Improving clinical trials in higher-risk myelodysplastic syndromes

Patients with higher-risk myelodysplastic syndromes (HR-MDS) have poor survival and are in need of more effective therapy options. Hypomethylating agents (HMAs) are the current standard of care and are being studied in combination with a number of novel therapies. Recent evidence, however, has delivered sub-optimal results, prompting the need to revisit patient selection criteria, treatment schedules, and clinical endpoints to better inform future studies and steer endpoints towards those that are clinically meaningful to patients.     

Granulocytic sarcoma: three unusual patients

This report describes three unusual patients with lesions due to myeloblasts. In one instance, the patient presented with massive adenopathy. The second patient had bone lesions and a pathologic fracture. The third patient, with myelodysplasia, had diffuse skin lesions infiltrated with myeloblasts. These cases fit the diagnostic category of granulocytic sarcoma. Granulocytic sarcoma is a tumor of immature myeloid cells that may involve any site in the body but that most commonly affects the skin, soft tissues, lymph nodes, bone, and periosteum. Lesions can predate leukemia or occur late in an established chronic granulocytic leukemia or acute granulocytic leukemia. The most common presentation occurs late in the course of acute granulocytic leukemia or in chronic granulocytic leukemia as a herald to blastic transformation. Therapy for localized lesions is radiotherapy, which produces prompt shrinkage of the lesions but relapse occurs subsequently. Systemic chemotherapy also produces satisfactory clinical results. In all instances, therapy can only be considered palliative since virtually all patients have a short survival following the appearance of an extramedullary myeloblastic lesion. Recognition of this pathologic entity at an early stage may give us information on the best management for these patients.     

Ras activation in myelodysplastic syndromes: clinical and molecular study of the chronic phase of the disease

We studied N-ras and Ki-ras point mutations respectively at codons 12-13 and 12 in 15 patients with myelodysplastic syndromes (MDS) using the polymerase chain reaction (PCR) method for DNA amplification, and slot blot hybridization to allele specific oligonucleotide (ASO) probes. We analysed peripheral blood and bone marrow samples collected at diagnosis and repeatedly during the chronic phase of the disease to define when the activation occurred and in which haemopoietic cell populations, in order to establish possible relationships between clinical and molecular features. In three cases the N-ras oncogene was mutated at codon 12 in every cell population, both at diagnosis and throughout the chronic phase. Point mutations were not seen at the 12 codon of the Ki-ras oncogene. In patients lacking activated ras oncogene at diagnosis, mutations were not discovered during the entire period of observation. Therefore in our cases disease progression and leukaemic transformation did not correlate with the presence of the activated N-ras. Our data suggest that ras activation occurs early in the pathogenesis of MDS and involves a haemopoietic progenitor with multiple differentiative capacity, without however conferring an apparent proliferative advantage on its progeny.     

Granulocytic sarcoma presenting as a thrombosed external hemorrhoid in a patient with myelodysplastic syndrome overt leukemia

A 67-year-old Japanese man complained of a painful lump in his anus. He had a 15-month history of myelodysplastic syndrome (MDS) and had been diagnosed with MDS overt leukemia. A solid lump measuring 1.0 cm in diameter was detected in the anal verge. Under a diagnosis of a thrombosed external hemorrhoid, thrombectomy was performed under local anesthesia. One week after thrombectomy, the wound had not healed, and grayish-green tissue was seen at the bottom. A biopsy of the wound revealed atypical mononuclear cell infiltration. Myeloperoxidase and lysozyme were positive on immunohistochemical staining. Finally, the diagnosis of granulocytic sarcoma (GS) was made. Though it is well known that perianal complications occur quite often in patients with leukemia, it is unusual for a diagnosis of GS of the anus to be definitely established. To our knowledge, there has not been a previous report of GS presenting as a thrombosed external hemorrhoid. The development of GS should be considered during the management of such lesions, especially in patients with bone marrow disorders, such as acute myeloid leukemia (AML) or high-risk MDS.     

Minimal residual disease in acute myelogenous leukaemia and myelodysplastic syndromes: a follow-up of patients in clinical remission

The majority of patients with acute myelogenous leukaemia (AML) and myelodysplastic syndromes (MDS) relapse, especially those with unfavourable cytogenetics.
This study was designed to investigate the presence and frequency of minimal residual disease (MRD) in patients with AML or MDS ( n  = 35) and numerical abnormalities of chromosomes 6, 7, 8, 9, 10, 17 and 18 in clinical remission by using a combination of fluorescence activated cell sorting (FACS), fluorescence in-situ hybridization (FISH) and labelling with bromodeoxyuridine (BUdR). The technique enables the detection of as few as three leukaemic cells in 10⁵ normal cells.
MRD was detected in 33/35 patients in complete remission (CR). 16 patients relapsed (8/11 with monosomy 7, 4/17 with trisomy 8, and 4/7 with other cytogenetic abnormalities) after a median of 4.8 months (range 3–13). Levels of MRD ( P  = 0.007) and proliferation index ( P  = 0.011) were significantly higher in patients with monosomy 7 than in patients with trisomy 8 or other cytogenetic abnormalities. The percentage of cells in S-phase, the number of abnormal cells and cytogenetic class were related to time to relapse ( P  = 0.001) with S-phase being the single most important prognostic factor ( P  = 0.0001).
We conclude that the combination of FACS/FISH/BUdR, which determines the number, phenotype and proliferation rate of very rare leukaemic cells in patients with AML or MDS in clinical remission, provides information that is useful in the identification of patients with high and low likelihood of relapse.     

Granulocytic sarcoma of the colon

Granulocytic sarcoma is an extramedullary tumor consisting of immature cells of the granulocytic series known to occur in patients with myelodysplastic syndrome, chronic myelogenous leukemia, or acute myelogenous leukemia. This tumor may involve nodes, cervix, bone and periosteum, and infrequently the small intestine. Granulocytic sarcoma rarely occurs in the colon and has not been previously described endoscopically. We encountered a 73-year-old man with myelodysplastic syndrome who presented with fever, diarrhea, and abdominal pain. Colonoscopic evaluation (focal ulceration, friability, and nodularity) was compatible with Crohn's disease, although histology showed a dense myeloid cell infiltrate characteristic of granulocytic sarcoma. In patients with myelodysplastic syndrome or acute or chronic myelogenous leukemia presenting with diarrhea, abdominal pain, and/or fever, colonoscopy and biopsy are indicated to determine if the colon is affected by granulocytic sarcoma.     

Granulocytic sarcoma developing in lymph nodes

A 77-year-old man was admitted to a hospital because of a left cervical tumor. He was initially diagnosed as having non-Hodgkin lymphoma, diffuse large cell type, Ann Arbor stage IV, and transferred to our hospital for chemotherapy. Flow cytometric analysis of the left axillary lymph node cells derived from a biopsy specimen showed that in addition to lymphoid surface markers (CD5, 7, 21), myeloid surface markers (CD11b, 33, 34) were also positive. The diagnosis of malignant lymphoma was therefore confirmed. The patient, was treated with THP-COP therapy, which proved very effective. Thereafter, a biopsy specimen was found to be positive for MT1 (CD43) staining but negative for myeloperoxidase and chloroacetate esterase staining on immunohistochemistry. Furthermore, no rearrangement of the IgH JH, TCR C beta 1 or TCR J gamma gene was detected by Southern blot analysis. On basis of these findings and the previous results of flow cytometry, we changed the diagnosis from malignant lymphoma to granulocytic sarcoma. THP-COP therapy was continued, and complete remission was achieved. Two months later, however, the patient developed acute myelocytic leukemia (AML M1) and received DCP therapy, but he died of pneumonia.     

Platelet function and its clinical significance in the myelodysplastic syndromes

The current study was aimed at investigating platelet function in MDS and its clinical significance. There were 23 patients with untreated MDS at presentation, including refractory anemia (RA), RA with ringed sideroblasts, RA and excess blasts and chronic myelomonocytic leukemia RAEBt. The mean platelet count was 167.9 x 109/L. Patients with a platelet count less than 70 x 109/l were excluded. The mean bleeding time (BT) was 2.7 min. Only four MDS patients had BT longer than the normal 1-4 min range. Platelet aggregation (PA) was studied with epinephrine (Epi), ADP, arachidonic acid (AA), ristocetin and collagen. Overall, 16 (70%) patients had PA abnormality, 65% had impaired Epi-induced PA, 57% demonstrated reduced ADP-induced PA. AA, ristocetin and collagen was decreased PA in 48, 22 and 17%, respectively. Five patients (22%) demonstrated spontaneous PA. Only seven patients (30%) were found to have normal PA with all five inducers. Six (26%) patients had spontaneous mild bleeding and all six bleeding MDS patients demonstrated at least one abnormal platelet function. The only bleeding patient with all five PA tests normal demonstrated prolonged BT. In the present study of 23 newly diagnosed MDS patients, PA abnormalities were relatively common, the BTs were usually normal, and bleedings were relatively uncommon and mild at platelet count between 70 and 397 x 109/l.     

骨髓增生异常综合征免疫表型分析

目的：探讨免疫表型测定在骨髓增生异常综合征（MDS）诊断及分型中的价值。方法：采用一组系列相关单克隆抗体和流式细胞术对19例MDS患者免疫表型进行检测，并对其中的10例进行了细胞遗传学检查。结果：MDS患者骨髓单个核细胞（MNC）CD13，CD33抗原表达率平均分别为36．69％和41．86％，而T淋巴系抗原CD3的表达平均仅为14．49％，且随着低危的难治性贫血（RA）向高危的难治笥贫血伴原始细胞增多（RAEB）或难治性贫血伴原始细胞增多－转变型（RAEB-t)的进展，较早期的髓系抗原CD13，CD33及干（祖）细胞抗原CD34的表达升高，并伴有T淋巴系抗原CD3的表达降低。10例进行了细胞遗传学检查的患者中，5例有染色体核型异常，染色体核型异常的患者与染色体核型正常的患者在抗原表达上存在区别。结论：对MDS患者进行免疫表型检查有助于MDS的诊断分型研究。     

Immunomodulation in myelodysplastic syndromes

The myelodysplastic syndromes (MDS) - bone-marrow stem-cell malignancies that share pathogenetic overlap with acute myeloid leukemia - are characterized by peripheral-blood cytopenias and, in more advanced subtypes, varied degrees of maturation arrest. Premature apoptosis of bone-marrow cellular elements contributes to ineffective hematopoiesis, which is exacerbated by stromal production of inflammatory cytokines. Abrogation of the effects of these cytokines represents an area of active clinical research, particularly in the treatment of low-risk MDS. Agents such as thalidomide, lenalidomide, and infliximab have shown promising efficacy and tolerability in clinical trials, and may represent a springboard for future treatment combinations.     

Infections in myelodysplastic syndromes

Myelodysplastic syndromes are associated with a risk of severe infections. While neutropenia is likely to be the main predisposing factor, several other immune defects have been reported, including impaired neutrophil function, B-, T- and NK-cell defects and the possible consequences of iron overload due to red blood cell transfusions. The advanced age of most patients, their frequent comorbidities, and the fact that drugs such as hypomethylating agents and lenalidomide, which are effective in myelodysplastic syndromes but can transiently worsen neutropenia, may increase the risk of infection and their severity in this context. The majority of infections in myelodysplastic syndromes are bacterial, while the incidence of fungal infections is not well known and viral infections seem to be rare. No prophylactic measures against infections have demonstrated efficacy in myelodysplastic syndromes. However, pending more data, we propose here some recommendations for the management of patients with myelodysplastic syndromes. In the future, an important contribution can be made by prospective trials testing the efficacy of prophylactic and therapeutic approaches to infection in these patients, especially in the context of the new drugs available for myelodysplastic syndromes.Key words: myelodysplastic syndromes, infection, bacterial, prophylaxis, therapy