ITD patients (p<0.0001). The 9 FLT3/ITD patients who were not transplanted in CR1 had issues related to lack of donor or overall comorbidities. There was one patient who went on to transplant after first relapse. The median relapse-free survival in the FLT3/ITD non- transplant group was 8.6 (range 5.3–43.3) months while the median relapse-free survival in the FLT3/ITD transplant group was 54.1 (range 6.4–69.9) months (p=0.02) (Figure 2).Historically, OS for FLT3/ITD AML patients is significantly worse than for AML patients lacking this mutation. However, the OS for the 31 FLT3/ITD patients reported here was comparable to the 102 patients with WT FLT3 over the same 4 year time period. One difference that might have contributed to the surprising outcomes for the FLT3/ITD group is our aggressive pursuit of allogeneic BMT in CR1 within this group (60% of FLT3/ITD vs 17% with WT). Our single institution study of consecutively treated AML patients supports the hypothesis that allogeneic transplant in early CR1 improves the long term outcomes for FLT3/ITD AML. [Display omitted] [Display omitted] Disclosures:Levis: Ambit Biosciences, Inc: Consultancy.

Arsenic trioxide improves event-free and overall survival for adults with acute promyelocytic leukemia: North American Leukemia Intergroup Study C9710

AbstractArsenic trioxide (As2O3) is a highly effective treatment for patients with relapsed acute promyelocytic leukemia (APL); its role as consolidation treatment for patients in first remission has not been defined. We randomized 481 patients (age ≥ 15 years) with untreated APL to either a standard induction regimen of tretinoin, cytarabine, and daunorubicin, followed by 2 courses of consolidation therapy with tretinoin plus daunorubicin, or to the same induction and consolidation regimen plus two 25-day courses of As2O3 consolidation immediately after induction. After consolidation, patients were randomly assigned to one year of maintenance therapy with either tretinoin alone or in combination with methotrexate and mercaptopurine. Ninety percent of patients on each arm achieved remission and were eligible to receive their assigned consolidation therapy. Event-free survival, the primary end point, was significantly better for patients assigned to receive As2O3 consolidation, 80% compared with 63% at 3 years (stratified log-rank test, P < .0001). Survival, a secondary end point, was better in the As2O3 arm, 86% compared with 81% at 3 years (P = .059). Disease-free survival, a secondary end point, was significantly better in the As2O3 arm, 90% compared with 70% at 3 years (P < .0001). The addition of As2O3 consolidation to standard induction and consolidation therapy significantly improves event-free and disease-free survival in adults with newly diagnosed APL. This trial was registered at clinicaltrials.gov (NCT00003934).

A Phase I Trial: Dose Escalation of Melphalan in the “BEAM” Regimen Using Amifostine Cytoprotection

With the eventual goal of reducing relapse and thus improving overall survival in selected lymphoma patients, a Phase I study was performed using the cytoprotectant amifostine to permit safe dose-augmentation of melphalan in the carmustine (BCNU), etoposide, cytarabine (arabinosylcytosine), and melphalan (BEAM) regimen before autologous hematopoietic stem cell transplantation. Between 30 July 2003 and 25 November 2008, a total of 32 lymphoma patients were entered, of which 28 were evaluable. We found the melphalan dose in BEAM could be safely escalated to at least 260 mg/m², a substantial increase from the usual dose of 140 mg/m² in BEAM while the trial was terminated early due to poor accrual, no maximal tolerated dose or dose-limiting toxicity was found. A Phase II trial is planned.

Treatment of therapy-related myeloid neoplasms with high-dose cytarabine/mitoxantrone followed by hematopoietic stem cell transplant

Few clinical protocols have focused on patients with therapy-related myeloid neoplasms (t-MN). Therefore, we enrolled 32 patients with previously untreated t-MN on a clinical trial testing the effectiveness of a unified induction regimen of high-dose cytarabine and mitoxantrone. The complete remission (CR) rate was 66% (95% CI 47–81%) and the partial remission (PR) rate was 16% (95% CI 5–33%), for an overall response rate of 82%. Day 30 treatment mortality was 9% (3/32), and the most serious induction toxicity was cardiac dysfunction. Among the patients with CR, 13 (62%) received consolidation therapy using an allogeneic hematopoietic cell transplant (HCT), four (21%) received an autologous HCT, and three (16%) received further chemotherapy. We observed long-term disease-free survival in patients who received all three types of consolidation therapy. The remission induction of high-dose cytarabine and mitoxantrone for t-MN is a well-tolerated efficacious combination, which allows aggressive consolidation and long-term disease-free survival.