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One hundred and six patients aged /= 6) vs. 75% among the MDR-Pgp-negative (neg(ve)) ones (MFI < 6) (P = 0.16). Conversely, in the controls, the CR rate was 44% among the MDR-Pgp-pos(ve) patients vs. 67% among the MDR-Pgp-neg(ve) ones (P = 0.02). The 4-year disease-free survival (DFS) and overall survival (OS) of MDR-Pgp-pos(ve) cases were significantly longer than those of MDR-Pgp-pos(ve) controls (DFS, 28.1% vs. 6.5%, P = 0.004; OS, 33.5% vs. 9.6%, P = 0.01). This difference was not found among the MDR-Pgp-neg(ve) patients. By univariate (P = 0.007) and multivariate (P = 0.007) analysis, the MDR-Pgp-pos(ve) phenotype was negatively correlated with CR and it emerged as the most important independent negative prognostic factor, after cytogenetics. Our study confirms the prognostic impact of the MDR phenotype in AML and strongly suggests fludarabine-based induction treatments as a promising strategy for MDR-Pgp-pos(ve) AML patients. In this setting of patients, large prospective randomised studies should be planned.

Aim: To test feasibility of transplantation of hemopoietic stem cells (THSC) with conditioning in low-intensity regimen associated with minimal toxic complications and engraftment in patients with hematological malignancy (HM) from a high risk group., Material and Methods: THSC was performed in 33 patients aged 18 to 65 years. Most of the patients suffered from acute leukemia and advanced forms of myelodysplastic syndrome. All the patients had severe complications excluding standard transplantation. Pretransplantation preparation was based on fludarabine and moderate doses of busulfane. Engraftment was achieved in 94% patients. Of complications, there were primarily infections, relapses, graft versus host reactions (45, 24, 57.5%, respectively). Overall survival was 53%, relapse-free--67%, follow-up median 23.6 months., Conclusion: THSC after conditioning in the regime of low intensity is an effective method of HM treatment in patients with contraindications to standard transplantation. The main problem is a high risk to develop graft versus host reaction, especially a chronic form.

Allogeneic stem cell transplantation (AlloSCT) has been currently recommended in the treatment of patients with chronic myeloid leukemia (CML) as a second option after imatinib failure or in selected group of patients with high-risk CML and low risk for transplant-related mortality. The actual role of reduced-intensity conditioning (RIC) before AlloSCT in CML patients has not been yet conclusively established. The Czech National Hematopoietic Stem Cell Transplantation Registry has conducted a retrospective analysis of all patients (n=29) transplanted after RIC from the Registry database containing 295 patients with CML transplanted in the Czech Republic in years 1988-2005 and compared them with patients at comparable age (median age 48.3 and 50.6 years, respectively; p=0.587) transplanted during the same period of time using conventional myeloablative conditioning (n=26). Survival advantage of patients transplanted after RIC has been confirmed by log rank test (p=0.036) despite the fact that the relapse rate was significantly higher in RIC group (44.8% versus 0%). Both groups did not differ significantly in the use of voluntary unrelated donors, type of the grafts and in incidence of acute graft versus host disease (GVHD). However, there were trends for higher risk of CML and higher use of unrelated donors in the myeloablative group while peripheral stem cell grafts and chronic GVHD were observed more frequently in the RIC group. Transplant-related mortality was the leading cause of death in both groups of patients. Our results should be interpreted with caution because they may be influenced by small groups of subjects and also the impact of patients with high EBMT risk score on inferior survival in the myeloablative group cannot be fully eliminated. More retrospective and prospective studies are needed to elucidate the actual role of RIC before AlloSCT for CML.

Background: Outcome after recurrence of childhood acute myeloid leukemia (AML) is poor. We performed this study to identify prognostic factors for recurrence and for survival after recurrence of AML., Methods: The clinical characteristics, biological features, treatment modalities, and outcomes of children with de novo AML who were enrolled on 3 consecutive clinical protocols from 1987 to 2002 at St. Jude Children's Research Hospital were studied. Regression modeling was used to identify prognostic factors for recurrence and for survival after recurrence., Results: The outcome after recurrence was poor, with a 5-year survival estimate of only 23.3% +/- 5.7%. Multivariable analysis indicated that male sex (P = .005), autologous stem cell transplant before recurrence (P = .097), each additional month from diagnosis to recurrence (P = .041), and stem cell transplant after recurrence (P < .001) were associated with a better survival after recurrence, whereas M5 or M7 morphology (P = .001) were significantly predictive of a lower survival estimate after recurrence., Conclusions: Survival after recurrence was poor in children with AML. Novel therapies are urgently needed to prevent or to treat recurring AML., ((c) 2006 American Cancer Society.)

One hundred and fifty-four acute myeloid leukemia patients with trisomy 8 were studied for their clinical and biological characteristics, and treatment outcome. Forty-seven patients presented with trisomy 8 as the sole aberration, 107 with trisomy 8 associated with other cytogenetic abnormalities (13 with favorable, 54 with intermediate, and 40 with unfavorable risk cytogenetics). Overall complete remission (CR) proportion was 48%. Median disease-free survival (DFS) and overall survival (OS) were 7.8 and 8.3 months, respectively. In multivariate analysis, age >or=60 years (P<0.0001) and association with unfavorable karyotype (P=0.03) were of poor prognostic value for CR achievement. Age >or=60 years (P<0.0001) and antecedents of dysmyelopoiesis (P=0.02) were of poor prognostic value for OS. Patients with trisomy 8 alone did not show any difference in terms of outcome as compared with those in whom trisomy 8 was associated to intermediate risk cytogenetics (P=0.0002). Trisomy 8 in addition to favorable karyotype maintained a good clinical outcome, while trisomy 8 in addition to unfavorable cytogenetics showed the worst prognosis.

Diagnostic cytogenetic abnormalities are considered important prognostic factors in patients with acute myeloid leukaemia (AML). However, the prognostic assessments have mainly been derived from patients with AML aged <60 years. Two recent studies of AML patients of 60 years and older proposed prognostic classifications with distinct discrepancies. To further study the prognostic value of cytogenetic abnormalities in this patient population, we have evaluated cytogenetic abnormalities in a series of 293 untreated patients with AML aged 60 years and older, included in a randomised phase 3 trial, also in relation to patient characteristics and clinical outcome. The most frequently observed cytogenetic abnormality was trisomy 8 (+8), in 31 (11%) patients. Abnormalities, such as -5, 5q-, abn(17p) and abn(17q), were almost exclusively present in complex karyotypes. A relatively favourable outcome was only observed in five patients with core-binding factor abnormalities t(8;21) and inv(16)/del(16)/t(16;16). However, most of the other evaluated cytogenetic abnormalities, such as 5q-, -7, +8, abn(17p), abn(17q), and complex aberrations expressed a more adverse prognosis when compared with patients with AML aged 60 years and older with a normal karyotype. Large studies to confirm the prognosis of individual cytogenetic aberrations are warranted.

Cell cycle control is a crucial event in normal hematopoiesis, and abnormalities of regulatory cell cycle genes have been found to contribute to the development of many hematologic malignancies. The present study investigates the immunohistochemical expression of seven essential cell cycle proteins (p21, p27, p14, p16, p53, mdm2, and cyclin E) in paraffin-embedded sections from 42 bone marrow biopsies obtained from an equal number of patients with newly diagnosed acute myeloid leukemia (AML). This study revealed (i) a high frequency of p53+/mdm2-/p21-phenotype, which is probably a result of p53 gene mutation and/or inhibition of mdm2 action by p14(ARF); (ii) expression of p27+/cyclinE-phenotype in most cases, suggesting that p27 may act as a potent cyclin-dependent kinase inhibitor; (iii) expression of p16 only in very few cases; and (iv) no relationship between the expression of any of the above proteins and survival as well as histologic subtype.

Goal of Work: The purpose of the study was to assess the effect of the reported availability of social support on the 2-year survival of patients with acute myelogenous leukaemia (AML)., Materials and Methods: Fifty patients with newly diagnosed AML were asked to rate the level of available social support after diagnosis was made, but before the start of chemotherapy. Social support was assessed with the F-SozU, and information about confounding variables (age, functional status, intensity of chemotherapy, cytogenetic risk group) was collected. Univariate and multivariate Cox regression analyses were used to analyze predictors of 2-year survival., Main Results: Higher levels of available social support predicted better survival, even after controlling for age, functional status, dosage of chemotherapy, and cytogenetic risk group. Within social support, the availability of instrumental support showed more consistent associations with 2-year survival than the availability of emotional support., Conclusions: For patients with AML, the availability of social support is relevant for decreased mortality, after accounting for age, functional impairment, dosage of chemotherapy and cytogenetic risk group.

Aim: Systematization of the results of 20-year multicenter randomized trial of the efficacy of treatment of acute myeloid leukemia (AML) of adults; presentation of the design of the study of the strategy of consolidation and maintenance therapy after high-dose consolidation initiated in 2007., Material and Methods: Treatment outcomes on the protocol AML-01.01 are presented for 354 AML patients from 29 hematological centers located in 22 towns of Russia and 2 towns of Ukraine. The patients were randomized into 3 groups by variant of therapy: 124 patients (62 males and 62 females; age median 42 years) received 4 courses of 7+3+VP-16 and 5 courses of maintenance therapy (7+3 with thioguanin); 130 patients (65 males and 65 females, age median 41 year) received 2 courses of 7+3+VP-16, 2 courses 7+3, maintenance--5 courses 7+3 with thioguanin; 126 patients (57 males and 68 females, age median 40 years) were given 2 courses of 7+3+VP-16, 2 HAD courses, treatment discontinuation., Results: A complete remission after the first course of 7+3+VP-16 was achieved in 55% patients, after the second course--in 30% after the course 7+3+VP-16 or 7+3 with mitoxantron, in 70%--after NAM. Overall and recurrence-free survival were 18 and 35%; 30 and 20%; 36 and 30%, respectively. There was no significant difference in efficacy of the treatment scheme., Conclusion: The multivariate analysis has shown that a leading factor having impact on treatment results was the number of randomized patients: the less patients were randomized, the worse were the results.

Resistance to chemotherapy is one of the major obstacles to effective treatment in acute myeloid leukemia (AML). The most extensively studied protein involved in multidrug resistance (MDR) is the transmembrane glycoprotein P (P-gp), the product of the multidrug resistance gene 1 (MDR1). MDR1/P-gp overexpression is frequently observed in hematological malignancies, especially in acute leukemia, and has been reported to correlate with poor prognosis in acute myeloid leukemia (AML). The aim of this study was to evaluate the level of MDR1 gene expression in bone marrow and/or peripheral blood samples in 92 AML patients in relation to their prognosis. The analyzed group was stratified according to presence or absence of prognostically favorable aberrations (PFAs), such as t(15;17) with PML/RARalpha fusion gene, t(8;21) with AML1/ETO fusion gene or inv(16)/ t(16;16) with CBFbeta/MYH11 fusion gene. These prognostically favorable aberrations were detected by RT-PCR and/or standard cytogenetic techniques. MDR1 expression was detected by semiquantitative comparative RT-PCR using software-based evaluation. The levels of MDR1 expression in the bone marrow predicted induction of complete remission in the whole group of analyzed patients (P = 0.032). They were significantly lower in PFA negative patients who achieved complete remission compared to those who failed to achieve complete remission (P = 0.008). In PFA negative patients, MDR1 expression was higher when compared to PFA positive patients (P = 0.055). No such difference was found when analyzing peripheral blood samples. Our experiments showed no impact of MDR1 expression in bone marrow or peripheral blood cells on overall survival (P = 1.000 and P = 0.903 respectively). In summary, the present study shows the prognostic impact of MDR1 expression on induction of complete remission in AML patients. We confirmed that MDR1 overexpression is an unfavorable prognostic factor in AML, which may help to stratify the risk rate of PFA negative patients. In future studies, quantitative detection of MDR1 expression might be a valuable tool to predict prognosis in this patient subset.

Frailty models are used in univariate data to account for individual heterogeneity. In the popular gamma frailty model the marginal hazard has the form of a Burr model. Although the Burr model is very useful and can offer insight on the data, it is far from perfect. The estimation of the covariate effects is linked to the baseline hazard and this makes the model coefficients hard to interpret. At the same time, the frailties are assumed constant over time, while biological reasoning in some cases may indicate that frailties may be time dependent. In this paper we present a relaxation of the Burr model which is based on loosening the link between the estimation of the covariate effects and the baseline hazard. This can be achieved by replacing the cumulative baseline hazard in the Burr model by a set of time functions, and the frailty variance by a vector of coefficients directly estimated from the data using a partial likelihood. We illustrate the similarities of the model with the Burr model and a further extension of the latter, a model with an autoregressive stochastic process for the frailty. We compare the models on simulated data sets with constant and time-dependent frailties and show how the relaxed Burr models performs on two different real data sets. We show that the relaxed Burr model serves as a good approximation to the Burr model when the frailty is constant, and furthermore it gives better results when the frailty is time dependent., (Copyright 2006 John Wiley & Sons, Ltd.)

The use of a mismatched allograft necessitates T cell depletion for prevention of uncontrolled graft-versus-host disease (GVHD), thus impairing a graft-versus-leukemia effect. Data on donor lymphocyte infusion (DLI) after mismatched stem cell transplantation are lacking. Our experience with 28 patients (treated with 59 mismatched DLIs; range, 1-7) is described. The procedure was prophylactic in 6 patients (9 DLIs) and therapeutic in 22 (50 DLIs). DLI dose ranged from 10(2) to 1.5 x 10(9) T cells/kg. In the 6 patients receiving prophylactic DLI, complete remission was maintained in 5; however, 2 died from GVHD. Clinical response to therapeutic DLI was seen in 6 of 22 (27.3%) patients; a greater tumor burden produced a lower response. GVHD appeared in 13 of 28 patients. Surprisingly, a greater HLA mismatch was associated with a lower risk of GVHD, with 3 of 19 DLIs in 3/6 matching and 16 of 29 DLIs in 5/6 matching with similar follow-up. Nevertheless, no correlation between efficacy and HLA mismatching was noted. Death was frequent and usually related to the basic disease rather than to DLI complications. We conclude that mismatched DLI is feasible and may be effective, especially if given soon after transplantation. Future developments using cell therapy with selective or targeted anticancer activity are warranted, with special attention to prophylactic treatment of T cell depleted mismatched allografts recipients.

To assess the prognostic impact of cytogenetics in elderly patients with acute myeloid leukemia (AML) receiving intensive induction and consolidation treatment according to a single protocol specifically designed for patients above age 60, pretreatment samples from 361 patients registered for the AML HD98-B trial of the German-Austrian AML Study Group were analyzed by chromosome banding and fluorescence in situ hybridization, and cytogenetic findings were correlated with outcome. Using a proportional hazards model with backward selection, 3 prognostic subgroups were identified based on the influence of cytogenetic abnormalities on overall survival (OS): low-risk, t(15;17), and inv(16) in 25 of 361 patients (7%); standard-risk, normal karyotype, t(8;21), t(11q23), +8 within a noncomplex karyotype, and +11 within a noncomplex karyotype in 208 of 361 patients (58%); high-risk, all other aberrations in 128 of 361 patients (35%). On multivariate analysis, high-risk cytogenetics (hazard ratio [HR], 2.24) and age above 70 years (HR, 2.34) were independent prognostic factors affecting OS, and stratification according to these parameters demonstrated that a large subgroup of patients (55%), characterized by age 70 or older or high-risk cytogenetics, or both, had very unfavorable treatment results despite intensive chemotherapy. Thus, karyotype and age are major determinants of outcome in elderly patients with AML.

Neuropilin-1 (NRP-1), a vascular endothelial growth factors and semaphorin receptor functioning as mediator of angiogenesis and neuronal guidance, is expressed by various solid tumors. The importance of NRP-1 in hematological malignancies such as acute myeloid leukemia (AML) remains to be elucidated. Therefore, we determined NRP-1 expression by immunohistochemical analysis of bone marrow biopsies of patients with newly diagnosed, untreated AML. The expression of NRP-1 was significantly increased in AML patients (n = 76; median 12.9 arbitrary units (a.u.)) as compared with controls (n = 38; median 2.75 a.u.). Survival was significantly poorer in patients with high (> median) versus low (< or = median) NRP-1 expression levels with 5-year overall survival rates of 16.9 versus 49.6% (P = 0.050). In conclusion, our data provide evidence of increased NRP-1 expression in AML with significant correlation to survival. Thus, NRP-1 might constitute a promising target for antileukemic and antiangiogenic treatment strategies in AML.

Acute myeloid leukaemia (AML) is mainly affecting elderly patients. Elderly patients are increasingly affected by impairment of functional status (FS). FS is of prognostic relevance for survival in different tumours. Data for patients with AML are rare. Within a prospective trial we recruited patients with newly diagnosed AML and measured FS by two different methods: Karnofsky performance status (KPS) and instrumental activities of daily living (IADL). Sixty-three patients aged 19-85 years (median 61.1) were included. Twenty-three had prior myelodisplastic syndrome (MDS), 7 favourable, 17 unfavourable karyotype. Fifty received induction chemotherapy, 13 palliative chemotherapy. Median survival was 15.2 months (95% CI, 10.8-22.3) in all patients. Age, cytogenetic risk group, and impaired KPS and IADL significantly influenced median survival in univariate analysis. Impairment of IADL was the single most predictive variable. In multivariate analysis, impairment of IADL Score (HR:4.3, 95% CI 1.7-10.5, P = 0.001) and of KPS (HR:4.8, 95% CI 1.9-12.3, P = 0.001), and unfavourable cytogenetic risk group (HR:6.0, 95% CI 2.5-14.3, P < 0.001) significantly predicted median survival. In patients with AML, FS and not age is a major predictor of survival. The influence of FS is independent from cytogenetic risk group. IADL measurement adds information to KPS. The results have to be confirmed in a large sample of patients.

We reviewed 136 patients with advanced acute myelogenous leukemia (AML) and myelodysplastic syndrome (MDS) undergoing allogeneic transplantation to assess the impact of conditioning regimen intensity on outcome. Thirty-nine patients receiving nonmyeloablative stem cell transplantation (NST) were compared with 97 patients receiving myeloablative transplantation. Patients receiving NST were at high risk for treatment-related complications given that they were older, 57 vs 43 years (P < .001), and more likely had received previous or myeloablative transplantation (54% vs 2%; P < .0001). The cumulative risk of relapse was higher for patients after NST (61% vs 38%; P = .02). The 100-day mortality was less after NST (15% vs 32%) Overall survival (OS) at 2 years was 28% for NST and 34% for myeloablative transplantation (P = .89). Progression-free survival (PFS) at 2 years was 20% for NST and 31% for myeloablative transplantation (P = .31). Cox regression analysis showed that the intensity of the conditioning regimen had no effect on either OS or PFS. Despite the high-risk features of patients with advanced AML or MDS undergoing NST, OS and PFS in these patients was similar to those in patients receiving myeloablative transplantation. These results demonstrate that dose intensity plays a significant role in control of disease after transplantation, but that this benefit is negated by increasing treatment-related mortality. These results suggest that NST is a reasonable alternative for patients with advanced AML and MDS at high risk for complications after myeloablative transplantation.

There is a paucity of epidemiological data on chronic myeloproliferative disorders and myelodysplastic syndromes (MDS), while subtypes of acute myeloid leukemia (AML) are rarely defined. We identified 2,112 adult myeloid malignancies in the South Thames area between 1999 and 2000. The incidence (European standard population) of AML was 3.00/100,000, that of MDS 3.47/100,000, chronic myelomonocytic leukemia (CMML) 0.46/100,000, idiopathic myelofibrosis (IMF) 0.37/100,000, polycythemia vera (PV) 1.08/100,000, primary thrombocythemia (PT) 1.65/100,000 and chronic myeloid leukemia (CML) 1.09/100,000. The 3-year survival for AML was 15%, MDS 45%, CMML 29%, IMF 48%, PV 80%, PT 81% and CML 50% We believe this study reflects the true incidence and outcome of myeloid malignancies in South East England.

Purpose: To improve prognosis in children with acute myeloid leukemia (AML) by randomized comparisons of (1) two short consolidation cycles versus the Berlin-Frankfurt-Muenster (BFM) -type biphasic 6-week consolidation and (2) the prophylactic administration of granulocyte colony-stimulating factor (G-CSF) versus no G-CSF. Further, therapy for standard risk patients was intensified by addition of a second induction, HAM (high-dose cytarabine and mitoxantrone)., Patients and Methods: Four hundred seventy-three patients younger than 18 years with de novo AML were enrolled in trial AML-BFM 98. Patients received five courses of intensive chemotherapy, cranial irradiation, and 1-year maintenance therapy., Results: Four hundred eighteen patients (88%) achieved remission. Compared with trial AML-BFM 93, early deaths decreased from 7.4 to 3.2% (P = .005), and 5-year overall survival increased from 58% to 62% (log-rank P = .03). Both types of consolidation therapy led to similar outcome (event-free survival, 51% v 50%), but in the two-cycle arm, treatment duration was shorter (median duration, 15 days), and treatment related mortality was lower (five v nine patients). G-CSF shortened neutropenia, but did not reduce the rate of severe infections. Intensification of induction therapy did not improve prognosis of standard-risk patients (event-free survival, 62% v 67%)., Conclusion: Overall results were improved by neither the administration of G-CSF nor by cycle therapy; however, the latter was easier to perform. Compared with study AML-BFM 93, therapy intensification with HAM in standard-risk patients did not result in improved prognosis. Future treatment designs have to balance intensification of treatment with higher toxicity, improve supportive care, and to consider alternative treatment strategies.

Background and Purpose: Heterogeneity in patient' s response to chemotherapy is consistently observed across populations. Pharmacogenomics, the study of inherited differences in drug disposition and effects, is emerging as a tool to predict efficacy and toxicity of drugs. Glutathione S-transferases (GST) are involved in the metabolism and detoxification of environmental carcinogens and some classes of chemotherapeutics. Polymorphism of GSTM1 and GSTT1, in the form of homozygous deletion, is encountered in varying frequencies in normal population. It has been associated with altered response and toxicity from cytotoxic chemotherapy. In this study, we investigated the impact of these polymorphisms on response and side effects of chemotherapy in adult acute myeloid leukaemia (AML) patients. Correlations between these genetic polymorphisms and other prognostic factors were also investigated., Patients and Methods: We genotyped GSTM1 and GSTT1 in 98 adult AML patients using multiplex PCR. Induction therapy included Doxorubicin and Cytosine arabinoside (3+7) regimen. Treatment outcomes were compared in those with or without GSTM1 and GSTT1 genes., Results: The frequencies of GSTM1 null and GSTT1 null genotypes were 56% and 14%, respectively. Six percent (6%) were double null. The rate of toxic death during induction was 3/7 (43%) and 17/56 (30%) in GSTT1 null and GSTT1 present patients, respectively, p=0.67. This constituted 75% and 42% of total deaths in each group, respectively, p=0.31. Differences were not statistically significant. On the other hand, the rate of complete remission (CR) in patients with GSTM1 present compared to those with GSTM1 null genotype was 12/27 (48%) versus 23/36 (64%), p=0.21. GSTT1 null genotype was significantly associated with lymphoid marker (mainly CD7) expression (p=0.03), known with its adverse effect on prognosis. Overall survival and disease-free survival were similar in patients with and without the genes. No significant associations were encountered between GST genotypes and treatment outcomes., Conclusion: Our data suggest possible association, though not significant, between GSTT1 null genotype and toxic death during induction and between GSTM1 present genotype and lower rate of CR. Studies on larger numbers are needed focusing on selection of anticancer agents to avoid adverse reactions and therapeutic failure, with special emphasis on drug toxicity and dose adjustment.

Patients with acute myeloid leukemia (AML) and normal karyotype are classified in an intermediate-risk group, albeit this subset is heterogeneous for clinical outcome. A recent complementary DNA microarray study identified a gene-expression signature that--when used to cluster normal karyotype patients--separated them into 2 prognostically relevant subgroups. We sought the first independent validation of the prognostic value of this signature. Using oligonucleotide microarrays to measure gene expression in samples from uniformly treated adults with karyotypically normal AML, we performed cluster analysis based on the previously identified signature. We also developed a well-defined classification rule using the signature to predict outcome for individual patients. Cluster analysis confirmed the prognostic utility of the signature: patient clusters differed in overall (P = .001) and disease-free (P = .001) survival. The signature-based classifier identified groups with differences in overall (P = .02) and disease-free (P = .05) survival. A strong association of the outcome classifier with the prognostically adverse FLT3 internal tandem duplication (FLT3 ITD) potentially explained the prognostic significance of the signature. However, in the subgroup of patients without FLT3 ITD there was a moderate difference in survival for the classifier-derived groups. Our analysis confirms the applicability of the gene-expression profiling strategy for outcome prediction in cytogenetically normal AML.

Most studies showing that autologous stem cell transplantation (ASCT) is feasible in older patients with acute myeloid leukemia (AML) referred to highly selected patients considered as eligible after complete remission (CR) achievement and bone marrow or peripheral blood stem cell (PBSC) collection. This study evaluated the feasibility of ASCT from 155 consecutive AML patients aged over 60 years (median age 72 years, range 61 - 94) programmed to receive ASCT by using PBSCs after CR achievement. Overall, 90 out of 155 patients (58%) were judged as eligible for aggressive chemotherapy and 45 (50%) achieved CR. Among these, 36 (80%) received consolidation and 32 (89% of consolidated) were monitored for PBSC mobilization. A successful collection was registered in 25/32 patients (78% of monitored). Finally, 20 patients received ASCT. Reasons for not autografting five mobilizing patients included relapse pre-ASCT, toxicity, and refusal. Median survival was 4 months for the whole patient population and 19 months for patients actually autografted. Overall, 20 out of 90 patients accrued into intensive chemotherapy (22%) and 20 out of the entire patient population (13%) underwent ASCT. It is concluded that APBSCT can result in an improvement of therapeutic results in AML of the elderly, but it is feasible in a minority of selected patients.

A sequential regimen of chemotherapy, reduced-intensity conditioning (RIC) for allogeneic stem cell transplantation (SCT), and prophylactic donor lymphocyte transfusion (pDLT) was studied in 103 patients with refractory acute myeloid leukemia (AML). According to published criteria, refractoriness was defined by primary induction failure (PIF; n = 37), early (n = 53), refractory (n = 8), or second (n = 5) relapse. Chemotherapy consisted of fludarabine (4 x 30 mg/m(2)), cytarabine (4 x 2 g/m(2)), and amsacrine (4 x 100 mg/m(2)), followed 4 days later by RIC, comprising 4 Gy total body irradiation (TBI), cyclophosphamide, and antithymocyte globulin. Patients without graft-versus-host disease (GvHD) at day +120 received pDLT in escalating doses. Patients' median age was 51.8 years. Before conditioning, 99 patients had active disease, 3 were aplastic, 1 was in second complete remission (CR2). Forty-one patients had family donors, 62 had unrelated donors. With a 25-month median follow-up, overall survival (OS) at 1, 2, and 4 years was 54%, 40%, and 32%; the respective leukemia-free survival (LFS) was 47%, 37%, and 30%. Patients with PIF showed a 2-year OS of 62.5%. OS was 87% in 17 patients receiving pDLT. One-year cumulative incidence of leukemic death and non-relapse-mortality was 28.7% and 17.2%. In a multivariate analysis, more than 2 courses of prior chemotherapy were the strongest predictor for poor outcome (P = .007; HR = 3.01 [OS]; P = .002; HR = 3.25 [LFS]). These results indicate a high activity of the regimen in refractory AML.

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.

To determine whether gene expression profiling could improve risk classification and outcome prediction in older acute myeloid leukemia (AML) patients, expression profiles were obtained in pretreatment leukemic samples from 170 patients whose median age was 65 years. Unsupervised clustering methods were used to classify patients into 6 cluster groups (designated A to F) that varied significantly in rates of resistant disease (RD; P < .001), complete response (CR; P = .023), and disease-free survival (DFS; P = .023). Cluster A (n = 24), dominated by NPM1 mutations (78%), normal karyotypes (75%), and genes associated with signaling and apoptosis, had the best DFS (27%) and overall survival (OS; 25% at 5 years). Patients in clusters B (n = 22) and C (n = 31) had the worst OS (5% and 6%, respectively); cluster B was distinguished by the highest rate of RD (77%) and multidrug resistant gene expression (ABCG2, MDR1). Cluster D was characterized by a "proliferative" gene signature with the highest proportion of detectable cytogenetic abnormalities (76%; including 83% of all favorable and 34% of unfavorable karyotypes). Cluster F (n = 33) was dominated by monocytic leukemias (97% of cases), also showing increased NPM1 mutations (61%). These gene expression signatures provide insights into novel groups of AML not predicted by traditional studies that impact prognosis and potential therapy.

Background: Conflicting results have been reported about the prognostic relevance of antecedent myelodysplastic syndrome (MDS) in acute myeloid leukemia (AML) of older adults., Patients and Methods: Data from 87 intensively treated AML patients (median age 69 years) were analyzed, with the aim of comparing therapeutic results and toxicity between de novo and AML secondary to a previous MDS (s-AML). Rate of CD34+ cells mobilization and feasibility of autologous stem cell transplantation (ASCT) were also compared., Results: Complete remission rate, death in induction and primary resistance were not statistically different between the two groups. Median time for neutrophil recovery was similar, while s-AML patients required a longer time for platelet recovery (P = 0.04). There was no difference as to eligibility for consolidation as well as for mobilization and feasibility of ASCT. S-AML had negligible impact on overall survival (OS) and disease-free survival (DFS). In the multivariate analysis the only parameter significantly related to either OS or DFS duration was adverse karyotype (P = 0.02 and 0.04, respectively)., Conclusions: A diagnosis of s-AML does not represent a clinically relevant prognostic factor in elderly AML patients treated with aggressive therapy. Furthermore, s-AML patients can be mobilized and autografted with comparable results as opposed to de novo cases.

We evaluated differences in outcome by ethnicity among children with acute myeloid leukemia (AML). We analyzed 791 children in the CCG 2891 trial and confirmed positive findings in 850 children in the CCG 2961 trial. Hispanic and black children treated with chemotherapy in CCG 2891 had significantly inferior overall survival (OS) from study entry compared with white children (37%+/- 9% vs 48%+/- 4% [P = .016] and 34% +/- 10% vs 48% +/- 4%, [P = .007], respectively). Significantly fewer black children had related donors. Analyses of CCG 2961 confirmed that black children had significantly decreased OS rates compared with white children (45% +/- 12% vs 60% +/- 4%; P = .007) The difference in OS rates between Hispanic and white children approached statistical significance (51% +/- 8% vs 60% +/- 4%; P = .065) Only 7.5% of black children on CCG 2961 had an available family donor. In conclusion, Hispanic and black children with AML have worse survival than white children. Access to chemotherapy, differences in supportive care or leukemia phenotype, and reduced compliance are unlikely explanations for this difference because therapy was given intravenously according to CCG protocols. Fewer black children than expected had an available family marrow donor.

We retrospectively assess the long-term outcome and determined prognostic factors correlated with outcomes in adults with acute myeloid leukemia (AML) undergoing autologous hematopoietic stem cell transplantation (HSCT) in our institution over a 19-year period. A total of 78 adults who received autologous HSCT for AML in first complete remission (CR) and of 21 adults in further CR were included in the study. Bone marrow (n = 14) or peripheral blood stem cells (PBSC) (n = 85) transplantation was performed at a median of 2.9 months from CR. Hematologic recovery was significantly reduced in the PBSC group. Five-year cumulative incidences of relapse were 56 and 49%, respectively. Corresponding 5-year probabilities of event-free survival (EFS) were 33 and 35%, while those of overall survival (OS) were 38 and 49%, respectively. In multivariate analyses, cytogenetics was the main prognostic factor for outcome. Treatment-related mortality (TRM) was of 15% at 5 years, but higher in females as compared to males (p = 0.04). We confirmed that long-term EFS can be achieved after autologous HSCT in adult patients with AML. Results in adults who experience a relapse after conventional chemotherapy support the use of autologous HSCT as salvage therapy if such patients achieve a subsequent CR.

Background: The prognostic significance of age among pediatric patients with acute myeloid leukemia (AML) was investigated., Methods: The authors reviewed the outcome of 424 patients who were

Manganese superoxide dismutase (MnSOD) protects cells against oxidative stress by eliminating superoxides. Hypothetically, decreased MnSOD levels in cancer might lead to increased oxidative stress and, thus, to increased sensitivity of cells to chemotherapy agents. Eighty-nine patients with acute myeloid leukemia (AML) were analyzed for a functional C to T polymorphism of MnSOD, which could potentially lead to decreased enzyme concentrations inside mitochondria. A significant survival advantage (p=0.02) was observed for those AML patients carrying T-containing alleles of MnSOD compared to the patients with the CC genotype. These preliminary results may indicate an important role for genetic factors regulating the cellular redox state in determining the outcome of leukemia chemotherapy.

Children with Down syndrome (DS) and myeloid leukaemia have a significantly higher survival rate than other children, but they also experience considerable treatment-related toxicity. We analysed data on 56 children with DS who were treated on the Nordic Society for Paediatric Haematology and Oncology-acute myeloid leukaemia (NOPHO-AML)88 and NOPHO-AML93 protocols and reviewed the literature. In the dose-intensive NOPHO-AML88 protocol, 8 out of 15 patients (53%) experienced an event. In the less dose-intensive NOPHO-AML93 protocol, 7 out of 41 patients (17%) had an event. Therapy was reduced in 29 patients (52%) with in average 75% and 67% of the scheduled dose of anthracycline and cytarabine, respectively. Treatment-related death occurred in seven who all received full treatment. Relapse and resistant disease occurred at a similar rate in those receiving full and reduced treatment. Review of major series of myeloid leukaemia of DS showed no clear relationship between dose and survival; however, it appears that both a reduction in treatment dose and a less intensively timed treatment regimen improved the outcome. Further studies are needed to define the optimal regimen for treating myeloid leukaemia of DS.

Most patients aged>or=55 to 60 years who are treated for newly diagnosed acute myeloid leukemia (AML) receive a combination of an anthracycline plus cytarabine (ara-C). A principal thesis of this chapter is that such therapy is unsatisfactory for the great majority of such patients. In particular, the >or=15% risk of death in the month following the start of treatment is difficult to justify given median survivals of less than 1 year in the patients who do not die early. Thus, investigational therapy should be recommended for most, if not all, older patients. In patients for whom such therapy is not feasible, low-dose ara-C is a reasonable alternative except for patients with de novo disease and a normal karyotype, who might benefit more from an anthracycline+ara-C combination, and patients with either a poor performance status, abnormal organ function, or age>or=80, for whom supportive/palliative care only is recommended. Distinctions are made between investigational therapies likely associated with lower and higher risks of treatment-related mortality (TRM). The former are preferable initial treatment in patients aged 70 and above, or with abnormal cytogenetics. Three topics are discussed that are likely to be relevant to future clinical research in older patients: the possibility of delaying therapy to gain information about prognosis with initial induction therapy, the clinical value of responses less than conventional complete remission (CR), and the possibility of looking for larger differences between treatments in randomized clinical trials.

Objective: To evaluate trends in survival and treatment for myeloid leukaemia in South Australia during 1977-2002, using population-based survival data plus data on survival and treatment of patients at three teaching hospitals., Methods: Population data were analysed using relative survival methods and hospital registry data using disease-specific survival. Univariate and multivariable analyses were undertaken. Multiple logistic regression analysis was used to investigate factors associated with first-line chemotherapy., Results: South Australia recorded 1,572 new cases of acute myeloid leukaemia (AML) in 1977-2002, together with 536 cases of chronic myeloid leukaemia (CML). Of these cases, 42.6% were recorded in teaching hospital registries. The five-year survival for AML at the teaching hospitals of 14.5% was similar to the corresponding 12.0% for South Australia as a whole. The five-year survival for CML at these hospitals was higher, however, at 48.1% compared with 37.5% for all South Australian cases. Younger patients had higher survivals, both for AML and CML. An increase in survival was evident for more recently diagnosed cases for both leukaemia types, after adjusting for age. This increase in survival was accompanied by an increase over time in the proportion of patients at teaching hospitals having a primary course of chemotherapy. Cytarabine in combination with other agents was the most common induction therapy for AML. While hydroxyurea was the most common first-line treatment of CML, there were changes in clinical policies towards higher-dose treatments, plus trials of new agents and combination therapies., Conclusions: Secular gains in survival have occurred from AML and CML in association with an increased use of chemotherapy.

The DR15 allele at the HLA DRB1 locus is a marker for immune-mediated bone marrow failure syndromes. We hypothesized that HLA DR15 plays a role in T-cell interactions with hematopoiesis and investigated the role of HLA DR15 on graft-versus-host disease (GVHD) and graft-versus-leukemia effects in HLA-matched allogeneic blood or marrow transplantation (BMT) performed for myeloid malignancies. We performed a retrospective analysis of 119 consecutive related and 48 consecutive unrelated allogeneic BMT for myeloid malignancies treated between 1991 and 2005 to investigate the influence of HLA DR15 on overall survival (OS), progression-free survival (PFS), and incidence of grades II to IV acute GVHD. HLA DR15 was determined by either molecular (n = 108) or serologic (n = 59) methods. The incidence of HLA DR15 was similar to the general white population (35/167 = 21%). There were no significant differences in transplantation characteristics between the HLA DR15-positive and -negative groups. There was no significant difference in chronic GVHD, OS, or PFS between the HLA DR15-positive versus-negative groups in any disease or donor relation subgroups. The HLA DR15-positive group experienced a significantly lower incidence of acute GVHD grades II to IV: 23% versus 42% (P = .041). These results suggest that HLA DR15 reduces the risk of acute GVHD.

Down syndrome (DS) children are at an increased risk of developing myelodysplasia and acute myeloid leukaemia (AML). We retrospectively analysed the population-based data on 81 children with myeloid leukaemia of Down syndrome (ML-DS) from the UK National Registry of Childhood Tumours and experience in the Medical Research Council (MRC) AML 10 and AML 12 trials, which enrolled 46 children with ML-DS from 1988 to 2002. Eight per cent of UK children with AML had DS, but DS children comprised only 5% of children registered in MRC trials. The unique clinical characteristics of ML-DS were confirmed. Overall survival (OS) of ML-DS at 5 years increased from 47% in UK children diagnosed from 1988 to 1995 to 75% in children diagnosed from 1996 to 2002. OS for DS children registered in AML 10 and AML 12 was 74% in 5 years and improved from AML 10 to AML 12 (56% vs. 83%) There was no significant difference in OS between DS and non-DS children (OS: 74% vs. 62%, P = 0.4) in the trials, but this result masked a significant increase in early death amongst DS children, with a significant reduction in mortality later on. Relapse was significantly reduced (3% vs. 39%, P = 0.0003), leading to the improved disease-free survival (83% vs. 56%, P = 0.02). Given the increased number of early treatment-related deaths, future treatment protocols should aim to reduce chemotherapy dosage or intensity whilst maintaining low rates of resistant and recurrent disease.

Most acute myeloid leukaemia (AML) patients lack human leucocyte antigen-identical sibling donors for transplantation. Autotransplants and unrelated donor (URD) transplants are therapeutic options. To compare autologous versus URD transplantation for AML in first (CR1) or second complete remission (CR2), we studied the outcomes of 668 autotransplants were compared with 476 URD transplants reported to the Center for International Blood and Marrow Transplant Research. Proportional hazards regression adjusted for differences in prognostic variables. In multivariate analyses transplant-related mortality (TRM) was significantly higher and relapse lower with URD transplantation. Adjusted 3-year survival probabilities were: in CR1 57 (53-61)% with autotransplants and 44 (37-51)% URD (P = 0.002), in CR2 46 (39-53)% and 33 (28-38)% respectively (P = 0.006). Adjusted 3-year leukaemia-free survival (LFS) probabilities were: CR1 53 (48-57)% with autotransplants and 43 (36-50)% with URD (P = 0.021), CR2 39 (32-46)% and 33 (27-38)% respectively (P = 0.169). Both autologous and URD transplantation produced prolonged LFS. High TRM offsets the superior antileukaemia effect of URD transplantation. This retrospective, observational database study showed that autotransplantation, in general, offered higher 3-year survival for AML patients in CR1 and CR2. Cytogenetics, however, were known in only two-thirds of patients and treatment bias cannot be eliminated.

Combination chemotherapy may induce remission from acute myeloid leukemia (AML), but validated criteria for treatment of elderly are lacking. The remission intention (RI) rate for elderly patients, as reported to the Swedish Leukemia Registry, was known to be different when comparing the six health care regions, but the consequences of different management are unknown. The Leukemia Registry, containing 1672 AML patients diagnosed between 1997 and 2001, with 98% coverage and a median follow-up of 4 years, was completed with data from the compulsory cancer and population registries. Among 506 treated and untreated patients aged 70-79 years with AML (non-APL), there was a direct correlation between the RI rate in each health region (range 36-76%) and the two-year overall survival, with no censored observations (6-21%) (chi-squared for trend=11.3, P<0.001; r2=0.86, P<0.02, nonparametric). A 1-month landmark analysis showed significantly better survival in regions with higher RI rates (P=0.003). Differences could not be explained by demographics, and was found in both de novo and secondary leukemias. The 5-year survival of the overall population aged 70-79 years was similar between the regions. Survival of 70-79-year-old AML patients is better in regions where more elderly patients are judged eligible for remission induction.

Results were analyzed for 48 consecutive patients with acute myeloid leukemia not in remission who underwent unrelated donor bone marrow or stem cell transplantation between 1991 and February 2003 at 2 transplant centers. Forty-six were adults with a median age of 32 years (range, 4-58 years). Forty-two were HLA-A, -B, and -DR matched with their respective donors, and 6 were mismatched at 1 of these loci. The conditioning regimen was myeloablative in all cases: busulfan/cyclophosphamide/etoposide in 34 patients, busulfan/cyclophosphamide in 10 patients, and total body irradiation based in 4 patients. Median follow-up for survivors was 540 days (range, 145-2716 days). Only patients with <5000 peripheral blood blasts per microliter at the time of transplantation survived 2 years (18% versus 0%; P = .003). Similarly, patients with <20% blasts in the marrow at the time of transplantation had superior 2-year survival compared with those who had > or =20% (33% versus 5%; P = .04). Patients with <20% blasts who had > or =3 prior therapies also fared poorly. Cause of death was more commonly treatment related rather than relapse related. This study confirms that patients with acute myeloid leukemia not in remission can achieve prolonged survival with myeloablative conditioning and unrelated donor cell transplantation. However, sustained survival occurs only in patients with a low disease burden at the time of unrelated donor stem cell transplantation, and patients with a high disease burden may benefit from added counseling regarding the high risk of death due to both treatment-related toxicities and disease relapse.

The recent WHO classification for acute myeloid leukemias (AML) separates entities by recurrent cytogenetic abnormalities and immunophenotypic features presenting prognostic impact. We have examined the expression of several lineage and maturation linked antigens used in routine immunophenotyping of patients with de novo AML, using a 3-color two-step panel. Cases were diagnosed by peripheral blood counts, bone marrow cytology, cytochemistry, cytogenetics and immunophenotyping (CD2, CD3, CD7, CD19, CD13, CD33, myeloperoxydase -- MPO, CD14, CD15, HLA-DR, CD34, CD56 and CD45). Antigen expression was measured by mean fluorescence intensity (MFI) by flow cytometry (Paint-a-gate software). Thirty five patients were analyzed. Median age: 51 years (15-79). Predominant FAB types were M2 and M4. In 6 cases more than one phenotypically distinct blast subpopulation could be detected. Although our set was small, we tried to analyze the impact of MFI of the examined antigens on the overall survival of the patients. In Cox univariate analysis, age, peripheral leukocytes (WBC) at diagnosis, MFI of CD45, and MPO were significant for worse a survival. In the multivariate analysis only MFI of CD45 and WBC remained in the model (p=0.018 and p=0.014 respectively). After bootstrap resampling, MFI of CD45 entered the model in 69%, WBCin 60%, age in 42% and MFI of MPO in 35% of the sets. Analysis of antigen expression by MFI permitted to detect cases presenting phenotypically distinct blast subpopulations. This may represent a pitfall in studies of minimal residual disease by flow cytometry, as chemotherapy may select one of these subsets.

Background: Valproic acid (VPA) inhibits histone deacetylase activity and, synergizing with all-trans retinoic acid (ATRA), achieves differentiation induction of myeloid blast cells in vitro., Methods: We used VPA in 58 patients with acute myeloid leukemia (AML) who were too old and/or medically unfit to receive intensive chemotherapy (32 AML secondary to myelodysplastic syndrome [MDS], 22 de novo AML, 4 AML secondary to myeloproliferative syndrome). VPA serum concentrations were 50-100 mug/mL. Thirty-one patients received VPA monotherapy. ATRA was added later in 13 patients who did not respond or who relapsed. Another 27 patients received VPA plus ATRA from the start. Median treatment duration was 93 days for VPA and 88 days for ATRA., Results: The response rate was only 5% according to International Working Group (IWG) criteria for AML but was 16% when IWG response criteria for MDS were used, which capture hematologic improvement and stabilization of the disease. These endpoints, which are not necessarily correlated with diminishing blast counts, are relevant for the patients' quality of life. Among 23 patients with a peripheral blast count > 5%, 6 (26%) showed a diminishing blast count, and 5 of these had a complete peripheral blast clearance., Conclusions: Future trials should combine VPA with chemotherapy or demethylating agents., (Copyright 2005 American Cancer Society.)

Purpose: YKL-40 is secreted by cancer cells, macrophages, and neutrophils. It may be a growth or differentiation factor, play a role in angiogenesis, or protect against apoptosis. High serum YKL-40 is associated with poor prognosis in solid carcinomas. The aim was to examine serum YKL-40 in patients with acute myeloid leukemia (AML)., Experimental Design: YKL-40 was measured by ELISA in serum from 77 patients recently diagnosed with AML before and during the first month of chemotherapy., Results: Forty (52%) of the AML patients had elevated serum YKL-40 (compared with age-matched healthy subjects) and their survival was shorter than in patients with normal serum YKL-40 (median, 128 days; interquartile range, 18-629 days versus 386 days; interquartile range, 180-901; P=0.018 Mann-Whitney test). Univariate analysis of serum YKL-40 (logarithmically transformed and treated as a continuous covariate) showed significant association with survival within the first month after start of chemotherapy [hazard ratio (HR), 1.7; 95% confidence interval (CI), 1.2-2.4; P=0.002], first 12 months (HR, 1.6; 95% CI, 1.2-2.0; P=0.0002), and overall survival (HR, 1.3; 95% CI, 1.1-1.6; P=0.003). Multivariate Cox analysis showed that serum YKL-40 was an independent prognostic variable for survival (first month: HR, 1.7; P=0.011; 12 months: HR, 1.6; P=0.0002; overall survival: HR, 1.4; P=0.002). High serum YKL-40 at start of chemotherapy was a risk factor for pneumonia within the first month, and serum YKL-40 increased (P=0.002) at time of pneumonia and was unchanged in patients without infections., Conclusions: Serum YKL-40 is a prognostic biomarker of survival in AML patients. Its role in AML and infections needs to be determined.

Background and Objectives: Translocation (9;11) is the most common t(11q23) in acute myeloid leukemia (AML). A considerable number of patients with this cytogenetic abnormality relapse and die of their disease. We evaluated the clinical significance of minimal residual disease (MRD) monitoring in t(9;11)(p22;q23)-positive AML patients using real-time quantitative reverse transcriptase polymerase chain reaction (RQ-PCR) analysis., Design and Methods: We identified 34 newly diagnosed patients with t(9;11)(p22;q23)-positive AML treated within three multicenter trials of the AML Study Group. MRD could be investigated by RQ-PCR in 19 patients during and after therapy. Because of the relatively low sensitivity of the RQ-PCR (10(-3) to 10(-4) at the cellular level), samples from RQ-PCR-negative patients were also analyzed by nested polymerase chain reaction (nPCR; sensitivity 10-4 to 10-5 at the cellular level)., Results: RQ-PCR monitoring revealed two groups of patients: group 1 (n=11) had negative RQ-PCR in all samples collected in hematologic complete remission whereas group 2 (n=8) had at least one positive RQ-PCR in samples collected in complete remission during therapy. Group 1 had a significantly lower cumulative incidence of relapse (p=0.004) and better overall survival (p=0.003) compared to group 2. nPCR did not add information to that gained from RQ-PCR. Molecular relapse was detected in two patients by RQ-PCR four and six weeks, respectively before hematologic relapse occurred. Quantitative MLL-AF9 levels at diagnosis or during and after therapy had no prognostic impact., Interpretation and Conclusions: Early achievement of sustained RQ-PCR negativity appears to be a prerequisite for long-term hematologic complete remission in t(9;11)-positive AML. Furthermore, RQ-PCR might be useful for early detection of relapse. Additional patients need to be studied to corroborate these findings.

To assess the prognostic relevance of mutations in the NPM1 gene encoding a nucleocytoplasmic shuttle protein in younger adults with acute myeloid leukemia (AML) and normal cytogenetics, sequencing of NPM1 exon 12 was performed in diagnostic samples from 300 patients entered into 2 consecutive multicenter trials of the AML Study Group (AMLSG). Treatment included intensive double-induction therapy and consolidation therapy with high cumulative doses of high-dose cytarabine. NPM1 mutations were identified in 48% of the patients including 12 novel sequence variants, all leading to a frameshift in the C-terminus of the nucleophosmin 1 (NPM1) protein. Mutant NPM1 was associated with specific clinical, phenotypical, and genetic features. Statistical analysis revealed a significant interaction of NPM1 and FLT3 internal tandem duplications (ITDs). NPM1 mutations predicted for better response to induction therapy and for favorable overall survival (OS) only in the absence of FLT3 ITD. Multivariable analysis for OS revealed combined NPM1-mutated/FLT3 ITD-negative status, CEBPA mutation status, availability of a human leukocyte antigen (HLA)-compatible donor, secondary AML, and lactate dehydrogenase (LDH) as prognostic factors. In conclusion, NPM1 mutations in the absence of FLT3 ITD define a distinct molecular and prognostic subclass of young-adult AML patients with normal cytogenetics.

This study evaluated whether amifostine protects against mucositis and other toxicities in patients with advanced, refractory, or recurrent hematologic malignancies undergoing high-dose chemotherapy and total body irradiation. Thirty-five patients (20 with non-Hodgkin lymphoma, 12 with Hodgkin disease, and 3 with acute myelogenous leukemia) who underwent autologous stem cell transplantation were conditioned with total body irradiation 2 Gy twice daily on days -8 through -6; cyclophosphamide 6 g/m(2), etoposide 1.8 g/m(2), and carboplatin 1 g/m(2) on days -5 through -3; and amifostine 500 mg/m(2) on days -8 through -2. Prior institutional experience in patients treated without amifostine was used as a historical comparison (no-amifostine group). Severe mucositis occurred in 14 (40%) of 35 patients in the amifostine group, compared with 33 (94%) of 35 in the no-amifostine group (P < .0001). Total parenteral nutrition was used by 4 (11%) of 35 amifostine-treated patients and 34 (97%) of 35 no-amifostine patients (P < .0001). The median duration of narcotic use decreased from 15.5 days with no amifostine to 11 days with amifostine (P = .002). Granulocyte and platelet engraftment times were similar. Prospective trials with innovative designs and clearly defined stopping rules are warranted to confirm whether amifostine reduces the toxicities of a myelosuppressive conditioning regimen before autologous stem cell transplantation without compromising therapeutic response.