Acute myelogenous leukemia (AML) arises from myeloid precursor cells in the bone marrow. These immature cells or blasts give rise to myeloblasts, monoblasts, erythroblasts, and megakaryoblasts. The symptoms of AML are similar to other acute leukemias and may present with flu-like symptoms, bleeding, and occasionally hepatosplenomegaly and lymphadenopathy. The identification of several chromosomal abnormalities has led to tremendous advances in leukemia research. Some investigators have proposed new classification systems based upon any possible association with myelodysplasia and cytogenetic abnormalities.
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EPIDEMIOLOGY CHARACTERIZATION SYNONYMS Acute non-lymphoblastic leukemia (ANLL) INCIDENCE 2.1/100,000 in USA M0 5-10% of cases of AML M1 10-20% M2 30-45% M3 5-10% M4 15-25% M5A 5-8% M5B 3-6% M6 5% M7 8-10% AGE (MEDIAN AND RANGE) M0 All age groups M1 Median 46 years M2 20% <25 years
40% >60 years
M3 Median 38 years M4 Median 50 years M5A Median 16 years
75% <25 years
M5B Median 49 years M6 Median 54 years M7 All age groups
FAB CLASSIFICATION CHROMOSOME ABNORMALITY FREQUENCY (PERCENTAGE) M3 t(15;17)(q22;q11-12) 95-100 M4EO inv(16)(p13q22) or t(16;16)(p13;q22) 100 M2 t(8;21)(q22;q22) 18-20 M1-M2 t(9;22)(q34;q11) 8 M1, M2, M4, M5, M6 +8 9 M1, M4, M5 t(v;11)(v;q23)
v=vary chromosomes 9 and 19
Realistic Pathologic Classification of Acute Myeloid Leukemias
Daniel A. Arber
Am J Clin Pathol 2001;115:552-560 Abstract quote
Most classification systems of acute myeloid leukemia (AML) rely largely on the criteria proposed by the French-American-British (FAB) Cooperative Group. The recently proposed World Health Organization (WHO) classification of neoplastic diseases of the hematopoietic and lymphoid tissues includes a classification of AMLs.
The proposed WHO classification of AMLs includes traditional FAB-type categories of disease, as well as additional disease types that correlate with specific cytogenetic findings and AML associated with myelodysplasia. This system includes a large number of disease categories, many of which are of unknown clinical significance, and there seems to be substantial overlap between disease groups in the WHO proposal. Some disease types in the WHO proposal cannot be diagnosed without detailed clinical information, or they are diagnosed only by the cytogenetic findings. In this report, a realistic pathologic classification for AML is proposed that includes disease types that correlate with specific cytogenetic translocations and can be recognized reliably by morphologic evaluation and immunophenotyping and that incorporates the importance of associated myelodysplastic changes.
This system would be supported by cytogenetic or molecular genetic studies and could be expanded as new recognizable clinicopathologic entities are described.
CHARACTERIZATION LYSOZYME, SERUM Inceased in 50% of cases of AML M5A PCR
A novel method for the detection, quantitation, and breakpoint cluster region determination of t(15;17) fusion transcripts using a one-step real-time multiplex RT-PCR.
Choppa PC, Gomez J, Vall HG, Owens M, Rappaport H, Lopategui JR.
IMPATH, 5300 McConnell Ave, Los Angeles, CA 90066, USA.
Am J Clin Pathol 2003 Jan;119(1):137-44 Abstract quote
Individuals with acute promyelocytic leukemia (APL) usually express 1 of 3 primary hybrid transcripts associated with a t(15;17). The 3 fusion transcripts are the result of heterogeneous breakpoint cluster regions (bcr) within the promyelocytic leukemia (PML) gene and are denoted bcr1 (long), bcr2 (variant), and bcr3 (short) forms. Many researchers have shown that real-time quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) of the involved transcript is a valuable tool for monitoring APL and its treatment. In addition, some research suggests that identification of a specific breakpoint region may be used to predict an individual's likelihood of relapse and possibly their response to all-trans retinoic acid treatment.
We describe the first reported 1-step multiplex RT-PCR assay capable of t(15;17) fusion transcript real-time relative quantitation and simultaneous transcript form identification in 2 reactions. This assay uses a novel dual-probe technique to achieve what has required a laborious procedure of 2 or more reactions followed by postamplification analysis.
We found a correlation of 100% in detection and breakpoint determination of the long, short, and variant forms with a breakpoint 5' to nucleotide 1709 compared with results from traditional methods.
GROSS AND CLINICAL DISEASE VARIANTS CHARACTERIZATION
Cutaneous promyelocytic sarcoma at sites of vascular access and marrow aspiration. A characteristic localization of chloromas in acute promyelocytic leukemia?
Sanz MA, Larrea L, Sanz G, Martin G, Sempere A, Gomis F, Martinez J, Regadera A, Saavedra S, Jarque I, Jimenez C, Cervera J, de La Rubia J.
Servicio de Hematologia, Hospital Universitario La Fe, Av. Campanar 21, 46009 Valencia, Spain.
Haematologica 2000 Jul;85(7):758-62 Abstract quote
Extramedullary disease (EMD) is a rare clinical event in acute promyelocytic leukemia (APL). Although the skin is involved in half of the reported EMD cases, the occurrence of cutaneous promyelocytic sarcoma (PS) has been described very rarely.
We report here three cases of PS which have the peculiarity of appearing at sites of punctures for arterial and venous blood and marrow samples (sternal manubrium, antecubital fossa, wrist over the radial artery pulse, catheter insertion scar).
At presentation, all patients had hyperleukocytosis and a morphologic diagnosis of microgranular acute promyelocytic leukemia variant confirmed at the genetic level by demonstration of the specific chromosomal translocation t(15;17). A BCR3 type PML/RARa transcript was documented in the two patients for whom diagnostic RT-PCR was available. Patients had morphologic bone marrow remission at the time the PS appeared. A predilection for the development of cutaneous PS at sites of previous vascular damage has been noted, but the pathogenesis remains largely unknown. A potential role for all-trans retinoic acid has been advocated, although one of the three patients in our series had received no ATRA.
A review of the literature revealed six similar cases and hyperleukocytosis at diagnosis was a consistent finding in all of them. A careful physical examination of these particular sites in the follow-up of patients at risk, as well as cutaneous biopsy and laboratory examination of suspected lesions are strongly recommended.
Sweet's syndrome in acute myelogenous leukemia presenting as periorbital cellulitis with an infiltrate of leukemic cells
Kelli W. Morgan, MD
Jeffrey P. Callen, MD
J Am Acad Dermatol 2001;45:590-5 Abstract quote
Sweet's syndrome is characterized by the abrupt onset of fever, neutrophilic leukocytosis, and erythematous, tender pseudovesiculated plaques or nodules that respond readily to corticosteroid therapy. It is usually distinguished by the presence of mature neutrophils on histopathologic examination.
We describe a 38-year-old man with acute myelogenous leukemia who had an erythematous vesicular eruption of the left eye develop that resembled cellulitis.
A biopsy specimen revealed a dermal infiltrate of mature neutrophils and immature myeloblastic precursors. He later had hemorrhagic pseudovesiculated plaques develop bilaterally on his hands. A biopsy specimen again revealed abundant neutrophils with immature forms. A similar eruption developed at the site of a Hickman catheter placement 4 months later. His skin lesions responded rapidly to oral corticosteroids.
This case is unique in that his initial presentation of Sweet's syndrome resembled orbital cellulitis that was characterized by immature myeloid precursors on histopathology.
HISTOLOGICAL TYPES CHARACTERIZATION BLASTS Type I myeloblast Fine nuclear chromatin with 2-4 distinct nucleoli
Moderate rim of pale to basophilic cytoplasm without azurophilic granules
Type II myeloblast
Similar to type 1 blast with addition of up to 20 delicate azurophilic granules in the cytoplasm
Promyelocyte is larger than type II blast and has numerous azurophilic granules
Type III myeloblast Numerous azurophilic granules but smaller than promyelocyte FRENCH-AMERICAN-BRITISH CLASSIFICATION (FAB)
By definition, acute leukemia is diagnosed with 20%of type I and II blasts but some variants such as M3 rarely have 20% blasts
MPO is myeloperoxidase
SBB is Sudan Black B
NSE is non specific esterase
Acute myeloblastic leukemia, minimally differentiated
>/= 20% blasts
<3% blasts reactive for MPO, SBB, or NSE
>/= 20% blasts express one or more myeloid antigens: CD13, CD14, CD33
May be TdT positive but blasts negative for lymphocyte antigens
Diagnostic Criteria for Minimally Differentiated Acute Myeloid Leukemia (AML-M0) Evaluation and a Proposal
Zahid Kaleem, MD, and Glenda White, MT(ASCP)
Am J Clin Pathol 2001;115:876-884 Abstract quote
We studied immunophenotypic features of 30 cases of minimally differentiated acute myeloid leukemia (AML-M0) using multiparameter flow cytometry and immunohistochemistry and evaluated the immunophenotypic features of previously reported cases to facilitate correct identification of myeloid lineage. All but 1 of our 30 cases expressed CD13 and/or CD33; 2 expressed CD19; 1 expressed CD10; none expressed both CD10 and CD19. Eleven of 30 cases expressed T-cell–associated antigens. All but 2 cases expressed CD34 and/or HLA-DR. Twelve of 27 cases expressed terminal deoxynucleotidyl transferase. Myeloperoxidase (MPO) expression was seen in 22 of 22 cases by immunohistochemistry and 1 of 4 by flow cytometry. None of 27 cases expressed cyCD3 and cyCD79a.
We propose following modified criteria for AML-M0: (1) standard criteria for acute leukemia; (2) undetectable or less than 3% MPO or Sudan black B staining in blasts; (3) lack of expression of lymphoid-specific antigens, cyCD3 for T lineage and cyCD79 and cyCD22 for B lineage; and (4) positivity for any of the myelomonocytic lineage antigens known not to be expressed on normal T or B lymphocytes or positivity for MPO as detected by ultrastructural cytochemistry, immunohistochemistry, or flow cytometry.
Acute myeloblastic leukemia, without maturation
>/= 20% blasts
>/= 3% blasts reactive for MPO or SBB
<10% or marrow nucleated cells are promyelocytes or more mature neutrophils
Blasts positive for CD13, CD14, CD33
Acute myeloblastic leukemia, with maturation
>/= 20% blasts
>/= 3% blasts reactive for MPO or SBB
>/= 10% of marrow nucleated cells are promyelocytes or more mature neutrophils
Blasts myeloid antigen positive
40-80% t(8;21) associated cases are CD19+
20% of t(8;21) associated cases are Tdt+
Acute promyelocytic leukemia
>/= 20% blasts and abnormal promyelocytes
Intense MPO and SBB positivity
Promyelocytes and blasts with mulitiple Auer rods (faggot cells)
t(15;17) chromosomal abnormality
Promyelocytes are HLA-DR negative in most cases
Microgranular (hypogranular) M3 Morphologic, Cytogenetic, and Molecular Abnormalities in Therapy-Related Acute Promyelocytic Leukemia
C. Cameron Yin, MD, PhD, Armand B. Glassman, MD, Pei Lin, MD, Jose R. Valbuena, MD, Dan Jones, MD, PhD, Rajyalakshmi Luthra, PhD, and L. Jeffrey Medeiros, MD
Am J Clin Pathol 2005;123:840-848 Abstract quote
We describe 17 cases of therapy-related acute promyelocytic leukemia (tAPL). Treatment for the initial neoplasms (mostly carcinomas and non-Hodgkin lymphomas) included radiation and chemotherapy in 11 patients, radiation in 3, and chemotherapy in 3. The interval between the initial neoplasm and tAPL ranged from 17 to 116 months (median, 40 months).
Morphologically, all 13 cases with available bone marrow aspirate smears showed tAPL. Dyserythropoiesis or dysmegakaryopoiesis was identified in 11 cases. In 2 cases, too few nonneoplastic cells and, in all cases, too few maturing granulocytes were present to assess for dysplasia. Conventional cytogenetics or fluorescence in situ hybridization (FISH) showed the t(15;17)(q22;q21) in all cases; 6 as a sole abnormality, 9 with additional abnormalities, and 2 assessed only by FISH. Reverse transcription–polymerase chain reaction (PCR) studies showed PML/RARa in 13 cases (8 short form, 5 long form). Mutations of the flt3 gene were detected by PCR in 5 (42%) of 12 cases.
We conclude that dysplastic features, secondary cytogenetic abnormalities, and flt3 mutations are common in tAPL.
Acute myelomonocytic leukemia
>/= 20% myeloblasts, monoblasts, and promonocytes
>/= 80% monocytic cells in marrow
>/= 5x10*9/L monocytic cells in blood
>/= 20% neutrophils and precursors in marrow
Monocytic cells reactive for NSE
Abnormal eosinophils in M4 with associated inv(16) chromosome abnormality
Varying proportions of blasts and monocytic cells positive for CD13, CD14, CD15, CD33
Monocytes positive for CD36
Acute myelomonocytic leukemia with increased marrow eosinophils
Dysplasia and High Proliferation Rate Are Common in Acute Myeloid Leukemia With inv(16)(p13q22)
Xiaoping Sun, MD, PhD, L. Jeffrey Medeiros, MD, Di Lu, MD, PhD, George Z. Rassidakis, MD, and Carlos Bueso-Ramos, MD, PhD
Am J Clin Pathol 2003;120:236-245 Abstract quote
Acute myeloid leukemia (AML) with inv(16)(p13q22), also known as M4Eo, is a distinct type of AML with a favorable prognosis associated with abnormal bone marrow eosinophils.
We reviewed the morphologic findings of archival bone marrow specimens with M4Eo, specifically assessing for dysplasia, and performed immunohistochemical studies to assess the growth fraction using the MIB-1 (Ki-67) antibody. We also assessed the apoptotic rate by terminal deoxynucleotidyl transferase–mediated deoxyuridine triphosphate–nick end labeling. All assessable cases had more than 10% dysplastic forms in at least 1 lineage. Seventeen cases had 10% or more dysplastic forms, and 3 cases had more than 50% dysplastic forms in at least 2 lineages. Immunoreactivity for Ki-67 was higher in M4Eo than in other AML types (P = .000). The apoptotic rate in M4Eo was similar to other AML types (P = .724).
Our data show that dysplasia is a prominent feature, but not a prognostic indicator, in M4Eo. M4Eo is associated with a significantly higher proliferation rate than other AML types.
Acute monoblastic leukemia, poorly differentiated
>/= 80% monocytic cells
Monoblasts >/=80% of monocytic cells
Monoblasts and promonocytes NSE positive although 10-20% cases are negative
Monoblasts usually MPO and SBB negative
Varying proportions of CD13, CD14, CD15, and CD33 positive
Monoblasts CD36 and usually CD4+
Acute monoblastic leukemia, differentiated
>/=80 monocytic cells
Monoblasts<80% of monocytic cells
Monoblasts and promonocytes NSE positive
Promonocytes scattered MPO and SBB positive granules
Varying proportions of CD13, CD14, CD15, and CD33 positive
Monoblasts and promonocytes CD36+
>/= 50% erythroid precursors
>/= 20% of nonerythroid precursors are myeloblasts
Auer rods may be present in myeloblasts
Erythroid precursors frequently PAS positive
Myeloid antigens in myeloblasts
Erythroid precursors express glycophorin A, hemoglobin A, and express CD36
Acute megakaryoblastic leukemia
>/= 30% blasts
>/= 50% megakaryocytic cells by morphology, immunophenotype studies, or electron microscopy
Megakaryocytes cells express myeloid antigen CD33
Platelet glycoproteins (CD41 and CD61)
ADDITIONAL VARIANTS 3(q21;q26) t(6;9)(p23;q34) Acute Myeloid Leukemia With t(6;9)(p23;q34) Is Associated With Dysplasia and a High Frequency of flt3 Gene Mutations
Mauricio P. Oyarzo,MD , Pei LinMD, , Armand GlassmanMD, , Carlos E. Bueso-RamosMD, PhD, , Rajyalakshmi LuthraPhD, , and L. Jeffrey MedeirosMD,
Am J Clin Pathol 2004;122:348-358 Abstract quote
We report 12 cases of t(6;9)(p23;q34)-positive acute myeloid leukemia (AML), all classified using the criteria of the World Health Organization classification.
There were 10 women and 2 men with a median age of 51 years (range, 20-76 years). Dysplasia was present in all cases (9 previously untreated), and basophilia was present in 6 (50%). Immunophenotypic studies showed that the blasts were positive for CD9, CD13, CD33, CD38, CD117, and HLA-DR in all cases assessed. CD34 was positive in 11 (92%) of 12, and terminal deoxynucleotidyl transferase was positive in 7 (64%) of 11 cases. The t(6;9) was the only cytogenetic abnormality detected in 7 cases (58%), and 5 cases had additional chromosomal abnormalities. Of 8 cases assessed, 7 (88%) had flt3 gene mutations.
We conclude that t(6;9)-positive AML cases have distinctive morphologic features, an immunophenotype suggesting origin from an early hematopoietic progenitor cell, and a high frequency of flt3 gene mutations.
- Correlation between karyotype and quantitative immunophenotype in acute myelogenous leukemia with t(8;21).
Khoury H, Dalal BI, Nantel SH, Horsman DE, Lavoie JC, Shepherd JD, Hogge DE, Toze CL, Song KW, Forrest DL, Sutherland HJ, Nevill TJ.
1Department of Cellular and Molecular Biology, Princess Margaret Hospital, Toronto, Ontario, Canada.
Mod Pathol. 2004 Oct;17(10):1211-6 Abstract quote.
Acute myelogenous leukemia with t(8;21) is a distinct clinicopathologic entity in which the malignant myeloblasts display a characteristic pattern of surface antigen expression. Quantitative analysis of surface marker expression in patients with this chromosomal abnormality compared to acute myelogenous leukemia patients with a different karyotype has not been reported.
From 305 consecutive newly diagnosed acute myelogenous leukemia patients underwent immunophenotyping and cytogenetic analysis at our center; 16 patients (5.2%) had a t(8;21). Fluorescence intensity values were obtained, using a set of reference microbeads, by conversion of mean channel fluorescence to molecular equivalent of soluble fluorochrome. Patients with t(8;21) displayed higher levels of CD34, HLA-DR and MPO expression (P<0.001 for each) and lower levels of CD13 (P=0.03) and CD33 (P=0.02) expression. In order to study the sensitivity, specificity and predictive value of these markers, molecular equivalent of soluble fluorochrome thresholds were statistically determined. The statistically established threshold for each of the individual markers (CD34>60.5 x 10(3), HLA-DR>176.1 x 10(3), MPO>735.1 x 10(3), CD13<24.3 x 10(3) and CD33<17.3 x 10(3)) had a sensitivity of 100%, a specificity of 62-92% and a positive predictive value of 7-45%.
In multivariate analysis, two quantitative patterns (CD34>60.5 x 10(3) and MPO>176.1 x 10(3); CD33<17.3 x 10(3) and MPO>176.1 x 10(3)) had a sensitivity, specificity and positive predictive value of 100%. These aberrant phenotypic patterns might help identify patients with t(8;21) at diagnosis and could be useful in minimal residual disease monitoring.
Acute basophilic leukemia >/= 20% blasts
Evidence of differentiation to basophils by light or EM
Usually + for metachromatic stains
HYPOCELLULAR AML Acute myeloid leukemia and transient myeloproliferative disorder of Down syndrome ACUTE MYELOFIBROSIS BIPHASIC
Biphasic acute myeloid leukemia with near-tetraploidy and immunophenotypic transformation.
Imkie M, Davis MK, Persons DL, Cunningham MT.
Department of Pathology, University of Kansas Medical Center, Kansas City, Kan 66223, USA.
Arch Pathol Lab Med. 2004 Apr;128(4):448-51. Abstract quote
This report describes a case of acute myeloid leukemia (subtype M1) with biphasic morphology. The bone marrow biopsy showed 2 distinct regions of blasts, one containing large cells and the other small cells. Morphometric and DNA ploidy analysis showed that the mean nuclear area and mean DNA index for the large cell region were 2-fold higher than those for the small cell region. Cytogenetic analysis showed an abnormal near-tetraploid clone. The tumor relapsed following aggressive therapy. The cells from the relapse specimen were similar to the original small cell region with respect to nuclear area and DNA index; however, there was immunophenotypic transformation with gain of CD7 and gain of CD56.
Cytogenetically, the relapse specimen showed no evidence of the near-tetraploid clone, but instead had a previously unidentified abnormal clone containing 46 chromosomes and structural abnormalities of 2q and 7q. Biphasic morphology in acute myeloid leukemia may be predictive of a near-tetraploid subclone and immunophenotypic transformation.
GRANULOCYTIC SARCOMA (LEUKEMIA CUTIS)
Concurrent Chronic Lymphocytic Leukemia Cutis and Acute Myelogenous Leukemia Cutis in a Patient with Untreated CLL
Michael K. Miller, M.D.; James A. Strauchen, M.D.; Khanh T. Nichols, M.D.; Robert G. Phelps, M.D.
From the Departments of Dermatopathology, Dermatology, and Pathology, Mount Sinai School of Medicine, New York, New York.
Am J Dermatopathology 2001;23:334-340 Abstract quote
Patients who have chronic lymphocytic leukemia (CLL) are known to have a high frequency of second malignant neoplasms. However, acute myelogenous leukemia (AML) occurring concurrent with or after a diagnosis of CLL is extremely rare.
In this article we report a case of AML developing in a 55-year-old male with a 6-year history of untreated CLL. The diagnosis was facilitated by touch preparation of a skin punch biopsy specimen. The patient presented with a two-week history of fever, weakness, anasarca, and a skin rash. Physical examination revealed pink to skin-colored firm papules, which coalesced into indurated plaques on his trunk, upper extremities, and face. The lesions, in combination with generalized edema, produced a leonine facies.
Touch prep of the biopsy showed medium to large blasts, large monocytoid cells, and numerous small mature lymphocytes, providing the preliminary diagnosis of a second, previously undiagnosed myelomonocytic malignancy in this patient.
The initial diagnosis was subsequently confirmed by histologic, cytochemical, immunohistochemical and flow cytometry studies. This is the first reported case of CLL with concurrent AML in which rapid touch prep of a skin punch biopsy facilitated diagnosis.
PSEUDO-CHEDIAK-HIGASHI ANOMALY Acute Myeloid Leukemia With Pseudo–Chédiak-Higashi Anomaly Exhibits a Specific Immunophenotype With CD2 Expression
Hong Chang, PhD, MD, FRCPC, and Qi Long Yi, PhD
Am J Clin Pathol 2006;125:791-794Abstract quote
Acute myeloid leukemia (AML) with pseudo–Chédiak-Higashi (PCH) anomaly is a rare morphologic entity.
We characterized 5 cases by multiparameter flow cytometry and found that in all cases, the blasts aberrantly expressed CD2, a pan–T cell–associated marker, in addition to their myeloid-associated markers.
In contrast, CD2 was expressed in only 25 (17.9%) of 140 cases of newly diagnosed AML without PCH anomaly. CD2 expression correlated strongly with AML with PCH anomaly (P < .01), suggesting a link between a specific immunophenotypic marker, CD2, and AML with PCH anomaly.
CHARACTERIZATION Sudan Black B (SBB) Positive in cells of neturophili, eosinophil, and monocyte lineage Nonspecific esterase (NSE) Positive in monocytes Myeloperoxidase (MPO) Positive in cells of neturophili, eosinophil, and monocyte lineage
Evaluation of Bone Marrow Specimens With Acute Myelogenous Leukemia for CD34, CD15, CD117, and Myeloperoxidase Comparison of Flow Cytometric and Enzyme Cytochemical Versus Immunohistochemical Techniques
Cherie H. Dunphy, MD, Jacek M. Polski, MD, H. Lance Evans, MD, and Laura J. Gardner, MD
From the Division of Hematopathology, Department of Pathology, St Louis University Health Sciences Center, St Louis, Mo (Drs Dunphy, Evans, and Gardner); and the Department of Pathology, University of South Alabama, Mobile, Ala (Dr Polski).
Arch Pathol Lab Med 2001;125:1063–1069. Abstract quote
Context. —Immunophenotyping of bone marrow (BM) specimens with acute myelogenous leukemia (AML) may be performed by flow cytometric (FC) or immunohistochemical (IH) techniques. Some markers (CD34, CD15, and CD117) are available for both techniques. Myeloperoxidase (MPO) analysis may be performed by enzyme cytochemical (EC) or IH techniques.
Objective. —To determine the reliability of these markers and MPO by these techniques, we designed a study to compare the results of analyses of these markers and MPO by FC (CD34, CD15, and CD117), EC (MPO), and IH (CD34, CD15, CD117, and MPO) techniques.
Materials and Methods. —Twenty-nine AMLs formed the basis of the study. These AMLs all had been immunophenotyped previously by FC analysis; 27 also had had EC analysis performed. Of the AMLs, 29 had BM core biopsies and 26 had BM clots that could be evaluated. The paraffin blocks of the 29 BM core biopsies and 26 BM clots were stained for CD34, CD117, MPO, and CD15. These results were compared with results by FC analysis (CD34, CD15, and CD117) and EC analysis (MPO).
Results. —Immunodetection of CD34 expression in AML had a similar sensitivity by FC and IH techniques. Immunodetection of CD15 and CD117 had a higher sensitivity by FC analysis than by IH analysis. Detection of MPO by IH analysis was more sensitive than by EC analysis. There was no correlation of French-American-British (FAB) subtype of AML with CD34 or CD117 expression. Expression of CD15 was associated with AMLs with a monocytic component. Myeloperoxidase reactivity by IH analysis was observed in AMLs originally FAB subtyped as M0.
Conclusions. —CD34 can be equally detected by FC and IH techniques. CD15 and CD117 are better detected by FC analysis and MPO is better detected by IH analysis.
- Immunoreactivity of MIC2 (CD99) and terminal deoxynucleotidyl transferase in bone marrow clot and core specimens of acute myeloid leukemias and myelodysplastic syndromes.
Kang LC, Dunphy CH.
Division of Hematopathology, Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill, NC 27599-7525, USA.
Arch Pathol Lab Med. 2006 Feb;130(2):153-7. Abstract quote
CONTEXT: MIC2 ("thymus leukemia") antigen has been shown to be expressed by T cells and monocytes, as well as B cells and granulocyte-lineage cells. It is most intensely expressed by the most immature thymus T-lineage cells and is more intensely expressed by CD34-positive/CD33-positive myeloid cells (compared to more mature myeloid cells) and the earliest CD34-positive/CD10-positive B-cell precursor cells (compared to cells of later B-cell precursor stages). CD99 (MIC2) is characteristically expressed in precursor B- and T-cell lymphoblastic lymphomas/leukemias, as well as in Ewing sarcoma/primitive neuroectodermal tumors (ES/PNET). It has also been shown to be expressed in a few terminal deoxynucleotidyl transferase (TdT)-positive myeloid processes, but has been uniformly negative in TdT-negative myeloid processes. A more recent study showed that 43% of acute myeloid leukemias (AMLs) and 55% of chloromas express CD99, concluding that CD99 is commonly expressed in AML and rarely seen in myeloproliferative disorders, myelodysplastic syndromes, or normal bone marrow. Although this study speculated that MIC2 expression was probably not limited to TdT-positive AML, there was no comparison with TdT reactivity in this study.
OBJECTIVE: Since AML and high-grade myelodysplastic syndrome may occasionally be difficult to distinguish morphologically from acute lymphoblastic leukemia and ES/ PNET, we undertook a study to analyze MIC2 expression in conjunction with TdT reactivity in distinguishing AML or high-grade myelodysplastic syndrome from acute lymphoblastic leukemia and ES/PNET.
DESIGN: We studied bone marrow core and clot paraffin specimens from AML (classified according to criteria of the World Health Organization; n = 49), myelodysplastic syndromes (n = 4), precursor B-cell acute lymphoblastic leukemia (n = 4), ES/PNET (n = 1), and normal bone marrow (n = 3) with MIC2 (CD99) and TdT immunohistochemistry.
RESULTS: Overall, CD99 was expressed in 24 (49%) of 49 AML cases, including all (11/11) TdT-positive cases. CD99 was expressed in all subtypes of AML except M5. Myelodysplastic syndromes and normal bone marrow specimens were uniformly CD99 negative. Expression of TdT was limited to a subset of AML-M0, -M1, -M2, and -M4, and AML with multilineage dysplasia.
CONCLUSIONS: In contrast to a previous study, CD99 expression was not restricted to TdT-positive hematologic proliferations. In particular, the CD99-positive M3 and M7 AMLs were TdT negative. An M5 AML may likely be excluded based on a uniform TdT-negative/CD99-negative immunophenotype. In addition, in our experience, CD99 should be routinely evaluated on bone marrow clots, owing to decreased reactivity or loss of reactivity in rapid decalcifying (RDO) solution-decalcified specimens.
Usefulness of Anti-CD117 in the Flow Cytometric Analysis of Acute Leukemia
Christine P. Hans, MD, William G. Finn, MD, Timothy P. Singleton, MD,* Bertram Schnitzer, MD, and Charles W. Ross, MD
Am J Clin Pathol 2002;117:301-305 Abstract quote
We assessed the diagnostic usefulness of adding anti-CD117 to our existing flow cytometric profile in the analysis of 150 consecutive cases of acute leukemia (de novo or relapsed acute myelogenous leukemia [AML], AML arising in myelodysplastic syndrome, blast crisis of chronic myelogenous leukemia [CML], acute lymphoblastic leukemia, acute unclassifiable leukemia, and biphenotypic leukemia).
CD117 was expressed on more than 10% of blasts in 64% of de novo AMLs (42/66), 95% of relapsed AMLs (19/20), 75% of AMLs arising from a myelodysplastic syndrome (6/8), and 25% of myeloid blast crisis in CMLs (1/4). CD117 was not expressed in acute lymphoblastic, acute biphenotypic, or unclassified leukemia or lymphoid blast crisis of CML. The specificity, positive predictive value, sensitivity, and negative predictive value of CD117 for AML were 100%, 100%, 69%, and 62%, respectively. CD117 is a specific marker for myeloblastic leukemias. Sensitivity is greatest in French-American-British M2 and relapsed AML. Intensity of CD117 expression is dim.
Despite the high specificity and positive predictive value, the addition of anti-CD117 to our panel did not prove essential for the assignment of blast lineage.
PODOCALYXIN PodocalyxinA Marker of Blasts in Acute Leukemia
Todd W. Kelley, MD, etal.
Am J Clin Pathol 2005;124:134-142 Abstract quote
Podocalyxin is a CD34 family member expressed by podocytes, vascular endothelium, mesothelium, and a subset of hematopoietic progenitors. Podocalyxin expression was not observed in the hematopoietic cells of normal adult bone marrow samples. However, podocalyxin was expressed by blasts in 30 (77%) of 39 cases of acute myeloid leukemia (AML), 22 (81%) of 27 cases of acute lymphoblastic leukemia (ALL), and 13 (87%) of 15 cases of cutaneous myeloid sarcoma.
No correlation with CD34 expression by immunohistochemical analysis was seen. Wilms tumor 1 (WT1) expression was detected in blasts in 17 AML cases (44%) and 21 ALL cases (78%). There was no correlation between WT1 and podocalyxin expression. We conclude that podocalyxin is expressed commonly by blasts in ALL and AML. Analysis of the expression of CD34 and podocalyxin increases sensitivity for the immunophenotypic detection of leukemic blasts compared with the analysis of CD34 alone.
Therefore, podocalyxin seems to complement CD34 as a useful hematopoietic blast marker. The physiologic role of podocalyxin in leukemic blasts remains unknown.
VGEF Immunohistochemical Detection of VEGF in the Bone Marrow of Patients With Acute Myeloid Leukemia
Correlation Between VEGF Expression and the FAB Category
Minoo Ghannadan, PhD,1 Friedrich Wimazal, MD,1 Ingrid Simonitsch, MD,2 Wolfgang R. Sperr, MD,1 Matthias Mayerhofer, MD,1 Christian Sillaber, MD,1 Alexander W. Hauswirth, MD,1 Helmut Gadner, MD,3 Andreas Chott, MD,2 Hans-Peter Horny, MD,4 Klaus Lechner, MD,1 and Peter Valent, MD
Am J Clin Pathol 2003;119:663-671 Abstract quote
We studied vascular endothelial growth factor (VEGF) expression in bone marrow sections obtained from 3 healthy donors and 41 patients with acute myeloid leukemia (AML) of various French-American-British (FAB) subtypes by immunohistochemical analysis using an anti-VEGF antibody. In normal bone marrow, the anti-VEGF antibody reacted with myeloid progenitor cells and megakaryocytes but not with erythroid cells or mature granulocytic cells.
High levels of VEGF were found in the bone marrow in patients with AML-M1, -M2, -M3, -M4, -M4Eo, and -M5. In these leukemias, the vast majority of myeloblasts (>90%) expressed VEGF. By contrast, in AML-M0, the percentage of VEGF-positive blasts was lower in most cases (median, 42%), and if at all detectable, these blast cells contained only trace amounts of VEGF. In AML-M3 and -M4Eo, maturing granulocytes failed to express VEGF similar to granulocytes in normal bone marrow.
In AML-M6, myeloblasts exhibited VEGF, whereas erythroid cells did not. In AML-M7, blast cells and megakaryocytes were identified as major sources of VEGF. In summary, VEGF expression in the bone marrow is restricted to certain stages of differentiation and maturation of myeloid cells and correlates with the FAB category.
DIFFERENTIAL DIAGNOSIS CHARACTERIZATION ACUTE PANMYELOSIS WITH MYELOFIBROSIS
- Acute panmyelosis with myelofibrosis: an entity distinct from acute megakaryoblastic leukemia.
Orazi A, O'malley DP, Jiang J, Vance GH, Thomas J, Czader M, Fang W, An C, Banks PM.
1Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, Indiana, USA.
Mod Pathol. 2005;18:l603-614 Abstract quote
The WHO criteria for diagnosing acute panmyelosis with myelofibrosis are somewhat distinct from those for acute megakaryoblastic leukemia. However, clinical and hematopathologic findings partially overlap. This has raised questions as to whether these are indeed separate, definable entities.
To determine the potential importance of bone marrow biopsy supplemented by immunohistochemistry in distinguishing between these two conditions, we studied 17 bone marrow biopsies of well-characterized cases of acute panmyelosis with myelofibrosis (six cases) and acute megakaryoblastic leukemia (11 cases). We compared blast frequency, reticulin content, CD34 expression, and the degree of megakaryocytic differentiation of the blast cells in these two conditions. Our results demonstrate important differences.
Acute panmyelosis with myelofibrosis is characterized by a multilineage myeloid proliferation with a less numerous population of blasts than acute megakaryoblastic leukemia (P<0.01). In the former condition, blasts are always positive with CD34, while in acute megakaryoblastic leukemia they express CD34 in 60% of the cases. The blasts in acute panmyelosis with myelofibrosis only rarely express megakaryocytic antigens. By contrast, acute megakaryoblastic leukemia has a significantly higher proportion of blasts expressing megakaryocytic antigens (P<0.01 with CD42b).
Our results confirm that histology supplemented by immunohistochemistry permits the distinction of these conditions in routinely processed bone marrow biopsies.
ACUTE PROMYELOCYTIC LEUKEMIA (M3)
Leukemias resembling acute promyelocytic leukemia, microgranular variant.
Nagendra S, Meyerson H, Skallerud G, Rosenthal N.
Department of Pathology, University of Iowa College of Medicine, Iowa City, USA.
Am J Clin Pathol 2002 Apr;117(4):651-7 Abstract quote
Acute promyelocytic leukemia (APL) should be distinguished from other subtypes of acute myeloid leukemia (AML) because of the increased risk of disseminated intravascular coagulation (DIC) and its response to arsenic compounds and retinoids. Some cases of AML seem morphologically similar to the microgranular variant of APL (French-American-British [FAB] AML-M3v) but lack the t(15;17).
We evaluated 8 cases of APL-like leukemias for subtle morphologic, cytochemical, immunophenotypic, and cytogenetic differences compared with 5 cases of promyelocytic leukemia/retinoic receptor alpha (PML/RARalpha)-positive APL (FAB AML-M3v). We also evaluated both groups for the presence of DIC. No differences among the groups were noted in blast size, chromatin pattern, nuclear morphologic features, intensity of myeloperoxidase staining, or presence of Auer rods. Immunophenotypes were similar; both types of cases lacked CD34 and HLA-DR and were CD13+ and CD33+. Two cases of APL-like leukemias also were CD56+. DIC was present in 2 patients with M3v.
Our study shows that there are no definitive morphologic, cytochemical, or immunophenotypic findings that can distinguish these cases from PML/RARalpha-positive APL.
Expression of CD117 and CD11b in Bone Marrow Can Differentiate Acute Promyelocytic Leukemia From Recovering Benign Myeloid Proliferation
Edgar G. Rizzatti, MD, Aglair B. Garcia, MT, Fernando L. Portieres, MD, Dirceu E. Silva, MD, Sérgio L.R. Martins, MD, PhD, and Roberto P. Falcão, MD, PhD
Am J Clin Pathol 2002;118:31-37 Abstract quote
The morphologic characteristics of bone marrow aspirates from patients recovering from acute agranulocytosis may be closely similar to the pattern observed in cases of acute promyelocytic leukemia (APL).
The clinical manifestation also can be ambiguous in a substantial number of cases. The immunophenotypic features of bone marrow from 5 patients recovering from acute agranulocytosis, showing an increase in the percentage of promyelocytes (26%-66%), were compared with the immunophenotype of 31 consecutive patients with APL whose diagnosis was confirmed by PML-RAR alpha gene rearrangement. All markers were similarly expressed, except for CD117 and CD11b. CD117 was positive in 24 (77%) of the APL cases and in none of the acute agranulocytosis cases. On the other hand, CD11b was positive in 5 (100%) of the acute agranulocytosis cases and in only 2 (6%) of the APL cases.
Thus, the CD117CD11b+ phenotype was detected in all patients recovering from agranulocytosis and in only 1 (3%) of 31 APL cases. Therefore, we suggest that the combination of both markers is helpful in the differentiation of APL from recovering benign myeloid proliferation.
Atypical blasts and bone marrow necrosis associated with near-triploid relapse of acute promyelocytic leukemia after arsenic trioxide treatment.
Chim CS, Lam CC, Wong KF, Man C, Kam S, Kwong YL.
Department of Medicine and Pathology, Queen Mary Hospital and Department of Pathology, Queen Elizabeth Hospital, Hong Kong.
Hum Pathol 2002 Aug;33(8):849-51 Abstract quote
The pathologic features of acute promyelocytic leukemia (APL) with t(15;17)(q22;q21) are highly characteristic, which with few exceptions enable a firm diagnosis to be made on morphologic grounds.
An APL patient in first relapse presented with large, bizarre circulating blasts and bone marrow necrosis 2 weeks after chemotherapy consolidation for an arsenic trioxide-induced remission. Although a morphologic diagnosis could not be reached, cytogenetic investigations showed a near-triploid clone with t(15;17), confirming APL in second relapse.
This case showed that clonal evolution with additional karyotypic aberrations might alter the blast morphology and pathologic features in APL.
THROMBOPOIETIN Thrombopoietin Administered During Induction Chemotherapy to Patients With Acute Myeloid Leukemia Induces Transient Morphologic Changes That May Resemble Chronic Myeloproliferative Disorders
Vonda K. Douglas, MD,1 Martin S. Tallman, MD,3 Larry D. Cripe, MD,4 and LoAnn C. Peterson, MD
Am J Clin Pathol 2002;117:844-850 Abstract quote
Thrombopoietin (TPO), a potent stimulator of megakaryocyte and platelet production, has been used in clinical trials to reduce thrombocytopenia after chemotherapy in patients with acute myeloid leukemia (AML).
We report that TPO therapy is associated with peripheral blood and bone marrow findings that can mimic myeloproliferative disorders. Peripheral blood and bone marrow samples of 13 patients with AML who received TPO were examined. A subset of bone marrow samples exhibited hypercellularity, megakaryocytic hyperplasia, and reticulin fibrosis after TPO administration. Cases demonstrated as many as 58.4 megakaryocytes per high-power field (MHPF) compared with 3.7 MHPF in the control group. Megakaryocytic atypia, increased mitoses, emperipolesis, intrasinusoidal megakaryocytes, and thickened trabeculae also were seen. Peripheral blood findings included leukoerythroblastosis, leukocytosis, thrombocytosis, and circulating megakaryocyte nuclei. Changes resolved within 3 months after discontinuation of TPO.
This rapid resolution of the morphologic abnormalities induced by TPO distinguishes these findings from those seen in true chronic myeloproliferative disorders.
PROGNOSIS AND TREATMENT CHARACTERIZATION PROGNOSIS
Poor prognostic factors:
Value of combined morphologic, cytochemical, and immunophenotypic features in predicting recurrent cytogenetic abnormalities in acute myeloid leukemia.
Arber DA, Carter NH, Ikle D, Slovak ML.
Hum Pathol. 2003 May;34(5):479-83. Abstract quote
To evaluate the reliability of previously described morphologic, cytochemical and immunophenotypic criteria for the identification of acute myeloid leukemias (AMLs) with t(8;21), inv(16)/t(16;16) and t(15;17), 300 cases were reviewed retrospectively. Eighteen AMLs with features of t(8;21), 31 with features of inv(16)/t(16;16), and 22 with features of t(15;17) were identified.
Cytogenetic studies were available for 228 cases and identified 15 cases of t(8;21), 30 cases of inv(16)/t(16;16), 18 cases of t(15;17) and 11 cases 11q23 AML. The true positive rate for pre-cytogenetic evaluation was 95% for t(15;17), 88% for inv(16)/t(16;16) and 87.5% for t(8;21). No difference in 5-year survival was identified in the precytogenetic and corresponding cytogenetic disease groups. No specific features to predict 11q23 abnormalities were identified.
This study confirms the reliability of a combined morphologic, cytochemical and immunophenotypic approach to the initial classification of AML. Cytogenetic studies are still needed on all cases to identify the small proportion of cases that will be missed by these methods and to identify other significant cytogenetic abnormalities in AML.
BODY MASS INDEX
- Mortality in overweight and underweight children with acute myeloid leukemia.
Lange BJ, Gerbing RB, Feusner J, Skolnik J, Sacks N, Smith FO, Alonzo TA.
Division of Oncology, The Children's Hospital of Philadelphia, Philadelphia, Pa 19104, USA.
JAMA. 2005 Jan 12;293(2):203-11 Abstract quote.
CONTEXT: Current treatment for acute myeloid leukemia (AML) in children cures about half the patients. Of the other half, most succumb to leukemia, but 5% to 15% die of treatment-related complications. Overweight children with AML seem to experience excess life-threatening and fatal toxicity. Nothing is known about how weight affects outcomes in pediatric AML.
OBJECTIVE: To compare survival rates in children with AML who at diagnosis are underweight (body mass index [BMI] < or =10th percentile), overweight (BMI > or =95th percentile), or middleweight (BMI = 11th-94th percentiles).
DESIGN, SETTING, AND PARTICIPANTS: Retrospective review of BMI and survival in 768 children and young adults aged 1 to 20 years enrolled in Children's Cancer Group-2961, an international cooperative group phase 3 trial for previously untreated AML conducted August 30, 1996, through December 4, 2002. Data were collected through January 9, 2004, with a median follow-up of 31 months (range, 0-78 months).
MAIN OUTCOME MEASURES: Hazard ratios (HRs) for survival and treatment-related mortality.
RESULTS: Eighty-four of 768 patients (10.9%) were underweight and 114 (14.8%) were overweight. After adjustment for potentially confounding variables of age, race, leukocyte count, cytogenetics, and bone marrow transplantation, compared with middleweight patients, underweight patients were less likely to survive (HR, 1.85; 95% confidence interval [CI], 1.19-2.87; P = .006) and more likely to experience treatment-related mortality (HR, 2.66; 95% CI, 1.38-5.11; P = .003). Similarly, overweight patients were less likely to survive (HR, 1.88; 95% CI, 1.25-2.83; P = .002) and more likely to have treatment-related mortality (HR, 3.49; 95% CI, 1.99-6.10; P<.001) than middleweight patients. Infections incurred during the first 2 courses of chemotherapy caused most treatment-related deaths.
CONCLUSION: Treatment-related complications significantly reduce survival in overweight and underweight children with AML.
CD2 Expression of CD2 in Acute Promyelocytic Leukemia Correlates With Short Form of PML-RARa Transcripts and Poorer Prognosis
Pei Lin, MD, Suyang Hao, MD, L. Jeffrey Medeiros, MD, Elihu H. Estey, MD, Sherry A. Pierce, Xuemei Wang, MS, Armand B. Glassman, MD, Carlos Bueso-Ramos, MD, PhD, and Yang O. Huh, MD
Am J Clin Pathol 2004;121:402-407 Abstract quote
We studied the immunophenotype of 100 cases of acute promyelocytic leukemia (APL) with cytogenetic evidence of t(15;17)(q22;q21), 72 hypergranular (M3) and 28 microgranular (M3v), and correlated the results with molecular and clinical features. Most neoplasms (75/100 [75%]) had a typical immunophenotype: CD13+CD33+CD34–HLA-DR–. CD64, CD2, CD34, and HLA-DR were expressed in 27% (24/88), 23% (22/94), 21% (21/100), and 9% (9/98), respectively. CD34 expression was restricted to M3v; HLA-DR and CD2 were expressed more often in M3v than in M3 ( P < .001). PML-RAR a fusion transcripts were detected by reverse transcriptase–polymerase chain reaction in all 70 patients assessed.
The short form of PML-RAR a transcripts was found more frequently in M3v ( P < .002) and CD2+ APL ( P < .0001) than in M3 and CD2– APL, respectively. The median follow-up was 128 weeks. CD2+ APL was associated significantly with leukocytosis ( P = .004), shorter complete remission duration ( P = .03), and a trend toward shorter overall survival ( P = .07) than CD2– APL.
Overall survival for M3v vs M3 ( P = .68) and short vs long transcripts ( P = .21) was not significantly different. Immunophenotyping is useful for predicting the biologic and clinical behavior of APL.
CHROMOSOMAL CHANGES Prognostic Implications inv(16) or t(16;16) Favorable +8,
Intermediate -7 or del(7q), complex defects Unfavorable Normal chromosomes
Two to three miscellaneous defects
Undetermined Prognostic Impact of Acute Myeloid Leukemia Classification
Importance of Detection of Recurring Cytogenetic Abnormalities and Multilineage Dysplasia on Survival
Daniel A. ArberMD
Anthony S. SteinMD
Nora H. CarterMS
Stephen J. FormanMD
Marilyn L. SlovakPhD
Am J Clin Pathol 2003; 119:672-680 Abstract quote
To evaluate the prognostic impact of acute myeloid leukemia (AML) classifications, specimens from 300 patients with 20% or more bone marrow myeloblast cells were studied. Specimens were classified according to the French-American-British Cooperative Group (FAB), the World Health Organization (WHO), the Realistic Pathologic Classification, and a cytogenetic risk group scheme.
Cases with fewer than 30% blast cells did not have a 5-year survival significantly different from cases with 30% or more blast cells, and survival was similar for the low blast cell count group and cases with multilineage dysplasia and 30% or more blasts.
Categories of AML with recurrent cytogenetic abnormalities of t(15;17), t(8;21), inv(16)/t(16;16), and 11q23 showed significant differences in 5-year survival. No significant difference was identified between AMLs arising from myelodysplasia and de novo AMLs with multilineage dysplasia, but all cases with multilineage dysplasia had a worse survival than all other AMLs and other AMLs without favorable cytogenetics. FAB types M0, M3, and M4Eo showed differences in survival compared with all other FAB types, with M0 showing a significant association with high-risk cytogenetics and 11q23 abnormalities. Other FAB groups and WHO AML, not otherwise categorized subgroups did not show survival differences.
These findings suggest that the detection of recurring cytogenetic abnormalities and multilineage dysplasia are the most significant features of current AML classification.
Combination chemotherapy with maintenance chemotherapy
Bone marrow transplantation for relapse
Long-term follow-up of patients >or=60 yr old with acute myeloid leukaemia treated with intensive chemotherapy.
Oberg G, Killander A, Bjoreman M, Gahrton G, Grimfors G, Gruber A, Hast R, Lerner R, Liliemark J, Mattson S, Paul C, Simonsson B, Stalfelt AM, Stenke L, Tidefelt U, Uden AM, Bjorkholm M; LGMS.
Department of Medicine, University Hospital, Uppsala, Sweden. Gunnar.
Eur J Haematol 2002 Jun;68(6):376-81 Abstract quote
It is still controversial how to treat elderly patients with acute myeloid leukaemia (AML), and results have been poor with most regimens.
We report the long-term results of a randomised study performed by the Leukaemia Group of Middle Sweden during 1984-88 comparing two intensive chemotherapeutic drug combinations. Ninety patients >or=60-yr old with untreated AML were randomly allocated to treatment with daunorubicin, cytosine arabinoside (ara-C), and thioguanine (TAD) (43 patients) or a combination in which aclarubicin was substituted for daunorubicin (TAA) (47 patients). Forty-four patients (49%) entered complete remission (CR), 22/43 (51%) in the TAD group and 22/47 (47%) in the TAA group (ns). The CR rate in patients <or=70 yr of age was 30/42 (71%) and in patients >70 yr 14/48 (29%) (P<0.0001). Early death within 30 d after treatment initiation was more often seen in patients >70 yr than in patients <or=70 yr of age, 40% and 12%, respectively (P<0.005). The median cause-specific survival time was 178 d in the total patient group, and the 2-, 5-, and 10-yr survivals were 22%, 11%, and 8%, respectively.
The cause-specific survival was not significantly different between the two treatment arms. At long-term follow-up >or=10 yr after inclusion of the last patient, 5/90 patients (one in the TAD group and four in the TAA group, respectively) were still alive, four in continuous complete remission and one in second complete remission.
Thus, both treatment regimens appear to have similar efficacy, with a relatively high complete remission rate, and a reasonable survival as compared to other studies including some long-term survivors. However, early deaths are still numerous, particularly in patients above 70 yr of age, and the relapse rate is substantial.
Busulfan plus cyclophosphamide compared with total-body irradiation plus cyclophosphamide before marrow transplantation for myeloid leukemia: long-term follow-up of 4 randomized studies.
Socie G, Clift RA, Blaise D, Devergie A, Ringden O, Martin PJ, Remberger M, Deeg HJ, Ruutu T, Michallet M, Sullivan KM, Chevret S.
Service d'Hematologie Greffe de Moelle and Departement de Bio-Informatique, Hopital Saint Louis, Paris, France.
Blood 2001 Dec 15;98(13):3569-74 Abstract quote
In the early 1990s, 4 randomized studies compared conditioning regimens before transplantation for leukemia with either cyclophosphamide (CY) and total-body irradiation (TBI), or busulfan (Bu) and CY.
This study analyzed the long-term outcomes for 316 patients with chronic myeloid leukemia (CML) and 172 patients with acute myeloid leukemia (AML) who participated in these 4 trials, now with a mean follow-up of more than 7 years. Among patients with CML, no statistically significant difference in survival or disease-free survival emerged from testing the 2 regimens.
The projected 10-year survival estimates were 65% and 63% with Bu-CY versus CY-TBI, respectively. Among patients with AML, the projected 10-year survival estimates were 51% and 63% (95% CI, 52%-74%) with Bu-CY versus CY-TBI, respectively. At last follow-up, most surviving patients had unimpaired health and had returned to work, regardless of the conditioning regimen. Late complications were analyzed after adjustment for patient age and for acute and chronic graft-versus-host disease (GVHD). CML patients who received CY-TBI had an increased risk of cataract formation, and patients treated with Bu-CY had an increased risk of irreversible alopecia. Chronic GVHD was the primary risk factor for late pulmonary disease and avascular osteonecrosis. Thus, Bu-CY and CY-TBI provided similar probabilities of cure for patients with CML.
In patients with AML, a nonsignificant 10% lower survival rate was observed after Bu-CY. Late complications occurred equally after both conditioning regimens (except for increased risk of cataract after CY-TBI and of alopecia with Bu-CY).
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Auer rod-Azurophilic linear structure found in the cytoplasm of 60-70% cases of AML. Caused by an alignment of the azurophilic granules. If there is a blast proliferation of 30% or more, one Auer rod in one or more blasts is considered definitive evidence of AML.
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