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Background

The myelodysplastic syndromes (MDS) are a group of bone marrow disorders usually presenting with symptoms related to deficiencies of one or more of the bone marrow elements. Anemia, bleeding problems, and infections are all presenting symptoms. The diagnosis can only be made by the pathologist by examining a bone marrow aspirate and biopsy.

OUTLINE

Epidemiology  
Disease Associations  
Pathogenesis  
Laboratory/Radiologic/
Other Diagnostic Testing
 
Gross Appearance
and Clinical Variants
 
Histopathological Features
and Variants
 
Special Stains/
Immunohistochemistry/
Electron Microscopy
 
Differential Diagnosis  
Prognosis  
Treatment  
Commonly Used Terms  
Internet Links  

EPIDEMIOLOGY CHARACTERIZATION
SYNONYMS MDS, Preleukemia
INCIDENCE The following percentages are from a total number of MDS patients
Refractory Anemia (RA)
28%
Refractory anemia with ringed sideroblasts (RARS)
24%
Refractory anemia with excess of blasts (RAEB)
23%
Refractory anemia with excess of blasts in transformation (RAEB-T)
16%
Chronic myelomonocytic leukemia (CMML)
9%
AGE RANGE-MEDIAN Most cases >50 years

 

DISEASE ASSOCIATIONS CHARACTERIZATION
LANGERHANS CELL HISTIOCYTOSIS  
Langerhans cell histiocytosis associated with myelodysplastic syndrome in adults.

Billings SD, Hans CP, Schapiro BL, Martin RW 3rd, Fivenson D, Fruland JE, Moores WB, Cotton J.

Departments of Pathology and Dermatology, Indiana University School of Medicine, Indianapolis, IN.

J Cutan Pathol. 2006 Feb;33(2):171-4. Abstract quote  

Background: Myelodysplastic syndrome (MDS) is a group of bone marrow disorders associated with dyplasia of myeloid elements that may have cutaneous manifestations including infections, vasculitis, Sweet's syndrome, pyoderma gangrenosum, erythema elevatum diutinum, and leukemia cutis. These cutaneous manifestations are attributed to the underlying bone marrow defect. Langerhans cell histiocytosis (LCH) is primarily a pediatric disease, and rarely LCH has been described in association with pediatric MDS. We are aware of only a single case report of LCH associated with MDS in an adult.

Methods: We report two new cases of LCH in elderly patients with underlying MDS. The specimens were examined by routine microscopy as well as immunohistochemical stains for S100 protein and CD1a.

Results: Both patients were elderly men with established diagnoses of MDS. One presented with a solitary pruritic papule while the other had a 2-year history of erythematous papules involving the trunk and extremities. Histologic examination revealed intraepidermal and dermal collections of mononuclear cells with reniform nuclei. The cells were strongly positive for S100 and CD1a, confirming their identity as Langerhans cells.

Conclusion: Cutaneous LCH may be associated with underlying MDS in adults and should be considered in the differential diagnosis of cutaneous eruptions in patients with MDS.
RELAPSING POLYCHONDRITIS  

Myelodysplastic syndrome associated with relapsing polychondritis: unusual transformation from refractory anemia to chronic myelomonocytic leukemia.

Shirota T, Hayashi O, Uchida H, Tonozuka N, Sakai N, Itoh H.

Department of Internal Medicine, Tokyo Medical College Hospital, Japan.

Ann Hematol 1993 Jul;67(1):45-7 Abstract quote

The authors report an unusual case of myelodysplastic syndrome (MDS) associated with relapsing polychondritis (RP), which developed at almost the same time as MDS.

The initial diagnosis was MDS, refractory anemia (RA) subtype, according to the FAB classification. Symptoms of RP were apparently controlled by oral administration of prednisolone (PSL), although MDS was not. Within 1 month after the diagnosis, monocytosis and thrombocytopenia without excess of blasts became prominent and transformation from RA to chronic myelomonocytic leukemia (CMML) was recognized. Combination chemotherapy including daunorubicin (DNR) and cytosine arabinoside (ara-c) did not subdue the progressive monocytosis and thrombocytopenia. Finally, the patient died of pulmonary hemorrhage 3 months after the onset of the disease.

The prognosis of MDS may be poorly influenced by association with RP.

Association of myelodysplastic syndrome and relapsing polychondritis: further evidence.

Hebbar M, Brouillard M, Wattel E, Decoulx M, Hatron PY, Devulder B, Fenaux P.

Department of Internal Medicine, CHU, Lille, France.

Leukemia 1995 Apr;9(4):731-3 Abstract quote

We report five patients with both a myelodysplastic syndrome (MDS) and relapsing polychondritis (RP), that represented 0.6% of all MDS and 28% of all RP diagnosed over a period of 14 years.

Ten other cases had previously been reported (four in detail), supporting a non-fortuitous association between the two disorders, already suggested for MDS and some other immunological disorders.

Relapsing polychondritis, smouldering non-secretory myeloma and early myelodysplastic syndrome in the same patient: three difficult diagnoses produce a life threatening illness.

Hall R, Hopkinson N, Hamblin T.

Department of Rheumatology and Haematology, Royal Bournemouth Hospital, UK.

Leuk Res 2000 Jan;24(1):91-3 Abstract quote

Multiple myeloma, relapsing polychondritis and myelodysplastic syndrome are all serious diseases in which making a clear diagnosis can be difficult.

This case of a 72-year-old man found after extensive investigation to have all three of the above, demonstrates how difficult diagnosis and treatment can be, producing in this case a life threatening clinical syndrome.

We also postulate that the association of these three diseases may be an immune-derived complication of myelodysplastic syndrome.

 

PATHOGENESIS
CHARACTERIZATION
CHROMOSOMAL ABNORMALITIES
70-80% of cases
Favorable
Normal chromosomes
5q-(Single defect)
Intermediate
+8
Unfavorable
Complex defects
Monosomy 7 or 7q-

 

LABORATORY/
RADIOLOGIC/
OTHER TESTS
CHARACTERIZATION
General Variable findings depending upon the cell line affected and variant of MDS
FLOW CYTOMETRY  
Four-color flow cytometry shows strong concordance with bone marrow morphology and cytogenetics in the evaluation for myelodysplasia.

Kussick SJ, Fromm JR, Rossini A, Li Y, Chang A, Norwood TH, L Wood B.

Department of Laboratory Medicine, University of Washington, Seattle.
Am J Clin Pathol. 2005 Aug;124(2):170-81. Abstract quote  

The ability of 4-color flow cytometry (FC) to help identify myelodysplastic syndromes (MDSs) was evaluated in 124 bone marrow aspirates from unselected patients with unexplained cytopenias and/or monocytosis.

The morphologic features of bone marrow aspirate smears were correlated with FC and cytogenetic findings blindly, and patterns of antigen expression were compared with patterns seen in nonneoplastic and normal marrow specimens. Of 124 cases, 58 (46.7%) had definitive FC abnormalities ("flow-abnormal"), 19 cases (15.3%) had mild FC abnormalities of indeterminate significance, and 47 cases (37.9%) had essentially normal FC.

Highly significant differences were identified between the flow-abnormal group and other groups in mean myeloid blast percentages and numbers of abnormal antigens expressed, even when the analysis was limited to cases with fewer than 5% myeloid blasts.

Strikingly, flow-abnormal cases constituted 50 (89%) of the 56 morphologically abnormal cases and 31 (94%) of the 33 cytogenetically abnormal cases, demonstrating the strong concordance of FC-identified antigenic abnormalities with morphologic features and cytogenetics in the evaluation of patients with unexplained cytopenias.

 

CLINICAL VARIANTS CHARACTERIZATION
THERAPY RELATED

May occur with prior treatment with cytotoxic agents and radiotherapy
Usually alkylating agents leading to panmyeloisis and abnormalities of chromosomes 5 and 7

More aggressive course than usual de novo forms of MDS
Median survival time 4-8 months

Poor prognostic factors:
>5% marrow blasts
Platelet count<100x10*9/L
>65 years age
Prior history of Hodgkin's disease, myeloma, or ovarian cancer with therapy with alkylating agents,nitrosoureas, or procarbazine

Therapy-Related Acute Myeloid Leukemia/Myelodysplasia With Balanced 21q22 Translocations

Daniel A. Arber, MD
Marilyn L. Slovak, PhD
Leslie Popplewell, MD
Victoria Bedell
David Ikle, PhD
and Janet D. Rowley, MD

for the International Workshop on Leukemia Karyotype and Prior Therapy

Am J Clin Pathol 2002;117:306-313 Abstract quote

The morphologic and immunophenotypic findings of 36 cases of 21q22 acute myeloid leukemia (AML) and myelodysplasia (MDS) were compared, including 14 de novo t(8;21) AMLs, 11 t(8;21) therapy-related AML/MDS cases, and 11 therapy-related AML/MDS cases with other 21q22 balanced translocations [t(n;21)].

Cases were evaluated for the presence of Auer rods, distinct chunky cytoplasmic blast cell granules, promyelocyte increase, cytoplasmic perinuclear clearing (hofs) of blast cells, eosinophil increase, and features of associated trilineage dysplasia. Results of immunophenotyping studies for CD19, CD34, and CD56 expression were compared. Cases of de novo and therapy-related t(8;21) disease shared common morphologic features of chunky cytoplasmic granules, perinuclear hofs, and promyelocyte increases that were not seen consistently in the t(n;21) group of t-AML/MDS cases. Immunophenotypic similarities also were observed between the 2 t(8;21) groups.

De novo and therapy-related t(8;21) disease, however, differed by the frequent presence of associated dysplasia in both t-AML/MDS groups, which was infrequent in the de novo t(8;21) group.

Therapy-related AML/MDS with t(8;21) shares characteristic morphologic and immunophenotypic features with de novo t(8;21) AML, but frequently also occurs with associated myelodysplastic changes, similar to other therapy-related acute leukemias.

 

HISTOLOGICAL TYPES CHARACTERIZATION
General

MDS must show dysplastic changes in the myeloid cell lines which include the red blood cells, megakaryocytes, granulocytes, and monocytes

In general, severe fibrosis is uncommon. There is a rare variant of myelodsyplasia with myelofibrosis which is usually an aggressive disorder with a clinical course similar to acute myeloid leukemia

Refractory Anemia (RA)

Normochromic normocytic to microcytic red blood cells
Ringed sideroblasts<15%
No peripheral blood blasts
Mild dyserythropoiesis

Bone marrow blasts<5%
Marked erythroid hyperplasia

Refractory anemia with ringed sideroblasts (RARS) >15% ringed sideroblasts in bone marrow
Erythroid hyperplasia in marrow
Refractory anemia with excess of blasts (RAEB) 5-19% blasts in the bone marrow
Peripheral blood <5% blasts
Neutrophil abnormalities common
Usually hypercellular bone marrow with abnormal localization of immature precursors (ALIP)-immature myeloid cells are present in positions different from usual locations of paratrabecular or perivascular-three or more are associated with increased incidence of leukemic evolution
Refractory anemia with excess of blasts in transformation (RAEB-T)

Similar changes as in RAEB except:

20-29% blasts in bone marrow
5-29% blasts in peripheral blood
Auer rods in myeloblasts or other cells of the neutrophil cell line

Auer rods present in 70% of cases
Ringed sideroblasts may be numerous

Hypercellular marrow in 80-90% of cases

Chronic myelomonocytic leukemia (CMML)

Must exclude CML and other myeloproliferative diseases first
Usually splenomegaly and elevated WBC count but Philadelphia chromosome negative

Bone marrow blasts<20%
Peripheral blood blasts<5%
Absolute monocytes count of >1x10*9/L
Monocytes are NSE positive
(Note: If there is a high percentage of promonocytes, consider AML-M4 or M5)

50% of patients will have polyclonal hypergammaglobulinemia

Chronic myelomonocytic leukemia: the role of bone marrow biopsy immunohistology.

1Clarian Pathology Laboratory, Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN, USA.

 

Mod Pathol. 2006 Dec;19(12):1536-45. Abstract quote

The World Health Organization criteria for diagnosing chronic myelomonocytic leukemia (CMML) are largely based on findings observed in the peripheral blood and bone marrow aspirate. A specific diagnostic role for the bone marrow biopsy has not been adequately explored.

We examined whether bone marrow biopsy supplemented by immunohistochemistry may be helpful in distinguishing CMML from cases of chronic myelogenous leukemia and atypical chronic myeloid leukemia (aCML).

We immunostained 25 cases of CMML with paraffin reactive antibodies which included CD68 (KP1), CD68R (PG-M1), and CD163, and compared the results with those observed in six cases of chronic myelogenous leukemia and in three cases of atypical CML. In addition, we examined whether CD34 immunohistochemistry could be useful in separating cases of CMML with less than 10% blasts (type-1) from cases of CMML with blasts accounting for 10-19% (type-2), and cases of CMML in acute transformation to acute myeloid leukemia (blasts>/=20%).

The presence of nodules of plasmacytoid monocytes was investigated by CD123 staining. CD42b was used to highlight abnormal megakaryocytes. Our results demonstrate significant differences between the groups. CD34 analysis allowed separating CMML type-1 from type-2 and the former from CMML in acute transformation. CD123-positive plasmacytoid monocyte nodules were found only in CMML and not in the other two disease groups. Overlap between CMML and the other two groups were observed with CD68 immunostaining. CD68R was more restricted to bone marrow macrophages and monocytes than CD68, but the differences between CMML and chronic myelogenous leukemia or atypical CML were still not significant.

Although CD42b immunostaining facilitated the detection of dwarf megakaryocytes often present in CMML, the distinction between those and the small forms seen in chronic myelogenous leukemia was still problematic.
Chronic myelomonocytic leukemia in transformation (CMML-T) Hematologic features of CMML and one or more of the three findings associated with RAEB-T
Auer rods are abundant
Myelodysplastic syndrome, unclassifiable (MDS-U) Marrow blasts<5%
May have marked dysgranulopoiesis and dysmegakaryoctyopoiesis
Ringed sideroblasts may be present
Marrow usually hypercellular with panhyperplasia
5q- syndrome

Isolated 5q- chromosomal abnormality
(Usually 5q23-31 region)
Macrocytic anemia
Hypolobated megakaryocytes (</=3 lobes)
Prolonged clinical course

Patients with therapy related MDS or AML associated with 5q- have a poor prognosis with rapid progression and shorter survival times

Monosomy 7 Syndrome of childhood Median age 10 months
Males
Recurrent infections with splenomegaly
HISTOLOGIC VARIANTS  
AUER RODS  
Low blast count myeloid disorders with auer rods: a clinicopathologic analysis of 9 cases.

Willis MS, McKenna RW, Peterson LC, Coad JE, Kroft SH.

Department of Pathology, University of Texas Southwestern Medical Center, Dallas.

Am J Clin Pathol. 2005 Aug;124(2):191-8. Abstract quote  

Auer rods are a hallmark of acute myeloid leukemia but occasionally are seen in myelodysplastic syndromes (MDSs) or chronic myelomonocytic leukemia, rarely in cases with fewer than 5% blasts. The significance of this finding is unclear.

We report 9 cases of this unusual phenomenon. All patients had cytopenias, isolated to a single lineage in 4. Circulating blasts were present in 8 cases (rare to 2.5%). Bone marrow blasts ranged from 0.4 to 4.9%; 1% to 32% of blasts contained Auer rods. There were variable degrees of dysplasia; 1 case closely mimicked refractory anemia with ringed sideroblasts. Cytogenetic studies in 8 cases showed clonal changes in 4. In 5 patients, acute myelogenous leukemia (AML) developed 6, 6, 5, 13, and 24 months after diagnosis; the patients subsequently died. Three patients died at 1, 1, and 8 months without progression to AML, and only 1 was alive at 10 months.

MDSs with fewer than 5% blasts and Auer rods seem to be a heterogeneous group, but rapid progression to death or AML in most cases suggests that Auer rods signify an aggressive biology in MDSs with a low blast count.


IMMUNO-HISTOCHEMISTRY CHARACTERIZATION
CD99  
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.

 

DIFFERENTIAL DIAGNOSIS KEY DIFFERENTIATING FEATURES
HEAVY METAL INTOXICATION Especially with arsenic
May cause MDS changes
CONGENITAL DYSERYTHROPOIETIC ANEMIAS Usually in childhood
ACUTE ALCOHOL INTOXICATION Inteferes with folic acid metabolism leading to megaloblastic features in neutrophils and red blood cell precursors
SPURIOUS DYSERYTHROPOIESIS  

Spurious Dyserythropoiesis

Li Juan Wang, MD, PhD
Lewis Glasser, MD

Am J Clin Pathol 2002;117:57-59 Abstract quote

We documented the occurrence and severity of dyserythropoiesis as an artifact of storage in bone marrow aspirates collected in EDTA. Bone marrow samples were obtained from 7 patients without myelodysplasia. Specimens were stored at room (20C-24C) or refrigerated (1C-6C) temperature and examined for dyserythropoiesis at 0, 1, 2, and 3 days. Initial specimens showed few dyserythropoietic abnormalities; nuclear aberrations occurred in 1.07% 0.06% (mean SEM) of the erythroid population.

At room temperature, dyserythropoietic changes increased significantly with each day of storage. Nuclear and cytoplasmic alterations occurred; the former are diagnostically more important in the diagnosis of myelodysplastic syndromes.

Cytoplasmic changes were more extensive than nuclear abnormalities. The mean SEM percentage of erythroblasts with cytoplasmic vacuoles increased with each day of storage: day 0, 1.1% 0.2%; day 1, 22.1% 1.8%; day 2, 29.4% 2.0%; day 3, 35.6% 1.9%. Nuclear shape changes increased to 6.21% 1.12%, 11.36% 1.12%, and 12.85% 1.20% on days 1, 2, and 3, respectively.

After 1 day of storage, sufficient dysplastic changes occur to cause difficulty in the diagnosis of a myelodysplastic syndrome. Changes are inhibited significantly by refrigerated storage.

VALPROATE-ASSOCIATED DYSMYELOPOIESIS  
Valproate-Associated Dysmyelopoiesis in Elderly Patients


Chi-chiu So, MRCPath, and Kit-fai Wong, MD

Am J Clin Pathol 2002;118:225-228 Abstract quote

Sodium valproate is widely prescribed for patients with epilepsy and psychiatric disorders. Hematologic toxic effects have been largely described in pediatric patients, and dysmyelopoiesis is reported rarely.

We describe 2 elderly patients with valproate-associated dysmyelopoiesis and postulate that this particular side effect may be much more common than currently recognized. A correct diagnosis is important for acute patient management and for prognostication.

VITAMIN B12 and folic acid deficiency Should always exclude this possibility

 

PROGNOSIS AND TREATMENT CHARACTERIZATION
Prognostic Factors-Scoring

Bournemouth System scores MDS, excluding RAEB-T, into prognostic groups

Score of 1 given for each of the following:
Marrow blasts>5%
Platelets 100x10*9/L or less
Neutrophils 2.54x10*9/L or less
Hgb<10 g/dL

A (0-1)
Most favorable
B (2-3)
 
C (4)
 
Prognostic Factors-Percentage of patients progressing to acute leukemia Patients with RAEB-T and CMML-T have a rapid clinical course often leading to anemia or bone marrow failure
Refractory Anemia (RA) 12
Refractory anemia with ringed sideroblasts (RARS) 8
Refractory anemia with excess of blasts (RAEB) 44
Refractory anemia with excess of blasts in transformation (RAEB-T) 60
Chronic myelomonocytic leukemia (CMML) 14
Median Survival (Months)  
Refractory Anemia (RA) 50
Refractory anemia with ringed sideroblasts (RARS) 51
Refractory anemia with excess of blasts (RAEB) 11
Refractory anemia with excess of blasts in transformation (RAEB-T) 5
Chronic myelomonocytic leukemia (CMML) 11
JUVENILE MDS  


Prospective study of 90 children requiring treatment for juvenile myelomonocytic leukemia or myelodysplastic syndrome: a report from the Children's Cancer Group.

Woods WG, Barnard DR, Alonzo TA, Buckley JD, Kobrinsky N, Arthur DC, Sanders J, Neudorf S, Gold S, Lange BJ.

AFLAC Cancer Center, Emory University/Children's Healthcare, Atlanta, GA, USA.

J Clin Oncol 2002 Jan 15;20(2):434-40 Abstract quote

PURPOSE: We report the first large prospective study of children with myelodysplastic syndrome (MDS) and juvenile myelomonocytic leukemia (JMML) treated in a uniform fashion on Children's Cancer Group protocol 2891.

PATIENTS AND METHODS: Ninety children with JMML, various forms of MDS, or acute myeloid leukemia (AML) with antecedent MDS were treated with a five-drug induction regimen (standard or intensive timing). Patients achieving remission were allocated to allogeneic bone marrow transplantation (BMT) if a matched family donor was available. All other patients were randomized between autologous BMT and aggressive nonmyeloablative chemotherapy. Results were compared with patients with de novo AML.

RESULTS: Patients with JMML and refractory anemia (RA) or RA-excess blasts (RAEB) exhibited high induction failure rates and overall remission of 58% and 48%, respectively. Remission rates for patients with RAEB in transformation (RAEB-T) (69%) or antecedent MDS (81%) were similar to de novo AML (77%). Actuarial survival rates at 6 years were as follows: JMML, 31% +/- 26%; RA and RAEB, 29% +/- 16%; RAEB-T, 30% +/- 18%; antecedent MDS, 50% +/- 25%; and de novo AML, 45% +/- 3%. For patients achieving remission, long-term survivors were found in those receiving either allogeneic BMT or chemotherapy. The presence of monosomy 7 had no additional adverse effect on MDS and JMML.

CONCLUSION: Childhood subtypes of MDS and JMML represent distinct entities with distinct clinical outcomes. Children with a history of MDS who present with AML do well with AML-type therapy. Patients with RA or RAEB respond poorly to AML induction therapy. The optimum treatment for JMML remains unknown.

TREATMENT  
CHEMOTHERAPY  


High remission rate, short remission duration in patients with refractory anemia with excess blasts (RAEB) in transformation (RAEB-t) given acute myelogenous leukemia (AML)-type chemotherapy in combination with granulocyte-CSF (G-CSF).

Estey EH, Kantarjian HM, O'Brien S, Kornblau S, Andreeff M, Beran M, Pierce S, Keating M.

Department of Hematology, University of Texas MD Anderson Cancer Center, Houston, USA.

 

Cytokines Mol Ther 1995 Mar;1(1):21-8 Abstract quote

A study was made to determine CR rate, response duration and survival in patients with RAEB or RAEB-t given AML-type chemotherapy, in particular the newer agents idarubicin and fludarabine. Eighty-five adults (58 RAEB-t, 27 RAEB) received either IA (idarubicin 12 mg/m2 daily on days 1-3, ara-C 1.5 g/m2 daily on days 1-4 CI), FA (fludarabine 30 mg/m2 daily on days 1-5, ara-C 2 g/m2 daily on days 1-5) or FLAG (FA + G-CSF 400 micrograms/m2 daily from day-1 until CR). IA was given exclusively to patients with better prognosis (as assessed by pretreatment karyotype), while FA and FLAG were given first to patients with worse and then to those with better prognosis.

In remission, patients received lower doses of the same regimens for 6-12 months. The 85 patients comprise the largest reported series of RAEB or RAEB-t patients given AML-type chemotherapy. Their median age was 61 years, 33% had chromosome 5 or 7 abnormalities (-5/-7), and 55% were treated in laminar air flow rooms. The CR rate was 66%. While rates were highest in younger patients with a normal karyotype, CR rates in excess of 50% were also obtained in patients over age 60 (27/47; 57%) and in patients with -5/-7 (17/29; 59%). In 11 of the 14 cytogenetically abnormal patients in whom cytogenetic analysis was repeated at the time of CR, only normal metaphases were found. In the remaining 3 the number of abnormal metaphases was substantially reduced. However, the probability of continued CR was low (e.g. 452 +/- 0.08 at 12 months), and the only patients alive in CR beyond two years were patients under age 60 without -5/-7 and with RAEB-t. Survival probability was 0.35 +/- 0.05 at one year. Eight of 56 patients died in CR.

While current AML-type chemotherapy can produce higher CR rates than is perhaps usually appreciated, in some patients with RAEB or RAEB-t (e.g. older patients with -5/-7) the brevity of the remissions and the risk entailed suggest that new post-remission therapies are needed to make this approach generally worthwhile.


Intensive chemotherapy followed by allogeneic or autologous stem cell transplantation for patients with myelodysplastic syndromes (MDSs) and acute myeloid leukemia following MDS.

de Witte T, Suciu S, Verhoef G, Labar B, Archimbaud E, Aul C, Selleslag D, Ferrant A, Wijermans P, Mandelli F, Amadori S, Jehn U, Muus P, Boogaerts M, Zittoun R, Gratwohl A, Zwierzina H, Hagemeijer A, Willemze R.

University Medical Center St Radboud, Nijmegen, The Netherlands.

Blood 2001 Oct 15;98(8):2326-31 Abstract quote

This study investigated the feasibility of allogeneic (alloSCT) and autologous stem cell transplantation (ASCT) as postconsolidation therapy for patients with myelodysplastic syndromes (MDSs) or acute myeloid leukemia after MDS. Patients with a histocompatible sibling were candidates for alloSCT and the remaining patients for ASCT. Remission-induction therapy consisted of 1 or 2 courses with idarubicin, cytarabine, and etoposide, followed by one intensive consolidation course with cytarabine and mitoxantrone. Initially, bone marrow cells were used for ASCT. Subsequently, mobilized blood stem cells were used in an attempt to shorten posttransplantation hypoplasia.

With a median follow-up of 3.6 years the 184 evaluable patients showed a 4-year survival rate of 26% and a median survival of 13 months. The remission-induction chemotherapy induced complete remission (CR) in 100 patients (54%). The 4-year disease-free survival (DFS) rate was 29% and the median DFS was 12 months. Twenty-eight of 39 patients (72%) with a donor were allografted in CR-1, including 2 patients who underwent transplantation in CR-1 without a consolidation course. Thirty-six of 59 patients (61%) without a donor received ASCT in CR-1. The 4-year DFS rates in the group of patients with or without a donor were 31% and 27%, respectively. The 4-year survival rates from CR were 36% and 33%, respectively. This large prospective study shows the feasibility of both alloSCT and ASCT.

This treatment approach leads to a relatively high remission rate, and the majority of patients in remission received the SCT in CR-1. The ongoing study investigates whether this approach is better than treatment with chemotherapy only.

ENTANERCEPT  


Soluble TNF receptor fusion protein (etanercept) for the treatment of myelodysplastic syndrome: a pilot study.

Deeg HJ, Gotlib J, Beckham C, Dugan K, Holmberg L, Schubert M, Appelbaum F, Greenberg P.

Fred Hutchinson Cancer Research Center, Seattle, WA, USA.

Leukemia 2002 Feb;16(2):162-4 Abstract quote

Blockade of tumor necrosis factor (TNF)alpha by a soluble TNF receptor fusion protein (etanercept; Enbrel) improved in vitro hemopoiesis from the marrow of patients with myelodysplastic syndrome (MDS).

Therefore, we enrolled 14 MDS patients (4 RA, 2 RARS, 6 RAEB, 2 CMML), 44-80 (median 60) years old, in a pilot trial. Etanercept, 25 mg, was given twice a week s.c. for 16 weeks (increased to three times a week if no response at 8 weeks). Among 12 evaluable patients, four had rises in hemoglobin by 1-1.5 gm/dl (three) or decreased transfusion requirements (one). Two patients had increased platelet counts (54% and 73%), and two increased neutrophils (63% and 120%). Baseline TNFalpha levels, determined in all patients, did not correlate with responses. Among eight marrows available for sequential in vitro assays, four showed increases in CFU-GM of 1.5- to 5-fold at 8 weeks, whereas three showed 3- to 10-fold decrements relative to baseline.

Thus, etanercept treatment resulted in moderate improvements of cytopenias in some patients, while cell counts declined in others. Additional trials are needed to evaluate its clinical efficacy in MDS.

STEM CELL TRANSPLANTATION  


Hematopoietic stem-cell transplantation for treatment-related leukemia or myelodysplasia.

Witherspoon RP, Deeg HJ, Storer B, Anasetti C, Storb R, Appelbaum FR.

Clinical Research Division of the Fred Hutchinson Cancer Research Center, Seattle, WA 98109-1024, USA.

J Clin Oncol 2001 Apr 15;19(8):2134-41 Abstract quote

PURPOSE: This report describes results of related or unrelated hematopoietic stem-cell transplants in 111 patients with treatment-related leukemia or myelodysplasia performed consecutively at the Fred Hutchinson Cancer Research Center between December 1971 and June 1998, and identifies patient and treatment characteristics associated with survival and relapse.

PATIENTS AND METHODS: At transplantation, 56 patients had treatment-related secondary acute myeloid leukemia (AML), 15 had refractory anemia with excess blasts in transition (RAEB-T), 23 had refractory anemia with excess blasts (RAEB), 15 had refractory anemia (RA), and two had refractory anemia with ringed sideroblasts (RARS). Conditioning regimens were total-body irradiation (TBI) and chemotherapy for 60 patients, busulfan (BU) 14 to 16 mg/kg and cyclophosphamide (CY) 120 mg/kg (BUCY) for 27 patients, BU targeted to 600 to 900 ng/mL plasma steady-state concentration with 120 mg/kg CY (BUCY-t) for 22 patients, and miscellaneous chemotherapy for two patients. The donors were HLA-identical or partially identical family members for 69 patients and unrelated donors for 42 patients.

RESULTS: The 5-year disease-free survival was 8% for TBI, 19% for BUCY, and 30% for BUCY-t (P =.006). The 5-year cumulative incidence of relapse was 40% for secondary AML, 40% for RAEB-T, 26% for RAEB, and 0% for RA or RARS (P =.0009). The 5-year cumulative incidence of nonrelapse mortality after TBI was 58%; after BUCY, 52%; and after BUCY-t, 42% (P =.02).

CONCLUSION: Patients at risk for treatment-related leukemia or myelodysplasia should be followed closely and be considered for stem-cell transplantation early in the course of myelodysplasia using conditioning regimens such as BUCY-t designed to reduce nonrelapse mortality.

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Commonly Used Terms

Abnormal localization of immature precursors (ALIP)-Immature myeloid cells present in positions different from usual locations of paratrabecular or perivascular-three or more are associated with increased incidence of leukemic evolution.

Hematology and Lymphoid System

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Refractory Anemia Bone Marrow Smear
Refractory Anemia with Ringed Sideroblasts Bone Marrow Smear
Refractory Anemia with Excess Blasts Bone Marrow Smear
Refractory Anemia with Excess Blasts in Transformation Bone Marrow Smear
Chronic Myelomonocytic Leukemia Bone Marrow Smear
Chronic Myelomonocytic Leukemia Bone Marrow Smear
Chronic Myelomonocytic Leukemia Bone Marrow Smear

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