Case report of isochromosome 17q in acute myeloid leukemia with myelodysplasia-related changes after treatment with a hypomethylating agent

Isochromosome 17q is a relatively common karyotypic abnormality in medulloblastoma, gastric, bladder, and breast cancers. In myeloid disorders, it is observed during disease progression and evolution to acute myeloid leukemia in Philadelphia-positive chronic myeloid leukemia. It has been reported in rare cases of myelodysplastic syndrome, with an incidence of 0.4-1.57%. Two new agents have been approved for treatment of myelodysplastic syndrome/chronic myelomonocytic leukemia. These are the hypomethylating agents, 5-azacytidine and decitabine, recommended by consensus guidelines for high-risk myelodysplastic syndrome patients not eligible for hematopoietic stem cell transplantation. We present a case of chronic myelomonocytic leukemia with normal cytogenetics at diagnosis treated with decitabine (with good response); however, the patient evolved to acute myeloid leukemia with i(17q) shortly after suspending treatment. To the best of our knowledge, this is the first report of acute myeloid leukemia with myelodysplasia-related changes with i(17q) after the use of a hypomethylating agent.     

异基因造血干细胞移植治疗耳道复发的急性早幼粒细胞白血病一例并文献复习

目的:探讨急性早幼粒细胞白血病(APL)髓外复发的相关因素及治疗。方法:对1例APL缓解后耳道复发患者的临床资料进行回顾性分析,并复习相关文献。结果:患者2015年8月诊断为APL(低危型),经诱导后达完全缓解,随后进行巩固、维持治疗,并多次行腰椎穿刺术及椎管内注射化疗药物预防中枢神经系统白血病。2017年3月发现左外耳道新生物,活检确诊外耳道髓系肉瘤,示髓外复发。随后出现骨髓复发。经诱导巩固化疗后行异基因造血干细胞移植,存活至今。结论:对于髓外复发的急性早幼粒细胞白血病,其预后较差,异基因造血干细胞移植治疗有较好疗效。     

Monosomy 7 in donor cell-derived leukemia after bone marrow transplantation for severe aplastic anemia: Report of a new case and review of the literature

Monosomy 7 arises as a recurrent chromosome aberration in donor cell leukemia after hematopoietic stem cell transplantation. We report a new case of donor cell leukemia with monosomy 7 following HLA-identical allogenic bone marrow transplantation for severe aplastic anemia (SAA). The male patient received a bone marrow graft from his sister, and monosomy 7 was detected only in the XX donor cells, 34 months after transplantation. The patient’s bone marrow microenvironment may have played a role in the leukemic transformation of the donor hematopoietic cells.     

Extramedullary Relapse of the AML Transformed from MDS Following Auto-HSCT: A Case Report

The treatment for AML (Acute myeloid/myelogenous leukemia) transformed from MDS (myelodysplastic syndrome) is difficult and controversial clinically, especially in elder patients. In this case report, we diagnosed a 59-year-old female patient with AML-M2a transformed form MDS which might be caused by her chemotherapy for mastocarcinoma. After achieving complete remission (CR) through combined chemotherapy, autologous peripheral blood stem cell transplantation (auto-PBSCT) was attempted. Following auto-HSCT, marrow showed continuous CR but the patient later developed extramedullary bone-infiltration relapse. Then local radiotherapy has been applied, and the patient now has prolonged survival. This is the first (or a successful) case report of auto-HSCT in an elderly patient with AML transformed from MDS.     

Biphenotypic acute leukemia: a case report

We describe an uncommon case of acute leukemia in which leukemic blasts expressed myeloid antigens and cyCD79alpha molecule. In this 49-year old male patient, two distinct blast populations were detected in peripheral blood and bone marrow samples: one of small size resembling lymphoblasts and another with pink cytoplasmic granules resembling myeloblasts. Cytochemical reaction for myeloperoxidase was negative in both cell types. Conventional cytogenetic analysis showed a normal karyotype (46 XY) in all metaphases studied, while gene rearrangement analysis by seminested PCR of the immunoglobulin heavy chain (Ig-H) and T-cell-gamma chain (TCR-gamma) receptor, showed a germline configuration of the TCR and clonal rearrangement of Ig-H chain genes. Multicolour cytofluorimetric analysis showed that bone marrow and peripheral blood blasts expressed CD19, CD79alpha bright, CD22 and terminal deoxynucleotidyl transferase (TdT) as lymphoid markers, CD13, CD117, CD15 as myeloid markers, CD34, HLA-DR as stem cell markers. CD33 myeloid antigen was expressed by 50% of the blastic population. No differences in the immunophenotypic profile were detected in the two blast populations which were identified by morphology. According to EGIL (European Group of Immunological Classification of Leukemias) and WHO (World Health Organization) criteria, a diagnosis of biphenotypic acute leukemia (BAL) was made. The patient was treated with AML induction therapy followed by autologous stem cell transplantation, but relapse free survival was 6 months. The patient died a few weeks later due to unresponsiveness to salvage chemotherapy regimens. We conclude that patients with BAL should have a risk stratification with treatment tailored to their immunophenotype and gene rearrangement profiles.     

Diagnosis of unexpected acute myeloid leukemia and chronic lymphocytic leukemia: a case report demonstrating the perils of restricted panels in flow cytometric immunophenotyping

We report on the flow cytometric identification of concomitant acute myeloid leukemia and chronic lymphocytic leukemia in cytology specimens submitted with minimal clinical information. A 64-year-old man presented with fever and progressive dyspnea on exertion. Chest X-ray and computed tomography scan showed a left upper lobe pulmonary mass. Pulmonary capillary pullback specimens were collected to determine infectious verses neoplastic etiology. The pulmonary capillary pullback specimens showed atypical mononuclear cells with enlarged, slightly irregular nuclei; visible nucleoli; and basophilic cytoplasm. Flow cytometric analysis of the specimen for lymphoma was requested. Flow cytometric immunophenotypic studies showed that 78% of the cells were CD34 positive, CD45 dim positive and CD11c positive, consistent with acute myeloid leukemia. About 0. 75% of the cells expressed CD5 as well as dim CD20 and were monoclonal for kappa light chains: consistent with chronic lymphocytic leukemia/small lymphocytic lymphoma. At this time the clinician communicated a history of myelodysplastic syndrome of refractory anemia subtype. Peripheral blood was obtained for further immunophenotyping and the patient was immediately treated for his acute myeloid leukemia. This case demonstrates that a diagnostic antibody panel should allow evaluation of all cell types as per the U.S./Canadian consensus recommendations on the immunophenotypic analysis of hematologic neoplasia by flow cytometry (Stewart et al.: Cytometry 30:231-235, 1997). Published 2000 Wiley-Liss, Inc.     

Risks of leukemia in Japanese atomic bomb survivors, in women treated for cervical cancer, and in patients treated for ankylosing spondylitis.

The dose-response relationship for radiation-induced leukemia was examined in a pooled analysis of three exposed populations: Japanese atomic bomb survivors, women treated for cervical cancer, and patients irradiated for ankylosing spondylitis. A total of 383 leukemias were observed among 283,139 study subjects. Considering all leukemias apart from chronic lymphocytic leukemia, the optimal relative risk model had a dose response with a purely quadratic term representing induction and an exponential term consistent with cell sterilization at high doses; the addition of a linear induction term did not improve the fit of the model. The relative risk decreased with increasing time since exposure and increasing attained age, and there were significant (P < 0.00001) differences in the parameters of the model between datasets. These differences were related in part to the significant differences (P = 0.003) between the models fitted to the three main radiogenic leukemia subtypes (acute myeloid leukemia, acute lymphocytic leukemia, chronic myeloid leukemia). When the three datasets were considered together but the analysis was repeated separately for the three leukemia subtypes, for each subtype the optimal model included quadratic and exponential terms in dose. For acute myeloid leukemia and chronic myeloid leukemia, there were reductions of relative risk with increasing time after exposure, whereas for acute lymphocytic leukemia the relative risk decreased with increasing attained age. For each leukemia subtype considered separately, there was no indication of a difference between the studies in the relative risk and its distribution as a function of dose, age and time (P > 0.10 for all three subtypes). The nonsignificant indications of differences between the three datasets when leukemia subtypes were considered separately may be explained by random variation, although a contribution from differences in exposure dose-rate regimens, inhomogeneous dose distribution within the bone marrow, inadequate adjustment forcell sterilization effects, or errors in dosimetry could have played a role.     

Coexistence of ochronosis and B 27 positive ankylosing spondylitis

We describe a 49-year-old man with coexistence of ochronosis and B27 positive ankylosing spondylitis. This is the first report documenting the simultaneous occurrence of ochronosis and B27 positive ankylosing spondylitis, with no positive familiar history for seronegative spondylarthropathies. The relations of these rheumatic diseases are discussed.     

Prevalence of vertebral compression fractures due to osteoporosis in ankylosing spondylitis.

OBJECTIVE--To determine the prevalence of vertebral compression fractures due to osteoporosis in patients with ankylosing spondylitis. DESIGN--Prospective study of 111 consecutive patients; patients with vertebral compression fractures were entered into a case-control study. SETTING--Outpatient clinic at the centre for rheumatic diseases, Glasgow. PATIENTS--111 Consecutive patients with ankylosing spondylitis. Patients with compression fractures were matched for age and sex with two controls selected from the rest of the group. Patients with biconcave vertebral fractures were also studied. MAIN OUTCOME MEASURES--Assessments of spinal deformity and mobility and analysis of lateral radiographs of spines for presence of syndesmophytes. RESULTS--Fifteen patients with compression fractures and five with biconcave fractures were studied. Compared with the controls the patients with compression fractures had increased formation of syndesmophytes in the lumbar spine, whereas those with biconcave fractures had increased formation throughout the spine. Patients with compression fractures also had a greater degree of spinal deformity (distance from wall to tragus 24.5 cm v 12.7 cm in controls), less spinal mobility (20 v 45.6 degrees of flexion), and reduced chest expansion (2 cm v 3cm). CONCLUSION--Vertebral compression fractures due to osteoporosis are a common but frequently unrecognised complication of ankylosing spondylitis and may contribute to the pathogenesis of spinal deformity and back pain.     

Stem cell transplantation in pediatric leukemia and myelodysplasia: state of the art and current challenges

The role of stem cell transplantation in the treatment of leukemia and myelodysplasia (MDS) in children has changed over the past decade. In pediatric acute lymphoblastic leukemia (ALL), the overall cure-rate is high with conventional chemotherapy. However, selected patients with a high-risk of relapse are often treated with allogeneic hematopoietic stem cell transplantation (allo-HSCT) in first remission (CR1). Patients with a bone-marrow relapse who attain a second remission frequently receive HSCT. High minimal residual disease (MRD) levels directly prior to HSCT determines the relapse risk. Therefore, MRD positive patients are eligible for more experimental approaches such as intensified or experimental chemotherapy pre-HSCT, as well as immune modulation post-HSCT. In pediatric acute myeloid leukemia (AML) the role of allo-HSCT in CR1 is declining, due to better outcome with modern multi-agent chemotherapy. In relapsed AML patients, allo-HSCT still seems indispensable. Targeted therapy may change the role of HSCT, in particular in chronic myeloid leukemia, where the role of allografting is changing in the imatinib era. In MDS, patients are usually transplanted immediately without prior cytoreduction. New developments in HSCT, such as the role of alternative conditioning regimens, and innovative stem cell sources such as peripheral blood and cord blood, will also be addressed.     

Myeloid sarcoma and adenocarcinoma of the large bowel as collision tumors: a case report

Myeloid sarcoma is a rare tumor composed of myeloid cells, localized in an extramedullary site, which may be associated with a concurrent myeloid neoplasm involving the bone marrow, although such an association is not required. Most patients present with acute myeloid leukemia and their prognosis is poor. We describe the case of a 76-year old woman with an adenocarcinoma of the right colon infiltrating the subserosa synchronous with a myeloid sarcoma at the same site; one pericolic lymph node was infiltrated by both tumors. The peculiarities of this case are the clinical presentation (as an acute abdomen due to subserosa infiltration by the myeloid sarcoma), the coexistence of a myeloid sarcoma with an adenocarcinoma of the right colon, and the absence of progression to acute leukemia. Coexistence of myeloid sarcoma and adenocarcinoma in the colon is probably incidental, and so it appears likely that the two different tumours arose from different mechanisms. However, a possible common background is conceivable. Some authors have found that p53 has a pivotal role in driving the maturation of myeloid stem cells and p53 is, also, involved in colon carcinogenesis. In our case, it may be hypothesized that synchronous heterogeneous mutations occurred in different types of committed cells or in stem cells secondary to p53 loss. Since only one case report has evaluated the correlation between myeloid sarcoma and adenocarcinoma of the large bowel, further immunohistochemical and molecular studies are needed to clarify the pathogenetic relationship between them.     

A case of pulmonary aspergillosis with lack of response to caspofungin

Currently, susceptibility testing of Aspergillus isolates towards caspofungin is hampered by a lack of interpretative cut-off values. Nevertheless, caspofungin has been widely recommended for the treatment of invasive aspergillosis. This antifungal, however, could lead to therapy failure as demonstrated by the case in this report of a 55-year-old patient, who eight months after the diagnosis of leukemia and successful allogenic hematopoietic stem cell transplantation (HSCT), succumbed to a fatal pulmonary aspergillosis infection, which resisted treatment with caspofungin.     

Acute myelogenous leukemia relapsing as granulocytic sarcoma of the cervix. A case report

BACKGROUND: Granulocytic sarcoma of the uterine cervix is an unusual manifestation of acute myeloid leukemia, representing soft tissue masses of leukemic myeloblasts. An often misdiagnosed entity, it is often confused with other inflammatory or neoplastic conditions, including large cell lymphoma. CASE: A 67-year-old female presented with acute myelogenous leukemia and a normal karyotype. After eight years in complete remission, abdominal pain and an ulcerated mass in the uterine cervix developed, with a normal peripheral blood smear. Vaginal cytology examination revealed myeloid blasts, which, on subsequent cervical biopsy, stained positive for leukocyte common antigen, Kp-1 (CD68), antimyeloperoxidase, lysozyme and chloroacetate esterase, confirming the cytologic diagnosis. K-ras was not mutated at codon 12 or 13. Chemotherapy induced a complete remission, followed nine months later by central nervous system and then systemic relapse. The patient died 13 months after being diagnosed with granulocytic sarcoma of the cervix. CONCLUSION: This case illustrates the value of vaginal cytology and histologic biopsy evaluation in patients with acute myelogenous leukemia, including those without evidence of systemic disease. The characteristic cytologic features of granulocytic sarcoma led to the correct diagnosis. Histologic biopsy evaluation, including immunohistochemistry for myeloid markers, proved of value in confirming the diagnosis.     

Atypical Diabetes Mellitus Associated with Bone Marrow Transplantation

ObjectiveTo describe 3 cases of atypical diabetes mellitus following bone marrow transplantation.MethodsWe describe the clinical presentation and relevant laboratory findings of 3 patients who presented with new-onset diabetes mellitus after bone marrow transplantation and discuss the possible mechanisms.ResultsA 52-year-old white man with chronic myelogenous leukemia, a 51-year-old white woman with acute myelogenous leukemia, and a 38-year-old Hispanic woman with acute myelogenous leukemia presented with acute onset of diabetes mellitus after bone marrow transplantation. Although blood glucose levels were initially very high, the patients required only small insulin dosages for glycemic control. Both the acute onset and requirement of relatively small insulin dosages were characteristic of type 1 diabetes mellitus. Onset of diabetes appeared to be unrelated to immunosuppressive drug therapy because it happened several months after starting these drugs. C-peptide was detectable, and glutamic acid decarboxylase antibodies were absent. Diabetes mellitus remitted spontaneously after a few months while the immunosuppressive drugs were continued.ConclusionAlthough the underlying mechanisms are unknown, cytokine changes after bone marrow transplantation may have led to temporary b-cell dysfunction in these patients. (Endocr Pract. 2010;16:93-96)     

Might axial myofascial properties and biomechanical mechanisms be relevant to ankylosing spondylitis and axial spondyloarthritis?

Ankylosing spondylitis and axial spondyloarthropathy have characteristic age- and sex-specific onset patterns, typical entheseal lesions, and marked heritability, but the integrative mechanisms causing the pathophysiological and structural alterations remain largely undefined. Myofascial tissues are integrated in the body into webs and networks which permit transmission of passive and active tensional forces that provide stabilizing support and help to control movements. Axial myofascial hypertonicity was hypothesized as a potential excessive polymorphic trait which could contribute to chronic biomechanical overloading and exaggerated stresses at entheseal sites. Such a mechanism may help to integrate many of the characteristic host, pathological, and structural features of ankylosing spondylitis and axial spondyloarthritis. Biomechanical stress and strain were recently documented to correlate with peripheral entheseal inflammation and new bone formation in a murine model of spondyloarthritis. Ankylosing spondylitis has traditionally been classified by the modified New York criteria, which require the presence of definite radiographic sacroiliac joint lesions. New classification criteria for axial spondyloarthritis now include patients who do not fulfill the modified New York criteria. The male-to-female sex ratios clearly differed between the two patient categories - 2:1 or 3:1 in ankylosing spondylitis and 1:1 in non-radiographic axial spondyloarthritis - and this suggests a spectral concept of disease and, among females, milder structural alterations. Magnetic resonance imaging of active and chronic lesions in ankylosing spondylitis and axial spondyloarthritis reveals complex patterns, usually interpreted as inflammatory reactions, but shows similarities to acute degenerative disc disease, which attributed to edema formation following mechanical stresses and micro-damage. A basic question is whether mechanically induced microinjury and immunologically mediated inflammatory mechanisms operate in both ankylosing spondylitis and degenerative disc disease but differ in relative degrees. The hypothesized biomechanical properties raised in this commentary require documentation of their association with the onset risk and course of ankylosing spondylitis and axial spondyloarthritis. If particular subsets of ankylosing spondylitis and axial spondyloarthritis patients are confirmed to have altered axial myofascial properties, their biological basis and underlying biomechanical mechanisms promise to become clarified. Understanding how biomechanical and physical properties can affect symptomatic and structural manifestations of these disorders could also improve their management.     

Natural killer cell mediated missing-self recognition can protect mice from primary chronic myeloid leukemia in vivo

Background

Natural Killer (NK) cells are thought to protect from residual leukemic cells in patients receiving stem cell transplantation. However, multiple retrospective analyses of patient data have yielded conflicting conclusions regarding a putative role of NK cells and the essential NK cell recognition events mediating a protective effect against leukemia. Further, a NK cell mediated protective effect against primary leukemia in vivo has not been shown directly.

Methodology/Principal Findings

Here we addressed whether NK cells have the potential to control chronic myeloid leukemia (CML) arising based on the transplantation of BCR-ABL1 oncogene expressing primary bone marrow precursor cells into lethally irradiated recipient mice. These analyses identified missing-self recognition as the only NK cell-mediated recognition strategy, which is able to significantly protect from the development of CML disease in vivo.

Conclusion

Our data provide a proof of principle that NK cells can control primary leukemic cells in vivo. Since the presence of NK cells reduced the abundance of leukemia propagating cancer stem cells, the data raise the possibility that NK cell recognition has the potential to cure CML, which may be difficult using small molecule BCR-ABL1 inhibitors. Finally, our findings validate approaches to treat leukemia using antibody-based blockade of self-specific inhibitory MHC class I receptors.     

Risk of adult acute and chronic myeloid leukemia with cigarette smoking and cessation

BackgroundCigarette smoking is an established risk factor for adult myeloid leukemia, particularly acute myeloid leukemia (AML), but less is known about the nature of this association and effects of smoking cessation on risk.MethodsIn a large population-based case–control study of myeloid leukemia that included 414 AML and 185 chronic myeloid leukemia (CML) cases and 692 controls ages 20–79 years, we evaluated risk associated with cigarette smoking and smoking cessation using unconditional logistic regression methods and cubic spline modeling.ResultsAML and CML risk increased with increasing cigarette smoking intensity in men and women. A monotonic decrease in AML risk was observed with increasing time since quitting, whereas for CML, the risk reduction was more gradual. For both AML and CML, among long-term quitters (≥30 years), risk was comparable to non-smokers.ConclusionsOur study confirms the increased risk of myeloid leukemia with cigarette smoking and provides encouraging evidence of risk attenuation following cessation.     

Increased PRAME-Specific CTL Killing of Acute Myeloid Leukemia Cells by Either a Novel Histone Deacetylase Inhibitor Chidamide Alone or Combined Treatment with Decitabine

As one of the best known cancer testis antigens, PRAME is overexpressed exclusively in germ line tissues such as the testis as well as in a variety of solid and hematological malignant cells including acute myeloid leukemia. Therefore, PRAME has been recognized as a promising target for both active and adoptive anti-leukemia immunotherapy. However, in most patients with PRAME-expressing acute myeloid leukemia, PRAME antigen-specific CD8⁺ CTL response are either undetectable or too weak to exert immune surveillance presumably due to the inadequate PRAME antigen expression and PRAME-specific antigen presentation by leukemia cells. In this study, we observed remarkably increased PRAME mRNA expression in human acute myeloid leukemia cell lines and primary acute myeloid leukemia cells after treatment with a novel subtype-selective histone deacetylase inhibitor chidamide in vitro. PRAME expression was further enhanced in acute myeloid leukemia cell lines after combined treatment with chidamide and DNA demethylating agent decitabine. Pre-treatment of an HLA-A0201⁺ acute myeloid leukemia cell line THP-1 with chidamide and/or decitabine increased sensitivity to purified CTLs that recognize PRAME^100–108 or PRAME^300–309 peptide presented by HLA-A0201. Chidamide-induced epigenetic upregulation of CD86 also contributed to increased cytotoxicity of PRAME antigen-specific CTLs. Our data thus provide a new line of evidence that epigenetic upregulation of cancer testis antigens by a subtype-selective HDAC inhibitor or in combination with hypomethylating agent increases CTL cytotoxicity and may represent a new opportunity in future design of treatment strategy targeting specifically PRAME-expressing acute myeloid leukemia.     

缓解与未缓解髓系白血病干细胞表面抗原CD34~+CD123~+表达差异研究

目的:探索缓解与未缓解急性髓系白血病干细胞表面抗原表达差异,为判定化疗疗效及其预后提供依据。方法:按照急性白血病诊断标准,根据患者入院时骨髓白血病细胞数量多少分成临床缓解与未缓解两组,以流式细胞仪分别检测骨髓中白血病干细胞表面相关抗原表达情况,比较二者之间差异。其中经标准化疗方案治疗结束后,通过复查骨髓象判定疗效并比较化疗前后白血病干细胞表面相关抗原表达变化。结果:与缓解的急性髓系白血病患者骨髓白血病干细胞相关抗原表达值相比,未缓解的患者骨髓白血病干细胞表面相关抗原表达明显升高,差异具有统计学意义(P0.05,0.001);未缓解的患者经标准方案化疗后骨髓虽然已经获得完全缓解,但依然具有白血病干细胞表面抗原高表达,提示这部分患者依然有复发的可能性。结论:急性髓系白血病患者的白血病干细胞相关抗原表达值升高是急性白血病复发难治的根源之一。     

Chronic myelogenous leukemia following radiation therapy for testicular seminoma

A 43-year-old man was treated with orchiectomy and radiotherapy for testicular seminoma. Four years later, he developed a typical Philadelphia chromosome positive chronic granulocytic leukemia. Since the patient was not eligible for bone marrow transplantation, he was treated with busulfan. Long term follow-up of patients who received radiotherapy for testicular seminoma is warranted in order to detect possible secondary tumors.