Etiology and Management of Therapy-Related Myeloid Leukemia

University of Chicago, MC-2115, 5841 S. Maryland Avenue, Chicago, IL 60637, USA.
Hematology (Impact Factor: 0.81). 02/2007; 2007(1):453-9. DOI: 10.1182/asheducation-2007.1.453
Source: PubMed


The diagnosis of therapy-related myeloid leukemia (t-MDS/t-AML) identifies a group of high-risk patients with multiple and varied poor prognostic features. These neoplasms are thought to be the direct consequence of mutational events induced by cytotoxic therapy. Their outcomes have historically been poor compared with those of people who develop acute myeloid leukemia (AML) de novo. The question arises whether a diagnosis of t-AML per se indicates a poor prognosis, or whether their bad outcomes result from other clinical and biologic characteristics. Because of lingering damage from prior cytotoxic therapy and, in some cases, the persistence of their primary disorder, patients with t-AML are often poor candidates for intensive AML therapy. The spectrum of cytogenetic abnormalities in t-AML is similar to de novo AML, but the frequency of unfavorable cytogenetics, such as a complex karyotype or deletion or loss of chromosomes 5 and/or 7, is higher in t-AML. Survival varies according to cytogenetic risk group, with better outcomes observed in patients with t-AML with favorable-risk karyotypes. Treatment recommendations should be based on performance status and karyotype. Patients with t-AML should be enrolled on front-line chemotherapy trials, appropriate for de novo AML patients with similar disease characteristics. Allogeneic hematopoietic cell transplantation can cure some patients with t-AML. Most important , the molecular and genetic differences that appear to determine the phenotype and the outcome of these patients need to be investigated further.

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    • "During the last years, adjuvant chemotherapy and radiotherapy for breast cancer have significantly improved the number of long-term survivors, but these patients are at high risk of developing a therapy-related myelodysplastic syndrome and/or an AML (t-MDS/AML). Despite recent progress in AML treatment, t-AML is still associated to a poor prognosis, with a lower complete remission rate following conventional induction treatment and a shorter median survival compared to de novo AML.6 Patients with t-AML are therefore candidate to an allogeneic transplant if the performance status, donor availability and former neoplastic disease allow this approach.7 Azacitidine, a nucleoside analog of cytidine with hypometilating effects, is approved for the treatment of high-risk MDS and AML with 20–30% bone marrow blast count, and has shown a significant survival benefit compared to conventional chemotherapy regimens. "
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    ABSTRACT: Mucormycosis is the third cause of invasive mycosis after candidiasis and aspergillosis in AML patients, representing a poor prognostic factor associated with a high rate of fatal outcome. We report a case of a patient with AML and a concomitant pulmonary mucormycosis at diagnosis, who obtained a complete remission both of her AML and of the fungal infection. The incidence of the infection at the onset of leukemia is extremely unusual, and, to our knowledge, the sporadic cases reported in the literature are included in heterogeneous series retrospectively examined. In our case, Liposomal Amphotericin B as single agent appeared incapable of controlling the infection, so anti-infective therapy was intensified with posaconazole and simultaneously antileukemic treatment with 5-azacitidine was started, with the understanding that the only antifungal treatment would not have been able to keep the infection under control for a long time if not associated with a reversal of neutropenia related to the disease. We observed a progressive improvement of the general conditions, a healing of pneumonia and a complete remission of the leukemic disease, suggesting that a careful utilization of the new compounds available today, in terms of both antifungal and antileukemic treatment, may offer a curative chance a patient who would have otherwise been considered unfit for a potentially curative therapeutic strategy.
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    • "The main rationale for such a combined approach has been to improve a relapse-free survival.[27] It has not yet been possible to determine whether the development of t-AML is a stochastic event, occurring by chance, or whether certain individuals are at higher risk; perhaps due to a heritable predisposition,[29] or because of the hormonal misbalance in pregnancy. The identification of such an underlying pre-existing conditions would help the screening and counseling of patients at the time of treatment for their primary disease. "
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    ABSTRACT: Treatment for Hodgkin's lymphoma (HL) has resulted in excellent survival rates but is associated with increased risks of secondary therapy-related acute myeloid leukemia (t-AML). Gingival enlargement associated with bleeding and ulceration is the most common rapidly appearing oral manifestations of leukemic involvement. An 8 months pregnant patient reported with generalized gingival enlargement, with localized cyanotic and necrotic papillary areas. Co-relating the hematological report with the oral lesions and her past medical history of HL, a diagnosis of t-AML secondary to treatment for HL was made by the oncologist. As oral lesions are one of the initial manifestations of acute leukemia, they may serve as a significant diagnostic indicator for the dental surgeons and their important role in diagnosing and treating such cases. Furthermore, this case report highlights the serious complication of t-AML subsequent to HL treatment and the important role that a general and oral health care professional may play in diagnosing and treating such cases.
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    ABSTRACT: Dendritic cells (DC) play a central role in connecting innate with specific adoptive immunity resulting in target specific activation T-cells. As professional antigen presenting cells (APC) DC specifically stimulate T-effector cells, especially tumor-cytotoxic T-cells. Therefore they are regarded as interesting candidates for anti-tumor or anti-leukemic vaccination strategies. The insufficient expression of costimulatory antigens, MHC molecules and tumor-associated antigens (TAA) on the surface of cancer cells and disturbed mechanisms of apoptosis are the main reason for an ineffective immune response in oncologic diseases. It was shown that acute myeloid leukemic cells can be differentiated to leukemia-derived DC (DCleu ), regaining the stimulatory capacity of professional DC while potentially presenting the whole leukemic antigen repertoire. Thus, vaccination strategies, using ex vivo or in vivo generated DC, might induce a highly specific anti-leukemic T-cell response circumventing the cumbersome identification of leukemia-associated antigens. In this thesis DC antigen (DCA) expression profiles of mononuclear cells (MNC) and dendritic cells (DC) generated from these MNC should be analyzed. The generated MNC and DC should be compared with respect to their DC antigen (DCA) expression profiles and the DCAs value to detect and quantify (leukemia-derived) DC in different AML/MDS subtypes and under different culture conditions. Therefore MNC and DC were generated from 137 patients with acute myeloid leukemia (AML) and 49 patients with myelodysplastic syndromes (MDS) under 6 different serum free culture conditions. DCA studied were: CD1a/1b/1c, CD206, CD25, CD137L, CD83, CD86, CD80 and CD40. DC-generating media were chosen according to their different mechanisms of inducing DC-differentiation: 1. ‚Basic method‘: TNF/GM-CSF/IL-4, 2. MCM-Mimic, 3. Ca Ionophore, 4. Picibanil, 5. Poly I:C and 6. Cytokines. Quality and quantity of generated DC was estimated by Flow cytometry applying a specified, ‘DC-based’ gating-strategy. Expression and coexpression profiles of 10 different DCA as well as various costimulatory molecules, maturation markers and blast antigens were evaluated. Only those DCA qualified for the quantification of leukemia-derived DC that were not expressed on uncultured MNC fractions. AML patients presented with an average of 58 % blasts, MDS patients with 13 % blasts in MNC fractions. DCA were expressed on average on less than 7% of uncultured MNC, however some of the markers could be expressed on up to 77% of uncultured cells in single AML cases. Consequently these DCA did not qualify for detection of DC in those cases. Highest expression rates were found for CD86 and CD40 in naïve AML and for CD137L and CD40 in naïve MDS samples. Other DCA (e.g. CD1a, 1b, 1c) were only rarely found on naïve blasts. DCA expression on uncultured AML and MDS MNC varied with FAB types and cytogenetic risk. After culture in different DC-differentiating media, on average 28% DC could be generated from AML MNC and 30% from MDS MNC, depending on methods used, with an average DC viability of more than 60% and an average DC maturity of 49% (AML) and 56% (MDS). On average 36% of leukemic blasts could be converted to DC. Proportions of DCleu in the total DC fraction varied from 40-58% and were on average 49% (AML) and 43% (MDS) after culture. Average results of all culture methods tested were comparable, however every method failed to create DC in some individual cases. The most important results of this thesis are: 1. It could be shown that DCA are expressed on naïve blasts in AML and MDS in individual patients. That means that the individual patients’ DCA-profiles have to be evaluated before DC-culture to find suitable DCA to detect and quantify (leukemia-derived) DC after culture. 2. Different methods of DC-generation qualify with varying individual efficiency to generate leukemic, mature, migratory and viable DC in individual cases. 3. To select the best DC-generating method the best DC-marker (no expression on naïve blasts, high expression on DC) has to be chosen to quantify DC in individual samples. 4. The use of only one method is not sufficient to create DC in every single AML and MDS sample. However, a successful, quantitative DC/DCleu -generation is possible in every case of AML and MDS by the combination of 3 different DC-generating media, but not every blast is convertible to DC leu . 5. There is a need for new, specific DC-markers that are not expressed on naïve blasts.
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