Multiparameter flow cytometry can be used to
|
|
- Abel Anthony
- 6 years ago
- Views:
Transcription
1 Minimal residual disease testing in Acute Leukemia Anjum Hassan MD Assistant Professor of Pathology and Immunology, Director FISH laboratory in Anatomic Pathology, Washington University in St Louis, School of Medicine, St Louis Missouri, USA, Acute leukemia (AL) is a complex disease with considerable phenotypic and morphologic heterogeneity. The phenotype is often assessed by multiparameter flow cytometry ideally on aspirated bone marrow. These leukemia associated phenotypes (LAPs) are crucial for disease monitoring. In addition, there are more than 100 recurring cytogenetic abnormalities encountered in acute myeloid leukemia (AML) and similarly, multiple acquired genetic abnormalities are responsible for aberrant proliferation and differentiation arrest seen in acute lymphoblastic leukemia (ALL). WHO requires a combination of both immunophenotypic and cytogenetic studies to definitively classify AL. Outgrowth of minimal residual disease (MRD) in AL is responsible for the occurrence of relapses. These are cells present in the bone marrow after treatment and these can be monitored by molecular, biologic and or immunophenotypic detection methods. Defining MRD is thought to be crucial in defining patient-tailored post remission therapy which might reduce the risk of relapse or diminish morbidity and mortality in AL. This may also allow detection of impending relapses for early intervention. Immunophenotyping by flow cytometry (FC) is a cost effective and fast tool for detection of MRD. Essentially all cases of AL possess a unique phenotype with multiple aberrancies which tend to remain stable during the course of relapses. By defining these LAPs on malignant cells at diagnosis, flow cytometry can be highly reliable in MRD parameter assessment at different stages AL, consequently predicting survival and forthcoming relapses. Multiparameter flow cytometry can be used to detect MRD in acute leukemia because the malignant cells have phenotypic differences that are reproducible and not present in normal cells of similar lineage. In acute leukemia there can be malignant cells at the time of diagnosis. 1 Complete remission (CR) is defined as less than 5% blasts in the bone marrow, however, several studies have shown the presence of up to neoplastic cells in patients with CR and from the point of complete remission to overt clinical relapse with 5% or more blasts. There are no well established guidelines to monitor the level of residual blasts if the patients are in clinical remission. Thus, patients with 1010 blasts are essentially treated with regimens not too different from those with much lower levels of blasts. 2 Several studies have already established the direct relationship between tumor load and prognostic outcome therefore, it is logical to assume that if more sensitive methods of detection of tumor cells are made available, this will increase the chances of early intervention before the clinically evident relapse and possibly reduce disease recurrence and reduce the likelihood of developing drug- resistant mutants. 3-7 Later is dependent on the ability of blasts to undergo cell division and as these malignant cells emerge by mutations, the larger volume of these cells in a CR setting is likely to lead to more drug-resistant blasts. 8,9 This highlights the importance of detecting minimal residual disease and subsequent section will address the general approach for this testing in acute myeloid and acute lymphoblastic leukemia. Several methods have been employed for detection of MRD in AL with different sensitivities and advantages. For a comparison of these different strategies please see Table 1. This review will focus on immunological mechanisms of MRD testing specifically, multicolor flow cytometry (MFC). MRD testing in acute myeloid leukemia For AML, previously described aberrations include asynchronous antigen expression such as expression of CD34, an early marker, and CD15 a late marker; lineage infidelity such as expression of lymphoid markers on myeloid blasts; antigen over expression and absence of lineage specific antigens, normally expected in a particular leukemic blast (Table 2). These features specify a certain leukemia associated phenotype (LAP) which, ideally, should either be absent or only infrequently present on normal bone marrow or peripheral blood cells MFC can be em-ployed to study the LAPs. In AML, LAPs are not well defined due to inherent heterogeneity of this disease. However, high levels of sensitivity can be reached by using multiple antibodies and MFC The ideal assay for detec- 306
2 tion of small numbers of leukemic cells should fulfill the following criteria: a) applicable in most cases, b) specific for neoplastic cell type, c) sensitive, d) allows quantization of tumor burden for prognostic purposes. Al-Mawali et al demonstrated in their study of 54 AML samples that, using 5 color flow cytometry, LAPs could be identified in 94% of cases. The post induction MRD levels in that study influenced both relapse free survival and overall survival as independent prognostic variables. 16 Using five color flow cytometry, specific LAPs will allow detection of very low levels of blasts considering the criteria outlined above. However, compared to ALL, AML LAPs are more heterogeneous and co-existence of several blast populations with different LAPs can be observed. When different LAPs are present, those with the largest logarithmic difference to normal bone marrow cells should be chosen for MRD monitoring. This guarantees better specifity and sensitivity when compared to approaches using more general inclusion of all LAPs in to one assay. Usage of three, four, five and up to ten color flow cytometry strategies using a wide panel of antibodies (see Table 2) has improved the sensitivity of MRD in most AML cases to between 0.1% and 0.01% of all nucleated bone marrow cells. One large study evaluating the prognostic relevance of MRD load involved 126 AML patients, all in morphologic remission. They summarized their patients into four risk groups: 1) very low risk=<10-4 residual leukemic cells- no relapses. 2) Low risk=10-4 to 10-3 residual AML cells-14% relapse rate 3) intermediate risk= >10-3 to 10-2 residual blasts- 50% relapse rate 4) high risk=>10-2 blasts- 84% relapse rate. Thus, MFC allowed highly differentiated risk stratification among patients in morphologic remission. 17 The timing of MRD monitoring is a subject of ongoing debate. Various studies have used post-induction and post-consolidation MRD monitoring to establish their relative prognostic significance. In a study of 100 AML patients, a threshold of leukemic cells was reportedly able to stratify poor and good risk groups both after induction and post consolidation. In this study, patients without detectable MRD post consolidation fared much better in terms of overall survival and relapse free survival (P<0.001) regardless of their MRD level post induction. Best treatment results were shown with post induction MRD load of < residual leukemic cells, however, relapse rates did not differ much in those with similar or higher levels of MRD. The impact on relapse rate was much stronger post consolidation with MRD cut off of greater than or equal to varying from 77% to 17% (P<0.001). 18,19 In summary, MRD monitoring has proven to be highly reliable in predicting survival and forth coming relapses in AML. Monitoring of MRD cells by molecular, cytogenetic or immunophenotypic methods are of crucial value for defining individualized patient management. Based on MRD frequencies, patient-tailored post remission chemotherapy could be designed, which might reduce either the risk of relapse or, diminish morbidity and mortality by avoiding unnecessary intervention (Figure 2). In an event, when impending relapses are predictable, early therapeutic intervention may be less intense than otherwise required in an overt relapse. One, very important application of MRD testing could be to quantify leukemia cell contamination in autologous peripheral blood stem cell product in order to guide the decision to whether or not to purge, and, in the later case to establish the efficacy of leukemia cell eradication. 20 Table 1. Methods of detection of MRD in AL TECHNIQUE PROS CONS SENSITIVITY MORPHOLOGY FISH PCR FC >5% Blasts Fast ; no dividing cells required Limited to leukemias with available primers for common recurrent abnormalities Applicable in ~80% of cases; cost effective; accurate for normal and abnormal cell types; rapid turnaround (1-2 days) Low sensitivity; not suitable for subclinical disease Labor intensive; low level of sensitivity especially with low cell counts High likelihood of false-positive results, expensive; applicable in only a subset of AML and ALL Not as specific as PCR; phenotypic shifts post treatment or therapy; subpopulations of blasts 1% to 5% 0.3% to 5% 10-4 to 10-5 Comparison of morphology, Florescent-in-situ Hybridization (FISH), Polymerase chain reaction (PCR) and Flow cytometry (FC) in detection of MRD Adapted from A. Al-Mawali et al. Am J Clin Pathol 2009; 131:
3 MRD testing in acute lymphoblastic leukemia Childhood ALL is highly sensitive to chemotherapy. Nearly all patients receive complete remission following therapy and majority achieve complete cure. About a third of patients subsequently relapse and most of these ultimately die of their disease. Detection of minimal residual disease has been established as an independent prognostic variable of high clinical relevance in de-novo and relapsed cases of pediatric and adult ALL. 21 It is already incorporated as a valuable tool in most American and European protocols as a stratification tool. Leukemia lymphoblasts differ from physiologic counterparts in qualitative and quantitative antigen expression patterns. In addition, immature phenotypes outside the context of normal tissues can also serve as unique identifiers of blasts. Such LAPs are present in vast majority of ALL cases if a panel of 6 to 8 antibodies is employed in strategic combinations. This approach currently reaches sensitivities of 10-3 to Use of MFC has greatly improved the sensitivity/ specificity of this assay and allowed for simultaneous determination of multiple phenotypic patterns in leukemic cells. The stability of LAP is of major interest for purposes of targeted follow up. Comparing the patterns of immunophenotypic aberrancy to those of normal hematogones, Chen Weina et al found stable and reliable phenotypic differences which were retained in 80% of cases at relapse. However, there is increasing evidence documenting immunophenotypic changes in ALL during the course of disease with 30% to 70% of cases commonly reporting loss of CD10, HLA-DR, TdT and CD20 in addition to gain and/ or loss of myeloid antigens. Hence initial phenotypes only serve as orientation and guidelines and should not be used for planning strict gating strategies in follow ups. 22,23 Increased numbers of hematogones may also cause problems in MRD assessments especially in pediatric ALL setting. Hematogones are found in small numbers in most marrow specimens; however, they can occur in large numbers in healthy children 308
4 and in some disease states such as patients with autoimmune and congenital cytopenias, neoplasms and AIDS. They also commonly share overlapping morphologic features with blasts (Figure 2). In a study of immunophenotypic analysis of hemtogones involving 662 consecutive bone marrow specimens, McKena R W et al showed that hematogones exhibited a complex spectrum of antigen expression that followed the normal evolution of B- cells and completely lacked aberrancies such as asynchronous co-expression of earliest and latest antigens such as concurrent CD34 and CD20, and aberrant over- or under-expression of antigens normally present at a particular B-cell stage (Figure 2). In contrast, lymphoblasts in 49 cases of precursor B- ALLs exhibited at least one and often multiple immunophenotypic aberrancies. 24,25 Several other studies have suggested reliable methods of differentiating hematogones from neoplastic cells. Rimza et al found an increase in number of more mature precursor cells relative to least mature (CD34+ and TdT+) in bone marrow samples rich in hematogones. They also reported heterogeneous expression of adhesion molecules such as CD44 and CD54 on hematogones. 25,26 One should be mindful that an increase in immature cells including left shifted hematogones can be seen in the setting of early bone marrow recovery 309
5 such as post chemotherapy or transplant 27,28 In these setting there is even greater potential for mistaking hematogones with neoplastic cells, however, the maturational sequence is the rule among hematogones even in these cases and aberrant expression patterns are not noted. Other methods of detecting MRD which are in current use include sequencing of rearranged TCR or Immunoglobulin genes in ALL and PCR based detection of gene fusions resulting from recurrent cytogenetic abnormalities. Assays based on PCR or flow cytometry can detect one ALL cells among 10,000 to 100,000 normal cells in clinical samples. In most cases, MRD positivity is defined as the presence of 0.01% or more ALL cells; the risk of relapse generally is proportional to the level of MRD especially in the post chemotherapy induction phase. MRD is currently being used in several clinical protocols of risk adapted therapy. There is, however, considerable variability in time points selected for MRD testing and in the levels of MRD used to define risk of relapse. Nevertheless, its utility for treatment stratification and definition varies with the different protocols. The current COG protocol for instance recommends MRD testing at the end of remission induction (day 29) and the cut off levels used to assign risk are 0.1% and 1%. 29 Summary FC based MRD diagnostics has the distinct advantage of instant availability with regards to testing for blasts and normal marrow constituents at various time points in the natural history of acute leukemias. FC is widely used as a useful adjunct to diagnose remission status, overt relapse and MRD. Recent technical advances in routine flow cytometry with three lasers and up to eight colors and the new developments in software for data analysis make it a very reliable tool for MRD assessment provided the limitations of sensitivity, and treatment induced phenotypic shifts and difficulties in discriminating ALL cells from hematogones are carefully considered and standardized. This can only be achieved if a high degree of standardization can be reached for technical aspects and data interpretation and quality assurance programs are established to ensure reliable results. Intensive networking and open collaboration between clinical and diagnostic research groups will be the key to high level standardization and quality control for further improvements in MRD diagnostics. 310
6 References 1. D. Campana and C.-H. Pui. Detection of minimal residual disease in acute leukemia: methodologic advances and clinical significance. Blood, vol. 85, no. 6, pp , Hagenbeek A, Lowenberg B (eds): Minimal residual disease in Acute Leukemia. Dordrecht, the Netherlands,Nijhoff, Stow P, Key L, Chen X, et al. Clinical significance of low levels of minimal residual disease at the end of remission induction therapy in childhood acute lymphoblastic leukemia Blood 2010; 115: Bruggemann M, Raff T, Flohr T, et al. Clinical significance of minimal residual disease quantification in adult patients with standard-risk acute lymphoblastic leukemia. Blood 2006;107: Venditti A, Buccisano F, Del Poeta G, et al. Level of minimal residual disease after consolidation therapy predicts outcome in acute myeloid leukemia. Blood. 2000;96: Feller N, van der Pol M A, van Stijn A, et al. MRD parameters using immunophenotypic detection methods are highly reliable in predicting survival in acute myeloid leukaemia. Leukemia (2004) 18, Macedo A, San Miguel J F, Vidriales M B,et al Phenotypic changes in acute myeloid leukaemia: implications in the detection of minimal residual disease. J Clin Pathol 1996;49: Goldie J, Coldman A. Genetic instability in the development of drug resistance. Semin Oncol 1985; 12: Secker-Walker LM. Leukemia Research fund International Research Symposium: Chromosomes and genes in leukemia. Leukemia1988 ; 2: Macedo A, Orfao A, Vidriales MB, et al. Characterization of aberrant phenotypes in acute myeloblastic leukemia. Ann Hematol. 1995;70: Macedo A, Orfao A, Gonzalez M, et al. Immunological detection of blast cell populations in acute myeloblastic leukemia diagnosis: implications for minimal residual disease studies. Leukemia 1995;9: Kern W, Danhauser-Riedi S, Ratei R, et al. Detection of minimal residual disease in unselected patients with acute myeloid leukemia using multiparameter flow cytometry to define leukemia-associated immunophenotypes and determine their frequencies in normal bone marrow. Haematologica.2003;88: Voskova D, Valekova L, Fedorova J, et al. Leukemic cells and aberrant phenotypes in acute leukemia patients: a flow cytometry analysis. Neoplasma. 2003;50: Venditti A, Maurillo L, Buccisano F, et al. Multidimensional flow cytometry for detection of minimal residual disease in acute myeloid leukemia. Leuk Lymphoma. 2003; 44: Orfao A, Schmitz G, Brando B, et al. Clinically useful information provided by the flow cytometric immunophenotyping of hematological malignancies: current status and future directions. Clin Chem. 1999;45: Al-Mawali A, Gillis D, Lewis I. The Role of Multiparameter Flow Cytometry for Detection of Minimal Residual Disease in Acute Myeloid Leukemia. Am J Clin Pathol 2009;131: San Migual JF, Vidriales MB, Lopez-Berges C, et al. Early immunophenotypical evaluation of minimal residual disease in acute myeloid leukemia identifies different patient risk groups and may contribute to post induction treatment stratification. Blood 2001;98: Buccisano F, Maurillo L, Gattei V, et al. The kinetics of reduction of minimal residual disease impacts on duration of response and survival of patients with acute myeloid leukemia. Leukemia 2006;20: Venditti A Venditti A, Buccisano F, Del Poeta G, et al. Level of minimal residual disease after consolidation therapy predicts outcome in acute myeloid leukemia. Blood ;96: Vellenga E, van Putten WL, Boogaerts MA, et al. Peripheral blood stem cell transplantation as an alternative to autologous marrow transplantation in the treatment of acute myeloid leukemia? Bone Marrow Transplant 1999; 23: Campana D. Role of minimal residual disease monitoring in adult and pediatric acute lymphoblastic leukemia. Hematol Oncol Clin North Am,2009,23: Bruggemann M, Schrauder A, Raff T, et al. Standardized MRD quantification in European ALL trials: Proceedings of the Second International Symposium on MRD assessment in Kiel, Germany, September 2008 Leukemia (2010) 24, Chen W, Karandikar NJ, McKenna RW et al. Stability of Leukemia-Associated Immunophenotypes in Precursor B-Lymphoblastic Leukemia/Lymphoma. Am J Clin Pathol 2007; 127: McKenna RW, Washington LT, Aquino DB, et al. Immunophenotypic analysis of hematogones ( B- lymphocyte precursors) in 662 consecutive bone marrow specimens by 4-color flow cytometry. Blood. 2001;98: Rimsza LM, Larson RS, Winter SS, et al. Benign hematogone-rich lymphoid proliferations can be distinguished from B-lineage acute lymphoblastic leukemia by integration of morphology, immunophenotype, adhesion molecule expression, and architectural features. Am J Clin Pathol. 2000;114: van den Doel L, Pieters R, Huismans D, et al. Immunological phenotype of lymphoid cells in regenerating bone marrow of children after treatment of acute lymphoblastic leukemia. Eur J Haematol. 1988;41: van Wering ER, van der Linden-Schrever BEM, Szczepanski T, et al. Regenerating normal B-cell precursors during and after treatment of ALL. Br J Haematol 2000; 110: 139? Dworzak, M.N., Fritsch, G., Fleischer, C., et al. Multiparameter phenotype mapping of normal and post-chemotherapy B lymphopoiesis in pediatric bone marrow. Leukemia, , Schultz KR, Pullen DJ, Sather HN, et al. Risk- and response-based classification of childhood B-precursor acute lymphoblastic leukemia: a combined analysis of prognostic markers from the Pediatric Oncology Group (POG) and Children s Cancer Group (CCG). Blood 2007; 109:
CME. The Role of Multiparameter Flow Cytometry for Detection of Minimal Residual Disease in Acute Myeloid Leukemia
Hematopathology / Minimal Residual Disease in AML The Role of Multiparameter Flow Cytometry for Detection of Minimal Residual Disease in Acute Myeloid Leukemia Adhra Al-Mawali, PhD, 1-3 David Gillis, MBBS,
More informationMRD detection in AML. Adriano Venditti Hematology Fondazione Policlinico Tor Vergata Rome
MRD detection in AML Adriano Venditti Hematology Fondazione Policlinico Tor Vergata Rome Determinants of Treatment Response Leukemia Tumor burden Growth potential Drug resistance Karyotype Genetics Host
More informationMRD in ALL: Correct interpretation in clinical practice. Deepak Bansal Prof., Pediatric Hematology-Oncology unit PGIMER, Chandigarh
MRD in ALL: Correct interpretation in clinical practice Deepak Bansal Prof., Pediatric Hematology-Oncology unit PGIMER, Chandigarh Minimal residual disease Subclinical level of residual leukemia Below
More informationMixed Phenotype Acute Leukemias
Mixed Phenotype Acute Leukemias CHEN GAO; AMY M. SANDS; JIANLAN SUN NORTH AMERICAN JOURNAL OF MEDICINE AND SCIENCE APR 2012 VOL 5 NO.2 INTRODUCTION Most cases of acute leukemia can be classified based
More informationMinimal residual disease (MRD) in AML; coming of age. Dr. Mehmet Yılmaz Gaziantep University Medical School Sahinbey Education and Research hospital
Minimal residual disease (MRD) in AML; coming of age Dr. Mehmet Yılmaz Gaziantep University Medical School Sahinbey Education and Research hospital 1. The logistics of MRD assessment in AML 2. The clinical
More informationSignificant CD5 Expression on Normal Stage 3 Hematogones and Mature B Lymphocytes in Bone Marrow
Hematopathology / CD5 Expression on Normal B Cells Significant CD5 Expression on Normal Stage 3 Hematogones and Mature B Lymphocytes in Bone Marrow Franklin S. Fuda, DO, Nitin J. Karandikar, MD, PhD, and
More informationFirst relapsed childhood ALL Role of chemotherapy
First relapsed childhood ALL Role of chemotherapy Thirachit Chotsampancharoen, M.D. Division of Pediatric Hematology/Oncology Department of Pediatrics Prince of Songkla University Hat-Yai, Songkhla 25
More informationDr Prashant Tembhare
Dr Prashant Tembhare docprt@gmail.com FCM very powerful technology in Identification and characterization of neoplastic plasma cells as it allows - simultaneous assessment of multiple antigens large numbers
More informationVUmc Basispresentatie
Clinical diagnostic cytometry Gerrit J Schuurhuis Dept of Hematology VU University Medical Center Amsterdam, Netherlands Use of immunophenotyping at diagnosis to trace residual disease after therapy 1.
More informationJournal of the Egyptian Nat. Cancer Inst., Vol. 13, No. 3, September: , 2001
Journal of the Egyptian Nat. Cancer Inst., Vol. 13, No. 3, September: 191-201, 2001 Expression of the C-KIT Molecule in Acute Myeloid Leukemias: Implications of the Immunophenotypes CD117 and CD15 in the
More informationMyelodysplasia/Myeloproliferative Neoplasms (MDS/MPN) Post-HCT Data
Instructions for Myelodysplasia/Myeloproliferative Neoplasms (MDS/MPN) Post-HCT Data (Form 2114) This section of the CIBMTR Forms Instruction Manual is intended to be a resource for completing the Myelodysplasia/Myeloproliferative
More informationTools for MRD in AML: flow cytometry
ACUTE MYELOID LEUKEMIA MEETING Ravenna - October 27, 2017 Tools for MRD in AML: flow cytometry Francesco Buccisano Can MRD improve outcome determina3on? No. of leukemic cells 10 12 10 10 10 8 10 6 10 4
More informationMinimal Residual Disease as a Surrogate Endpoint in Acute Myeloid Leukemia Clinical Trials
Minimal Residual Disease as a Surrogate Endpoint in Acute Myeloid Leukemia Clinical Trials Fda.gov Adriano Venditti Hematology, University Tor Vergata, Rome, Italy Minimal Residual Disease 10 12 Relapse
More informationOriginal article. Key words: Lymphoblastic leukemia, Acute, Childhood, Minimal residual disease, Flow cytometry
Original article DOI: 10.5/kjp.2010.5.11.957 Korean J Pediatr 2010;5(11):957-96 Prognostic significance of minimal residual disease detected by a simplified flow cytometric assay during remission induction
More informationNUMERATOR: Patients who had baseline cytogenetic testing performed on bone marrow
Quality ID #67 (NQF 0377): Hematology: Myelodysplastic Syndrome (MDS) and Acute Leukemias: Baseline Cytogenetic Testing Performed on Bone Marrow National Quality Strategy Domain: Effective Clinical Care
More informationSWOG ONCOLOGY RESEARCH PROFESSIONAL (ORP) MANUAL LEUKEMIA FORMS CHAPTER 16A REVISED: DECEMBER 2017
LEUKEMIA FORMS The guidelines and figures below are specific to Leukemia studies. The information in this manual does NOT represent a complete set of required forms for any leukemia study. Please refer
More informationElisabeth Koller 3rd Medical Dept., Center for Hematology and Oncology, Hanusch Hospital, Vienna, Austria
Elisabeth Koller 3rd Medical Dept., Center for Hematology and Oncology, Hanusch Hospital, Vienna, Austria Incidence Diagnosis Prognostic factors Treatment Induction therapy - HSCT Indications for HSCT
More informationAcute myeloid leukemia. M. Kaźmierczak 2016
Acute myeloid leukemia M. Kaźmierczak 2016 Acute myeloid leukemia Malignant clonal disorder of immature hematopoietic cells characterized by clonal proliferation of abnormal blast cells and impaired production
More informationHEMATOLOGIC MALIGNANCIES BIOLOGY
HEMATOLOGIC MALIGNANCIES BIOLOGY Failure of terminal differentiation Failure of differentiated cells to undergo apoptosis Failure to control growth Neoplastic stem cell FAILURE OF TERMINAL DIFFERENTIATION
More informationN Engl J Med Volume 373(12): September 17, 2015
Review Article Acute Myeloid Leukemia Hartmut Döhner, M.D., Daniel J. Weisdorf, M.D., and Clara D. Bloomfield, M.D. N Engl J Med Volume 373(12):1136-1152 September 17, 2015 Acute Myeloid Leukemia Most
More informationETP - Acute Lymphoblastic Leukaemia
ETP - Acute Lymphoblastic Leukaemia Dr Sally Campbell - Royal Children s Hospital Melbourne 24 February 2017 T-ALL 12-15% of all newly diagnosed ALL cases in pediatrics are T-ALL T-ALL behaves differently
More informationHematology Measure #1: Myelodysplastic Syndrome (MDS) and Acute Leukemias: Baseline Cytogenetic Testing Performed on Bone Marrow
Hematology Measure #1: Myelodysplastic Syndrome (MDS) and Acute Leukemias: Baseline Cytogenetic Testing Performed on Bone Marrow This measure may be used as an Accountability measure Clinical Performance
More informationAcute Lymphoblastic and Myeloid Leukemia
Acute Lymphoblastic and Myeloid Leukemia Pre- and Post-Disease Form Acute Lympoblastic Leukemia Mary Eapen MD, MS Acute Lymphoblastic Leukemia SEER Age-adjusted incidence rate 1.6 per 100,000 men and women
More informationHandout for lecture on lymphoblastic neoplasms presented by Rob McKenna
Handout for lecture on lymphoblastic neoplasms presented by Rob McKenna The following slides represent a near final version of the presentation that will be given in Maui, January 23,2018. Minor changes
More informationRisk Stratification in Childhood Leukemia
Risk Stratification in Childhood Leukemia Why is risk stratification important? Toxicities Deepa Bhojwani, MD May 11, 2018 To determine intensity of therapy - When to intensify therapy - When to de-intensify
More informationMolecular Pathology Evaluation Panel and Molecular Pathology Consortium Advice Note
Molecular Pathology Evaluation Panel and Molecular Pathology Consortium Advice Note MPEP/MPC Advice Note 2016-02 June 2016 Test evaluated: Tumour Protein p53 (TP53) Molecular Pathology Evaluation Panel
More informationAbstract. Hematopathology / HEMATOGONE POPULATIONS
Hematopathology / HEMATOGONE POPULATIONS Benign Hematogone-Rich Lymphoid Proliferations Can Be Distinguished From B-Lineage Acute Lymphoblastic Leukemia by Integration of Morphology, Immunophenotype, Adhesion
More informationJohann Hitzler, MD, FRCPC, FAAP Jacqueline Halton, MD, FRCPC Jason D. Pole, PhD
Photo by Tynan Studio Johann Hitzler, MD, FRCPC, FAAP Jacqueline Halton, MD, FRCPC Jason D. Pole, PhD 96 Atlas of Childhood Cancer in Ontario (1985-2004) Chapter 6: Leukemia 6 Leukemia Atlas of Childhood
More informationStandard risk ALL (and its exceptions
Mahshid Mehdizadeh Standard risk ALL (and its exceptions WBC at diagnosis below 50 109/L - age 1 year - no central nervous system (CNS) involvement - ETV6/RUNX1 positivity - MRD at Day
More informationCorporate Medical Policy. Policy Effective February 23, 2018
Corporate Medical Policy Genetic Testing for FLT3, NPM1 and CEBPA Mutations in Acute File Name: Origination: Last CAP Review: Next CAP Review: Last Review: genetic_testing_for_flt3_npm1_and_cebpa_mutations_in_acute_myeloid_leukemia
More informationTest Utilization: Chronic Lymphocytic Leukemia
Test Utilization: Chronic Lymphocytic Leukemia Initial Evaluation Diagnostic Criteria Selection of Tests for Prognosis Response to Therapy Challenges Assessment for persistent disease Paul J. Kurtin, M.D.
More informationACUTE LYMPHOBLASTIC LEUKEMIA
ACUTE LYMPHOBLASTIC LEUKEMIA YOUNG ADULT PATIENT Highlights clonoseq Tracking (MRD) Testing in the peripheral blood revealed early signs of relapse post-transplant Patient achieved remission after CAR-T
More informationDifferential diagnosis of hematolymphoid tumors composed of medium-sized cells. Brian Skinnider B.C. Cancer Agency, Vancouver General Hospital
Differential diagnosis of hematolymphoid tumors composed of medium-sized cells Brian Skinnider B.C. Cancer Agency, Vancouver General Hospital Lymphoma classification Lymphoma diagnosis starts with morphologic
More informationStandard immunophenotyping of leukemia cells in acute myeloid leukemia (AML)
Clinical immunology Standard immunophenotyping of leukemia cells in acute myeloid leukemia (AML) ` JOLANTA WOZNIAK, JOANNA KOPEÆ-SZLÊZAK Department of Haematological Cytobiology, Institut of Haematology
More informationFlow cytometry for MRD detec1on: Focus on AML. Sindhu Cherian University of Washington, Sea6le, WA, USA
Flow cytometry for MRD detec1on: Focus on AML Sindhu Cherian University of Washington, Sea6le, WA, USA Residual disease in hematopoie1c malignancy Residual disease has tradi:onal been defined by morphology
More informationCase Report Blasts-more than meets the eye: evaluation of post-induction day 21 bone marrow in CBFB rearranged acute leukemia
Int J Clin Exp Pathol 2014;7(7):4498-4502 www.ijcep.com /ISSN:1936-2625/IJCEP0000851 Case Report Blasts-more than meets the eye: evaluation of post-induction day 21 bone marrow in CBFB rearranged acute
More informationThe spectrum of flow cytometry of the bone marrow
The spectrum of flow cytometry of the bone marrow Anna Porwit Lund University Faculty of Medicine Dept. of Clinical Sciences Div. Oncology and Pathology anna.porwit@med.lu.se Disclosure of speaker s interests
More informationExtramedullary precursor T-lymphoblastic transformation of CML at presentation
Extramedullary precursor T-lymphoblastic transformation of CML at presentation Neerja Vajpayee, Constance Stein, Bernard Poeisz & Robert E. Hutchison Clinical History 30 year old man presented to the emergency
More informationNormal Blood and Bone Marrow Populations
4 CHAPTER 4 Normal Blood and Bone Marrow Populations It is essential to have a sound understanding of the nature and immunophenotypic characteristics of the normal cell populations encountered in bone
More informationInstructions for Chronic Lymphocytic Leukemia Post-HSCT Data (Form 2113)
Instructions for Chronic Lymphocytic Leukemia Post-HSCT Data (Form 2113) This section of the CIBMTR Forms Instruction Manual is intended to be a resource for completing the CLL Post-HSCT Data Form. E-mail
More informationPDF of Trial CTRI Website URL -
Clinical Trial Details (PDF Generation Date :- Wed, 19 Dec 2018 02:45:15 GMT) CTRI Number Last Modified On 25/12/2017 Post Graduate Thesis Type of Trial Type of Study Study Design Public Title of Study
More informationTherapy-related MDS/AML with KMT2A (MLL) Rearrangement Following Therapy for APL Case 0328
Therapy-related MDS/AML with KMT2A (MLL) Rearrangement Following Therapy for APL Case 0328 Kenneth N. Holder, Leslie J. Greebon, Gopalrao Velagaleti, Hongxin Fan, Russell A. Higgins Initial Case: Clinical
More informationFLOW CYTOMETRIC ANALYSIS OF NORMAL BONE MARROW
XI International Conference Hematopoiesis Immunology Budapest, June 6-7, 2014 FLO CYTOMETRIC ANALYSIS OF NORMAL BONE MARRO Bruno Brando and Arianna Gatti Hematology Laboratory and Transfusion Center Legnano
More informationTest Name Results Units Bio. Ref. Interval. Positive
LL - LL-ROHINI (NATIONAL REFERENCE 135091533 Age 28 Years Gender Male 1/9/2017 120000AM 1/9/2017 105415AM 4/9/2017 23858M Ref By Final LEUKEMIA DIAGNOSTIC COMREHENSIVE ROFILE, ANY 6 MARKERS t (1;19) (q23
More informationImmunopathology of Lymphoma
Immunopathology of Lymphoma Noraidah Masir MBBCh, M.Med (Pathology), D.Phil. Department of Pathology Faculty of Medicine Universiti Kebangsaan Malaysia Lymphoma classification has been challenging to pathologists.
More informationEarly Clearance of Peripheral Blood Blasts Predicts Response to Induction Chemotherapy in Acute Myeloid Leukemia
Early Clearance of Peripheral Blood Blasts Predicts Response to Induction Chemotherapy in Acute Myeloid Leukemia Martha Arellano, MD 1 ; Suchita Pakkala, MD 1 ; Amelia Langston, MD 1 ; Mourad Tighiouart,
More informationNUP214-ABL1 Fusion: A Novel Discovery in Acute Myelomonocytic Leukemia
Case 0094 NUP214-ABL1 Fusion: A Novel Discovery in Acute Myelomonocytic Leukemia Jessica Snider, MD Medical University of South Carolina Case Report - 64 year old Caucasian Male Past Medical History Osteoarthritis
More informationAppendix 6: Indications for adult allogeneic bone marrow transplant in New Zealand
Appendix 6: Indications for adult allogeneic bone marrow transplant in New Zealand This list provides indications for the majority of adult BMTs that are performed in New Zealand. A small number of BMTs
More informationSponsored and reviewed by ICCS Quality and Standards Committee Title: Expression of CD5 on Normal Hematolymphoid Cells Written by:
Sponsored and reviewed by ICCS Quality and Standards Committee Title: Expression of CD5 on Normal Hematolymphoid Cells Written by: Weina Chen and Buddy Frank Fuda Date: Jan 25, 2019 INTRODUCTION CD5 was
More informationTHE USE OF WT1-QPCR TO MEASURE AND DETECT MINIMAL RESIDUAL DISEASE IN ACUTE MYELOID LEUKEMIA. Ava Greco
THE USE OF WT1-QPCR TO MEASURE AND DETECT MINIMAL RESIDUAL DISEASE IN ACUTE MYELOID LEUKEMIA Ava Greco REVIEW OF LITERATURE What is Leukemia? Abnormal growth of cells in the blood stream Progresses rapidly
More informationChanges to the 2016 WHO Classification for the Diagnosis of MDS
Changes to the 2016 WHO Classification for the Diagnosis of MDS Welcome to Managing MDS. I am Dr. Ulrich Germing, and today, I will provide highlights from the 14th International Symposium on MDS in Valencia,
More informationRelapsed acute lymphoblastic leukemia. Lymphoma Tumor Board. July 21, 2017
Relapsed acute lymphoblastic leukemia Lymphoma Tumor Board July 21, 2017 Diagnosis - Adult Acute Lymphoblastic Leukemia (ALL) Symptoms/signs include: Fever Increased risk of infection (especially bacterial
More informationMulti-color flow cytometric immunophenotyping for detection of minimal residual disease in AML: past, present and future
Bone Marrow Transplantation (2014) 49, 1129 1138 2014 Macmillan Publishers Limited All rights reserved 0268-3369/14 www.nature.com/bmt REVIEW Multi-color flow cytometric immunophenotyping for detection
More information7 Omar Abu Reesh. Dr. Ahmad Mansour Dr. Ahmad Mansour
7 Omar Abu Reesh Dr. Ahmad Mansour Dr. Ahmad Mansour -Leukemia: neoplastic leukocytes circulating in the peripheral bloodstream. -Lymphoma: a neoplastic process in the lymph nodes, spleen or other lymphatic
More informationCorporate Medical Policy
Corporate Medical Policy Hematopoietic Cell Transplantation for CLL and SLL File Name: Origination: Last CAP Review: Next CAP Review: Last Review: hematopoietic_cell_transplantation_for_cll_and_sll 2/2001
More informationMultidimensional Flow Cytometry for Detection of Rare Populations in Hematological Malignancies
TZU CHI MED J March 2009 Vol 21 No 1 available at http://ajws.elsevier.com/tcmj Tzu Chi Medical Journal Original Article Multidimensional Flow Cytometry for Detection of Rare Populations in Hematological
More informationSUPPLEMENTARY INFORMATION
Supplementary Information S1 Frequency of DNMT3A mutations in hematologic disorders and their associated clinical phenotypes. Disease Patient population Frequency (%) Associated Clinical Characteristics
More informationFerrata Storti Foundation
Published Ahead of Print on November 30, 2009, as doi:10.3324/haematol.2009.018911. Copyright 2009 Ferrata Storti Foundation. Early Release Paper Enhanced sensitivity of flow cytometry for routine assessment
More informationMast Cell Disease Case 054 Session 7
Mast Cell Disease Case 054 Session 7 Rodney R. Miles, M.D., Ph.D. Lauren B. Smith, M.D. Cem Akin, M.D. Diane Roulston,, Ph.D. Charles W. Ross, M.D. Departments of Pathology and Internal Medicine University
More informationAcute Myeloid Leukemia: A Patient s Perspective
Acute Myeloid Leukemia: A Patient s Perspective Patrick A Hagen, MD, MPH Cardinal Bernardin Cancer Center Loyola University Medical Center Maywood, IL Overview 1. What is AML? 2. Who gets AML? Epidemiology
More informationSuccessful flow cytometric immunophenotyping of body fluid specimens
Successful flow cytometric immunophenotyping of body fluid specimens Fiona E. Craig, MD Division of Hematopathology Mayo Clinic Arizona 2017 MFMER slide-1 Financial disclosure No conflicts 2017 MFMER slide-2
More informationWBCs Disorders 1. Dr. Nabila Hamdi MD, PhD
WBCs Disorders 1 Dr. Nabila Hamdi MD, PhD ILOs Compare and contrast ALL, AML, CLL, CML in terms of age distribution, cytogenetics, morphology, immunophenotyping, laboratory diagnosis clinical features
More informationLeukemias. Prof. Mutti Ullah Khan Head of Department Medical Unit-II Holy Family Hospital Rawalpindi Medical College
Leukemias Prof. Mutti Ullah Khan Head of Department Medical Unit-II Holy Family Hospital Rawalpindi Medical College Introduction Leukaemias are malignant disorders of the haematopoietic stem cell compartment,
More informationLymphoblastic Leukemia / Lymphoma
1 5014 - Topics in Pediatric Hematopathology: Acute Lymphoblastic Leukemia, Including Changes in the Revised WHO Classification, and Unusual Pediatric Myeloid Neoplasms Robert W. McKenna, MD MASCP * Elizabeth
More informationCase #16: Diagnosis. T-Lymphoblastic lymphoma. But wait, there s more... A few weeks later the cytogenetics came back...
Case #16: Diagnosis T-Lymphoblastic lymphoma But wait, there s more... A few weeks later the cytogenetics came back... 46,XY t(8;13)(p12;q12)[12] Image courtesy of Dr. Xinyan Lu Further Studies RT-PCR
More informationADVANCES IN CHILDHOOD ACUTE LEUKEMIAS : GENERAL OVERVIEW
ADVANCES IN CHILDHOOD ACUTE LEUKEMIAS : GENERAL OVERVIEW Danièle SOMMELET European Scientific Seminar Luxemburg, 3.11.2009 1 Definition of acute leukemias Malignant process coming from lymphoid (85 %)
More informationPacharapan Surapolchai, MD Associate Professor Department of Pediatrics, Faculty of Medicine, Thammasat University, Thailand October 2018
Pacharapan Surapolchai, MD Associate Professor Department of Pediatrics, Faculty of Medicine, Thammasat University, Thailand October 2018 Outline Case study Introduction of Current management of infantile
More informationRole of FISH in Hematological Cancers
Role of FISH in Hematological Cancers Thomas S.K. Wan PhD,FRCPath,FFSc(RCPA) Honorary Professor, Department of Pathology & Clinical Biochemistry, Queen Mary Hospital, University of Hong Kong. e-mail: wantsk@hku.hk
More informationMinimal residual disease: optimal methods, timing, and clinical relevance for an individual patient
DYNAMIC DISCOVERIES AND DIRECTIONS IN PEDIATRIC LEUKEMIAS Minimal residual disease: optimal methods, timing, and clinical relevance for an individual patient Martin Schrappe 1 1 Department of Pediatrics
More informationJordi Esteve Hospital Clínic (Barcelona) Acute Leukemia Working Party. The European Group for Blood and Marrow Transplantation
36th EBMT & 9th Data Management Group Annual Meeting Vienna, 23 March 2010 Jordi Esteve Hospital Clínic (Barcelona) Acute Leukemia Working Party The European Group for Blood and Marrow Transplantation
More informationMUD SCT for Paediatric AML?
7 th South African Symposium on Haematopoietic Stem Cell Transplantation MUD SCT for Paediatric AML? Alan Davidson Haematology / Oncology Service Red Cross Children s Hospital THE SCENARIO A 10 year old
More informationGuideline on the use of minimal residual disease as a clinical endpoint in multiple myeloma studies
1 2 3 26 July 2018 EMA/CHMP/459559/2018 Committee for Medicinal Products for Human Use (CHMP) 4 5 6 Guideline on the use of minimal residual disease as a clinical endpoint in multiple Draft Draft agreed
More informationa resource for physicians Recommended Referral Timing for Stem Cell Transplant Evaluation
a resource for physicians Recommended Referral Timing for Stem Cell Transplant Evaluation This resource has been developed to help guide you regarding the appropriate timing and conditions for a referral
More informationNormal & Leukaemic haematopoiesis. Dr. Liu Te Chih Dept of Haematology / Oncology National University Health Services Singapore
Normal & Leukaemic haematopoiesis 2010 Dr. Liu Te Chih Dept of Haematology / Oncology National University Health Services Singapore Use of Immunophenotyping today Lineage assignment Differentiation of
More informationCleveland Clinic Laboratories Hematology Diagnostic Services. Trust in us for everything you need in a reference lab.
Cleveland Clinic Laboratories Hematology Diagnostic Services Trust in us for everything you need in a reference lab. Our Mission The Pathology and Laboratory Medicine Institute contributes to excellent
More informationCurrent Indications of Bone Marrow Transplantation (BMT) in Pediatric Malignant Conditions; a Review
EXPERT OPINION Current Indications of Bone Marrow Transplantation (BMT) in Pediatric Malignant Conditions; a Review Chi-Kong Li Department of Pediatrics, Prince of Wales Hospital, The Chinese University
More informationHAEMATOLOGICAL MALIGNANCY
HAEMATOLOGICAL MALIGNANCY Reference Compulsory reading Haematology at Glance 2 nd ed. Atul Mehta & Victor Hoffbrand Chapters: 20 to 31 Pages: 46 to 69 Pathogenesis of Haematological Malignancy Figure (a)
More informationSupplementary Appendix
Supplementary Appendix This appendix has been provided by the authors to give readers additional information about their work. Supplement to: Schlenk RF, Döhner K, Krauter J, et al. Mutations and treatment
More informationBumps on the Neck and Groin of a 2-Year-Old Male. Laboratory Findings: Table 1, Table 2; Figure 1; Image 1, Image 2, Image 3
Bumps on the Neck and Groin of a 2-Year-Old Male 1 Erikakelly Strand, BS* Clinical History Patient: 2-year-old white male. Chief Complaint: Bumps on neck and groin. History of Present Illness: A 2-year-old
More informationMeeting VAKB 8 februari 2011 Nancy Boeckx, MD, PhD
Meeting VAKB 8 februari 2011 Nancy Boeckx, MD, PhD What is it? clonal expansion of myeloid precursor cells with reduced capacity to differentiate as opposed to ALL/CLL, it is limited to the myeloid cell
More informationMyeloid neoplasms. Early arrest in the blast cell or immature cell "we call it acute leukemia" Myoid neoplasm divided in to 3 major categories:
Myeloid neoplasms Note: Early arrest in the blast cell or immature cell "we call it acute leukemia" Myoid neoplasm divided in to 3 major categories: 1. AML : Acute myeloid leukemia(stem cell with myeloid
More informationClassification of Hematologic Malignancies. Patricia Aoun MD MPH
Classification of Hematologic Malignancies Patricia Aoun MD MPH Objectives Know the basic principles of the current classification system for hematopoietic and lymphoid malignancies Understand the differences
More informationRecommended Timing for Transplant Consultation
REFERRAL GUIDELINES Recommended Timing for Transplant Consultation Published jointly by the National Marrow Donor Program /Be The Match and the American Society for Blood and Marrow Transplantation BeTheMatchClinical.org
More informationLEUKAEMIA and LYMPHOMA. Dr Mubarak Abdelrahman Assistant Professor Jazan University
LEUKAEMIA and LYMPHOMA Dr Mubarak Abdelrahman Assistant Professor Jazan University OBJECTIVES Identify etiology and epidemiology for leukemia and lymphoma. Discuss common types of leukemia. Distinguish
More informationCorrelation of Sex and Remission of Acute Lymphoblastic Leukemia-L1 (ALL-L1) in Children
International Journal of Clinical and Experimental Medical Sciences 2015; 1(2): 11-15 Published online July 6, 2015 (http://www.sciencepublishinggroup.com/j/ijcems) doi: 10.11648/j.ijcems.20150102.12 Correlation
More informationAcute myeloid leukemia: prognosis and treatment. Dimitri A. Breems, MD, PhD Internist-Hematoloog Ziekenhuis Netwerk Antwerpen Campus Stuivenberg
Acute myeloid leukemia: prognosis and treatment Dimitri A. Breems, MD, PhD Internist-Hematoloog Ziekenhuis Netwerk Antwerpen Campus Stuivenberg Patient Female, 39 years History: hypothyroidism Present:
More informationTest Name Results Units Bio. Ref. Interval. Positive
Lab No 135091548 Age 35 Years Gender Female 1/9/2017 120000AM 1/9/2017 103420AM 4/9/2017 23753M Ref By Dr UNKNWON Final Test Results Units Bio Ref Interval LEUKEMIA DIAGNOSTIC COMREHENSIVE ROFILE 3 t (1;19)
More informationFLOCK Cluster Analysis of Mast Cell Event Clustering by High-Sensitivity Flow Cytometry Predicts Systemic Mastocytosis
FLOCK Cluster Analysis of Mast Cell Event Clustering by High-Sensitivity Flow Cytometry Predicts Systemic Mastocytosis David M. Dorfman, MD, PhD, Charlotte D. LaPlante, Olga Pozdnyakova, MD, PhD, and Betty
More informationPersonalized Therapy for Acute Myeloid Leukemia. Patrick Stiff MD Loyola University Medical Center
Personalized Therapy for Acute Myeloid Leukemia Patrick Stiff MD Loyola University Medical Center 708-327-3216 Major groups of Mutations in AML Targets for AML: Is this Achievable? Chronic Myeloid Leukemia:
More informationRAEB-2 2 Transforming to Acute Erythroleukemia Case # 165
RAEB-2 2 Transforming to Acute Erythroleukemia Case # 165 Sebastian J. Sasu, M.D. UCLA Medical Center, Hematopathology Los Angeles, CA and Saint John s s Health Center Santa Monica, CA Clinical History
More informationReactive and Neoplastic Lymphocytosis
Reactive and Neoplastic Lymphocytosis Koranda A. Walsh, VMD, BS Assistant Professor, Clinical Pathobiology University of Pennsylvania School of Veterinary Medicine PLEASE NOTE: These notes are meant as
More informationPathology. #11 Acute Leukemias. Farah Banyhany. Dr. Sohaib Al- Khatib 23/2/16
35 Pathology #11 Acute Leukemias Farah Banyhany Dr. Sohaib Al- Khatib 23/2/16 1 Salam First of all, this tafreegh is NOT as long as you may think. If you just focus while studying this, everything will
More informationModule 3: Multiple Myeloma Induction and Transplant Strategies Treatment Planning
Module 3: Multiple Myeloma Induction and Transplant Strategies Treatment Planning Challenge Question: Role of Autologous Stem Cell Transplant Which of the following is true about eligibility for high-dose
More informationMolecular Detection of BCR/ABL1 for the Diagnosis and Monitoring of CML
Molecular Detection of BCR/ABL1 for the Diagnosis and Monitoring of CML Imran Mirza, MD, MS, FRCPC Pathology & Laboratory Medicine Institute Sheikh Khalifa Medical City, Abu Dhabi, UAE. imirza@skmc.ae
More informationHematopathology Case Study
Hematopathology Case Study AMP Outreach Course 2009 AMP Annual Meeting John Greg Howe Ph.D. Department of Laboratory Medicine Yale University School of Medicine November 19, 2009 HISTORY Case History An
More informationIf unqualified, Complete remission is considered to be Haematological complete remission
Scroll right to see the database codes for Disease status and Response Diagnosis it refers to Disease status or response to treatment AML ALL CML CLL MDS or MD/MPN or acute leukaemia secondary to previous
More informationIf unqualified, Complete remission is considered to be Haematological complete remission
Scroll right to see the database codes for Disease status and Response Diagnosis it refers to Disease status or response to treatment AML ALL CML CLL MDS or MD/MPN or acute leukaemia secondary to previous
More informationMolecular Advances in Hematopathology
Molecular Advances in Hematopathology HOW MOLECULAR METHODS HAVE CHANGED MY PRACTICE Objectives Understand the importance of cytogenetic/molecular studies in hematolymphoid diseases Know some of the important
More informationADx Bone Marrow Report. Patient Information Referring Physician Specimen Information
ADx Bone Marrow Report Patient Information Referring Physician Specimen Information Patient Name: Specimen: Bone Marrow Site: Left iliac Physician: Accession #: ID#: Reported: 08/19/2014 - CHRONIC MYELOGENOUS
More informationProtocol. Hematopoietic Stem-Cell Transplantation for Acute Myeloid Leukemia
Hematopoietic Stem-Cell Transplantation for Acute Myeloid (80126) Medical Benefit Effective Date: 07/01/14 Next Review Date: 05/15 Preauthorization Yes Review Dates: 04/07, 05/08, 05/09, 05/10, 05/11,
More information