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acute lymphocytic leukemia [keywords]
- Effects of Rapid Donor T-lymphocyte Engraftment on Disease Control and Graft versus Host Disease in Persons Undergoing Reduced-Intensity Conditioning Allotransplantation for Advanced CLL. [JOURNAL ARTICLE]
- Exp Hematol 2013 May 17.
Eradication of minimal residual disease (MRD) after allotransplantation in persons with chronic lymphocytic leukemia (CLL) is associated with lower rates of relapse. Rapid engraftment of donor lymphocyte elements may contribute to MRD control but it remains unclear if this strategy will benefit patients. Here we report incidence of MRD eradication and graft versus host disease (GvHD) in persons with rapid versus later donor T-lymphocyte engraftment after lymphodepleting chemotherapy and reduced intensity conditioning (RIC) allotransplantation. Twenty-seven subjects received lymphodepleting chemotherapy to facilitate donor engraftment followed by fludarabine and cyclophosphamide RIC and a blood cell allograft. MRD was monitored by multicolor flow cytometry post transplantation. Complete donor T-lymphoid (TLC) and myeloid (MC) chimerism were achieved in 25 subjects at a median of 28 days (range 14-60 days) and 21 days (range 14-180 days). Achieving complete donor TLC by day 14 versus day ≥28 correlated with occurrence of ≥grade-2 acute GvHD (90% [95% confidence interval (CI), 78-100%] versus 35% [95% CI, 16-54%], P=0.014) and better control of minimal residual disease in the bone marrow at day 100, median 0% (range, 0-0.1%) versus 8.5% (range, 0-92%; P=0.016). Among 11 persons with early donor TLC none had progressive disease (PD) and 7 died of treatment related mortality (TRM). In persons with later development of TLC 8 of 16 had PD and 2 died of TRM. Time to donor myeloid chimerism had no impact on outcomes. Rapid establishment of donor TLC results in more complete eradication of early MRD but greater incidence of acute GvHD and TRM in persons with CLL undergoing RIC allotransplantation.
- Squamous cell lung carcinoma presenting with erythema annulare centrifugum. [Journal Article]
- Acta Dermatovenerol Croat 2013 May; 21(1):52-8.
Erythema annulare centrifugum (EAC) is a permanent or migrating eruption characterized by annular, arcuate, or polycyclic erythematous lesions that expand to the periphery when the medial parts fade. Darier was the first to described it in 1916 (1,2). Defining the incidence and prevalence of EAC is difficult because the literature mostly consists of case reports and brief reviews. Although its etiology is not known for certain, it is assumed to be hypersensitivity reaction to malignancies, infections, and drugs. However, there have not been any underlying factors detected in the majority of cases. The prognosis for EAC is excellent, except when associated with an underlying malignancy and other systemic disease (1-3). A diagnosis of EAC should be followed by diagnostic work-up because it may result in discovery of an underlying disease. We describe a 52-year-old man affected by EAC, who upon further examination was diagnosed with squamous cell carcinoma of the lung (SCCL). A 52-year-old male patient was admitted to our department with itchy, erythematous, annular, polycyclic plaques, with a trailing scale present on the inner aspect of the advancing edges (Figs. 1 and 2). The plaques had been present on his trunk, extremities, and face for more than 3 months. The patient reported that the itchy lesions had first appeared on his forearms, then spread to his trunk, lower extremities, and face in a few weeks. Skin punch biopsy revealed orthokeratotic, parakeratotic hyperkeratosis observed occasionally on the epidermis, and mild vascular proliferation and perivascular mononuclear cell infiltration on the papillary dermis. The deep dermis, subcutis, and epidermal appendages were normal. The patient was diagnosed as EAC based on histopathologic and clinical findings. There was no history of antecedent infections or recent initiation of a new drug. Routine blood count and other chemistry tests produced normal results. Chest x-ray showed changes in the paracardiac areas of the middle and lower zones of the left lung, nodular opacities with peripheral reticulolinear extensions, and tubular radiolucent areas compatible with bronchiectasis in this region (Fig. 3). Thoracic computed tomography scan revealed a thick-walled, cavitary lesion, 4.5 cm in diameter, centrally located in the suprahilar region of the upper lobe of the left lung, observed to have a subsidiary of the upper lobe bronchus, micronodules and branching linear opacities on the parenchyma, intra-interlobular irregular septal thickening, and tractional bronchiectasis with pleuroparenchymal density increments in peripheral areas (Fig. 4). In consultation with pulmonologist, the patient was diagnosed with lung cancer; laboratory findings: CA 15-3, 32.7 U/mL (reference range: 0-31.3); CEA 7.75 ng/mL (reference range: 0-3); and erythrocyte sedimentation rate 21 mm/h (reference range: 0-15). The patient was hospitalized for treatment at department of pulmonary disease. Tumorous cells were observed on histopathologic examination of the lung biopsy obtained during bronchoscopy, which stained positive for P63 and negative for CYT7-20, CEA, TTF1, and MUC31. Clinical and histopathologic findings, and in consultation with a pulmonologist, indicated SCCL presented with superficial EAC. The patient was referred to thoracic surgery department for surgical treatment. Erythema annulare centrifugum is among diseases of unknown etiology (4). Erythema giratum repens and EAC are figure erythemas associated with malignancy (5). A review of medical literature reveals that malignancies related to EAC are squamous cell carcinoma, nasopharyngeal carcinoma, acute myelocytic leukemia, peritoneal carcinomatosis, primary bronchial carcinoid, Hodgkin's lymphoma, chronic lymphocytic leukemia, multiple myeloma, prostate carcinoma, malignant histiocytosis, mucinous ovarian carcinoma, and breast cancer (3,4,6-9). Monsieur et al. report on EAC, pulmonary osteoarthropathy, palmoplantar hyperkeratosis, inappropriate secretion of antidiuretic hormone, ectopic secretion of adrenocorticotropic hormone and calcitonin in poorly differentiated lung adenocarcinoma (10). Some other publications also report on a random relationship of EAC and malignancy (4). One study of 66 cases identified cutaneous fungal infection as the most important etiologic factor (72%), while other causes included benign internal neoplasm (13%), skin diseases (18%) and internal diseases (21%) (11). A study involving 73 EAC patients revealed neoplasia in 7% of deep type EAC cases (12). Squamous cell carcinoma of the lung accounts for 25%-30% of all lung cancers. Most lung carcinomas are diagnosed at an advanced stage, conferring a poor prognosis. The need to diagnose lung cancer at an early and potentially curable stage is thus obvious. Approximately 7%-10% of patients with lung cancer are asymptomatic, and their cancers are diagnosed incidentally after a chest radiograph performed for other reasons. Paraneoplastic syndromes may be the first or most prominent manifestation. Most paraneoplastic syndromes are caused by small cell lung cancer (SCLC). However, many paraneoplastic syndromes also occur in non-small cell lung cancer (NSCLC) patients. The symptoms may be endocrine, neuromuscular, musculoskeletal, cardiovascular, cutaneous, hematologic, gastrointestinal, renal, or miscellaneous in nature. Cutaneous itching is the most frequent cutaneous manifestation in patients with cancer. Herpes zoster, ichthyosis, flushes, alopecia, acanthosis nigricans, dermic melanosis, or hypertrichosis may also be observed. When a patient is diagnosed as a "typical" paraneoplastic syndrome, a diagnosis of cancer should be considered and investigated (13). Although our patient did not have any symptoms of lung carcinoma, etiologic study of EAC revealed early stages of SCCL. To our knowledge, this is the first case of EAC presented with SCCL. Etiology oriented research performed in EAC patients will help in early diagnosis and treatment of malignancies. This report is presented to emphasize the importance of etiologic research of EAC and EAC association with SCCL.
- Acute Lymphocytic Leukemia Presented as Back Pain and Revealed by Bone Scintigraphy. [JOURNAL ARTICLE]
- Clin Nucl Med 2013 May 1.
A previously healthy 8-year-old girl underwent MDP bone scintigraphy to evaluate possible spondylolysis due to worsening back pain. Unexpectedly, the bone scan images revealed intense activity in several thoracic and lumbar vertebrae, which was not consistent with spondylolysis. Further examinations proved that the patient had acute lymphocytic leukemia.
- Efficacy of adoptive immunotherapy with donor lymphocyte infusion in relapsed lymphoid malignancies. [Journal Article]
- Immunotherapy 2013 May; 5(5):457-66.
Aims:There is a perceived benefit associated with the administration of donor lymphocyte infusion (DLI) in patients with lymphoid malignancies relapsing after allogeneic hematopoietic cell transplantation. However, it is unclear if and how this benefit varies according to specific diseases. Because administration of DLI is not universally effective and could be associated with significant toxicities resulting in morbidity and mortality, it is imperative to identify cases where benefits outweigh harms of the procedure. Materials & methods: We conducted a systematic review of the published literature and extracted and pooled data independently for each disease cohort: acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL), multiple myeloma (MM), non-Hodgkin's lymphoma (NHL) and Hodgkin's lymphoma (HL).
Results:In summary, 39 studies met inclusion criteria. The pooled proportion (95% CI) for complete response was 27% (16-40) in ALL, 55% (15-92) in CLL, 26% (19-33) in MM, 52% (33-71) in NHL and 37% (20-56) in HL.
Conclusion:Complete response rates appear higher when DLI is used for relapsed CLL and lymphomas (NHL and HL), and less pronounced in ALL or MM. Absence of data pertaining to disease-specific prognostic determinants, such as adverse genetic or molecular abnormalities, or quantitative disease burden when applicable, limit our ability to identify cases in whom benefits from DLI outweigh risks associated with the procedure within a particular disease.
- Changes in megakaryocytes in cases of thrombocytopenia: bone marrow aspiration and biopsy analysis. [Journal Article]
- J Clin Diagn Res 2013 Mar; 7(3):473-9.
Background:Thrombocytopenia (platelet counts less than 150,000/μl) is commonly encountered in various hematological disorders including myelodysplastic syndromes as well as various non-myelodysplastic hematological conditions.
Aim:The present study was undertaken to calculate the prevalence of various conditions associated with thrombocytopenia and to record the megakaryocytic alterations in various cases of thrombocytopenia. Apart from this by means of statistical analysis it was tried to analyze whether a significant difference existed in megakaryocytic alteration noted in myelodysplastic versus non- myelodysplastic conditions. Materials and
Methods:A prospective series of 60 bone marrow aspirations along with concomitant bone marrow biopsies was conducted in a tertiary care centre catering to both urban as well as rural population in north India. Statistical Analysis: The distribution of morphological changes in cases of non myelodysplastic conditions and myelodysplastic were compared using Chi-Square test. A p-value less than 0.05 was considered significant.
Results:The commonest cause of thrombocytopenia for which bone marrow examination was sought was dimorphic anaemia (18 cases, 30%), followed by myelodysplastic syndrome (06 cases, 10%) which was followed equally by acute lymphocytic leukemia and blast crisis of chronic myeloid leukemia (CML). Of all the non-MDS conditions apart from dimorphic anaemia, idiopathic thrombocytopenic purpura and chronic myeloid leukemia (blast crisis); megakaryocytic dysplastic forms were not noted in any other condition. In cases of myelodysplasia; dysplastic forms, bare megakaryocytic nuclei, hypogranular forms and micromegakaryocytes were seen. Comparison between frequencies of normal, high and low number of nuclear lobes among MDS (n=9) and non MDS (n=68) conditions were found to be statistically significant.
Conclusion:Further studies on the evaluation of megakaryocytic alteration and their contribution to thrombocytopenia can provide growing knowledge to the pathogenesis of numerous hematopoietic disorders that may identify broader clinical applications of the newer strategies to regulate platelet count and functioning.
- Results of inotuzumab ozogamicin, a CD22 monoclonal antibody, in refractory and relapsed acute lymphocytic leukemia. [JOURNAL ARTICLE]
- Cancer 2013 Apr 30.
BACKGROUND:CD22 expression occurs in >90% of patients with acute lymphocytic leukemia (ALL). Inotuzumab ozogamicin, a CD22 monoclonal antibody bound to calicheamicin, is active in ALL.
METHODS:Patients with refractory-relapsed ALL received treatment with inotuzumab. The first 49 patients received single-dose, intravenous inotuzumab at doses of 1.3 to 1.8 mg/m2 every 3 to 4 weeks. In the next 41 patients, the schedule was modified to inotuzumab weekly at a dose of 0.8 mg/m2 on day 1 and at a dose of 0.5 mg/m2 on days 8 and 15, every 3 to 4 weeks, based on higher in vitro efficacy with more frequent exposure.
RESULTS:Ninety patients were treated; 68% were in salvage 2 or beyond. Overall, 17 patients (19%) achieved a complete response (CR), 27 (30%) had a CR with no platelet recovery (CRp), and 8 (9%) had a bone marrow CR (no recovery of counts), for an overall response rate of 58%. Response rates were similar for single-dose and weekly dose inotuzumab (57% vs 59%, respectively). The median survival was 6.2 months overall, 5.0 months with the single-dose schedule, and 7.3 months with the weekly dose schedule. The median survival was 9.2 months for patients in salvage 1 (37% at 1 year), 4.3 months for patients in salvage 2, and 6.6 months for patients in salvage 3 or later. The median remission duration was 7 months. Reversible bilirubin elevation, fever, and hypotension were observed less frequently on the weekly dose. In total, 36 of 90 patients (40%) underwent allogeneic stem cell transplantation. Veno-occlusive disease was noted in 6 of 36 patients after stem cell transplantation (17%), was less frequent after the weekly schedule (7%), and with less alkylators in the preparative regimen.
CONCLUSIONS:Inotuzumab single-agent therapy was highly active, safe, and convenient in patients with refractory-relapsed ALL. A weekly dose schedule appeared to be equally effective and less toxic than a single-dose schedule. Cancer 2013;. © 2013 American Cancer Society.
- Phase II study of CD4+guided pentostatin lymphodepletion and pharmacokinetically-targeted busulfan as conditioning for hematopoietic cell allografting. [JOURNAL ARTICLE]
- Biol Blood Marrow Transplant 2013 Apr 27.
One limitation of reduced intensity preparative regimens is potential for graft failure. We developed a regimen that targets CD4(+) lymphodepletion to ensure early and durable engraftment. Primary endpoint was achievement of ≥50% CD3(+) donor chimerism by day +28. Forty-two patients, median age 53 (29-73) years, received pentostatin 4 mg/m(2) IV on days -28, -21, and -14 if CD4(+) was >100 cells/μL; and on days -4 and -3 regardless of the CD4(+) levels. Rituximab 375 mg/m(2) was administered to CD20(+) malignancies on days -21, -14, -7, +1, and +8. Busulfan IV 200 mg/m(2) was administered on day -4 and on day -2 at a dose to target a cumulative AUC dose of 16,000 (±10%) micromol*min/L. Graft-versus-host disease prophylaxis consisted of tacrolimus plus methotrexate in 86% of cases. Donors were matched-related (47%), matched unrelated (43%) or mismatched unrelated donors (10%). Chronic lymphocytic leukemia and follicular non-Hodgkin lymphoma were the most common diagnoses, representing 45% and 14%, respectively. Disease status at initiation of the preparative regimen was: CR=22%, PR=55%, and stable/progression=24%. Median CD4(+) percentage decrease from baseline (day -28) to days -21, -14, -7, and 0 were 52%, 66%, 62%, and 91%, respectively. At day +28, all 42 (100%) patients had ≥ 50% CD3(+) donor chimerism. None experienced graft failure. Overall response rate was 82% (CR=67%). Cumulative incidence of grade II-IV acute GVHD by day +100 was 59% (grade III-IV=19%). Chronic GVHD at 2 years was 69% (moderate/severe=58%). Non-relapse mortality at 100-days was 2% and at 2-years 17%. Two-year PFS was 55% and OS was 68%. This regimen ensures durable engraftment, is effective against persistent disease, and results in relatively low mortality from causes other than relapse.
- [Effects of eEF1A1 Re-expreesion on Proliferation and Apoptosis of Jurkat Cells with Knocked Down eEF1A1 Gene and Its Mechanisms]. [English Abstract, Journal Article]
- Zhongguo Shi Yan Xue Ye Xue Za Zhi 2013 Mar; 21(2):279-84.
This study was aimed to explore the effects of expressing eukaryotic elongation factor 1A1 (eEF1A1) on proliferation and apoptosis in human acute T lymphocytic leukemia (T-ALL) cell line Jurkat with knocked down eEF1A1 gene and its mechanisms. eEF1A1-expressing lentivirus (LV) was constructed and used to transfect the Jurkat cells with knocked down eEF1A1 gene. Then, the expressions of eEF1A1 mRNA and protein were detected by real time PCR(RT-PCR) and Western blot respectively.Cell proliferation, apoptosis and cycle were detected by MTT method, Annexin V-APC labeling and DNA ploidy analysis respectively. The related protein expressions of phosphatidylinositol-3-kinase (PI3K)/serine/threonine kinase (Akt) signaling pathway were detected by Western blot. The results indicated that eEF1A1 mRNA and protein expressions of Jurkat cells with knocked down eEF1A1 gene were re-established by constructing eEF1A1-expression LV. Compared with negative control group (transfected with negative control LV and eEF1A1-shRNA LV), cell proliferation in eEF1A1 expression group was significantly enhanced, cell apoptosis was remarkably inhibited, percentage of cells in G0/G1 phase was significantly reduced alone with increased percentage of cells in S and G2/M phase, and the expression levels of p-Akt (Ser 473), nuclear factor kappa B (NF-κB), p-NF-κB (Ser 468), mammalian target of rapamycin (mTOR) and p-mTOR (Ser 2448) protein significantly increased. It is concluded that eEF1A1 may have a carcinogenic effect in T-ALL cells. eEF1A1 expression has noticeable effects on the proliferation enchancement and apoptosis inhibition of Jurkat cells, which may be mediated by the up-regulation of PI3K/Akt/NF-κB and PI3K/Akt/ mTOR signaling pathway.
- Low-dose cytarabine and aclarubicin combined with granulocyte colony-stimulating factor for the treatment of relapsed or primary refractory acute lymphocytic leukemia: a retrospective study of 25 Chinese patients. [JOURNAL ARTICLE]
- Hematol Oncol 2013 Apr 25.
Despite improvements in treatment, the prognosis of relapsed or primary refractory acute lymphocytic leukemia (ALL) remains poor, and outcomes are worse in older adults with the short first complete remission (CR). Attainment of the second CR by salvage therapy would improve the survival of these patients and may enable them to undergo curative treatment with allogeneic hematopoietic stem cell transplantation. The fact that there are diverse salvage protocols for these adult patients but without a striking CR-induction efficacy indicates that efforts are still needed to indentify new effective reinduction regimens. In this study, the CAG regimen (cytarabine, 10 mg/m(2) subcutaneously every 12 h on days 1-14; aclarubicin, 5-7 mg/m(2) intravenously daily on days 1-8; and concurrent granulocyte colony-stimulating factor, 200 µg/m(2) /day subcutaneously) was administered to 25 patients with relapsed or refractory ALL, including 11 T-cell ALL (T-ALL) and 14 B-cell (B-ALL) patients (age range, 11-61 years; median age, 26 years), to assess its efficacy as a salvage therapy. One course of the CAG regimen resulted in an overall response [CR or partial remission (PR)] rate of 64%, a CR rate of 56% and generally mild adverse effects. An overall response was observed in all 11 T-ALL patients (10 CR and 1 PR) and 35.7% of B-ALL patients (p = 0.0009). The significant treatment potential of CAG regimen for relapsed or primary refractory ALL, especially for T-ALL patients, described in this report would prepare them for a second CR to pursue longer survival. Copyright © 2013 John Wiley & Sons, Ltd.
- [The immunophenotypic and clinical characteristics of NPM1 mutated acute myeloid leukemia patients]. [English Abstract, Journal Article]
- Zhonghua Xue Ye Xue Za Zhi 2013 Feb; 34(2):98-103.
To compare the immunophenotypic and clinical characteristics between NPM1 mutated acute myeloid leukemia (AML) (NPM1m(+)AML) and unmutated AML(NPM1m(-)AML) not otherwise characterized (NOS) under similar FAB subtypes constituent ratio.Immunophenotyping and NPM1 gene mutation type-A, B and D and other leukemic related fusion genes were detected by multiparamter flow cytometry and real time RT-PCR or PCR, respectively. 104 AML patients with NPM1m(+)AML and performed immunophenotyping assay were included, 97 with NPM1m(-)AML.There were significant difference between the two groups at presentation in terms of sex, white blood count(WBC), platelet counts (PLT), blast ratio, normal karyotype ratio, WT1 expression level, FLT3-ITD mutation positive rate and remission rate of first course of induction therapy (P < 0.05). On the immunophenotype, the expression of early differentiation antigens (CD34, HLA-DR, CD117, CD38), lymphocytic antigens (CD7, CD4, CD19, CD2), myeloid and monocytic differentiation-associated antigens (CD13, CD14, CD15) were lower, and that of CD33 as well as CD123 were higher in NPM1m(+)AML patients. Among them, only CD34, HLA-DR, CD7, and CD4 positive cases were significantly lower in NPM1m(+)AML group than in NPM1m(-)AML group (P < 0.05), the rest of them had significant difference in the number of positive cells (P < 0.05). Above features were further analyzed between the M1/M2 and M4/M5 subgroups. M1/M2 cases retained the women prominent and had a higher WT1 expression level (P < 0.05). The expression of monocytic differentiation-associated antigens including HLA-DR and lymphocytic antigens were higher and that of CD117 were lower in M4/M5 subtype (P < 0.05). Among them, the positive rates of HLA-DR, CD64, CD11b, CD10, CD15, and CD4 were significantly higher in M4/M5 than in M1/M2 in NPM1m(+)AML group (P < 0.05).The most clinical characteristics in NPM1m(+)AML patients are consistent with reports, but some immunophenotype are different to the previous reports under similar FAB subtypes constituent ratio. The major immunophenotypic features of NPM1m(+)AML patients are lower expression of progenitor, myeloid and lymphoid lineage antigens. Monocytic differentiation-associated antigens are only higher expression in M4/M5 cases when comparison with M1/M2 cases within NPM1m(+)AML group.