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Prepublished online as a Blood First Edition Paper on November 27, 2002; DOI 10.1182/blood-2002-09-2928.
CLINICAL OBSERVATIONS, INTERVENTIONS, AND THERAPEUTIC TRIALS
From the Division of Hematology and Internal Medicine,
Cancer Center Statistics Unit, Division of Hematopathology, and
Division of Nuclear Medicine, Mayo Clinic, Rochester, MN; and Celgene,
Warren, NJ.
Single-agent thalidomide (THAL) at "conventional" doses
(> 100 mg/d) has been evaluated in myelofibrosis with myeloid
metaplasia (MMM) based on its antiangiogenic properties and the
prominent neoangiogenesis that occurs in MMM. THAL monotherapy at such
doses produces approximately a 20% response rate in anemia but is
poorly tolerated (an adverse dropout rate of > 50% in 3 months). To
improve efficacy and tolerability, we prospectively treated 21 symptomatic patients (hemoglobin level < 10 g/dL or symptomatic
splenomegaly) with MMM with low-dose THAL (50 mg/d) along with a
3-month oral prednisone (PRED) taper (beginning at 0.5 mg/kg/d).
THAL-PRED was well tolerated in all enrolled patients, with 20 patients (95%) able to complete 3 months of treatment. An objective clinical response was demonstrated in 13 (62%) patients, all improvements in
anemia. Among 10 patients who were dependent on erythrocyte transfusions, 7 (70%) improved and 4 (40%) became transfusion independent. Among 8 patients with thrombocytopenia (platelet count
< 100 × 109/L), 6 (75%) experienced a 50% or higher
increase in their platelet count. In 4 of 21 patients (19%), spleen
size decreased by more than 50%. Responses observed were mostly
durable after discontinuation of the PRED. The dose of THAL in this
study (50 mg/d) was better tolerated than the higher doses used in
previous studies. Adverse events associated with corticosteroid therapy
were mild and transient. Clinical responses did not correlate with
improvements in either intramedullary fibrosis or angiogenesis.
THAL-PRED is well tolerated and preliminarily appears to be a promising
drug regimen for treating cytopenias in patients with MMM.
(Blood. 2003;101:2534-2541) Myelofibrosis with myeloid metaplasia (MMM) is a
clonal hematopoietic stem cell disorder characterized by progressive
anemia, leukoerythroblastosis, splenomegaly, progression to acute
leukemia, and premature death.1 Median survival in
patients afflicted with MMM is 3 to 5 years2 and has not
yet been improved by currently available medical therapy. Allogeneic
hematopoietic stem cell transplantation is potentially curative in a
subset of young patients with MMM,3 yet it carries
significant risks of transplantation-related mortality and
graft-versus-host disease. Autologous hematopoietic stem cell
transplantation is also of potential palliative benefit in the
management of MMM,4 but it lacks a clear survival benefit
and may be too rigorous for many patients with MMM to endure.
Currently, only modest benefits have been reported with medical
therapies for the palliation of either MMM-associated anemia
(erythropoietin,5 androgens6,7) or
splenomegaly (hydroxyurea,8
interferon- The current pathogenetic hypothesis in MMM is that clonal proliferation
of megakaryocytes and monocytes is accompanied by an abnormal cytokine
release (transforming growth factor-beta [TGF- Thalidomide (THAL), initially developed in the 1950s as a
sedative hypnotic agent, exhibits potent antiangiogenic18
properties through the inhibition of bFGF and possibly vascular
endothelial growth factor (VEGF).18,19 Clinically, THAL
has activity in patients with another
angiogenesis-associated20 intramedullary clonal disorder,
multiple myeloma.21 Subsequent pilot trials using THAL
were conducted in MMM based on the agent's antiangiogenic and
anticytokine properties.22-27 To date, 79 patients with
MMM in these studies have been treated with escalating THAL daily doses
of 100 to 800 mg orally. Palliative benefit was observed in
MMM-associated anemia (0%-50%) and thrombocytopenia (25%-80%), with
minimal impact on disease-associated splenomegaly. Unfortunately, although THAL was active, it was also poorly tolerated at the doses
used. Up to 91% of patients with MMM discontinued therapy because of
side effects.22 In addition, undesired exuberant myeloproliferation was observed with adverse clinical consequences in
some MMM patients.28 However, in our later trial, we found that in 3 patients who had their doses of THAL reduced secondary to
side effects (200 mg down to 50 mg), the agent was better tolerated and
responses were maintained at the lower dose.24
We hypothesized that a low daily dose of THAL (50 mg/d) might be
preferred in the treatment of MMM, because tolerability of THAL appears
to be dose dependent and because the therapeutic benefit of THAL in MMM
was maintained with dose reduction. Furthermore, we felt that a
better therapeutic benefit might be achieved if THAL were combined with
corticosteroids. The combination of THAL and corticosteroids results in
an improved response in multiple myeloma.29,30
Corticosteroids, alone or in combination, occasionally have palliative
benefit in managing the anemia associated with MMM,1
presumably via the effects on the excess cytotoxic
(CD3+/CD56+) T lymphocytes.31 We
speculate that because corticosteroids are occasionally helpful in MMM,
their combination with low-dose THAL may augment each of these agents'
individual activities in this disease, and be better tolerated than
higher doses of either agent.
Patients
THAL was administered by rigorously adhering to the Celgene STEPS
program for THAL safety; patients received an oral 50-mg daily dose.
For the first 3 months, a tapering regimen of prednisone (PRED) was
also administered (0.5 mg/kg/d for 1 month; 0.25 mg/kg/d for the second
month; 0.125 mg/kg/d for the third month). Patients showing any
evidence of response after 3 months of combination therapy were treated
for an additional 3 months with only 50 mg THAL daily. Primary end
points for response were improvements in anemia, thrombocytopenia, or
hepatosplenomegaly. Secondary end points of response included
improvement in either constitutional symptoms (fatigue, night sweats,
fever, bone pain), bone marrow features of MMM (reticulin fibrosis,
osteosclerosis, angiogenesis, karyotype), or radiographic evidence of
extramedullary hematopoiesis (EMH) (99mTc-SC
scans). The National Cancer Institute Common Toxicity Criteria (version 2.0) were used to evaluate side effects.
Estimation of effects of therapy on the in vitro myeloid
progenitor growth
Estimation of antiangiogenic effect of therapy on patients with MMM To assess the effect of THAL-PRED on angiogenesis, 2 methods were used: immunohistochemistry and cytokine analyses. First, bone marrow trephines were subjected to immunohistochemistry with an antibody to CD34 and graded in a semiquantitative fashion consistent with our previously published method.16 Estimations of intramedullary angiogenesis were performed at the time of registration and after 6 months of therapy by 2 of the authors in a blinded fashion (R.A.M. and C.-Y.L.). The second method of assessing the effects of THAL-PRED on angiogenesis was by serial measurements of proangiogenic cytokines in the urine of the enrolled patients with MMM. Enzyme-linked immunosorbent assays (ELISAs) were performed on the urine of the enrolled patients at the time of registration and after 3 and 6 months of therapy with THAL-PRED, respectively, for the cytokines VEGF, bFGF, and thrombospondin 1 (TSP-1). Cytokine measurements were then corrected for urinary creatinine measurements as has been previously been reported.33Estimation of effect of therapy on EMH by 99mTc-SC scans Technetium 99m sulfur colloid (99mTc-SC), a radiopharmaceutical that is phagocytosed by reticuloendothelial cells, is an accepted method for imaging both bone marrow and EMH.34 99mTc-SC (14-16 mCi [518-592 MBq]) scans were performed at the time of registration and after 3 months of therapy and were reviewed in a blinded fashion by an experienced nuclear medicine specialist. Uptake in the spleen, liver, bone marrow (volume and distribution), and lungs were graded from 2
(markedly decreased) to 0 (normal) to +2 (markedly increased). Scans
were then serially assessed for radiographic changes in EMH as a result
of the THAL-PRED therapy.
Statistical analysis Twenty-one patients were enrolled in a one-stage phase 2 clinical trial to test the null hypothesis that the true response probability is 10% or less versus the hypothesis that the true response probability is more than 10%. The final decision rule was that at least 6 of the first 20 patients needed to experience a response to conclude that the drug combination shows evidence of promising activity. An exact 95% binomial confidence interval was used to estimate the true response rate.To determine whether there is an association between response and various bone marrow features of MMM or response and radiographic evidence of EMH (99mTc-SC scans), the following analyses were conducted. Fisher exact test was used to assess the significance of the difference between distributions of categorical data. The Wilcoxon rank sum test or the Kruskal-Wallis test was used to assess whether continuous variables differ significantly between categories. All data were analyzed using SAS software (SAS, Cary, NC). Corrections were made for multiple comparisons.
Patients and drug toxicity Twenty-one patients meeting the entry criteria enrolled in this trial. The patients exhibited a typical patient demographic and symptomatic distribution for the disorder. The median age at the time of enrollment was 63 years (range, 46-74 years), and 5 of the patients (24%) were women. Fifteen of the patients (47%) had AMM, with the remainder having developed myelofibrosis following pre-existing myeloproliferative disorders (PPMM and PTMM). At registration, 10 patients were dependent on erythrocyte transfusions, and 8 patients had clinically relevant thrombocytopenia (baseline platelet count < 100 × 109/L). In addition, the patients had active disease, with 16 patients (76%) having an adverse Dupriez35 MMM prognostic score ( 1). Additional
baseline clinical characteristics are summarized in Table
1. The patients were begun on oral THAL,
50 mg/d, and the tapering dose of PRED.
Therapy with THAL-PRED was very well tolerated. Twenty patients
(95%) were able to complete the first 3 months of treatment without
dose modification. One patient (patient no. 10) experienced blastic
transformation of his disease shortly after beginning the THAL-PRED
therapy and discontinued therapy. Adverse events associated with
THAL-PRED were mild and included constipation (38%), leukocytosis
(38%), mild neuropathy (
Although undesired leukocytosis and thrombocytosis were observed in 38% and 19% of the patients, respectively, a clinical consequence was observed in only one patient (deep venous thrombosis). In the patient with thrombosis, the platelet count at registration was 446 × 109/L and rose to 570 × 109/L at the time of the thrombotic event. Exuberant and undesirable myeloproliferation was a noted adverse event in the prior trials with THAL as a single agent at higher doses. To assess for the development of any undesired EMH, serial assessments of 99mTc-SC scans were performed. After blinded review by an experienced nuclear medicine specialist, there was no demonstrable increase in uptake of the radiocolloid in either the liver, spleen, or any other anatomic site as a result of the THAL-PRED regimen. THAL-PRED improves cytopenias THAL-PRED was very active in alleviating MMM-associated cytopenias. An objective and sustained clinical response occurred in the anemia of 13 patients (62%; 95% exact CI, 38%-82%). Overall, the median hemoglobin value increased by 1.8 g/dL (range, 0.1-5.1 g/dL). Seven of the 10 patients who were dependent on erythrocyte transfusions at study entry had a clinical response; 4 (40%) became transfusion independent (Figure 1), and the rest had a meaningful decrease in transfusion requirements ( 50%). Among those not dependent on transfusions (n = 11; 7 [64%] with hemoglobin level < 10 g/dL), the hemoglobin value
increased by 2.1 g/dL (range, 0.1-5.1 g/dL). All 8 patients who had
clinically relevant thrombocytopenia on study entry (platelet count
< 100 × 109/L) had an increase in their platelet
count, of whom 6 (75%) had a more than 50% increase in their platelet
count (Table 3; Figure 2).
Additional effects of THAL-PRED Only modest palliative benefits with the THAL-PRED therapy occurred with respect to splenomegaly. Four patients (19%) developed a more than 50% decrease in palpable splenomegaly (Table 3). No significant or persistent decrease in the amount of splenic EMH occurred as measured by serial assessments of splenic uptake of 99mTc-SC radiocolloid. No consistent decrease in constitutional symptoms was observed; however, improvements in constitutional symptoms are subjective and improvements are difficult to quantify.Little appreciable change in intramedullary manifestations of disease
occurred among MMM patients who responded to THAL-PRED therapy (Table
4). No significant changes occurred in
the bone marrow cellularity, reticulin fibrosis, or osteosclerosis
among responders. In addition, karyotype abnormalities did not change during the treatment course; however, no new karyotypic abnormalities developed. No appreciable changes in the markers of intramedullary angiogenesis occurred as assessed by microvessel density grading by
light microscopy of marrow trephines subjected to immunohistochemistry for CD34, urinary excretion of the proangiogenic cytokines VEGF or
bFGF, or plasma TSP-1 levels (Table 3). Furthermore, no consistent changes in the in vitro growth of immature myeloid progenitors in the
methylcellulose cultures occurred in response to therapy. This included
a lack of change in erythroid progenitors (BFU-Es or CFU-Es) in
patients with an anemic response, or myeloid colony growth (ie,
granulocyte-erythrocyte-macrophage-megakaryocyte colony-forming units
[CFU-GEMMs], CFU-GMs, or other colony type) in patients with
leukocytosis. Changes that occurred in lymphocyte number or subtype
were inconsistent and did not correlate with either response or adverse
events.
Results after discontinuation of PRED Among the 13 patients who experienced a clinical benefit with the THAL-PRED therapy, 12 continued on the second phase of the trial (THAL 50 mg/d only). The one patient who had responded to THAL-PRED but did not continue on the study stopped the drugs due to progression of hypercatabolic symptoms, which were not alleviated by the THAL-PRED therapy. Ten of the MMM patients completed both the THAL-PRED phase and subsequent THAL only (3 months 50 mg/d) phase of the trial. After discontinuation of the PRED, clinical responses were maintained in 8 of 13 (62%), 4 of 6 (66%), and 2 of 4 (50%) patients in terms of anemia, thrombocytopenia, and splenomegaly, respectively.Prognostic indicators of clinical response Improvements in anemia correlated with lower pretherapy CD34+ cell counts in the peripheral blood (median, 81.2 CD34+ cells/µL versus 554 CD34+ cells/µL [nonresponders]; P = .03) as well as lower numbers of circulating blasts (median, 0.8% versus 4.7% in nonresponders; P = .03; Table 5). Individuals with less neoangiogenesis in the marrow were more likely to respond (P = .03). Improvements in clinically significant thrombocytopenia were associated with older ages (median, 71.4 versus 61.7 years; P = .04), smaller pretreatment spleens (median, 6.5 cm versus 16.1 cm below the left costal margin; P < .01), and hypocellular marrows (median cellularity, 18% versus 58% for nonresponders; P < .01). Thrombocytopenic responders had more splenic uptake on their baseline 99mTc-SC scans, as well as higher levels of the antiangiogenic cytokine TSP-1 in the urine (P = .03; Table 5). Splenic responses were infrequent (n = 4); however, they did correlate with erythrocyte transfusion dependence (P = .03) as well as increased uptake of the radiocolloid into the lungs and marrow on the 99mTc-SC scans (P = .02 and .03, respectively; Table 5). Responses in either splenomegaly or thrombocytopenia were strongly correlated with a concurrent response in anemia (P < .01).
THAL-PRED is better tolerated than high-dose THAL Based on the results of several prospective, unblinded, single-arm clinical trials, THAL monotherapy appears to have clinical activity with MMM,22-27 but unfortunately the doses used in published trials have been poorly tolerated. In the later trials (Table 6), the starting dose of THAL ranged from 100 to 200 mg, with a goal of achieving a dose of 600 to 1000 mg. These higher THAL doses were poorly tolerated. Of the 79 patients reported in these trials, 48 (61%) were intolerant of THAL and up to 91% discontinued therapy.22 However, in our previous trial,24 reduction of the THAL dose to 50 mg/d in a subset of patients improved drug tolerability without loss of activity. This current report confirms the impression of our previous work, because 95% of patients treated with THAL, 50 mg/d, were able to complete the first 3 months of therapy with the THAL-PRED regimen. The only discontinuation in the first 3 months was secondary to blastic transformation. Although blastic transformation is a potential occurrence in 10% to 15% of patients with MMM,1 only 2 cases of acute leukemia (including this latter patient) have occurred in the 100 MMM patients (2%) who have taken THAL. Therefore, these latter 2 cases of acute leukemia are within the expected range of transformation and are probably not related to the therapy.
The types and severity of the adverse events in the remaining 20 patients who completed the 3 months of THAL-PRED were significantly less than our prior trial of THAL monotherapy that used higher doses (Table 2).24 Specifically, fatigue, constipation, depression, bradycardia, and orthostatic symptoms were significantly reduced by the THAL-PRED regimen. In addition, the exuberant myeloproliferative reactions observed in the prior THAL trials in MMM were significantly diminished. Indeed, our serial assessments of EMH by 99mTc-SC scans confirmed the lack of significant myeloproliferation at the THAL dose used. Furthermore, we did not see any increase in the in vitro growth of myeloid progenitors among the patients with MMM after THAL-PRED therapy. One patient in the THAL-PRED trial experienced a deep venous thrombosis (leg) at the time of an increase in the platelet count. Although the combination of THAL and corticosteroids has been associated with thrombogenic potential,36 our patient had multiple potential contributing risk factors for thrombosis (myeloproliferative disorder, thrombocytosis, immobility) making it impossible to determine the exact etiology of this patient's thrombotic event. THAL-PRED has significant activity for anemia and thrombocytopenia in MMM THAL-PRED was not only better tolerated than higher dose THAL monotherapy, but it also appeared to have greater efficacy for palliation of both the anemia and thrombocytopenia associated with MMM. In the current study, we observed a meaningful improvement in anemia in 62% of the patients as compared to the 0% to 50% responses described with the THAL monotherapy trials (Table 6). The degree of palliative benefit for anemia compares favorably with other palliative measure for MMM, including autologous stem cell transplantation (58%),4 erythropoietin (33%),5 and androgens (20%-57%).6,7 The latter therapies are often toxic, precluding their common implementation (ie, autologous transplant toxicity, applicability, and expense) or frequently
ineffective (erythropoietinusually only works if serum erythropoietin
level is inadequate for degree of anemia; and androgensnot
traditionally useful if patient has chromosomal abnormalities). The
data on the use of corticosteroids as single-agent therapy in MMM is
very limited and suggests a possible response rate of 26% with
steroids alone for MMM-associated anemia.37 Of particular
note is the 70% response rate we observed among individuals in the
THAL-PRED trial who were dependent on erythrocyte transfusions. This
latter observation is especially significant because transfusion
dependence adversely affects quality of life and can lead to iatrogenic
iron overload, alloimmunization, and exposure to infectious agents.
Patients who responded with improvement in anemia displayed features of
MMM characteristic of an earlier stage of the disease, with decreased
angiogenesis, decreased peripheral blood CD34 count, and less advanced
angiogenesis in the marrow compared with nonresponders. Canepa and
colleagues23 also reported a trend for patients with
cellular phase MMM to have a more favorable response to THAL. Combined
with our present observations, we suggest that THAL-PRED should be
considered even in earlier phases of symptomatic MMM.
THAL increased the platelet counts both in our current trial and the previously reported monotherapy trials. A meaningful platelet response occurred in 75% of patients with thrombocytopenia treated with THAL-PRED; this response rate is as good or better than the platelet responses seen in the previous trials (response rate, 25%-80%; Table 6). Indeed, thrombocytopenia is a known adverse prognostic factor in MMM,38 and in the past has been successfully palliated only with autologous stem cell transplantation.4 THAL monotherapy and THAL-PRED appear to raise the platelet count in patients with MMM regardless of their baseline platelet count. Accordingly, patients with pre-existing thrombocytosis should have adequate platelet control prior to initiation of therapy. Although we saw less undesired thrombocytosis with THAL-PRED than thalidomide at higher doses, one patient had a thrombotic event on the combination therapy, so diligent control of thrombocytosis while on THAL-PRED is advised. THAL-PRED does not appear to decrease EMH Decreases in splenomegaly were rare and not durable with THAL-PRED. Even the higher THAL doses previously used resulted in only modest reductions in splenomegaly (0%-30%; Table 6). The lack of decrease in palpable splenomegaly correlated with the lack of benefit we observed in decreasing hepatosplenic EMH by the 99mTc-SC scans. Concordant with a lack of effect of THAL-PRED on EMH (manifest as splenomegaly), we did not see significant improvement in the intramedullary disease manifestations. THAL-PRED did not change karyotypic abnormalities, nor did it normalize the marrow cellularity or decrease the amount of reticulin fibrosis or osteosclerosis. Additionally, THAL-PRED did not decrease the aberrantly high number of circulating myeloid progenitors even in patients with a clear clinical response to therapy. In fact, there was no evidence from our correlative studies that THAL-PRED has a direct effect on the overt intramedullary manifestations of MMM, yet changes may have occurred in the fibrogenic cytokine milieu, adhesion molecules, or prostaglandins not adequately reflected in our ancillary studies.THAL-PRED does not significantly affect angiogenesis in MMM Angiogenesis is markedly increased in the marrows of patients with MMM,16 perhaps to as great a degree as any hematologic malignancy.39 However, whether the increases in microvasculature are causal in the pathogenesis of MMM is unclear. Because various cytokines that are increased in MMM patients (bFGF,12 TGF- ,10,11 VEGF40)
share both profibrotic and proangiogenic capabilities, it is possible
that the increased angiogenesis in MMM is not causal, but instead
incidental to the fibrosing process.
Although THAL is antiangiogenic in in vitro systems,18 it is unclear whether this is the predominant mechanism for its activity in MMM. In our previous study of THAL monotherapy in MMM, we observed a decrease in angiogenesis only in 2 patients (13%). Variable decreases in angiogenesis (by intramedullary light microscopy) and decreases in serum bFGF and VEGF were reported by Piccaluga and colleagues26 in some of their responders. However, in our current trial we did not observe a clear decrease in intramedullary angiogenesis in any patient, even for patient 5 who had a very favorable response to the therapy. We also measured the effect of therapy on the level of proangiogenic cytokines in the urine of treated patients. Neoangiogenesis in malignancy is felt to arise from an imbalance between proangiogenic (ie, VEGF, bFGF) and antiangiogenic cytokines (TSP-1).41 In this trial the lack of change in immunohistochemical evidence of angiogenesis correlated with a lack of change in the angiogenic cytokines. Several possibilities may explain the apparent lack of effect of THAL-PRED on the angiogenesis in MMM. First, the therapy may inhibit the formation of new vasculature and therefore not produce a reduction in baseline microvasculature proliferation that was already present. Second, urinary assays of angiogenic cytokines may not adequately reflect changes in the bone marrow microenvironment for these cytokines. Also, THAL may either have a variable effect on angiogenesis in MMM patients or THAL has an alternative mechanism of action in MMM. Other potential mechanisms of action for THAL-PRED THAL-PRED is clinically active in alleviating the cytopenias associated with this disorder; however, no effect of THAL-PRED on karyotype, intramedullary fibrosis, or angiogenesis could be determined. THAL is also active in multiple myeloma, yet the mechanism for this is unclear.42 THAL inhibits tumor necrosis factor (TNF-) expression43 by destabilizing its mRNA,
which might be potentially relevant to both conditions. We have
recently reported clinical activity of the TNF- inhibitor,
etanercept, in MMM.44 In contrast to the present trial,
however, clinical benefit was manifested by palliation of
constitutional symptoms, and a major effect on cytopenias was not seen
in the etanercept trial.
Corticosteroids might be synergistic with THAL in MMM by their
direct inhibitory effect on interleukin 6 (IL-6)
production.45 This property, coupled with thalidomide's
effects on IL-1 Conclusions The combination of low-dose THAL and PRED is well tolerated and appears promising for the alleviation of disease-associated cytopenias in patients with MMM. Further follow-up will be necessary to determine the durability of the responses observed. Although the current trial was not designed to determine a possible survival advantage of THAL-PRED over supportive care, it is conceivable that a significant reduction in the detrimental effects of anemia and thrombocytopenia on patients with MMM may well lead to better long-term outcomes. The mechanism of action of THAL-PRED in MMM still remains unclear, but it does not appear to involve a direct improvement in intramedullary fibrosis, angiogenesis, or EMH. Future trials in MMM should look at extending the activity seen in THAL-PRED by the inclusion of therapeutic agents, which may have an effect against the aberrant clonal process.
The authors acknowledge Celgene for providing thalidomide for this clinical trial.
Submitted September 19, 2002; accepted November 19, 2002.
Prepublished online as Blood First Edition Paper, November 27, 2002; DOI 10.1182/blood-2002-09-2928.
Supported by research funding from Celgene, Warren, NJ.
One of the authors (J.B.Z.) is Chief Medical Officer and Vice President for Medical Affairs for Celgene, whose product was studied in the present work.
The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked "advertisement" in accordance with 18 U.S.C. section 1734.
Reprints: Ayalew Tefferi, Division of Hematology and Internal Medicine, Mayo Clinic, 200 First St, SW, Rochester, MN 55905; e-mail: tefferi.ayalew{at}mayo.edu.
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© 2003 by The American Society of Hematology.
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  A. Quintas-Cardama, H. M. Kantarjian, T. Manshouri, D. Thomas, J. Cortes, F. Ravandi, G. Garcia-Manero, A. Ferrajoli, C. Bueso-Ramos, and S. Verstovsek Lenalidomide Plus Prednisone Results in Durable Clinical, Histopathologic, and Molecular Responses in Patients With Myelofibrosis J. Clin. Oncol., October 1, 2009; 27(28): 4760 - 4766. [Abstract] [Full Text] [PDF]
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 A. M. Vannucchi, P. Guglielmelli, and A. Tefferi Advances in Understanding and Management of Myeloproliferative Neoplasms CA Cancer J Clin, May 1, 2009; 59(3): 171 - 191. [Abstract] [Full Text] [PDF]
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 R. A. Mesa, X. Yao, L. D. Cripe, C. Y. Li, A. Tefferi, and M. S. Tallman Lenalidomide and Prednisone for Primary and Post Polycythemia Vera/Essential Thrombocythemia Myelofibrosis (MF): An Eastern Cooperative Oncology Group (ECOG) Phase II Trial. Blood (ASH Annual Meeting Abstracts), November 16, 2008; 112(11): 1753 - 1753. [Abstract]
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R. A. Mesa, C. Y. Li, S. Schwager, and A. Tefferi Increased Intramedullary T Cells Corresponds with Response to Thalidomide (THAL) Therapy in Primary Myelofibrosis Blood (ASH Annual Meeting Abstracts), November 16, 2008; 112(11): 5234 - 5234. [Abstract]
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 R. Weinkove, J. T. Reilly, M. F. McMullin, N. J. Curtin, D. Radia, and C. N. Harrison Low-dose thalidomide in myelofibrosis Haematologica, July 1, 2008; 93(7): 1100 - 1101. [Full Text] [PDF]
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 A. Rambaldi, T. Barbui, and G. Barosi From Palliation to Epigenetic Therapy in Myelofibrosis Hematology, January 1, 2008; 2008(1): 83 - 91. [Abstract] [Full Text] [PDF]
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A. Berrebi, E. Feldberg, I. Spivak, and L. Shvidel Mini-dose of thalidomide for treatment of primary myelofibrosis. Report of a case with complete reversal of bone marrow fibrosis and splenomegaly Haematologica, February 1, 2007; 92(2): e15 - e16. [Abstract] [Full Text] [PDF]
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R. A. Mesa Navigating the Evolving Paradigms in the Diagnosis and Treatment of Myeloproliferative Disorders Hematology, January 1, 2007; 2007(1): 355 - 362. [Abstract] [Full Text] [PDF]
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 D. P. Steensma and R. E. Richard Myeloproliferative disorders ASH Self-Assessment Program, January 1, 2007; 2007(1): 172 - 227. [Full Text] [PDF]
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T. Y. Kang, C. J. Lowe, and M. A. Sekeres Thalidomide Use and Digital Gangrene J. Clin. Oncol., November 20, 2006; 24(33): 5328 - 5328. [Full Text] [PDF]
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R. A. Mesa, A. Pardanani, D. P. Steensma, M. Litzow, W. Hogan, S. Geyer, W. Wu, J. Zeldis, and A. Tefferi Phase II Study of the Combination of Low-Dose Thalidomide, Prednisone, and Oral Cyclophosphamide (TPC Regimen) in the Treatment of Anemia, Splenomegaly, and Constitutional Symptoms Associated with Myelofibrosis with Myeloid Metaplasia (MMM). Blood (ASH Annual Meeting Abstracts), November 16, 2006; 108(11): 2689 - 2689. [Abstract] [PDF]
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 C. Arana-Yi, A. Quintas-Cardama, F. Giles, D. Thomas, A. Carrasco-Yalan, J. Cortes, H. Kantarjian, and S. Verstovsek Advances in the Therapy of Chronic Idiopathic Myelofibrosis Oncologist, September 1, 2006; 11(8): 929 - 943. [Abstract] [Full Text] [PDF]
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A. Tefferi, G. Barosi, R. A. Mesa, F. Cervantes, H. J. Deeg, J. T. Reilly, S. Verstovsek, B. Dupriez, R. T. Silver, O. Odenike, et al. International Working Group (IWG) consensus criteria for treatment response in myelofibrosis with myeloid metaplasia, for the IWG for Myelofibrosis Research and Treatment (IWG-MRT) Blood, September 1, 2006; 108(5): 1497 - 1503. [Abstract] [Full Text] [PDF]
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A. Tefferi, J. Cortes, S. Verstovsek, R. A. Mesa, D. Thomas, T. L. Lasho, W. J. Hogan, M. R. Litzow, J. B. Allred, D. Jones, et al. Lenalidomide therapy in myelofibrosis with myeloid metaplasia Blood, August 15, 2006; 108(4): 1158 - 1164. [Abstract] [Full Text] [PDF]
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A. Tefferi Pathogenesis of Myelofibrosis With Myeloid Metaplasia J. Clin. Oncol., November 20, 2005; 23(33): 8520 - 8530. [Abstract] [Full Text] [PDF]
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R. A. Mesa, D. P. Stensma, C. Y. Li, A. Hoering, J. B. Allred, H. L. Powell, and A. Tefferi Phase II Study of the Combination of Low-Dose Thalidomide, Prednisone, and Etanercept (PET Regimen) in the Treatment of Anemia, Splenomegaly, and Constitutional Symptoms Associated with Myelofibrosis with Myeloid Metaplasia (MMM). Blood (ASH Annual Meeting Abstracts), November 16, 2005; 106(11): 2576 - 2576. [Abstract]
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R. T. Silver The ABCCs of myelofibrosis Blood, October 15, 2005; 106(8): 2598 - 2599. [Full Text] [PDF]
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G. Barosi, D. Bordessoule, J. Briere, F. Cervantes, J.-L. Demory, B. Dupriez, H. Gisslinger, M. Griesshammer, H. Hasselbalch, R. Kusec, et al. Response criteria for myelofibrosis with myeloid metaplasia: results of an initiative of the European Myelofibrosis Network (EUMNET) Blood, October 15, 2005; 106(8): 2849 - 2853. [Abstract] [Full Text] [PDF]
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 A. Tefferi and T. Barbui bcr/abl-Negative, Classic Myeloproliferative Disorders: Diagnosis and Treatment Mayo Clin. Proc., September 1, 2005; 80(9): 1220 - 1232. [Abstract] [PDF]
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R. A. Mesa, D. P. Steensma, C. Y. Li, A. Hoering, H. Powell, and A. Tefferi Phase II Study of the Combination of Low-Dose Thalidomide, Prednisone, and Etanercept ("PET regimen") in the Treatment of Anemia, Splenomegaly, and Constitutional Symptoms Associated with Myelofibrosis with Myeloid Metaplasia (MMM). Blood (ASH Annual Meeting Abstracts), November 16, 2004; 104(11): 1520 - 1520. [Abstract]
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 V. Eleutherakis-Papaiakovou, A. Bamias, and M. A. Dimopoulos Thalidomide in cancer medicine Ann. Onc., August 1, 2004; 15(8): 1151 - 1160. [Abstract] [Full Text] [PDF]
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R. T. Silver Myelofibrosis: Thalidomide Finds a New Disease Mayo Clin. Proc., July 1, 2004; 79(7): 857 - 858. [PDF]
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R. A. Mesa, M. A. Elliott, G. Schroeder, and A. Tefferi Durable Responses to Thalidomide-Based Drug Therapy for Myelofibrosis With Myeloid Metaplasia Mayo Clin. Proc., July 1, 2004; 79(7): 883 - 889. [Abstract] [PDF]
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S. V. Rajkumar Thalidomide: Tragic Past and Promising Future Mayo Clin. Proc., July 1, 2004; 79(7): 899 - 903. [PDF]
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S. Kumar, T. E. Witzig, and S. V. Rajkumar Thalidomide: Current Role in the Treatment of Non-Plasma Cell Malignancies J. Clin. Oncol., June 15, 2004; 22(12): 2477 - 2488. [Abstract] [Full Text] [PDF]
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M. Marchetti, G. Barosi, F. Balestri, G. Viarengo, S. Gentili, S. Barulli, J.-L. Demory, F. Ilariucci, A. Volpe, D. Bordessoule, et al. Low-Dose Thalidomide Ameliorates Cytopenias and Splenomegaly in Myelofibrosis With Myeloid Metaplasia: A Phase II Trial J. Clin. Oncol., February 1, 2004; 22(3): 424 - 431. [Abstract] [Full Text] [PDF]
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S. O'Brien, A. Tefferi, and P. Valent Chronic Myelogenous Leukemia and Myeloproliferative Disease Hematology, January 1, 2004; 2004(1): 146 - 162. [Abstract] [Full Text] [PDF]
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A. Tefferi The Forgotten Myeloproliferative Disorder: Myeloid Metaplasia Oncologist, June 1, 2003; 8(3): 225 - 231. [Abstract] [Full Text] [PDF]
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J. L. Spivak, G. Barosi, G. Tognoni, T. Barbui, G. Finazzi, R. Marchioli, and M. Marchetti Chronic Myeloproliferative Disorders Hematology, January 1, 2003; 2003(1): 200 - 224. [Abstract] [Full Text] [PDF]
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Abstract
Introduction
grade 2; 29%), and mild sedation (29%;
Table 
