bluuebunny/crossref_metadata_2025 huggingface dataset:
Management of Chronic Myelogenous Leukemia Using Therapeutic Drug Monitoring of Imatinib: The French Experience of a Centralized Laboratory
Authors: Molimard Mathieu , Bouchet Stephane , Etienne Gabriel , Legros Laurence , Rea Delphine , Huguet Francoise , Titier Karine , Moore Nicholas , Reiffers Josy , Belanger Coralie , Mahon Francois-Xavier
Published: April 2020

Pharmacokinetic monitoring is widely used in different medical specialities, but it has been rarely applied in clinical oncology practice. The current gold standard treatment of chronic myelogenous leukemia (CML) is imatinib, a tyrosine kinase inhibitor. We have previously shown the necessity to obtain a trough plasma threshold of 1000 ng/mL for efficient treatment with imatinib. We routinely perform centralized quantification for patients in France and this has allowed the assessment of imatinib therapeutic monitoring and its use in a real-life setting.

After 16 months of data collection, we had gathered 1607 samples for 1044 CML patients (mean age 55 years, F/M sex ratio 0.67) treated with imatinib 400 mg (median) range (100–800mg). We received only one sample for 739 patients and more than one sample for 305 patients.

The mean trough plasma concentration of imatinib (Cmin) was 1043 ng/mL (median: 876 ng/mL) and 596 of the 1044 CML patients (57%) had a Cmin <1000ng/ml at first determination. Plasma concentration increased with dose, but there was a large inter-individual variability (64%) and intra-individual variability was twice as small. For plasma concentrations < 1000 ng/mL, mean dose was 420 mg and for those ≥ 1000 ng/mL, this was 510 mg.

For the 189 patients having had at least 2 correct Cmin determination, 70% had initial Cmin< 1000 ng/mL (mean concentration of 1st determination: 583 ng/mL). Among the 62 patients who initially had a Cmin below 1000 ng/mL that subsequently rose above this threshold, 63% had their imatinib dose increased; the rest did not have a dose modification. For the latter, it is probable in view of low intra-individual variability that this was due to enhanced compliance. For the 32 patients with a first Cmin <1000 and no CCyR, none of those with Cmin remaining below 1000 ng/mL achieved CCyR, wheras 5 (28%) achieved CCyR when Cmin rose above 1000 ng/mL. In cases where there was suspicion of a drug–drug interaction, the most frequently combined drugs were proton pump inhibitors (such as omeprazole), diuretics, allopurinol and NSAIDs. The most recurrent adverse effects were digestive, hematological and muscular.

Although the studied population had characteristics generally described for this pathology (age, sex ratio), there was probably selection bias at the beginning of study: we received first and foremost the patients having an insufficient response, and therefore low plasma concentration. Therapeutic drug monitoring of imatinib appears to be helpful for the management of CML patients and the resulting database allows a better understanding and use of this treatment.
Clonal Heterogeneity in TEL/AML1+ Acute Lymphoblastic Leukemia (ALL): A Clinical Appraisal
Authors: Papadhimitriou Stefanos I , Paisiou Anna , Tsagarakis Nikolaos , Papadakis Vassilios , Kentrou Nektaria , Paterakis Georgios , Parcharidou Agapi , Tsakiridou Anastasia A , Tsitsikas Konstantinos , Kostopoulos Ioannis , Pavlidis Dimitrios , Georgiakaki Maria , Polychronopoulou Sophia
Published: April 2020

Introduction: In TEL/AML1+ ALL, the formation of the fusion gene is frequently followed by clonal evolution, with the acquisition of additional aberrations, some involving the TEL and AML1 genes. The resulting variant subclones often coexist at diagnosis, but the clinical significance of this heterogeneity is unclear.

Patients and Methods: The study included a group of 28 children with ALL, found TEL/AML1+ on interphase FISH. In all cases, 500 nuclei were assessed and all signal patterns indicative of a typical t(12;21) or any deviation were recorded. The patients were treated according to the BFM-95 protocol and followed-up for 5,3 to 101,10 (median 66,40) months.

Results: In 19 cases, a single clone was found. In 12 of them (Group A), the typical pattern was obtained, while in 7 (Group B) there were additional aberrations (deletion of the non-rearranged TEL in 4; fusion duplication in 1; both in 2). In the rest 9 cases (Group C), we found coexistence of two (7) or three subclones (1). Certain variations (i.e. fusion triplication or AML1 deletion) were not seen in cases with a single clone, typical or variant. Epidemiological and biological variables and outcome were comparable between the three groups. However, 8 of the 9 children in Group C had residual disease detectable by flow cytometry on D15, versus only 2 and 1 patients in Group A and B respectively (p< 0,05). One patient in Group A relapsed and subsequently died with the same signal pattern as in diagnosis. There was another relapse in Group C, but the patient entered a second remission on re-induction. Interestingly, in this latter case, involving the only patient with three subclones seen on diagnosis, all three were also present on relapse, at comparable percentages as in diagnosis.

Conclusions: Clonal heterogeneity is frequent in TEL/AML1+ ALL. It is associated with a slower clearance of the marrow on induction but not with the long-term outcome. However, this is unlikely to reflect the presence of a more resistant subclone with regard to additional aberrations of TEL and AML1 genes, since the presence of residual disease on day 15 was seen in similar frequency in patients with a typical t(12;21) and in those with a single variant clone. It is possible that patients with clonal heterogeneity may harbor other cytogenetic abnormalities involving other genes or chromosomes. Further study will be necessary to endorse this hypothesis and, perhaps, identify new pathways in the development of TEL/AML1+ ALL.
Veno-Occlusive Disease of the Liver during Induction Therapy for Acute Lymphoblastic Leukemia
Authors: Papadopoulos Athanasios , Ntaios George , Kaiafa Georgia , Girtovitis Fotios I , Saouli Zoi , Kontoninas Zisis , Diamantidis Michael D. , Andreadis Charalambos , Savopoulos Christos , Hatzitolios Apostolos
Published: April 2020

Veno-occlusive disease (VOD) of the liver constitutes a well known complication of high-dose chemotherapy during hematopoietic stem cell transplantation. We present a fatal case of VOD during conventional induction chemotherapy for acute lymphoblastic leukemia. A 51-year-old woman was admitted in our department due to fatigue and malaise since 2 weeks. She was diagnosed with T-acute lymphoblastic leukemia. Liver and lymph nodes were not palpable. Routine biochemistry was within normal range, except a slightly increased lactate dehydrogenase. Induction therapy was started with vincristine, daunorubicin, prednisone, L-asparaginase and methotrexate. On day 12, the patient became slightly icteric (total bilirubin 2.87mg/dl) and complained of epigastric and right upper quadrant pain, vomiting and flatulence. On physical examination, her liver was now palpable and tender. Within the next two days, her clinical status progressively deteriorated with further increase in bilirubin levels, significant hepatomegaly and ascites. As a result, we had to interrupt treatment on day 14 and start antibiotics and parenteral fluid administration. However, on day 17 her clinical status was further aggravated with low-grade fever and increase of body weight by 5kgs, which makes 9% of her original weight. We aspirated 1500cc of ascitic fluid. Laboratory tests revealed pancytopenia, hyperbilirubinemia, mild transaminasaemia and slightly impaired renal function. Coagulation status was normal. Serologic tests for infectious hepatitis (HBV, HCV) were negative. Ultrasound and computed tomography scan of the abdomen revealed hepatomegaly, ascites, patent splenic and portal veins, no mass lesions of the liver and normal appearance of the gallbladder and bile ducts. We administered recombinant tissue plasminogen activator at a dose of 1mg/kg over four days. On day 22, the clinical status of the patient was critical with high fever, and central nervous system involvement with drowsiness, paresis of the hypoglossal and facial nerves, right hemiparesis and hypaesthesia. On day 25, the patient became stuporous, with large abdominal distention and deep jaundice (total/direct bilirubin 34/20mg/dl) and she finally died the next day. To our knowledge, this is the first fatal case of hepatic VOD during induction therapy for acute lymphoblastic leukemia.
Outcomes of Children with Acute Lymphoblastic Leukemia Treated with 2 Consecutive Protocols: Ramathibodi Hospital Experience
Authors: Surapolchai Pacharapan , Pakakasama Samart , Sirachainan Nongnuch , Anurathapan Usanarat , Chuansumrit Ampaiwan , Hongeng Suradej
Published: April 2020

We determined the outcomes and prognostic factors of children (age, 0.8 to 14.8 years) with acute lymphoblastic leukemia (ALL) treated with 2 consecutive protocols between 1997 and 2008. The risk classification was followed NCI criteria. One hundred and one patients, (60 males and 41 females), were enrolled to the first protocol (modified St Jude Total XIII) (1997–2003). Ninety seven patients (96%) of these 101 patients achieved remission after induction. The event free survival (EFS) rates were 90.1 ± 3%, 85 ± 3.6%, and 83.8 ± 3.7%, and the cumulative risk of CNS relapse were 2.1 ± 1.5%, 3.2 ± 1.8%, and 3.2 ± 1.8%, at 3, 5, and 10 years, respectively. The median follow-up time for patients remaining free of adverse events was 6.8 years (4.2–10.3 years). The adverse prognostic factors included obesity (p =0.013), high risk group (p= 0.012), minimal residual leukemia (MRD) presence (> 0.01%) on day 15 of induction (p <0.001) and sepsis during treatment (p= 0.003). For the second protocol (modified St Jude Total XV) (2004–2008), 80 patients, 43 males and 37 females, were enrolled. Seventy nine (98.8%) of these 80 patients achieved remission after induction. The EFS rates were 92.1 ± 3.1% and 88.9 ± 3.7% at 1 and 3 years, respectively. The median follow-up time was 2.6 years (0.1–4.3 years) without evidence of CNS relapse. The adverse prognostic factor included mucositis during treatmenrt (p = 0.014). The EFS rates up to 85% in childhood ALL treated with two consecutive protocols attest the effectiveness of risk-adaptive therapy and multidisciplinary approach. Regarding to the second protocol, the efficacy of intensive systemic and intrathecal chemotherapy further supports the probability of eliminating cranial radiation and early therapeutic intervention on patients with persistent MRD leading to improve outcome overall, irrespective of patient’s risk groups. Further studies on pharmacogenetic, genetic and proteomic profiles of leukemic cells ascertain the precise risk classification and treatment regimen of childhood ALL in the future.
Hyper-CVAD Plus Nelarabine: A Pilot Study for Patients with Newly Diagnosed T Cell Acute Lymphoblastic Leukemia (ALL)/Lymphoblastic Lymphoma (LL)
Authors: Faderl Stefan , Thomas Deborah A. , Koller Charles A. , Ravandi Farhad , Burger Jan , O’Brien Susan , Dara Samuel , Kantarjian Hagop M.
Published: April 2020

Despite improvement in the prognosis of patients (pts) with T-ALL/LL relapses remain frequent and prognosis of relapsed patients is poor. New drugs specific for T-cell lymphoproliferative disorders and treatment programs combining successful strategies of the past with new agents remain critical. Nelarabine is the water-soluble prodrug of the deoxyguanosine analogue guanosine arabinoside (ara-G) and has activity in pts with relapsed/refractory T cell hematologic malignancies. Here we combine hyper-CVAD (fractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone alternating with methotrexate and high-dose cytarabine for a total of 8 courses, Kantarjian et al. JCO 18:547, 2000) with nelarabine to try and improve response duration and survival of patients with T-ALL/LL. Nelarabine was given at 650 mg/m2 i.v. daily × 5 days q 28 days for two courses following completion of the hyper-CVAD sequence and prior to the POMP maintenance (vincristine, prednisone, 6-mercaptopurin, methotrexate). CNS prophylaxis consisted of 8 intrathecal (IT) treatments (2 with each of the first 4 cycles of hyper-CVAD, but not concomitant with nelarabine) alternating IT methotrexate with IT cytarabine. Starting in August 2007, 7 pts with pre-T ALL/LL have been enrolled. Three pts were in CR at study start following prior therapy with hyper-CVAD for a maximum of 3 cycles. Median age was 38 yrs (range 21–76). All pts had a pre-T immunophenotype. One pt had nodal-based disease only, 6 pts had marrow involvement and 4 pts presented with mediastinal masses. No patient had CNS involvement. Cytogenetics were diploid in 6 pts and abnormal in 1 [translocation t(1;14), del(13)]. All patients achieved or maintained a complete remission. Three patients completed the nelarabine consolidations (too early for the remaining pts). The dose of nelarabine had to be reduced to 650 mg/m2 on alternate days (1,3, 5) in one pt because of grade 2 toxicity from previous vincristine. No exacerbation of neurotoxicity was noted in any of the patients following nelarabine. The study continues to accrue. Hyper-CVAD achieves a high CR rate in T-ALL/LL. Administration of nelarabine is feasible following the hyper-CVAD induction. Assessment of impact of the nelarabine consolidation on DFS and survival requires higher patient numbers and longer follow up.
N-Terminal-ProB-Type Natriuretic Peptide as a Marker for Anthracycline Cardiotoxicity in Children with Acute Lymphoblastic Leukaemia
Authors: Jackowska Teresa , Golabek Malgorzata
Published: April 2020

Background: Anthracyclines (ANTR) are very effective agents in treatment of acute lymphoblastic leukaemia (ALL). However, a potential heart damage caused by ANTR in patients who have been cured of ALL may lessen the success of this cure. Plasma brain B-type natriuretic peptide (BNP) levels are highly sensitive biochemical markers for myocardial damage.

Objectives of the study: Our purpose was to evaluate N-terminal proBNP (Nt-proBNP) as a screening test for detecting cardiac dysfunction in children with ALL.

Subjects: 156 asymptomatic children (72 girls and 84 boys) who had received ANTR during treatment for ALL were evaluated. They had received ANTR doses of 180 to 480mg/m2 (according to the protocol treatment) at median age of 6.6 years at diagnosis. 47 healthy children constituted the control group.

Methods: Concentration of plasma N-terminal proBNP was measured in 420 samples by enzyme immunoassay (Biomedica) before treatment, after 6 months, 2 and 4 years and longer than 5 years after ANTR therapy. 261 echocardiograms (ECHO) were performed in 128 children. Nt-proBNP was measured at the same time. Shortening fraction (%SF) and ejection fraction (%EF) were determined as systolic left ventricular function.

Results: Mean Nt-proBNP plasma levels in children with ALL were higher in comparison with the control group (90.7 and 66.2pg/ml respectively) but the difference was not significant (p=0.2). The levels of Nt-proBNP before ALL treatment were significantly the lowest (51.5pg/ml). Later, they were respectively: 108.3pg/ml after 6 months, 97.4pg/ml after 2 years and 92.9pg/ml after 4 years (p=0.0019). The highest levels of NT-proBNP were observed in children with cumulative ANTR doses of 240, 330 and 480mg/m2 (98.8pg/ml, 102.8pg/ml, 86.1pg/ml respectively) (p=0.0008). The lowest levels were observed with the cumulative doses of 180mg/m2 and 300mg/m2 (60.7pg/ml and 58.8pg/ml respectively). The average value of %SF in children with ALL was 39.4% (26 to 52%) and the average value of %EF was 69.95% (51.1 do 83.4%). In children with %SF and %EF lower than the average in both study and control group Nt-proBNP was insignificantly higher than in children whose %SF and %EF were higher than the average in both groups (respectively for %SF: 107.1pg/ml and 97.3pg/ml and for %EF: 106.3pg/ml and 98.8pg/ml).

Conclusion: Increased Nt-proBNP levels were observed more often in children who received higher doses of ANTR and in all children after the end of treatment. Independently of ECHO assessment of the left ventricular function, the Nt-proBNP is of value in the detection of subclinical left ventricular dysfunction in children with ALL who were treated with ANTR therapy.
Is It Better to Treat Adolescents with Acute Lymphoblastic Leukemia as Old Children or as Young Adults?
Authors: Alves Marta , Daudt Liane , Mazzucco Karina L. M. , Taniguchi Adriano , Nava Tiago , Moreno Fabio L. , Gonzalez Alice , Silla Lucia
Published: April 2020

PURPOSE: To compare pediatric and adult therapeutic practices in the treatment of acute lymphoblastic leukemia (ALL) in adolescents.

PATIENTS AND METHODS: From January 1997 to December 2007, 34 and 11 adolescents (10 to 20 years of age) were treated according to German pediatric BFM 90 and 95 and adult BFM 84 protocols, respectively. Age, B/T lineage, WBC count, complete remission, cytogenetics, and response to steroids were analyzed. Age, B/T lineage and WBC count were similar. Poor risk-cytogenetics (t (9;22),t(4;11) and hypodiploidy less than 45 chromosomes were present only in BFM 90 and 95 group. Among the different prognostic factors, we retrospectively analyzed the effect of the trial on achieving overall survival (OS) and event-free survival (EFS).

RESULTS: OS in 10 years and EFS was, respectively, 68.6% and 68.7% for the pediatric protocol and 31.4% and 21.6% for the adult protocol.

CONCLUSION: This study’s findings were similar to others in USA, UK, France, Italy and Holland that clearly demonstrate that current pediatric regimens are more effective for adolescents and may contribute to indicate that adolescents should be included in intensive pediatric protocols. Keywords: leukemia, survival, adolescent.
A Cross-Sectional Study Comparing Variation in Body Surface Area and Chemotherapy Dosing in Pediatric Oncology Using Two Different Methods
Authors: Jastaniah Wasil , Aseeri Mohammed
Published: April 2020

Abstract: Standardizing Body Surface Area (BSA) determination is essential for avoiding variation in chemotherapy dosage calculations. In this study we compared variation in BSA calculation using weight and height by the Mosteller formula with weight alone using recently adapted table at the Princess Norah Oncology Center (PNOC).

Methods: Cross-sectional study of pediatric oncology patients presenting to the pediatric oncology clinic at PNOC over a week period of time.

Results: One hundred consecutive pediatric oncology patients presented to the clinic. The mean BSA calculated by the Mosteller formula was 0.83m2 (Standard Deviation = 0.24) and the mean BSA determined by the table (based on weight alone) was 0.82m2 (Standard Deviation = 0.25). The mean variation in dosing between the two methods was 1.64% (Standard Deviation = 3.4). Only 13 out of 100 patients (13%) had equal dosing using both methods and 21 out of 100 patients (21%) had dosing variation greater than 5%. When comparing both methods, using paired t-test, the difference was statistically significant (t(99) = 3.99 and P < 0.001).

Conclusion: Significant differences in BSA-based chemotherapy dosing exist in our center. The Mosteller method should remain the standard until prospective studies are performed to determine the significance of this dosing variability on toxicity and survival outcome.
Elevated Vanin1 and Advillin Expression Is Associated with Progression to Chronic ITP in Children
Authors: Zhang Bing , Sood Ruchira , Jones Carol , Wong Wendy , Jeng Michael , Zehnder James L.
Published: April 2020

The majority of pediatric ITP patients recover spontaneously within 6 months (acute ITP), while about 20% of the patients develop chronic ITP. The ability to distinguish patients at higher risk of developing chronic disease during the acute phase of the illness could give prognostic information and serve as a basis for clinical trials to study earlier or more aggressive interventions to prevent morbidity associated with long-term immunosuppression. We have previously described the gene expression pattern of pediatric ITP patients. This data set was used to search for genes which would predict progression to chronic ITP. We identified 8 samples from patients with acute self-limited ITP and 4 samples from patients who progressed to chronic ITP, all tested during the acute phase of the disease. At a false discovery rate of 0, two genes—VNN1 (vanin1) and AVIL (advillin) were the most significantly different between the groups. To validate these findings from microarray analysis, real-time PCR experiments were performed using unamplified whole blood RNA from the original cohort, with 4 additional patients (for a total of 9 samples in self-limited acute ITP group and 7 samples in progressed to chronic ITP group), and a control group of 5 normal children. All real-time data was normalized to housekeeping gene (GADPH) expression. Both VNN1 and AVIL expression were significantly increased in the group which developed chronic ITP compared to patients with acute self-limited ITP (VNN1 p=0.008, AVIL p=0.006) and normal controls (VNN1 p=0.044, AVIL p=0.009). Table 1 shows the medians and ranges of the normalized real-time PCR results of the three groups. The mechanism of these over-expressed genes in pediatric ITP patients who progress to chronic ITP is currently being investigated. VNN1 is a GPI anchored protein involved in T cell trafficking and has a pro-inflammatory role as an oxidative-stress response gene. AVIL, whose gene product is a member of the gelsolin/villin family of actin regulatory proteins, is involved in monocyte/macrophage phagocytosis and cytoskeletal remodeling. Thus both of these genes have functions consistent with recent reports implicating T cell regulation and trafficking as well as immune-mediated destruction of platelets in chronic ITP. These findings represent the first candidate biomarkers in predicting prognosis in pediatric ITP and at the same time open the door for further investigation of the molecular mechanism underlying the clinical transition from acute to chronic ITP. A prospective study to validate these findings is in progress.

Table1:

Normalized VNN1 (Vanin1) Normalized AVIL (Advillin) Median Range Median Range Self-limited Acute ITP group 0.461 0.170~0.813 8.535 0.953~17.395 Progress to chronic ITP group 1.827 0.326~4.723 25.601 6.031~44.296 Normal control group 0.350 0.202~1.029 5.491 1.449~8.585
BCL2 Gene Polymorphism Could Predict the Treatment Outcomes in Patients with De Novo Acute Myeloid Leukemia
Authors: Kim Kyoung Ha , Kim Dong Hwan , Lee Su Jin , Moon Joon Ho , Chang Myung Hee , Lee Myung Hoon , Jung Chul Won , Sohn Sang Kyun
Published: April 2020

The bcl-2 protein inhibits apoptosis (programmed cell death) of hematopoietic stem cells induced by a variety of noxious stimuli, thus mediate chemoresistance and decrease chemosensitivity. Higher bcl-2 expression was demonstrated to correlate with an adverse outcome in acute myeloid leukemia (AML). The current study attempted to determine whether BCL2 gene single nucleotide polymorphism (SNP) could affect treatment outcomes of 109 AML patients. Two genotypes were tested including BCL2 −938 C>A (rs2279115) and +21 A>G (rs1801018) using Light cycler-assisted analyses. Neither −938 C>A nor +21 A>G BLC2 genotype was not associated with the difference of the probability to achieve complete remission (CR) after chemotherapy. While −938 A>C BCL2 genotype did not affect leukemia free survival (LFS), event free survival (EFS) or overall survival (OS), of interest, BCL2 +21 A>G genotype correlated with LFS and EFS significantly. The group with +21 AA genotype had a significantly longer median LFS (p<0.001) or EFS (p=0.014), and marginally better OS (p=0.08). The multivariate analyses confirmed that BCL2 gene SNP is independent prognostic factor for LFS (p=0.05, HR 2.57, 95% C.I. [1.02–6.62]) and EFS (p=0.02, HR 2.38, 95% C.I. [1.11–5.13]), but not for OS (p=0.3) considering previously known risk factors. These data indicate that chemotherapy resistance may involve the bcl-2 mediated mechanism in AML.
Characterization of Leukemic Stem Cells in a Newly Established Acute Myeloid Leukemia (AML) Cell Line 2006-5
Authors: Zhong Rui-kun , Lane Thomas A. , Ball Edward D
Published: April 2020

AML cell line 2006-5 was established by serial culture of an AML patients’ PBMC (M5).

Compared to primary AML cells, this line expresses CD13, CD33, CD15, CD4, CD86, CD54 but lost CD34, CD64, CD123 and HLA-Dr. A group of CD13−/CD33− cells was detected consisting of 0.2% of total cells, but no significant CD34, CD90 or CD123 expression cells could be detected by FACS. After depleting of CD13+/CD33+ cells by magnetic beads, the CD13−/CD33− cells were enriched to 95%. Significant CD34+, CD90+ or CD123+ cells (0.2–0.5%) appeared in the CD13−/CD33− enriched fraction of AML cells. Leukemia colony forming (LCF) cell assay analyzed at day 14 demonstrated CD34+, CD90+ or CD123+ cells selected by magnetic beads formed typical compact large colonies of more than 1000 cells representing 40–60% of total colonies (Fig left panel). The CD13−/CD33− enriched fraction formed medium colonies with a dense center surrounded by a halo of migrating cells (80–90% of total colonies) (Fig right). Untreated 2006-5 cells formed small diffuse colonies (70–80%). Re-plating of compact colonies selected from CD34+, CD90+ or CD123+ cell LCF assays formed the above 3 type of colonies in one culture dish. Although a daughter line can be generated from a single colony formed by CD13-CD33− cells, no compact colonies could be observed in re-plating experiment. After 14 days of culture, immature erythroid cell clusters were observed in the area surrounding compact colonies suggesting that the progenitors of the colony forming leukemia cells were at the GEMM stage. Small colonies of untreated cells gradually became apoptotic and necrotic after 10 days. These results support the theory that AML is organized as a hierarchy similar to the normal hematopoietic system. CD34+, CD90+ or CD123+ cells with very low frequency of 1–2 in 1×105 2006-5 line cells demonstrated high proliferation and differentiation potential, and may represent leukemia stem cells. CD13−/CD33− cells with lower proliferation rate may belong to more differentiated leukemia progenitors without self renew potential. If additional experiments support the notion that cells forming compact colonies are leukemia stem cells, they may serve as a useful resource to test the biology of leukemia and its therapy.

Figure Figure Figure Figure
Analysis of Clinical Features and Survival in 42 Cases of Acute Monocytic Leukemia
Authors: Qiu Hongxia , Wu Hanxin , Ju Songwen , Xu Wei , Xu Ji , Lv Xin , Shao Jinzhang , Zhang Ri
Published: April 2020

Background: Acute monocytic leukemia (M5) is a distinct subtype of acute myeloid leukemia (AML) with characteristic biologic and clinical features. This study was designed to analyze the clinical and laboratory features, and management and survival of newly diagnosed patients at with M5.

Methods: The white blood counts, immunophenotype and karyotypes were retrospectively analyzed in 42 patients (pts) with M5. The overall survival(OS)was estimated by Kaplan-Meier analysis, and the different groups were compared using log-rank test.

Results: Of the 42 pts, 7 had M5a and 35 had M5b. The incidence rates of M5 in newly diagnosed patients with acute leukemia and acute myelocytic leukemia were 13.7% and 22%, respectively. 28(66.7%) pts with M5 had a higher white blood counts more than 25×109/L. 36 pts obtained the outcomes of karyotype, 14(39%) pts with an abnormal cytogenetic clone, seven (19.4%) of these patients had trisomy 8 as the sole or accompanied complex cytogenetic aberration, 5(13.8%) had a translocation involving 11q23. An immunophenotype consistent with acute monocytic leukemia (CD14) was seen in 24(57.1%) of 42 pts. 16 pts (38.1%) gave up the chemotherapy at diagnosis and the complete remission rate was 73.1% for 26 pts who received induction chemotherapy. The OS for all M5 pts was 90 days (95%CI, 51.3~128.7) and the median survival for all M5 pts was 137.5 days. The median OS for the 19 CR pts was 273 days (95% CI, 226~320.1) and 85 days (95% CI, 72.2~97.8) for the 16 NR pts (95% CI, 72.2~97.8). For 16 pts who didn’t receive chemotherapy, the median OS was 35 days (95% CI, 33~37)(P<0.0001). M5 presents hyperleukocytosis, 86.1% pts of M5 has a normal clone or trisomy 8 or a translocation involving 11q23. The overall survival of M5 pts with currently available therapy is poor.
Acute Myeloid Leukemia Occurring in Responders to the 9/11 Attack on the World Trade Center: A Single Institution Case Series
Authors: Allen Steven L. , Bayer Ruthee-Lu , Patel Dilip , Kolitz Jonathan E.
Published: April 2020

Responders to the 9/11/01 attack on the World Trade Center (WTC) were exposed to a variety of toxins resulting from the combustion of jet fuels, collapse of the towers, smoldering fires, and diesel exhaust generated by heavy equipment during debris removal. These toxins included polycyclic aromatic hydrocarbons, polychlorinated biphenyls and furans, and dioxins. The potential for subsequent development of secondary malignancies has been of concern. We report a single institution series of 6 cases of acute myeloid leukemia (AML) occurring in responders to the WTC disaster. All spent extended periods of time at Ground Zero.

Case Age WTC Role 9/11 to Dx (months) FAB Karyotype Response Status 1 38 Construction worker 29 M2 46, XY CR Relapse at 33 mos; expired 2 43 Bus driver 57 M4 48, XY, +8, +11 CMMoL Alive s/p allo SCT 3 38 Glass cutter 71 M3 46, XY, t (15;17) CR Alive 4 53 Police 74 M4 46, XY CR Relapse at 8 mos; alive 5 45 Police 79 M1 46, XY CR Alive 6 62 Police 79 M5a 46, XY CR Alive

AML arising in WTC responders after a latency period of at least 29 months raises the possibility of an association. There are no distinctive characteristics apparent in this small single institution series. Case 2 has myelodysplasia at a relatively young age, consistent with a possible toxic etiology. AML patients should be questioned regarding activity at Ground Zero and identified cases should be asked about the duration and types of exposure at the WTC, in addition to other occupational or environmental exposures. Clinicians should report cases of hematologic malignancy in WTC responders to the appropriate state cancer registry to facilitate epidemiologic investigation. Studies of cancer among persons exposed to the 9/11 disaster are ongoing by the New York City Fire Department, the WTC Medical Monitoring and Treatment Program and the WTC Health Registry.
Rasburicase Effectively Lowers Serum Uric Acid Levels in High Risk, Poor Performance Status Patients with Hematologic Malignancies
Authors: Ponce Doris , Liu Delong , Rasul Muhammad , Ahmed Nasir , Dimicco Marie , Seiter Karen
Published: April 2020

Tumor lysis remains a significant cause of morbidity and mortality in patients with highly proliferative hematologic malignancies. Traditionally, intravenous hydration and oral allopurinol have been the mainstays of therapy. However in some patients, hyperuricemia and renal failure still occur. The resultant renal failure precludes the administration of full doses of chemotherapy and results in a poor treatment outcome. Recently we participated in a large phase III randomized trial comparing rasburicase with standard allopurinol therapy. Rasburicase is a recombinant urate oxidase that effectively reduces serum uric acid due to conversion of uric acid into allantoin, a readily excretable and soluble substance. The results of that study are reported in a separate abstract. However while the study was open, we treated 12 extremely high risk, newly diagnosed hematologic malignancy patients who were ineligible for the study with commercially available rasburicase off study. The reasons for study ineligibility were ECOG Performance Status 4 and/or expected survival of less than one month. Other baseline characteristics: Diagnosis: Burkitts ALL: 3, AML: 7, CML-BP: 1, T-ALL: 1; Age: 64 (27–85), Sex: 6M/6F; WBC: 58,000/mm3 (1.6- 245,000); LDH: 2201 U/l (1068- >2500); # of preexisting comorbid medical conditions: 4 (0–7); chemotherapy: hyper-CVAD: 4, standard ara-c based rx: 5, high dose ara-C based rx: 3. Nine patients received one dose of rasburicase (0.2 mg/kg IV), 3 patients required a second dose. The median uric acid levels were: pretreatment : 9.2 mg/dl (2.8–28.6), at 24 hours: <0.2 (0.2–7.5) and at 48 hours: <0.2 (<0.2–4.9). All patients achieved normal serum uric acid level by day 2. The median baseline creatinine was 2.6 mg/dl (0.7 – 5.6); by day seven 10 patients had a serum creatinine less than 2 mg/dl (day 7 median creatinine 0.9, range 0.4–5.5). Four patients achieved CR to chemotherapy, 5 had refractory disease and 3 had induction death. Administration of rasburicase in this extremely high risk group of patients resulted in a rapid decrease in serum uric acid levels. In many patients this allowed for preservation of or improvement in renal function and administration of chemotherapy. Although some patients had a poor outcome due to the aggressive nature of their underlying disease, 4 of 12 patients (33%) attained CR and were able to receive subsequent cycles of intensive chemotherapy without incident.
Assessment of Response to Therapy in Primary Myeloid Sarcoma Using Positron Emission Tomography/Computer Tomography Imaging: A Case Report
Authors: Schöndube Daniel , Dresel Stefan , Ludwig Wolf-Dieter , Hildebrandt Martin
Published: April 2020

Myeloid sarcoma or chloroma, an extramedullary myeloid tumor, is observed in a minority of patients with acute non-lymphocytic leukaemia. Very few cases may present without bone marrow involvement (i.e., primary myeloid sarcoma). Among the various sites of disease manifestation reported, solitary bone lesions may occur. Diagnosis and, even more so, assessment of response to systemic therapy is strikingly more difficult than in systemic disease, i.e. acute leukaemia. We report the case of a patient diagnosed with primary myeloid sarcoma involving thoracic vertebral bones and associated with spinal cord compression. Here, positron emission tomography/computer tomography imaging allowed assessment of the initial extent of the disease as well as the response to a combined radiochemotherapeutic approach.

A male, 60 years old patient presented with pain in the flanks extending to the left leg. MRI imaging revealed an intraspinal mass in close proximity to the eleventh thoracic vertebral bone. Surgical resection of the mass including biopsy of the vertebral bone allowed the histopathological diagnosis of a myeloid sarcoma. Upon presentation, the assessment of bone marrow and meningeal involvement yielded negative results. MRI imaging revealed changes suggestive of residual manifestations albeit remaining inconclusive with regard to an enhancement secondary to the surgical intervention.

PET/CT imaging revealed a distinct signal located to the eleventh vertebral bone as a result of enhanced metabolic turnover (SUV 8.8) that was interpreted as active myelosarcoma tissue. Induction chemotherapy was initiated consisting of high-dose Ara C and Mitoxantrone (HAM). Following induction therapy, PET/CT assessment showed no change in metabolic activity. Extended field radiation therapy was performed, involving the two adjacent upper and lower vertebral bones, with a total dose of 30 Gy. This time, response assessment via PET/CT showed only a slight enhancement in metabolic turnover, suggestive of remission. As a consolidation, high dose Ara C therapy was initiated. Until now the patient is fine and shows no sign of residual myeloid sarcoma.

PET/CT in this case was the only method which reliably allowed the assessment of tumor location, extent and activity in a previously operated vertebral bone and, as a tool for the assessment of response, was guiding therapeutic decisions. In our opinion, the exposure to substantial radiation exposure due to PET/CT imaging is outweighed by the obvious diagnostic benefit.
Successful Treatment of Acute Myelocytic Leukemia in Pregnancy Complicated with Lung Abscess
Authors: Lan Jianping , Wang Xiaogang , Peng Ye , Qian Meihua , Wang Lianmin , Huang He
Published: April 2020

Acute leukemia in pregnancy is a rare event and the cytotoxic treatment during pregnancy remains controversial due to the concerns on significant teratogenicity led by chemotherapeutic agents. We here reported a woman who was diagnosed as acute myelocytic leukemia and lung abscess underwent a standard chemotherapy of DA regimen at her early third trimester of gestation and delivered a healthy baby without any abnormalities by Caesarean section. A 24-year-old woman at her 29th weeks of pregnancy was admitted because she experienced shortness of breath for one month and fever and cough with expectoration for three days. At admission, she had a moderate fever and looked severely anemic with no lymphadenopathy and hepatosplenomegaly. The whole blood counts showed her hemoglobin was 31 g/L, WBC 8.5 × 109/L with 42% blasts and platelet 13 × 109/L. The morphologic, immunophenotyping and cytogenetic findings of the bone marrow samples met the criteria of acute myelocytic leukemia (AML-M2a) diagnosis. Computerized tomography of chest indicated pneumonia with the formation of right lung abscess. Ultrasound examination revealed a normal-appearing fetus and an anterior placenta. Since the patient insisted maintaining the pregnancy, a standard induction regimen of daunorubicin and cytarabine was initiated and broad-spectrum antibiotics were simultaneously prescribed to control the pulmonary infection. During profound myelosuppression, granulocyte stimulating factor and anti-fungal agents were also administrated. After 4 weeks of induction, the patient’s symptoms all disappeared and her peripheral blood counts completely recovered. A repeat bone marrow aspirate confirmed complete leukemia remission. A living baby boy weighed 2200g was delivered by Caesarean section 2 weeks later (at the 35th week of gestation). Physical examinations and laboratory tests showed a healthy baby without any abnormalities. The mother is still in good condition and receives scheduled consolidation and maintenance therapy. The growth and development of the baby is also normal at the time of writing (8 months after birth). Our experience suggested chemotherapy of acute leukemia at the third trimester may not require termination of pregnancy since a remission of leukemia and delivery of a healthy baby can be obtained.
Trousseau’s Syndrome Revisited: Should We Screen Extensively for Malignancy in Patients with Venous Thromboembolism? a Systematic Review and Meta-Analysis
Authors: Carrier Marc , Le Gal Gregoire , Wells Philip , Fergusson Dean , Ramsay Tim , Rodger Marc A
Published: April 2020

Background: Identifying previously undiagnosed malignancy in patients with newly diagnosed venous thromboembolism (VTE) is important. Malignancy screening can potentially diagnose more cancers and at earlier stage, thereby preventing malignancy associated morbidity and perhaps mortality.

Purpose: To summarize the period prevalence of previously undiagnosed malignancy at baseline (within 1 month of VTE diagnosis), 6 and 12 months following VTE. To quantify the additional value of an “extensive” malignancy screening strategy at baseline compared to a more “limited” screen (history, physical exam and simple widely available tests) at baseline.

Data Source: A systematic literature search strategy was conducted using MEDLINE, EMBASE, the Cochrane Register of Controlled Trials and all EBM Reviews.

Study Selection: We selected 36 studies that reported the prevalence of undiagnosed malignancies at baseline, at 6 and 12 months. Fourteen articles and one abstract also met inclusion criteria for the assessment of “extensive” versus “limited” malignancy screening.

Data extraction: Two reviewers independently extracted data onto standardized forms.

Data Synthesis: The period prevalence of previously undiagnosed malignancy in patients with unprovoked VTE is 6.1% (95% confidence intervals (CI): 5.0 to 7.1) at baseline and 10.0% (95% CI: 8.6 to 11.3) from baseline to 12 months. An “extensive” malignancy screening strategy using computed tomography of the abdomen/pelvis significantly increases the proportion of previously undiagnosed malignancy detected from 49.4% (95% CI: 40.2 to 58.5) (limited screening alone) to 69.7% (95% CI: 61.1 to 77.8) in patients with unprovoked VTE.

Limitations: Unable to determine complication rates, cost-effectiveness and difference in morbidity and mortality associated with “extensive” screening strategies.

Conclusion: Previously undiagnosed malignancies are frequent in patients with unprovoked VTE. Malignancy screening using an “extensive” screening strategy detects more malignancies compared to a limited screening strategy. Computed tomography of the abdomen/pelvis should be considered in the diagnostic work up of previously undiagnosed malignancy in patients with unprovoked VTE.
A Murine AML Model for the Development of Resistance to NRAS(G12V) Oncogene Repression and/or Ara-C Treatment in Vivo
Authors: Kim Won-IL , Rathe Susan K , Diers Miechaleen D , Largaespada David A
Published: April 2020

We previously reported the development of a model of AML in mice induced by the combined expression of a conditionally expressed NRASG12V oncogene and the MLL fusion oncogene MLL-AF9. This mouse model combines a Vav promoter-Tet transactivator (Vav-tTA) transgene, a doxycycline (DOX)-repressible tet-regulated element promoter-NRASG12V (TRE-NRASG12V) transgene, and Mll-AF9 “knock-in” transgene. When we transplanted triple transgenic Vav-tTA; TRE-NRASG12V; Mll-AF9 AML into SCID mice we found that doxycycline (DOX) treatment via the drinking water could prevent AML engraftment or eliminate AML cells after growth to full-blown leukemia. However, these mice eventually develop DOX-resistant AML, which does not re-express the NRASG12V transgene. In more recent data, we find that the Vav-tTA; TRE-NRASG12V; Mll-AF9 AML cells are also Ara-C sensitive as we can repeatedly induce temporary remission in transplant recipients of these cells by 5 day courses of 50 mg/kg Ara-C given once per day intra-peritoneally. Although Ara-C is the backbone of human Ara-C treatment, many patients develop Ara-C resistant AML over time. In our model, fully Ara-C resistant AML develops after 4 to 5 courses of treatment. Nevertheless, a combination of Ara-C treatment and NRASG12V transgene suppression using DOX can extend remission and survival compared to treatment with either approach alone suggesting that some benefit could be obtained by combining RAS pathway inhibitors with conventional chemotherapy. However, even in this case, AML that is resistant to both Ara-C and NRASG12V transgene suppression eventually develops in all mice. Primary AML samples that have been selected in vivo for resistance to Ara-C, NRASG12V oncogene suppression, or both, have been collected and are being analyzed by mRNA microarray for changes in gene expression that might be responsible for the acquisition of resistance.
Oral Anticoagulation in Atrial Fibrillation. Comparison Between Patients Younger and Older Than 75 Years
Authors: Colorio Cecilia Claudia , Puente Dolores P , Rossi Andrea , Tabares Maria , Pombo Gonzalo , Forastiero Ricardo
Published: April 2020

Atrial fibrillation (AF) is the most common cardiac rhythm disorder. The prevalence is nearly 10 % in patients (pts) older than 75 years (yrs). Some authors are reluctant to give oral anticoagulant therapy for older pts based on their higher incidence of bleeding

Objective : to compare characteristics, incidence of thrombosis and bleeding in 2 groups of pts with AF, under OA for at least 3 months.

Methods: we retrospectively analyzed 184 pts below 75 yrs (Group A) and 133 pts with 75 yrs and older (Group B), between Jan 2002 and Aug 2007.

Results: the mean follow-up was 514 pts/year for the A group and 382 pts/year for group B. The features of each group are listed in the table below:

Group A Group B p Age (mean- range) 64,9 (33/74) 79,8 (75/91) Gender (M/F) 116/68 (1,7/1) 55/78 (0,7/1) Rheumatic AF 89/184 61/114 Non valvular AF 80/184 53/114 Previous thrombosis 21/184 (11.4%) 29/133 (21.8%) 0,01 Diabetes mellitus 28/184 (15.2%) 10/133 (7.5%) 0,05 Arterial Hypertension 78/184 (42.3 %) 53/133 (39.8%) Hyperthyroidism 29/184 (15.7%) 18/133 (13.5%) Left Mega Atrium 43/174 (24.7%) 32/110 (29%) Coronary Artery Disease 38/184 (20.6%) 31/133 (23.3%) Cardiomegaly 53/170 (31.1%) 41/122 (33.6%) Ejection Fraction ≤30% 26/175 (14,8%) 20/112 (17.8%) Creatinin ≥ 2 mg/dl 8/184 (4.3%) 8/133 (6.1%) Thromboses 4/184 (2.1%) 3/133 (2.2%) Bleeding minor 59/184 (32%} 49/133 (36.8%) major 5/184 (2.7%) 2/133 (1.5%) fatal 0 2/2 (100%) Controls with INR 2-3 61 % 60,5 %

Conclusion: There was no difference in the incidence of major and minor bleeding/thrombotic complications between the groups.

Group B disclosed a higher number of thromboses previous to OA therapy, and fewer pts with diabetes. In our experience, OA seemed to be equally safe and effective when we compared both populations. There was no difference in the incidence of major and minor bleeding/thrombotic complications between the groups.
The Evaluation of a Prothrombotic Risk in a Human Fibrinogen Concentrate
Authors: Dickneite Gerhard , Joch Christine , Bergman Garrett E.
Published: April 2020

Fibrinogen is a circulating coagulant protein which is converted to polymerizable fibrin by thrombin. The human fibrinogen concentrate (FC) (CSL Behring) has been used for the treatment of bleeding in fibrinogen deficiency. In this investigation we investigated the prothrombotic potential of FC using the in-vivo, Wessler venous stasis assay in rabbits Thrombogenicity in clinical use was assessed in a postmarketing drug surveillance review. Forty-five rabbits were randomized to receive either placebo or 40 mg/kg of one of four different lots of FC, injected into a marginal ear vein. Thirty seconds thereafter, a segment of the right jugular vein (1.5 – 2.0 cm) was ligated. After 15 minutes the segment was removed and evaluated for thrombus formation according to a score system from 0 –3. Thrombogenic materials, such as activated prothrombin complexes, have consistently shown high scores of thrombus formation in this assay. The mean score in the FC treated rabbits (0.85 ± 1.04) was not different from that in the placebo-treated rabbits (0.8 ± 0.84). Postmarketing data was comprised of spontaneous reports to a postmarketing surveillance system for Adverse Drug Reports (ADR). The number of ADR reports was expressed relative to the number of estimated single standard doses. The estimated dose per patient was adjusted to the degree of bleeding (between one to eight gram). Between January 01, 1986 and April 30, 2008 in total 983,195 g of Haemocomplettan® P had been distributed. Very few reports (n=9) of thromboembolic events have been reported throughout postmarketing surveillance, corresponding to one case report for every 13,655 treatments of 8 grams FC. The reported thromboembolic events occurred in patients with congenital afibrinogenemia or acquired hypofibrinogenemia. In most cases, patients had additional risk factors (e.g. concomitant administration of blood products prothrombin complex concentrate, platelet concentrates, activated factor VII, etc.). Although a causal relationship to administration of FC could not be definitely excluded, the occurrence of thromboembolic events is very rare. From congruent results of both a classical preclinical model of thrombogenicity and analysis of postmarketing data, FC appears to have a very low risk of thrombogenicity.