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Background
Chronic myeloid leukemia (CML) is a leukemia which has been grouped in a category of blood diseases known as chronic myeloproliferative diseases. Included in this group are the following disorders:
Chronic myeloid leukemia (CML)
Polycythemia vera (PV)
Essential thrombocythemia (ET)
Idiopathic myelofibrosis (IM) or Agnogenic myeloid metaplasiaAll of these disorders have both clinical and morphologic overlap and indeed hybrid forms are noted. CML represents one of the breakthroughs in molecular biology with virtually all of the cases harboring a characteristic chromosomal translocation known as the Philadelphia chromosome (Ph). This finding has enabled pathologists to diagnose and separate CML with accuracy from the other myeloproliferative disorders. In addition, the molecular events associated with this translocation have shed important information on oncogenesis.
Patients usually present with anemia, splenomegaly, and fatigue. Spontaneous bleeding and lymphadenopathy may also be present. If there are high basophil counts, symptoms of hyperhistaminemia may occur. In about 12% of adults and 60% of patients less than 20 years of age, there are signs of leukostasis, secondary to the high white blood cell counts.
OUTLINE
EPIDEMIOLOGY CHARACTERIZATION SYNONYMS CML
Chronic myelogenous leukemiaAGE RANGE-MEDIAN Median 53 years
36%>60 years<5% of all childhood leukemias
Slight Male predominance
GROSS APPEARANCE/
CLINICAL VARIANTSCHARACTERIZATION ATYPICAL CML Lacks Ph chromosome
Dysplastic changes in the neutrophils
Basophils usually normal in number
Thrombocytopenia common
Monocytes usually >3% of peripheral bloodCHRONIC MYELOMONOCYTIC LEUKEMIA Myelodyslastic syndrome CHRONIC NEUTROPHILIC LEUKEMIA Leukocyte counts >30x10*9/L and splenomegaly
Lack Ph chromosome and neutrophil alkaline phosphatase is increased
Usually >60 years of ageExpression of µ-BCR-ABL Transcripts in Chronic Neutrophilic Leukemia
Adina M. Cioc, MD, and Gerard J. Nuovo, MD
Am J Clin Pathol 2002;118:842-847 Abstract quote
The classification of chronic neutrophilic leukemia (CNL) is controversial.Our purpose was to correlate clinical, pathologic, and molecular analyses in 2 cases of CNL. In both cases, the patients were referred because of a substantially increased peripheral WBC count noted during routine examination.
Bone marrow biopsies and aspirate smears revealed hypercellularity with myeloid/erythroid ratios of 4:1 and 11:1, respectively. The bone marrow aspirate results were as follows: case 1: blasts, 2%; promyelocytes, 2%; myelocytes, 6%; metamyelocytes, 16%; band neutrophils, 13%; segmented neutrophils, 34%; and case 2: blasts, 1%; promyelocytes, 2%; myelocytes, 15%; metamyelocytes, 20%; band neutrophils, 24%; neutrophils, 19%. Reverse transcriptase in situ polymerase chain reaction studies demonstrated expression of µ-BCR-ABL transcripts in 13% and 25% of the bone marrow cells, respectively. In both cases, the positive signal was noted mainly in the early granulocytic precursors and was present in occasional mature neutrophils.
To our knowledge, this is the first in situ demonstration of µ-BCR-ABL expression in CNL. Our findings reinforce the usefulness of this messenger RNA as a molecular marker of CNL.
JUVENILE CML Adult type is identical to CML in adults
Juvenile type has a clinically aggressive course similar to acute myeloid leukemia
Fetal hemoglobin level is markedly increased ranging in levels from 40-55%
No Ph chromosome
HISTOLOGICAL TYPES CHARACTERIZATION Chronic phase Usually lasts 3-4 years followed by blast transformation or accelerated phase This has the most important findings
Leukocyte count usually >50x10*9/L with 70-90% >100x10*9/L
May have increased basophils and platelets
Blasts usually 2-3% or less
Usually hypercellular with increase in granulocytes and usually megakaryocytes
Myelofibrosis usually associated with advanced disease but increased reticulin fibers common early in diagnosis (80% of cases within 3 months of diagnosis)
Rarely collagen fibrosis
Blast transformation 30% or more blasts in peripheral blood
Blasts may be myeloid or lymphoid but 70% are myeloidOccasionally, blasts may be focal findings in the bone marrow
May occasionally present in extramedullary locations such as spleen and lymph nodes, resembling malignant lymphoma
T-cell blast crisis of chronic myelogenous leukemia manifesting as a large mediastinal tumor.Ye CC, Echeverri C, Anderson JE, Smith JL, Glassman A, Gulley ML, Claxton D, Craig FE.
Department of Pathology, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA.
Hum Pathol 2002 Jul;33(7):770-3 Abstract quote We report an unusual case of T-cell blast crisis of chronic myelogenous leukemia (CML) with a clinical presentation more typical of de novo T-cell lymphoblastic lymphoma. The patient was a 32-year-old man who presented with acute superior vena cava syndrome 19 months after an initial diagnosis of CML and 5 months after allogeneic bone marrow transplantation.
The tumor was composed of primitive lymphoid cells expressing CD2, CD3, CD4, CD5, CD7, CD8, and CD10. Although the clinical features were more typical of acute lymphoblastic leukemia/lymphoma, fluorescence in situ hybridization analysis showed the bcr-abl fusion gene within blastic tumor cells. This finding confirmed that the mass represented a blastic transformation of CML.
We use the unusual features of the current case and the previous reports to suggest that the development of T-cell blast crisis of CML is dependent on the presence of both marrow and extramedullary disease and a mechanism to evade apoptosis.
Accelerated phase Occurs in 30% of patients
Characterized by one or more of the following:
Myelofibrosis
Basophilia >20%
Hgb <7.0 g/dL
Platelets <100x10*9/L
Karyotypic evolution
Increased blasts but <30%DYSGRANULOPOIESIS Diagnostic Significance of Detecting Dysgranulopoiesis in Chronic Myeloid Leukemia
Yin Xu, MD, PhD, Michelle M. Dolan, MD, and Phuong L. Nguyen, MDAm J Clin Pathol 2003;120:778-784 Abstract quote
We examined whether the detection of dysgranulopoiesis in blood or bone marrow would predict chronic myeloid leukemia (CML) in transformation in 31 cases that fulfilled World Health Organization criteria for disease transformation, including 14 in accelerated phase (AP), 10 in myeloid blast crisis (MBC), and 7 in lymphoid blast crisis (LBC). Dysgranulopoiesis was detected in 7 cases, 6 in AP and 1 in MBC, but not in LBC or chronic phase cases. In 3 AP cases, dysgranulopoiesis was identified 2 to 5 months before the morphologic diagnosis of transformation.
Two AP cases showed no dysgranulopoiesis in previous blood or marrow smears. For 2 cases (1 AP and 1 MBC), no previous blood or marrow specimens were available. Cytogenetic information was available for 6 of 7 cases with and 22 of 24 cases without dysgranulopoiesis. All cases with dysgranulopoiesis had secondary chromosome abnormalities in addition to t(9;22). In 5 (83%) of 6 cases with dysgranulopoiesis, the secondary chromosome abnormalities included abnormalities of 17p. In contrast, none of the 22 cases of CML in AP or BC but without dysgranulopoiesis showed 17p abnormalities ( P = .001).
Our findings demonstrated that dysgranulopoiesis was associated strongly with chromosome 17p abnormalities and may indicate the onset of or impending disease transformation.ERYTHROBLASTS
- Detection of BCR/ABL Fusion Product in Normoblasts in a Case of Chronic Myelogenous Leukemia.
McFarlane R, Sun T.
Department of Pathology, University of Colorado School of Medicine, and the Pathology & Laboratory Medicine Service, Veterans Affairs Medical Center, Denver, CO.
Am J Surg Pathol. 2004 Sep;28(9):1240-4. Abstract quote
Erythroblast phase of chronic myelogenous leukemia (CML) and Philadelphia chromosome-positive acute erythroid leukemia are rare events. The distinction between these two entities is poorly defined. The World Health Organization (WHO) classification requires the presence of more than 50% of erythroblasts in the bone marrow for the diagnosis of both the erythroid/myeloid or pure erythroid subtypes of acute erythroid leukemia. However, in previous studies of erythroblast crisis CML, the percentage of erythroid series in the bone marrow is seldom mentioned and the direct relationship of the erythroblasts and the Philadelphia chromosome has never been established.
We report a well-documented case of acute erythroid leukemia transformed from CML. The studies in morphology, immunohistochemistry, and flow cytometry fulfill the WHO criteria for the diagnosis of acute erythroid leukemia, and yet the complex karyotype containing Philadelphia chromosome indicates genetic evolution. Finally, the direct demonstration of the BCR/ABL fusion product by fluorescence in situ hybridization in the erythroblasts provides concrete evidence that the erythroblasts are part of the leukemic process and not an innocent bystander.GLEEVAC TREATMENT CHANGES Chronic Myeloid Leukemia Following Therapy With Imatinib Mesylate (Gleevec)
Bone Marrow Histopathology and Correlation With Genetic Status
John L. Frater, MD,1 Martin S. Tallman, MD,2 Daina Variakojis, MD,1 Brian J. Druker, MD,3 Debra Resta, RN,4 Mary Beth Riley, RN, MSN, OCN,1 Mary Ann Hrisinko, MT(ASCP),1 and LoAnn C. Peterson, MDAm J Clin Pathol 2003;119:833-841 Abstract quote
We evaluated bone marrow pathologic features and cytogenetic and molecular genetic status of 13 patients with interferon-resistant, chronic-phase chronic myeloid leukemia (CML), treated with imatinib mesylate (Gleevec).
All had morphologic evidence of CML in the blood and bone marrow and were positive for bcr-abl by reverse transcriptase–polymerase chain reaction, fluorescence in situ hybridization (FISH), or both. Follow-up marrow biopsies, interphase FISH for bcr-abl, and conventional cytogenetics were performed at 3-month intervals (up to 24 months) after therapy initiation. All patients exhibited a reduction in bone marrow cellularity with decreases in myeloid/erythroid ratios at 3 to 6 months after therapy.
The percentage of bcr-abl–positive cells by FISH decreased in all patients (pretherapy median, 73%; 3 months median, 47%). Cytogenetic and FISH data defined 2 groups after 6 months of follow-up: 5 patients became negative for bcr-abl by FISH; 8 remained positive, 4 of whom developed signs of clonal cytogenetic evolution. Patients who became negative for bcr-abl had no morphologic evidence of CML at 15 to 24 months of follow-up, whereas patients who remained positive redeveloped morphologic features of CML as cellularity increased. Some bcr-abl–positive patients showed signs of progression, including 2 patients who developed myeloid blast phase.
Although all patients demonstrated an initial decrease in bone marrow cellularity after imatinib mesylate therapy, continued follow-up showed that histopathologic findings correlated with genetic response.
SPECIAL STAINS/
IMMUNO-HISTOCHEMSTRYCHARACTERIZATION CD33
Differences in CD33 intensity between various myeloid neoplasms.Jilani I, Estey E, Huh Y, Joe Y, Manshouri T, Yared M, Giles F, Kantarjian H, Cortes J, Thomas D, Keating M, Freireich E, Albitar M.
Department of Hematopathology, University of Texas M.D. Anderson Cancer Center, Houston 77030, USA.
Am J Clin Pathol 2002 Oct;118(4):560-6 Abstract quote We measured the concentration of CD33 antigen on the surface of cells in 315 bone marrow (BM) samples and 114 corresponding peripheral blood (PB) samples from patients with various leukemias (acute myeloid leukemia [AML], chronic myelogenous leukemia [CML], myeloproliferative disorder [MPD] other than CML, myelodysplastic syndrome [MDS]) and from control subjects.
Overall CD33 intensity in total CD33+ cells was significantly higher in BM than in PB. CD33 intensity in total BM CD33+ cells differed significantly with the type of disease. The median number of CD33 molecules per cell was highest in AML, followed by MDS, CML, and control subjects and lowest in MPD. When only CD34+/CD33+ cells were examined, CD33 molecules per cell were highest in CD34+ cells in AML and lowest in MPD (P = .027). Patients with AML or MDS younger than 60 years had significantly higher intensity of CD33 expression on CD34+ cells than patients 60 years or older. Levels of CD33 intensity did not correlate with cytogenetics in patients with AML or MDS.
There was no correlation between CD33 intensity and response to therapy or overall survival in 35 patients treated with protocols including Mylotarg. These data demonstrate variation in CD33 intensity between various leukemias.
DIFFERENTIAL DIAGNOSIS KEY DIFFERENTIATING FEATURES Chronic myeloid leukemia (CML)
Polycythemia vera (PV)
Essential thrombocythemia (ET)
Idiopathic myelofibrosis (IM) or Agnogenic myeloid metaplasia
PROGNOSIS AND TREATMENT CHARACTERIZATION Poor Prognostic Factors Progression to fibrosis or progression from focal to diffuse pattern of fibrosis FIBROSIS IN BONE MARROW
Evaluating the volume ratio of bone marrow affected by fibrosis: A parameter crucial for the prognostic significance of marrow fibrosis in chronic myeloid leukemia.Buesche G, Georgii A, Duensing A, Schmeil A, Schlue J, Kreipe HH.
Department of Pathology, Medizinische Hochschule Hannover, Germany; Department of Pathology, Brigham and Women's Hospital, Boston, MA.
Hum Pathol 2003 Apr;34(4):391-401 Abstract quote Marrow fibrosis (MF) is a complication of bone marrow neoplasms that usually impairs quality of life and shortens survival time. Proof and exact quantification of MF is not yet standardized, thus impeding the comparability of results and the evaluation of its prognostic impact.
In this study on 360 bone marrow biopsy specimens from 135 patients with either chronic idiopathic myelofibrosis (CIMF) (evaluation group) or chronic myeloid leukemia (CML) (test group), marked differences were detected between six different approaches systematically compared with respect to proof and quantification of MF. A new volumetric approach quantifying the marrow volume affected by fibrosis turned out to be superior to all of the other morphometric methods considering practicability and specificity of results, and superior to a semiquantitative procedure considering sensitivity, precision, and reproducibility (P < 0.00005). The assessment of the marrow volume with fibrosis was the only feature of MF independently influencing the survival time of patients (test group with CML; multivariate analysis, P = 0.0008).
We conclude that an approach estimating the marrow volume affected by fibrosis is the method of choice to exactly quantify and prove MF. The loss of marrow volume due to fibrosis appears to be crucial with respect to the prognostic significance of MF in CML.Survival 60-65 months after treatment
Complete or partial remission is achieved in patients with accelerated phase or blast crisis in 30% of cases with median survival of 7 months
VASCULAR ENDOTHELIAL GROWTH FACTOR (VEGF)
We studied expression of vascular endothelial growth factor (VEGF) in paraffin-embedded bone marrow sections obtained from 15 patients with chronic myeloid leukemia (CML) in chronic phase (CP), 3 in accelerated phase (AP), 7 in myeloid blast phase (BPM), 6 in lymphoid blast phase (BPL), and in 3 normal bone marrow samples. VEGF expression was determined immunohistochemically by using an anti-VEGF antibody.
In CML-CP, the distribution of VEGF showed a pattern similar to that of normal marrow. VEGF was expressed in myeloid progenitors and megakaryocytes and less abundantly in mature granulomonocytic cells, whereas erythroid cells did not stain positively for VEGF. In CML-BPM, myeloblasts expressed substantial amounts of VEGF. By contrast, little if any VEGF was detectable in blast cells in CML-BPL. VEGF messenger RNA (mRNA) was detected in leukemic cells in CML-BPM by reverse transcriptase–polymerase chain reaction, whereas blast cells in CML-BPL did not express substantial amounts of VEGF mRNA.
Our data show that VEGF is expressed in immature myeloid cells in CML. The extent of VEGF expression depends on the phase of disease and the cell type involved in disease progression.TREATMENT Chemotherapy
Alpha interferon
Bone marrow transplantation may be good option in patients<40 years of afeBusulfan 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).
IMATINIB MESYLATE
- Proposal of a morphologic bone marrow response score for imatinib mesylate treatment in chronic myelogenous leukemia.
Lugli A, Ebnoether M, Cogliatti SB, Gratwohl A, Passweg J, Hess U, Korte W, Hawle H, Tinguely M, Borisch B, Mach-Pascual S, Von Juergensonn S, Tichelli A, Dirnhofer S.
Hum Pathol. 2005 Jan;36(1):91-100. Abstract quote
Summary Cytogenetic and molecular analyses are essential disease-monitoring parameters in chronic myelogenous leukemia (CML) treated with imatinib. However, a bone marrow morphologic response has not been defined.
We reviewed bone marrow histology and cytology of 39 imatinib-treated patients with CML over 49 weeks and introduced a morphologic response score. A significant positive correlation with a complete cytogenetic response was shown for absence of dry tap ( P = .04) and abnormal megakaryocytes ( P < 0.001), normalization of cellularity ( P = .001) and reduction of fibrosis ( P = .01), myelopoiesis:erythropoiesis index ( P = .001), blast ( P = .001) and basophil count ( P < 0.001). The morphologic score integrating these parameters showed an early and late correlation with cytogenetic response.
In conclusion, morphologic criteria for complete cytogenetic response in patients with CML treated with imatinib can be defined. Persistent high-level morphologic abnormalities herald early on a high likelihood to fail treatment and call for more intense or alternative therapy.STI571 (GLEEVEC) ST1571 (imatinib mesylate) reduces bone marrow cellularity and normalizes morphologic features irrespective of cytogenetic response.
Hasserjian RP, Boecklin F, Parker S, Chase A, Dhar S, Zaiac M, Olavarria E, Lampert I, Henry K, Apperley JF, Goldman JM.
Dept of Pathology, Baystate Medical Center, Springfield, MA 01199, USA.
Am J Clin Pathol 2002 Mar;117(3):360-7 Abstract quote The tyrosine kinase inhibitor STI571 (imatinib mesylate, Gleevec) is an effective treatment for chronic myeloid leukemia (CML).
We examined bone marrow samples from 53 patients with CML who were receiving STI571 in 3 multicenter phase 2 trials to assess morphologic changes and cytogenetic response to this drug. In most patients with initially increased blasts, the bone marrow blast count rapidly decreased during STI571 therapy. Reductions in cellularity, the myeloid/erythroid ratio (commonly with relative erythroid hyperplasia), and reticulin fibrosis (if present pretreatment) also were seen in most patients, resulting in an appearance resembling normal marrow in many cases. Eighteen patients (34%) had some degree of cytogenetic response. Surprisingly, these striking morphologic changes occurred irrespective of any cytogenetic response to STI571.
Thus, STI571 seems to affect the differentiation of CML cells in vivo, causing even extensively Philadelphia chromosome-positive hematopoiesis to exhibit features resembling normal hematopoiesis.
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