Type Of AML Research Articles

Treatment-Related AML Is An Independent Adverse Prognostic Factor for Relapse-Free and Overall Survival. An Analysis of 2,868 Adult Patients with Newly Diagnosed AML Enrolled On Seven AMLSG Treatment Trials.

Abstract 578▪▪This icon denotes an abstract that is clinically relevant. Background:Therapy-related AML (t-AML) is a recognized clinical syndrome occurring as a complication following cytotoxic and/or radiation therapy. The etiology and specific factors that predispose to t-AML largely remain unknown. Survival of t-AML patients has been poor compared with that of patients with de novo AML. However, there is a paucity of studies evaluating the impact of t-AML as a risk factor, in particular in the context of other clinical and biological prognostic markers. Aims:To study the clinical impact of t-AML in a large cohort of patients with newly diagnosed AML, in the context of clinical characteristics as well as cytogenetics and mutational status of the NPM1 and FLT3 genes. Methods:The study included 3,139 adult patients (median age, 53.5 years; range, 16-85 years) with newly diagnosed AML entered on 7 protocols of the German-Austrian AML Study Group (AMLSG) between 1993 and 2008. In all protocols intensive induction and consolidation therapy was used. Information on type of AML, karyotype and molecular marker status of NPM1 and FLT3 (internal tandem duplication [ITD] and tyrosine kinase domain mutation [TKD]) was availabel in 2,858 of 3,139 (91%) and 2,126 of 3,139 (68%) patients, respectively. Since this report focuses on the comparison of t-AML versus de novo AML, patients with secondary AML following myelodysplastic syndrome (s-AML) and those lacking information on type of AML were excluded (n=151, n=120, respectively). Results:Two hundred of the 2,868 patients (7%) were classified as t-AML. In more than two thirds of t-AML cases, a solid cancer was the primary malignancy with breast cancer being the most common (55%), followed by gastrointestinal (7.5%), prostate (7%) and testicular cancer (7%). In 27% of the cases, a hematologic neoplasm was the primary malignancy with non-Hodgkin (43%) and Hodgkin lymphoma (35%) being the most common. Three patients received cytotoxic treatment for autoimmune diseases. The median latency period between diagnosis of primary malignancy and occurrence of t-AML was 4 years (range, 4 months to 44 years). Patients with t-AML were significantly older compared to patients with de novo AML (58 versus 53 years; p<0.0001), and they had significantly lower median white blood counts (WBC) (7.4 vs 12.5 ×109/L; p=0.002). The frequencies of cytogenetic risk groups in t-AML versus de novo AML were as follows: favorable [t(8;21), t(15;17), inv(16) or t(16;16)] (16% vs. 16%), intermediate [all cytogenetic abnormalities not classified as favorable or adverse] (46% vs. 66%), and adverse [t(v;11q23), inv(3) or t(3;3), t(9;22), -5 or 5q-, -7 or 7q-, abn(17p), complex karyotype] (38% vs. 18%, respectively). Response to induction therapy was not significantly different between t-AML (64%) and de novo AML (69%) in uni- (p=0.18) and multivariable (p=0.58) analysis. In contrast, for the clinical endpoints relapse-free (RFS) and overall survival (OS), t-AML was an adverse prognostic factor in univariable (p<0.00001, p<0.00001, respectively) and multivariable analyses (HR, 1.69, p=0.001; HR, 1.3, p=0.004, respectively). The negative prognostic impact of t-AML on RFS was due to both a higher cumulative incidence of relapse (p=0.01) and death in complete remission (CR) (p=0.0001). In cytogenetic subgroup analyses, t-AML was an unfavorable factor for OS in particular in patients with inv(16) or t(16;16) (p=0.008), whereas this was not the case in t(8;21) and t(15;17). In cytogentically normal AML, OS was significantly inferior in t-AML patients (p=0.009), and this negative impact was due to a significant inferior OS in the molecularly defined subgroups NPM1mut/FLT3-ITDneg (p=0.05) and the triple negative group (p=0.004), whereas there was no difference in the subgroup FLT3-ITD and CEBPAmut. In as treated analyses in patients younger than 61 years with t-AML, allogeneic hematopoietic stem cell transplantation (HSCT) in first CR had a beneficial effect in cytogenetic intermediate- and adverse-risk (OS, p=0.008), but not favorable-risk patients. Conclusions:In this large cohort of adult patients with newly diagnosed AML, t-AML was an independent adverse prognostic factor for RFS and OS. The negative impact on RFS was not only due to an increased relapse rate but also to a higher rate of deaths in CR, possibly reflecting cumulative toxicity of primary and secondary cancer therapy. Allogeneic HSCT appears to have a beneficial impact in younger adults with t-AML. Disclosures:No relevant conflicts of interest to declare.

Secondary AML After a History of Myelodysplastic Syndrome Is An Independent Adverse Prognostic Factor for Achievement of Complete Remission, Relapse-Free and Overall Survival. An Analysis of 2,819 Adult Patients with Newly Diagnosed AML Enrolled On Seven AMLSG Treatment Trials.

Abstract 2621▪▪This icon denotes an abstract that is clinically relevant.Poster Board II-597 Background:AML patients with a prior history of a myelodysplastic syndrome (MDS) or myelodysplastic/myeloproliferative neoplasm (MDS/MPN) (in the following referred to as secondary AML [s-AML]) in the new WHO classification are listed in the category “AML with myelodysplasia-related changes”. Patients with s-AML are considered to have an inferior outcome compared with de novo AML. Even after accounting for clinical and cytogenetic risk factors, s-AML is believed to remain an important predictor of poor outcome although mechanisms for this effect remain elusive. The minimal time period between diagnosis of MDS and occurrence of s-AML has been defined differently, 3 months by Cheson et al. (J Clin Oncol 1990) versus 6 months according to the WHO 2001 classification. Aims:To study the clinical impact of s-AML in a large cohort of patients with newly diagnosed AML, in the context of clinical characteristics as well as cytogenetics and mutational status of the NPM1, CEBPA and FLT3 genes. Methods:The study included 3,139 adult patients (median age, 53.5 years; range, 16-85 years) with newly diagnosed AML entered on 7 protocols of the German-Austrian AML Study Group (AMLSG) between 1993 and 2008. In all protocols intensive induction and consolidation therapy was used. Information on type of AML, karyotype and molecular marker status of NPM1 and FLT3 (internal tandem duplication [ITD]) was available in 2,858 of 3,139 (91%) and 2,126 of 3,139 (68%) patients, respectively. Since this report focuses on the comparison of s-AML versus de novo AML, patients with therapy-related AML (t-AML) and those lacking information on type of AML were excluded (n=200, n=120, respectively). Results:151 of the 2,819 patients (5.4%) were classified as s-AML, 122 with at least a 6-month (s-AML-6), and 29 with a 3- to 6-month (s-AML-3) time period of a preceding MDS or MDS/MPN. Compared with patients with de novo AML, those with s-AML-6 and s-AML-3 were significantly older (62 and 58 years vs 53 years; p<0.0001), and they had significantly lower median white blood counts (WBC) (6.9 and 4.6 vs 12.5 ×109/L; p=0.005), lower percentage of bone marrow blast (50 and 52 vs 75%; p<0.0001) and of peripheral blast counts (22 and 20 vs 55%; p=0.004). Compared to patients with de novo AML, those with s-AML-6 or s-AML-3 showed more frequently MDS-related cytogenetic changes (as defined by WHO 2008) (22% and 31% vs 16%, p=0.02), whereas the frequency of cytogenetically normal AML was equally distributed (48% and 52% vs 49%). However, the distribution of molecularly defined subgroups in cytogenetically normal AML was significantly different (p<0.0001) with a lower frequency of the subgroups CEBPAmut, NPM1mut/FLT3-ITDneg and FLT3-ITDpos in s-AML-6 and s-AML-3 and a higher frequency of the triple-negative genotype (75% and 45% vs 28%). In univariable analyses for the clinical endpoints achievement of complete remission (CR), relapse-free (RFS) and overall survival (OS), s-AML-6 and s-AML-3 showed a significant inferior outcome (p<0.0001, equivalent for all endpoints). Therefore s-AML-6 and s-AML-3 were combined as s-AML for further multivariable analyses. In multivariable analyses, s-AML was consistently an independent adverse prognostic factor for the endpoints achievement of CR (OR, 0.48, p=0.0001), RFS (HR, 1.38, p=0.0005) and OS (HR, 1.27, p=0.02). In cytogenetic subgroup analyses, s-AML was an unfavorable factor for OS particularly in patients with cytogenetically normal karyotype AML (p=0.01) and in patients with the molecularly defined genotype NPM1neg, FLT3-ITDneg as well as CEBPAneg (p=0.04). In as treated analysis, younger adult patients (age <61 years) with s-AML had a beneficial effect from allogeneic hematopoietic stem cell transplantation (HSCT) on OS (p=0.008). Conclusions:In this large cohort of adult patients with newly diagnosed AML, s-AML showed consistent features irrespective of duration of prior history of MDS (>6 months versus 3 to 6 months) and was an adverse prognostic factor for achievement of CR, RFS and OS. Younger adult patients with s-AML appear to benefit from allogeneic HSCT. Disclosures:No relevant conflicts of interest to declare.

Role of Etoposide in Combination with All-Trans Retinoic Acid in the Treatment of Elderly Patients with Acute Myeloid Leukemia and NPM1 Mutation

Rationale: In a previous randomized trial (AML HD98B) in elderly (>60 yrs) patients with AML (excluding APL), we could demonstrate that all-trans retinoic acid (ATRA) given as adjunct to intensive induction therapy with idarubicin, cytarabine and etoposide significantly improved outcome; this beneficial effect appeared to be restricted to patients having NPM1 mutation without concomitant FLT3-ITD (NPM1mut/FLT3-ITDneg). In our subsequent trial in elderly patients (AMLSG 06-04), all patients received ATRA with a similar backbone of chemotherapy, except that for induction therapy idarubicin was intensified and etoposide was omitted. NPM1mut AML is associated with myelomonocytic/monocytic differentiation, and etoposide is believed to have a particular effect in these morphologic subtypes of AML.Aims: To evaluate the impact of etoposide in combination with ATRA in elderly patients with AML exhibiting NPM1 mutation enrolled into two consecutive AMLSG protocols.Methods: 171 patients with NPM1mut AML were included in this retrospective analysis; 78 patients from trial AML HD98B (trial A; accrual from 1998 to 2004); and 95 patients from trial AMLSG 06-04 (trial B, 2004–2008). Twenty-nine of 78 (37%) patients and 87 of 93 (94%) received ATRA in trials A and B, respectively.Results: Initial patient characteristics, such as median age (67.8 and 67.9 years for trial A and B, respectively), type of AML (de novo, secondary or therapy-associated), white blood cell count (WBC), LDH, and FLT3-ITD mutation status (41% and 47%), were not significantly different between the two cohorts. The rates of complete remission (CR) were 68% and 71% for NPM1mut patients in trial A and B, respectively. Lower age and lower WBC counts were significantly associated with achievement of CR; study, treatment with ATRA, type of AML, and FLT3-ITD mutation status had no impact. Univariable survival analyses revealed no significant difference for the end points event-free (EFS), relapse-free (RFS) and overall survival (OS) between the two patient cohorts from trial A and B. However, when restricting the analysis to patients who had received ATRA, a significant better EFS (p=0.05) and RFS (p=0.03) was found for patients with the genotype NPM1mut/FLT3-ITDneg in trial A (that included etoposide) compared to trial B (in which etoposide was omitted); there was no difference in EFS (p=0.18) and RFS (p=0.09) for patients with the genotype NPM1mut/FLT3-ITDpos. In addition, no difference was seen either in patients with the genotype NPM1mut/FLT3-ITDpos or in patients with the genotype NPM1mut/FLT3-ITDneg in terms of OS mainly due to a high second CR rate in patients with the genotype NPM1mut/FLT3-ITDneg.Conclusion: The data from this retrospective subgroup analysis suggest that etoposide in combination with ATRA may exert a beneficial synergistic effect in elderly patients with AML having NPM1 mutation without concurrent FLT3-ITD.

Clinicopathological characteristics of erythroblast-rich RAEB and AML M6a in children

The distinction between RAEB, RAEB-T and AML M6a is difficult when erythroblasts in the bone marrow (BM) exceed 50%. We analyzed 19 children (2 RAEB, 13 RAEB-T and 4 AML M6a) enrolled in a prospective pathological central review in Japan and divided them into two groups according to the myeloblasts percentage among non-erythroid cells in BM: group A (n = 8), 5-19% myeloblasts; group B (n = 11), 20% or more myeloblasts. Their characteristics were very similar except for the number of myeloblasts. The median WBC was in the range of 1.0-5.0 x 10(9) L(-1), the median Hb was around 7.5 g/dL, the median MCV was greater than 90 fL and both group had Auer rods at 60-65%. Severe multilineage dysplasia was observed in most of the patients in two groups. Six with group A and seven with group B treated with AML type chemotherapy achieved complete remission. Five with group A and seven with group B undergoing SCT are alive at a median of 3 years after diagnosis. Erythroblast-rich RAEB and AML M6a in children have similar characteristics and may belong to a single disease entity.

The Impact of Therapy-Related and Secondary AML in Relation to Karyotype and Molecular Markers: A Study of the AMLSG.

Background: Patients (pts) with therapy-related AML (t-AML) or secondary AML (s-AML) after a myelodysplastic syndrome are considered to have an inferior outcome compared to de novo AML. Whether this is due to an adverse cytogenetic risk profile or by the fact of t/s-AML per se has not yet been determined.Aims: To evaluate the frequency and prognostic impact of cytogenetic abnormalities and molecular markers in t/s-AML in comparison to de novo AML in a large cohort of adult AML pts.Methods: Patients were entered on seven AMLSG treatment trials. The key inclusion criteria for this analysis were availability of cytogenetics and molecular markers. Genotypic groups were defined as follows: Acute promyelocytic leukemia (APL) [t(15;17)], core binding factor (CBF)-AML [t(8;21), inv(16)/t(16;16)], cytogenetically normal (CN)-AML, t(11q23), adverse cytogenetics outside a complex karyotype (AC) [abn(3q), −5/5q-, -7/7q-, abn(12p), abn(17p)], complex karyotype (CK, ≥3 aberrations) and all remaining aberrations (various).Results: Between 1993 and 2006, 3083 adults (age range: 16–85 years) were registered and in 2604 karyotype and information about the type of AML were available; 196 (7.5%) had t-AML, 374 (14.5%) s-AML, and 2034 (78%) de novo AML. The median age was lower in de novo AML (50 years) compared to t-AML (58 years) and s-AML (57 years) (p<0.0001). Median WBC and LDH levels were higher (p<.0001) in de novo AML compared to t/s-AML. The distribution of genotypic groups according to type of AML revealed highest incidences of t-AML in the groups t(11q23) (23%), CK (17%), AC (14%), and of s-AML in the groups CK (23%), various (22%), and AC (21%), whereas incidences of de novo AML were highest in APL (92%), CBF (87%) and CN (82%). Response to induction therapy was higher in de novo AML (CR 72%) compared to t-AML (59%) and s-AML (52%). The logistic regression model for response to induction therapy revealed s-AML (OR, 0.53; p<0.001), age diff: of 10 years (OR, 0.71; p<0.0001), log10(WBC) (OR, 0.74; p<0.0001), and cytogenetics with CBF (OR, 2.77; p<0.0001), CK (OR, 0.22; p<0.0001), AC (OR, 0.29; p<0.0001), and various (OR, 0.69; p=0.01) in comparison to CN-AML as significant variables. Cox regression model on overall survival (OS) revealed s-AML (HR, 1.29; p=0.0004), age diff: of 10 years (HR, 1.40; p<0.0001), log10(WBC) (HR, 1.33; p<0.0001), and cytogenetics with CBF (HR, 0.53; p<0.0001), CK (HR, 3.20; p<0.0001), t(11q23) (HR, 1.76; p<0.0001) and AC (HR 1.97, p<0.0001) in comparison to CN-AML as significant variables. To better define the role of t/s-AML, subgroup analyses were performed according to genotypic groups. Of note, survival rates of de novo AML, t- and s-AML were almost identical in the genetically defined groups APL (p=0.93), CBF-AML (p=0.34), CK (p=0.33), AC (p=0.38) and t(11q23) (p=0.23), whereas differences were found in the groups various (p=0.0005) and CN-AML (p=0.02). Analyses of CN-AML including the FLT3-ITD and NPM1 status revealed significant differences in the subgroups defined by FLT3-ITDpos (p=0.05) and double negative (p=0.05), whereas in the group with a favorable genotype NPM1mut/FLT3-ITDneg survival rates were nearly identical (p=0.65).Conclusions: The prognostic impact of t/s-AML is restricted to patients with CN-AML exhibiting an unfavourable genotype and patients within the heterogeneous group exhibiting various aberrations.

Congenital Amniotic Band Syndrome and MLL Rearranged Neonatal Leukemia in an Infant with Multiple Pre-Conception and In Utero Exposures.

Introduction: Patients with birth defects have a higher incidence of cancer; however, an association of amniotic band syndrome (vascular disruption syndrome) with congenital leukemia has never been reported. We characterized a case of MLL-rearranged leukemia in a neonate affected with this birth defect.Methods: The MLL translocation was characterized in peripheral AML blasts by karyotype analysis, multicolor FISH, Southern blot analysis and genomic and cDNA panhandle PCR. NQO1 genotype was determined by real-time PCR.Clinical history and results: The infant was born at 38 weeks gestation by C-section for suboccipital encephalocele to a 21 year-old gravida 3 para 2 mother with a history of cigarette, marijuana, cocaine and opiate use, and antidepressant, antipsychotic, barbiturate, caffeine and proton pump inhibitor treatment during pregnancy. Drug screen at delivery was positive for opioids and barbiturates. In addition to the encephalocele, a circular constriction of the right arm, consistent with amniotic band syndrome, and blueberry muffin lesions were noted at delivery. The CBC showed mild thrombocytopenia that resolved the next day. Congenital infection was excluded. The encephalocele was repaired. At 19–20 days of age the infant became septic and hepatosplenomegaly and hyperleukocytosis were observed. The peripheral smear and flow cytomery revealed acute myeloid leukemia with monocytic differentiation (CD45+ population positive for CD4, CD14, CD33, CD38, HLA-DR). Karyotype analysis showed a complex structural abnormality disrupting chromosomes 4, 11 and 19 involving MLL. M-FISH showed insertion of chromosome 11 material into a chromosome 19 and translocation between chromosomes 11q and 4q. The infant received cytosine arabinoside and daunomycin but succumbed to AML, sepsis and multi-organ failure within 4 days. Autopsy showed marrow, viscera, brain and skin infiltration with AML and Chiari type III brain malformation. Southern blot analysis detected two MLL bcr rearrangements. Panhandle PCR demonstrated fusion of MLL intron 6 and intron 1 of ELL from band 19p13.1. Short sequence homologies at the breakpoint junction suggested DNA damage resolution by NHEJ repair. The corresponding transcript joined MLL exon 6 to ELL exon 2. The infant was wild-type at NQO1 C609T.Conclusions: This is the first association of amniotic band syndrome and congenital AML, both of which are rare conditions. Although the cause(s) are unknown, both conditions originate in utero and maternal exposures during pregnancy may be relevant. There was a history of maternal fetal loss, which is a risk factor for leukemia in infants. The NQO1 substrate p-benzoquinone in cigarette smoke is a topoisomerase II poison, but the infant did not harbor the NQO1 variant that predisposes to leukemia. Cocaine is an in utero exposure implicated in amniotic band syndrome. The occurrence of amniotic band syndrome and congenital AML in this infant raises questions about potential host predisposition or gene-environment interactions common to both conditions. Alternatively, both rare conditions may have occurred by chance alone in the setting of the many in utero exposures.

Comparable Results of HLA Identical Sibling Donor Peripheral Blood Hematopoietic Stem Cell Transplantation after Reduced-Intensity and High-Dose TBI-Based CD34+-Positive Cell Selection Myeloablative Preparative Regimens for High-Risk Myelodysplasia or Acute Myeloid Leukemia in First Remission: Results from a Prospective Study.

We prospectively compared the efficacy of allogeneic PBSCT from an HLA-identical sibling in adults with poor-risk AML or MDS in an early disease status (AML or RAEB type 2 in first CR after chemotherapy or RAEB type 1 with poor prognosis). Poor-risk AML/MDS was defined as the presence at diagnosis of one or more of the following: poor-risk karyoype, normal karyotype with flt-3 duplications or MLL mutations, high level of MRD after consolidation (>0.1%), and, in RAEB type 1, an IPSS3Int-2. Based only on the patients' age, the transplant protocol consisted in conditioning with cyclophosphamide-TBI and use of CD34+-selected PBSCT (CyTBI-CD34+ group, if £ 50 y.o.) or a reduced-intensity conditioning (RIC) with fludarabine and oral busulphan (FluBu-RIC, If > 50 y.o.). Between 1998 and 2005, 74 consecutive patients entered the study (35 in the CyTBI-CD34+ and 39 in the FluBu-RIC group). Both groups differed in some baseline characteristics, mainly younger age in the CyTBI-CD34+ group (median 42 vs. 59 years, p<0.01), a higher transplant comorbidity index in the FluBu-RIC group (median 0 vs. 3 points, respectively, P<0.01), a higher proportion of AML (with respect to RAEB) in CyTBI-CD34+ group (82% vs 54%, respectively, P=0.02), and a higher proportion of poor-risk karyorypes in the FluBu-RIC group (32% vs 72%, respectively, P<0.01). The median follow-up exceeds 4 years in both groups. All patients had sustained donor-engraftment by day +60, except for one lethal graft failure in the CyTBI-CD34+ group. The 4-year probability of OS was and LFS were similar in both groups (52% and 53% in the CyTBI-CD34+ group vs. 53% and 53% in the FluBu-RIC group, respectively, P>0.8 for OS and LFS). In addition, the 4-year cumulative incidence of non-relapse mortality (NRM) was 25% (95% CI 11–38%) and 22% (95% CI 5–39%), respectively (P>0.8), while the incidence of relapse was 22% (95% CI 5–39%) and 25% (95% CI 6–44%), respectively (P>0.8). In univariate analysis, the only variable that decreased OS and LFS by increasing NRM was the patient male/donor female sex combination (n=18 cases). The OS and NRM in these 18 cases were 37% and 40%, respectively, while the 56 cases with other sex combinations had much better outcomes (66% OS and 8% NRM, P=0.004 and P==0.001 for the comparison of OS and NRM, respectively). Trends were seen for improved OS and lower NRM in the CyTBI-CD34+ group in patients less than 40 years of age (P=0.1) and in patients receiving higher doses of CD34+ cells/kg in the FluBu-RIC group (P=0.1). Our single-center results suggest comparable outcomes for RIC alloPBSCT in high-risk adults with poor-risk AML and MDS in an early disease phase.

Mutations Can Predict Relapse in Common Type of AML

Mutations Can Predict Relapse in Common Type of AML

Long-term follow-up and potential for cure in acute promyelocytic leukaemia

Acute promyelocytic leukaemia (APL) may be characterized simultaneously as the most potentially rapidly fatal human acute leukaemia if untreated, yet the most frequently cured acute leukaemia if promptly diagnosed and treated without delay. Co-operative group and single-institution studies which include large numbers of patients with relatively long follow-up demonstrate that, with all- trans retinoic acid (ATRA) plus anthracycline-based chemotherapy, the majority of newly-diagnosed patients appear cured of their disease. The 5-year disease-free survival rates range from 75 to 85%. Early death is still observed in approximately 10% of patients and remains a difficult obstacle to increasing the cure rate. Prognostic factors which identify patients at high risk for recurrence are becoming increasingly recognized. Older age (over age 55–60 years), elevated white blood cell count at presentation (higher than 5000–10 000/μl), and expression of CD56 unfavourably influence outcome. The treatment of such patients remains a challenge, although it is important to note that APL is the only type of AML in which a significant proportion of older patients may be cured. Because more patients are cured of their disease, potential long-term consequences may become increasingly recognized. These include the emergence of extramedullary disease, the development of secondary myelodysplasia or acute myeloid leukaemia and the potential for late-onset cardiac toxicity.

M0 AML, clinical and biologic features of the disease, includingAML1 gene mutations: a report of 59 cases by the Groupe Français d'Hématologie Cellulaire (GFHC) and the Groupe Français de Cytogénétique Hématologique (GFCH)

Mutations of the AML1 gene are frequent molecular abnormalities in minimally differentiated acute myeloblastic leukemia (M0 AML), a rare type of AML. In this retrospective multicenter study, morphologic, immunophenotypical, cytogenetic, and molecular features of 59 de novo M0 AML cases were analyzed and correlated to AML1 mutations. Point mutations of AML1 gene were observed in 16 cases (27%). They were correlated with higher white blood cell (WBC) count (P =.001), greater marrow blast involvement (P =.03), higher incidence of immunoglobulin H/T-cell receptor (IgH/TCR) gene rearrangement (P <.0001), and with a borderline significant lower incidence of complex karyotypes. In the 59 patients, FLT3 mutations were the only significant prognostic factors associated with short survival.

Acute erythremic myelosis (true erythroleukaemia): a variant of AML FAB-M6

Aims—Classic erythroleukaemia (acute myeloid leukaemia M6, or M6 AML) is defined as an excess of myeloblasts in an erythroid predominant background. Leukaemia variants in which the primitive blast cells are...

A New Translocation, t(2;4;12)(p21;q12;p13), in CD7-Positive Acute Myeloid Leukemia: A Variant Form of t(4;12)

We describe a 41-year-old man with CD7-positive acute myeloid leukemia (AML-M0) with trilineage-myelodysplasia. Chromosome analysis of the bone marrow cells showed 46,XY,t(2;4;12)(p21;q12;p13). Cytological and clinical features of our case were quite similar to those of AML with t(4;12)(q11∼12;p13). The karyotypic interpretation was confirmed by fluorescence in situ hybridization (FISH) by using the whole-chromosome painting probes specific for chromosomes 2, 4, and 12. FISH analysis with the use of the YAC 936e2 probe, which covers the TEL gene, did not show the split signal, suggesting that a gene other than TEL was involved in the leukemogenesis of the present case. Our case with AML with t(2;4;12)(p21;q12;p13) appears to be the first case of a variant type of AML with t(4;12)(q11∼12;p13).

ＡＭＬ型人工股関節置換術の短期術後成績

We reviewed 40 primary arthroplasties (in 36 patients) in which AML type hip prostheses were used and evaluated these cases clinically and radiographically.The mean age of patients at surgery was 60 years (range 44 to 77 years) and they were followed up for an average of 39 months (range 24 to 72 months). All patients had osteoarthritis.24 hips were hybrid type and the others were cementless type.Clinical results using JOA score were excellent in all cases with marked relief of pain; preoperative total average score of 49 points was improved to 94 points postoperatively.Radiographical evaluation was done of both the outer head and stem sites (initial gap, clear zone, osteolysis, pedestal formation, etc).For acetabular dysplasia cases, massive bone grafting or high positioning of the socket during THA may be required.In this study, 6 hips were settled in a position higher than the original acetabular position to obtain cup containment without acetabular bone-grafting. We achieved a comparatively good result in these cases: preoperative total average JOA score of 43 points was improved to 83 points postoperatively. Positioning of the socket higher may sometimes be recommended in such cases where a bone defect may arise if the socket is settled in the original acetabular position.

ＡＭＬ型人工股関節術後ｓｏｃｋｅｔ破損例の検討

We report our experience of revision surgery for 4 socket failure after AML type cementless total hip replacement.Case 1; A right THR was performed in March 1990, in a 61-year-old woman suffered from avascular necrosis. The prosthesis was dislocated 3 times post-operatively and it was replaced under general anesthesia. After the 3rd dislocation, the inner head migrated lateral-superiority and metallosis was suspected. Revision of the socket was performed. Intra-operatively, we recognized polyethylene wear and failure but no metallosis findings were found, so we revised the inner head and the polyethylene liner.Case 2; A left (March, 1990) THR and a right THR (with bone graft) (April, 1990) were performed in a 55-year-old woman for rapidly destructive coxopathy. 1 year and 5 months after the operation, the grafted bone was collapsed and the socket was migrated lateral-superiority at the right side. We recognized contact of the metal back with the inner head in X-P in May, 1995 so we performed socket revision in June. Intra-operatively, we recognized severe metallosis and wear of polyethylene and the metal back was replaced with cement, inner head and polyethylene liner.Trauma and grafted bone collapse are suspected as the cause on the above 2 examples, but a weak point in the construction of the polyethylene liner of AML type total hip replacement must be also taken under consideration.

Minimally differentiated erythroleukaemia (AML M6 'variant'): a rare subset of AML distinct from AML M6. Groupe Français d'Hématologie Cellulaire.

We describe eight cases of erythroleukaemia distinct from FAB-AML M6, which demonstrate minimal erythroid differentiation not associated with a myeloblastic component. Three infants (including a Down's syndrome) and two adults presented with a de novo leukaemia. One case was preceded by an untreated refractory anaemia with excess of blasts and one by polycythaemia vera. One case presented with an inaugural blast crisis of chronic myeloid leukaemia. In four patients the leukaemic cells showed a proerythroblast-like morphology. The four other were initially classified as undifferentiated AL (two cases) or AML MO (two cases) because of the immature aspect of the cells, their lack of myeloperoxidase activity and the absence of B, T lymphoid and myeloid (My) marker expressions apart from the CD33 antigen. Immunophenotyping in three cases showed an immature erythroblast profile (glycophorins A and B+, spectrin+). In the five others the erythroid nature was recognized by the expression of ABH blood group system on fresh cells (four cases) and glycophorin A on cells after 3 d in vitro culture with erythropoietin (EPO) + IL3 (two cases). Moreover, an erythroid colony growth of leukaemic origin was observed in three patients. In conclusion, the study of erythroid marker expression is of particular importance when immunophenotyping leukaemic cells with a proerythroblast-like morphology or an undifferentiated aspect and a HLA DR-, CD36++, B-, T-, My- (CD33 +/-) phenotype. We propose the term AML M6 'variant' for this rare type of AML.

Acute myeloid leukemia M4 with bone marrow eosinophilia (M4Eo) and inv(16)(p13q22) exhibits a specific immunophenotype with CD2 expression

Extensive immunologic marker analysis was performed to characterize the various leukemic cell populations in eight patients with inv(16)(p13q22) in association with acute myeloid leukemia with abnormal bone marrow eosinophilia (AML-M4Eo). The eight AML cases consisted of heterogeneous cell populations; mainly due to the presence of multiple subpopulations, which varied in size between the patients. However, the immunophenotype of these subpopulations was comparable, independent of their relative sizes. Virtually all AML-M4Eo cells were positive for the pan-myeloid marker CD13. In addition, the AML were partly positive for CD2, CD11b, CD11c, CD14, CD33, CD34, CD36, CDw65, terminal deoxynucleotidyl transferase (TdT), and HLA-DR. Double immunofluorescence stainings demonstrated coexpression of the CD2 antigen and myeloid markers and allowed the recognition of multiple AML subpopulations. The CD2 antigen was expressed by immature AML cells (CD34+, CD14-) and more mature monocytic AML cells (CD34-, CD14+), whereas TdT expression was exclusively found in the CD34+, CD14- cell population. The eight AML-M4Eo cases not only expressed the CD2 antigen, but also its ligand CD58 (leukocyte function antigen-3). Culturing of AML-M4Eo cell samples showed a high spontaneous proliferation in all three patients tested. Addition of a mixture of CD2 antibodies against the T11.1, T11.2, and T11.3 epitopes diminished cell proliferation in two patients with high CD2 expression, but no inhibitory effects were found in the third patient with low frequency and low density of CD2 expression. These results suggest that high expression of the CD2 molecule in AML-M4Eo stimulates proliferation of the leukemic cells, which might explain the high white blood cell count often found in this type of AML.

Acute Myeloid Leukemia M4 With Bone Marrow Eosinophilia (M4Eo) and inv(16)(p13q22) Exhibits a Specific Immunophenotype With CD2 Expression

Abstract Extensive immunologic marker analysis was performed to characterize the various leukemic cell populations in eight patients with inv(16)(p13q22) in association with acute myeloid leukemia with abnormal bone marrow eosinophilia (AML-M4Eo). The eight AML cases consisted of heterogeneous cell populations; mainly due to the presence of multiple subpopulations, which varied in size between the patients. However, the immunophenotype of these subpopulations was comparable, independent of their relative sizes. Virtually all AML-M4Eo cells were positive for the pan-myeloid marker CD13. In addition, the AML were partly positive for CD2, CD11b, CD11c, CD14, CD33, CD34, CD36, CDw65, terminal deoxynucleotidyl transferase (TdT), and HLA-DR. Double immunofluorescence stainings demonstrated coexpression of the CD2 antigen and myeloid markers and allowed the recognition of multiple AML subpopulations. The CD2 antigen was expressed by immature AML cells (CD34+, CD14-) and more mature monocytic AML cells (CD34-, CD14+), whereas TdT expression was exclusively found in the CD34+, CD14- cell population. The eight AML-M4Eo cases not only expressed the CD2 antigen, but also its ligand CD58 (leukocyte function antigen-3). Culturing of AML-M4Eo cell samples showed a high spontaneous proliferation in all three patients tested. Addition of a mixture of CD2 antibodies against the T11.1, T11.2, and T11.3 epitopes diminished cell proliferation in two patients with high CD2 expression, but no inhibitory effects were found in the third patient with low frequency and low density of CD2 expression. These results suggest that high expression of the CD2 molecule in AML-M4Eo stimulates proliferation of the leukemic cells, which might explain the high white blood cell count often found in this type of AML.

The expression and possible roles of protein kinase C in haematopoietic cells.

Protein kinase C (PKC) activation and/or modulation of its isoenzyme expression play key roles in regulating the response of haematopoietic cells to both growth factors and non-physiological inducers of cell growth and differentiation. The level of PKC activities for both cytosol and particulate fractions of ALL and CLL cells are lower than those of AML type. Atypical AML blasts expressing T-cell associated CD2 and CD7 determinants have significantly lower PKC activities compared to typical AML blasts. Analyses of PKC isoforms (-alpha, -beta, and -gamma) show considerable variation with respect to leukaemic cell distributions and subcellular localisations. PKC-alpha and -beta are usually the major species in cytosolic fractions, whereas PKC-gamma is the predominant type in particulate fractions. All lymphoid cells express PKC-gamma in the cytosol, albeit as a minor component, while the occurrence of cytosol PKC-gamma in AML cells appears to be associated in particular with a typical lymphoid antigen expression.