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T Haferlach

Publications and source records attributed to T Haferlach.

At least 37 records · Page 2Linked to original sources
PubMed2004

Modern diagnostics in chronic myeloproliferative diseases (CMPDs).

According to the new WHO classification a group of chronic myeloproliferative diseases (CMPDs) were defined: chronic myeloid leukemia (CML), chronic neutrophilic leukemia (CNL), chronic eosinophilic leukemia and hypereosinophilic syndrome (CEL/HES), polycythemia vera (PV), chronic idiopathic myelofibrosis (with extramedullary hematopoiesis, CIMF), essential thrombocythemia (ET), and so called CMPD/unclassifiable. As clinical features and laboratory findings differ widely between these diseases several diagnostic approaches are mandatory at diagnosis for classification and are needed also for follow up studies, especially for the measurement of minimal residual disease (MRD). We here outline the laboratory set up at diagnosis and during follow up in CMPDs with specific focus on the respective therapeutical consequences. Only by using a comprehensive diagnostic panel including cytomorphology, cytogenetics, and molecular genetic methods establishing the correct diagnosis, optimizing treatment as well as evaluating treatment response is possible in CMPDs today.

Blood Cell Count↗
PubMed2004

Pediatric acute lymphoblastic leukemia (ALL) gene expression signatures classify an independent cohort of adult ALL patients.

Recent reports support a possible future application of gene expression profiling for the diagnosis of leukemias. However, the robustness of subtype-specific gene expression signatures has to be proven on independent patient samples. Here, we present gene expression data of 34 adult acute lymphoblastic leukemia (ALL) patients (Affymetrix U133A microarrays). Support Vector Machines (SVMs) were applied to stratify our samples based on given gene lists reported to predict MLL, BCR-ABL, and T-ALL, as well as MLL and non-MLL gene rearrangement positive pediatric ALL. In addition, seven other B-precursor ALL cases not bearing t(9;22) or t(11q23)/MLL chromosomal aberrations were analyzed. Using top differentially expressed genes, hierarchical cluster and principal component analyses demonstrate that the genetically more heterogeneous B-precursor ALL samples intercalate with BCR-ABL-positive cases, but were clearly distinct from T-ALL and MLL profiles. Similar expression signatures were observed for both heterogeneous B-precursor ALL and for BCR-ABL-positive cases. As an unrelated laboratory, we demonstrate that gene signatures defined for childhood ALL were also capable of stratifying distinct subtypes in our cohort of adult ALL patients. As such, previously reported gene expression patterns identified by microarray technology are validated and confirmed on truly independent leukemia patient samples.

Adult↗
PubMed2004

Karyotype is an independent prognostic parameter in therapy-related acute myeloid leukemia (t-AML): an analysis of 93 patients with t-AML in comparison to 1091 patients with de novo AML.

The aim of this study was to compare the pattern of karyotype abnormalities of therapy-related acute myeloid leukemia (t-AML) (n=93) with de novo AML (n=1091), and to evaluate their impact on prognosis. Favorable, intermediate, and unfavorable cytogenetics were observed in 25.8, 28.0, and 46.2% of t-AML, and in 22.2, 57.3, and 20.4% of de novo AML. The median overall survival (OS) was shorter in t-AML than in de novo AML (10 vs 15 months, P=0.0007). Favorable and unfavorable cytogenetics had a prognostic impact with respect to OS in both t-AML (P=0.001 and 0.0001) and de novo AML (P<0.0001 and <0.0001). To define the overall prognostic impact of cytogenetics and t-AML, a multivariate Cox's regression analysis was performed for OS with favorable cytogenetics, unfavorable cytogenetics, t-AML, age, and white blood cell (WBC) count as covariates. All parameters proved to be independently related to OS (P=0.001 for t-AML, P<0.0001 for all other parameters). Within patients with t-AML, there were significant correlations between OS and both unfavorable (P<0.0001) and favorable cytogenetics (P=0.001), while age and WBC count had no impact on OS. In conclusion, these data indicate that cytogenetics are an important prognostic parameter in t-AML. Furthermore, t-AML is an unfavorable factor independent of cytogenetics with respect to survival.

Acute Disease↗
PubMed2004

An update: 12-year follow-up of patients with hairy cell leukemia following treatment with 2-chlorodeoxyadenosine.

Long-term results of both pretreated and previously untreated patients (pts) with hairy cell leukemia (HCL) using uniformly a single 7-day course of 2-chlorodeoxyadenosine (2-CdA) by continuous infusion are reported. In addition, the probability of obtaining another response with this drug in pts who relapsed after 2-CdA treatment will be addressed. A total of 44 consecutive pts (34 males, 10 females) with a median age of 57 years (range 33-77) at the time of initiation of 2-CdA treatment were analyzed. In all, 11 pts were pretreated with either splenectomy (n=6), interferon alpha (n=9) or deoxycoformycin (dCF) (n=3) or all procedures in sequence. Two pts treated with dCF did not respond to dCF, but only 2-CdA. The median time to the start of 2-CdA treatment of the 11 pretreated pts was 47 months (mo) (10-160). Out of 44, 43 (98%) achieved complete response (CR) (13 pts with residual disease-RD), one pt reached a good partial response with a single cycle of 2-CdA. Out of 44 pts, 13 had no nonhematologic toxicities at all. Toxicities (WHO grade I-IV) were mainly of grade I and II, in one pt grade IV infectious complication. Bone marrow biopsies were performed at the time of recovery of hematopoiesis, thereafter at 2-3 mo intervals, thereafter at 6 mo, and finally annually in 35 pts. The median follow-up is 8.5 years (0.1-12.2). Disease-free survival from the start of 2-CdA treatment is 36% at 12 years (median 8.4 years), 17/44 pts relapsed. Nine of these pts were treated with 2-CdA again, eight achieved a second CR (median 2.5 yrs), one pt did not respond. Eight of our cohort had a second malignancy before receiving 2-CdA. Six pts died in CR due to the second malignancy. The overall survival at 12 years after the start of 2-CdA treatment is 79%. 2-CdA is a safe and effective treatment of HCL inducing complete remissions in the majority of pts with only a single cycle of 2-CdA, and a paucity of toxicities. Responses are durable and long-lasting. Pts who relapsed following treatment with 2-CdA responded to subsequent retreatment with 2-CdA.

Adult↗
PubMed2003

Myelodysplastic syndrome (RARS) with +i(12p) abnormality in a patient 10 months after diagnosis and successful treatment of a mediastinal germ cell tumor (MGCT).

We report on a 21-year-old man with a mediastinal germ cell tumor (MGCT) who developed a myelodysplastic syndrome (MDS) (refractory anemia with ringed sideroblasts, RARS) 10 months after the start of successful treatment with cisplatin, etoposide, ifosfamide, and paclitaxel. A very rare early occurrence of a therapy-related MDS was suspected. Cytogenetic analysis of the bone marrow revealed an aberrant karyotype, showing a deletion in 12p, an isochromosome 5p, as well as gain of an isochromosome 12p. Isochromosome 12p is a specific aberration frequently observed in MGCT. It also was described in patients who developed hematological transformation of a mediastinal germ cell tumor. In this report the association between mediastinal germ cell tumors and hematological malignancies including the possibility of a common genetic origin is discussed.

Adult↗
PubMed2003

German multicenter study group for adult ALL (GMALL): recruitment in comparison to ALL incidence and its impact on study results.

Due to eligibility criteria not all patients with the disease under investigation can be recruited for therapeutic studies. Thus, the external validity of study results cannot per se be taken for granted. The representativity of the admitted patients is the most relevant determinant for external validity and has to be assessed. As an example we examined the representativity of the patients recruited for the German multicenter study group for adult acute lymphoblastic leukemia (ALL) (GMALL). Lacking nationwide ALL incidence figures available in Germany, a methodology was developed to estimate incidence figures, too. All relevant study groups, hospitals, and diagnostic labs were asked to provide data about patients with ALL newly diagnosed between 1997 and 1998. A matching procedure was developed, as heterogeneous databases had to be pooled and checked for duplicates. Age- and sex-specific incidences of ALL were estimated and compared with the number of patients recruited for the GMALL in the same time period. The purpose was to develop a methodology for estimating incidence figures and evaluating the representativity of patients of the GMALL. The combination of various data sources allowed estimation of reliable incidence data for ALL in Germany. Comparisons with the incidence figures for ALL in other countries and crosschecks within Germany confirm our results. Sixty-two percent of all ALL patients in Germany were admitted to the GMALL study. The recruitment rate of more than 60% of the annual incidence of ALL to the GMALL suggests a high external validity as well as an impact of the study on the patterns of treatment and referral of ALL in adults in Germany. There is no selection bias of patients admitted to the GMALL compared to those patients not included in the study.

Adolescent↗
PubMed2003

Bioinformatics for medical diagnostics: assessment of microarray data in the context of clinical databases.

MOTIVATION: To identify genes suitable for medical diagnostics microarray data is assessed in the context of clinical databases, which store complex information about the patient phenotype. The wealth of data and lacking standards make it difficult to analyse this kind of data. RESULTS: We present a workflow for exploratory analysis of microarray data together with clinical data consisting of four steps: definition of clinically meaningful research questions in a masterfile, generation of analysis files, selection and characterization of differentially expressed genes, and estimation of classification accuracy. We applied this workflow to large data sets from the field of cardiology and oncology (n~500 patients). Systematic data management of microarray data and clinical data helps to make results more transparent and comparable.

Cardiology↗
PubMed2003

New insights into the biology of acute myeloid leukemia and their impact on treatment.

Acute myeloid leukemia (AML) is a heterogeneous group of disorders that can be discriminated by morphology, immunophenotyping or more recently by cytogenetic and molecular techniques. By cytogenetics two major groups of AML can be discriminated: One group with detectable chromosomal aberrations accounting for approximately 52 % of all de novo AML and the second group without cytogenetically detectable karyotype abnormalities. In the first group two major subtypes can be further distinguished. The first group comprises AML with balanced aberrations mainly consisting in t(8;21), t(15;17) and inv(16). The second group comprizes cases with unbalanced aberrations including particularly 5q-, 17q- -5 and AML with complex karyotypes. AMLs with balanced aberrations have a good prognosis with long term survival being achieved in approximately 60 %-80 % of cases. AMLs with non-balanced aberrations on the other hand have a poor prognosis with only 10 %-15 % long-term survivors. AMLs with no detectable abnormalities or other cytogenetic aberrations comprise a group with an intermediate prognosis in which long term survival is achieved in approximately 25 %-30 % of cases. Biologically, AMLs with balanced aberrations regularly involve the deregulation of transcription factors resulting in an impairment of cell differentiation and proliferation. AMLs with unbalanced aberrations are mostly characterized by a loss of genetic material resulting in an alteration of cell cycle control and DNA repair. A new view on the biology of AML has recently been made possible through the analysis of gene expression profiles. This technique is still under investigation. First results, however, already show that gene expression patterns have a high diagnostic potential and allow to detect biology subgroups with a high accuracy. Furthermore, by this technique pathways can be identified that are altered in the leukemic process. Gene expression profiling therefore opens a new and exciting perspective in leukemia biology and therapy that may have substantial impact on the improvement of diagnosis and more importantly may guide therapeutic strategies.

Acute Disease↗
PubMed2002

Comparison of chromosome banding analysis, interphase- and hypermetaphase-FISH, qualitative and quantitative PCR for diagnosis and for follow-up in chronic myeloid leukemia: a study on 350 cases.

For the diagnosis of CML and for monitoring of treatment response the detection of the t(9;22)(q34;q11) or the BCR-ABL rearrangement is necessary. Chromosome banding analysis (CA) is still the gold standard but other techniques like Southern blot, fluorescence in situ hybridization (FISH) and polymerase chain reaction (PCR) are available. We analyzed 350 CML patients at different stages of disease in parallel with CA, interphase-FISH (IP-FISH), hypermetaphase-FISH (HM-FISH) and RT-PCR. In 20 cases with no Ph(+) metaphases in CA, HM-FISH detected 0.2 to 10% BCR-ABL(+)metaphases. After IP-FISH 107 samples were judged as negative. However, in 17 of these samples HM-FISH detected BCR-ABL(+) metaphases (0.3-11%), and in eight cases CA detected Ph(+) metaphases (2.5-25%). A comparison of IP-FISH performed on uncultivated cells vs cells cultivated for 48 h in 70 cases revealed a higher proportion of BCR-ABL+ cells in the cultivated samples. If nested PCR was negative, all other methods were negative in all cases too. In addition, 94 cases were evaluated using real-time PCR (LightCycler technology). The BCR-ABL/cABL ratio measured showed a high correlation with all other methods. Interestingly, a wide range in the BCR-ABL/ABL ratio was observed especially in patients who showed 100% Ph-positive metaphases in CA. In conclusion, CA, IP-FISH, HM-FISH and real-time PCR give reliable results but differences due to measurement of different target structures have to be kept in mind when using these data for definition of remission status.

B-Lymphocytes↗
PubMed2002

Karyotype instability between diagnosis and relapse in 117 patients with acute myeloid leukemia: implications for resistance against therapy.

The instability of the karyotype may play a role in the development of refractoriness of acute myeloid leukemia (AML) to anti-leukemic therapy. Therefore, in the current study cytogenetic analyses were performed in 117 patients with AML both at diagnosis and at relapse. Changes in karyotype were observed in 38% (36% of initially normal karyotypes, 39% of initially aberrant karyotypes). An evolution of karyotype, ie the acquisition of further aberrations in addition to those present at diagnosis, occurred more frequently in patients with unfavorable karyotypes at diagnosis as compared to all others (60% vs 32%, P = 0.0095). The duration from initial diagnosis to relapse was significantly shorter in cases with an evolution of the aberrant karyotype as compared to cases with no changes in the aberrant karyotype between diagnosis and relapse or with solely regression of aberrations at relapse (9.2 +/- 4.4 vs14.0 +/- 8.5 months, P = 0.0081). In an additional analysis, another cohort of 120 patients with refractory and relapsed AML who were treated uniformly within the respective trial of the German AML Cooperative Group was analyzed cytogenetically at diagnosis and at relapse to further prove the prognostic impact of karyotype aberrations at relapse. Karyotypes were prognostically favorable, intermediate, unfavorable and not available in 8%, 50%, 17% and 25% at diagnosis and in 8%, 49%, 21% and 22% at relapse, respectively. Karyotype aberrations at diagnosis had no impact on response to therapy (P = 0.32) but influenced survival and event-free survival significantly (P = 0.03 and P = 0.02). In contrast, karyotype aberrations at relapse strongly influenced response to therapy (P = 0.05), survival (P = 0.01), and event-free survival (P = 0.002). These data suggest that the instability of the karyotype between diagnosis and relapse and thus karyotype aberrations at relapse in particular contribute to the refractoriness of AML to anti-leukemic therapy.

Acute Disease↗