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Introduction: Ibrutinib is a first-in-class small molecule inhibitor that binds irreversibly to Bruton's Tyrosine Kinase (BTK) and has shown remarkable efficacy in the treatment of CLL. Current guidelines recommend life-long therapy with administration at a fixed daily dose of 420 mg. However, lower doses of ibrutinib have been demonstrated to adequately abrogate kinase function. Limited clinical data suggests that dose reductions are not associated with inferior outcomes. Hypothetically, judicious dose reductions to manage toxicities could result in improved tolerance and decreased discontinuation rates. Our objective was to study the impact of dose reductions on outcomes in CLL patients treated with ibrutinib in a real-world setting. Methods: We conducted a retrospective chart review of all CLL patients treated with ibrutinib at Roswell Park Comprehensive Cancer Center between January 2014 and June 2017. Patients who underwent ibrutinib dose reduction were identified. Baseline characteristics and outcomes were compared between patients who underwent dose reductions vs those who did not. Reason and timing of dose reduction was also elucidated. Mann-Whitney U and Fisher's Chi Square test were used to compare groups, Kaplan Meier methods were used for time to event analysis, and Cox regression was used to obtain hazard ratios (HR). Overall survival (OS) was calculated as time from start of ibrutinib until death or last follow-up, freedom from progression (PFS) was taken as time from start of ibrutinib until progression or last follow-up. All analyses were performed in SAS v9.4 (Cary, NC). Results: A total of 70 CLL patients treated with ibrutinib were followed for a median period of 21.9 months. Most patients had RR disease (n = 63) and 7 received ibrutinib as frontline therapy. All patients received a fixed dose regimen with the standard dose of 420 mg once daily. Twenty-three (31.3%) patients required dose reductions and received ibrutinib at a median dose of 140 mg . Eleven (47.8%) of these had dose reductions within 3 months of treatment initiation. There was no statistically significant difference in baseline characteristics including age, number of prior lines of treatment, WBC count, hemoglobin or LDH level in the dose reduced group (DRG) and standard dose group (SDG). Patients in the DRG had a lower median platelet count at initiation of ibrutinib than patients in the SDG (86 x 103/mm3 vs 145 x 103/mm3, p Disclosures No relevant conflicts of interest to declare.

We analyzed the mutational profile of idiopathic cytopenia of undetermined significance (ICUS) compared with that of myelodysplastic syndrome (MDS). Targeted sequencing of 88 genes associated with myeloid malignancies was performed using samples of bone marrow mononuclear cells from ICUS and MDS patients. Forty patients with ICUS and 128 patients with MDS were included in this study. The median mutational burden was 0.7 mutation/person in the ICUS group and 2.2 mutation/person in the MDS group. ASXL1 (seven patients) was the most frequently mutated gene. ASXL1 was an independent significant prognostic factor for event-free survival (EFS) and overall survival (OS) (hazard ratio (HR) = 10.07 and 30.63, p = .004 and .003, respectively). The ASXL1 mutation which is frequently detected in elderly patients is a molecular predictor for pancytopenia and survival in patients with ICUS. A larger prospective study is needed to validate the role of this genetic mutation in an ICUS prognosis.

Hydroxyurea (Hu) is widely used as first-line cytoreductive therapy for patients with high-risk Philadelphia-negative myeloproliferative neoplasms (Ph-neg MPN), but a small proportion of patients have refractory disease or experience adverse effects. Studies have demonstrated busulfan (Bu) to be an active first-line agent, but data on its role as second-line or later therapy are minimal. To evaluate its efficacy and safety in this context, we undertook a multicenter audit of Ph-neg MPN patients who had received Bu as therapy for Hu intolerance or failure. Of 51 patients identified, 38 (75%) achieved either complete or partial hematological response following at least one Bu cycle. Bu was generally well tolerated, with only 21/135 (15%) cycles complicated by adverse effects, predominantly cytopenia; only 6% of cycles were ceased due to treatment complications. Bu is an effective and well-tolerated agent in patients with Ph-neg MPN in the setting of Hu intolerance or unresponsiveness.

Iron overload and transfusion dependance portend poor risk in myelodysplastic syndromes (MDS); bone marrow macrophages store iron and limit oxidative damage through heme oxygenase-1 (HO1). We assessed iron stores and macrophage HO1 expression in MDS using image analysis of intact diagnostic bone marrow biopsies and qualitative scoring of marrow aspirate iron among 129 cytopenic patients, 67 with MDS and 62 similarly aged patients with benign cytopenias. Using double immunofluorescence and sequential iron and immunohistochemistry staining, we showed that marrow iron colocalizes with HO1 and H-ferritin to CD163 + macrophages. Marrow iron was elevated in MDS independent of transfusion status, a finding of potential utility in distinguishing benign cytopenia from MDS. Among MDS patients only, CD163 + macrophage density and HO1 and H-ferritin expression by CD163 + macrophages increased in tandem with marrow iron. High HO1 was significantly associated with shorter overall survival among MDS patients independent of IPSSR and history of transfusion.

T-cell large granular lymphocytic leukemia (T-LGL) is a cytotoxic lymphocyte disorder with distinctive clinicopathological features. While patients typically experience an indolent clinical course,...

Anemia and thrombocytopenia at chronic lymphocytic leukemia (CLL) presentation have long been considered to be predictive of a poor prognosis, irrespective of the cause of cytopenia, yielding an advanced stage of the disease. We identified 86 patients with CLL who were diagnosed after year 2000 with Binet C disease at first presentation. Cytopenia was considered related to autoimmune conditions in 27 (31.3%; stage C "immune") or secondary to bone marrow failure in 59 (68.6%; stage C "infiltrative"). No difference in clinical characteristics, mutational status, cytogenetics, TP53 and NOTCH1 mutations was observed between stage C "immune" and "infiltrative." Patients with stage C "immune" had a trend toward a better overall survival than patients with stage C "infiltrative" (median 74 vs. 63 months), but the difference was not statistically significant (p = 0.30). This difference was not modified by adjustment for CLL tumor burden at presentation, and survival of stage C "immune" patients was significantly inferior compared to an unselected cohort of patients with stage A, but similar to stage B. Our findings suggest that autoimmune cytopenias at CLL diagnosis have a negative impact on patient outcome.

In 1976 the French–American–British (FAB) Leukemia Working Group proposed the first definitions of patients with myelodysplastic syndromes (MDS), namely refractory anemia with excess blasts (RAEB) and chronic myelomonocytic leukemia (CMML). Subsequent publications resulted in additional subgroups that had prognostic significance. Incorporation of the subgroupings by the World Health Organization and additional fine tuning of the degrees of morphologic dysplasia and percentage of blasts have enhanced the classification. Several prognostic scoring systems have added degrees of cytopenia, cytogenetic aberrations and molecular genetic mutations that allow care providers to subdivide cases into lower, intermediate and higher grade categories.

Myelofi brosis (MF), including primary myelofi brosis (PMF), post-polycythemia vera MF, and post-essential thrombocythemia MF, are characterized by excess pro-infl ammatory and pro-angiogenic cytokines linked to MF-related constitutional symptoms, transfusion dependence, splenomegaly, thrombocytopenia and overall survival [1]. Although allogeneic stem-cell transplant can lead to cure, few patients are eligible for this therapy [2]. Th erefore, improvement of symptoms and quality of life (QoL) is a major end point of novel treatment strategies. Th e relevance of the hyperactive JAK – STAT (Janus kinase/signal transducers and activators of transcription) pathway as a molecular target has led to the development of JAK1 and JAK2 inhibitors. Ruxolitinib, known to be eff ective in alleviating constitutional symptoms in the majority of patients with MF, was approved based on data from two pivotal phase 3 studies, Controlled Myelofi brosis Study with Oral JAK Inhibitor Treatment-I (COMFORT-I) and COMFORT-II, respectively [3,4]. Th e hematologic adverse eff ects [3,4] of ruxolitinib are anemia (34 – 45%), thrombocytopenia (13 – 43%) and neutropenia (7.1%), and hence, for those patients with cytopenia, the use of this drug is still open to discussion [5]. Pomalidomide, an immunomodulatory drug (IMiD) compound, showed improvement in MFassociated cytopenia, with lower toxicity and better tolerability when compared with thalidomide and lenalidomide [6]. Th erefore, we wish to report a new drug combination

Hemophagocytic lymphohistiocytosis (HLH) is characterized by fever, splenomegaly, cytopenia, hypertriglyceridemia and/or hypofibrinogenemia, hemophagocytosis, low or absent natural killer (NK)-cell...

Excess apoptosis leading to ineffective hematopoiesis is a common feature of myelodysplastic syndrome (MDS). CD178 (Fas ligand/APO-1 ligand) and CD137 ligand (CD137L), 2 molecules involved in the regulation of apoptosis, have previously been found in sera of patients with malignancies and have been hypothesized to participate in the pathogenesis of various diseases. We analyzed sera of patients with MDS and found that while time to progression of MDS correlated with the IPSS score there was no correlation of CD137L or CD178 serum levels with this score or with karyotype, bone marrow blast count or cytopenia. However, when cut-off-values for significant differentiation between cases with higher/lower levels of these molecules were determined we found that high levels of soluble CD137L (sCD137L) and low serum levels of soluble CD178 (sCD178) correlate with statistical significance to rapid progression of disease as estimated by log-rank-test. Conversely, low levels of sCD137L and high levels of sCD178 correlate significantly with prolongation of time to progression of disease. Our results indicate that serum levels of sCD137L and sCD178 represent valuable novel indicators for prognosis and disease progression and may be a useful parameter for treatment decisions in patients with MDS.

Myelofi brosis (MF) is a chronic Philadelphia-negative myeloproliferative neoplasm characterized by bone marrow fi brosis, extramedullary hematopoiesis, a leukoerythroblastic blood picture and various degrees of cytopenia [1]. Th e median survival of patients with primary myelofi brosis (PMF) ranges from 3 to 5 years and most patients will fi nally die from bone marrow failure or leukemic transformation (LT) [2]. It has been demonstrated that approximately 20% of patients with MF over a 10-year period will transform to acute leukemia, and the median survival of patients with LT is about 3 months [3]. Th e aim of this study was to evaluate the risk factors, clinical outcome and therapeutic options for patients with LT in MF. A total of 77 patients with PMF ( n 42) and post-polycythemia vera/essential thrombocythemia (PV/ET) MF ( n 35) diagnosed between 1999 and 2010 were included in the study. Th ere were 41 females and 36 males, with a median age of 61 at diagnosis (range 19 – 81 years). All patients gave informed consent and the study was approved by the Local Ethics Committee of Silesian Medical University. Before a patient entered the study, reactive causes of myelofi brosis were carefully excluded. Bone marrow trephine biopsy was performed at diagnosis and the grade of fi brosis was assessed according to the well-known classifi cation [4]. Lille score and international prognostic scoring system (IPSS) score were established at the time of MF diagnosis in all patients [2,5]. Due to the small sample size for LT preceded by PMF, post-PV MF and post-ET MF were grouped together. A diagnosis of LT required peripheral blood or bone marrow blasts to be greater than 20%. Chromosomes were analyzed using the conventional G-banding technique and the JAK2V617F point mutation was detected using a commercially available kit, MutaScreen O (Ipsogen, Marseille, France). Th e survival of patients with LT was defi ned as the interval from the date of diagnosis of LT to either death or last contact. Th e distribution of overall survival and leukemia-free survival was estimated using the method of Kaplan and Meier. Variables describing patient characteristics at diagnosis

Marrow dysplasia is a major characteristic of patients with myelodysplastic syndrome (MDS), along with marrow blastosis, cytopenia and cytogenetic anomalies. However, the impact of the degree of marrow dysplasia on survival has not been fully assessed. In this retrospective analysis of 111 patients selected according to the IPSS criteria of MDS diagnosis, the presence or absence of 21 dysplasia characteristics recognizable in bone marrow smears stained by the May-Grünwald-Giemsa method was correlated with patient survival. Using Cox proportional hazards regression analysis, megaloblastosis (MEGALO), neutrophil agranularity (AGRAN) and hypogranularity (HYPOGRAN) were highly significant predictors (p0.005), and Pelger-Huët anomaly (PELGHUET) a significant predictor (p = 0.05), of patient survival. The regression analysis yielded a dysplasia-based risk index (DI) where DI = 1.26 MEGALO + 0.82 AGRAN - 1.08 HYPOGRAN + 0.45 PELGHUET. The two subgroups of 60 and 47 patients with DIor = 0 and0 showed highly significant differences in median survivals (2.6 vs 1.1 yrs; p0.0001). Multivariate analysis further showed that DI offered additional predictive power that was independent of that provided by the IPSS (p=0.002 and 0.001 respectively). Analysis of survival curves stratified for IPSS and DI showed that the additional predictive power offered by inclusion of the DI essentially concerned the IPSS low/INT-1 risk categories. Further stratification for age did not improve survival prediction. The data indicate that a set of 4 dysplasia parameters can offer some prediction for survival of MDS patients in addition to that provided by the IPSS. Further multicenter studies should aim at including some form of evaluation of the degree of dysplasia in prognostic systems.

Malignant histiocytosis-like B-cell lymphoma (MH-like BCL) is characterized clinically by hemophagocytic syndrome (HPS), bone marrow involvement at presentation, and an aggressive clinical course. Yet, it remains an ill-defined disease entity. We recently described five cases of MH-like BCL and suggested that these may be regarded as a peculiar variant of intravascular lymphomatosis (IVL), based on clinical and pathological observation. Interestingly, this type of lymphoma has been reported exclusively among Asians, with few reports from Western countries, and therefore we propose that this variant be noted as an Asian variant of IVL(AIVL). To evaluate the incidence of this variant, we performed a literature search for English or Japanese studies dealing with MH-like BCL or B-cell IVL associated with HPS (IVL with HPS). We found 18 reports of MH-like BCL and 16 reports of IVL with HPS and re-evaluated the clinicopathologic aspects of each study with respect to AIVL. Although several differences were noted, such as gender, presence of respiratory changes, bone marrow invasion and disseminated intravascular coagulopathy, there were also overlapping profiles and they appeared to be consistent with the AIVL single disease entity. Of particular note was the absence of peripheral lymphadenopathy and tumor formation which posed diagnostic problems in the initial phase of the presentations. Thus, based on analysis of the clinical findings of these 34 cases, the diagnostic criteria for AIVL consists primarily of cytopenia (anemia and/or thrombocytopenia), hepatosplenomegaly, absence of peripheral lymphadenopathy and tumor formation, and erythrocyte-hemophagocytosis along with intravascular proliferation of the neoplastic B cells. The pathologic findings of the 19 autopsied cases which fulfilled the criteria are also summarized, and they reveal morphologic, immunologic, and genotypic features of typical IVL.

The clinical safety and efficacy of IPI-926 was evaluated in 14 patients with myelofibrosis in a phase II study. Patients received 160-mg IPI-926 orally in continuous 28-day cycles. The median treatment duration was 5.1 months, and all patients had discontinued treatment by 7.5 months. Nine patients discontinued due to lack of response as determined by the treating physician, two after developing acute leukemia and one due to disease progression/loss of response. Twelve patients had slight reductions in spleen size (less than 50% from baseline), but symptoms did not improve consistently. One patient achieved transfusion independence lasting 5 months. Reductions in GLI1 mRNA and protein levels, JAK2V617F allele burden, degree of fibrosis, or cytokine levels were observed in some patients, but were not significant when evaluated for the cohort. Low-grade gastrointestinal/liver abnormalities were the most common toxicities. The results did not support continued evaluation of IPI-926 as a monotherapy in myelofibrosis.

For most patients with myelodysplastic syndromes (MDS), treatment options are limited to non-curative approaches, most of which aim at counteracting cytopenia(s). Apart from continuous transfusions...

The paradox of pancytopenia despite cellular bone marrows (BM) was investigated in 120 patients with myelodysplastic syndromes (MDS). Detailed cell cycle kinetics were examined following in vivo infusions of iodo--and/or bromodeoxyuridine (IUdR/BrdU), while the incidence of apoptosis was measured by in situ end labeling (ISEL) of fragmented DNA. Results showed that MDS are highly proliferative disorders with an equally high incidence of apoptotic intramedullary cell death accounting for the paradox of cellularity/cytopenia. By double-labeling BM biopsy sections for ISEL/BrdU we found the peculiar situation of "signal antonymy" where S-phase cells were frequently apoptotic, a phenomenon so far only seen in MDS biopsies. The cause-effect relationship of this excessive proliferation/apoptosis is discussed at length.

Chronic proliferations of natural killer (NK) cells (CD3- CD16+) are identified initially by detecting large granular lymphocyte (LGL) excess in a peripheral blood smear and subsequent lymphocyte immunophenotyping by flow cytometry. A related disease, T-LGL leukemia, has an indolent clinical course with chronic neutropenia and a close association with rheumatoid arthritis. Herein are described the clinical presentation and long-term clinical course of patients with chronic NK cell lymphocytosis (CNKL). The majority of the 14 patients followed up for a median of 4 years presented with severe cytopenias or vasculitic syndromes that were responsive to immunosuppressive therapy. Other manifestations included fever and arthralgias. In general, the disease was nonprogressive and had a course similar to that of T-LGL leukemia.

The prevalence of humoral immune dysfunction has not been defined in a large series of patients with T-cell large granular lymphocyte leukemia (T-LGL) confirmed to be clonal by T-cell receptor analysis. Therefore we evaluated the presence of multiple autoantibodies in 27 patients with this disease. Humoral immune abnormalities included: rheumatoid factor (RF) (15/27 patients), antinuclear antibody (ANA) (13/27 patients), polyclonal hypergammaglobulinemia (15/24 patients), elevated serum immunoglobulins (17/26 patients), immune complex formation (18/25 patients), elevated beta-2 microglobulin (13/18 patients) and neutrophil-reactive IgG (18/20 patients). Disease manifestations in these patients were due to complications of cytopenia or autoimmune abnormalities. Infection was a common finding (21/27 patients) and likely reflected their neutropenia. Rheumatoid arthritis (11/27 patients), anemia (12/27 patients) and thrombocytopenia (10/27 patients) were less common but still frequently observed. This study demonstrates the presence of multiple autoantibodies in a large series of patients with documented clonal T-LGL proliferations.

Myelodysplastic syndromes (MDS) are a heterogeneous group of disorders of hematopoiesis involving hyperproliferative and ineffective hematopoiesis associated with morphologic evidence of marrow cell dysplasia resulting in refractory cytopenia(s), and an increased risk of transformation into acute myeloblastic leukemia (AML). The administration of colony-stimulating factor(s) (CSFs) to patients with MDS increased blood neutrophil concentrations, in most patients, and was also expected to be beneficial and to prevent infections. However, the progression to AML during the treatment with CSFs was suspected in some patients. Therefore, extensive in vitro studies were expected to lead to the establishment of criteria for selection of patients who are likely to benefit from CSF's as well as to establish the overall value of the different types of CSFs therapy. For this purpose, in vitro colony assays provide an excellent tool for investigating the biologic characteristics of MDS progenitor cells. However, conditions of the culture must be such that each progenitor can express its full potential for proliferation and differentiation. Because of the above, MDS progenitor cells cannot be used because they carry an impairment in proliferation and differentiation. To address this problem, one needs to know how many cells are being handled and the maximum numbers of colonies and clusters expected. CD34, a stem cell phenotype, is at present one of the best markers of progenitor cells, and can be used for purposes of purification. Using a defined number of CD34+ cells, it was feasible to make direct investigations on MDS progenitor cells. In this review the properties of MDS progenitor cells are described, in association with proliferation and differentiation, with special emphasis on the phenotypic subpopulations of MDS CD34+ cells.

Ninety-three patients with myelodysplastic syndrome with either excess blasts or life-threatening cytopenia received cyclophosphamide and total body irradiation (88 patients) or busulfan (5 patients) followed by allogeneic (90 patients) or syngeneic (3 patients) marrow infusion. Thirty-eight patients are disease-free survivors between 1.8 and 11.3 years (median 6.1 years) after transplantation. The median Karnofsky performance status of the survivors is 100%, and only 2 have a performance status of < 80%. Eighteen patients relapsed and the remaining 37 died without evidence for relapse. The 5-year actuarial disease-free survival, relapse, and non-relapse mortality rates are 40%, 29%, and 44%, respectively. The actuarial relapse rate was higher among patients with excess blasts at the time of transplantation compared to those without excess blasts (49% vs. 4%, p = 0.0001), resulting in a lower disease-free survival (31% vs. 54%, p = 0.07). Increasing age was associated with a lower disease-free survival (p = 0.02). In a multivariate analysis, younger age, shorter disease duration, and absence of excess blasts were associated with improved outcome. We recommend that patients with myelodysplasia with appropriate marrow donors, especially patients less than age 40, undergo marrow transplantation early during the disease course, before the disease progresses or life-threatening complications develop.

The association of hemolytic anemia and other autoimmune cytopenias with chronic lymphocytic leukemia (CLL) is well known. The etiology of these immune syndromes is still uncertain, despite evidence that the putative cell of origin of the B-CLL cell produces naturally occurring autoantibodies. Cyclosporine A is effective in treating the immune manifestations associated with CLL and, occasionally, has shown anti-leukemic activity. We report two cases in which cyclosporine A treatment of autoimmune hemolytic anemia resulted in reduction of CLL cell burden. We then discuss the possible mechanism of action of cyclosporine A and the nature of the autoimmune processes involved.

Six patients with either acceleration or blast crisis of transformed chronic myeloid leukemia (CML.) were treated with high-dose interferon alpha in combination with hydroxyurea. All patients responded to the treatment by reversal to stable chronic phase. Two of these patients responded repeatedly during their course of disease. Median time for return to chronic phase was 4 weeks. Adverse side-effects such as nausea, vomiting, hairloss, fever, prolonged cytopenia were not observed.

We report the case of a 76-year old patient with third relapse of AML who was successfully treated with Imatinib. The decision to try Imatinib was guided by bright expression of c-kit on the patient's blasts. Treatment was well tolerated but the dose was reduced for pancytopenia and later stopped completely because of pneumonia. The patient recovered with i.v. antibiotics, antimycotics and s.c. G-CSF. Reevaluation of the bone marrow after the end of treatment demonstrated the absence of malignant blasts. Treatment with Imatinib was started again with the intention to prolong remission duration. During the following months peripheral blood counts stabilized in the normal range indicating that a fourth complete remission has been achieved in this patient. This is the first report demonstrating that Imatinib can induce complete remission in relapsed c-kit positive AML in an elderly patient. Prolonged cytopenia remains a considerable problem indicating that normal haematopoiesis is not completely independent of the signalling cascades inhibited by Imatinib. Nevertheless our report supports further study of this drug in c-kit positive AML.

We examined bone marrow specimens from 19 patients with malignant histiocytosis (MH) and/or malignant lymphoma (ML) with concurrent hemophagocytic syndrome (HS) who suffered from high fever, hepatosplenomegaly, liver dysfunction, profound cytopenia, and erythrophagocytosis. There was little lymph-node enlargement or no tumor formation. The neoplastic cells in 3 patients exhibited histiocytes/macrophages phenotype with positive reactions for fluoride-sensitive nonspecific esterase, lysozyme and CD68 (KP1). Twelve other patients showed a T-cell (CD3) phenotype, in which 5 patients expressed CD30 (BerH2) as well. B-cell characteristics with CD20 (L26), CIg. nu lambda and gamma kappa were manifest in 2 patients, but indeterminate markers were found in the 2 remaining patients. Eighteen patients showed an infiltration of large neoplastic cells mainly with noncohesive interstitial growth pattern, ranging from 1.7% to 74.2% of the nucleated cells in the bone marrow. A large number of histiocytes/macrophages and dendritic cells was diffusely observed in 15 patients. Severely decreased hematopoiesis in all three series of hematopoietic cells was found in 16 patients. Bone marrow infiltration by the neoplastic cells and numerous reactive cells with erythrophagocytosis appears to be an important factor of profound cytopenia in patients of MH and/or ML with HS. The infiltrating pattern of the neoplastic and reactive cells in the bone marrow of MH and/or ML with HS was different from that of other types of peripheral T-cell ML, B-cell ML in high grade malignancy, and Hodgkin's disease. Cell characteristics and lineage of the neoplastic cells in MH and/or ML with HS are also discussed in this study.

Peripheral blood stem cells (PBSC) in autografts (PBSCT) were given to 16 children with high-risk acute lymphoblastic leukemia (ALL) or non-Hodgkin's lymphoma (NHL). Harvest of PBSC is a safe, reliable procedure with low morbidity in children with cancer, and cryopreserved PBSC are useful in reducing cytopenia following marrow-ablative chemotherapy. The CFU-GM content of the thawed grafts is an important determinant of hematopoietic recovery after PBSCT. Whereas not all collections from children who had received intensive chemotherapy yielded sufficient progenitors for a safe graft, the value of preleukapheresis use of granulocyte colony-stimulating factor to expand the transplantable stem cell pool was not proven. After marrow-ablative chemotherapy without total body irradiation, three children who underwent PBSCT at refractory relapse died within 3 months. However, eight of the remaining 13 children are currently alive and disease-free, 5-29 months after PBSCT.

A bone marrow examination in a young woman with anemia and β-thalassemia trait showed dyserythropoiesis in less than 10% of erythroblasts without other myelodysplastic changes, and cytogenetic analysis revealed trisomy of chromosome 8. Although she did not fulfill the current World Health Organization (WHO) criteria for diagnosis of a myelodysplastic syndrome, her acquired bone marrow disorder behaved as such, and she later developed acute myeloid leukemia.

CASE A 67 year old English male presented with a six month history of shortness of breath, malaise, lethargy, fever, and night sweats. He had not suffered pruritus or alcohol-induced pain. There was no history of recent travel. He had no hepatomegaly, lymphadenopathy, splenomegaly or abnormal findings in the chest. Results of laboratory tests were: Hb 10 g/dl, MCV 89 fl, WBC 3.8 × 109/1, neutrophil count 2.5 × 109/1, lymphocyte count 1.1 × 109/1, monocyte count 0.04 × 109/1, platelet count 269 × 109/1, ESR 116 mm/hr, aspartate transferase 44IU/1 (NR