Angiogenesis and anti-angiogenic therapy in myelofibrosis with myeloid metaplasia

Myelofibrosis with myeloid metaplasia (MMM) is a clonal stem cell disorder that is characterized by florid bone marrow stromal reaction including collagen fibrosis, osteosclerosis, and angiogenesis. Almost all patients with MMM display increased bone marrow microvessel density (MVD) and the extent is among the highest in hematological malignancies. This particular information has encouraged the therapeutic use of anti-angiogenic drugs in MMM. In the current review, we summarize the general concepts regarding angiogenesis, assessment of angiogenesis in hematological malignancies and then the current literature on angiogenesis and anti-angiogenic therapy in MMM.     

Modest activity of pomalidomide in patients with myelofibrosis and significant anemia

We evaluated single agent pomalidomide for myelofibrosis-associated anemia. First, 21 patients received pomalidomide 3.0 mg/day on 21-day-on/7-day-off schedule. Due to poor tolerance the study was quickly suspended. Second, 29 patients received pomalidomide 0.5 mg/day continuously. Three patients (10%) experienced clinical improvement in hemoglobin per International-Working-Group criteria (median time to response 1.6 months; median response duration 6.7 months). Ten patients were RBC-transfusion-dependent per Delphi criteria; 2 (20%) achieved RBC-transfusion-independence (time to response 0.9 months in both; response duration of 8.3 and 15 months). One grade 3/4 toxicity (neutropenia) occurred. Pomalidomide at low dose is well tolerated but has modest clinical activity in myelofibrosis.     

Phase II study of pomalidomide in combination with prednisone in patients with myelofibrosis and significant anemia

We evaluated pomalidomide with prednisone for myelofibrosis (MF) with significant anemia (hemoglobin < 10 g/dL). Patients (n = 29; 18 RBC-transfusion dependent) received 0.5 mg pomalidomide daily in continuous 28-day cycles with prednisone given for the first 3 cycles only. Six (21%) patients responded (median response duration 11.4 months), including four who achieved RBC-transfusion-independence per the Delphi criteria and two who achieved clinical improvement (in platelets and spleen, respectively) per the International Working Group for Myelofibrosis Research and Treatment criteria. Grade 3 toxicity occurred in 1 patient (fatigue). Pomalidomide with prednisone is safe therapy with modest activity in patients with MF and anemia.     

原发性骨髓纤维化转急性髓系白血病一例并文献复习

 目的　提高对原发性骨髓纤维化（PMF）诊断、治疗及疾病转化的认识。方法　报告1例PMF转为急性髓性白血病（AML）的过程以及基因突变特点,并作相关文献复习。结果　患者符合WHO 2008年PMF诊断标准,自初诊至转化为AML共2.5年。疾病转化前后JAK2 V617F基因突变始终阳性,小剂量化疗疗效维持时间短。结论　PMF转化为AML后JAK2 V617F基因突变阳性,药物治疗难以控制病情进展。     

Analysis of risk factors of the evolution of myelofibrosis in pre-fibrotic chronic idiopathic myelofibrosis: a retrospective study based on follow up biopsies of 70 patients by using the RECPAM method

The advanced, fibrotic phase of chronic idiopathic myelofibrosis (CIMF) is preceded by a pre-fibrotic stage. However, the factors which may influence or predict the development of myelofibrosis are not well established. Thus we investigated follow up biopsies of 70 patients with CIMF, diagnosed in stages of no or only scant fiber increase, for the development of myelofibrosis. The influence of histopathological (megakaryocytes, initial fiber content), clinical (age, gender, splenomegaly, chemotherapy) and hematological (Hb, leukocyte- and platelet count) parameters on the development of myelofibrosis was evaluated by using the univariate Log Rank method and the multivariate recursive partition and amalgamation (RECPAM) analysis. Surveying a mean observation period of 47 months we found a development of significant myelofibrosis in 30 of the 70 patients. In the univariate analysis, the development of myelofibrosis was associated with increased megakaryocytes, initial fiber content and age of the patient. In the RECPAM analysis, the patients with a high megakaryocytic count and older age showed the highest risk of developing myelofibrosis (mean 58.3 and 60.1 months). The group with the best prognosis comprised the patients under 60 years which have a low content of megakaryocytes (mean 137 months). We found that the development of myelofibrosis in CIMF was best predicted by an increase of megakaryocytes within the bone marrow, possibly reflecting the release of growth factors by these cells. The next important risk factor was the age of the patients.     

芦可替尼治疗骨髓纤维化患者的疗效及其预测模型

目的 探讨芦可替尼治疗骨髓纤维化的疗效及其预测指标.方法 选取2017年11月至2020年12月在复旦大学附属中山医院血液科诊治的采用芦可替尼治疗的64例骨髓纤维化患者为研究对象,以治疗12周时脾脏体积较基线缩小≥35％为终点事件.采用LASSO回归筛选芦可替尼治疗骨髓纤维化的疗效预测指标,二分类Logistic回归建...     

Integrating clinical,morphological, and molecular data to assess prognosis in patients with primary myelofibrosis at diagnosis: A practical approach

Currently available prognostic scoring systems in primary myelofibrosis (PMF) do not integrate clinical, histological, and molecular data, or they also required information on “other” mutations that are available in the clinical practice only in a very limited number of laboratories. In the present multicenter study, including 401 PMF patients, an integrated International Prognostic Scoring System (I‐IPSS) was developed by combining IPSS, grade of bone marrow fibrosis (GBMF), and driver mutations molecular status (MS) to define PMF prognosis at diagnosis. Four prognostic categories were identified: I‐IPSS–low risk (113 patients), I‐IPSS–intermediate‐1 risk (56 patients), I‐IPSS–intermediate‐2 risk (154 patients), and I‐IPSS–high risk (78 patients). Median overall survival was 26.7 years in I‐IPSS–intermediate‐1, 10.8 in I‐IPSS–intermediate‐2, and 6.4 in I‐IPSS‐high‐risk patients (log‐rank test <0.0001); instead, it was not reached in the I‐IPSS–low‐risk cohort because of the extremely low number of registered deaths. The addition of GBMF and MS to IPSS improved the efficacy for predicting the risk of death. Indeed, the sensitivity of I‐IPSS was significantly higher (P < .05) than that of IPSS, considering both total deaths and 5‐ and 10‐year mortality. This comprehensive approach allows clinicians to evaluate mutual interactions between IPSS, GBMF, and MS and identify high‐risk patients with poor prognosis who may benefit from aggressive treatments. More importantly, this integrated score can be easily applicable worldwide as it only required information that represent the good clinical practice in the management of PMF patients.     

The clinical dilemma of JAK inhibitor failure in myelofibrosis: Predictive characteristics and outcomes

Two Janus-associated kinase inhibitors (JAKi) (initially ruxolitinib and, more recently, fedratinib) have been approved as treatment options for patients who have intermediate-risk and high-risk myelofibrosis (MF), with pivotal trials demonstrating improvements in spleen volume, disease symptoms, and quality of life. At the same time, however, clinical trial experiences with JAKi agents in MF have demonstrated a high frequency of discontinuations because of adverse events or progressive disease. In addition, overall survival benefits and clinical and molecular predictors of response have not been established in this population, for which the disease burden is high and treatment options are limited. Consistently poor outcomes have been documented after JAKi discontinuation, with survival durations after ruxolitinib ranging from 11 to 16 months across several studies. To address such a high unmet therapeutic need, various non-JAKi agents are being actively explored (in combination with ruxolitinib in first-line or salvage settings and/or as monotherapy in JAKi-pretreated patients) in phase 3 clinical trials, including pelabresib (a bromodomain and extraterminal domain inhibitor), navitoclax (a B-cell lymphoma 2/B-cell lymphoma 2-xL inhibitor), parsaclisib (a phosphoinositide 3-kinase inhibitor), navtemadlin (formerly KRT-232; a murine double-minute chromosome 2 inhibitor), and imetelstat (a telomerase inhibitor). The breadth of data expected from these trials will provide insight into the ability of non-JAKi treatments to modify the natural history of MF.     

Cytogenetic studies in patients with myelofibrosis and myeloid metaplasia

Serial cytogenetic studies were performed in 20 documented cases of myelofibrosis with myeloid metaplasia. Of those cases studied at the time of initial diagnosis, 64% were aneuploid while the overall incidence of aneuploidy was 75%. In six patients in this series, the disease terminated in leukemia; two of these patients had normal karyotypes, one had a normal karyotype initially and developed aneuploidy nearly three years later, and three had varying degrees of aneuploidy. Of the 14 cases who showed no evidence of leukemia, only three had completely normal karyotypes. These studies demonstrate that extensive chromosomal abnormalities of a complex and non-specific nature are common in myelofibrosis. The cytogenetic data reflect the relationship which exists between leukemia and the various myeloproliferative disorders, and also indicates a myelofibrosis should in fact be considered as an expression of another, underlying myeloproliferative disorder rather than as a separate disease. A change in karyotype may herald the appearance of a malignant clone and subsequent development of leukemia.     

Dynamics of fibrosis in chronic idiopathic (primary) myelofibrosis during therapy: a follow-up study on 309 patients

Controversial issues in chronic idiopathic myelofibrosis (IMF) are amongst others the evolution of the disease process and the influence of therapy on the dynamics of fibrosis. For this reason, a multicenter observational study was performed on 309 patients with IMF that had a long follow-up including 822 bone marrow biopsies at a median interval of 32 months. In addition to a control group (156 patients) with symptomatic treatment, monotherapy consisted of busulfan (30 patients), hydroxyurea (52 patients), interferon (26 patients) and various combinations (48 patients). Density and quality (reticulin/collagen) of fibers was determined by a semiquantitative scoring system. Independent of therapeutic regimens at the time of the last bone marrow biopsy 67% of the patients with grades 0-2 fibrosis revealed a progression, 42% stable state and 6% regression of myelofibrosis. Because of significant differences concerning frequencies of biopsies and endpoints of examinations, individual changes in the grades of fibrosis were evaluated with regard to treatment applied at standardized intervals of 20 months. According to this calculation no relevant differences in the dynamics of myelofibrosis (progression, stable state) was detectable in the control group compared to the other therapeutic modalities. The few patients with a regression of myelofibrosis usually presented with severe hypoplasia compatible with a myelo-ablative effect by aggressive chemotherapy. In conclusion, persuasive evidence has been produced that myelofibrosis in IMF is characterized by a stepwise progression and that this process is not significantly influenced by current treatment strategies.     

Evaluating the serial use of the Myelofibrosis Symptom Assessment Form for measuring symptomatic improvement: performance in 87 myelofibrosis patients on a JAK1 and JAK2 inhibitor (INCB018424) clinical trial

BACKGROUND:

Symptomatic burden from constitutional symptoms, anemia, and splenomegaly‐related symptoms are common and morbidity inducing in patients with myelofibrosis (MF). The authors previously developed a MF‐specific instrument for capturing the burden of MF‐associated disease‐related symptoms, the Myelofibrosis Symptom Assessment Form.

METHODS:

The authors evaluated the usefulness of serial administration of the Myelofibrosis Symptom Assessment Form as an instrument for the assessment of symptomatic burden and improvement in conjunction with the therapeutic clinical trial of the open label phase 2 trial of the JAK1 and JAK2 inhibitor INCB018424 in patients with MF.

RESULTS:

The analysis cohort of 87 patients treated in this trial demonstrated that the instrument was comprehensive and sensitive to symptoms present at trial enrollment. In addition, baseline Myelofibrosis Symptom Assessment Form symptom scores correlated well with objective parameters such as splenomegaly and impaired performance status assessed by the 6‐minute walk test. Serial administration while on therapy with INCB018424 demonstrated the instrument to be sensitive to symptomatic change, and that improvements in symptoms correlated well with objective improvements in both weight loss and performance status (6‐minute walk test).

CONCLUSIONS:

The use of the Myelofibrosis Symptom Assessment Form in this phase 2 trial helped characterize the symptomatic improvements observed with use of INCB018424 in MF patients. In an era of many targeted therapies undergoing testing for MF with potential symptomatic benefit, the Myelofibrosis Symptom Assessment Form may provide a useful tool for objective symptomatic assessment and potentially allow some nonrandomized comparison between therapeutic agents. Cancer 2011;. © 2011 American Cancer Society.     

Acute panmyelosis with myelofibrosis: clinical, immunophenotypic and cytogenetic study of twelve cases

The clinical, cytogenetic, and immunophenotypic features in 12 adult patients with acute panmyelosis with myelofibrosis (APMF; ICD-0-3: 9931/3; C42.1) are reported (median age: 57 years; f/m = 1.4). The white cell count (WBC) was normal in 3 patients; 9 had leucopenia. The median hemoglobin value was 64.5 g/l, and median platelet count 12 x 10(9)/l. Bone marrow biopsy showed a hypercellular marrow in 10/12 patients with a significant infiltration of pathological blasts (range: 30 - 60%). All the cases had marked reticulin fibrosis. Immunophenotyping of bone marrow blast cells showed the expression of early (CD34) and lineage-unspecified antigens (HLA-DR) in 6/7, and 7/7 patients, respectively. "Early" myeloid antigens (CD13, CD33) were seen in 6/7 and 4/6 patients respectively. Monocyte antigen (CD14) was expressed in 3/7 patients. Megakaryocyte antigen (CD61) and erythroid cell antigen (GpA) were each expressed in only 1 patient. Two patients had expression of CD34, HLA-DR and "early" myeloid antigens by their bone marrow blast cells and 1 of these also had a co-expression of the antigens from a differentiated monocytic cell proliferation (lysozyme+, CD68+). Nonspecific chromosomal aberrations were recorded in 8/10 patients. The median survival was 2 months. These findings suggest an immature myeloid phenotype of blast cells in APMF. In 6/9 patients a leukemic cell differentiation into monocytic, megakaryocytic or erythroid lineage was also demonstrated.     

Relationship between cytokine levels and clinical classification of gastric cancer

Complex symptoms often make it difficult to choose optimized strategies suitable for gastric patients. Therefore, molecular markers are needed to assist doctor' s diagnoses. In this study, to determine if the mRNA levels of Th1 and Th2 cytokines in peripheral blood mononuclear cells (PBMC) of patients with gastric cancer were correlated with their various stages, gastric patients, patients with benign gastric disease, and heathy people were recruited for detection of cytokine mRNA levels. Only the relative levels in comparison with levels of each patient's own α-actin were subjected to further statistical analyses. We found that there were significantly more positive detection of IL-4, IL-6, IL-10 mRNA expression in stage III and IV than those in patients with gastic cancer in stage I and II. It was also found that IL-4, IL-6, IL-10 mRNA expression in patients with low-level differentiations possessed significantly higher positive detection ratios than patients with moderate or high-level differentiation. These results suggest that positive detection of IL-4, IL-6 and IL-10 mRNA may be useful as a molecular marker approach for distinguishing the stage II and III of gastric cancer, as well as low-level and moderate cancer differentiation.     

Running in the family: MALT lymphoma and autoimmune disease in mother and daughter

Gastric B-cell lymphoma of the mucosa associated lym-phoid tissue(MALT) lymphoma is one of the most com-mon forms of extranodal lymphoma.In addition to in-fection with Helicobacter pylori(H.pylori),the presence of an underlying autoimmune disease has also been associated with MALT lymphoma development.To date,no familial predisposition for MALT lymphomas has been reported as opposed to other types of lymphoma.A 65-year-old woman was admitted at our institution in 1998 with a diagnosis of H.pylori positive gastric MALT lymphoma and the presence of chronic autoim-mune thyroiditis was established on further work-up.H.pylori eradication did not result in regression of the lymphoma and RT-PCR showed the presence of the t(11;18)(q21;q21) translocation.About 1.5 years after H.pylori eradication,chemotherapy with cladribine resulted in complete remission.Due to lymphoma re-currence 13 mo later,radiotherapy to the stomach(46 Gy) resulted in minimal residual disease without further progression.The patient developed a second malig-nancy(Epstein-Bar virus-associated anaplastic large cell lymphoma in the mediastinum) in 2004 which initially responded to two courses of chemotherapy,but she re-fused further therapy and died of progressive lympho-ma in 2006.In 2008,her 55 years old daughter with a long standing Sj gren’s syndrome was diagnosed with MALT lymphoma of the right parotid,but no evidence of gastric involvement or H.pylori infection was found.Currently,she is alive without therapy and undergoing regular check-ups.To our knowledge,this is the first report of MALT lymphoma in a f irst-degree relative of a patient with gastric MALT lymphoma in the context of two autoimmune diseases without a clearly established familial background.     

MALT lymphoma in patients with autoimmune diseases: a comparative analysis of characteristics and clinical course.

MALT lymphoma, especially of extragastric origin, is thought to be associated with an underlying autoimmune disease (AD) in a significant proportion of patients. No systematic assessment of the clinical characteristics of MALT lymphoma arising in AD as opposed to patients without AD has been performed so far. Therefore, all patients diagnosed and treated for MALT lymphoma at our institution have prospectively undergone routine clinical and serological assessment for AD since 1997. In total, 158 patients were available for analysis, and 61 out of 158 patients (39%) were diagnosed with an underlying AD. Patients with AD were predominantly women and significantly younger at lymphoma diagnosis (56 versus 67 years, P=0.004), with a significantly higher rate of extragastric lymphomas (P=0.012). Furthermore, lymphomas in these patients showed a lower frequency of trisomy 3 (P=0.04) and a significantly lower response rate to Helicobacter pylori eradication therapy in the case of gastric lymphomas (P=0.03). All other parameters including estimated median time to relapse were comparable between both groups. Our data suggest that patients with AD develop MALT lymphoma significantly earlier in life. The clinical course, however, does not appear to be adversely influenced by the presence of AD, as neither rate of relapse nor times to relapse or survival are significantly different.     

Identifying and addressing unmet clinical needs in Ph-neg classical myeloproliferative neoplasms: A consensus-based SIE,SIES, GITMO position paper

This article presents the results of group discussion among experts from SIE, SIES and GITMO societies aimed at highlighting unmet challenges in the management of Ph-neg myeloproliferative neoplasms (MPNs). The issues analyzed were: diagnosis of prefibrotic myelofibrosis; diagnosis of Ph-neg MPNs in the setting of splanchnic vein thrombosis (SVT); management of low-risk PV and low-risk ET patients with JAK2V617F mutation; molecular biomarkers in the prognostic evaluation of myelofibrosis (MF); ruxolitinib therapy in low-risk MF; therapy in patients with SVT-associated Ph-neg MPN; indications of splenectomy in MF. For each of these issues, proposals for advancement in clinical research were addressed.     

骨髓纤维化的发病机制及临床表现

骨髓纤维化是骨髓增殖性肿瘤的一种,预后差,生存期短。最近的研究对其发病的分子机制、临床表现及并发症都有进展,对此种疾病的临床诊断、治疗及预后评估都有帮助。本文对以上内容的研究进展进行综述。     

Negligible clinical effects of thalidomide in patients with myelofibrosis with myeloid metaplasia

We conducted a nonrandomized prospective phase II study of thalidomide in anemic patients with myelofibrosis with myeloid metaplasia (MMM), with or without preceding polycythemia vera or essential thrombocythemia, with a primary aim to improve anemia. Thalidomide was given in escalating doses with a target dose of 800 mg daily, but the median dose of thalidomide that was actually tolerated was 400 mg daily. Fifteen patients were entered into the study and 14 were evaluable for response. Five of 14 (36%) patients discontinued thalidomide before 3 mo because of side effects, and none of these five patients had a response at the time when thalidomide was stopped. When evaluated after 3 mo of therapy, none of the remaining nine patients exhibited a discernible clinical response. Three patients showed progressive disease defined as >50% increase in the need for red cell transfusions. Treatment was poorly tolerated, with all patients reporting side effects of thalidomide, the most prominent being fatigue documented in 80% of patients. Two patients died while on study, one from acute myelogenous leukemia and one from pneumonia. We conclude that thalidomide given in doses employed in the treatment of multiple myeloma gives no clinically relevant hematological effects in advanced MMM and is hampered by a very high incidence of side effects.