Acute Myeloid Leukemia Who Research Articles

Prognostic Factors For Children With Acute Myeloid Leukemia Who Achieve Minimal Residual Disease-Negative Status After Induction Therapy

BackgroundDespite successful remission induction, a significant proportion of children with acute myeloid leukemia (AML) experience relapse. In our previous AML02 study, adjusting treatment intensity according to levels of minimal residual disease (MRD) after remission induction has contributed to improved outcome. Because relapse still occurred in a proportion of patients who achieved MRD-negative status after remission induction therapy, we searched for presenting features associated with outcome in this patient cohort. ObjectivesTo identify presenting features predictive of relapse among children with newly diagnosed AML who achieve MRD-negative status after remission induction therapy. MethodsAmong patients enrolled in AML02 who were MRD-negative (<0.1% leukemic cells among bone marrow mononuclear cells by flow cytometry) at the end of remission induction therapy, we evaluated the association between presenting features [age, gender, race, WBC count, 11q23 non-t(9;11), acute megakaryoblastic leukemia (AMKL) without t(1;22), FLT3-ITD, CBF rearrangement [t(8;21), inv(16)/t(16;16)], and provisional risk classification at study entry as defined by cytogenetics and AML FAB subtype] and risk of relapse. Event free survival (EFS) and overall survival (OS) were analyzed by a Cox proportional regression model. A stepwise model selection of predictors identified in the univariate analysis was then performed in the multivariate analysis. ResultsOf the 197 patients enrolled in AML02 with evaluable bone marrow after induction I, 126 (64%) had negative MRD. Three-year EFS for this group was 75.4% and OS was 82.5%. Of the 193 patients evaluable for MRD after induction II, 155 (80.3%) had negative MRD and their 3-year EFS and OS were 71.6% and 78.1%, respectively. Patients with negative MRD had significantly better EFS and OS than those with positive MRD in each course.In a univariate analysis, 11q23 non-t(9;11), AMKL without t(1;22), or standard risk (compared to low risk) were associated with an inferior EFS (p <0.05) among patients with negative MRD after induction I and/or induction II. In a multivariable analysis performed with the cohort of 126 patients who achieved MRD negativity after induction I, a worse outcome was associated with 11q23 non-t(9;11) (HR 3.21, p =0.021 for EFS; HR 5.84, p =0.005 for OS), AMKL without t(1;22) (HR 7.83, p =0.034 for OS), and age ≥ 10 years (HR 5.97, p<0.001 for EFS; HR 10.05, p <0.001 for OS). The same factors also emerged as significant predictors of adverse outcome in a multivariable analysis focused on patients who were MRD negative after induction II: 11q23 non-t(9;11) (HR 3.48, p =0.01 for EFS; HR 5.82, p =0.003 for OS), AMKL without t(1;22) (HR 4.43, p =0.016 for EFS; HR 9.7, p =0.002 for OS), and age ≥10 years (HR 3.83, p =0.003 for EFS; HR 4.13, p =0.014 for OS). Black race also predicted a worse EFS for patients who were MRD negative after induction II (HR 3.1, p =0.01). In contrast, patients with CBF rearrangement had significantly better outcomes: EFS (HR 0.18, p =0.003) and OS (HR 0.15, p =0.021) after induction I and EFS (HR 0.15, p =0.001) and OS (HR 0.22, p =0.025) after induction II. ConclusionsAmong children with AML who achieve MRD negativity after remission induction therapy, 11q23 non-t(9;11), AMKL without t(1;22), and age ≥ 10 years are associated with a higher risk of relapse. Close post-remission MRD monitoring for detection of emerging relapse and complementary molecular methods of MRD detection might be indicated in these patients. Disclosures:No relevant conflicts of interest to declare.

Expectations of Serious Adverse Events at the End of Life of Patients With Acute Myeloid Leukemia Who Receive Salvage Therapy

Patients with AML and refractory disease receive investigational therapies within 2 months of their death. The attribution of serious AEs in this phase to disease progression vs. drug toxicity is tenuous. We aimed to determine the incidence of serious AEs in the last 2 weeks of life of patients with refractory-relapsed AML undergoing salvage therapy (ST). Adults who received ST from September 2010 to December 2011 were evaluated. Data collected included incidence of serious AEs, type of ST, medical complications, length of hospital stay, and Intensive Care Unit stays, organ dysfunctions, and use of life support therapies. A total of 122 patients received ST. Most 64 patients (52%) received intensive chemotherapy; 39 patients (32%) had single investigational drug therapies, and 19 patients (16%) received therapy with hypomethylating agents. Common complications were pneumonia (82%), disseminated intravascular coagulopathy 72 patients (59%), and septic shock 60 patients (49%). Notable complications included: acute respiratory failure justifying invasive mechanical ventilation in 60 patients (42%), renal failure requiring dialysis in 33 patients (27%), atrial fibrillation in 37 patients (30%), and prolonged prothrombin time (grade 3) in 68 patients (56%). There was no difference in the incidence of these complications by type of ST. Baseline expectations of serious AEs at the end of life of patients with AML undergoing ST were established. The AE profiles of new investigational interventions or therapies could be compared with what would be expected in such circumstances from the combined effect of disease progression, expected complications of the AML therapy, and therapies delivered in previous historical contexts.

TREATMENT OF ACUTE MYELOID LEUKEMIA WITH 20-30% BONE MARROW BLASTS

The transition of patients with ≥20% <30% bone marrow (BM) blast from the FAB category of myelodysplasia to the family of acute myeloid leukemia (AML) according to the recent WHO classification has not resolved the argument as to whether the natural history and responsiveness to therapy of these diseases is comparable to that of AML with > 30% BM blast. These controversies are even more manifest when it comes to elderly patients in whom concern for intensive chemotherapy (IC) related toxicity is the critical determinant for the therapeutic choice. In fact, due to concerns of treatment-related morbidity and mortality associated with delivery of IC, approximately only 30% of all patients ≥65 years are considered eligible for this approach. Therefore, a great deal of attention has been dedicated to alternative agents such as hypomethylators (azacitidine and decitabine). Actually, these agents have shown efficacy with reduced toxicity when administered to elderly patients with 20–30% BM blasts and not eligible for IC. In the present review, we will discuss the clinical results achieved in the treatment of elderly patients with 20%–30% BM blasts AML using intensive chemotherapy (IC) or hypomethylating agents. Overall, our survey of the literature suggests that only controlled, randomized, clinical trials will answer the question as to whether hypomethylating agents has the potential to substitute for IC even in elderly patients with an optimal functional status.

Curability of Patients With Acute Myeloid Leukemia Who Did Not Undergo Transplantation in First Remission

The aims of this study were to quantify the prospects of salvage treatment of patients who did not undergo transplantation in first complete remission (CR1) and to assess the contribution of allograft in second complete remission (CR2) with respect to major risk groups. This evaluation can inform the decision whether to offer a transplant in CR1. Of 8,909 patients who entered the Medical Research Council AML10, AML12, and AML15 trials, 1,271 of 3,919 patients age 16 to 49 years who did not receive a transplant in CR1 relapsed. Of these patients, 19% are alive beyond 5 years compared with 7% of patients who relapsed after an allograft in CR1. Overall survival and the contribution of a transplant in CR2 were assessed overall and by cytogenetic risk group by using Mantel-Byar analysis. Fifty-five percent of patients who relapsed entered CR2. This percentage varied by risk group as follows: favorable (82%), intermediate (54%), adverse (27%), and unknown (53%), which resulted in 5-year survivals of 32%, 17%, 7%, and 23%, respectively. Sixty-seven percent of remitters received an allotransplant that delivered superior survival compared with patients who did not receive a stem-cell transplant (42% v 16%). A more-stringent assessment of a transplant by using delayed-entry (Mantel-Byar) analysis confirmed the benefit of transplant overall and within intermediate and adverse risk groups but not the favorable subgroup. Successful salvage treatment of patients who do not undergo transplantation in CR1 and relapse can be achieved in 19% of patients, which is improved by a transplant except in favorable risk disease. This result suggests that, for intermediate-risk patients in particular, equivalent overall survival can be achieved by delaying transplantation until after relapse, which would require many fewer transplants.

A Phase II Study of Elacytarabine/Idarubicin As Second Course Remission-Induction in Patients with Acute Myeloid Leukemia Who Failed Cytarabine/Anthracycline

AbstractAbstract 46 BackgroundElacytarabine, a fatty acid derivative (elaidic acid ester) of cytarabine, has pharmacokinetic and pharmacodynamic properties that may lead to improved clinical outcomes (Adema et al., 2011) compared to cytarabine. A phase I study had established 1000 mg/m2/d continuous infusion on d 1 – 5 as a safe and effective dose of elacytarabine given in combination with idarubicin at 12 mg/m2/d IV d 1 – 3 (Giles et al., 2012). Mechanism of ActionThe mechanism of action is similar to cytarabine, but unlike cytarabine, plasma elimination half-life is long, intracellular distribution is prolonged and activity is independent of membrane nucleoside transporters. Resistance to cytarabine has been associated with decreased expression of the human equilibrative nucleoside transporter 1 (hENT1) (Hubeek et al., 2005). AimsThe aim of the study is to determine the efficacy and safety of elacytarabine given in combination with idarubicin; to explore the relationship between the hENT1 status in AML cells and response to cytarabine and to elacytarabine; to evaluate the safety and toxicity of the combination therapy. MethodsAdult patients with AML who have not attained blast clearance after the first induction course with a standard dose cytarabine based regimen, assessed from day 12 on, were enrolled in the study. Patients received a combination of elacytarabine and idarubicin scheduled as described above, as second induction course. Patients treated with further courses received either the combination therapy or elacytarabine monotherapy at 2000 mg/m2/d on d 1 – 5, at the investigator‘s discretion.hENT1 expression level was analysed retrospectively by immunocytochemistry at time of initial AML diagnosis (pre-therapeutic) and/or before elacytarabine/idarubicin treatment (baseline). ResultsIn the on-going study which will recruit up to 50 evaluable patients, 47 patients [27 male, 20 female, median age 60 years (range 18–78), ECOG 0–2] have currently been treated. 40 patients have been evaluated for response, of whom 35% suffered from secondary leukemia. Median time from start of first induction course to start of elacytarabine treatment was 36 days (range 13 – 189).After treatment with elacytarabine and idarubicin, 18/40 evaluable patients attained a CR/CRi. Median time to remission was 36 days (range 25 – 60).Incidence of low hENT1 expression was approximately 50%. Preliminary data shows a higher response rate of elacytarabine compared to cytarabine in this low hENT1 population (47% versus 37%).The most frequently reported non haematological adverse events grades 3 and 4 were fatigue, infections/sepsis, hypoalbuminaemia, hypokalaemia and hypoxia.Three deaths occurred within 30 days after start of treatment, all due to sepsis. Additional two patients died from progressive AML within 60 days after start of treatment. All these five patients suffered from secondary leukaemia. Summary/ConclusionAt the time of this abstract (August 2012) elacytarabine in combination with idarubicin shows a promising clinical activity with a CR/CRi rate of approximately 45% in patients failing a first induction course. Low expression of the hENT1 transporter is associated with a lower probability of achieving remissions following cytarabine treatment. Preliminary data indicates that assessment of hENT1 expression in blast cells could be used to identify patients less likely to benefit from cytarabine and for whom elacytarabine could be an effective therapy. The emerging safety profile is as expected for these groups of cytotoxic therapies. Results of the completed study will be presented at the meeting. Disclosures:Kindler:Novartis: Honoraria. Johansen:Clavis Pharma: Employment. Bergeland:Clavis Pharma: Employment. Gianella-Borradori:Clavis Pharma: Employment. Flem Jacobsen:Clavis Pharma: Employment. Rao:Clavis Pharma: Honoraria.

A Phase II Study of Elacytarabine/Idarubicin As Second Course Remission-Induction in Patients with Acute Myeloid Leukemia Who Failed Cytarabine/Anthracycline, and Evaluation of the Impact of the Nucleoside Transporter hENT1 on Response

Abstract 1533 Background:Elacytarabine is a fatty acid derivative (elaidic acid ester) of cytarabine. The mechanism of action is similar to cytarabine, but unlike cytarabine, cellular uptake and activity of elacytarabine are independent of nucleoside transporters. Resistance to cytarabine has been associated with decreased expression of the human equilibrative nucleoside transporter 1 (hENT1) (Hubeek et al., 2005). An agent such as elacytarabine, active in low hENT1 expressing, cytarabine resistant acute myeloid leukemia (AML), could therefore improve clinical outcome in patients. Aims:To determine the efficacy and safety of elacytarabine given in combination with idarubicin to patients who have failed the first ”standard” induction course with a cytarabine based regimen, as well as to explore the relationship between the hENT1 status in AML cells and response. Methods:Study therapy consisted of one course elacytarabine 1000 mg/m2/d CIV on d1-5 administered in combination with idarubicin 12 mg/m2/d IV d1-3 in adult patients with AML who after a first cytarabine based induction course have not attained blast clearance (bone marrow (BM) >5 % blasts, circulating blasts, or chloroma etc). Assessment of response was at least 12d after induction start. Responding patients could receive the same course or elacytarabine 2000 mg/m2/d CIV on d1-5 d and then consolidation therapy with two courses of either elacytarabine monotherapy or combination with idarubicin as described above or could proceed to allogeneic SCT at any time point. The hENT1 expression level of BM blasts was analyzed by immunocytochemistry at time of initial AML diagnosis (pre-cytarabine course) and/or before elacytarabine treatment.The planned sample size is 50 evaluable patients, and with a target of 40% CR/CRi rate, the lower limit of the 90% confidence interval for the CR/CRi rate will be greater than 22% with at least 80% probability. The CR/CRi rate will be estimated and its corresponding two-sided 90% confidence interval will be provided.The significance of the association between the hENT1 expression level and response status will be assessed through a Chi-square test of hENT1 expression level (high, low) versus CR/CRi (yes, no). Results:In the ongoing study, 26 patients [16 male, 10 female, median age 61 years (range 18–71), ECOG PS 0–2] have been treated with elacytarabine and idarubicin. 23 patients have currently been response evaluated, and 11 attained a CR/CRi and 3 a PR (post one elacytarabine course). The most frequently reported related non-hematologic adverse events (AEs) CTCAE grade ≥ 3 were febrile neutropenia, infections/sepsis and increased liver function tests. 30 patients have been scored for hENT1 expression level at time of diagnosis. Preliminary results indicate that approximately 50 % of the patients hENT1 expression is low (defined as less than 10% of blasts stained). As to response, only approximately 1/3 of patients with low hENT1 blasts respond to cytarabine while for the high hENT1 2/3 respond.Three deaths occurred within 30 days after start of treatment and were all due to sepsis. All 3 patients had secondary leukemia. Summary/Conclusion:Elacytarabine administered at 1000 mg/m2/d CIV d1-5 in combination with idarubicin 12mg/m2/d IV d1-3 showed promising clinical activity with a CR/CRi rate of approximately 45 %. The adverse event profile, is as expected for cytarabine combination therapy. Preliminary data indicate that the assessment of hENT1 transporter expression in blasts could be used to select patients less likely to benefit from cytarabine and for whom elacytarabine could be an effective therapy. Disclosures:Gianelli-Borradori:Clavis Pharma: Employment. Flem Jacobsen:Clavis Pharma: Employment. Krug:MedA Pharma: Honoraria; Novartis: Honoraria; Alexion: Honoraria; Boehringer Ingelheim: Research Funding; Sunesis: Honoraria.

Identifying Older Patients With Acute Myeloid Leukemia Who May Be Candidates for Reduced-Intensity Hematopoietic Cell Transplantation

Recent studies show that with reduced-intensity and nonmyeloablative conditioning regimens, allogeneic hematopoietic cell transplantation can now be performed with relative safety in patients with acute myeloid leukemia up to 75 years of age, and therefore chronologic age itself should no longer be considered a contraindication for this procedure. Best results are generally seen in patients undergoing transplant during first remission. Results appear superior to what might be expected with conventional chemotherapy but prospective randomized trials have not been completed. If a decision is made to delay transplant until first relapse, a careful monitoring plan should be established.

2008 WHO Classification of Pediatric AML.

AbstractAbstract 1044 Background:Acute myeloid leukemia (AML) represents approximately 15% of cases of childhood leukemia. In children, overall survival rates have improved to 65% but early relapse and poor response to induction therapy are significant reasons for failure. The classification of AML has evolved from the FAB system based on morphology, to the more prognostically useful 2008 WHO Classification based upon morphology, cytogenetics and molecular features (Vardiman JW et al, Blood. 114 p.937 (2009)). As the classification relied heavily on data from adults, the epidemiology and prognostic significance of these categories in children remains to be fully explored. In the current study we review 106 consecutive cases of AML diagnosed between 1993–2010 at Lucile Packard ChildrenÕs Hospital and classify them according to the 2008 WHO AML categories. Methods:A retrospective chart review was performed. Data on karyotype, treatment, remission status or death was recorded. Bone marrow morphology was reviewed for all cases lacking a recurrent genetic abnormality and DNA was recovered from archived bone marrow aspirate smears for PCR analysis of NPM1, CEBPA and FLT-3 ITD. Results:Our cohort consisted of 54 (51%) females and 52 (49%) males. Overall survival at 4 years was 58.3% (Figure 1). The breakdown of subgroups according to the WHO 2008 Classification is outlined in Table 1.Table 1Classification of 106 cases of pediatric AMLClassificationNo. of pts% of total (106)AML with recurrent genetic abnormalities5249AML with t(8;21)(q22;q22); RUNX1-RUNX1T11514AML with inv(16)(p13.1q22) or t(16;16)(p13.1;q22);CBFB-MYH1133Acute promyelocytic leukemia with t(15;17)(q22;q12);PML-RARA109AML with t(9;11)(p22;q23);MLLT3-MLL88AML with t(6;9)(p23;q34); DEK-NUP21422AML with inv(3)(q21q26.2) or t(3;3)(q21;q26.2); PRN1-EVI100AML (megakaryoblastic) with t(1;22)(p13;q13); RBM15-MKL144Provisional entity: AML with mutated NPM1/FLT-3 wild type77Provisional entity: AML with mutated NPM1/FLT-3 ITD22Provisional entity: AML with mutated CEBPA11AML with myelodysplasia-related changes1211Therapy-related myeloid neoplasms1110AML NOS1716AML with minimal differentiation00AML without maturation22AML with maturation00Acute myelomonocytic leukemia22Acute monoblastic /moncytic leukemia22Acute monoblastic/monocytic leukemia with t(v;11q23)66Acute erythroid leukemia, with t(v;11q23)11Acute megakaryoblastic leukemia44Acute leukemia of ambiguous lineage11Myeloid sarcoma, not otherwise classified11Myeloid leukemia associated with Down Syndrome1211 [Display omitted] Discussion:Our results vary from the adult literature, reflecting the increased prevalence of AML with recurrent genetic abnormalities, with some categories occurring almost exclusively in children, such as t (1;22) and t(9;11). Data from cases without one of the seven recurrent cytogenetic abnormalities shows a similar frequency to that seen other pediatric series (Manola. Euro J Haematol 83 p.391 (2009)). Twelve cases (11%) fall under the diagnosis of AML with myelodysplasia related changes, the majority of which share an MDS-related karyotype. This category was previously considered rare in children. Two cases of AML with mutated NPM1 also met diagnostic criteria for the AML-MRC category, including one with multilineage dysplasia, and one with a history of prior MDS. Cases of AML with variant 11q23 were nearly as common as those with the t(9;11). Cases of biphenotypic leukemia were rare (less than 1%), reflecting the more stringent criteria now utilized. Ten percent of cases are therapy-related AML, three times higher than the adult cohort at Stanford (Weinberg et al. Blood 113 p. 1906(2009)). This highlights a serious issue facing pediatric oncologists and their patients. Conclusions:Our pediatric retrospective cohort highlights that important differences exist between adult and pediatric AML. When compared with adults, recurrent genetic abnormalities are more frequently represented as well as treatment related AML. The data also indicate that morphology with myelodysplastic changes is much more frequent than previously thought.KLD and AHM contributed equally to this work. Disclosures:No relevant conflicts of interest to declare.

High Prevalence of FLT3 - ITD Mutations in Patients (pts) with Acute Myeloid Leukemia (AML) Who Present with Central Nervous System (CNS) Relapse.

Abstract 1020Poster Board I-42Despite achievement of complete remission (CR) rates of 70% with modern chemotherapeutic regimens, most pts with AML eventually relapse. CNS extramedullary relapses have become uncommon with the use of high-dose cytarabine (HDAC; > 1.0 g/m2) containing regimens. The clinical and molecular features associated with a higher risk of CNS relapse are not defined. We analyzed adults who presented with AML and CNS relapses from 2005 until 2009. CNS leukemia was diagnosed by the presence of leukemic blasts in a cytocentrifuge preparation of cerebrospinal fluid (CSF). Patients with blasts in the CSF together with high numbers of red blood cells (> 5) were not considered to have CNS disease if the blasts were high in the peripheral blood ( 5 × 109/L). All pts with evidence of CNS disease underwent a marrow examination. There were 10 pts with a diagnosis of AML and CNS relapse observed during the above mentioned time period. Median age was 38 years (range 23-56) and 80% were female. At time of first diagnosis the median WBC was 61×109/L and 50% had M4/M5 phenotype by FAB. Six pts had received induction chemotherapy containing standard doses of cytarabine; five of them received HDAC as consolidation courses afterwards. Four pts received induction regimens containing HDAC. The CR rate was 80% (8 of 10 pts). The median CR duration was 6 months (range 3-7). CNS involvement was detected at a median of 8 months after diagnosis (range 5-29). No pt had isolated CNS relapse. CNS disease was detected in the setting of refractory AML (N=2), 1st systemic relapse (N=4) or 2nd and subsequent relapses (N=4). Eight pts had neurologic symptoms at time of CNS relapse, including headache (N=3), involvement of cranial nerves (N=2), visual impairment (N=1), seizures (N=1), confusion (N=1) and feet neuropathy (N=1) (one pt had more than one symptom). CNS imaging was done in 8 pts, and three pts had abnormal findings by MRI suggestive of CNS disease. The median cell count on CSF was 305 (range 0-880) and median blast percentage was 89%. Two pts had zero cells with blasts detected on cytocentrifuge preparation only. None of the 2 pts had circulating blasts and both had abnormal findings on brain MRI suggestive of CNS relapse. Cytogenetic information was available at initial diagnosis for 9 pts, being diploid in 6 pts. The pt without cytogenetic information was diploid at time of relapse. FLT3 mutation status was unknown at time of diagnosis in six pts, being positive for the ITD mutation in 4 pts. At time of 1st relapse, FLT3 mutation status was positive in 8 pts (80%; all cases were FLT3-ITD). Treatment for CNS disease consisted of intrathecal chemotherapy (methotrexate alternating with cytarabine) in all pts and whole brain radiation therapy in one (24 Gy in 12 fractions). Therapy was successful in clearing all signs of CNS disease in 9 pts. One pt persisted with disease after 4 intrathecal injections and expired 6 weeks afterwards. Five pts had additional CNS relapses at a median of 3 months (range 2-15) after being first diagnosed with CNS disease. Stem cell transplantation (SCT) was done in 3 pts, 2 with active disease and one in CR. All three relapsed with CNS disease after SCT. Only one pat currently remains alive and with active disease. Median survival after CNS relapse was 3 months (range 1-28). In conclusion, CNS relapse is a rare occurrence in AML and is associated with a poor prognosis. A high prevalence of FLT3-ITD mutations was observed in these pts; FLT3 mutations are associated with elevated WBC counts, which are traditionally considered a risk factor for CNS relapse. Analysis of merged data from larger databases may help to better discern the association between FLT3-ITD mutations and CNS relapse. If confirmed, prophylactic measures might be considered for such pts. Disclosures:Jabbour:Novartis: Speakers Bureau; Bristol Myers Squibb : Speakers Bureau.

妊娠初期に急性骨髄性白血病を発症し，増悪期に赤芽球症，無顆粒細胞症，骨髄低形成を伴った未熟児を出産した1例

妊娠初期に急性骨髄性白血病を発症し，増悪期に赤芽球症，無顆粒細胞症，骨髄低形成を伴った未熟児を出産した1例

Azacitidine Prolongs Overall Survival (OS) and Reduces Infections and Hospitalizations in Patients (Pts) with WHO-Defined Acute Myeloid Leukemia (AML) Compared with Conventional Care Regimens (CCR)

Background. Azacitidine (AZA), as demonstrated in the phase III trial (AZA-001), is the first MDS treatment to significantly prolong OS in higher-risk MDS pts (Blood 2007; 110:817). Approximately one third of the pts enrolled in AZA-001 were FAB RAEB-T (≥20%–30% blasts) and now meet the WHO criteria for AML (Blood 1999; 17:3835). Considering the poor prognosis (median survival <1 year) and the poor response to chemotherapy in these pts, this subgroup analysis evaluated the effects of AZA vs CCR on OS and on response rates in pts with WHO AML.Methods. The AZA-001 trial enrolled higher-risk MDS pts (FAB: RAEB, RAEB-T, CMML and IPSS: Int-2 or High). Prior to randomization, site investigators preselected (based on age, performance status, and comorbidities) 1 of 3 CCR: best supportive care only (BSC); low-dose ara-C (LDAC), or intensive chemotherapy (IC). Pts were subsequently randomized 1:1 to AZA (75 mg/m2/d SC × 7d q 28d) or CCR; pts randomized to CCR received their investigator preselected treatment. Karyotypes were reclassified using AML standards: favorable {inv 16, t(8;21)}, unfavorable (−7/7q- or complex) and intermediate (all others including normal). OS was assessed by Kaplan-Meier (KM) methods and Cox proportional hazards model; and IWG AML criteria (J Clin Oncol 2003; 214642–9) were used to assess morphologic complete remissions (CR). Efficacy analyses included all WHO AML pts randomized. All pts were followed until death or study closure.Results. Of 358 enrolled pts, 113 met the definition for WHO AML (median: 23% blasts) of whom 86% were considered unfit for IC and were preselected by investigators to receive a low intensity regimen (BSC or LDAC). 55 of the 113 pts were randomized to AZA and 58 pts to CCR. AZA and CCR groups had comparable baseline demographic and clinical characteristics. Of the 58 pts randomized to CCR, 5 withdrew without receiving treatment and 53 were treated with their investigator preselected treatment as follows: IC (19%;10/53), LDAC (34%; 18/53) and BSC (47 %; 25/53). Of the 55 pts randomized to AZA, 2 withdrew without receiving treatment. Median age was 70 years; 24% had an unfavorable karyotype, 72% had an intermediate karyotype (including 46% normal); no pts had a favorable karyotype. Median follow-up for OS was 20.1 months. Median (min–max) number of treatment cycles was 8 (1–39) for AZA, 2.5 (1–3) for IC; 5.5 (1–14) for LDAC; and 6 months (2 – 19) for BSC. KM median OS was 24.5 vs. 16.0 months, respectively, in the AZA and CCR groups, hazard ratio (HR)=0.47, 95% CI, 0.28 to 0.79, p=0.004, Figure. OS rates at 2 yrs were 50% and 16%, respectively, in the AZA and CCR groups, p=0.0007. There was no statistical difference in the morphologic CR rate between the AZA (18%, 10/55) and CCR groups (16%, 9/58; p=0.80). OS results in cytogenetic intermediate pts showed a significant HR favoring the AZA group (N=38) over CCR (N=43, HR= 0.47 [95% CI: 0.24, 0.91], p=0.024) but not in pts with unfavorable cytogenetics: AZA (N=14) vs CCR (N=13, HR=0.66 [95% CI: 0.26, 1.68], p=0.381); however, pt numbers were low. WHO AML pt outcome measures showed significant benefits with AZA: fewer infections requiring IV antibiotics per pt-year in the AZA group (0.58) vs CCR (1.14, HR=0.51 [95% CI 0.29, 0.78], p=0.003); and reduced rates of hospitalization in the AZA group (3.4 per pt-year) vs CCR (4.3 per pt-year, HR=0.79 [95% CI 0.62, 1.00], p=0.028). AZA was generally well tolerated.Conclusion. AZA significantly prolongs OS with significant improvements in important pt outcomes in elderly WHO AML pts with low marrow blast counts, who currently have limited therapeutic options. Trials are ongoing to confirm the effect of AZA in elderly AML pts with more proliferative disease. [Display omitted]

Clinical Characterization of Acute Myeloid Leukemia with Myelodysplasia-Related Changes as Defined by the 2008 WHO Classification System.

Background: Although some studies have validated the 2001 WHO classification of acute myeloid leukemia (AML), including the importance of multilineage dysplasia, others have suggested that multilineage dysplasia correlates with unfavorable cytogenetics but has no independent impact on prognosis. In 2008, the revised WHO classification system has expanded this category into “AML with myelodysplasia-related changes” (AML-MRC) that now includes 1) AML arising from myelodysplastic syndrome (MDS), 2) AML with MDS-related cytogenetic abnormalities, and 3) AML with multilineage dysplasia. An individual case may fall into this category by meeting any of the criteria. The goal of the current study is to clinically characterize this newly defined AML-MRC subgroup.Methods: One-hundred consecutive AML patients diagnosed at Stanford University Hospital between 2005 and 2007 with adequate material for mutation analysis were studied. Cases were classified using the 2008 WHO criteria. Diagnostic cytogenetic findings were reviewed and patients were stratified into risk groups using Southwest Oncology Group criteria. Available flow cytometry immunophenotyping results were reviewed and all samples were tested for NPM, FLT3 (ITD and D835) and CEBPA mutations. Clinical parameters including hemogram data at time of diagnosis were reviewed. Clinical follow-up including overall survival (OS), progression free survival (PFS) and complete remission (CR) rates were retrospectively determined. Kaplan-Meier methods and univariate and multivariate Cox proportional hazards regression analysis were used to compare the clinical data.Results: The cases included 57 males and 43 females with a median age of 56 (range 17–81). Cytogenetic risk-group stratification resulted in 9 patients with favorable, 65 with intermediate and 19 with unfavorable risk status. Using the 2008 WHO criteria, there were 48 AML-MRC, 40 AML not otherwise specified (AML-NOS), 9 AML with either t(8;21), inv(16) or t(15;17), and 3 therapy related AMLs. Overall, 26 patients had a NPM1 mutation (16 of which were FLT3 mutated), 25 had FLT3-ITD, 8 had FLT3-D835 and 9 had a CEBPA mutation (3 of which were FLT3 mutated). Compared to AML-NOS, patients with AML-MRC were significantly older (59 vs 51 years, p=0.014) and presented with lower hemoglobin (9 vs 11.2 g/dL, p=0.044), lower platelets (47 vs 54 K/uL, p=0.059), unfavorable cytogenetics (14/46 vs 3/36, p=0.014) and exhibited a decreased frequency of CEBPA mutation (0/46 vs 7/40, p=0.001) as compared to AML-NOS. Based on the flow cytometry immunophenotyping, the blasts from patients with AML-MRC more frequently expressed CD14 compared to AML-NOS (10/46 vs 4/36, p=0.048). Clinical outcome data showed that patients with AML-MRC had a significantly worse OS, PFS and CR compared to AML-NOS (Figure, all p<0.0001). Even after excluding the 14 patients with unfavorable cytogenetics from the AML-MRC group, the remaining patients with AML-MRC (defined solely by the presence of multilineage dysplasia) had worse outcomes compared to all AML-NOS patients (OS, p=0.013; PFS, p=0.012; CR, p=0.0076). Among 65 patients with intermediate risk cytogenetics, the outcome difference between the AML-MRC and AML-NOS groups remained significant (OS, p=0.0292; PFS, p=0.0232), also indicating prognostic significance of multilineage dysplasia. Within the AML-MRC group, univariate analysis showed that low platelets (<20,000/mm3), FLT3-D835 mutation and MDS-related cytogenetics correlated with OS (p=0.0456, p=0.0265, p=0.002 respectively) and PFS (p=0.0478, p=0.0626, p=0.001). A multivariate Cox proportional hazard analysis, performed on the entire group, identified unfavorable cytogenetic risk group, advanced age (> 60), FLT3-ITD and AML-MRC status as significant predictors of worse OS with the following respective hazard ratios: 2.82 (95% CI, 1.52–5.26), 2.11 (1.01–4.42), 1.98 (1.01–3.90), 1.92 (1.01–3.65).Conclusion: The newly defined WHO category of AML-MRC exhibits a significantly worse clinical outcome compared to AML-NOS and is predictive of worse overall survival in the multivariate analysis of AML patients, independent of age or cytogenetic risk group. These findings support the clinical, morphologic and cytogenetic criteria for this 2008 WHO AML category. [Display omitted]

AML with Translocation T(8;16) Shows Unique Cytomorphological, Cytogenetic, Molecular, and Prognostic Features and Therefore Qualifies as An Own Entity According to WHO Criteria.

Balanced chromosomal rearrangements define distinct biological subsets in acute myeloid leukemia (AML). It is recognized that recurrent balanced aberrations, such as t(15;17), t(8;21), inv(16), and 11q23/MLL translocations, show a close correlation to cytomorphology and also harbor specific gene expression signatures. We here present a cohort of 13 AML cases with t(8;16)(p11;p13). This translocation is rare with only 13 cases (6 males, 7 females) diagnosed from our overall cohort of 6124 cases of AML over recent years, and is more frequently found in therapy-related AML than in de novo AML (7/438 t-AML, and 6/5686 de novo, p=0.00001). Prognosis was poor with median overall survival of 4.7 months. Five patients deceased within the first month after diagnosis. AML with t(8;16) is characterized by striking cytomorphologic features: In all 13 cases the positivity for myeloperoxidase (MPO) on bone marrow smears was >30% (median: 85%) and intriguingly, in parallel also >40% (median: 88%) of blast cells stained strongly positive for non-specific esterase (NSE) in the same cell, suggesting that AML with t(8;16) arise from a very early stem cell with both myeloid and monoblastic differentiation potential. Therefore, AML with t(8;16) cases can not be classified according to standard FAB categories. Morphologically we also detected erythrophagocytosis in 7/13 cases, a specific feature in AML with t(8;16) that was previously described. With respect to cytogenetics, 6/13 patients had t(8;16)(p11;p13) as sole abnormality. 7/13 patients demonstrated additional non-recurrent abnormalities, 4 cases with single additional aberrations, and 3 cases with two or more additional aberrations. Molecular analyses detected the MYST3- CREBBP fusion transcript in all cases tested (12/12). We then compared gene expression patterns in 7 cases of AML with t(8;16) to: (i) AML FAB subtypes M1 and M4/5 with strong MPO or NSE with normal karyotype and to (ii) distinct AML subtypes with balanced chromosomal aberrations according to WHO classification. In a first series using Affymetrix HG-U133A+B microarrays 4 cases of AML with t(8;16) were compared to FAB M1 (n=46), M4 (n=41), M5a (n=9), and M5b (n=16). Hierarchical clustering and principal component analyses revealed that AML with t(8;16) were intercalating rather with FAB subtypes M4 and M5b and did not cluster near to FAB M1, although strong positivity for MPO was seen in all t(8;16) cases. Thus, monocytic characteristics influence the gene expression pattern stronger than myeloid features. When further compared to AML WHO subtypes t(15;17) (n=43), t(8;21) (n=43), inv(16) (n=49), and 11q23/MLL (n=50), AML with t(8;16) samples were repeatedly grouped in the vicinity of the 11q23/MLL cases. This can be explained by a similar expression of genes such as EAF2, HOXA9, HOXA10, PRKCD, or HNMT. Yet, in a subsequent pairwise comparison AML with t(8;16) could also be clearly discriminated from 11q23/MLL with differentially expressed genes including CAPRIN1, RAN, SMARCD2, LRRC41, or H2BFS, higher expressed in AML with t(8;16) and SOCS2, PRAME, RUNX3, or TPT1, lower expressed in AML with t(8;16), respectively. Moreover, the respective FAB-type or WHO-type signatures were validated on a separate cohort of patients (n=3 AML with t(8;16); n=107 other AML subtypes as above), all prospectively analyzed with the successor HG-U133 Plus 2.0 microarray. Again, in direct comparison to FAB-type or WHO-type cases, dominant and unique gene expression patterns were seen for AML with t(8;16), confirming the molecular distinctiveness of this rare AML entity. Using a classification algorithm we were able to correctly predict all AML with t(8;16) cases by their gene expression pattern. This accuracy was observed not only for both FAB-type and WHO-type signatures, but also correctly classified the cases across the different patient cohorts and microarray designs. In conclusion, AML with t(8;16) is a specific subtype of AML with very poor prognosis that often presents as treatment-related AML and with particular characteristics not only in morphology and clinical profile, but also on a molecular level. Due to these unique features, it qualifies as a specific recurrent entity according to WHO criteria.

Prospective study of 174 de novo acute myelogenous leukemias according to the WHO classification: subtypes, cytogenetic features and FLT3 mutations

We report a prospective study of 174 unselected adult de novo acute myeloid leukemia (AML) cases diagnosed using the WHO classification. Of those, 57 (33%) were AML with recurrent cytogenetic abnormalities, 41 were (24%) AML with multilineage dysplasia, 74 (42%) were AML not otherwise categorized, and two were acute leukemias of ambiguous lineage. Clonal cytogenetic abnormalities were detected in 64% of the WHO AML cases with t(15;17) (15%), t(8;21) (12%), +8 (11%), -7/del7q (8%) and del9q (5%) being the most common ones. The FLT3/ITD mutations (FMS-like tyrosine kinase 3/internal tandem duplication) were observed in 12% of the WHO AML cases, which is much lower than ones in the literature, while the 6% incidence of the FLT3-activating loop mutations (either FLT3/D835 or FLT3/I836) was comparable with others. Both mutations were associated with leukocytosis. Our study also suggests that the FLT3 mutations are biomarkers independent of cytogenetic characteristics.

Response Rates in Patients with Acute Myeloid Leukemia (AML), Treated with Azacitidine, Using WHO and International Working Group (IWG) Criteria for Myelodysplastic Syndrome (MDS).

The CALGB conducted a series of clinical trials with azacitidine (Vidaza®) administered subcutaneously or intravenously in patients with MDS using the FAB classification (JCO 2002; 20:2429). Since completion of these CALGB studies (8421, 8921, 9221), a new classification system was developed by the WHO that distinguishes MDS from AML (blasts > 20%). Although studies with azacitidine in patients with AML had previously shown activity, the 75 mg/m2/day dose in the CALGB studies was lower than previously studied. Using the WHO system, the diagnosis for CALGB study patients was redefined and patients with AML were analyzed separately. Most of the 105 patients were previously considered refractory anemia with excess blasts in transformation (RAEB-T). Also, new treatment response criteria for MDS were published by the IWG (Blood 2000; 96:3671). Using IWG response criteria, azacitidine patients with WHO AML in studies 8421, 8921, or 9221 had an overall response rate (CR+PR+HI) of 48% (12/25), 32% (9/28), and 37% (10/27), respectively. [Display omitted] Median duration of any response (CR, PR or HI) in the 33 azacitidine-treated responders was 279 days (range: 61 to 724 days). The median duration of CR in the 8 azacitidine-treated responders was not achieved; however, the 25th percentile was 115 days (range: 92 to 274+ days). In Study 9221, the median duration of transfusion independence (defined as ≥56 days) in patients independent at baseline was significantly longer in the azacitidine group compared with supportive care for red blood cells (azacitidine [n=8]: 411 days vs. supportive care [n=9]: 133 days, p=0.02) and platelets (azacitidine [n=13]: 363 days vs. supportive care [n=18]: 125 days, p=0.004). In the azacitidine group, 22% (6/27) of patients had a hemoglobin improvement to >11 g/dL that was maintained for ≥56 days compared with 8% (2/25) in the supportive care group (p=0.2). The proportions of patients with ANC >1500/m3 and platelets >100,000/mm3 lasting for ≥56 days were similar between the treatment arms. Azacitidine patients with WHO AML had a longer median survival (19.3 months) compared with the supportive care group (12.9 months) (p=0.2). Further studies investigating azacitidine in patients with AML with dysplasia are warranted.

Megadose CD34＋Hemopoietic Stem Cell Transplantation for Patients with High Risk Acute Myeloid Leukemia Who Have No HLA Matched Donor - A Pilot Study of a Full Haplotype Mismatch Transplantation -

Background :Haploidentical transplantation has become a popular modality of treatment for acute myeloid leukemia (AML) patients lacking donors with matching HLA. We attempted to assess the success rate and ramifications of full haplotype mismatch transplantation.Methods :Four patients received stem cell transplantation from their full haplotype mismatched family donors. The conditioning regimen included total-body irradiation, intravenous busulfan, antithymocyte globulin, and fludarabine. Megadose CD34+ stem cell transplants were performed, in a dosage range between 10.9×106/kg and 20.6×106/kg. Neither GvHD prophylaxis nor post-transplant G-CSF were administered. We monitored patients’ bone marrow cellularity and peripheral blood chimerism using real-time PCR.Results :All patients evidenced stable engraftment. The most frequent side effect was severe mucositis, but all patients recovered successfully, without early death. No patients exhibited acute GvHD. Two refractory patients relapsed soon after transplantation. The other 2 patients have remained in good clinical condition, with a follow-up duration of 1–4 months.Conclusion :Using a newly-developed conditioning regimen, we were able to circumvent GvHD and graft failure, which are the main limitations associated with full haplotype mismatch transplantation. According to our analysis of the relevant literature, it appears that this is the first report of such a conditioning regimen.

Clinical Significance of FLT3 Internal Tandem Duplication in Patients with Acute Myeloid Leukemia Who Underwent Allogeneic Bone Marrow Transplantation.

Since the introduction of high-dose cytarabine therapy, there are still controversies for the role of allogeneic or autologous stem cell transplantation (SCT) in acute myeloid leukemia (AML), but the SCT, especially allogeneic, has a benefit in AML patients with intermediate risk. However, it is needed to investigate for a new prognostic factor, in addition to the cytogenetics, to the further stratifying approach. Internal tandem duplications (ITD) within FLT3 are present in 20–30% of patients with AML and have a prognostic implication in the disease. However, there was no report in AML patients who underwent allogeneic bone marrow transplantation (BMT). In this study, we evaluated the prognostic relevance of FLT3/ITD in 42 patients with AML who underwent allogeneic BMT. FLT3/ITD mutations were studied on bone marrow samples at diagnosis using PCR. As a baseline study, we firstly analyzed the incidence of FLT3/ITD in BM samples at diagnosis of 214 patients with AML. Of the patients, FLT3/ITD were found in 68 patients (31.8%). In this study, 64% of the patients who underwent allogeneic BMT were positive for FLT3/ITD mutations. Methologically, FLT3/ITD detections by melting curve analysis showed higher sensitivity (66.7%) than those by gel electrophoresis (61.9%). There were no significant differences in the engraft periods and the incidence of acute and chronic GVHD according to the presence of FLT3/ITD mutations. When we analyze patient's survival according to the presence or absence of FLT3/ITD, the probability of overall survival (OS) at 3 years in the AML patients with FLT3/ITD tended to be shorter than those lacking FL3/ITD (53.9 ± 9.9% vs. 60.6 ± 14.7%, P=0.46). In addition, the probability of disease free survival (DFS) at 3 years in the AML patients with and without FLT3/ITD was 57.3±10.3% and 85.7±13.2%, respectively (P=0.046). Among the cytogenetic risk group, low-risk and high-risk groups were no significant differences according to FLT3/ITD despite of the limited number of patients studied. However, patients with intermediate-risk were significantly shorter DFS in the presence of FLT3/ITD than those in the absence of FLT3/ITD (P=0.048). These findings suggest that the presence of FLT3/ITD mutations is a poor prognostic factor for disease free survival in AML patients, especially with cytogenetically intermediate-risk, who underwent allogeneic BMT and melting curve analysis to detect the presence of FLT3/ITD mutations is a useful tool with high sensitivity.