A critical role for phosphatase haplodeficiency in the selective suppression of deletion 5q MDS by lenalidomide

Lenalidomide is the first karyotype-selective therapeutic approved for the treatment of myelodysplastic syndromes (MDS) owing to high rates of erythroid and cytogenetic response in patients with chromosome 5q deletion [del(5q)]. Although haploinsufficiency for the RPS14 gene and others encoded within the common deleted region (CDR) have been implicated in the pathogenesis of the del(5q) phenotype, the molecular basis of the karyotype specificity of lenalidomide remains unexplained. We focused our analysis on possible haplodeficient enzymatic targets encoded within the CDR that play key roles in cell-cycle regulation. We show that the dual specificity phosphatases, Cdc25C and PP2Acα, which are coregulators of the G₂-M checkpoint, are inhibited by lenalidomide. Gene expression was lower in MDS and acute myeloid leukemia (AML) specimens with del(5q) compared with those with alternate karyotypes. Lenalidomide inhibited phosphatase activity either directly (Cdc25C) or indirectly (PP2A) with corresponding retention of inhibitory phospho-tyrosine residues. Treatment of del(5q) AML cells with lenalidomide induced G₂ arrest and apoptosis, whereas there was no effect in nondel(5q) AML cells. Small interfering RNA (shRNA) suppression of Cdc25C and PP2Acα gene expression recapitulated del(5q) susceptibility to lenalidomide with induction of G₂ arrest and apoptosis in both U937 and primary nondel(5q) MDS cells. These data establish a role for allelic haplodeficiency of the lenalidomide inhibitable Cdc25C and PP2Acα phosphatases in the selective drug sensitivity of del(5q) MDS.     

Myelodysplastic syndrome with isolated deletion of chromosome 20q: an indolent disease with minimal morphological dysplasia and frequent thrombocytopenic presentation

The present study analysed the clinicopathological features of nine myelodysplastic syndrome (MDS) patients in which del(20q) was the sole cytogenetic abnormality and a control group of 17 adult patients with idiopathic thrombocytopenic purpura (ITP). Seven of nine del(20q) patients were thrombocytopenic and six of nine were mildly anaemic at presentation. There was no significant morphological dysplasia identified in the del(20q) group as compared with the ITP group. These results indicate that MDS with del(20q) commonly presents with thrombocytopenia and has minimal morphological dysplasia. Cytogenetic analysis on adult patients undergoing bone marrow sampling for thrombocytopenia may help avoid misdiagnosis of MDS with del(20q) as ITP.     

Cause of death and excess mortality in patients with lower-risk myelodysplastic syndromes (MDS): A report from the European MDS registry

Information on causes of death (CoDs) and the impact of myelodysplastic syndromes (MDS) on survival in patients with lower-risk MDS (LR-MDS) is limited. A better understanding of the relationship between disease characteristics, clinical interventions and CoDs may improve outcomes of patients with LR-MDS. We prospectively collected data on patients with LR-MDS in the European MDS registry from 2008 to 2019. Clinical, laboratory and CoDs data were obtained. To examine MDS-specific survival, relative survival (RS) was estimated using national life tables. Of 2396 evaluated subjects, 900 died (median overall survival [OS]: 4.7 years; median follow-up: 3.5 years). The most common CoDs were acute myeloid leukaemia/MDS (20.1%), infection (17.8%) and cardiovascular disease (CVD; 9.8%). Patients with isolated del(5q) and with red cell transfusion needed during the disease course, had a higher risk of fatal CVD. The 5-year OS was 47.3% and the 5-year RS was 59.6%, indicating that most patients died due to their underlying MDS. Older patients (aged >80 years) and the lowest-risk patients were more likely to die from competing causes. This study shows that MDS and its related complications play crucial role in the outcome of patients with LR-MDS.     

骨髓增生异常综合征-难治性中性粒细胞减少1例及文献复习

目的:总结1例骨髓增生异常综合征-难治性中性粒细胞减少(MDS-RN)患者的诊疗体会.方法:对1例MDS-RN患者进行形态学、细胞化学、染色体核型分析,并用流式细胞术检测免疫表型,同时进行融合基因多重PCR扩增.结果:患者血常规示白细胞0.86×109/L,中性粒细胞绝对值0.25×109/L,红细胞3.86×1012...     

Necrobiotic xanthogranuloma with IgA multiple myeloma: a case report and literature review

The association between necrobiotic xanthogranuloma of the dermis and paraproteinemia and/or B-cell malignancy is best described in the ophthalmologic literature. We report a case which occurred in the eyelid and orbit of a 64 year old man that led to the diagnosis of an IgA multiple myeloma. To our knowledge, this is the first report of an IgA type paraproteinemia and IgA type multiple myeloma associated with necrobiotic xanthogranuloma.     

非清髓性造血干细胞移植加供者淋巴细胞输注治疗多发性骨髓瘤1例报告并文献复习

目的研究非清髓性造血干细胞移植(NST)治疗多发性骨髓瘤(MM)的疗效,观察移植相关并发症的发生.方法1例42岁MM患者,供者为其胞姐,HLA配型完全相合.动员方案粒细胞集落刺激因子(G-CSF)10 μg·kg-1·d-1×5 d.预处理方案抗胸腺细胞球蛋白(ATG)8 mg·kg-1·d-1×3 d,马法兰(MEL)120 mg/m2×1 d.移植单个核细胞数(MNC) 6.5×108/kg;CD34+细胞 4.4×106/kg.环胞菌素A(CsA)和短程甲氨蝶呤(MTX)预防移植物抗宿主病(GVHD).移植后分别于+41 d、+76 d和+112 d进行3次供者淋巴细胞输注(DLI).结果移植后15 d中性粒细胞计数> 0.5×109/L,21 d血小板计数>50×109/L,24 d性染色体和微卫星法DNA指纹图监测显示为混合嵌合体,随着DLI的进行,逐渐转为供者型完全嵌合体,骨髓瘤细胞和血清M蛋白均逐渐消失,移植后8个月达完全缓解.在+180 d(第三次DLI后68 d)发生II度急性GVHD,经甲泼尼龙和CsA治疗得以控制.现随访36个月,患者情况良好,仍处于完全缓解状态.结论非清髓性造血干细胞移植加供者淋巴细胞输注治疗MM是可行和有效的.     

Haematopoietic stem cell transplantation for patients with myelo-dysplastic syndromes and secondary acute myeloid leukaemias: a report on behalf of the Chronic Leukaemia Working Party of the European Group for Blood and Marrow Transplantation (EBMT)

Allogeneic stem cell transplantation from an HLA-identical sibling donor is a curative treatment option for a young patient with myelodysplastic syndrome, limited by age and lack of sibling donors. Alternative stem cell sources have been used more recently, such as unrelated donors, non-identical family members or autologous transplants. This analysis of 1378 transplants reported to the European Group for Blood and Marrow Transplantation (EBMT) addresses the outcome of the varying procedures according to the known risk factors. The estimated disease-free survival (DFS) and estimated relapse risk at 3 years were both 36% for 885 patients transplanted with stem cells from matched siblings. In the multivariate analysis, age and stage of disease had independent prognostic significance for DFS, survival and treatment-related mortality. Patients transplanted at an early stage of disease had a significantly lower risk of relapse than patients transplanted at more advanced stages. The estimated DFS at 3 years was 25% for the 198 patients with voluntary unrelated donors, 28% for the 91 patients with alternative family donors and 33% for the 126 patients autografted in first complete remission. The non-relapse mortality was 58% for patients with unrelated donors, 66% for patients with non-identical family donors and 25% for autografted patients. The relapse rate of 18% was relatively low for patients with non-identical family donors, 41% for patients with unrelated donors and 55% for patients treated with autologous stem cell transplantation. Both allogeneic and autologous stem cell transplantation have emerged as treatment options for patients with myelodysplastic syndromes. Transplantation with an HLA-identical sibling donor is the preferred treatment option. Patients without an HLA-identical sibling donor may be treated with either autologous stem cell transplantation or an alternative donor transplantation. Patients younger than 20 years may be treated with an unrelated donor transplantation. Patients older than 40 years, and probably also patients between 20 and 40 years, may benefit most from an autologous stem cell transplantation.     

以肺动脉高压为首要表现的原发性浆细胞白血病一例报道并文献复习

目的 探讨浆细胞白血病患者肺动脉高压可能的发生机制.方法 发介绍我院收治的1例以肺动脉高压为首要表现的原发性浆细胞白血病的临床特点和实验室检查结果 ,并结合国内外文献,分析其肺动脉高压的发生机制.结果 患者男性,24岁,以胸闷、气喘伴右侧胸腔积液起病,超声心动图发现肺动脉高压(肺动脉收缩压=52 mm Hg),外周血白细胞最高达82.80×10<'9>/L,分类不明细胞占89%,伴贫血和血小板减少,血γ-球蛋白、IgG及血、尿免疫球蛋白L轻链明显升高,骨髓检查确诊为原发性浆细胞白血病,经COMEP方案化疗,随白血病病情缓解,肺动脉高压也迅速缓解.国外文献报道6例多发性骨髓瘤伴肺动脉高压,大多与自体干细胞移植和沙立度胺化疗有关.结论 经 原发性浆细胞白血病以肺动脉高压起病,国内外罕见.白细胞淤滞、高黏滞及高凝状态、纤溶活性降低均可能参与其发生机制.     

Mammalian‐target of rapamycin inhibition with temsirolimus in myelodysplastic syndromes (MDS) patients is associated with considerable toxicity: results of the temsirolimus pilot trial by the German MDS Study Group (D‐MDS)

The mammalian‐target of rapamycin (also termed mechanistic target of rapamycin, mTOR) pathway integrates various pro‐proliferative and anti‐apoptotic stimuli and is involved in regulatory T‐cell (TREG) development. As these processes contribute to the pathogenesis of myelodysplastic syndromes (MDS), we hypothesized that mTOR modulation with temsirolimus (TEM) might show activity in MDS. This prospective multicentre trial enrolled lower and higher risk MDS patients, provided that they were transfusion‐dependent/neutropenic or relapsed/refractory to 5‐azacitidine, respectively. All patients received TEM at a weekly dose of 25 mg. Of the 9 lower‐ and 11 higher‐risk patients included, only 4 (20%) reached the response assessment after 4 months of treatment and showed stable disease without haematological improvement. The remaining patients discontinued TEM prematurely due to adverse events. Median overall survival (OS) was not reached in the lower‐risk group and 296 days in the higher‐risk group. We observed a significant decline of bone marrow (BM) vascularisation (P = 0·006) but were unable to demonstrate a significant impact of TEM on the balance between TREG and pro‐inflammatory T‐helper‐cell subsets within the peripheral blood or BM. We conclude that mTOR‐modulation with TEM at a dose of 25 mg per week is accompanied by considerable toxicity and has no beneficial effects in elderly MDS patients.     

Donor cell myelodysplastic syndrome after allogeneic stem cell transplantation responding to donor lymphocyte infusion: case report and literature review

Allogeneic hematopoietic stem cell transplantation (SCT) is a potentially curative treatment for patients with myelodysplastic syndrome (MDS). Relapses after transplantation however, are not uncommon and are usually due to re-emergence of a recipient derived, neoplastic, stem cell clone. We report a unique case of MDS recurring 5 months after non-myeloablative, sibling, allogeneic SCT. Interestingly, chimerism analysis at relapse showed hematopoiesis to be entirely of donor origin confirming donor cell MDS. Donor lymphocyte infusion (DLI) produced a hematological response lasting several months. Our review of the literature shows donor-derived MDS to be very rare, with only four such cases described previously. In this report, we describe the details of our case and discuss putative mechanisms underlying the genesis of donor cell MDS and the observed response to DLI.     

Investigation of 305 patients with myelodysplastic syndromes and 20q deletion for associated cytogenetic and molecular genetic lesions and their prognostic impact

In patients with myelodysplastic syndromes (MDS), sole 20q deletion [del(20q)] is a recurrent favourable abnormality. We studied additional molecular and cytogenetic lesions and their prognostic impact in 305 MDS patients with del(20q) (229 males/76 females; 29–90 years). All patients were investigated by cytomorphology and chromosome banding analysis (CBA), subsets by fluorescence in situ hybridization, molecular mutation screening, and array comparative genomic hybridization (aCGH). By aCGH (n = 30), the minimal common deleted region (CDR) was flanked by PTPRT (20q13·11) and EYA2 (20q13·12). 210 (68·9%) patients had ‘early MDS’ without blast increase, 95 (31·1%) ‘advanced’ MDS with blast increase (5–19%). Additional chromosomal abnormalities (ACAs) were detected in 88/305 (28·9%) patients. Patients with advanced MDS more frequently had ACAs (P = 0·003) and had a higher mean number of ACAs (P = 0·020) and of molecular mutations (P = 0·060). Spliceosome mutations were frequent (U2AF1: n = 31/155; 20·0%; SRSF2: n = 31/159; 19·5%; SF3B1mut: n = 8/159; 5·0%). ASXL1mut (25/153; 16·3%) were associated with advanced MDS (P = 0·001). Presence of ≥3 ACAs (P = 0·003) and ASXL1mut (P = 0·002) were associated with worse 2‐year survival. In conclusion, the cytogenetic subgroup of MDS with del(20q) has a good prognosis but may be further subclassified by additional cytogenetic and molecular lesions. U2AF1mut is overrepresented in MDS with del(20q), and ASXL1mut is prognostically adverse.     

多发性骨髓瘤伴胸膜浸润1例

1病历资料患者女,77岁。2010年2月起反复出现胸闷、气急,无发热、咳嗽、盗汗、胸痛、心悸等不适,夜间尚可平卧。既往有"高血压"病史20余年,血压最高达180/110 mmHg(1 mmHg=0.133 kPa),平素服用降压药,血压控制良好。入院体检:神志清楚,消瘦,全身皮肤无黄染,无皮下出血点,球结膜无水肿,颈     

Effect of high-dose melphalan and peripheral blood stem cell transplantation on renal function in patients with multiple myeloma and renal insufficiency: a case report and review of the literature

 Multiple myeloma with IgG-lambda monoclonal gammopathy and severe renal impairment with light-chain deposit disease was diagnosed in a 51-year-old man. Following conventional therapy with VAD (vincristine, adriamycin, dexamethasone) a partial remission was achieved. Peripheral blood stem cells (PBSC) were then collected following mobilization with cyclophosphamide and recombinant human granulocyte colony-stimulating factor and enriched for CD34-positive cells by immunoaffinity column. Fourteen months after diagnosis high-dose melphalan was given, followed by infusion of CD34-positive PBSC. Aside from mild oral mucositis and trigonitis, high-dose therapy was tolerated well. After he underwent PBSC transplantation his renal function improved, and the patient has been in in continuous complete remission for 1 year. Thus, high-dose chemotherapy can be safely administered to patients with multiple myeloma and severe renal impairment. Our findings confirm previous reports summarized in the current presentation. Received: August 3, 1998 / Accepted: November 2, 1998