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Biomedical subjects

A Tefferi

Publications and source records attributed to A Tefferi.

At least 19 recordsLinked to original sources
PubMed2006

Risk stratification for survival and leukemic transformation in essential thrombocythemia: a single institutional study of 605 patients.

Unlike the case with thrombosis, prognostic models for survival and leukemic transformation (LT) in essential thrombocythemia (ET) are not available. Among 605 patients with ET seen at our institution and followed for a median of 84 months, 155 died and LT was documented in 20 patients (3.3%). In a multivariable analysis, hemoglobin level below normal (females<120 g/l; males<135 g/l) was identified as an independent risk factor for both inferior survival and LT. Additional risk factors for survival included age > or =60 years, leukocyte count> or =15 x 10(9)/l, smoking, diabetes mellitus and thrombosis. For LT, platelet count> or =1000 x 10(9)/l but not cytoreductive therapy was flagged as an additional independent risk factor. In fact, four of the 20 patients (20%) with LT were untreated previously. We used the above information to construct prognostic models that effectively discriminated among low-, intermediate- and high-risk groups with respective median survivals of 278, 200 and 111 months (P<0.0001), and LT rates of 0.4, 4.8 and 6.5% (P=0.0009) respectively. Presence of JAK2V617F did not impact either survival or LT and mutational frequency was similar among the different risk groups.

Adolescent↗
PubMed2006

'Idiopathic' eosinophilia with an Occult T-cell clone: prevalence and clinical course.

In a study of 99 consecutive patients with "idiopathic" eosinophilia, clonal T-cells were demonstrated in blood, bone marrow, or other tissue samples of 14 patients including 6 who had an overt T-cell malignancy. The remaining eight patients (approximately 8%) with an "Occult" T-cell clone had predominantly cutaneous disease and FIP1L1-PDGFRA was absent in all six evaluable patients. Two patients were effectively treated with low-dose oral cyclophosphamide or methotrexate whereas Gleevec treatment was ineffective in another two patients. Two patients (25%) transformed into cutaneous T-cell lymphoma after 3-8 years of eosinophilic prodrome.

Adult↗
PubMed2006

Janus kinase 2 (V617F) mutation status, signal transducer and activator of transcription-3 phosphorylation and impaired neutrophil apoptosis in myelofibrosis with myeloid metaplasia.

An activating point mutation in Janus kinase 2 (JAK2 V617F) was recently identified in myelofibrosis with myeloid metaplasia (MMM). To further elucidate the pathogenic significance, we examined the JAK2 mutation burden, phosphorylation of JAK2 substrates and neutrophil apoptotic resistance. Immunoblotting revealed phosphorylation of signal transducer and activator of transcription-3 (STAT3) in all four JAK2 with high V617F mutant allele burden and seven of eight with intermediate mutant allele burden, but only one of eight with wild-type JAK2 (P<0.001). In contrast, STAT5 phosphorylation was undetectable in patient MMM neutrophils; and phosphorylation of Akt and extracellular signal-regulated kinases (ERKs) failed to correlate with JAK2 mutation status. Apoptosis was lower in MMM neutrophils (median 41% apoptotic cells, n=50) compared to controls (median 66%, n=9) or other myeloproliferative disorder patients (median 53%, n=11; P=0.002). Apoptotic resistance in MMM correlated with anemia (P=0.01) and the JAK2-V617F (P=0.01). Indeed, apoptotic resistance was greatest in MMM neutrophils with high mutant allele burden (median 22% apoptosis, n=5) than with intermediate burden (median 39%, n=23) or wild-type JAK2 (median 47%, n=22; P=0.008). These results suggest that mutant JAK2 contributes to MMM pathogenesis by constitutively phosphorylating STAT3 and diminishing myeloid cell apoptosis.

Alleles↗
PubMed2006

The third International Congress on Myeloproliferative and Myelodysplastic Syndromes.

This meeting was convened by Richard T. Silver and co-chaired by Jerry L. Spivak. It was held from 27 to 29 October 2005 in Washington, DC. Thirty-one invited speakers from seven different countries participated in the conference, which was attended by more than 300 individuals from 23 countries. As in previous years, a clinical symposium for patients, held the day before the symposium, was sponsored by the Cancer Research and Treatment Fund, Inc., New York, NY 10021. This meeting report provides a summary of the five sessions prepared and highlighted by one of the session chairs. In addition to the formal presentations on the biology, clinical aspects and management of these diverse marrow stem cell disorders, there was considerable interest generated because of the availability of several new agents that have been recently approved. A special luncheon satellite symposium was devoted to the dramatic changes in the therapeutic options for the myelodysplastic syndromes, sponsored by MGI Pharma, Inc. The keynote address was presented by Dr. George Q. Daley from Harvard Medical School and the Children's Hospital Medical Center. He reviewed the molecular steps in the formation of the Philadelphia chromosome and some of the newly described mutations leading to resistance to chemotherapy (see Section 4).

Humans↗
PubMed2006

FIP1L1-PDGFRA in eosinophilic disorders: prevalence in routine clinical practice, long-term experience with imatinib therapy, and a critical review of the literature.

We previously studied clinico-pathologic features of 89 consecutive adult patients with moderate-to-severe eosinophilia, and reported a FIP1L1-PDGFRA prevalence of 12%. In that series, all 11 FIP1L1-PDGFRA+ patients receiving imatinib achieved a complete response. We now extend our observations through a study of 741 unselected patients with eosinophilia for FIP1L1-PDGFRA, and present longer term follow up data for the imatinib-treated cohort. We also include data for three previously unreported FIP1L1-PDGFRA+ patients. Among the 741 requests, only 21 (3%) were found to carry the FIP1L1-PDGFRA mutation. While all 14 FIP1L1-PDGFRA+ patients receiving imatinib achieved a complete response, the 4 patients who attempted to discontinue imatinib all relapsed. We also find that it is possible to maintain patients in clinical remission with an empirically derived schedule of low-dose (50-100 mg), intermittent (once daily to once weekly) imatinib. Lastly, we present a comprehensive review of the literature pertaining to FIP1L1-PDGFRA in order to address several key aspects of this mutation from a clinical standpoint.

Adult↗
PubMed2006

Allogeneic stem cell transplantation and donor lymphocyte infusions for chronic myelomonocytic leukemia.

Prognosis in chronic myelomonocytic leukemia (CMML) is unfavorable and the optimal therapy remains uncertain. Currently, allogeneic stem cell transplantation is the only known curative therapeutic option. However, the data available are limited and restricted to small retrospective series. There is even less information on the use of donor lymphocyte infusions (DLI) for this disease. We reviewed our experience of allogeneic stem cell transplantation and DLI for adults with CMML. Seventeen consecutive adults underwent allogeneic stem cell transplantation from related (n=14) or unrelated (n=3) donors. Median age was 50 years (range 26-60). Seven patients (41%) demonstrated relapse or persistent disease at a median of 6 months (range 3-55.5). Five patients underwent DLI for morphologic relapse and one for mixed donor chimerism. Two patients achieved durable complete remissions of 15 months each. The overall transplant-related mortality was 41% (n=7). With a median follow-up of 34.5 months, three patients (18%) currently remain alive and in continuous CR. The current study demonstrates a graft-versus-leukemia effect in CMML, both for allogeneic stem cell transplantation and for DLI. Nevertheless, consistent with reported experience of others, overall outcomes remain less than optimal and unpredictable.

Adult↗
PubMed2006

Autologous hematopoietic stem cell transplantation for older patients with relapsed non-Hodgkin's lymphoma.

To evaluate autologous stem cell transplant (ASCT) in older patients with intermediate grade non-Hodgkin's lymphoma (NHL), the Mayo Clinic Rochester BMT database was reviewed for all patients 60 years of age and older who received ASCT for NHL between September 1995 and February 2003. Factors evaluated included treatment-related mortality (TRM), event-free survival (EFS) and overall survival (OS). Ninety-three patients were identified, including twenty-four (26%) over the age of 70 years. Treatment-related mortality (5.4%) was not significantly different when compared to a younger cohort (2.2%). At a median follow-up of 14 months (0.6-87.6 months), the estimated median survival is 25 months (95% confidence interval (CI) 12-38) in the older group compared to 56 months (95% CI 37-75) (P=0.037) in the younger group. The estimated 4-year EFS was 38% for the older group compared to 42% in the younger cohort (P=0.1). By multivariate analysis, the only factor found to influence survival in the older group was age-adjusted International Prognostic Index at relapse, 0-1 better than 2-3 (P=0.03). Autologous stem-cell transplant can be safely performed in patients 60 years or older with chemotherapy sensitive relapsed or first partial remission NHL. The outcome may not be different from that of younger patients in terms of TRM and EFS.

Adolescent↗
PubMed2006

Absolute lymphocyte count recovery after induction chemotherapy predicts superior survival in acute myelogenous leukemia.

Absolute lymphocyte count (ALC) recovery postautologous stem cell transplantation is an independent predictor for survival in acute myelogenous leukemia (AML). The role of ALC recovery after induction chemotherapy (IC) in AML is unknown. We hypothesize that ALC recovery after IC has a direct impact on survival. We have now evaluated the impact of ALC recovery after IC on overall survival (OS) and leukemia-free survival (LFS) in 103 consecutive, newly diagnosed AML patients treated with standard IC and consolidation chemotherapy (CC) from 1998 to 2002. ALC recovery was studied at days 15 (ALC-15), 21 (ALC-21), 28 (ALC-28) after IC and before the first CC (ALC-CC). Superior OS and LFS at each time point were observed with an ALC-15, ALC-21, ALC-28, and ALC-CC > or = 500 cells/microl. Patients with an ALC > or = 500 cells/microl at all time points vs those who did not have superior OS and LFS (not reached vs 13 months, P<0.0001; and not reached vs 11 months, P<0.0001, respectively). Multivariate analysis demonstrated ALC > or = 500 cells/microl at all time points to be an independent prognostic factor for survival. Our data suggest a critical role of lymphocyte (immune) recovery on survival after IC in AML.

Adolescent↗
PubMed2006

JAK2 V617F is a rare finding in de novo acute myeloid leukemia, but STAT3 activation is common and remains unexplained.

Signal transducer and activator of transcription (STAT) proteins are phosphorylated and activated by Janus kinases (JAKs). Recently, several groups identified a recurrent somatic point mutation constitutively activating the hematopoietic growth factor receptor-associated JAK2 tyrosine kinase in diverse chronic myeloid disorders - most commonly classic myeloproliferative disorders (MPD), especially polycythemia vera. We hypothesized that the JAK2 V617F mutation might also be present in samples from patients with acute myeloid leukemia (AML), especially erythroleukemia (AML-M6) or megakaryoblastic leukemia (AML-M7), where it might mimic erythropoietin or thrombopoietin signaling. First, we documented STAT3 activation by immunoblotting in AML-M6 and other AML subtypes. Immunoperoxidase staining confirmed phosphorylated STAT3 in malignant myeloblasts (21% of cases, including all AML-M3 samples tested). We then analyzed genomic DNA from 162 AML, 30 B-cell lymphoma, and 10 chronic lymphocytic leukemia (CLL) samples for JAK2 mutations, and assayed a subset for SOCS1 and FLT3 mutations. Janus kinase2 V617F was present in 13/162 AML samples (8%): 10/13 transformed MPD, and three apparent de novo AML (one of 12 AML-M6, one of 24 AML-M7, and one AML-M2 - all mixed clonality). FLT3 mutations were present in 5/32 (16%), while SOCS1 mutations were totally absent. Lymphoproliferative disorder samples were both JAK2 and SOCS1 wild type. Thus, while JAK2 V617F is uncommon in de novo AML and probably does not occur in lymphoid malignancy, unexplained STAT3 activation is common in AML. Janus kinase2 extrinsic regulators and other proteins in the JAK-STAT pathway should be interrogated to explain frequent STAT activation in AML.

Acute Disease↗
PubMed2006

Testing the safety of clinical-grade mature autologous myeloid DC in a phase I clinical immunotherapy trial of CML.

BACKGROUND: We conducted a phase I clinical immunotherapy trial of CML to evaluate the safety of a clinical-grade leukemic DC product standardized for purity and mature phenotype. METHODS: We injected autologous DC into patients in late chronic or accelerated phases of CML. The patients received mature CD83+ and bcr-abl+ DC prepared from CD14+ cells. Two cohorts of three patients received four injections each of 3 x 10(6) DC and 15 x 10(6) DC/injection, respectively. The first patient was studied before imatinib mesylate (IM) was available, four patients were treated concurrently with IM therapy and one did not tolerate the IM and was off the drug at the time of DC therapy. IM effects on WBC counts precluded DC preparation in numbers sufficient for further dose escalation. The first patient received DC s.c. and all subsequent patients received DC into a cervical lymph node under ultrasound guidance. RESULTS: DC injections were well tolerated. We observed no clinical responses. T cells drawn later in the course of therapy were more sensitive to stimulation by CML DC in vitro. DISCUSSION: The increase in T-cell sensitivity to CML-specific stimulation that accompanied active immunization by CML DC justifies further clinical studies, possibly with modifications such as an increased frequency and number of DC injections.

Aged↗
PubMed2005

A phase I study of 153Sm-EDTMP with fixed high-dose melphalan as a peripheral blood stem cell conditioning regimen in patients with multiple myeloma.

Despite response rates of 30% after high-dose chemotherapy with autologous hematopoietic stem cell transplant, patients with multiple myeloma are not cured. 153Samarium ethylenediaminetetramethylenephosphonate (153Sm-EDTMP; Quadramet) is a short-range, beta-emitting therapeutic radiopharmaceutical with avid skeletal uptake. In total, 12 patients were treated with escalating doses of 153Sm-EDTMP (N=3/group; 6, 12, 19.8, and 30 mCi/kg) and a fixed dose of melphalan (200 mg/m(2)). No dose limiting toxicity was seen. To better standardize the marrow compartment radiation dose, the study was modified such that an additional six patients were treated at a targeted absorbed radiation dose to the red marrow of 40 Gy based on a trace labeled infusion 1 week prior to the therapy. Despite rapid elimination of unbound radiopharmaceutical via kidneys and bladder, no episodes of nephrotoxicity, hemorrhagic cystitis, or delayed radiation nephritis were observed with a median follow-up of 31 months (range 8.5-44). Median times to ANC>0.5 and platelet >20 x 10(6)/l were 12 and 11 days, respectively, with no graft failures. Overall response rate was 94% including seven very good partial responses and five complete responses. Addition of 153Sm EDTMP to melphalan conditioning appears to be safe, well-tolerated and worthy of further study.

Adult↗
PubMed2005

Thrombosis and haemorrhage in polycythaemia vera and essential thrombocythaemia.

Despite decades of clinical and laboratory research, relatively little has been accomplished concerning the pathogenesis as well as the identification of risk factors for thrombosis and bleeding in myeloproliferative disorders. In polycythaemia vera, the pro-thrombotic effect of an elevated haematocrit is well established. In contrast, thrombocytosis per se has not been similarly incriminated in essential thrombocythaemia. In both conditions, advanced age and the presence of a prior event identify thrombosis-prone patients. There is increasing evidence to suggest an additional role by leucocytes that might partly explain the antithrombotic effects of myelosuppressive therapy. A substantial minority of affected patients display reduced levels of high molecular weight von Willebrand protein in the plasma during extreme thrombocytosis and it is believed that this might explain the bleeding diathesis of such patients. Recent controlled studies support the therapeutic value of hydroxyurea and aspirin in essential thrombocythaemia and polycythaemia vera, respectively. The current communication will address the incidence, phenotype, pathogenesis, risk factors, prevention, and treatment of both thrombosis and haemorrhage in these disorders.

Aged↗
PubMed2005

Modern diagnosis and treatment of primary eosinophilia.

The recent discovery of an eosinophilia-specific, imatinib-sensitive, karyotypically occult but fluorescence in situ hybridization-apparent molecular lesion in a subset of patients with blood eosinophilia has transformed the diagnostic as well as treatment approach to eosinophilic disorders. Primary (i.e. nonreactive) eosinophilia is considered either "clonal" or "idiopathic" based on the presence or absence, respectively, of either a molecular or bone marrow histological evidence for a myeloid neoplasm. Clonal eosinophilia might accompany a spectrum of clinicopathological entities, the minority of whom are molecularly characterized; Fip1-like-1-platelet-derived growth factor receptor alpha (FIP1L1-PDGFRA(+)) systemic mastocytosis, platelet-derived growth factor receptor beta (PDGFRB)-rearranged atypical myeloproliferative disorder, chronic myeloid leukemia, and the 8p11 syndrome that is associated with fibroblast growth factor receptor 1 (FGFR1) rearrangement. Hypereosinophilic syndrome (HES) is a subcategory of idiopathic eosinophilia and is characterized by an absolute eosinophil count of > or =1.5 x 10(9)/l for at least 6 months as well as eosinophil-mediated tissue damage. At present, a working diagnosis of primary eosinophilia mandates a bone marrow examination, karyotype analysis, and additional molecular studies in order to provide the patient with accurate prognostic information as well as select appropriate therapy. For example, the presence of either PDGFRA or PDGFRB mutations warrants the use of imatinib in clonal eosinophilia. In HES, prednisone, hydroxyurea, and interferon-alpha constitute first-line therapy, whereas imatinib, cladribine, and monoclonal antibodies to either interleukin-5 (mepolizumab) or CD52 (alemtuzumab) are considered investigational. Allogeneic transplantation offers a viable treatment option for drug-refractory cases.

Antineoplastic Agents↗