Flow-cytometric detection of minimal residual disease with atypical antigen combinations in patients with de novo acute myeloid leukemia

 The immunophenotypic features in adult de novo acute myeloid leukemia (AML) patients at diagnosis using flow cytometry double marker analysis and the detection of minimal residual disease with atypical leukemia-associated antigen combinations during remission were investigated. Fifty adult patients with de novo AML at diagnosis were studied. Bone marrow samples from 21 patients with AML were analyzed upon achievement of complete remission and during continuous complete remission. Ten bone marrow samples of normal donors were also studied. CD34/CD13, CD34/CD33, CD33/CD7, CD33/CD10, CD33/CD19 and CD33/TdT are the leukemia-associated antigen combinations used for the detection of minimal residual disease. The outcome of 19 patients has been evaluated. Of these 19 patients, 10 were found to be in immunophenotypic remission (median follow-up after the study: 837 days, range 620–1343 days). Only one patient in this group has relapsed so far. In the other nine patients residual disease was detected. Seven of these patients developed systemic relapse following a median follow-up time of 86 days after the study (range 34–273 days), one received allogeneic bone marrow transplantation 70 days after the study, and another has been in complete remission and off chemotherapy for 36 months. The presence of cells with atypical antigen combinations identified at diagnosis in certain patients is valuable for monitoring the disease in remission. The persistence of such a population in remission has indicated the impending relapse in this study. Received: 11 October 1999 / Accepted: 11 February 2000     

Prognostic significance of chromosome analysis in de novo acute myeloid leukemia (AML)

Summary Between 1981 and 1986 cytogenetic studies of bone marrow and/or blood cells in 139 patients with de novo acute myeloid leukemia (AML) were performed. The overall incidence of chromosomal aberrations was 53%, and this was not significantly influenced by sex, age nor the FAB classification. The aberrations most often found were: complex anomalies (n=13), t(8; 21) (n=10), trisomy 8 (n=9), monosomy 7 (n=6), monosomy 5, 5q-, trisomy 11, 12p- (n=4) and trisomy 6, 11q-, inv [16] (n=3). The prognostic significance of chromosomal findings was evaluated in 112 patients treated by combination chemotherapy. The chromosomal status NN, AN, AA did neither significantly influence complete remission rate (NN: 68%, AN: 71%, AA: 60%) nor mean survival (NN: 24, AN: 26.6, AA: 35.6 months). On the other hand, certain types of chromosomal anomalies were of prognostic value. CR was obtained in all 10 patients with t(8; 21) but only in 2 out of 9 patients with complex aberrations. Median duration of CR in patients with t(8; 21) was significantly longer than in patients with a normal karyotype (30 vs 7 months).     

Effect of mast cell growth factor on clonogenic blast cell growth in acute myelogenous leukemia

 The effect of the mast cell growth factor (MGF), also known as stem cell factor, steel factor, and kit ligand, alone or in combination with other GFs on clonogenic blast cell growth in 23 patients with acute myeloblastic leukemia (AML) was investigated. MGF alone enhanced colony formation by about 35%, being clearly stimulatory (>20% increase in colony numbers) in nine patients. The additive effect of MGF on colony growth was observed in combination with interleukin-3 (IL-3). Preincubation of the cells with MGF in suspension did not sensitize them to the effect of IL-3, granulocyte-macrophage colony-stimulating factor (GM-CSF), G-CSF, or IL-4 in a clonogenic cell culture assay. Although almost all the blast cell samples expressed the c-kit the receptor for MGF, at the mRNA and/or the protein level, the cells did not necessarily respond to exogenous MGF. On the other hand, blast cells were able to respond to exogenous MGF even when the cells themselves expressed MGF. Neither the expression of MGF nor the response of blast cells to exogenous MGF was related to the capability of the cells to form colonies spontaneously. In conclusion, MGF alone, but especially combined with IL-3, was a potent growth factor for clonogenic blast cells in AML. Autocrine production of MGF by AML blast cells analyzed at the mRNA level was not related to autonomous growth of the cells. Received: 5 December 1995 / Accepted: 2 May 1996     

Occurrence of T-cell lymphoma in a patient with acute myelogenous leukemia

 We describe a patient with AML with a monocytic component who developed a T-lymphoblastic lymphoma. Lymphoma was diagnosed 9 months following AML diagnosis. To our knowledge, this is the first report of phenotypically documented T-cell lymphoma following AML. The questions relating to the pathogenesis of the two malignancies are discussed. Received: 22 January 1996 / Accepted: 12 April 1996     

Excellent disease eradication by myeloablative therapy and stem-cell transplantation in patients with acute myelogenous leukemia

 Between February 1982 and 1999, 118 consecutive patients (65 male, 53 female) with acute myelogenous leukemia (AML), with a median age of 35 years (range 17–56 years), received stem-cell grafts from a human leukocyte antigen-identical sibling (n=71), one-antigen-mismatched family member (n=2), matched unrelated donor (n=15), one-antigen-mismatched unrelated donor (n=4) or an autologous (n=26) graft. At the time of transplant, 56 patients were in the first complete remission (CR), 27 in the second CR, 6 in untreated relapse, 17 in primary refractory, and 12 in refractory relapse. The French-American-British classification (FAB) subtypes were as follows: M1 (n=25), M2 (n=28), M3 (n=11), M4 (n=32), M5 (n=16), M6 (n=6). For conditioning, most patients underwent total body irradiation-containing regimens. As of 28 February, 1999, probability of leukemia-free survival (LFS) is 58% for patients after related and 45% after unrelated stem-cell transplantation (SCT). The probability of LFS is 70% for patients given allogeneic transplants in the first CR compared with 33% for those beyond the first CR at SCT. In autologous stem-cell graft recipients, the probability of LFS is 37%. Transplant-related mortality was 28% after related, 20% after unrelated, and 4% after autologous SCT. Probability of relapse for patients given related-donor stem-cell grafts in the first CR and beyond the first CR is 30% and 67%, 55% after unrelated and 63% after autologous stem-cell grafting. Thus, myeloablative therapy followed by allogeneic stem-cell infusion has a high curative potential for patients with AML in remission and offers substantial benefits to patients in advanced disease. Received: 26 May 1999 / Accepted: 20 August 1999     

Leukemic hypopyon in acute myelogenous leukemia

We encountered a patient with acute myelogenous leukemia (AML) who developed leukemic hypopyon. Leukemia initially spread into the pharynx, gingiva, lymphnode, and bone marrow. He achieved complete remission after chemotherapy but developed blurred vision and hypopyon. Anterior chamber paracentesis disclosed leukemic infiltration of the anterior chamber. Infiltration of the central nervous system also occurred. He received systemic chemotherapy, intrathecal chemotherapy, and local chemotherapy. However, he did not achieve prolonged remission. These findings suggest that these chemotherapy treatments have an inadequate effect for AML with anterior chamber infiltration. This rare complication is associated with extramedullary infiltration of leukemia. Received: 13 September 1999 / Accepted: 23 December 1999     

Prognostic significance of HOXB4 in de novo acute myeloid leukemia

As research into hematopoiesis advances, new factors associated with hematopoietic stem cell (HSC) activity have been discovered, and the contribution of HSC factors to hematopoiesis is now actively being investigated. Since the involvement of stem cells is considered to be important in hematological malignancies as well as normal hematopoiesis, we examined the expression of newly defined HSC factors including HOXB4, TCFEC, HMGB-1, FOS, and SPI-1 in the bone marrow (BM) from de novo acute myeloid leukemia (AML) patients. Expression levels of mRNA extracted from frozen specimens of AML patients and normal controls were measured by real-time polymerase chain reaction (PCR). Among the HSC factors, HOXB4 exhibited significantly higher expression in the BM of AML as compared with normal controls. Immunostaining for HOXB4 revealed that the HOXB4-positive cell ratios correlated well with the expression levels of mRNA for HOXB4 in AML BM. Based on the HOXB4-positive cell ratio, AML patients were divided into two groups (cases with higher ratios and lower ratios). The group with higher HOXB4-positive cell ratios had better prognoses as compared with the group with lower ratios. Multivariate analysis confirmed the HOXB4-positivity as an independent predictor of overall survival of AML patients. Lastly, mRNA expression levels for HOXB4 were inversely correlated with the expression levels of at least two genes, including ABCB1, which is known to be a multidrug-resistance gene. Our study distinguishes a subgroup of AML with higher HOXB4 expression and better prognosis, and this might be reflected by relative drug sensitivity in leukemic cells.     

Generation of dendritic cells from patients with chronic myelogenous leukemia

 Dendritic cells (DCs) are professional antigen-presenting cells (APCs) specialized to internalize, process, and present antigen. They have the capacity to stimulate the primary immune response of resting T-cells. We generated DCs from the adherent cell fraction of peripheral blood, as well as from purified CD34⁺ cells from CML patients. Characterizing DCs from ten CML patients by flow cytometry, we found that these cells are highly positive for HLA-DR, CD1a, CD23, and CD80 and negative for CD14, CD15, and CD16. The yield of DCs ranged from 19.5 to 68%. In addition, we used a functional test of FITC-dextran uptake to verify that early DCs take up large particles (0.5–3 μm) by macropinocytosis while monocytes do not. FITC-dextran uptake was detected by flow cytometry, showing that DCs had accumulated these fluorescent particles. Electron-microscopic analysis showed no major morphological differences between normal and CML-derived DCs. Furthermore, cultured DCs were isolated by FAC sorting for CD1a and HLA-DR expression. In these highly purified cells the Ph chromosome was detected by interphase fluorescence in situ hybridization (FISH) and by fluorescence immunophenotyping and interphase cytogenetics as a tool for the investigation of neoplasms (FICTION); 30–85% of DCs generated were Ph-chromosome positive. It might therefore be possible not only to prime T-cells with bcr/abl-specific synthetic peptides, but also to stimulate T cells directly with Ph-positive DCs. Use of DCs might serve as a novel therapeutic approach in CML patients, due to their ability to induce highly specific T-cell responses in an autologous system. Received: August 17, 1998 / Accepted: January 15, 1999     

Association between structural and numerical chromosomal aberrations in acute myeloblastic leukemia: a study by RT-PCR and FISH in 447 patients with de-novo AML

 We analyzed 447 patients with de novo AML using α-satellite probes for the chromosomes 7, 8, X, and Y and RT-PCR for t(8;21), t(15;17) and inv(16). In 130/447 patients (29%) chromosomal aberrations were found. Thirty-three patients (7%) had a t(8;21); 11 of these had the additional loss of a sex chromosome (p<0.001) and two a trisomy 8. Twenty-nine patients (6%) had a t(15;17); four of these had a trisomy 8. Sixteen patients (4%) displayed an inv(16); four of these had a trisomy 8. Twenty-two patients (5%) had a sole trisomy 8 and one patient the combination of trisomy 8 and trisomy X. Five patients (1%) displayed the loss of a Y-chromosome as the sole abnormality and two patients had a sole trisomy X. In 22 patients (5%) a monosomy 7 was found, and in none of these patients were additional chromosomal aberrations detected by RT-PCR (p<0.05). In conclusion, trisomy 8 and the loss of a gonosome are frequently associated with structural chromosomal aberrations with a significant association of –X/Y and t(8;21). The absence of these genomic lesions in AMLs with monosomy 7 suggests that the monosomy 7 has a specific role in the development of these leukemias and their clinical course. Received: October 23, 1998 / Accepted: February 5, 1999     

Granulocytic sarcoma of the ovary in patients with acute myelogenous leukemia

Two cases of granulocytic sarcoma of the ovary found at the time of relapse of acute myelogenous leukemia (AML) are presented. Almost 5 years after the initial diagnosis of AML, both cases presented ovarian tumors which were discovered to be myeloblastoma of the ovary on laparotomy in one case and at the time of autopsy in the other. Evidence of hematological relapse followed the presentation of the ovarian tumor within a month. Both patients were treated with surgery and/or chemotherapy.     

Expression and functional activity of P-glycoprotein in adult acute myelogenous leukemia patients

 Expression and functional activity of P-glycoprotein (P-gp) were measured in 182 acute myelogenous leukemia (AML) patients: 136 patients were treated with the AML-6 protocol (EORTC), containing daunorubicin, vincristine, and conventional-dose cytarabine (ara-C), and 21 patients received idarubicin, vepeside, and conventional-dose ara-C (ICE-AML-10 protocol/EORTC). An additional 25 patients were treated with a dose of idarubicin and ara-C, modified as compared with the ICE protocol, but with the same dose of etopside (ICE-I protocol). P-gp was determined using monoclonal antibody 4E3.16 and functional activity using the rhodamine 123 accumulation test. P-gp positivity was defined as a Kolmogorov Smirnov (KS) D value ≥0.15, P-gp negativity as a KS D value <0.15. P-gp activity was defined as a ratio of mean rhodamine 123 accumulation with/without verapamil. In AML patients at primary diagnosis and early relapse/refractoriness a significant (p<0.05) difference between P-gp-positive and P-gp-negative patients was ascertained using the AML-6 protocol; the difference corresponded to the complete remission rate. For ICE- and ICE-I-treated AML patients at primary diagnosis this significance was not shown. Compared with AML patients at primary diagnosis and patients at early relapse or refractoriness, a significantly (p<0.05) increased incidence of non-pumping P-gp and a trend (p=0.054) to a higher percentage of non-P-gp-related mechanisms in AML patients at late relapse was determined. When the AML-6 protocol is used, age, activated P-gp, and CD34 expression are independent prognostic factors in AML patients. A test system which determines a functional P-gp overexpression is a major tool for identifying a group of AML patients with a poor prognosis. In order to effectively use so-called P-gp modulator substances, the degree of P-gp expression, the activated or nonactivated P-gp condition, and detection of non-P-gp-related resistance mechanisms are of utmost interest for optimal design and analysis of P-gp modulator trials and for understanding the complexity of chemotherapy-related resistance mechanisms in patients. Received: 26 March 1997/Accepted: 10 June 1997     

Comparison of toxicity and outcome in patients with acute myeloid leukemia treated with high-dose cytosine arabinoside consolidation after induction with a regimen containing idarubicin or daunorubicin

 The toxicity and outcome after high-dose ara-C/daunorubicin (HDara-C/DNR) consolidation therapy in de novo AML was compared in 11 patients who received an idarubicin-containing induction therapy (IDA; from June 1995 to March 1997) and 16 patients pretreated with daunorubicin (DNR; from July 1990 to May 1995) for induction. The DNR group consisted of two cohorts, one (n=6) of patients who had received, as had the IDA group, two induction and one intermediate-dose ara-C consolidation courses, and another (n=10) of patients who had been pretreated with one induction and one consolidation course prior to HDara-C/DNR. There was no difference in the relative dose between the three cohorts. Following HDara-C/DNR, the IDA-pretreated patients experienced a more prolonged myelosuppression during consolidation therapy compared with the DNR group. Duration of neutropenia (<500 neutrophils/μl) following HDara-C/DNR was 31.2 ± 16 days (mean ±SEM) in the IDA group compared with 18.7 ± 5 days in the DNR group (p<.001 Mann-Whitney U-test). The duration of thrombocytopenia (platelets <25 000/μl) was 34.8 ± 20 days in the IDA group vs. 18.5 ± 6 days in the DNR group (p<.005). The more prolonged myelosupression was associated with a longer duration of fever (18.9 ± 24 vs. 6.9 ± 5.2 days). A greater incidence, length (11 ± 8 vs. 1.2 ± 2 days), and severity of diarrhea were observed in the IDA-pretreated group. Three of 11 IDA patients experienced WHO grade III-IV diarrhea. In the IDA group two patients developed severe enterocolitis with Candida septicemia, and one of these patients died. One patient in the IDA group died during prolonged aplasia. In the DNR group 6/16 patients experienced grade I-II diarrhea. Two patients in each group died during consolidation therapy. The CR rate was 87% in the IDA group and 79% in the DNR group. Relapse-free survival after HDara-C is 50% at a median follow-up of 60 months in the DNR group and 45% after a median follow-up of 17 months in the IDA group. Whether the advantage of the superior response rate in the IDA-treated patients may be lost during HDara-C consolidation treatment due to increased toxicity remains to be proven in larger trials. Received: 27 October 1997 / Accepted: 28 January 1998     

Absence of mutations in the RET gene in acute myeloid leukemia

 Expression of the tyrosine kinase receptor RET has previously been detected in normal hematopoietic cells, and especially in cells of the myeloid lineage. Furthermore, RET was shown to be differentially expressed in acute myeloid leukemia (AML), a disease characterized by excessive cell growth and aberrant maturation of cells, with the highest levels of expression in leukemias with monocytic differentiation. RET is known to be expressed in cells from the excretory system and from the developing central and peripheral nervous system. Both activating and inactivating aberrations in the RET gene have been detected in disorders derived from these tissues. To investigate whether the differential expression is a primary defect in AML, the presence of RET alterations was scanned by Southern blot analysis on DNA of blasts obtained from 17 AML patients. However, no RET gene aberrations were found. Subsequently, denaturing gradient gel electrophoresis (DGGE) analysis was performed on the DNA of blasts from ten selected cases. All five variants detected turned out to represent neutral DNA polymorphisms, including a novel polymorphism in exon 14. Since we were unable to detect mutations of RET in AML, it is unlikely that it plays an important role in leukemogenesis. Received: 14 August 1997 / Accepted: 15 August 1997     

Long-term survival after induction therapy with idarubicin and cytosine arabinoside for de novo acute myeloid leukemia

 We treated 153 patients with de novo acute myeloid leukemia (AML) with two induction courses of conventional-dose cytosine arabinoside (ara-C) and idarubicin (AIDA) followed by either a third course of AIDA, high-dose ara-C or bone-marrow transplantation. The complete remission (CR) rate for all patients was 63.4%, with a higher CR rate for patients with a normal (versus unfavorable) karyotype (73.2% vs 52.5%;P=0.038). The probability of overall survival (OS) was 30.7% after 5 years (26.3% after 7 years). Improved OS at 5 years could be observed for patients up to 50 years old versus patients older than 50 years of age (37.6% vs 19.9%;P=0.001) and patients with a normal (versus unfavorable) karyotype (42.9% vs 14.1%;P=0.0016). Disease-free survival (DFS) after 5 years was 33.2% for all 97 CR patients and was significantly better for patients with a normal (versus unfavorable) karyotype (44.3% vs 12.3%;P=0.003). Multivariate analysis revealed that the age for OS (P<0.02) and the karyotype for both OS (P<0.03) and DFS (P<0.05) were independent prognostic factors. In conclusion, AIDA is an effective and well-tolerated induction regimen (even in elderly patients) with a 5-year survival of more than 30% when combined with ara-C-containing postremission therapy. The karyotype is the most powerful prognostic factor for predicting the outcome of patients treated with this protocol. Received: 10 December 1999 / Accepted: 25 February 2000     

Prognostic impact of cytogenetic abnormalities in patients with de novo acute nonlymphocytic leukemia

Detailed cytogenetic analyses were performed on specimens from 198 patients with de novo acute nonlymphocytic leukemia (ANLL), including high-resolution banding studies in 79 patients. One hundred ninety-two patients received induction therapy with daunorubicin and cytosine arabinoside (Ara-C) with an overall complete response rate (CR) of 63%. Responding patients received repetitive cycles of Ara-C-based intensification therapy. Clonal abnormalities were detected in 69% of the patients with specimens adequate for cytogenetic analysis. Certain cytogenetic changes were closely associated with French-American- British (FAB) morphology, age, and outcome: t(8;21) (closely associated with FAB M2), t(15;17) (associated with FAB M3), and abn 16q22 (associated with FAB M4EOS) tended to occur in younger patients and were associated with favorable outcomes in terms of both CR rate and long-term disease-free survival. In contrast, 19% of patients who had - 5/5q- and or -7/7q- and seven patients with trisomy 8 were older, had a poor prognosis, and usually failed to achieve remission (CR) because of chemotherapy-resistant leukemia. The adverse effect on CR rate and duration in this group of patients was independent of age, and there was no association with particular morphologic subtypes. These data suggest that cytogenetic findings should influence future therapeutic choices. In particular, patients with abnormalities associated with poor responses may be considered for investigational approaches and may also provide insights into mechanisms of drug resistance.     

N-ras mutations in adult de novo acute myelogenous leukemia: prevalence and clinical significance

Point mutations of the N-ras proto-oncogenes have been previously detected in 20% to 60% of samples of acute myelogenous leukemia (AML), but the clinical significance of these mutations is presently unclear. We directly sequenced polymerase chain reaction (PCR) amplified N-ras fragments to determine the frequency of N-ras point mutations in 55 adult patients with de novo AML. Mutations were present in 8 of 55 (15%) patients. These mutations were usually in codon 12, 13, or 61, but one patient had mutations in both codons 13 and 61, and another had an unusual point mutation in N-ras codon 60. A comparison of patients with and without N-ras mutations showed no statistically significant differences in pretreatment clinical variables, response to induction therapy, or survival, except for a possibly higher percentage of FAB M4 subtypes in patients with the N-ras mutation. These data together with previous reports suggest that the presence of N-ras point mutations do not clearly define a unique clinical or biologic subset of AML patients.     

Loss of heterozygosity in childhood de novo acute myelogenous leukemia

A genome-wide screening for loss of heterozygosity (LOH), a marker for possible involvement of tumor suppressor genes, was conducted in 53 children with de novo acute myelogenous leukemia (AML). A total of 177 highly polymorphic microsatellite repeat markers were used in locus-specific polymerase chain reactions. This comprehensive allelotyping employed flow-sorted cells from diagnostic samples and whole-genome amplification of DNA from small, highly purified samples. Nineteen regions of allelic loss in 17 patients (32%) were detected on chromosome arms 1q, 3q, 5q, 7q (n = 2), 9q (n = 4), 11p (n = 2), 12p (n = 3), 13q (n = 2), 16q, 19q, and Y. The study revealed a degree of allelic loss underestimated by routine cytogenetic analysis, which failed to detect 9 of these LOH events. There was no evidence of LOH by intragenic markers for p53, Nf1, or CBFA2/AML1. Most lymphocytes lacked the deletions, which were detected only in the leukemic myeloid blast population. Analysis of patients' clinical and biologic characteristics indicated that the presence of LOH was associated with a white blood cell count of 20 x 10(9)/L or higher but was not correlated with a shorter overall survival. The relatively low rate of LOH observed in this study compared with findings in solid tumors and in pediatric acute lymphoblastic leukemia and adult AML suggests that tumor suppressor genes are either infrequently involved in the development of pediatric de novo AML or are inactivated by such means as methylation and point mutations. Additional study is needed to determine whether these regions of LOH harbor tumor suppressor genes and whether specific regions of LOH correlate with clinical characteristics. (Blood. 2001;98:1188-1194)     

Cerebellar myeloblastoma formation in CD7-positive, neural cell adhesion molecule (CD56)-positive acute myelogenous leukemia (M1)

 We present a first report of a CD7⁺ acute myelogenous leukemia patient who developed intracranial myeloblastomas. The patient was neurologically normal on physical examination at presentation. The peripheral leukocyte count was extremely high (203.6×10⁹/l). The blasts expressed CD7 and CD56 (neural cell adhesion molecule) in addition to CD13, CD33, CD34, and HLA-DR. The karyotype of bone marrow cells was normal. The patient was diagnosed as having acute myelogenous leukemia (AML, M1). Following a short period of complete remission, bone marrow relapse and meningeal leukemia occurred, and the patient died of respiratory failure. Autopsy revealed that blasts had invaded the subarachnoid space and cerebellum, and two myeloblastomas were found in the cerebellar hemisphere. Both CD7⁺ and CD56⁺ AML have been reported to have a high incidence of central nervous system involvement. CD7⁺ CD56⁺ AML calls for prophylaxis of central nervous system leukemia. Received: 2 May 1997 / Accepted: 17 July 1997     

XPD gene polymorphisms and the effects of induction chemotherapy in cytogenetically normal de novo acute myeloid leukemia patients

Background

Cytogenetically normal acute myeloid leukemia (AML) represents nearly half of newly diagnosed de novo AML cases. XPD is one of the DNA repair proteins, whose genetic polymorphisms are thought to affect their function as regards response to chemotherapeutic drugs and chemotherapy-induced toxicities.

Subjects and methods

We investigated the XPD Asp312Asn and Lys751Gln polymorphisms by polymerase chain reaction-restriction fragment length polymorphism in 51 newly diagnosed cytogenetically normal de novo AML patients. The response to the standard induction chemotherapy protocol and chemotherapy-induced toxicities were monitored.

Results

The XPD Asp312Asn GG genotype was the most frequent (57%) followed by the GA variant (37%), and the AA variant was the least frequent (6%). As regards the XPD Lys751Gln polymorphism, the AA genotype was the most frequent (49%), followed by the AC (39%) and CC (12%) variants. These variants were not associated with age, sex, FAB subtype, CNS infiltration, chemotherapy-induced hepatotoxicity, nephrotoxicity, or metabolic toxicity. The XPD Lys751Gln CC polymorphic variant was associated with chemotherapy-induced cardiotoxicity and lower chance to achieve response to induction chemotherapy.

Conclusion

XPD Lys751Gln and not Asp312Asn polymorphism was associated with chemotherapy-induced cardiotoxicity and response to induction chemotherapy in newly diagnosed cytogenetically normal AML patients. Pretreatment assay of XPD Lys751Gln may help to anticipate cardiotoxicity in those at risk. Moreover, it may be considered a prognostic marker in AML cases. However, further large scale research is needed to verify its usefulness.     

Prognostic significance of CD20 expression in adults with de novo precursor B-lineage acute lymphoblastic leukemia

Immunophenotypic classification of acute lymphoblastic leukemia (ALL) has well-recognized prognostic implications. The significance of CD20 expression has been evaluated in childhood precursor B-lineage ALL with conflicting results. We retrospectively analyzed the influence of CD20 expression on outcome in 253 adults with de novo precursor B-lineage ALL treated with either conventional (VAD/CVAD) or intensive (hyper-CVAD) frontline chemotherapy regimens in the pre-rituximab era. Overall, CD20 positivity of at least 20% was associated with lower 3-year rates of complete remission duration (CRD; 20% vs 55%, P < .001) and overall survival (OS; 27% vs 40%, p = .03). In the CD20 negative subset, the 3-year rates for CRD (58% vs 42%, p = .04) and OS (60% vs 28%, P < .001) were superior for hyper-CVAD compared with VAD/CVAD; rates were particularly favorable for the CD20 negative younger age group (68% and 85%, respectively). In contrast, 3-year CRD and OS rates were uniformly poor for the CD20-positive group regardless of therapy (27% or less). Multivariate analysis for event-free survival identified older age, leukocyte count higher than 30 x 10(9)/L, presence of Philadelphia chromosome, high systemic risk classification, and CD20 positivity as independent predictors of worse outcome. In conclusion, CD20 expression in de novo adult precursor B-lineage ALL appears to be associated with a poor prognosis. Incorporation of monoclonal antibodies directed against CD20 into frontline chemotherapy regimens warrants investigation.