scholarly journals Low-dose, single-fraction, whole-lung radiotherapy for pulmonary hypertension associated with myelofibrosis with myeloid metaplasia

2002 ◽  
Vol 118 (3) ◽  
pp. 813-816 ◽  
Author(s):  
David P. Steensma ◽  
C. Christopher Hook ◽  
Scott L. Stafford ◽  
Ayalew Tefferi
Keyword(s):  
Pulmonary Hypertension ◽  
Low Dose ◽  
Myeloid Metaplasia ◽  
Single Fraction ◽  
Myelofibrosis With Myeloid Metaplasia ◽  
Lung Radiotherapy

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 ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 2576-2576 ◽  
Author(s):  
Ruben A. Mesa ◽  
David P. Stensma ◽  
Chin Y. Li ◽  
Antje Hoering ◽  
Jacob B. Allred ◽  
...  
Keyword(s):  
Phase Ii ◽  
Low Dose ◽  
Phase Ii Study ◽  
Patient Choice ◽  
Necrosis Factor Alpha ◽  
Myeloid Metaplasia ◽  
Therapeutic Value ◽  
Transfusion Requirements ◽  
Grade 3 ◽  
Myelofibrosis With Myeloid Metaplasia

Abstract BACKGROUND: Disease manifestations in myelofibrosis with myeloid metaplasia (MMM) that require therapy include anemia, thrombocytopenia, hepatosplenomegaly, and constitutional symptoms. We have previously reported on the therapeutic value of low-dose thalidomide in combination with prednisone for the treatment of both anemia and thrombocytopenia in MMM (Blood2003;101:2534), and of etanercept (tumor necrosis factor-alpha antagonist) for alleviation of constitutional symptoms (Blood2002;99(6):2252). In the current study, we investigated the value of combining all three drugs (PET). METHODS: Study eligibility criteria included a histologically confirmed diagnosis of MMM and either severe anemia (hemoglobin < 10 g/dL) or symptomatic splenomegaly. Protocol treatment was initiated with 50 mg of oral thalidomide (THAL) daily, etanercept (ETAN) 25 mg subcutaneously twice-a-week, and a three month prednisone taper starting at 0.5 mg/kg/day for the first month followed by a 50% reduction for the second months and a further 50% reduction for the third and final month of treatment with prednisone. Patients with a demonstrable clinical response after three months were able to remain on thalidomide and etanercept. RESULTS: 15 patients were enrolled to the trial (median age 66 years, range, 54–77; 14 males). Twelve patients (80%) completed the planned three cycles (i.e. 3 months) of treatment (progression (n=2) and patient choice (n=1) accounted for the withdrawals), nine (60%) patients with evidence of response continued on an additional three months of THAL/ETAN alone (of which 3 progressed prior to study completion). At enrollment, 11 patients (73%) were anemic (7 (47%) were red cell transfusion dependent), 7 (47%) were at least moderately thrombocytopenic (platelet count < 100 x 109//L), and 6 had severe constitutional symptoms (night sweats or disease related fever). Anemia response were seen in 6 (of the 11 eligible; 54%) patients (2 in the non-transfusion dependent (sustained increases of 1.5 and 4.9 g/dL hemoglobin); 4 in transfusion dependent (1 transfusion independent, 3 >50% decrease in transfusion requirements)). All thrombocytopenic patients experienced an increase in platelet counts (median 55% increase (range(10–229) with 2 returning to the normal range (>150 x 109/L)). A greater than 50% decrease in organomegaly was documented in 3 patients with splenomegaly (25% of eligible), and 1 patient with hepatomegaly (25%). Constitutional symptoms resolved, or signifcantly improved in all afflicted. Therapy overall was well tolerated with the majority of toxicities being transient. Neuropathy (grade 1; n=3; grade 2; n=1) and hyperglycemia (grade 2; n=1) were minimal. The only greater or equal to grade 3 toxicities were (grade 3: elevated bilirubin, infection, and blurred vision; grade 4: anemia). Follow-up bone marrow examination, when available, did not show post-treatment histological changes. CONCLUSIONS: This phase II study of combination therapy with thalidomide-prednisone-etanercept in patients with MMM confirms the previously recognized value of etanercept in alleviating constitutional symptoms. However, the PET regimen does not appear to be superior to thalidomide-prednisone combination in terms of therapeutic value for anemia, thrombocytopenia, or splenomegaly.

Responses to Thalidomide Combined with Prednisone Therapy for Myelofibrosis with Myeloid Metaplasia.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 3623-3623
Author(s):  
Shenxian Qian ◽  
Junfeng Tan ◽  
Pengfei Shi ◽  
Gaqian Gao
Keyword(s):  
Bone Marrow ◽  
Low Dose ◽  
Single Agent ◽  
Drug Effects ◽  
Myeloid Metaplasia ◽  
Baseline Status ◽  
Myelofibrosis With Myeloid Metaplasia ◽  
Sequential Phase

Abstract Myelofibrosis with myeloid metaplasia (MMM) is currently classified as a classic (i.e. not yet molecularly defined) myeloproliferative disorder (MPD), along with essential thrombocythemia (ET) and polycythemia vera (PV). All three MPDs represent stem-cell-derived clonal myeloproliferation that, in the case of MMM, is accompanied by an intense bone marrow stromal reaction that includes collagen fibrosis, osteosclerosis, and angiogenesis. To present the results of a long-term analysis of 2 sequential phase 2 trials of thalidomide (alone or in combination) for palliation of myelofibrosis with myeloid metaplasia (MMM). We analyzed (March 2003 to August 2005) initial and long-term outcomes from 33 patients with symptomatic MMM who had enrolled in either our thalidomide single-agent trial (n=12) or our trial of low-dose thalidomide (50 mg/d) combined with prednisone (n=21). Among the 33 study patients, 18 (54%) showed some improvement in their clinical course. Response rates for specific end points included improvements in anemia (12 of 33 [36%]), thrombocytopenia (8 of 12 [66%]), or splenomegaly (5 of 30 [17%]). The combination of low-dose thalidomide and prednisone, as opposed to single-agent thalidomide, was better tolerated and more efficacious. After a median follow-up of 17 months (range, 9–27 months), 10 of 33 patients (33%) showed an ongoing response, including 8 patients in whom protocol treatment has been discontinued for a median of 21 months (range, 16–27 months). Durable treatment responses were documented for only anemia and thrombocytopenia. Treatment response was not affected by the baseline status of bone marrow fibrosis, angiogenesis, osteosclerosis, cytogenetics. Unusual drug effects, all reversible, included leukocytosis (8 patients) and/or thrombocytosis (6 patients). Thalidomide (alone or combined with prednisone) is an effective first-line treatment of symptomatic anemia or thrombocytopenia in MMM. Thalidomide-based therapy has the potential to produce durable responses in MMM-associated cytopenias, even after discontinuation of the drug.

Low-Dose Thalidomide Ameliorates Cytopenias and Splenomegaly in Myelofibrosis With Myeloid Metaplasia: A Phase II Trial

2004 ◽  
Vol 22 (3) ◽  
pp. 424-431 ◽  
Author(s):  
Monia Marchetti ◽  
Giovanni Barosi ◽  
Francesca Balestri ◽  
Gianluca Viarengo ◽  
Sara Gentili ◽  
...  
Keyword(s):  
Disease Severity ◽  
Phase Ii ◽  
Low Dose ◽  
Drop Out ◽  
Current Therapy ◽  
Myeloid Metaplasia ◽  
High Baseline ◽  
Fatigue Score ◽  
Drop Out Rate ◽  
Myelofibrosis With Myeloid Metaplasia

Purpose A phase II dose-escalation trial was conducted to ascertain low-dose thalidomide safety and response in patients with advanced myelofibrosis with myeloid metaplasia (MMM). Patients and Methods Thalidomide was administered together with current therapy to 63 patients, starting at 50 mg daily and increasing to 400 mg as tolerated. Results Half of the patients sustained daily doses more than 100 mg and the drop-out rate was 51% at 6 months: the drop-out rate was lower in patients with high baseline fatigue score. At efficacy analysis, anemia was ameliorated in 22% of the patients and transfusions were eliminated in 39% of transfusion-dependent patients. Platelet count increased by 50 × 109/L or more in 22% of patients with an initial count lower than 100 × 109/L. Splenomegaly decreased by more than 50% of the initial size in 19% of patients. Reduction of an overall disease severity score occurred in 31% of patients and was associated with a significant reduction of fatigue. Disease severity amelioration was independently predicted by a high baseline myeloproliferative index (ie, large splenomegaly, thrombocytosis, or leukocytosis). Conclusion Low-dose thalidomide displays an acceptable toxicity profile and provides an objective and subjective advantage to a relevant portion of MMM patients.

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

Blood ◽  
2003 ◽  
Vol 101 (7) ◽  
pp. 2534-2541 ◽  
Author(s):  
Ruben A. Mesa ◽  
David P. Steensma ◽  
Animesh Pardanani ◽  
Chin-Yang Li ◽  
Michelle Elliott ◽  
...  
Keyword(s):  
Platelet Count ◽  
Low Dose ◽  
Oral Prednisone ◽  
Single Agent ◽  
Dropout Rate ◽  
Drug Regimen ◽  
Myeloid Metaplasia ◽  
Phase 2 Trial ◽  
Objective Clinical Response ◽  
Myelofibrosis With Myeloid Metaplasia

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.

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 ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 1520-1520
Author(s):  
Ruben A. Mesa ◽  
David P. Steensma ◽  
Chin Y. Li ◽  
Antje Hoering ◽  
Heather Powell ◽  
...  
Keyword(s):  
Phase Ii ◽  
Low Dose ◽  
Phase Ii Study ◽  
Red Cell ◽  
Eligibility Criteria ◽  
Necrosis Factor Alpha ◽  
Myeloid Metaplasia ◽  
Therapeutic Value ◽  
Red Cell Transfusion ◽  
Myelofibrosis With Myeloid Metaplasia

Abstract BACKGROUND: Disease manifestations in myelofibrosis with myeloid metaplasia (MMM) that require therapy include anemia, thrombocytopenia, hepatosplenomegaly, and constitutional symptoms. We have previously reported on the therapeutic value of low-dose thalidomide in combination with prednisone for the treatment of both anemia and thrombocytopenia in MMM (Blood2003;101:2534) and of etanercept (tumor necrosis factor-alpha antagonist) for alleviation of constitutional symptoms (Blood2002;99(6):2252). In the current study, we investigated the value of combining all three drugs (PET). METHODS: Study eligibility criteria included a histologically confirmed diagnosis of MMM and either severe anemia (hemoglobin < 10 g/dL) or symptomatic splenomegaly. Protocol treatment was initiated with 50 mg of oral thalidomide daily, etanercept 25 mg subcutaneously twice-a-week, and a three month prednisone taper starting at 0.5 mg/kg/day for the first month followed by a 50% reduction for the second months and a further 50% reduction for the third and final month of treatment with prednisone. Patients with a demonstrable clinical response after three months were able to remain on thalidomide and etanercept. RESULTS: To date 12 patients have been enrolled to the trial (median age 67 years, range, 54–77; 11 males). At enrollment, all patients were severely anemic (6 were red cell transfusion dependent), 6 were at least moderately thrombocytopenic (platelet count < 100 x 109//L), and 4 had severe constitutional symptoms. The responses to date included resolution of constitutional symptoms in all 4 pertinent patients, a 12–326% improvement in thrombocytopenia in 4 of 6 pertinent patients, and anemia response in 4 patients including one patient who became red cell transfusion independent. A more than 50% decrease in splenomegaly was documented in 3 patients. Only one patient experienced greater or equal to grade 3 toxicity (i.e. elevated bilirubin and infection). Follow-up bone marrow examination, when available, did not show post-treatment histological changes. CONCLUSIONS: The preliminary findings from the current ongoing phase II study of combination therapy with thalidomide-prednisone-etanercept in patients with MMM confirms the previously recognized value of etanercept in alleviating constitutional symptoms. However, at least preliminarily the PET regimen does not appear to be superior to thalidomide-prednisone combination in terms of therapeutic value for anemia, thrombocytopenia, or splenomegaly.

Additon of Low-Dose Interferon-alpha (LD-IFN-a) and Lenalidomide after Failure to a Combination of Thalidomide and Prednisone in Myelofibrosis with Myeloid Metaplasia (MMM).

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 4645-4645
Author(s):  
Lisa Reale ◽  
Emmanuel C. Besa
Keyword(s):  
Low Dose ◽  
Treatment Options ◽  
Objective Response ◽  
Clinical Activity ◽  
Spleen Size ◽  
Myeloproliferative Disease ◽  
Myeloid Metaplasia ◽  
Cell Counts ◽  
Number Of Patients ◽  
Myelofibrosis With Myeloid Metaplasia

Abstract Primary myelofibrosis with myeloid metaplasia (MMM) is an uncommon myeloproliferative disease with limited effective treatment options. Therapy using thalidomide and prednisone (TP) or lenalidomide (L) show variable objective response of improvement of 22% in L to 62% in TP for anemia, 50% in L to 75% in TP for thrombocytopenia, and decrease in splenomegaly in 19% with TP to 33% with L and was well-tolerated. Additional clinical benefits show resolution of leukoerythroblastosis, and a decrease in medullary fibrosis and abnormal angiogenesis. Prolonged therapy with alpha-interferon (IFN-a) can improve hematopoiesis and reverse marrow fibrosis but doses used were poorly tolerated. Methods and Patients: Here we present five patients treated with combination T at 50 mg daily, P at 0.5 mg/kg po for 2 weeks then to 20 mg daily every other day for 3 months with no response. If this was tolerated, low-dose IFN-a (LD-IFN-a) at 1.5 million units sc. three times a week was added. The clinical and hematologic criterion of the European Myelofibrosis Network (EUMNET) were used as response criteria for our study. Three males, 2 females, age ranged from 60 to 85 years who had failed previous treatments from EPO, hydrea and transfusion support. White blood cell counts ranged from 4.3 to 29.7 B/L. Hemoglobin levels ranged from 7.3 to 11.6 g/dL. Platelets ranged from 13,000 to 283,000 B/L. Three patients developed iron overload from rbc transfusions and required iron-chelation therapy. Results: Of the five patients, one had a CR, one had a PR and two had regression that did not meet criteria for response and one unresponsive with no splenomegaly but stable disease. We noted that the addition of LD-IFN-a decreased the elevated WBC counts and Improvement in spleen size was seen about three months after the start of treatment. One patient had a CR in his WBC count approximately a month after starting therapy. The patient with CR had normal hemoglobin but had to discontinue after a year of T due to grade 2 neuropathy and was started on 10 mg/day of L while staying on IFN-a and P. She developed anemia and required transfusions for 3 months and achieved CR with shrinkage of her spleen size from 15 to 4 cm. The patient who was unresponsive to the combination of IFN-a- TP changed from T to L was stopped after the patient developed hemolytic anemia and splenomegaly. Conclusion: Addition of LD-IFN-a to the reported TP or L to replace T show clinical activity in patients with refractory MMM and is well tolerated with minimal toxicity. The use of lenalidomide may alleviate neuropathy but may induce hemolysis as an undesirable side effect. Further studies using low doses of these agents with varying activities to MMM in combination is needed to define their clinical use in the treatment of this disease entity in a much larger number of patients.

High Circulating CD34 Cells, Dacrocytes, Clonal Hematopoiesis, and JAK 2 Mutation Differentiate Secondary Myelofibrosis Associated with Pulmonary Hypertension from Myelofibrosis with Myeloid Metaplasia.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 2589-2589
Author(s):  
Uday Popat ◽  
Enli Liu ◽  
Yongli Guan ◽  
Josef T. Prchal
Keyword(s):  
Pulmonary Hypertension ◽  
Somatic Mutation ◽  
Peripheral Blood ◽  
Myeloproliferative Disorders ◽  
Fisher Exact Test ◽  
Myeloid Metaplasia ◽  
Clonal Hematopoiesis ◽  
Myelofibrosis With Myeloid Metaplasia ◽  
Secondary Myelofibrosis ◽  
Marrow Fibrosis

Abstract Myelofibrosis with myeloid metaplasia (MMM) is a clonal myeloproliferative disorder, characterized by splenomegaly and myelofibrosis. Like all myeloproliferative disorders, it is due to an acquired somatic mutation of a hematopoietic progenitor resulting in clonal erythrocytes, platelets, and granulocytes. A single acquired point mutation of JAK2 1849G&gt;T (V617F), a tyrosine kinase with a key role in signal transduction from growth factor receptors, occurs in 50%–97% of patients with MMM, essential thrombocythemia (ET) and polycythemia vera (PV). We studied 25 myelofibrosis patients with myeloid metaplasia and myelofibrosis complicating PV or ET. These were compared to 19 patients with secondary myelofibrosis of equivalent severity associated with pulmonary hypertension (PH) treated by epoprostenol. In these two groups we compared peripheral blood CD34 counts, clonality of granulocytes and platelets in peripheral blood, mutational status of JAK 2 kinase gene, and morphology of peripheral blood and bone marrow. Heterozygosity for JAK 2 1849G&gt;T somatic mutation was seen in 17 of 23 (74%) patients with MMM including 10 of 15 patients (67%) with idiopathic myelofibrosis and 7 of 8 patients (88%) with myelofibrosis complicating PV or ET, but was absent in all 19 patients with myelofibrosis associated with PH (P&lt;0.0001, Fisher exact test 2 tailed). The number of peripheral blood CD 34 cells was significantly higher in patients with MMM compared to patients with secondary myelofibrosis associated with PH; 1.1% (95% CI, 0.58%–1.64%) in patients with MMM versus 0.08% (95% CI, 0.04%–0.12%) in patients with PH, or 0.05% (95% CI, 0.03%–0.06%) in normal healthy controls (P&lt;0.01). Further, patients with PH lacked dacrocytes, erythroid precursors, or myeloid precursors (leukoerythroblastic picture) on examination of the blood smear. Clonal hematopoiesis was found only in those women with marrow fibrosis due to MMM, PV and ET and not in patients with secondary marrow fibrosis (P &lt; 0.0001). We conclude that a high circulating CD34 count, clonal platelets and granulocytes, presence of dacrocytes, and JAK2 1849G&gt;T (V617F) mutation of clonal progenitors are the intrinsic features present in patients with myelofibrosis due to myeloproliferative disorders and that these features are not due to the abnormal marrow architecture that is seen in secondary myelofibrosis.

High levels of circulating CD34 cells, dacrocytes, clonal hematopoiesis, and JAK2 mutation differentiate myelofibrosis with myeloid metaplasia from secondary myelofibrosis associated with pulmonary hypertension

Blood ◽  
2006 ◽  
Vol 107 (9) ◽  
pp. 3486-3488 ◽  
Author(s):  
Uday Popat ◽  
Adaani Frost ◽  
Enli Liu ◽  
Yongli Guan ◽  
April Durette ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Peripheral Blood ◽  
Myeloproliferative Disorders ◽  
Kinase Gene ◽  
Jak2 Mutation ◽  
Myeloid Metaplasia ◽  
Peripheral Blood Cd34 ◽  
Mutational Status ◽  
Myelofibrosis With Myeloid Metaplasia ◽  
Secondary Myelofibrosis

We studied 25 patients with myelofibrosis with myeloid metaplasia and 19 patients with secondary myelofibrosis associated with pulmonary hypertension (PH). In these 2 groups, we compared the peripheral-blood CD34 count, the clonality of granulocytes and platelets in peripheral blood, the mutational status of the JAK2 kinase gene, and the morphology of the peripheral blood and bone marrow. We found that the following were distinctive features of myelofibrosis with myeloid metaplasia but not of secondary myelofibrosis due to PH: high circulating CD34 cell count, the presence of clonal platelets and granulocytes and of peripheral-blood dacrocytes, and a JAK2 1849G>T (V617F) mutation. We conclude that these are intrinsic features of clonal progenitors present in patients with myelofibrosis due to myeloproliferative disorders and that these features are not due to the abnormal marrow architecture seen in secondary myelofibrosis.

Sign in / Sign up

Export Citation Format

Share Document