Search

Myelodysplasia associated with a complex karyotype is usually associated with advanced stage myelodysplastic syndrome (MDS) and an enhanced risk to develop secondary leukemia. We report on a 36-year-old female patient who was first presented in 1997 because of ‘Pseudo Pelger–Huet’ neutrophils. The remaining blood and differential counts were normal. Bone marrow examination revealed dysplasia in the erythroid and granulocytic series, no increase in blasts, and a karyotype with complex aberrations involving chromosomes 7, 13, 20 and 22. Almost all metaphases examined appeared to be affected. During the next few months, the patient was closely monitored and considered as candidate for bone marrow transplantation. However, blood counts remained stable without occurrence of significant cytopenias or an increase in blasts. Re-examinations of the bone marrow in 1998 and 1999 disclosed identical results compared to that obtained in 1997. After a total follow up of 6 years, the patient is still in good health with normal blood counts and persisting ‘Pseudo Pelger–Huet’ neutrophils. This exceptional case supports the notion that complex chromosomes are not invariably associated with rapid disease evolution in MDS.

High dose intermittent ARA-C (2x3 g/m(2) i.v., days 1, 3, 5)=HiDAC was introduced as consolidation in AML by the CALGB-group in 1994. We treated 44 de novo AML patients in CR with up to four cycles of HiDAC (four cycles: 56.8%; three cycles: 22.7%; two cycles: 6.8%; one cycle: 13.7%). Median duration of aplasia (ANC

Aggressive systemic mastocytosis (ASM) is a hematopoietic neoplasm characterized by infiltration of visceral organs by neoplastic mast cells (MCs) with consecutive organopathy and respective clinical and laboratory findings (so called C-Findings). Whereas, it is generally appreciated that patients with ASM are candidates for pharmacological intervention, no ideal drug or drug combination have been identified yet. One drug proposed to work in ASM is interferon alpha-2b (IFN-alpha2b). However, little is known so far about the quality of responses to IFN-alpha2b and actual response rates. We here report on five ASM patients treated with either a combination of IFN-alpha2b (3x3 million units per week) and prednisolone (n=4), or IFN-alpha2b alone (n=1). During therapy, two of the five patients showed a major response defined by complete resolution of C-Finding(s), one a partial response (partial regression of C-Findings), and one a stable disease (no changes in C-Findings). In one patient, progression to mast cell leukemia was seen after 3 months. In contrast to the other patients, this patient exhibited10% MCs in his bone marrow (bm) smear at first presentation. In summary, our data confirm beneficial effects of IFN-alpha2b (plus prednisolone) for a group of patients with ASM, whereas patients with mast cell leukemia may require more aggressive therapy. Prospective trials with more patients are now required to further document these drug effects and to better define subgroups of patients with ASM who show good and long-lasting responses to IFN-alpha2b.

Systemic mastocytosis (SM) is a clonal hematologic disease showing abnormal growth and accumulation of mast cells (MC) in visceral organs with or without skin involvement. The clinical course in SM is variable. In fact, indolent and aggressive variants have been described. In addition, SM patients may acquire an associated hematologic clonal non-MC lineage disease (AHNMD). In some cases, hematologic parameters are indicative of slowly progressing SM although the clinical course remains indolent over years. These cases have been referred to as smouldering SM. We report on a smouldering patient presenting with typical skin lesions, hypercellular marrow with focal MC aggregates, persistent leukocytosis (20,000-30,000/microl) with eosinophilia (5-10%), marked lymphadenopathy, and splenomegaly. The C-KIT mutation Asp-816-Val confirmed the diagnosis of SM. The clinical picture remained stable during an observation period of 10 years without signs of progression to an AHNMD or a high grade MC disease. These data show that some patients with SM can remain in a clinically indolent smouldering state over years even when presenting with marked eosinophilia and lymphadenopathy.

Mastocytosis is a term used for a group of disorders characterized by abnormal growth and accumulation of tissue mast cells (MC) in one or more organ systems. In patients with systemic mastocytosis (SM) the clinical course may be indolent or aggressive or even complicated by leukemic progression or an associated clonal hematologic non mast cell lineage disease (AHNMD). However, at first presentation (diagnosis) it may be difficult to define the category of disease and the prognosis. We report on a 48-year-old female patient with SM with urticaria pigmentosa-like skin lesions and mediator-related symptoms. She was found to have splenomegaly, a high infiltration grade (MC) in bone marrow biopsies (>30%), mild anemia, and a high serum tryptase level (>500 ng/ml). In addition, she exhibited discrete histologic signs of myeloproliferation in the 'non-affected' marrow and monoclonal blood cells established by C-KIT 2468A-->T mutation (Asp-816-Val) -analysis and HUMARA assay. Despite these findings, however, the clinical course was stable over years and no AHNMD or organ impairment developed. Because of the 'intermediate' clinical signs and absence of progression to aggressive disease, we proposed the term 'smouldering mastocytosis'.

Although mast cells (MC) appear to be myeloid cells, MC lineage involvement in myelogenous malignancies has been described only rarely. Based on clonal evolution, biology of afflicted cells, and disease criteria, three major groups of patients have been recognized: The first meets criteria for both diagnoses 'systemic mastocytosis' and 'associated hematologic clonal non-mast cell lineage disease (AHNMD)'. In such patients, myeloproliferative (MPS) or myelodysplastic syndromes (MDS), or acute myeloid leukemia (AML) is diagnosed apart from mastocytosis. In a second group of patients, large numbers of very immature MC-lineage cells (metachromatically granulated blast-like cells) are detectable, but the criteria to diagnose mastocytosis are not met. These patients have advanced myeloid neoplasms (MDS or MPS with blast cell increase, or AML) and variably suffer from mediator-related symptoms (flush, GI-tract ulcer, diarrhoea, coagulopathy). In some cases, the disease mimics mast cell- or basophilic leukemia. In contrast to basophilic leukemia, however, the metachromatic cells are strongly KIT+ and tryptase+. In contrast to true mast cell leukemia (MCL), MC do not form multifocal dense infiltrates in the bone marrow. Also, MC lack CD2 and CD25, and the C-KIT mutation Asp-816-Val. We propose the term 'myelomastocytic leukemia' or 'myelodysplastic mast cell syndrome' for these cases. In a third group of patients, myeloid neoplasms (MDS, MPS, AML) show constitutive expression of MC-associated antigens (tryptase, histamine) or mastocytosis-related gene defects (mutated C-KIT) without significant increase in metachromatic cells or criteria of mastocytosis. Whether these neoplasms display aberrant gene expression (or gene defects) or represent 'pre-pre-mast cell leukemias', remains unknown.

Several prognostic factors for patients with myelodysplastic syndromes (MDS) have been defined in the past. One of these factors appears to be the serum lactate dehydrogenase (LDH) activity. However, the precise predictive value of an elevated LDH level with regard to AML transformation remains uncertain. In this study, the prognostic value of the LDH activity was examined in a cohort of 180 patients with de novo MDS (median age 71 years [27-93]; f/m-ratio 1:1.2; RA: n=53; RARS: n=37; RAEB: n=50; RAEBT: n=19; CMML: n=21). Significant differences in LDH activities were found among FAB groups (P0.05), and especially among IPSS groups (HIGH: 411+/-574; INT-2: 221+/-90; INT-1: 254+/-145; LOW: 192+/-47 U/l; P0.05). An LDH level of/=300 U/l was found to be associated with a significantly shorter median survival (10.3 months) when compared to300 U/l (33.7 months; P0.01). Moreover, an LDH activity of/=300 U/l indicated a reduced AML-free survival in our MDS patients (P0.01). As assessed by Cox regression, the inclusion of LDH as additional variable into the IPSS system resulted in an improved prediction concerning survival, but not with regard to AML evolution. Together, our data show that a serum LDH activity of/=300 U/l in MDS is associated with a significantly shorter survival and higher risk to transform to AML. The LDH activity should be considered as an important prognostic factor in MDS.

We assayed granulocyte-macrophage committed progenitor cells (CFU-GM), erythroid committed progenitor cells (BFU-E) and pluripotent hemopoietic progenitor cells (CFU-MIX) in the peripheral blood of patients with hairy cell leukemia (HCL), acute lymphocytic leukemia (ALL) and chronic lymphocytic leukemia (CLL). In 8 HCL patients retaining their spleens, the number of circulating CFU-GM, BFU-E and CFU-MIX were under the lower limits of normal controls in 6, 6 and 5 cases, respectively, and were in the lower normal ranges in the remaining cases. Six splenectomized HCL patients had generally more circulating progenitor cells than their nonsplenectomized counterparts. In the peripheral blood of 2 patients with ALL and 3 patients with CLL, progenitor cells of all types were markedly increased compared to their respective values in the blood of control subjects. Hairy cells from 2 HCL patients failed to inhibit CFU-GM, BFU-E and CFU-MIX derived colony growth from control peripheral blood mononuclear cells. In 3 HCL patients previously low circulating progenitor cells did not rise 5–7 months after RC-α 2 -IFN treatment despite normalization of peripheral blood counts. Our results suggest that a reduction of the committed and pluripotent progenitor cell compartment might be at least in part responsible for the pancytopenia in the majority of patients with HCL.

Using cell culture studies specific in-vitro characteristics have been reported for Philadelphia chromosome positive myelogenous leukemia (Ph+ CML) and for juvenile chronic myelogenous leukemia (JCML) previously. We performed cell culture studies in four patients with chronic myelomonocytic leukemia (CMML) and demonstrated the following in-vitro features: excessively increased circulating CFU-C, while BFU-E and CFU-mix were either moderately increased or not detectable; CFU-C colony formation from CMML mononuclear cells (MNC) without addition of exogenous colony stimulating activity (CSA), even after depletion from adherent cells; failing inhibition of CMML MNC on normal BFU-E colony formation. These in-vitro characteristics point to CMML as a distinct entity. In two CMML-patients investigated CFU-C proliferation appeared to some extent inhibited by the addition of IFN-alpha, IFN-gamma and TNF-alpha to cell cultures.

According to the criteria of the FAB classification we diagnosed acute promyelocytic leukemia in 19 out of 191 AML blast cell populations. The reaction pattern with the anti-myeloid monoclonal antibodies VIM2, MCS2 and MY9 and the MHC-class II antibody VID1 in all cases showed the characteristics which were expected from the normal granulopoiesis. The monoclonal antibody VIM-D5, which recognizes the myeloid cell surface structure 3-fucosyl-N-acetyllactosamine (3-FAL), was not reactive with the majority of promyelocytic blast cells, however. In 13 cases 3-FAL was not detectable and in 6 cases only low or moderate reactivity of VIM-D5 with blast cells was observed. The phenotype of leukemic promyelocytes thus differs from the majority of normal promyelocytes in this respect.