A phase 2 trial of combination low-dose thalidomide and prednisone for the treatment of myelofibrosis with myeloid metaplasia

Mesa, Ruben A.; Steensma, David P.; Pardanani, Animesh; Li, Chin Yang; Elliott, Michelle A.; Kaufmann, Scott H.; Wiseman, Gregory A.; Gray, Leigh A.; Schroeder, Georgene; Reeder, Terra L.; Zeldis, Jerome B.; Tefferi, Ayalew

doi:10.1182/blood-2002-09-2928

Cited by 262 publications

(177 citation statements)

References 41 publications

(45 reference statements)

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“…Thus, a wait-and-see approach is often adopted in asymptomatic patients, delaying treatment start until a change in the clinical situation is observed. In patients with anemia, besides transfusion therapy, treatment is based on the use of androgens [19,20], erythropoietin or erythropoietin-stimulating agents [17,18] and, more recently, immuuomodulatory drugs such as thalidomide, lenalidomide or pomalidomide [21][22][23]. With regard to symptoms of hyperproliferation of MF, they are usually managed with oral cytoreductive drugs, mainly HU [9,10], but also busulfan [24] or melphalan [25].…”

Section: Discussionmentioning

confidence: 99%

Efficacy and tolerability of hydroxyurea in the treatment of the hyperproliferative manifestations of myelofibrosis: results in 40 patients

et al. 2010

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Hydroxyurea (HU) is frequently given as treatment for myelofibrosis (MF), but data on its efficacy and tolerability are scarce. The results of HU therapy were evaluated in 40 patients with hyperproliferative manifestations of primary (n= 32), post-polycythemia vera (n= 6) or post-essential thrombocythemia (n= 2) myelofibrosis. Median interval between diagnosis and HU start was 6.2 months (range: 0-141.7). Reasons for treatment were: constitutional symptoms (55%), symptomatic splenomegaly (45%), thrombocytosis (40%), leukocytosis (28%), pruritus (10%), and bone pain (8%). The starting dose was 500 mg/day, subsequently adjusted to the individual efficacy and tolerability.Response was: bone pain 100%, constitutional symptoms 82%, pruritus 50%, splenomegaly 40%, and anemia 12.5%. According to the International Working Group for Myelofibrosis Research and Treatment criteria, clinical improvement was achieved in 16 patients (40%). Median duration of response was 13.2 months (range: 3-126.2). Worsening of the anemia or appearance of pancytopenia were observed in 18 patients, requiring administration of erythropoietin-stimulating agents (n=17) and/or danazol (n=9). Oral or leg ulcers appeared in 5 patients and one had gastrointestinal symptoms. HU is an effective and generally well-tolerated therapy for the hyperproliferative manifestations of MF. The accentuation of the anemia often induced by HU is usually manageable with concomitant treatment.Response to Reviewers: Answers to the comments by reviewer 1:1. Retrospective design of the study. As already stated in the Introduction and in the Discussion, although there is limited bibliographic support for the use of hydroxyurea (HU) in MF, in clinical practice, this drug has been considered for many years (and still is) as the standard therapy for the hyperproliferative manifestations of this disease. Actually, until the recent development of the JAK2 inhibitors, no real alternative therapy to HU was available for comparison. As a result, for the time being, a retrospective study is the only possibility to assess the efficacy and tolerability of HU in MF.Having said this, it must be remarked that the data from the present study have been generated in a single institution, in which the drug was used following uniform rules for the starting dose, the dose adjustments and the use of adjuvant drugs for the treatment of the associated anemia. Moreover, more than 80% of the patients in the study were treated by the same physician, with long-lasting and specific dedication to MF.2. Selection of the patients. As stated in the Patients and Methods, the 40 patients included in the study were the only ones receiving HU among the 157 with MF followed in our institution during the study period. As also stated in the same section, HU was given to these 40 patients exclusively as a treatment for the hyperproliferative manifestations of MF (i.e., constitutional symptoms, symptomatic splenomegaly, pruritus, bone pain, leukocytosis, and thrombocytosis). This means that a patient ...

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Section: Discussionmentioning

confidence: 99%

Efficacy and tolerability of hydroxyurea in the treatment of the hyperproliferative manifestations of myelofibrosis: results in 40 patients

et al. 2010

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“…2). First-line drugs of choice in such patients are hydroxyurea for symptomatic splenomegaly [125], androgens preparations [126], prednisone [126], danazol [127], thalidomide 6 prednisone [128][129][130] or lenalidomide 6 prednisone [131,132] for symptomatic anemia, splenectomy (or splenic radiotherapy for nonsurgical candidates) for splenomegaly that is resistant to conventional drug therapy [133], involved field radiotherapy for nonhepatosplenic EMH might and ruxolitinib for severe constitutional symptoms that are resistant to hydroxyurea therapy [133].…”

Section: Myelofibrosismentioning

confidence: 99%

Myeloproliferative neoplasms: A decade of discoveries and treatment advances

2015

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Myeloproliferative neoplasms (MPN) are clonal stem cell diseases, first conceptualized in 1951 by William Dameshek, and historically included chronic myeloid leukemia (CML), polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF). In 1960, Nowell and Hungerford discovered an invariable association between the Philadelphia chromosome (subsequently shown to harbor the causal BCR‐ABL1 mutation) and CML; accordingly, the term MPN is primarily reserved for PV, ET, and PMF, although it includes other related clinicopathologic entities, according to the World Health Organization (WHO) classification system. In 2005, William Vainchenker and others described a Janus kinase 2 mutation (JAK2V617F) in MPN and this was followed by a series of additional descriptions of mutations that directly or indirectly activate JAK‐STAT: JAK2 exon 12, myeloproliferative leukemia virus oncogene (MPL) and calreticulin (CALR) mutations. The discovery of these, mostly mutually exclusive, “driver” mutations has contributed to revisions of the WHO diagnostic criteria and risk stratification in MPN. Mutations other than JAK2, CALR and MPL have also been described in MPN and shown to provide additional prognostic information. From the standpoint of treatment, over the last 50 years, Louis Wasserman from the Unites States and Tiziano Barbui from Italy had skillfully organized and led a number of important clinical trials, whose results form the basis for current treatment strategies in MPN. More recently, allogeneic stem cell transplant, as a potentially curative treatment modality, and JAK inhibitors, as palliative drugs, have been added to the overall therapeutic armamentarium in myelofibrosis. In the current review, I will summarize the important advances made in the last 10 years regarding the science and practice of MPN. Am. J. Hematol. 91:50–58, 2016. © 2015 Wiley Periodicals, Inc.

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“…[39][40][41][42][43][44][45] With regard to therapeutic aspects, clinical improvement offered by treatment with the antiangiogenetic drug thalidomide has been recently reported in CIMF, although the efficacy of this drug in reducing MVD is still uncertain. 9,46 It is noteworthy that a recent preliminary report focused on CD105 suggested the efficacy of anti-CD105 MoAb therapy, in synergy with cyclophosphamide, in reducing tumor size in human skin/SCID (severe combined immunodeficiency) mouse chimeras bearing human breast cancer. 47 CD105 may represent a target for antiangiogenic therapy; 48 this belief is also supported by the concept that endothelial cells of tumor microvessels may be more susceptible to killing effects of anti-CD105 immunoconjugates than the vascular endothelium of normal tissues.…”

Section: Endoglin In Myelofibrosismentioning

confidence: 99%

“…7,8 Moreover, thalidomide, an antiangiogenic drug, is effective in combination with prednisone in counteracting cytopenia. 9 Finally, CD34-positive MVD has been reported to be an independent predictor of survival in CIMF patients. 8 Angiogenesis has been most commonly assessed by immunostaining in routinely processed bioptic tissue with antibodies reactive with endothelial cells, including CD31, factor VIII, and CD34.…”

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confidence: 99%

Chronic idiopathic myelofibrosis: independent prognostic importance of bone marrow microvascular density evaluated by CD105 (endoglin) immunostaining

et al. 2004

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Microvascular density (MVD) is substantially increased in bone marrow biopsies of patients with chronic idiopathic myelofibrosis (CIMF). CD105, a useful molecule for assessing MVD in various malignancies, is preferentially expressed by recently formed microvessels. Increased serum-soluble CD105 in patients with chronic myeloproliferative disorders, including CIMF, was documented. CD105 MVD has not so far been investigated in CIMF: to this end, the results in 55 patients with CIMF and 21 controls were compared with the conventional CD34 immunostaining as well as traditional histological and clinical disease features. The MVD mean values estimated by both CD105 and CD34 were significantly higher in CIMF patients than in controls (Po0.00001). In addition, the proportion of CD105-positive megakaryocytes was significantly higher in CIMF than in controls (Po0.0001). A degree of reticulin fibrosis 42 correlated with increased CD105 MVD (P ¼ 0.05). A multivariate analysis confirmed that CD105-positive MVD was an independent adverse prognosticator. This study demonstrates that while MVD, as assessed by both CD34 and CD105 immunostaining, is significantly increased in CIMF, only CD105-determined MVD correlates with the degree of fibrosis and is prognostically relevant. These findings provide a rationale for the investigational use of anti-CD105-targeted drugs in CIMF.

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A phase 2 trial of combination low-dose thalidomide and prednisone for the treatment of myelofibrosis with myeloid metaplasia

Cited by 262 publications

References 41 publications

Efficacy and tolerability of hydroxyurea in the treatment of the hyperproliferative manifestations of myelofibrosis: results in 40 patients

Efficacy and tolerability of hydroxyurea in the treatment of the hyperproliferative manifestations of myelofibrosis: results in 40 patients

Myeloproliferative neoplasms: A decade of discoveries and treatment advances

Chronic idiopathic myelofibrosis: independent prognostic importance of bone marrow microvascular density evaluated by CD105 (endoglin) immunostaining

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