High-dose Cytarabine Consolidation Research Articles

High-Dose Cytarabine-Based Consolidation Shows Superior Results for Elderly AML Patients with Intermediate Risk Cytogenetics in First Complete Remission

AbstractAbstract ▪3574▪This icon denotes a clinically relevant abstract Introduction:In elderly patients with acute myeloid leukemia (AML) treated intensively, the optimal post-remission strategy is unclear. High dose cytarabine (HiDAC) 3 g/m2 is the standard consolidation dose for younger adults with AML with favorable and intermediate risk disease, but is associated with high rates of severe toxicity and early death in older adults that counteract any improvement in efficacy when compared to standard dose cytarabine. We have used a modified high-dose cytarabine consolidation regimen, and compared this to a similar cohort receiving a conventional-dose regimen. Methods:164 patients with AML age 60 years and over, who achieved complete remission after standard induction therapy consisting of cytarabine 100 mg/m2/day continuous IV infusion × 7 days and dauorubicin 60 mg/m2 IV daily × 3 (7+3) from 1998 – 2008, received two different types of post-remission therapy in sequential cohorts. Group 1 (n=55), treated from 1998–2002, received 2 consolidation cycles, each consisting of cytarabine 1.5 g/m2 q12h × 6 doses + daunorubicin 45 mg/m2/day × 2, while group 2 (n=109), treated from 2003–2008, received a first consolidation using 7+3 followed by a second cycle consisting of mitoxantrone 10 mg/m2 IV daily × 5 plus etoposide 100 mg/m2 IV daily × 5 (NOVE). Results:The two groups did not differ with respect to median age (68 vs. 69 years), mean baseline WBC, gender, prior malignancy/AHD and proportion of patients undergoing allogeneic HSCT in CR-1 (9.1 vs.8.3%). 40 patients (72.7%) in the first group, and 86 patients (78.9%) in the second group received the intended consolidation regimen (p=0.38). Among the entire cohort (n=164), and in the subgroup with adverse risk cytogenetics, there was no significant difference in OS or DFS between the two groups. For patients with intermediate risk cytogenetics, on an intention-to-treat basis, the disease-free survival (DFS) was significantly higher for group 1 vs. group 2 (Table 1).Table 1Outcome for patients with intermediate risk cytogenetics.Group1 (N=38)Group 2 (N=84)P (log-rank)DFS (median), mos.13.48.50.0462 year DFS37%24%5 year DFS18%7%OS (median), mos.25.614.70.0872 year OS53%37%5 year OS27%17% Conclusion:Older patients with intermediate-risk cytogenetics, who received a modified high-dose cytarabine-based consolidation regimen combined with anthracycline, had a superior DFS and a trend toward superior OS, as compared to those who received conventional-dose consolidation therapy. These findings require further evaluation in a prospective randomized study but, if confirmed, suggest that older fit patients with intermediate risk cytogenetics should receive more intensified post-remission therapy with modified high-dose cytarabine. Disclosures:No relevant conflicts of interest to declare.

Sorafenib Versus Placebo in Addition to Standard Therapy in Adult Patients ≥60 Years with Newly Diagnosed Acute Myeloid Leukemia: Results From the Randomized-Controlled Soraml Trial

AbstractAbstract 144▪▪This icon denotes a clinically relevant abstract Background:Sorafenib is a multi-kinase inhibitor with activity against several oncogenic kinases, which may play a role in the pathogenesis of acute myeloid leukemia (AML). In-vitro data and results from non-randomized clinical trials suggest that sorafenib might be an effective drug for the treatment of AML. So far, no randomized-controlled data are available for treatment of newly diagnosed AML patients up to the age of 60 years. We present the first results from the randomized placebo-controlled SORAML trial of the Study Alliance Leukemia (SAL). Patients and Methods:Between March 2009 and October 2011, 276 patients from 25 centers were enrolled in the SORAML trial (NCT00893373). The main eligibility criteria were: newly diagnosed AML, age from 18 to 60 years and suitability for intensive therapy. The treatment plan for all patients included two cycles of induction with DA (daunorubicin 60 mg/m2 days 3–5 plus cytarabine 100 mg/m2 cont. inf. days 1–7), followed by three cycles of high-dose cytarabine consolidation (3 g/m2 b.i.d. days 1, 3, 5). Patients without response after DA I received second induction with HAM (cytarabine 3 g/m2 b.i.d. days 1–3 plus mitoxantrone 10 mg/m2 days 3–5). Allogeneic stem cell transplantation was scheduled for all intermediate-risk patients in first complete remission with a family donor and for all high-risk patients with a matched donor. At study inclusion, patients were randomized to receive either sorafenib (800 mg/day) or placebo as add-on to standard treatment. Block randomization at a ratio of 1:1 was performed within cytogenetic and molecular risk strata, allocation was concealed and treatment was double blinded. Study medication was given on days 10–19 of DA I+II or HAM, from day 8 of each consolidation until 3 days before the start of the next consolidation and as maintenance for 12 months after the end of consolidation. The primary endpoint of the trial is event-free survival (EFS) with an event being defined as either failure to achieve a complete remission (CR) after induction, relapse or death. Secondary endpoints were overall survival (OS), CR rate and incidence of adverse events (AE). We present the results of the planned interim analysis (intent to treat) after the occurrence of 50% of EFS events. The O’Brien/Fleming adjusted significance level was set at p=0.0052. Results:Out of 276 randomized patients, 264 were evaluable for EFS, 132 in each arm. Demographic and disease characteristics were equally distributed between the two arms; the FLT3-ITD incidence was 16%. The median cumulative dose of administered study medication was equal in both arms. The CR rates were 56% versus 60% in the placebo versus sorafenib arm (p=0.622). By the time of analysis, a total number of 100 events had occurred. After a median observation time of 18 months, the median EFS was 12.2 months in the placebo arm and was not reached in the sorafenib arm, corresponding to a 1-year EFS of 50% versus 64% (p=0.023). The median OS had not been reached in both arms, the 2-year OS was 66% versus 72% in placebo and sorafenib arms, respectively (p=0.367). The most common reported AEs CTC Grade ≥3 were infectious complications including fever and pneumonia, followed by bleeding events, cardiac and hepatic toxicity, hypertension, skin toxicity and headache. The risk for hepatic toxicity (relative risk 6.2, p=0.025) and bleeding events (relative risk 3.6, p=0.016) was significantly higher in the sorafenib arm while the incidence of all other AEs showed no significant differences. Conclusions:In younger AML patients, the addition of sorafenib to standard chemotherapy is feasible but associated with a higher risk of liver toxicity and bleeding events. Sorafenib treatment resulted in a marked EFS prolongation; this difference is not significant according to the adjusted significance level of this interim analysis. Results from the final analysis including post-hoc exploration of molecularly defined subgroups are necessary for drawing final conclusions on the efficacy of sorafenib. [Display omitted] Disclosures:Off Label Use: sorafenib for the treatment of acute myeloid leukemia. Serve:Bayer: Research Funding. Ehninger:Bayer: Research Funding.

No Benefit of Combining Additional Compounds with Standard High Dose Cytarabine Consolidation: Results of the Prospective Randomized AML2003 Study

Abstract 255 Introduction:Standard treatment of acute myeloid leukemia (AML) comprises one or two cycles of chemotherapy to induce complete remission (CR) followed by postremission treatment in order to prevent relapse of the disease (consolidation therapy). In 2003, we initiated a prospective multicenter randomized trial to investigate the impact of different consolidation strategies on long-term outcome in AML patients ≤ 60 years. Consolidation options comprised upfront allogeneic stem cell transplantation (allo SCT) in aplasia after induction therapy, autologous SCT, and three cycles of standard high-dose-cytarabine-based consolidation. For patients receiving high-dose cytarabine, the main study aim was to evaluate the benefit of adding additional mitoxantrone and amsacrine to cytarabine consolidation. Design:From 2003 to 2009, 1182 patients (median age, 48 years; range 16–60 years) with untreated AML were randomly assigned at diagnosis to different consolidation strategies after classical 7+3 induction. According to the risk-adapted treatment strategy of the trial, cytogenetically or molecular intermediate-risk (IR) and adverse-risk (AR) patients should receive an allo SCT as consolidation treatment if an HLA-identical-sibling donor (IR) or HLA-matched related or unrelated donor (AR) was available. IR and AR patients with no available donor should receive autologous SCT. All favorable risk patients and patients with no available donor were scheduled for high-dose cytarabine based consolidation. Half of the patients were randomized for high dose cytarabine based consolidation. Half of the patients were randomized for high dose cytarabine alone while the other half received high dose cytarabine with the addition of amsacrine and mitoxantrone. Standard chemotherapy consisted of three cycles with high dose cytarabine (2 × 3 g/m2, day 1,3,5) whereas combined consolidation contained two cycles of MAC (cytarabine 2 × 1g/m2, day 1–6, mitoxantrone 10 mg/m2, day 4–6) plus one cycle of MAMAC (cytarabine 2 × 1 g/m2, day 1–5, amsacrine 100 mg/m2, day 1–5). In order to evaluate the effect of the two cytarabine based consolidation strategies, we determined overall survival (OS) and event free survival (EFS) using the method of Kaplan Meyer. Survival distributions were compared using the log rank test. Results:1182 patients were randomized for further intervention (Arm A+B: n=582, 49.3%; Arm C+D: n=600, 50.7 %). Median follow-up was 41.4 months (95%-CI 39.3–43.6). A total number of 375 patients received allogeneic (n=322) or autologous SCT (n=53) and 807 patients were consolidated with cytarabine. Of these patients, 407 were randomized for cytarabine alone and 400were randomized to receive cytarabine plus mitoxantrone and amsacrine (MAC/MAC/MAMAC). Complete remission rate (CR) after second induction therapy was 59.1% (n=698). Between the four arms, there were no significant differences of the CR rates.Five-year OS of patients receiving high dose cytarabine alone was 47.1% (95%-CI 42.0–52.2%), for patients receiving MAC/MAMAC as consolidation therapy it was 46.8% (95%-CI 42.3–51.3%; p = 0.610). Three-year event free survival (EFS) was also not significant with 30.5% (95%-CI 26.6–34.4%) for patients receiving high dose cytarabine alone and 35.6% (95%-CI 31.7–39.5%; p = 0.059) for patients receiving MAC/MAMAC. Conclusions:According to our data, the addition of mitoxantrone and amsacrine to high dose cytarabine consolidation confers no benefit for treatment outcome in younger AML patients. Disclosures:No relevant conflicts of interest to declare.

Expression of Gli2, a Downstream Mediator of the Activated Hedgehog Pathway, Represents a Negative Prognostic Marker in AML,

Abstract 3535The cancer and leukaemia stem cell hypothesis was first proposed over 40 years ago. This hypothesis suggests that malignant stem cells serve as reservoir for leukaemia cell renewal. Stem cell activators such as Wnt/β-catenin, transforming growth factor β (TGF-β), Notch and Hedgehog signaling pathways have been implicated into stem cell capacity for self-renewal, production of heterogeneous progeny and resistance to chemotherapy. Until now, few data on the contribution of the Hedgehog pathway in acute myeloid leukaemia (AML) exist. Therefore, the aim of this study was to investigate the expression of members of the Hedgehog pathway in primary AML samples and to correlate expression with clinical outcome.Pre-treatment samples from 95 patients with newly diagnosed AML who were entered into the AMLSG 07–04 trial were analyzed. The trial was conducted between August 2004 and August 2009 (ClinicalTrials.gov Identifier: NCT00151242). In brief, the trial design was as follows: Patients between 18 and 60 years of age with de novo or secondary AML [excluding patients with t(15;17)] were entered into the study. All patients received two induction courses with cytarabine, idarubicin and etoposide. Patients with complete remission (CR) obtained high dose cytarabine consolidation. At study entry patients were randomized between additional therapy with valproic acid, ATRA, both or none. After an interim analysis the randomization to the valproic acid and the combination arm was suspended. Mean follow-up of the analyzed patients was 580 days.Expression of ligands Sonic, Indian and Dessert Hedgehog, receptors Patched and Smoothened as well as downstream transcription factors Gli1-3 were analyzed by qPCR. No appreciable expression of Sonic, Indian or Desert Hedgehog was found in 30 patients each, and thus no further samples were analyzed. Expression of Smoothened and Patched was found in 73% and 41% of cases, respectively. Mutations within exon 9 or 10 of the Smoothened gene represent a frequent genetic alteration in basal cell carcinomas and medulloblastomas. Therefore, both Smoothened exons have been analyzed by direct sequencing in AML samples. No mutations in Smoothened exon 9 or 10 were found in 30 AML patients. Measurable expression of Gli1, Gli2 and Gli3 was detected in 73%, 22% and 26% of cases, respectively. Patient characteristics including gender, age, categorized karyotype, FLT3 mutation, NPM-1 mutation or MLL status were correlated with the expression of the various members of the Hedgehog pathway. In this analysis, a significant association between FLT3 mutation and Gli2 expression could be established (p<0.001). Clinical outcome of patients was also correlated to Hedgehog expression variables. The CR rate was 57% for Gli2 expressors compared to 71% in Gli2 negative patients. Furthermore, Gli2 expression had a significant influence on relapse free survival and overall survival (p=0.026 and p=0.008, respectively). In conclusion, Gli2 expression in contrast to the more frequently expressed Gli1 is a negative prognostic factor in AML. Blockade of Smoothened activity by specific inhibitors may result in repression of the Gli2 gene and may therefore represent a new therapeutic approach in AML.Acknowledgment: Supported by a grant from Pfizer [Display omitted] [Display omitted] Disclosures:Fiedler:Pfizer: Research Funding.

Treatment of Acute Myeloid Leukemia in Children: Experience from a Tertiary Care Hematology Centre in India

To assess the treatment and outcome of children with acute myeloid leukemia. The Primary objectives were to assess remission rates, treatment related toxicity and disease free survival. Secondary objective was to assess prognostic factors associated with poor outcome. A retrospective analysis of all treated patients with acute myeloid leukemia, less than 18 year of age from Sept 2005 to Aug 2009 was done. Clinical laboratory, treatment and follow up records retrieved to calculate remission rate, treatment related toxicity, disease free survival and poor prognostic factors. This analysis included thirty five patients (male : female; 23:12), twenty seven (77.1%) achieved remission after one 3 + 7 induction and seven required two inductions. High dose cytosine arabinoside consolidation was given in thirty one patients while one underwent allogenic stem cell transplantation. Two patients died during chemotherapy (TRM- 5.7%), two did not complete the therapy, seventeen relapsed (48.5%) with 80% of relapses occurring within first year of remission and no relapse occurred after 2 years. Fourteen patients are in remission (40%, follow up 5-54 months) and cumulative median disease free survival is of 13 months. The present data suggests that 3 + 7 induction, followed by high dose cytarabine consolidation has low treatment related toxicity and resource utilization; however, relapse free survival is inferior to more intensive regimens, highlighting the need to intensify chemotherapy regimen once the treatment related mortality has been minimized.

Most Patients With CBF Leukemia Will Require HSCT for Long Term Disease Control: Results of Cohort of Unselected Patients

Patients with CBF-AML are regarded as having a favorable outcome when treated with anthracycline-based induction chemotherapy and multiple cycles of high-dose cytarabine consolidation. Most data indicating the favorable prognosis of CBF-AML with non-HSCT management originates from young selected patients participating in clinical trials with scarce information on salvage treatment. We performed a retrospective analysis of 30 consecutive patients diagnosed with CBF-AML (14 with t(8;21) and 16 with inv(16)) at a regional leukemia center over twelve years to assess long term survival and the likelihood of therapeutic success without ever requiring HSCT.

Most Patients with Core Binding Factor AML Require Hematopoietic Stem Cell Transplantation for Long-Term Survival: Long Term Follow-up of a Cohort of Unselected Patients.

AbstractAbstract 4560 Introduction:About 15% of acute myelogenous leukemia (AML) patients will have disruption of the core binding factor (CBF) transcription factor as indicated by the detection of t(8;21) or inv(16) on metaphase cytogenetic analysis. In general, patients with CBF-AML are younger and regarded as having a favorable outcome when treated with anthracycline-based induction chemotherapy and multiple cycles of high-dose cytarabine consolidation. Autologous and allogeneic hematopoietic stem cell transplantation (HSCT) are usually perceived as unnecessary in the management of CBF-AMLs. However, most data indicating the favorable prognosis of CBF-AML with non-HSCT management originates from young selected patients participating in clinical trials and information on relapse treatments is often lacking. We performed a retrospective analysis of consecutive patients diagnosed with CBF-AML at a regional leukemia center over the last twelve years to assess long term survival of unselected patients and the likelihood of therapeutic success without ever requiring HSCT. Methods:The study cohort was identified through a search of all AML reports issued by the institutional clinical cytogenetics laboratory since the introduction of electronic records (1998-2010). We subsequently reviewed the charts of all patients with CBF-AML (irrespective of other cytogenetic abnormalities) to extract demographic, treatment, and outcome information. Survival status and subsequent treatments in other institutions were determined by contacting the patient, attending physician or review of public death records. Data collection and analysis were approved by the Institutional Review Board. Results:Thirty patients with CBF-AML were identified, 14 with t(8;21) and 16 with inv(16) AML. Median follow up for survivors in this series is 35.3 months (range 6.4–117.4) with all survivors currently in remission. Median age at diagnosis was 43 years (range 18–69) with 10 (33%) patients older than 55. All patients initially received therapy with curative intent with anthracycline-based induction chemotherapy. Only 47% of the patients were treated on clinical trials. There was 1 death during induction therapy and 22/29 patients (73.3%) achieved a complete remission with initial induction therapy. Overall 13 patients (43.3%) have required some modality of HSCT. Six patients received HSCT in CR1 due to perceived high risk of relapse (5 autologous, 1 allogeneic). None of the 6 patients who underwent HSCT in CR1 (5 autologous, 1 allogeneic) have relapsed. Among the 16 patients receiving non-transplant consolidation in CR1, 6 have subsequently relapsed and required a HSCT (3 autologous, 3 allogeneic) and 3 of these patients are alive 20.9–117.4 months from the initial diagnosis. Seven patients received HSCT in CR2 or in relapse (4 autologous, 3 allogeneic) and 6 of these patients are long-term survivors. Estimated 5 year overall survival for the entire cohort is 58.8 +/− 10.8%, comparable to what has been described for younger patients entering clinical trials (Grimwade et al, 2010). However, the likelihood of survival at 5 years without requiring HSCT was only 28.1+/− 8.8% (Figure). Conclusions:The favorable outcome previously reported for CBF-AMLs was reproducible in unselected patients. However, only a minority of patients were long term survivors relying exclusively on conventional chemotherapy. In the near future, strategies for molecular risk stratification of CBF-AML patients need to be coupled with risk-adapted therapy, likely including early use of HSCT for high-risk patients. [Display omitted] Disclosures:No relevant conflicts of interest to declare.

Feasibility and Safety of Maintenance Therapy in the Treatment of Acute Myeloid Leukemia

Brief Abstract In this study, we present data about the feasibility and safety of a prolonged monthly myelosuppressive maintenance therapy as a postremission therapy for acute myeloid leukemia after induction and induction-type consolidation. Maintenance therapy could be started in 57% of CR patients assigned to maintenance and completed in 14%. Full Abstract Introduction We have previously shown that a prolonged monthly myelosuppressive chemotherapy proved superior to high-dose cytarabine consolidation therapy ( J Clin Oncol 2003; 21:4496) after induction therapy and induction-type consolidation therapy. In this study, feasibility and safety of this approach was evaluated in the AMLCG 1999 trial. Patients and Methods 827 patients with a CR before May 2005 were either randomized up front to receive maintenance therapy ( Results Out of the 827 patients, 326 patients (39%) did not receive maintenance therapy due to allogeneic (63; 7.6%) or autologous (6; 0.7%) stem cell transplantation (SCT); early relapse (126; 15.3%); withdrawal of consent (19; 2.3%); medical reasons other than relapse (60; 7.3%); other reasons not classified (9; 1.1%); or death in remission (43; 5.2%). In 30 patients (3.6%), the application of maintenance therapy cannot be followed due to loss of follow-up or incomplete documentation. For the remaining 471 patients (57.0%) with a documented start of the maintenance therapy, the median number of maintenance courses applied was 6 (first to third quartile: 2–16) over a median duration from achievement of CR of 10 months (first to third quartile: 5–24). A dose reduction was necessary in all patients. Out of the 471 patients who started maintenance, therapy was terminated early in 348 patients (73.9%) due to an allogeneic SCT in first CR (7 patients; 1.5%); relapse (205; 43.5%); withdrawal of consent (21; 4.5%); medical reasons other than relapse (89; 18.9%); other reasons not classified (17; 3.6%), loss of follow-up or incomplete documentation (55; 11.7%); and death in CR (8; 1.7%). 69 patients (14.4%) completed maintenance for 3 years. Conclusion These results show that a prolonged monthly myelosuppressive maintenance therapy as part of a postremission therapy in AML is feasible and safe.

A Phase 1b Study of Midostaurin (PKC412) in Combination with Daunorubicin and Cytarabine Induction and High-Dose Cytarabine Consolidation in Patients Under Age 61 with Newly Diagnosed De Novo Acute Myeloid Leukemia: Overall Survival of Patients Whose Blasts Have FLT3 Mutations Is Similar to Those with Wild-Type FLT3.

Abstract 634FLT3, a transmembrane receptor tyrosine kinase constitutively activated via mutation in blasts of patients (pts) with AML, is an important therapeutic target. Blasts from approximately 25% of pts have a length or internal tandem duplication (ITD) mutation in the juxtamembrane region or tyrosine kinase domain (TKD1) of FLT3, which is associated with reduced disease-free survival and overall survival (OS), particularly in pts with normal cytogenetics. Blasts from 5–10% of pts have a point mutation (typically D835Y) in the tyrosine kinase domain (TKD); the effect of this mutation on prognosis is uncertain. Midostaurin (PKC412) is a multi-targeted kinase inhibitor with demonstrated clinical activity in FLT3-mutant (FLT3–mut) and FLT3-wild-type (FLT3–wt) AML (peripheral blood blast reduction in 70% and 30% of pts, respectively) but rarely produces complete remissions). Preclinical studies demonstrated synergy between FLT3 inhibitors and chemotherapy. We conducted a Phase 1b trial to investigate the feasibility of administering daunorubicin (60 mg/m2 IV, days 1–3) and cytarabine (100 mg/m2 IVCI, days 1–7) induction and high-dose cytarabine post-remission therapy (3 gm/m2 over 3h every 12h, days 1, 3, and 5 for 3 cycles) plus oral midostaurin at 100 mg or 50 mg each twice daily on days 8–21 (sequentially) or days 1–7, 15–21 (concomitantly) with all chemo cycles in newly diagnosed pts under age 61 with de novo AML. Whereas 100 mg of midostaurin plus induction chemotherapy was poorly tolerated due to nausea and vomiting, the 40 pts who received 50 mg of midostaurin orally twice daily ( 20 each on the sequential and concomitant schedules; 27 FLT3–wt; 13 FLT3–mut [9 with an ITD]), tolerated the combination well. Median midostaurin exposure was 133 days (range 21–975) for the FLT3–mut pts and 90 days (range 7–1016) for FLT3–wt pts. Maintenance therapy with midostaurin was allowed with investigator discretion and was received by 5 pts (3 FLT3–mut, 2 FLT–wt). The median ages for the FLT3–wt and FLT3–mut pts were 50 years (range 25–60) and 46 years (range 20–65), respectively. 77% of the FLT3–mut pts displayed normal, 15% adverse and 8% other intermediate cytogenetics compared with 18.5%, 26%, and 26%, respectively, for FLT3-wt (also 18.5% favorable; 11% unknown). Complete response occurred in 32/40 (80%) of all pts (20/27 [74%] of FLT3–wt patients, 12/13 [92%] of FLT3–mut pts). Patients were censored at the last date they were known to be alive with a median post treatment follow-up for FLT3-mut pts of 1059 days and 1086 days for FLT3-wt. Even accounting for their differing cytogenetics and ages, the OS of the FLT3–mut subgroup was expected to be inferior to that of the FLT3–wt subgroup. However, we report that the 1 and 2 year OS for the pts with FLT3–mut AML was 85% and 62%, respectively, and was comparable to that of the FLT3–wt subgroup (81% and 59%, respectively). Although based on small numbers and not stratified for type of FLT3 mutation (TKD, ITD, ITD length, location, or allelic ratio), these long-term results suggest that combination therapy with a FLT3 inhibitor and chemotherapy might be effective enough to obviate the perceived need for allogeneic stem cell transplantation for FLT3–mut AML pts in first complete remission. Moreover, these data support the rationale for the ongoing international phase 3 study of induction, post-remission intensification, and maintenance with midostaurin (50 mg po bid) or placebo. Disclosures:Stone:Novartis: Research Funding, ad hoc consultancy; Cephalon: ad hoc consultancy. Off Label Use: midostaurin with chemothereapy for AML. Paquette:Novartis: Honoraria, Research Funding, Speakers Bureau. Schiller:Novartis: Research Funding, Speakers Bureau; Millenium: Research Funding, Speakers Bureau; Genzyme: Research Funding; Vion: Research Funding; Centocor: Research Funding; Eli Lilly: Research Funding; Celgene: Research Funding. Schiffer:Novartis: Consultancy, Research Funding; Genzyme: Consultancy. Ehninger:Novartis: Honoraria, Research Funding. Cortes:Novartis: Research Funding; Bristol-Myers Squibb: Research Funding; Wyeth: Research Funding. Kantarjian:Novartis: Research Funding. DeAngelo:Bristol-Myers Squibb: Speakers Bureau; Celgene: Speakers Bureau; Enzon: Speakers Bureau; Novartis: Speakers Bureau. Huntsman-Labed:Novartis: Employment, Equity Ownership. Dutreix:Novartis: Employment, Equity Ownership. Rai:Novartis: Employment, Equity Ownership. Giles:Novartis: Research Funding; Merck: Research Funding; Bristol-Myers Squibb: Research Funding; Vion: Research Funding. [Display omitted]

Safety, Feasibility, and Cost-Effectiveness with Outpatient Administration of High-Dose Cytarabine Consolidation in Acute Myeloid Leukemia

Introduction: High-dose cytarabine (HiDAC) consolidation chemotherapy is frequently used in acute myeloid leukemia (AML) patients less than 60 years of age. Traditionally, the potential risk for neurotoxicity, which has been reported to occur in 8–26% of patients, has limited its administration to the inpatient setting with a median length of stay of 5 days. Institutional retrospective data revealed the incidence to be much lower than previously reported with grade III/IV neurotoxicity in only 0.7% of cycles (N=267). As a result, we developed a comprehensive outpatient (OP) approach for the administration of HiDAC utilizing a pre-printed order and monitoring forms, pre-defined eligibility criteria/risk factors, administration/screening checklist, standard ancillary medications, designated scheduling, patient counseling, and written instructions for follow up. The benefits of OP administration may include improved patient satisfaction and decreased institutional costs and constraints on inpatient resources. However, there does not appear to be any published literature to date describing the OP administration of HiDAC. We report herein on the safety, feasibility, and outcomes of 43 patients receiving HiDAC consolidation therapy (n=88 cycles) between September 2006 and July 2008.Methods: Patients < 60 yo received 3 g/m2 over 1 hour every 12 hours on days 1, 3, and 5 and the dose was reduced to 1.5 g/m2 for pts ≥ 60 yo. All cycles of HiDAC were dosed based on age, renal, and hepatic function. There were no empiric dosage adjustments based on renal function alone. Post-treatment, patients received antibiotic prophylaxis and growth-factor support. Patients returned twice weekly for blood work until neutrophil and count recovery.Results: Forty-three patients received 88 cycles of HiDAC as an OP. The median patient age was 49 yrs (23–74) with 16% being over 60. Patient baseline characteristics of the OP group were similar to the inpatient group from our institutional review with respect to age, body surface area, gender, and race. Diagnosis, history of CNS radiation/disease, intrathecal chemotherapy, alcohol abuse, cumulative cytarabine dosage, and concurrent medications were also similar between the two groups. Only 1 patient was ineligible to receive OP therapy which was the result of both renal (estCL < 60mL/min) and hepatic (alk phos > 3X ULN) risk factors. Two patients with moderate renal insufficiency (est CL 30–60 mL/min) received full dose HiDAC without adverse event. All 43 patients successfully completed their full course of therapy. During the 88 cycles, there were no cases of clinically significant neurotoxicity (≥ grade III). There were 3 instances of grade I nystagmus. In all cases, therapy was completed without interruption. Rates of admission to the hospital post HiDAC OP consolidation for neutropenic fever (NF) was comparable to the inpatient group from our institutional review, occurring in 26% and 37% (p=0.07), respectively. All admissions post HiDAC OP was secondary to NF with the exception of one patient who was admitted for mucosal bleeding.Conclusions: In the present analysis, we confirm the safety and feasibility of OP-based HiDAC chemotherapy for the management of AML patients in remission. If patients are dosed and monitored properly, HiDAC can be successfully transitioned to the OP setting. With the implementation of this approach, we have improved patient convenience and satisfaction, decreased pressure on inpatient resources (nearly 450 days of hospital bed use), while maintaining similar rates of hospital re-admission. With proper patient selection, dosing, and education of both providers and patients, HiDAC can be safely administered in the OP setting and has become our standard of care.

Acute myeloid leukemia with t(8;21)(q22;q22) preceded by breast granulocytic sarcoma

Granulocytic sarcoma (GS) is a rare extramedullary tumor mass composed of immature cells derived from the hematopoietic myeloid series. It is usually associated with leukemia and other myeloproliferative disorders but can also occur without overt hematologic diseases. The breast has been reported to be an uncommon site of presentation. We report a case of acute myeloid leukemia preceded by GS of the breast. The immunohistochemistry revealed myeloperoxidase, CD68 and CD43 positivity, thus indicating a diagnosis of GS. Conventional cytogenetic analysis of peripheral blood cells showed t(8;21)(q22;22). Complete remission was achieved with Daunorubicin and Cytarabine induction therapy followed by three courses of high-dose Cytarabine consolidation. The patient remains in continuous complete remission at 27 months.

Patients With Acute Myeloid Leukemia and RAS Mutations Benefit Most From Postremission High-Dose Cytarabine: A Cancer and Leukemia Group B Study

RAS mutations occur in 12% to 27% of patients with acute myeloid leukemia (AML) and enhance sensitivity to cytarabine in vitro. We examined whether RAS mutations impact response to cytarabine in vivo. One hundred eighty-five patients with AML achieving complete remission on Cancer and Leukemia Group B study 8525 and randomly assigned to one of three doses of cytarabine postremission were screened for RAS mutations. We assessed the impact of cytarabine dose on cumulative incidence of relapse (CIR) of patients with (mutRAS) and without (wild-type; wtRAS) RAS mutations. Thirty-four patients (18%) had RAS mutations. With 12.9 years median follow-up, the 10-year CIR was similar for mutRAS and wtRAS patients (65% v 73%; P = .31). However, mutRAS patients receiving high-dose cytarabine consolidation (HDAC; 3 g/m(2) every 12 hours on days 1, 3, and 5 or 400 mg/m(2)/d x 5 days) had the lowest 10-year CIR, 45%, compared with 68% for wtRAS patients receiving HDAC and 80% and 100%, respectively, for wtRAS and mutRAS patients receiving low-dose cytarabine (LDAC; 100 mg/m(2)/d x 5 days; overall comparison, P < .001). Multivariable analysis revealed an interaction of cytarabine dose and RAS status (P = .06). After adjusting for this interaction and cytogenetics (core binding factor [CBF] AML v non-CBF AML), wtRAS patients receiving HDAC had lower relapse risk than wtRAS patients receiving LDAC (hazard ratio [HR] = 0.67; P = .04); however, mutRAS patients receiving HDAC had greater reduction in relapse risk (HR = 0.28; P = .002) compared with mutRAS patients treated with LDAC. AML patients carrying mutRAS benefit from higher cytarabine doses more than wtRAS patients. This seems to be the first example of an activating oncogene mutation favorably modifying response to higher drug doses in AML.

Prolonged Monthly Myelosuppressive Maintenance Chemotherapy in Acute Myeloid Leukemia: The AMLCG Experience.

We have previously shown that a monthly myelosuppressive chemotherapy proved superior to high-dose cytarabine consolidation therapy (J Clin Oncol 2003, 21:4496) after induction therapy and induction-type consolidation therapy. In the multicenter AMLCG 1999 trial, we reported that this maintenance therapy resulted in equal results with lower therapy-related morbidity and death-rate compared to autologous stem cell transplantation in patients <60 years of age. However, data about the feasibility and compliance of this prolonged maintenance therapy are still lacking. In the AMLCG 1999 trial, patients <60 years of age were randomized upfront to receive either an autologous stem cell transplantation or a maintenance therapy for three years from achievement of complete remission after consolidation therapy TAD. Patients ≥60 years of age were assigned to maintenance therapy following consolidation therapy. Maintenance courses were araC 100mg/m2 q 12 hr sc × 10 and either daunorubicin 45mg/m2 × 2 (AD), or thioguanine 100mg/m2 q 12hr × 10 (AT), or cyclophosphamide 1g/m2 iv (AC), and again AT-AD-AT-AC-. In patients with a leukopenia <1.000/μl or thrombocytopenia <20.000/μl after two following cycles, dosage was permanently reduced by 50%. Of all patients who achieved a CR before July 1st 2004, 269 patients <60 years were randomized to receive maintenance, and all 423 patients ≥60 years were assigned to maintenance. Out of the 692 patients, 211 patients (30.5%) did not receive maintenance therapy due to: allogeneic (49, 7.1%) or autologous (6, 0.9%) stem cell transplantation, early relapse (52, 7.5%), withdrawal of consent (17, 2.5%), medical reasons other than relapse (53, 7.7%), other reasons not classified (7, 1.0%) or death in CR (27, 3.9%). In 78 patients (11.3%) the application of maintenance therapy cannot be followed due to loss of follow-up or incomplete documentation. For the remaining 403 (58.2%) patients with a documented start of the maintenance therapy, the median number of maintenance courses applied was 6 (1st to 3rd quartile: 2–16) over a median duration from achievement of CR of 10 months (1st to 3rd quartile: 5–24). Due to fixed dose adjustment rules, the median dosage of the applied chemotherapy declined from 90.5% (range 8.2–183.3%) in the first course to 47.1% (range 6.6–128.6%) in the third course. From the fifth course on, the median dosage was between 22.2 and 26.3%. Out of the 403 patients who started maintenance, therapy was terminated early in 346 patients (85.9%) due to: an allogeneic stem cell transplantation in 1st CR (3 patients, 0.7%); relapse (175, 43.4%); withdrawal of consent (17, 4.2%); medical reasons other than relapse (72, 17.9%); other reasons not classified (13, 3.2%), loss of follow-up or incomplete documentation (56, 13.9%); and death in CR (10, 2.5%). Of the latter, 5 patients (1.2%) succumbed to therapy-related death. Of the 129 patients experiencing a relapse free survival of ≥ three years, the median number of applied courses was 20 (1st to 3rd quartile: 4–29) over a median duration of 31 months after achieving CR (1st to 3rd quartile: 11–36). Taken together, this results show that a prolonged monthly myelosuppressive maintenance therapy as part of a postremission therapy in AML is feasible and shows a high compliance and acceptance among patients.

A phase III randomized trial of intensive induction and consolidation chemotherapy ± oblimersen, a pro-apoptotic Bcl-2 antisense oligonucleotide in untreated acute myeloid leukemia patients &gt;60 years old

7012 Background: Overexpression of Bcl-2, an inhibitor of apoptosis, may render AML cells resistant to chemotherapy and has been associated with unfavorable outcome. Genasense is a phosphorothioate 18-mer antisense oligonucleotide directed against the first 6 codons of Bcl-2. In a phase I study of older (≥60 yrs) AML patients (pts) treated with Genasense in combination with cytarabine (Ara-C) and daunorubicin (DNR) induction and with high-dose cytarabine (HiDAC) consolidation, no antisense-related toxicity was reported. Furthermore, overexpression of Bcl-2 at diagnosis and down-regulation of the Bcl-2 target after antisense treatment was shown in pts achieving complete remission (CR). Methods: A phase III trial (CALGB 10201) randomized untreated older AML pts to induction treatment with Ara-C (100 mg/m2/d by CIVI on days 4–10) and DNR (60 mg/m2/d on days 4–6) followed by consolidation therapy with HiDAC (2 g/m2/d on days 4–8) with (Arm A) or without (Arm B) Genasense (7 mg/m2/d CIVI on days 1–10 for induction and days 1–8 for consolidation). The study was powered to identify a survival advantage for pts receiving Genasense. Results: 503 pts enrolled between 12/03 and 10/06; 76 had prior MDS and 24 prior chemoradiotherapy for unrelated cancers. The arms were balanced for age, sex, race, and performance status. No differences in toxicities were observed between the 2 arms. An interim futility analysis performed at 34 months from initiation of the study showed no differences in CR rates (48% vs 52%; p=0.75) or overall survival (OS; p=0.83) between the 2 arms. Estimated OS at 1 yr was 36% for Arm A and 40% for Arm B. Similarly, there were no differences in disease-free survival from date of CR (DFS; p=0.78) or event-free survival (EFS; p=0.77). DFS and EFS rates at 1 yr were 40% and 25% for Arm A, and 43% and 7% for Arm B, respectively. Conclusions: Addition of Genasense to induction and consolidation chemotherapy failed to improve the outcome of older AML pts. Pretreatment levels and post-antisense treatment changes in Bcl-2 expression are now being measured and correlated with outcome. No significant financial relationships to disclose.

Phase IB Study of PKC412, an Oral FLT3 Kinase Inhibitor, in Sequential and Simultaneous Combinations with Daunorubicin and Cytarabine (DA) Induction and High-Dose Cytarabine Consolidation in Newly Diagnosed Adult Patients (pts) with Acute Myeloid Leukemia (AML) under Age 61.

FLT3 (fms-like tyrosine kinase) activating mutations, either an ITD (repeat of 3->100 amino acids in the juxtamembrane region) or a point mutation in the activation loop, occur in blasts from 30% of AML patients (pts). ITD mutations are associated with a relatively poor prognosis. PKC412 is a multi-targeted kinase inhibitor that has clinical activity in mutant (reduction in peripheral blasts in 70%) and wild type (reduction in peripheral blast in 30%) FLT3 AML, but rarely produces complete remissions (Stone et al, Blood 2005; Estey et al, ASH 2003). We conducted a phase Ib trial with DA (daunorubicin 60 mg/m2 d 1–3 and cytarabine 100 mg/m2/d by IVCI x 7d) induction and post-remission therapy (cytarabine 3 gm/m2/3h q 12h, d1,3, and 5 for 3 cycles) plus PKC412 at 100 mg bid po continuously beginning on day 8 (arm 1) or day 1 (arm 2) (n=15) or an amended schedule: day 8–21 (arm 1) or day 1–7, 15–21 (arm 2) (n=15) in previously untreated adult AML pts ≤ age 60. Results demonstrated safety, but poor tolerability due to nausea and vomiting (Giles, et al, ASH 2004). The study was then amended to include the same chemotherapy, but with 50 mg PKC412 po bid (previously shown to lead to plasma levels sufficient to inhibit FLT3) on day 8–21 (arm 1) or day 1–7, 15–21 (arm 2); tolerability improved to acceptable levels with no patients withdrawing due to nausea, vomiting, or diarrhea (Stone at al, ASH 2005). The study has completed accrual (40 pts enrolled after the PKC412 50 mg po bid amendment) with 38 pts (26 with wild type FLT3 (FLT3wt) blasts and 12 with mutated FLT3 (FLT3mut) blasts) evaluable for efficacy and 37 pts for safety. Complete response (CR) occurred in 27/38 (71%). The CR rate in FLT3wt pts was 18/26 (69%); 9/13 (69%) pts achieved CR in each of the arms. CR occurred in 11/12 (92%) FLT3mut pts. CR rate in FLT3mut pts was 7/7 (100%) in Arm 1 and, 4/5 (80%) in arm 2. 4/11 CR pts relapsed after 7, 7, 10 and 15 months; 7 pts remain in first CR for 3–15 months. No drug-related deaths were reported. One patient withdrew due to Grade 4 increase in alkaline phosphatase. The most common serious Grade 3–4 side effects reported to date include thrombocytopenia 6/19 (31.5%), anemia 5/19 (26%) and neutropenia 5/19 (26%) in pts on arm 1; thrombocytopenia 2/18 (11%), anemia 1/18 (5.5%) and neutropenia 2/18 (11%) in pts on arm 2. All Grade 3–4 events were transient and/or reversible. No Grade 3 or 4 nausea and vomiting occurred in either arm. In conclusion, PKC412 at 50 mg po bid can be given safely and tolerably in newly diagnosed adult AML pts ≤ 60 years old in combination with DA and high dose cytarabine. The CR rate and preliminary DFS in FLT3mut pts is encouraging. A phase III study of chemotherapy +/− PKC 412 at 50 mg po bid on d8–21 per cycle in newly diagnosed pts ages 18–60 with mutant FLT3 AML is planned.

Minimal Residual Disease (MRD) Monitoring in CBFB-MYH11 Acute Myeloid Leukemia (AML) Is of Prognostic Relevance for Relapse-Free Survival.

Detection of minimal residual disease (MRD) in acute myeloid leukemia (AML) associated with specific gene fusions is an important tool for the assessment of response to treatment and the individual risk of relapse. The real-time quantitative RT-PCR (RQ-PCR) method allows the quantification of fusion transcript levels at distinct time points during treatment. While in acute promyelocytic leukemia (APL) MRD monitoring has been clearly shown to be predictive for clinical outcome, the prognostic value of MRD in CBFB-MYH11 AML could not consistently been demonstrated yet. Small patient populations and the availability of bone marrow (BM)/peripheral blood (PB) samples at defined time points mainly hamper most studies. We evaluated the prognostic impact of MRD in a large cohort of CBFB-MYH11 AML by RQ-PCR. A total of 44 patients (16–60 years) were treated within one of the AMLSG treatment trials (AMLHD93 n=4, AMLHD98A n=27, AMLSG07-04 n=13). Patient samples (BM and/or PB) were collected at study entry (n=75), during treatment (n=199), and during follow up (n=140). Following high-dose cytarabine (HiDAC) consolidation therapy, patients received a second course of HiDAC (n=25); autologous stem cell transplantation (SCT) (n=13) or allogeneic SCT from a matched related family donor (n=6) depending on the treatment protocol. Median follow up was 22.5 months. Quantitative CBFB-MYH11 fusion transcript expression was measured by RQ-PCR using TaqMan technology. Primers and probes were chosen according to Europe Against Cancer (EAC) standard protocols. Sensitivities ranged from 10−3 to 10−4.Transcript levels at diagnosis ranged from 6208 to 312987 (median 34293.5). There was no prognostic impact of pretreatment transcript levels on relapse free survival (RFS). The ratio of transcript levels after 2 induction cycles and pretreatment levels ranged from 0 to 0.0049; again, this ratio had no impact on RFS. In contrast, during consolidation therapy 63% of the patients became RQ-PCR negative and RFS was significantly superior (RFS after 2 years 75%) compared to RQ-PCR positive patients (RFS after 2 years 32%) (p=0.03). After consolidation, seven of the RQ-PCR negative patients became positive at least in one BM-sample during follow up. Four patients developed transcript levels above 10 and all relapsed, whereas the three patients with transcript levels remaining below 10 are in continuous remission (p=0.0001). In our study, transcript levels during and after consolidation therapy are significantly associated with clinical outcome in CBFB-MYH11 AML. Risk-adapted therapy may be considered for those patients remaining positive during consolidation therapy. The identification of transcript levels above 10 after consolidation therapy might allow early treatment decisions.

Granulocytic sarcoma of mesentery in acute myeloid leukemia with CBFB/ MYH11 fusion gene but not inv(16) chromosome: Case report and review of literature

Granulocytic sarcoma (GS) is a rare extra-medullary tumor and usually involves the skin, soft tissue, and lymph nodes. GS is found in 8% of acute myeloid leukemia (AML) patients, especially patients with t(8;21)AML. It has been suggested that GS is a poor prognostic factor in t(8;21)AML. Compared to t(8;21)AML, GS is rare in cases of inv(16)AML. Thus, the characteristics of inv(16) with GS are not well understood. Here, we describe a patient with AML and mesentery GS. The chromosomal analysis was normal, but molecular analysis detected the CBFB/ MYH11 fusion gene in the blasts. A complete remission was achieved with standard induction therapy followed by high-dose cytarabine consolidation. We have also summarized 12 reported cases of inv(16)AML with GS and found that GS was commonly found in abdominal lesions. These observations suggest that when abdominal GS is diagnosed, an analysis of the CBFB/ MYH11 fusion gene is necessary to make an appropriate decision regarding treatment options, even if no chromosomal abnormalities are found.

De novo acute myeloid leukemia in adults younger than 60 years of age: Socioeconomic aspects and treatment results in a Brazilian university center

We retrospectively studied the outcomes of adults with de novo acute myeloid leukemia treated in a reference center in Brazil and analyzed the association with the human development index (HDI) of the United Nations used as a socioeconomic factor. Among 123 patients, 46 (37%) died during induction, 65 (53%) reached complete remission and 45 (37%) received high-dose cytarabine (Hidac) consolidation. The 5-year overall survival and leukemia-free survival (LFS) were 17 and 26%, respectively, for all patients and 36 and 30%, respectively, for those receiving Hidac. In multivariate analysis, an HDI <0.660 was associated with a lower probability to receive Hidac (P = 0.001), a trend for higher mortality in remission induction (P = 0.062) and a decreased LFS (P < 0.0001). However, it was not associated with outcomes for patients receiving Hidac. In conclusion, survival for patients who received Hidac consolidation is satisfactory; however, socioeconomic factors may have selected patients to receive intensive Hidac consolidation.

Phase IB Study of PKC412, an Oral FLT3 Kinase Inhibitor, in Sequential and Simultaneous Combinations with Daunorubicin and Cytarabine (DA) Induction and High-Dose Cytarabine Consolidation in Newly Diagnosed Patients with AML.

Activating mutations in FLT3 (fms-like tyrosine kinase), either an ITD (repeat of 3–33 amino acids in the juxtamembrane region) or a point mutation in the activation loop, occur in blasts from 30% of AML patients, are associated with poor prognosis, and represent an attractive therapeutic target. PKC412 is a multi-targeted kinase inhibitor which has clinical activity in mutant (reduction in peripheral blasts in 70%) and wild type (reduction in peripheral blast in 30%) AML, but rarely produces remissions (Stone et al, Blood 2005; Estey et al, ASH 2003). We combined DA induction (daunorubicin 60 mg/m2 d 1–3 and cytarabine 100 mg/m2/d by IVCI x 7d) and post-remission therapy (cytarabine 3 gm/m2/3h q 12h, d1,3,5 for 3 cycles) plus PKC412 in previously untreated AML patients less than or equal to age 60 in a phase Ib trial. Results with the original dose schedules of PKC 412: 100 mg po bid from day 8 continuously (arm 1) or day 1 continuously (arm 2) (n=15) or an amended schedule: day 8–21 (arm 1) or day 1–7, 15–21 (arm 2) (n=15) demonstrated safety, but poor tolerability due to nausea and vomiting (Giles, et al, ASH 2004). We now report results with a new amendment in which pts receive the same chemo regimen plus PKC412 at a reduced dose of 50 mg po bid (previously has been shown that PKC at 50 mg bid produces plasma levels sufficient to inhibit FLT3) on day 8–21 (arm 1) or day 1–7, 15–21 (arm 2).None of the 19 pts treated to date have had drug-related death; the most common drug related toxicities during induction and consolidation cycles were nausea (53%), vomiting (47%), ALT increase (32%), AST increase (26%), diarrhea (26%) and rash (21%); all were transient and/or reversible. No Grade 3 or 4 nausea and vomiting were recorded. As of this report, 4 pts have completed the study, and 7 pts are still on study receiving consolidation after achieving CR. Causes of discontinuation include resistant disease (5), transplant after achieving CR (2), and non-drug related toxicity of sepsis and neutropenia (1). All 19 patients are evaluable for response: 9/12 (75%) achieved CR in Arm 1 and 5/7 (71%) achieved CR in Arm 2. Six out of six (100%) FLT3mut patients and 8/13 (62%) FLT3WT patients achieved CR. When a comparison of CR rate is made across all 49 patients in this study overall, there was a significant difference between the FLT3WT CR = 17/32 (53%), and FLT3mut CR=10/11 (91%) (p=0.033 by Fischers exact test). Median follow-up is short, 5 months (1–15). All ten FLT3mut patients that entered CR are alive with only one known relapse (at 15 months post-CR). Conclusions: PKC412 at 50 mg po bid can be given safely and tolerably in newly diagnosed ≤ 60 years old AML patients in combination with DA and high dose cytarabine. These combinations merit further study especially in patients with mutant FLT3 AML.

Myelodysplastic syndrome of donor origin subsequent to successful treatment of myeloid/NK-cell precursor leukaemia with allogeneic PBSCT: two very rare conditions in one patient

We report a 36-year-old male with myeloid/natural killer (NK)-cell precursor acute leukaemia with a complex aberrant karyotype, who was treated according to an acute-myeloid-leukaemia (AML) treatment protocol (idarubicine, cytarabine, and etoposide) followed by high-dose cytarabine consolidation and achieved complete remission. He underwent allogeneic matched unrelated donor (MUD) peripheral blood stem-cell transplantation (PBSCT) and remained in remission throughout his remaining life. Seven months posttransplantation, a myelodysplastic syndrome (MDS) with (20q-) of donor origin was diagnosed causing severe thrombocytopenia and finally leading to infection and death. This patient represents one of the few cases published achieving remission for a significant period of time after being diagnosed with myeloid/NK-cell precursor acute leukaemia, a very rare malignant disease. We conclude, despite the fatal outcome due to infection, that allogeneic PBSCT is a therapeutic option for patients with this entity. In addition, the development of a myelodysplastic syndrome of donor origin is extremely rare and only very few cases are published worldwide.