Rudiger Hehlmann

Age, not therapy intensity, determines outcomes of adults with acute myeloid leukemia.

Increasing age is strongly associated with worse therapy outcomes of persons with acute myeloid leukemia (AML). Why it is so is unclear and likely complex. Is it age per se or variables correlated with age such as a different types of AML, a different pattern of prognostic variables such as cytogenetics or mutations, different frequencies of comorbidities and of frailty, different therapy intensities, different tolerance to therapy or other identified or unidentified variables alone or combined? In 1999, the German Acute Myeloid Leukemia Cooperative Group designed a study to address this question (AMLCG99). Here we compared outcomes of subjects of similar age assigned to receive very different therapy intensities but who had similar outcomes. The study included 3540 subjects 18–85 years with untreated AML or with myelodysplastic syndrome with 11–19% bone marrow blasts (Figure 1). Protocol details are published; NCT00266136). This analysis focuses on the 576 subjects ⩾57 to o63 years of age. Subjects ⩾57 to o60 years were randomly assigned to remission induction therapy with 2 courses (double-induction) regardless of the percent of bone marrow blasts after the first course. The first course was TAD (thioguanine, standard dose cytarabine and daunorubicin) or HAM (high-dose cytarabine and mitoxantrone). All subjects received a second course of HAM. Subjects achieving complete remission received one consolidation course of TAD. Subjects were randomly assigned to receive 3 years of monthly maintenance therapy with reduced-intensity TAD or high-dose therapy and an autotransplant. Subjects with an HLA-identical sibling were recommended to receive a transplant. Subjects with unfavorable cytoor molecular genetics and a HLA-matched unrelated potential donor were also recommended to receive a transplant. Subjects ⩾60 to o63 years were also randomly assigned to double-induction therapy. The first course was TAD or HAM similar to the younger cohort. However, only subjects with ⩾5% bone marrow myeloblasts on day 16 after the first course received the second course of HAM. Also, the dose of cytarabine used in HAM was reduced substantially (18 to 6 g/mE+2). Subjects achieving complete remission after 1 or 2 courses received 1 consolidation course with TAD. Subjects still in remission received 3 years of monthly maintenance therapy with reduced-dose TAD. Consequently, postremission therapy of subjects ⩾60 to o63 years was identical to the monthly maintenance chemotherapy arm of subjects ⩾57 to o60 years. Older subjects could receive an allotransplant at the discretion

Monitoring of Residual Disease in Patients with Chronic Myelogenous Leukemia Using Specific Fluorescent Hybridization Probes for Real-Time Quantitative RT-PCR

In many ways, chronic myelogenous leukemia (CML) serves as a paradigm for the utility of molecular methods to diagnose malignancy or to monitor patient response to therapy [1]. CML constitutes a clinical model for molecular detection and therapy surveillance since this entity was the first leukemia known to be associated with a specific chromosomal rearrangement, the Philadelphia (Ph) translocation t(9;22)(q34;q11), and the presence of two chimeric genes, BCR-ABL on chromosome 22 and ABL-BCR on chromosome 9. BCR-ABL is transcribed to a specific BCR-ABL mRNA and encodes in most patients a 210-kDa chimeric protein with increased tyrosine kinase activity. The central role of BCR-ABL in several pathways which lead to uncontrolled proliferation has been shown in vitro and in vivo. Several approaches have been introduced that can specifically detect the Ph translocation or its products, such as fluorescent in situ hybridization, Southern blotting, western blotting, and reverse transcriptase polymerase chain reaction (RT-PCR) [2–4]. Of these, RT-PCR for BCR-ABL mRNA is by far the most sensitive and consequently has received the most attention in the context of minimal residual disease.

Erkrankungen des Blutes

Die hamatopoetischen Stammzellen sind charakterisiert durch die Fahigkeit zur Selbsterneuerung und Differenzierung in Progenitorzellen (Vorlauferzellen). Von diesen Vorlauferzellen stammen alle zellularen Bestandteile des Blutes ab. Die beim Erwachsenen im Knochenmark vorkommende pluripotente hamatopoetische Stammzelle steht somit am Beginn der Entwicklung aller hamatopoetischen Reihen (lymphozytar, myeloisch, erythrozytar und megakaryozytar). Die Proliferation und die Differenzierung dieser Zellen werden unter anderem durch das komplexe Zusammenspiel von Wachstumsfaktoren (Zytokinen) sowie von Zell-Zell-und Zell-Matrix-Interaktionen reguliert. Im Folgenden werden die zugrunde liegenden pathophysiologischen Konzepte dargestellt.