Essential thrombocythemia in children and adolescents — analysis of 31 cases

Introduction. Essential thrombocythemia is an extremely rare disorder in childhood. This disease is characterized by a persistent increase in the peripheral blood platelet count, associated with a proliferation of atypical megakaryocytes in the bone marrow.Aim — to analyze the clinical features of the course of essential thrombocythemia (ET) and the response to therapy in pediatric and adolescent patientsMaterials and methods. Thirty-one patients with ET under the age of 21 years were analyzed. All patients were diagnosed with ET in accordance with WHO criteria on the basis of an examination, including assessment of clinical data, laboratory tests (general clinical tests; morphological, genetic, and histological examinations of bone marrow), instrumental studies, and an assessment of response to treatment.Results. The average age of disease onset was 9 years 9 months, with a median of 9 years 6 months. Organomegaly was recorded in 16 (52 %) patients, of whom 6 (37.5 %) had isolated splenomegaly and 6 (37.5 %) had hepatosplenomegaly. Bleeding was noted in 6 (19.4 %) patients with a deep decrease in vWF:RCo (no more than 15 %) and an extreme increase in platelets (PLT) (more than 2000 × 109 /L). Twelve (38.7 %) patients suffered from microcirculation disorders (headaches, dizziness, melalgia), half of them had a platelet count of 1000–2000 × 109 /L, which is comparable to asymptomatic patients. No thrombosis was registered in our group. The JAK2V617F mutation was detected in 3 (9.7 %) patients, a mutation in the CALR gene was found in 9 (29.0 %) of patients, there was a mutation in the MPL gene in one (3.2 %) patient, and in the remaining cases (18 (58.1 %) patients), there was no damage to typical driver genes. Translocation t(12;12) was revealed in 1 (3.2 %) patient. The response to one-component cytoreductive therapy (CR+PR) was found to be quite high in young patients and constituted about 70–80 %. The complete response rate (CR) was as follows, respectively: 42.9 % (3) — to anagrelide therapy (ANA), 47.4 % (9) — to interferon therapy (INF), and 0 % — to hydroxycarbamide (HU). However, HU was not used in the fi rst line of therapy for the children in our group.Conclusion. In the pediatric population, ET patients are dominated by the group of “triple-negative” disease, which somewhat complicates the differential diagnosis with secondary thrombocytosis. Compared to the adult population, the risk of bleeding is higher for pediatric patients, which is associated with the large number of patients with extremely high levels of platelets. In the case of hemorrhagic syndrome development or microcirculatory disorders that cannot be stopped by taking antiplatelet agents, we recommend giving preference to INF and HU as fi rst-line therapy, due to the peculiarities of pharmacokinetics and the potential risk of progression of myelofi brosis during ANA therapy.

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JAK2 V617F Mutation Identifies a Biologically Distinct Subtype of Essential Thrombocythemia Which Resembles Polycythemia Vera.

Blood ◽

10.1182/blood.v106.11.253.253 ◽

2005 ◽

Vol 106 (11) ◽

pp. 253-253 ◽

Cited By ~ 1

Author(s):

Anthony Green ◽

Peter Campbell ◽

Linda Scott ◽

Georgina Buck ◽

Keith Wheatley ◽

...

Keyword(s):

Bone Marrow ◽

Platelet Count ◽

Polycythemia Vera ◽

Essential Thrombocythemia ◽

Response To Therapy ◽

Jak2 Mutation ◽

Mutation Status ◽

Cell Counts ◽

V617f Mutation

Abstract An acquired V617F mutation in JAK2 occurs in most patients with polycythemia vera (PV) but only half of those with essential thrombocythemia (ET) and idiopathic myelofibrosis. It is not known whether mutation-bearing patients are biologically distinct from those lacking the mutation, or why the same mutation is associated with different phenotypes. Two sensitive PCR-based methods were used to assess the JAK2 mutation status of 806 patients with ET, including 776 from the MRC PT-1 trial and two other prospective studies. The combined cohort provides a unique resource for studying ET, particularly in view of its large size, centralized review of end-points and comprehensive follow-up. The involvement of a large number of secondary and tertiary centers, together with the inclusion of patients in all risk categories, suggest the results are of general relevance. JAK2 mutation status divided the cohort into two distinct subgroups. Mutation-positive patients (53.4%) displayed multiple features resembling PV, with significantly increased hemoglobin levels (p<0.0001), neutrophil counts (p<0.0001), bone marrow erythropoiesis (p=0.001) and granulopoiesis (p=0.005). They suffered more venous thromboses in the year before diagnosis (p=0.04) and during follow-up (p=0.06), together with a higher incidence of polycythemic transformation (p=0.01). To explore the resemblance between V617F-positive ET and PV further, we analysed factors that might constrain erythropoiesis. Compared to mutation-negative patients with ET, mutation-positive patients had lower serum epo (p<0.0001), lower ferritin (p=0.01), and were more likely to be microcytic (p<0.0001). V617F-positive patients were more sensitive to hydroxyurea, requiring lower doses to control platelet count than V617F-negative patients (p<0.0001), a pattern not seen with anagrelide. Despite lower doses of hydroxyurea, V617F-positive patients had greater reductions in hemoglobin, platelet and white cell counts than V617F-negative patients, with no analogous differences noted between V617F-positive and negative patients randomized to anagrelide (p=0.004, p=0.04, p=0.0003 for platelet count, Hb and WCC). Mutation-negative patients did exhibit many clinical and laboratory features characteristic of a myeloproliferative disorder, including cytogenetic abnormalities, hypercellular bone marrow, abnormal megakaryocyte morphology, PRV1 over-expression, growth of epo-independent erythroid colonies, and a risk of myelofibrotic or leukemic transformation. JAK2 mutation status defines two biologically distinct subgroups of ET with differences in presentation, outcome and response to therapy. Our results suggest a model in which V617F-positive ET and PV form a continuum, with the degree of erythrocytosis determined by physiological or genetic modifiers, including iron stores, epo homeostasis, gender and V617F-homozygosity. This concept has major implications for the classification, diagnosis and management of MPDs.

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MPL Y252H and MPL F126fs mutations in essential thrombocythemia: Case series and review of literature

Hematology Reports ◽

10.4081/hr.2019.7868 ◽

2019 ◽

Vol 11 (1) ◽

Author(s):

Ahmed G. Elsayed ◽

Aeesha Ranavaya ◽

Muhammad Omer Jamil

Keyword(s):

Bone Marrow ◽

Somatic Mutation ◽

Essential Thrombocythemia ◽

Adult Population ◽

Case Series ◽

Clinical Importance ◽

The Other ◽

Review Of Literature ◽

Bone Marrow Disease ◽

Stat Pathway

Essential thrombocythemia (ET) is a clonal bone marrow disease, characterized by increased production of platelets along with other clinical and bone marrow findings. Most patients with ET will have a somatic mutation in one of the known gene locations of JAK2, CALR , or MPL that can upregulate the JAK-STAT pathway. MPL mutation is present in 5% of cases with the most common mutations being W515L and W515K. In this report we describe 2 cases of patients with clinical and laboratory picture of ET. One patient carried MPLY252H mutation which is previously unreported in the adult population but has been shown to be a gain-of-function mutation. The other patient carried MPL F126fs mutation which is not known to be of clinical importance and has not been previously reported.

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A Large Proportion of Patients With a Diagnosis of Essential Thrombocythemia Do Not Have a Clonal Disorder and May Be at Lower Risk of Thrombotic Complications

Blood ◽

10.1182/blood.v93.2.417 ◽

1999 ◽

Vol 93 (2) ◽

pp. 417-424 ◽

Cited By ~ 150

Author(s):

Claire N. Harrison ◽

Rosemary E. Gale ◽

Samuel J. Machin ◽

David C. Linch

Keyword(s):

Bone Marrow ◽

Platelet Count ◽

Essential Thrombocythemia ◽

Lower Risk ◽

Study Group ◽

Reactive Thrombocytosis ◽

Age Related ◽

Hemorrhagic Complications ◽

Thrombotic Complications

Abstract Essential thrombocythemia (ET) is traditionally considered to be a clonal disorder. No specific karyotypic abnormalities have been described, but the demonstration of clonality using X-chromosome inactivation patterns (XCIPs) has been used to differentiate ET from a non-clonal reactive thrombocytosis. However, these assays may be difficult to interpret, and contradictory results have been reported. We have studied 46 females with a diagnosis of ET according to the Polycythemia Vera Study Group (PVSG) criteria. XCIP results in 23 patients (50%) were uninterpretable due to either constitutive or possible acquired age-related skewing. Monoclonal myelopoiesis could be definitively shown in only 10 patients. Thirteen patients had polyclonal myelopoiesis, and in 8, it was possible to exclude clonal restriction to the megakaryocytic lineage. Furthermore, there was no evidence of clonal progenitors in purified CD34+CD33− and CD34+CD33+ subpopulations from bone marrow of 2 of these 13 patients. There was no difference between patients with monoclonal and polyclonal myelopoiesis with respect to age or platelet count at diagnosis, duration of follow-up, incidence of hepatosplenomegaly, or hemorrhagic complications. However, polyclonal patients were less likely to have experienced thrombotic events (P = .039). These results suggest that ET is a heterogeneous disorder, and the clinical significance of clonality status warrants investigation in a larger study.

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Essential Thrombocythemia in Patients with Platelet Counts below 600×109/L: Applicability of the 2008 World Health Organization Diagnostic Criteria Proposal

Blood ◽

10.1182/blood.v112.11.5239.5239 ◽

2008 ◽

Vol 112 (11) ◽

pp. 5239-5239

Author(s):

Mi Kwon ◽

Santiago Osorio Prendes ◽

Carolina Muñoz ◽

Jose Manuel Sanchez ◽

Monica Ballesteros ◽

...

Keyword(s):

Bone Marrow ◽

Platelet Count ◽

Essential Thrombocythemia ◽

World Health ◽

Jak2 Mutation ◽

Who Criteria ◽

Platelet Counts ◽

Bone Marrow Histology ◽

Health Organization

Abstract WHO criteria defines platelet counts above 600×109/L as the threshold for essential thrombocythemia (ET) diagnosis. It has been argued that such threshold excludes a number of patients with ET with platelet counts below 600×109/L. Recently, a proposal for revision of the World Health Organization (WHO) diagnostic criteria for ET has been published, which includes the combination of histological bone marrow study and testing of JAK2 mutation. Design and methods: Retrospective analysis of 92 patients with ET diagnosis between 1989 and February 2008, isolating the subgroup of patients with platelet counts below 600×109/L. The aim of this study was to analyze the applicability of the 2008 WHO criteria in this subgroup. Results: Of the 92 patients, 30 patients did not fulfill the WHO criteria due to platelet counts <600×109/L and in some cases also due to the coexistence of alternative causes of thrombocytosis. There were no significant differences between the entire group and the borderline platelet count subgroup in demographics, clinical and laboratory parameters (Table 1). The median age of the borderline platelet count group was 51 years (range 19–83 years) and 20 were female (70%). At diagnosis their median platelet count was 527×109/L (range 424–597). Fifteen patients (50%) showed the presence of JAK2 mutation. Remarkably, 74% of the patients presented as high-intermediate risk at diagnosis. From the 30 patients who did not fulfill the WHO criteria due to low platelet counts, 26 (87%) satisfied the modified criteria allowing ET diagnosis. Among them, 1 patient showed an alternative cause of thrombocytosis, however JAK2 mutation was positive confirming the primary cause of the disorder. Four patients remained not fulfilling the new criteria due to insufficient bone marrow sample or incompatible histology, however one of these patients showed JAK2 mutation confirming ET. The median follow-up was 2.54 years (range 0.07–18.7). During this period, none of the 30 patients had a spontaneous decrease of platelet count to within the normal range. Furthermore, transformation from ET to IMF was observed in 2 cases supporting the diagnosis of ET. During follow-up, 27 out of 30 patients were treated with antiaggregating drugs, 3 with antithrombotic therapy, and 20 with myelosuppressive therapy. The 11 patients who did not receive myelosuppressive therapy remained with platelet counts above 400×109/L. Conclusions: In our study, patients with platelet counts below 600×109/L did not show significant differences compared with the whole ET patients group. This subgroup can be diagnosed as having ET following the 2008 WHO criteria. The detection of JAK2 mutation in this setting enables the accurate diagnosis not only in cases with borderline thrombocytosis but more importantly in cases with alternative potential causes and also in cases where bone marrow sample is not available or incompatible. This observation raises de question of the role of bone marrow histology as a subjective diagnostic tool in ET diagnosis as opposed to JAK2 mutation detection. In JAK2 negative patients, subsequent follow-up of untreated patients confirmed the diagnosis since platelet counts remained high. The modified criteria facilitates the clinician to make an early diagnosis of ET in this subgroup of patients. Furthermore, a high proportion of these patients may be at risk of vascular complications, who may beneficiate from being correctly treated. TABLE 1 Total of patients Platelet count <600×10e9/L Number 92 30 Female (number, %) 59 (64%) 20 (70%) Age (median, range) 51 (19–84) 51 (19–83) Risk Low 26 (28%) 8 (26%) Intermediate 21(22%) 6 (19%) High 45 (48%) 16 (53%) Platelets ×10e9/L 693 (424–2,777) 527 (424–597) Hb g/dL 14.5 (11–18) 14.3 (11–16.8) Leucocytes ×10e9/L 8,5 (3,6–24,2) 8,5 (5,2–13,8) LDH UI/L 380 (39–1413) 337 (39–938) Splenomegaly 16 (17%) 5 (17%) JAK2 mutation 47 (51%) 15 (50%) Bone Marrow histology Celullarity >3.5 30/88 (34%) 8/28 (29%) Fibrosis grade I 2/90 (2%) 0 Compatible histology 79/89 (86%) 21/28 (75%) Abnormal Cytogenetics 2/26 (8%) 0 Symptoms 13 (14%) 4 (13%) Thrombotic event 16 (18%) 5 (17%) Haemorrhagic event 3 (4%) 0

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Efficacy and Safety of FCR (Fludarabine, Cyclophosphamide, Rituximab) Followed by Yttrium-90 Ibritumomab Tiuxetan in Relapsed Follicular Lymphoma (FL) Patients

Blood ◽

10.1182/blood.v112.11.5003.5003 ◽

2008 ◽

Vol 112 (11) ◽

pp. 5003-5003

Author(s):

Francesco Pisani ◽

Carlo Ludovico Maini ◽

Rosa Sciuto ◽

Laura Dessanti ◽

Antonio Spadea ◽

...

Keyword(s):

Bone Marrow ◽

Platelet Count ◽

Efficacy And Safety ◽

Ibritumomab Tiuxetan ◽

Prior Therapy ◽

Number Of Patients ◽

Grade 3 ◽

The Impact ◽

Yttrium 90

Abstract Background: FCR regimen has provided encouraging results in FL and Yttrium-90 Ibritumomab Tiuxetan (90Y-RIT) has been reported to be effective in patients with relapsed or refractory FL. Our study investigates the efficacy and safety of 90Y-RIT consolidation in relapsed FL patients, responding to second-line with FCR. Methods: At date reporting for this abstract we have recruited 10 patients median age 63 yrs (range 46–77). All enrolled patients were relapsed patients with histologically confirmed CD20-positive (grade 1 or 2) FL according to WHO classification. Major inclusion criteria were: age ≥ 18 years, WHO performance status of 0, 1 or 2, no prior therapy with Rituximab for 3 months and at the completion of FCR, patients achieving at least PR, with < 25% bone marrow involvement, with neutrophil count ≥ 1500/microlitre and platelet count ≥ 100000/microlitre. All patients at relapse received every 28 days FCR: F (25mg/m2×3 days), C (1gr/m2day1) and R (375mg/m2day4) for 4 cycles. Patients were restaged 4 to 8 weeks after the last course of FCR; who achieved at least a partial remission was eligible for Yttrium-90 Ibritumomab Tiuxetan 11.1 or 14.8 MBq/Kg (0.3–0.4 mCi/Kg) up to a maximum dose 1184 MBq at 3 months after the completion of FCR. The patients were restaged with total body CT scan, FDG-PET/CT and bilateral bone marrow biopsy at 4 to 8 weeks after the last cycle of FCR. A complete blood cell count was obtained once a week for 12 weeks after 90Y-RIT treatment. A history and physical examination were performed together with renal and liver function once a months for 3 months after 90Y-RIT. All patients received prophylaxis with trimethoprim-sulfamethoxazolo and valacyclovir from initiation of therapy until 3 ≥ months following therapy with 90Y-RIT. Results: Between August 2005 and March 2008 nine patients have completed the treatment: FCR followed by 90Y-RIT (6 patients at 0.4 mCi/Kg, 3 patients at 0.3 mCi/Kg) and one patient is under treatment. All 10 patients were relapsed patients: 6 patients received 1 or 2 prior therapy regimens and 4 patients had received 3 to 5 regimens. Eight of them were previously treated with Rituximab plus chemotherapy, 2 patients had no previous Rituximab treatment history, one also had ABMT. After FCR 6 patients obtained CR and 3 PR; after 90Y-RIT treatment the ORR was 100% and CCR was 100% with median follow up of 13 months (range 5–26) and all patients are alive in CR; 3 patients in PR after FCR regimen converted to CR by 90Y-RIT. The most common grade 3 or 4 adverse events were hematologic: grade 3 or 4 neutropenia occurred in 10/10 patients treated with FCR and grade 3 or 4 neutropenia and thrombocytopenia in 9/9 patients assessable after 90Y-RIT. Following treatment with 90Y-RIT the median neutrophil nadir was 0.5 × 109/L (range 0.3 – 1.09 ×109/L) at week 5; the median platelet count nadir was 40 × 109/L ( range 12–81 × 109/L ) at week 6. One patient developed herpes zoster infection after 8 months following valacyclovir discontinuation; another patient developed fungus infection. No other severe infection have been recorded, no nonhematologic adverse event have been registered so far. Conclusion: Our experience indicate feasibility, tolerability and efficacy of FCR regimen followed by 90Y-RIT in patients relapsed with FL. Hematologic toxicity occurring with FCR or with radio-immunotherapy are clinically controllable and acceptable in the population composed mainly of patients with a history of prior treatment using rituximab plus chemotherapy. A longer follow up and a larger number of patients with relapsed FL are required to determine the impact of this regimen on long-term duration of response and EFS.

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A Large Proportion of Patients With a Diagnosis of Essential Thrombocythemia Do Not Have a Clonal Disorder and May Be at Lower Risk of Thrombotic Complications

Blood ◽

10.1182/blood.v93.2.417.402a33_417_424 ◽

1999 ◽

Vol 93 (2) ◽

pp. 417-424 ◽

Cited By ~ 8

Author(s):

Claire N. Harrison ◽

Rosemary E. Gale ◽

Samuel J. Machin ◽

David C. Linch

Keyword(s):

Bone Marrow ◽

Platelet Count ◽

Essential Thrombocythemia ◽

Lower Risk ◽

Study Group ◽

Reactive Thrombocytosis ◽

Age Related ◽

Hemorrhagic Complications ◽

Thrombotic Complications

Essential thrombocythemia (ET) is traditionally considered to be a clonal disorder. No specific karyotypic abnormalities have been described, but the demonstration of clonality using X-chromosome inactivation patterns (XCIPs) has been used to differentiate ET from a non-clonal reactive thrombocytosis. However, these assays may be difficult to interpret, and contradictory results have been reported. We have studied 46 females with a diagnosis of ET according to the Polycythemia Vera Study Group (PVSG) criteria. XCIP results in 23 patients (50%) were uninterpretable due to either constitutive or possible acquired age-related skewing. Monoclonal myelopoiesis could be definitively shown in only 10 patients. Thirteen patients had polyclonal myelopoiesis, and in 8, it was possible to exclude clonal restriction to the megakaryocytic lineage. Furthermore, there was no evidence of clonal progenitors in purified CD34+CD33− and CD34+CD33+ subpopulations from bone marrow of 2 of these 13 patients. There was no difference between patients with monoclonal and polyclonal myelopoiesis with respect to age or platelet count at diagnosis, duration of follow-up, incidence of hepatosplenomegaly, or hemorrhagic complications. However, polyclonal patients were less likely to have experienced thrombotic events (P = .039). These results suggest that ET is a heterogeneous disorder, and the clinical significance of clonality status warrants investigation in a larger study.

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A focal extramedullary hematopoiesis of the spleen in a patient with essential thrombocythemia presenting with a complicated postoperative course: a case report

Surgical Case Reports ◽

10.1186/s40792-021-01119-5 ◽

2021 ◽

Vol 7 (1) ◽

Author(s):

Kiyotaka Hosoda ◽

Akira Shimizu ◽

Koji Kubota ◽

Tsuyoshi Notake ◽

Shinsuke Sugenoya ◽

...

Keyword(s):

Bone Marrow ◽

Platelet Count ◽

Essential Thrombocythemia ◽

Tumor Imaging ◽

Thrombus Formation ◽

Insertion Site ◽

Extramedullary Hematopoiesis ◽

Bleeding Tendency ◽

Compensatory Response ◽

Splenic Tumor

Abstract Background Extramedullary hematopoiesis is a compensatory response occurring secondary to inadequate bone marrow function and is occasionally observed in essential thrombocythemia (ET). This disease usually presents as multifocal masses in the paravertebral or intra-abdominal region; however, formation of a focal mass in the liver or spleen is rare. In addition, ET is characterized by increased platelet count and shows a tendency toward thrombosis and, occasionally, bleeding. Serious bleeding is common in ET patients, caused by the decrease in or abnormalities of von Willebrand factor (vWF) as a consequence of the precipitous rise in platelets. Therefore, strict management of platelet count using medication is crucial in patients with ET who require invasive procedures, especially splenectomy. Case presentation A 68-year-old man with ET was found to have an enlargement of a focal splenic tumor. Imaging findings revealed that the tumor was likely a hemangioma or hamartoma; however, the possibility of malignant disease could not be completely ruled out because of short-term tumor enlargement, and we conducted a splenectomy. The surgery was uneventful, but the patient presented with severe polycythemia and vWF abnormalities postoperatively, which resulted in bleeding from the drain insertion site and wound, epistaxis, and hemorrhoidal bleeding. Three months after discharge, polycythemia still persisted and the level of vWF gradually decreased. With a decrease in vWF, the patient suffered from an increased bleeding tendency. Therefore, the patient has been referred for bone marrow transplantation and is currently awaiting a suitable donor. Conclusions Extramedullary hematopoiesis should be listed as a differential diagnosis of focal enlarged splenic tumors, especially in patients with myeloproliferative disorders. Additionally, in splenectomy for ET patients, careful perioperative management taking into consideration the conflicting features of a tendency toward thrombus formation and bleeding is necessary.

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Bone Marrow Biopsy and Aspirate Evaluation in 90 Patients with Essential Thrombocythemia Treated with PEG Interferon alpha-2b. Preliminary Results.

Blood ◽

10.1182/blood.v104.11.1523.1523 ◽

2004 ◽

Vol 104 (11) ◽

pp. 1523-1523 ◽

Cited By ~ 4

Author(s):

L. Gugliotta ◽

S. Bulgarelli ◽

A. Tieghi ◽

S. Asioli ◽

G. Gardini ◽

...

Keyword(s):

Bone Marrow ◽

Platelet Count ◽

Bone Marrow Biopsy ◽

Essential Thrombocythemia ◽

Bone Marrow Fibrosis ◽

Minor Response ◽

Bone Marrow Biopsies ◽

Hematological Response ◽

Second Year ◽

Marrow Fibrosis

Abstract Ninety patients with Essential Thrombocythemia (ET) where object of a phase II prospective multicentre study designed to evaluate efficacy, safety and tolerability of a two years treatment with PEG Interferon α-2b (PEG Intron, Schering Plough). The patients, 30 M and 60 F, 18–72 years old (median 45), observed in 16 Hematological Institutions of the Gruppo Italiano Malattie Mieloproliferative Croniche (GIMMC), received the ET diagnosis according to the PVSG criteria. At PEG Intron treatment start the patients showed: previous cytoreduction 97% (IFN α 31%), platelet count >1000 x 109/L 81%, splenomegaly 22%. At the end of the first year The PEG Intron starting dose of 25 μg/week resulted increased to a mean value of 55 μg/week and the Hematological Response (HR = Plts <500x109/L) was registered in 79% of the patients still on treatment. At the end of second year 65 patient still receiving PEG Intron (mean dose 31 μg/week) showed a maintenance of the HR (66%), a Partial Response (17%) and a Minor Response (17%). By utilizing the data included in the study CRFs we preliminarily evaluated the bone marrow biopsy and aspirate both performed at baseline, after 1 and 2 years in 89 and 86, 79 and 67, 57 and 50 patients, respectively. Data concerning the bone marrow biopsies after 1 year of treatment are reported: BONE MARROW BIOPSY BASELINE % 1 YR % 2 YRS % Cellularity increased 56 51 48 Granulopoiesis increased 51 54 39 Erytropoiesis increased 29 24 23 MK number increased 99 90 84 MK size increased 78 69 62 MK ploidy 54 51 42 MK dystrophy 52 56 59 Fibrosis mild 40 37 46 Fibrosis moderate 7 25 26 The increase of bone marrow fibrosis registered after one year (representative also of second year data) resulted not related to patient gender, age >45 years, platelet count >1000 x109/L, Hb <12 g/dL, splenomegaly, previous IFN treatment, PEG Intron dose >50 μg/week. In conclusion, the present study shows that in ET patients a two years PEG Intron treatment, able to induce and to maintain the Hematological Response in the majority of cases, is associated to a decrease of bone marrow cellularity, granulopoiesis, erytropoiesis, MK number, size and ploidy and, moreover, with an increase of MK dystrophy and of bone marrow fibrosis. These preliminary data on bone biopsy and aspirate will be object of a planned centralized reevaluation by a Panel of Pathologists and Clinicians.

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Radiometric Quantitation of PAIgG Stratified Treatment Response in ITP Patients.

Blood ◽

10.1182/blood.v106.11.3986.3986 ◽

2005 ◽

Vol 106 (11) ◽

pp. 3986-3986

Author(s):

Dexter Estrada ◽

Kenneth A. Schwartz2

Keyword(s):

Platelet Count ◽

Treatment Response ◽

Conventional Treatment ◽

Retrospective Chart Review ◽

Response To Therapy ◽

Response To Treatment ◽

Platelet Surface ◽

Platelet Counts ◽

Cytotoxic Treatment

Abstract Because treatment response in ITP is variable, it would be useful to be able to assess which patients are likely to respond to conventional treatment. Toward this goal we correlated the number of platelet surface IgG molecules measured with a quantitative radiometric platelet antibody assay (PAIgG) with treatment related changes in platelet count. We tested the hypothesis that patients’ response to conventional treatment could be stratified based on quantitation of the patients’ PAIgG. Data was obtained via a retrospective chart review. Patients with a diagnosis of idiopathic thrombocytopenic purpura (ITP), age 18 or older with an initial platelet count of <150,000, and quantitation of antiplatelet IgG performed at the time of diagnosis were included in the study. Patients were treated using conventional approaches that included steroids, IVIgG, anti-D antibody, splenectomy, and or cytotoxic medications. Patient response to therapy was evaluated as the change in platelet count, computed as the difference in platelet count obtained at diagnosis and the latest stable platelet count available. There were 64 patients with at least 90 days between initial and follow-up platelet counts. Of the 31 patients whose PAIgG were ≤1,000 molecules/platelet (m/plt), only 1 had an initial platelet count of <50,000. Of the 33 patients who’s PAIgG were >1,000 m/plt 16 had platelet counts of <50,000 (p≤0.001. Patients with PAIgG levels >1000 m/plt exhibited a significantly greater increase in platelet count μ=73,000 ±92,000 as compared to those with PAIgG levels ≤1000 m/plt, μ=18,000 ±43,000 (p=0.03). Although a PAIgG level of 500 m/plt is 3 standard deviations above the mean of normals, a greater response to treatment was noted in patients if their PAIgG level was >1000 m/plt. Patients with PAIgG levels between 500 and 1000 m/plt respond in a similar fashion to those with PAIgG levels <499. In addition, more patients with PAIgG levels >1000 m/plt received conventional treatment (19/33 vs. 10/31; p<0.05). In particular, there were more patients who received cytotoxic treatment in this cohort, (11/33 vs. 3/31; p≤0.025). Similar results were observed in 74 patients with at least 30 days between initial and follow-up platelet counts. This study suggests that measuring the amount of antiplatelet IgG stratifies ITP patients into 2 groups: patients with PAIgG ≤1,000 m/plt with platelet counts over 50,000 and patients with PAIgG >1,000 m/plt platelet counts that are less than 50,000. Those patients whose PAIgG is >1,000 m/plt are more likely to receive treatment and have an increase in platelet count with conventional therapy. We conclude that radiometric quantitation of PAIgG is helpful for predicting a patient’s response to therapy.

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Pomalidomide Therapy in Myelofibrosis: 2-Year Follow-up of a Randomized Phase 2 Study.

Blood ◽

10.1182/blood.v114.22.1904.1904 ◽

2009 ◽

Vol 114 (22) ◽

pp. 1904-1904 ◽

Cited By ~ 1

Author(s):

Francesco Passamonti ◽

Elisabetta Gattoni ◽

Francisco Cervantes ◽

Heinz Gisslinger ◽

Ronald Paquette ◽

...

Keyword(s):

Bone Marrow ◽

Platelet Count ◽

Randomized Study ◽

Serum Lactate Dehydrogenase ◽

Phase 2 ◽

Median Response ◽

Monosomy 7 ◽

Mutational Status ◽

Number Of Patients

Abstract Abstract 1904 Poster Board I-927 BACKGROUND: Pomalidomide is an IMiDsó immunomodulatory drug that was created by chemical modification of thalidomide with the intent to reduce toxicity and enhance therapeutic activity. In a phase-2 randomized study of patients with myelofibrosis (MF), treatment with pomalidomide alone or in combination with a short course of prednisone was shown to be well tolerated and active in alleviating anemia ( JCO 2009). Herein, we report observations during the longer-term follow-up of those patients who had responded to a pomalidomide-containing treatment regimen. METHODS: Both primary and post polycythemia vera/essential thrombocythemia MF were included in the current study. Protocol eligibility criteria included absolute neutrophil count of × 109/L, platelet count of 50 × 109/L and hemoglobin level of < 10 g/dL. Patients with prior thalidomide or lenalidomide therapy were excluded from study participation. Response was assessed by the International Working Group for Myelofibrosis Research and Treatment criteria (IWG-MRT) (Blood. 2006). Pomalidomide was administered daily and continued indefinitely in responding patients. Prednisone was given for the first 3 months only, in a tapering dose schedule, starting at 30 mg/day. RESULTS: A total of 84 patients were enrolled from April 2007 through May 2008 and received treatment with pomalidomide alone 2 mg/day (n=22), pomalidomide 2 mg/day + prednisone (n=19), pomalidomide 0.5 mg/day + prednisone (n=22) or prednisone alone (n=21). Short-term toxicity details have previously been published (Tefferi et al. JCO 2009) and were remarkable for the lack of neuropathy and low prevalence of grade 3 or 4 myelosuppression (5–16%). Based on an intent-to-treat analysis, 16 (25%) of the 63 patients receiving pomalidomide alone or with a 3-month course of prednisone responded at a median of 1.8 months (range 0.9–6.9) from treatment initiation; all responses represented improvement in anemia with little or no effect on splenomegaly. Specifically, 12 of the 16 treatment responders became transfusion independent and the remaining 4 had a hemoglobin increase of > 2 g/dL (median best hemoglobin response = 11.9 g/dL; range 8.5–15.9). Responding patients usually displayed increases in platelet count but there was no consistent change in serum lactate dehydrogenase level. As of August 2009, ten (63%) of the 16 treatment responders were still in anemia remission and receiving pomalidomide therapy; median time on treatment was 19 months (range, 14–26) and median response duration was 17 months (range, 13-24). No new side effects emerged during this period. Six patients discontinued treatment because of either loss of response (n=5) or progressive splenomegaly/leukocytosis (n=1); 3 patients with continued anemia remission have had substantial increases in their spleen size, which qualifies as spleen progression per IWG-MRT. Among 9 patients with available cytogenetic information, all 3 with unfavorable karyotype relapsed while none of the 6 with favorable karyotype did. A small number of patients (n=7) had follow-up bone marrow examination at 1 to 2 years, at the discretion of their treating physician; none of these patients displayed any change in bone marrow fibrosis or JAK2V617F mutational status. Suppression of a monosomy 7 clone was documented in two patients. In one, the percentage of abnormal metaphases decreased from 90% to 15% after 11 months of treatment with pomalidomide but increased back to 100% four months later, when the patient relapsed while still on treatment. In the second patient, the percentage of abnormal metaphases was 65% at baseline, remained at 75% after 10 months of pomalidomide therapy, but decreased to 7% after one month of treatment discontinuation for relapse; a repeat examination in this patient after another 3 months (still off therapy) showed monosomy 7 and new additional abnormalities (including 4q21q25 deletion) in 65% of metaphases evaluated. CONCLUSION: Longer-term follow-up of pomalidomide-treated patients with myelofibrosis confirm the drug's favorable side effect profile. Also, the majority of treatment responders maintain their remission, which is exclusively anemia remission, for at least one year and several remain in remission after 2 years of therapy. The drug has limited effect on splenomegaly and progressive splenomegaly might occur in some patients despite continued remission in anemia. The presence of unfavorable cytogenetic abnormalities predicts relapse. Disclosures: Gale: Celgene: Employment.

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