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Priapism as a sign of a severe hematological disease is a rare event, which has to be considered as both a urological and a hematological emergency that requires immediate treatment. This article describes a clinical case of priapism as the first clinical manifestation of a hitherto undiagnosed chronic myeloid leukemia (CML) and discusses the results of a literature review on this topic.Der Priapismus als klinische Manifestation einer hämatologischen Erkrankung ist selten. In diesem Fall liegt ein sowohl urologischer als auch internistischer Notfall vor, der einer umgehenden Therapie bedarf. Dieser Artikel beschreibt den klinischen Fall eines Priapismus als Erstmanifestation einer bis dahin nicht diagnostizierten chronisch-myeloischen Leukämie (CML) und erläutert die Resultate einer Literaturrecherche zu dieser Thematik.

Chronic myeloid leukemia - update 2020

In this work different types of dysregulation of signaling proteins in the context of myeloproliferative neoplasms are examined. In this heterogeneous disease group, uncontrolled cell proliferation plays a crucial role for the initiation of tumorigenesis, which Robert Weinberg described as a "hallmark" for the development of cancer. Protein dysregulation in form of overexpression of GAB2, a protein involved in formation of the CML-pathognomonic BCR/ABL-translocation complex, results in an enhanced disease phenotype in a Bcr/Abl-positive mouse model and disease acceleration is associated with a change of the subcellular localization of GAB2 in human blasts in CML-bone marrow biopsies. Furthermore, analyses of a mouse model show that a protein dysregulation caused by a distinct translocation (Tel-Syk) leads to the formation of a specific and morphologically very characteristic phenotype in the bone marrow of diseased mice. Moreover, results were presented which show that in certain subgroups of Myeloproliferative Neoplasms the protein NFE2, which is initially known only as a translocating factor, is apparently regulated by altering its subcellular localization. The difference in the subcellular localization of NFE2 in erythroid bone marrow cells is so clear between Essential Thrombocythemia and Primary Myelofibrosis that quantitative NFE2 immunohistochemistry can be used as an ancillary tool to diagnostically discriminate these two entities in an early stage.

Diagnostischer Marker der chronischen myeloischen Leukämie (CML) ist der Nachweis des Philadelphia-Chromosoms beziehungsweise der Nachweis der reziproken Translokation t(9;22)(q34;q11). Mithilfe der BCR/ABL1-FISH (Fluoreszenz-in-situ-Hybridisierung) kann diese Aberration festgestellt werden. Die vorliegende Dissertation präsentiert eine vergleichende Analyse sechs kommerzieller FISH-Sondensätze zur Detektion der BCR/ABL1-Fusion, sowie den Vergleich unterschiedlicher FISH-Protokolle zur Optimierung dieser molekulargenetischen Untersuchungsmethode an formalinfixierten, paraffineingebetteten Knochenmarkstanzen.

A 83-year old patient with "myelodysplastic / myeloproliferative neoplasia", type chronic myelomonocytic leukemia (CMML), presented at our clinic with an intermittent bleeding, growing tumour located at the glabella. The tumour occurred after a trauma, and thus the suspected diagnosis was pyogenic granuloma. In the context of outpatient care, a severe and persistent bleeding occurred, so that the patient was hospitalized. EXAMINATIONS AND DIAGNOSES: Histopathological analyses of the excized tumour nodule revealed specific cutaneous leukemic infiltrates. Laboratory check-up showed thrombocytopenia with thrombocytopathy and hypofibrinogenaemia.Despite appropriate intraoperative hemostasis, sustained post-treatment bleeding occurred, necessitating the application of several erythrocyte concentrates as well as substitution of prothrombin, fibrinogen, and factor XIII. After stationary dismissal, the patient experienced a transition into acute myelomonocytic leukemia and died a short time thereafter.Skin lesions are frequent in "myelodysplastic / myeloproliferative neoplasias" and myelodysplastic syndromes. Specific cutaneous infiltrates associated with CMML may be a clinical indicator for a transition into acute leukemia.

Chronic myeloid leukemia (CML) is diagnostically defined by the reciprocal translocation t(9;22)(q34;q11). This aberration can be detected by the BCR-ABL fluorescence in situ hybridization (FISH) technique. This article presents a comparative analysis of different commercially available FISH probes and different FISH protocols in order to optimize this technique on formalin-fixed and paraffin-embedded bone marrow trephine biopsies.

The advent of tyrosine kinase inhibitors (TKI) has improved the prognosis and outcome of patients with chronic myelogenous leukemia (CML) considerably. Compared with imatinib, the first-line use of second-generation inhibitors nilotinib and dasatinib has led to faster and deeper molecular remissions accompanied by a differential adverse effect profile. An essential part of the management of CML patients is the guideline-based application of cytogenetics and standardized polymerase chain reaction techniques to regularly assess the remission status. Long-lasting treatment-free remission in a minority of patients led to hopes for the curability of CML in a significant minority of patients. The use of interferon alpha combined with or after TKI therapy is associated with the induction of an immune response toward the leukemic clone. This innovative treatment approach is currently under prospective investigation to improve long-term response. The coordinated cooperation of academic and regional hospitals, office-based hematologists, laboratories, and patient representatives allows for up-to-date patient care and the early use of new therapeutic options in patients at risk.

In patients with chronic myeloid leukemia, high-quality diagnostics is of paramount importance for the surveillance of treatment efficacy. The availability of new tyrosine kinase inhibitors providing more rapid and deeper responses requires the employment of standardized and highly sensitive diagnostic methods to ensure optimal monitoring of the patients. This review presents the current international diagnostic standards and the certified laboratories in Austria.

State of the art management of chronic myeloid leukemia (CML) patients with the selection of best available treatment options requires systematic cytogenetic and molecular monitoring. The choice of the first-line tyrosine kinase inhibitor depends on integration of comorbidities and individual treatment goals. Clinical prognostic scores should be used for cohort comparison and for stratification in randomized trials. Their relevance for individual treatment decisions has not yet been established. Essential for therapeutic decision-making is the achievement of predefined cytogenetic and molecular milestones in the course of the disease. In cases of treatment resistance or relapse the analysis of potential causes is required. After exclusion of compliance issues bone marrow analysis for the accurate characterization of the hematologic disease state and exclusion of clonal evolution is recommended. In parallel, BCR-ABL mutation analysis should be performed. The choice of second-line treatment depends on the predicted sensitivity of any BCR-ABL mutation detected and the clinical history of the patient. Most important is prevention of disease progression as treatment results in advanced disease are still not satisfying. Therefore, allogeneic stem cell transplantation should be considered early in resistant disease, when high-risk parameters (e.g. multiresistant mutations) have been detected.

Myeloproliferative neoplasms (chronic myeloproliferative disorders according to former nomenclature) comprise chronic myeloid leukemia, polycythemia vera, essential thrombocythemia, primary myelofibrosis, chronic eosinophilic leukemia, chronic neutrophilic leukemia and systemic mastocytosis. All disorders have excessive proliferation of one or more hematopoietic lineages in common and progress with different probability to blast crisis or fibrosis. A further common feature is provided by the activating mutation of tyrosin kinases and associated pathways of signal transduction (BCR-ABL, JAK2(V617F), MPL(W515L/K), KIT(D816V) and FIP1L1-PDGFRA) causative for the abnormal proliferation. With regard to diagnosis and therapy these mutations are of utmost importance because they enable the exclusion of reactive processes, contribute with varying specificity to subtyping of MPN and are at least partly sensitive to targeted therapy. The molecular mechanisms of blastic and fibrotic progression are not yet understood.

Survival of patients with chronic myeloid leukemia (CML) has dramatically improved with the introduction of the BCR-ABL-specific tyrosine kinase inhibitor imatinib. As a rule patients on therapy with imatinib achieve permanent complete cytogenetic and molecular remission. Patients who are primarily refractive to imatinib or lose remission achieved using imatinib are in the minority. This group has a poor prognosis. This article gives a transparent review of the diagnostics necessary when CML is primarily diagnosed and for assessment of the response during the course of the therapy. The guidelines developed for this procedure by the European leukemia network on the type and frequency of surveillance controls as well as the diagnostic criteria for imatinib resistance or suboptimal response will be presented. The indications for allogenic stem cell transplantation and the administration of second generation BCR-ABL inhibitors will be discussed as therapeutic alternatives in cases of imatinib failure in a stage-specific manner. Finally a view on therapy targets and forms of future first-line therapy of CML will be given.

Chronic myeloid leukemia (CML) is exceptional amongst neoplasias since its underlying pathomechanism has been elucidated, and potent well tolerated targeted drugs, the tyrosine kinase inhibitors (TKI), are available for treatment. They convincingly improve prognosis while retaining good quality of life. Aims of therapy are complete remissions as well as prolongation of life and cure. Imatinib 400 mg per day is current standard therapy. There are hints for a better outcome with a higher initial imatinib dose or with combination therapy. Even after achievement of complete molecular response continuous therapy might be necessary in most cases. In case of imatinib intolerance or failure, the second generation TKI dasatinib and nilotinib and allogeneic stem cell transplantation are available. The use of second generation TKI as first line treatment might further improve prognosis. The therapeutic response should be regularly monitored according to international recommendations.

Myeloproliferative neoplasms (MPNs) and related chronic disorders constitute a subgroup of myeloid malignancies which are defined according to clinical, morphological and molecular features by the actual World Health Organization classification of tumors of the haematopietic system. Screening procedures for a BCR-ABL fusion gene, JAK2, thrombopoietin receptor and KIT mutations are formally included in the diagnostic approach. Myelodysplastic/MPN overlap syndromes include rare entities such as refractory anemia with ringed sideroblasts characterized by a high proportion of JAK2V617F mutated cases. The paradigm of targeted treatment of chronic myeloid leukemia with imatinib has now been extended to eosinophilia-associated myeloid neoplasms with PDGFRA, PDGFRB or FGFR1 gene mutations. Pegylated interferon-alpha has convincingly been proved to reduce the JAK2 allele burden. JAK2 inhibitor drugs are currently being tested in clinical trials. The development of pathogenesis-targeted diagnostic and therapeutic approaches to the various MPNs will continue in the future.

Chronic myeloproliferative diseases (CMPD) are haematopoetic neoplasias with indolent course and preserved cellular function of the maturing malignant cells. In Philadelphia-positive chronic myeloid leukaemia the discovery of molecular disease mechanisms led to the successful introduction of targeted therapy with imatinib. Ph-negative CMPD are conventionally treated by cytoreduction and low dose ASS in order to minimise the risk of vascular complications. For all CMPD, lifelong surveillance and therapy are necessary.

Broad evidence exists that health care professionals are facing ethical difficulties in patient care demanding a spectrum of useful ethics support services. Clinical ethics consultation is one of these forms of ethics support being effective in the acute setting. An authentic case is presented as an illustration. We introduce an integrative model covering the activities being characteristic for ethics consultation and going beyond "school"-specific approaches. Finally, we formulate some do's and don'ts of ethics consultation that are considered to be key issues for successful practice.

Histomorphological evaluation of bone marrow trephines and smears represents the major approach to diagnose the chronic myeloproliferative diseases (CMPD) and the myelodysplastic syndromes (MDS). However, rising insights into molecular pathogenesis of human diseases strengthen the attempt of pathologists to define and to detect underlying defects beyond the microscope. Since discovery of the Philadelphia chromosome in chronic myeloid leukemia as the first specific molecular abnormality ever detected in a human neoplasia the gain of knowledge of molecular pathomechanisms in Philadelphia chromosome negative (Ph-) CMPD was rather sparse. A decisive breakthrough in Ph CMPD was the finding of JAK2 (V617F) derived from a somatic point mutation in the majority of patients with polycythemia vera (P.vera) and half of patients with essential thrombocythemia (ET) and primary myelofibrosis (PMF). It therefore can not be overestimated that detection of JAK2 (V617F) in a suspective myeloproliferation now enables a clearcut discrimination of a true Ph CMPD from a reactive state, e.g. P.vera from reactive erythrocytosis. Interestingly, a basic principle of molecular defects demonstrable in CMPD and related disorders seems to be the involvement of genes with kinase activities. Some of those genes will be discussed in more detail. In primary MDS, karyotyping via classical cytogenetics is the predominant molecular approach to estimate prognosis, e.g. -Y, del(5q) and del(20q) represent favourable anomalies. Indeed, in 5q- syndromes karyotyping enables definite subtyping and allows clinicians and patients to expect a good prognosis. Until now, dozens of molecular abnormalities such as mutations in AML1, FLT3 and Ras as well as epigenetic alterations of genes have been identified to various degrees in MDS subtypes. Some of them seem to be involved in disease initiation ("master event") and others might indicate disease progression. However, even though useful for further dissection of molecular pathomechanisms the majority of aberrations currently does not serve as potent markers in the daily routine. Nevertheless, in CMPD and MDS the importance of molecular analyses for diagnosis, estimation of prognosis, and disease monitoring will further increase in a foreseeable period of time.

Use of multidrug chemotherapy poses the risk of avascular osseous necroses in children. Depiction of the whole body, including clinically non-apparent sites is mandatory for starting early and proper treatment, including surgical approaches in lesions near the joints. We analyzed the value of whole-body MRI in the detection of osteonecrosis, (1) in relation to conventional X-ray imaging and clinical symptoms, (2) using different MRI sequences, (3) with follow-up examinations.5 patients suffering from an oncological disease, 13 to 16 years old (3 x ALL, 1 x medulloblastoma, 1 x CML), and recently developing bone pain were examined with X-ray imaging of the particular region and a whole-body MRI (T2w TIRM, T 1w TSE sequences, pre- and post-contrast GD-DTPA, including fat suppression techniques). Neck/thorax/abdomen/pelvis, and upper and lower extremities were acquired in the coronal plane, and the feet in sagittal orientation. 4 of 5 patients had at least one follow-up examination (in the mean after 10 +/- 4 months).None of the initial X-ray images revealed an abnormal finding. The whole-body MRI showed in 4 of 5 children bone marrow lesions compatible with osteonecrosis. The locations were around the knee joints (n = 3) and the tibiae/ankle joints (n = 4). In addition to the symptomatic sites, MRI revealed additional lesions at the following sites: humerus (n = 5), hip joints (n = 4), knee joints (n = 6), ankle joints (n = 4). The size varied from small focal lesions to lesions measuring 90 % of the whole transverse diameter of the bone. The lesions were able to be detected most easily with heavily T 2-weighted (TIRM) sequences, and the diagnosis was most easily established using the non-enhanced TSE T 1-weighted sequences. As a consequence of the results of the whole-body MRI, all patients with lesions compatible with osteonecrosis received symptomatic (n = 2) or specific (n = 2) therapy. In the follow-up examinations, a higher number of patients showed no changes in the lesions as to size and distribution. 2 patients showed partial resolution of the osteonecroses.Whole-body MR imaging allows early diagnosis of symptomatic as well as clinically non-apparent osteonecroses. It can be used in planning and monitoring surgical and pharmacological therapies.

A 17-year-old boy with chronic myelogenous leukemia received a bone marrow transplantation (BMT) from an unrelated donor. 22 days before BMT he had been HBs antigen and anti-HBc negative. 68 days after BMT he was tested again and showed a "seroconversion" for hepatitis B (anti-HBc positive, anti-HBs 59 IU/l), raising the suspicion of a posttransfusion hepatitis. The patient had not received any blood transfusion in the 6 months before BMT. From day 0 to day + 68 he received four red blood cell concentrates and 18 platelet concentrates. The bone marrow donor had been HBs ag and anti-HBc negative.A stored serum sample of the recipient obtained on day -8 was available and proved to be negative for HBsAg and Anti-HBc IgM, but positive for anti-HBc and anti-HBs. A serum sample from day -22 was negative for all these parameters.These results can be explained by the administration of 17.5 g of a polyvalent immunoglobulin (Ig) concentrate for CMV prophylaxis on day -9: anti-HBc and anti-HBs (1814 IU/l) were found in the lot that the patient had received. Nine further doses of immunoglobulin concentrates were given up to day + 68.Four months after the last administration of Ig concentrates, the patient was negative for HBs ag, anti-HBc and anti-HBs.Ig concentrates contain not only those antibodies, which are given to a patient for treatment, but also all other antibodies contained in the donor plasma pool. Thus administration of Ig concentrates can cause a "false-positive" hepatitis B serology by passive transfer of these antibodies. Such an artificial seroconversion may also lead to a false suspicion of a transfusion transmitted hepatitis B infection.

Chronic myelogenous leukemia is characterized by the Philadelphia-chromosome, a shortened chromosome 22 which is the result of a reciprocal translocation between chromosome 9 and 22. The fusion gene is called BCR-ABL. After transcription and translation the constitutively activated p210 BCR-ABL oncoprotein is formed. This leads to uncontrolled activation of the ABL tyrosin kinase. Deregulated cellular proliferation and diminished apoptosis of BCR-ABL transformed cells is the result. Expression of the BCR-ABL oncoprotein is sufficient and necessary for the development of a CML phenotype. Imatinib mesylate (Glivec) is a small molecule that binds to the ATP pocket of ABL and blocks downstream signalling events. Imatinib is very effective in the treatment of CML in all stages of the disease. Patients with newly diagnosed chronic phase CML were randomized to imatinib or to interferon plus cytarabine in the IRIS trial. Imatinib showed significantly superior tolerability, hematologic and cytogenetic resposes and increased time to progression. In patients with advanced phase CML, imatinib is less effective and response duration is short. Median overall survival of blast crisis patients is 6.9 months only. Additional BCR-ABL independent chromosomal abnormalities are common in advanced phase CML and result in resistance to imatinib. BCR-ABL kinase-domaine mutations are frequently found in imatinib resistant patients and confer diminished sensitivity to imatinib. Second generation, more powerful ABL kinase inhibitors, which are effective against most of the known mutations are currently tested in clinical trials.

Chronic myelogenous leukemia constitutes a clinical model for other neoplastic diseases. The cytogenetic hallmark of CML, the Ph chromosome with the molecular juxtaposition of BCR and ABL genes and the multistep pathogenesis with the stable chronic phase, the accelerated phase and the terminal blast crisis provide the background for the translation of molecular-cytogenetic findings into clinical practice. The systematic development of the selective BCR-ABL inhibitor imatinib was based on the discovery of the molecular pathogenesis of CML. Promising preclinical data were confirmed in phase I-III trials. Concerning hematologic and cytogenetic response and adverse effects imatinib is superior to interferon alpha. Open questions are treatment duration in patients with good response, long term side effects, persistence of minimal residual disease in almost all patients, development of resistance after long term therapy, and the efficacy of combination treatments. Prospective clinical trials, e. g. CML study IV of the German CML Study Group, should answer these questions. The impact of the various treatment modalities (imatinib, interferon alpha, ara-C, allogeneic stem cell transplantation) will be elucidated. The recruitment of newly diagnosed CML patients into CML-study IV is recommended.

In chronic myeloid leukemia following therapy with Imatinib (STI571) hematologic and cytogenetic response is associated with conspicuous changes of bone marrow morphology. However, it is not known to which extent these alterations are accompanied by a loss of the bcr/abl translocation. To study regression of the leukemic cell population we recruited 14 patients lacking pretreatment. Therapy resulted in a reduction of CD61(+) megakaryopoiesis. Dwarf megakaryocytes characteristic for this disorder were replaced by large, normally appearing cells of this lineage. Morphometric analysis confirmed the significant decrease in the number of micromegakaryocytes and yielded planimetric parameters in keeping with normalization. Moreover, a fluorescence in-situ hybridization study in five patients of this cohort revealed that before therapy 70% of all myeloid cells exhibited the bcr/abl gene. Regarding megakaryopoiesis about 65% of the micromegakaryocytes displayed positive signals. Following treatment these bcr/abl(+) cell populations decreased significantly while the emerging large megakaryocytes lacked a proper labeling. Because cytogenetic response and reduction of atypical micromegakaryocytes are linked, this feature may be useful to monitor therapeutic efficacy.

Chronic myeloid leukemia (CML) is a clonal stem cells disorder and belongs to the myeloproliferative diseases. Over the past decades seminal discoveries in the field of CML research have greatly contributed to our knowledge of leukemogenesis. The hallmark of the disease is the presence of the Philadelphia chromosome, the first described acquired non-random cytogenetic abnormality in human malignancies. This chromosomal abnormality is the result of a reciprocal translocation between chromosomes 9 and 22, t(9;22). At the molecular level this involves the fusion of the ABL protooncogene on chromosome 9 with the BCR (breakpoint cluster region) gene on chromosome 22. The fusion protein has increased tyrosine kinase activity and is a key event in the malignant transformation of a given progenitor cell in the bone marrow. Diagnosis of CML is based on the peripheral blood smear, bone marrow examination, the presence of the Philadelphia chromosome and its molecular correlate, the BCR-ABL transcript. Remarkable progress has been made in the treatment options over the last years which as a result rendered the therapeutic choices more complex and challenging. The current knowledge of treatment options is reviewed with particular emphasis on the newly introduced tyrosine kinase inhibitor Imatinib which opened an as yet unexpected promising avenue in the treatment of CML.

To elucidate the effect of first-line treatment with interferon (IFN), hydroxyurea (HU) and the tyrosine kinase inhibitor imatinib (STI571) on angiogenesis, we studied bone marrow (BM) biopsies in 104 patients with chronic myelogenous leukemia (CML) and 138 patients before and after allogeneic BM transplantation (BMT). After immunostaining (CD34) and morphometric analysis in comparison with a control group, CML specimens showed an increased vascularity and conspicuous morphological abnormalities of microvessels. A close relationship between microvessels and fiber density was detectable in initial biopsies and also in repeatedly performed examinations following therapy. Monotherapy by imatinib and HU generated a significant reduction of microvessels and reticulin fibers in contrast to changes after IFN administration or combination regimens of IFN and HU. A persistence of numerical and structural anomalies of vasculature was observable even several months after BMT. These anomalies shed some light on disturbances of the stroma compartment after myeloablative therapy. The relationship between BM vascularity and fibers is probably dependent on concomitant changes of megakaryopoiesis as the source of various mediators involved in the development of myelofibrosis and neo-angiogenesis acting within a complex functional network.

The spectrum of Philadelphia-chromosome negative leukemoid disorders displays a large heterogeneity of clinical and morphological findings at presentation. According to the FAB guidelines as well as the WHO classification, independent subtypes with different morphological features can be distinguished. In particular, based on the degree of dysgranulopoiesis, the extent of monocytosis, basophilia and the amount of immature and mature granulocytes in the peripheral blood and the percentage of erythroblasts, most of these cases can be correctly classified as either atypical chronic myeloid leukemia (aCML) or chronic myelomonocytic leukemia (CMML). An increase in immature and dysplastic granulocytes in the blood films at presentation accompanied by granulocytic dysplasia, is the most important diagnostic parameter of aCML. On the other hand, CMML is characterized by absolute monocytosis and, as explicitly outlined by the WHO classification, may show myelodysplastic and myeloproliferative features. However, in the absence of characteristic cytogenetic or molecular abnormalities for both diseases, a minority of patients still remain who are difficult to assign to a distinctive entity, since they either show overlapping features or do not fulfill the whole set of diagnostic criteria. Furthermore, controversy and discussion arise about aCML with monocytosis and its association to CMML. Finally, leukemoid reactions and the very rarely encountered chronic neutrophilic leukemia (CNL) should be considered in patients with chronic leukocytosis. In conclusion, careful morphological analysis of bone marrow histology as well as peripheral blood films and bone marrow smears, enables the identification of patients with different prognosis and therapeutic response.

The results of a number of animal experimental studies are in keeping with the finding that hematopoietic progenitors can generate cardiomyocytes and endothelial cells. As a consequence innovative therapeutic strategies have been suggested to possibly ameliorate the outcome of coronary artery disease. However, there is no information available at present whether this pathomechanism is also effective in humans, in particular without prior ischemic lesion of the myocardium. Therefore an autopsy study was performed on cadaver hearts derived from five male patients with chronic myeloid leukemia who received full unmanipulated bone marrow grafts from female donors 21-631 days before death. The purpose of this investigation was to detect and quantify a putative chimerism of cardiomyocytes and endothelial cells (intramural and subepicardial vessels). Genotyping was carried out by applying X- or Y-chromosome-specific DNA probes (fluorescence in-situ hybridisation) on routinely formalin-fixed specimens of the myocardium. To test the sensitivity of our method, cadaver hearts from two males and two females without a history of transplantation served as controls. In contrast to a totally corresponding sex-matched genotyping in 780 cardiomyocytes and 155 endothelial cells of the control group, the five male patients with a previous transplantation revealed significantly different results. A mixed chimerism was identifiable in 57 out of 890 counted cardiomyocytes (6.4%) and in 19 out of 322 endothelial cells (5.8%). These findings support the assumption that in addition to endothelial cells there is also a cardiomyogenic potential of bone marrow stem cells which exists without prior (ischemic) damage to the heart. However, further investigations are necessary to identify, isolate and enrich the cardiomyocytic stem cells more specifically for future curative therapeutic options in patients with severe ischemic cardiomyopathy.

In the treatment of leukemia by stem cell transplantation, the immunological effects of allogeneic T-lymphocytes presumably play a greater part than high-dosage total-body irradiation (TBI) and chemotherapy. Using this immunological effect, attempts are currently being made to reduce the dosage of pre-treatment that is toxic to stem cell, such as TBI, thereby making transplantation available for a larger group of patients at high risk for transplantation. This study presents preliminary results of three current studies of this approach.Elderly patients with chronic myeloid leukemia (CML) have an increased transplantation risk. They were conditioned with TBI that was reduced stepwise (n = 27). Patients with advanced and refractory myeloid leukemia were treated with chemotherapy and dose-reduced TBI (FLAMSA protocol; n = 54). In patients with multiple myeloma, autologous transplantation with high-dose chemotherapy preceded allogeneic transplantation possible after dose-reduced conditioning (Tandem protocol; n = 6).All three protocols of TBI gave results that were not worse than those of previous studies. Relapse ocurred not more frequently in patients with CML. In patients with high-risk AML the FLAMSA protocol gave better results. Autologous-allogeneic tandem transplantation was well tolerated and led to a good response in all patients.Allogeneic transplantation after dose-reduced conditioning opens up new possibilities with respect to widening indications for transplantation and improving results in hematological diseases with previously unsatisfactory treatment.

Gleevec (STI-571) is s selective inhibitor of the bcr/abl tyrosine kinase. Recent phase I and phase II studies in patients with bcr/abl positive CML and ALL showed a low rate of grade III/IV toxicity and good clinical efficacy. This report describes the preliminary results in patients relapsing post autologous or allogeneic peripheral blood stem cell transplantation. The focus of this analysis will include toxicity, feasibility and clinical efficacy.18 of 18 patients with cytogenetic and/or hematologic relapse in chronic phase CML post autologous stem cell transplantation achieved a complete hematologic remission upon therapy with Gleevec. The cytogenetic response rate was 75% with a complete cytogenetic response rate of 50%. After allogeneic stem cell transplantation, patients in cytogenetic or hematologic relapse also experienced high hematologic and cytogenetic response rates upon therapy with Gleevec. In these patients, Gleevec was shown to induce mixed chimerism. Overall, Gleevec was well tolerated after autologous and allogeneic stem cell transplantation. Most common side effects were mild to moderate gastrointestinal discomfort and edema. No symptoms of chronic extensive orgrade I acute GvHD could be observed. Hematologic toxicity was dependent on stage of disease. Grade III/IV granulocytopenia and/or thrombopenia could be observed in 50% of patients with transformed phases of CML. Management of these patients required frequent controls of peripheral blood counts and transfusion of blood products.These results show a new approach in treatment of patients with Philadelphia-chromosome-positive leukemia relapsing post autologous or allogeneic stem cell transplantation. Gleevec is able to induce mixed chimerism without induction of severe GvHD. The data suggest that early start of STI-571 therapy in MRD-positive patients is a promising approach. Recently, a multicenter phase II study to evaluate the toxicity and efficacy of Gleevec in CML patients with minimal residual disease post allogeneic transplantation was started.

According to the evidence-based guidelines for the therapy of chronic myelogenous leukemia (CML) the combination of interferon alpha (IFN) and hydroxyurea with or without low dose ara-C is the standard treatment for chronic phase CML, if no allogeneic stem cell transplantation is requested. STI571: In cases of IFN failure the new tyrosine kinase inhibitor STI571 (Glivec) shows high response rates. STI571 specifically inhibits the BCR-ABL fusion protein which is pathogenetically relevant for CML and shows abnormal tyrosine kinase activity. 91% of all CML patients in chronic phase achieve a hematologic remission within 11 months and 55% cytogenetic remission. In blast crisis, 29% achieve hematologic remission which may be durable.The available data represent response rates. Until survival data are available, the evidence-based recommendations will remain valid.