Diffuse alveolar hemorrhage in hematopoietic stem cell transplant recipients.
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Adrenal Cortex Hormones↗
Biomedical subjects
Ayalew Tefferi
Publications and source records attributed to Ayalew Tefferi.
Diagnostic and prognostic value of bone marrow angiogenesis and megakaryocyte c-Mpl expression in essential thrombocythemia.
The lack of diagnostic certainty in some patients makes it difficult to distinguish between primary and secondary forms of thrombocytosis. To augment current diagnostic studies for thrombocytosis, we retrospectively evaluated clinical records and bone marrow trephine specimens of 183 patients with thrombocytosis-164 with essential thrombocythemia (ET), 19 with reactive thrombocytosis (RT)-for bone marrow angiogenesis, bone marrow megakaryocyte c-Mpl staining, and morphologic evidence of megakaryocyte proliferation. Angiogenesis was increased in patients with ET compared with healthy controls (P <.0001) and patients with RT (P =.006). In addition, an increase in angiogenesis was associated with certain disease features such as splenomegaly (P =.004) and reticulin fibrosis (P =.005). Decreased megakaryocyte c-Mpl staining was observed in a heterogeneous pattern in ET compared with healthy controls (P <.0001) and RT (P <.0001). Histologic stratifying criteria incorporating increased angiogenesis, decreased megakaryocyte c-Mpl expression, and marked megakaryocyte proliferation in the bone marrow was highly sensitive (97%) and specific (95%) for distinguishing ET from RT (P <.0001). However, with the current duration of follow-up available on the patients, none of the histologic features evaluated have yet demonstrated prognostic value for subsequent clinical course, vascular events, or survival.
Adolescent↗
Phase 2 trial of imatinib mesylate in myelofibrosis with myeloid metaplasia.
In a phase 2 study, 23 patients with myelofibrosis with myeloid metaplasia were treated with imatinib mesylate at a constant dose of 400 mg/d. Treatment was held in 16 patients (70%), after 1 to 12 weeks, because of side effects (neutropenia, 6 patients; musculoskeletal pain, 5 patients; thrombocytosis, 4 patients; edema, 3 patients; diarrhea and hyperbilirubinemia, 1 patient). Including patients in whom retreatment at a reduced dose was possible, 11 patients (48%) were able to continue treatment beyond 3 months. None of the patients experienced a response in anemia, and only 2 had partial responses in splenomegaly. A greater than 50% increase in platelet count was documented in 11 (48%) patients, but not in those with baseline platelet counts of less than 100 x 10(9)/L. In vitro, imatinib mesylate caused variable degrees of growth suppression of myeloid and erythroid progenitors that unfortunately did not translate into clinical benefit.
Adult↗
Treatment of hypereosinophilic syndrome with imatinib mesilate.
Patients with hypereosinophilic syndrome show persistent eosinophilia without recognised cause. We treated five such patients with 100 mg imatinib mesilate (formerly STI-571) daily; four male patients with normal serum interleukin 5 showed complete haematological responses; a female patient who did not respond had raised serum interleukin-5 concentrations. One patient developed leucopenia after 4 days of treatment; counts returned to normal when treatment was stopped. After 1 month, eosinophilia recurred; with further treatment for 2 days, eosinophil counts again became normal. All patients who responded stopped other treatments and reduced imatinib mesilate to 200 mg per week. This drug effectively controls eosinophilia in patients with hypereosinophilic syndrome and normal interleukin-5 concentrations.
Administration, Oral↗
Selective serotonin reuptake inhibitors are effective in the treatment of polycythemia vera-associated pruritus.
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Aged↗
Etanercept, a soluble tumor necrosis factor receptor, palliates constitutional symptoms in patients with myelofibrosis with myeloid metaplasia: results of a pilot study.
Patients with myelofibrosis with myeloid metaplasia (MMM) often experience debilitating constitutional symptoms such as drenching night sweats, profound fatigue, unexplained fevers, and unintentional weight loss. Tumor necrosis factor (TNF) contributes to organ fibrosis and hypercatabolic symptoms in a variety of disease states. We conducted an open-label pilot study of etanercept, a soluble TNF receptor, administered at a dose of 25 mg subcutaneously twice weekly for up to 24 weeks in 22 patients with MMM. Of 20 evaluable patients, 12 (60%) experienced an improvement in constitutional symptoms, and 4 (20%) had an objective response (improvement in peripheral cytopenias or spleen size). The degree of marrow fibrosis was unchanged, and only minor changes in overall marrow cellularity were observed. Toxicity was mild, with injection site reactions (20%) and minor infections (10%) as the most common side effects. One patient developed reversible pancytopenia. Etanercept may be useful for palliation of constitutional symptoms in MMM.
Aged↗
Adverse events after imatinib mesylate therapy.
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Aged↗
Effects of the Bcr/abl kinase inhibitors STI571 and adaphostin (NSC 680410) on chronic myelogenous leukemia cells in vitro.
The adenosine triphosphate binding-site-directed agent STI571 and the tyrphostin adaphostin are undergoing evaluation as bcr/abl kinase inhibitors. The current study compared the effects of these agents on the survival of K562 cells, bcr/abl-transduced FDC-P1 cells, and myeloid progenitors from patients with chronic myelogenous leukemia (CML) compared with healthy donors. Treatment of K562 cells with 10 microM adaphostin resulted in decreased p210(bcr/abl) polypeptide levels in the first 6 hours, followed by caspase activation and accumulation of apoptotic cells in less than 12 hours. By 24 hours, 90% of the cells were apoptotic and unable to form colonies. In contrast, 20 microM STI571 caused rapid inhibition of bcr/abl autophosphorylation without p210(bcr/abl) degradation. Although this was followed by the inhibition of Stat5 phosphorylation and the down-regulation of Bcl-x(L) and Mcl-1, only 7% +/- 3% and 25% +/- 9% of cells were apoptotic at 16 and 24 hours, respectively. Instead, the cytotoxic effects of STI571 became more pronounced with prolonged exposure, with IC90 values greater than 20 microM and 1.0 +/- 0.6 microM after 24 and 48 hours, respectively. Consistent with these results, 24-hour adaphostin exposure inhibited CML granulocyte colony-forming units (CFU-G) (median IC50, 12 microM) but not normal CFU-G (median IC50, greater than 20 microM), whereas 24-hour STI571 treatment had no effect on CML or normal CFU-G. Additional experiments revealed that STI571-resistant K562 cells remained sensitive to adaphostin. Moreover, the combination of STI571 + adaphostin induced more cytotoxicity in K562 cells and in CML CFU-G than either agent alone did. Collectively, these results identify adaphostin as a mechanistically distinct CML-selective agent that retains activity in STI571-resistant cell lines.
Adamantane↗
Distinct bone marrow findings in T-cell granular lymphocytic leukemia revealed by paraffin section immunoperoxidase stains for CD8, TIA-1, and granzyme B.
Unlike other leukemia types in which the bone marrow findings are diagnostic, the bone marrow pathology of T-cell granular lymphocytic leukemia (GLL) is subtle and ill-defined. In this study, bone marrow biopsy specimens from 36 patients with T-cell GLL and from 25 control patients with cytopenias and relative or absolute increases in blood large granular lymphocytes were studied by immunohistochemistry using antibodies to the cytolytic lymphocyte antigens CD8, CD56, CD57, TIA-1, and granzyme B. The goals were to clarify the bone marrow pathology of T-cell GLL and to refine the diagnostic criteria for T-cell GLL. Most bone marrow specimens from the T-cell GLL patients contained interstitially distributed clusters of at least 8 CD8(+) (83%) or TIA-1(+) (75%) lymphocytes or clusters of at least 6 granzyme B(+) (50%) lymphocytes. Interstitial clusters of CD8(+), TIA-1(+), or granzyme B(+) cells were present in 36%, 12%, and 0%, respectively, of the control bone marrows (all values significantly different, P <.001). An additional T-cell GLL disease-specific finding was the presence of linear arrays of intravascular CD8(+), TIA-1(+), or granzyme B(+) lymphocytes, found in 67% of cases of T-cell GLL and in none of the 25 control samples (P <.001). Staining for CD56 and CD57 was noncontributory. These findings clarify the bone marrow histopathology of T-cell GLL and provide an additional tool by which the discrete, abnormal lymphocyte population required for a diagnosis of T-cell GLL can be identified.
Adult↗
Stem cell transplantation for the management of primary systemic amyloidosis.
PURPOSE: To review the characteristics and outcomes of amyloidosis patients treated with high-dose chemotherapy and stem cell reconstitution. SUBJECTS AND METHODS: Sixty-six patients with biopsy-proven amyloidosis received transplants between March 1996 and January 2001. All patients had evidence of a clonal plasma cell dyscrasia; those with nonimmunoglobulin forms of amyloidosis were excluded, as were those who had no symptoms of amyloidosis, purpura, carpal tunnel syndrome, or symptomatic multiple myeloma. RESULTS: Amyloid was seen clinically in the kidneys (n = 45 patients), heart (n = 32), peripheral nerves (n = 11), and liver (n = 11). A monoclonal protein was found in the serum in 46 patients and in the urine in 57 patients. The median daily urinary protein loss was 4.1 g. Septal thickness, measured by echocardiography, ranged from 7 to 24 mm (median, 12 mm); 8 patients had a septal thickness > or =16 mm. Ten patients received transplants 1 year or more after diagnosis. All patients received melphalan-based chemotherapy; 17 patients were conditioned with total body irradiation. Nine patients required dialysis, 7 of whom died. Treatment-related mortality for stem cell transplantation was 14% (9/66). After a median of 25 months of follow-up after transplantation, the percentage of patients alive with one organ involved was 91% (31 of 34); two organs, 82% (18 of 22); three organs, 33% (3 of 9); and four organs, 0% (0 of 1). Hematologic responses were seen in 33 patients and organ responses in 32 patients. The 2-year actuarial survival of all patients was 70%. CONCLUSION: The number of organs involved before stem cell transplantation for amyloidosis is the most important factor in predicting subsequent survival. Stem cell transplantation should be considered as a treatment option for selected patients with amyloidosis.
Adult↗
Immunohistochemical studies of c-kit, transforming growth factor-beta, and basic fibroblast growth factor in mast cell disease.
In 58 patients with mast cell disease (MCD) and three with basophilic leukemia, bone marrow (54 cases) or skin tissue (four cases) was studied immunohistochemically for expression of Kit (c-kit protein), the different isomers of transforming growth factor-beta (TGF-beta), basic fibroblast growth factor (bFGF), and their respective receptors. Kit was expressed in all cases of MCD but in none of basophilic leukemia. Expression pattern of cytokines and their receptors was variable in systemic MCD with (SMCD-HD) or without (SMCD) associated hematologic disorder. However, type I TGF-beta receptor (TGFbeta1R) was not expressed in 30% of SMCD-HD patients or in patients with mast cell leukemia, but the remaining cases of MCD showed near uniform expression. The associated hematologic disorders in TGFbeta1R-negative cases of SMCD-HD were prognostically less favorable than those associated with TGFbeta1R-positive cases of SMCD-HD. The results confirm the diagnostic value of Kit immunohistochemistry in MCD and suggest a biologically relevant heterogeneity in TGFbeta1R expression among patients with SMCD-HD.
Bone Marrow↗
Simultaneous measurement of serum thrombopoietin and expression of megakaryocyte c-Mpl with clinical and laboratory correlates for myelofibrosis with myeloid metaplasia.
OBJECTIVES: We sought to investigate potential mechanisms of increased serum thrombopoietin (TPO) concentrations in myelofibrosis with myeloid metaplasia (MMM) by simultaneously measuring serum TPO, platelet and megakaryocyte (MK) numbers, and MK c-Mpl expression. METHODS: We studied 17 consecutive patients who had MMM and were not receiving therapy at the time of evaluation. Serum TPO was measured by a two-site immunochemiluminometric assay. Immunohistochemical staining of c-Mpl was accomplished with an immunoperoxidase method on simultaneously obtained bone marrow specimens. RESULTS: Our findings confirmed the presence of inappropriately increased serum TPO despite mostly normal or increased peripheral platelet counts and markedly increased bone marrow MK numbers. In addition, we found an inverse correlation between platelet count and serum TPO (P<0.03) and splenic size (P<0.04). However, serum TPO did not correlate with either bone marrow MK number or c-Mpl expression. The lack of correlation of serum TPO and bone marrow megakaryocyte number may be accounted for by the unavoidable inaccuracies in quantifying megakaryocytopoiesis in a disorder of known altered hematopoietic progenitor cell distribution, both intramedullary and extramedullary. The significant inverse correlation between serum TPO and spleen size suggests that this site of extramedullary megakaryocytopoiesis may assume a role in the dysfunctional TPO regulatory axis. CONCLUSIONS: These observations suggest some preservation of the negative feedback regulation that appears to be dysfunctional at the MK c-Mpl level. Consistent with previous observations in animal models, our observations suggest the possibility that altered TPO regulation resulting in sustained ligand excess may have pathogenetic relevance in MMM.
Adult↗
Thalidomide treatment in myelofibrosis with myeloid metaplasia.
Myelofibrosis with myeloid metaplasia (MMM) is uniquely characterized by macroscopic bone marrow stromal changes that are believed to be both reactive and cytokine mediated. Furthermore, a prognostically detrimental increase in bone marrow angiogenesis has recently been demonstrated. These observations suggest a potential therapeutic role for agents that are inhibitory to angiogenesis as well as cytokines that are pathogenetically implicated in MMM. In a prospective study of 15 patients with MMM, thalidomide treatment, starting at a dose of 200 mg/d, resulted in increased platelet counts (12 of 15 patients), increased haemoglobin level (3 of 15), a modest decrease in spleen size (3 of 12), increased bone marrow megakaryopoiesis (5 of 9) and decreased bone marrow angiogenesis (2 of 9). Undesirable haematological effects included pericardial extramedullary haematopoiesis in one patient, marked leucocytosis in two patients and extreme thrombocytosis in three patients. The thrombocytosis occurred in both patients with post-thrombocythaemic myeloid metaplasia (PTMM) and was also associated with higher baseline levels of circulating CD34+ cells. Previously described toxicities of thalidomide were seen in the majority of patients and dose escalation to 400 mg/d was permitted in only two patients. In contrast, toxicity-related dose reductions to 50 mg/d did not appear to lessen drug efficacy. We conclude that thalidomide has both beneficial and potentially adverse biological activity in MMM. A lower dose of the drug might be more tolerable without compromising therapeutic value. Patients with PTMM and/or markedly increased circulating CD34+ cell counts might be susceptible to thalidomide-induced thrombocytosis.
Adult↗
Low-dose, single-fraction, whole-lung radiotherapy for pulmonary hypertension associated with myelofibrosis with myeloid metaplasia.
Pulmonary hypertension (PH) can complicate myelofibrosis with myeloid metaplasia (MMM), may arise in the absence of evidence for thromboembolic disease and carries a grim prognosis. Four patients with MMM and severe symptomatic PH were treated with whole-lung external beam radiotherapy in a single fraction of 100 cGy. Within 72 h, each patient noted marked symptomatic improvement and had relief of hypoxia and reduction of oedema and/or ascites. Three of the four patients enjoyed an objective improvement in pulmonary artery systolic pressure as measured by transthoracic Doppler echocardiography. Low-dose lung radiotherapy may be a useful palliative tool for patients with MMM complicated by PH.
Aged↗
Cutaneous findings associated with chronic natural killer cell lymphocytosis.
BACKGROUND: Chronic Natural Killer Cell Lymphocytosis (CNKL) is a recently described rare proliferative disorder. We noted an association of cutaneous disorders with CNKL in our clinical experience. METHODS: We reviewed the medical records of all known patients with CNKL at our institution. RESULTS: Five of 14 patients (36%) with CNKL had associated chronic cutaneous disease: two had livedoid vasculopathy; one, urticarial vasculitis; one, peripheral T-cell lymphoma; and one had complex recurrent aphthous stomatitis. In each case, except the one with lymphoma, the cutaneous disease was present before CNKL was diagnosed and CNKL persisted for the duration of the cutaneous disease. All five patients had increased numbers of large granular lymphocytes on a peripheral blood smear and three or four in the bone marrow (one patient did not undergo bone marrow biopsy). CONCLUSIONS: Although CNKL and the reported skin diseases have occurred in the same patients, a causal link cannot yet be established. With CNKL, dermatologists must recognize associated cutaneous diseases, monitor patients for systemic disorders and cytopenias, and appropriately refer patients to a hematologist.
Adult↗
Veno-occlusive disease of the liver after blood and marrow transplantation: analysis of pre- and post-transplant risk factors associated with severity and results of therapy with tissue plasminogen activator.
We reviewed our blood and marrow transplantation (BMT) database from April 1982 to July 1996 and identified 111 of 474 patients with serum bilirubin concentration (SBR) > or = 34 micromol/l for two consecutive days within the first 20 days after related allogeneic or autologous BMT. Of the 111, 73 fulfilled the Seattle criteria for veno-occlusive disease of the liver (VOD) and had no other obvious cause for liver dysfunction. The patients were 16-60 years old (median, 39 years), and 41 were male (56%). Fourteen patients (19%) had autologous BMT, and 59 (81%) had allogeneic BMT. Twenty-eight (38%), 12 (16%), and 33 (45%) patients had severe, moderate, and mild VOD, respectively, by Seattle criteria. None of 23 patients with maximum (max) SBR > or = 257 micromol/l survived, all patients with max SBR < or = 128 micromol/l survived, and 7 of 15 patients (47%) with max SBR 128-257 micromol/l survived. The only pre-transplantation risk factor predictive of severe VOD was advanced disease state (P = 0.035), and the only transplant factors that predicted severe VOD were max SBR (P = 0.01) and maximum blood urea level (P = 0.03). Ten patients (all with creatinine levels > or = 150 micromol/l) were treated with tissue plasminogen activator; only two had a significant response and only one survived beyond day 120.
Adolescent↗
Thalidomide in myelofibrosis with myeloid metaplasia: a pooled-analysis of individual patient data from five studies.
Trials to determine the effect of thalidomide in patients with Myelofibrosis with Myeloid Metaplasia (MMM) have produced inconclusive results due to different criteria for response and heterogeneous study participants. We undertook a pooled-analysis to assess the effects of such treatment on a larger series of cases and with a uniform assessment of response. We used updated data on 62 individual patients from 5 phase II trials that evaluated thalidomide therapy in MMM patients. Responsewas judged on individual disease parameters, on the improvement of the Dupriez risk categories and on the improvement of a 6 point "severity score" based on myeloproliferative and myelodepletive indexes of the disease. Overall, using standard dose of thalidomide, i.e. starting with no less than 100 mg/day, 49 patients (79%) had more than 4 weeks of therapy. Twenty-nine percent of patients with moderate to severe anemia showed an increase in hemoglobin or reduction/abolishment of blood transfusion requirements, 38% with moderate to severe thrombocytopenia had an increase in platelet counts, and 41% with high grade splenomegaly demonstrated a measurable reduction in splenic size. These effects led to an absolute decrease in the "severity" score in 44.9% of the patients. Major disease severity and high degrees of splenomegaly before therapy predicted response with a probability of 61.9%. However, worsening of the "severity" score was observed in 20.4% of the patients, 18% having a "myeloproliferative reaction" with leukocytosis and/or thrombocytosis. Sixty-six percent of the patients discontinued the drug before 6 months of treatment due to intolerance. In conclusion, there is a small but clear improvement of disease severity with thalidomide therapy in MMM. The potential for myeloproliferative reactions and the unfavorable dose-related toxicity profile argue for future studies using lower doses of this drug.
Adult↗
Current management of polycythemia vera.
Over a century has elapsed since the first description of polycythemia vera (PV), and current treatment recommendations are primarily based on the results of clinical trials that were performed in the late 1960s and early 1970s. Continued identification and appropriate utilization of PV-specific biologic parameters may allow substantial modification of early diagnostic criteria. New cytoreductive treatment agents are increasingly being used without any evidence of superiority over conventional therapy. The role of aspirin is being readdressed by an ongoing controlled study. Transformation of PV into either myelofibrosis with myeloid metaplasia or acute leukemia remains a major complication that may not be influenced by current therapy.
Acute Disease↗