The Clinical Guidelines for Myelodysplastic Syndrome

June-Won Cheong; Hoon Kook; Soo-Mee Bang; Je Hwan Lee; Yong-Don Joo; Inho Kim; Hyeoung Joon Kim; Chan-Jeoung Park; Hyeon-Jin Park; Jin Seok Ahn; Sung-Soo Yoon; Jong-Ho Won; Mark Hong Lee; Chul Won Jung; Deog-Yeon Jo; Bin Cho; Kyoung Ja Han; Yoo Hong Min; Sun Hee Kim

doi:10.5045/kjh.2007.42.2.71

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Cheong, Kook, Bang, Lee, Joo, Kim, Kim, Park, Park, Ahn, Yoon, Won, Lee, Jung, Jo, Cho, Han, Min, and Kim: The Clinical Guidelines for Myelodysplastic Syndrome

Review Article

Korean J Hematol 2007;42(2):71-90.

Published online: 19 June 2007

DOI: https://doi.org/10.5045/kjh.2007.42.2.71

The Clinical Guidelines for Myelodysplastic Syndrome

June-Won Cheong¹, Hoon Kook², Soo-Mee Bang³, Je Hwan Lee⁴, Yong-Don Joo⁵, Inho Kim⁶, Hyeoung Joon Kim⁷, Chan-Jeoung Park⁸, Hyeon-Jin Park⁹, Jin Seok Ahn¹⁰, Sung-Soo Yoon⁶, Jong-Ho Won¹¹, Mark Hong Lee¹², Chul Won Jung¹⁰, Deog-Yeon Jo¹³, Bin Cho¹⁴, Kyoung Ja Han¹⁵, Yoo Hong Min¹, Sun Hee Kim^16,

¹Department of Internal Meidicine, Yonsei University College of Medicine

²Department of Pediatrics, Hwasun Hospital, Chonnam National University Medical School

³Department of Internal Medicine, Bundang Hospital, Seoul National University College of Medicine

⁴Department of Internal Medicine, Asan Medical Center, University of Ulsan College of Medicine

⁵Department of Internal Medicine, Busan Paik Hospital, College of Medicine, Inje University

⁶Department of Internal Medicine, Seoul National University College of Medicine

⁷Department of Hematology-Oncology, Hwasun Hospital, Chonnam National University Medical School

⁸Department of Laboratory Medicine, Asan Medical Center, University of Ulsan College of Medicine

⁹Pediatric Oncology Branch, Specific Organs Cancer Center, National Cancer Center

¹⁰Department of Internal Medicine, Sungkyunkwan University School of Medicine

¹¹Department of Internal Medicine, Soonchunhyang University College of Medicine

¹²Department of Internal Medicine, Konkuk University College of Medicine

¹³Department of Internal Medicine, Chungnam National University College of Medicine

¹⁴Department of Pediatrics, St. Mary's Hospital, The Catholic University of Korea College of Medicine

¹⁵Department of Laboratory Medicine, St. Mary's Hospital, The Catholic University of Korea College of Medicine

¹⁶Department of Laboratory Medicine, Sungkyunkwan University School of Medicine

Correspondence to：Sun-Hee Kim, M.D., Ph.D. Department of Laboratory Medicine, Samsung Medical Center 50, Ilwon-dong, Gangnam-gu, Seoul 135-710, Korea Tel: +82-2-3410-2704, Fax: +82-2-3410-2719 E-mail: sunnyhk@smc.samsung.co.kr

Received 13 June 2007 Revised 14 June 2007 Accepted 15 June 2007

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

The myelodysplastic syndromes (MDS) are characterized by ineffective hematopoiesis associated with multilineage cytopenias leading to serious morbidity or mortality, and the additional risk of leukemic transformation. The management of patients with MDS can be very complex and varies according to both the clinical manifestations in individual patients as well as the presence of complicating medical conditions. However, therapeutic dilemmas still exist for MDS due to the multifactorial pathogenetic features of the disease, its heterogeneous stages, and the elderly patient population. For these reasons, proper guidelines for management are necessary. This review describes the proper diagnosis for MDS, decision-making approaches for optimal therapeutic options that are based on a consideration of patient

clinical factors and risk-based prognostic categories, and the use of recently available biospecific drugs such as hypomethylating agents that are potentially capable of abrogating the abnormalities associated with MDS. Proper indications and methods for transplantation, response criteria, management for iron overload for highly transfused patients and specific considerations for MDS in childhood are also described. All of these topics were discussed at the third symposium of AML/MDS working party on 3 March, 2007.

Keywords: Myelodysplastic syndrome, Guideline, Diagnosis, Hypomethylating agents, Transplantation, Response criteria, Iron chelating treatment, MDS in childhood

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Fig. 1

The maintenance of methylation process (top) and reactivation of gene expression (bottom) by hypomethylating agents such as AZA (azacytidine) and DAC (decitabine).

Fig. 2

Comparison of survival without leukemia between AZA (A) or DAC (B) treatment arm and supportive care arm and supportive care arm in two randomized phase III trials.

Fig. 3

Dosage modification according to the recovery of blood cell counts.

Table 1.

The WHO classification of myelodysplastic syndromes

Disease	Blood findings	Bone marrow findings
Refractory anemia (RA)	Anemia	Erythroid dysplasia only
	No or rare blasts	＜5% blasts
	＜1×10⁹/L monocytes	＜15% ringed sideroblasts
Refractory anemia with ringed	Anemia	Erythroid dysplasia only
sideroblasts (RARS)	No blasts	≥15% ringed sideroblasts
sideroblasts (RARS)		＜5% blasts
Refractory cytopenia with	Cytopenias (bicytopenia or	Dysplasia in ≥10% of cells in two or
multilineage dysplasia (RCMD)	pancytopenia)	more myeloid cell lineages
	No or rare blasts	＜5% blasts in marrow
	No Auer rods	No Auer rods
	＜1×10⁹/L monocytes	＜15% ringed sideroblasts
Refractory cytopenia with	Cytopenias (bicytopenia	Dysplasia in ≥10% of cells in
multilineage dysplasia	or pancytopenia)	two or more myeloid cell lineages
and ringed sideroblasts	No or rare blasts	≥5% ringed sideroblasts
(RCMD-RS)	No Auer rods	＜5% blasts
(RCMD-RS)	＜1×10⁹/L monocytes	No Auer rods
Refractory anemia with excess	Cytopenias	Unilineage or multilineage dysplasia
blasts-1 (RAEB-1)	＜5% blasts	5∼9% blasts
	No Auer rods	No Auer rods
	＜1×10⁹/L monocytes
Refractory anemia with excess	Cytopenias	Unilineage or multilineage dysplasia
blasts-2 (RAEB-2)	5∼19% blasts	10∼19% blasts
	Auer rods +/?	Auer rods +/?
	＜1×10⁹/L monocytes
Myelodysplastic syndrome,	Cytopenias	Unilineage dysplasia in granulocytes or
unclassified	No or rare blasts	megakaryocytes
(MDS-U)	No Auer rods	＜5% blasts
(MDS-U)		No Auer rods
MDS associated with isolateddel(5q)	Anemia	Normal to increased megakaryocytes with
	＜5% blasts	hypolobated nuclei
	Platelets normal or increased	＜5% blasts
		No Auer rods Isolated del(5q)

Table 2.

General guidelines of initial evaluation for MDS

Comprehensive history and physical examination

CBC with diff, reticulocyte count

Complete serum chemistry

BM aspiration and biopsy

Iron stain

Immunohistochemistry

Chromosome analysis including FISH

Exclusion of viral infections (HCV, HIV, CMV, EBV etc)

Serum B12 and RBC folate/methylmalonic acid and homo-

cysteine

Iron studies: iron/TIBC/ferritin

Table 3.

Current issues for preparing guidelines of stem cell transplantation for MDS

Indication for allogeneic transplantation

Optimal time for transplantation

Conditioning regimens

Donor selectino

Source of stem cells: BM or PB

Previous chemotherapy before transplantation

Indication for autologous stem cell transplantation

Table 4.

Clinical guideline of stem cell transplantation for MDS

Selection of patients	Should be individualized
Criteria	IPSS or WHO. Newer classification may be needed.
Age	65 years (60 years with unrelated donor) or younger
Timing of transplantation	Low risk: delayed until progression
	High risk: soon after diagnosis
Conditioning regimen	Low risk, old age, comorbid condition: RIC＞MC
	High risk: MC is preferred in young patients with good performance
	MC regimen: Busulfan-based＞TBI-based
	RIC regimen: various, no one preferred
Donor selection	Matched sibling donor is preferred.
	Matched unrelated or mismatched familial donor, or cord blood can be considered.
Hematopoietic cell source	High risk, RIC: BM＜G-PBMC
Pre-transplant chemotherap	High risk: Newer agents can be considered.
Autologous transplantation	High risk patients in CR after chemotherapy

Abbreviations: IPSS, International Prognostic Scoring System; low risk, BM blast＜5% or IPSS Low/INT-1 risk group; RIC reduced intensity conditioning; MC, myeloablative conditioning; TBI, total body irradiation; BM, bone marrow; G-PBMC G-CSF-mobilized peripheral blood mononuclear cell.

Table 5.

Proposed modified International Working Group response criteria for hematologic improvement

Category	Response criteria (responses must last at least 4 wk)
Complete remission ^†	Bone marrow: ≤5% myeloblasts with normal maturation of all cell lines
	Persistent dysplasia will be noted∗
	Peripheral blood
	Hgb ≥11g/dL ⁹
	Platelets ≥100×10⁹/L ⁹
	Neutrophils ≥1.0×10⁹/L∗
	Blasts 0%
Marrow CR^†	Bone marrow: ≤5% myeloblasts and decrease by ≥50% over pretreatment∗
Marrow CR^†	Peripheral blood: if HI responses, they will be noted in addition to marrow CR∗
Failure	Death during treatment or disease progression characterized by worsening of cytopenias,
	increase in percentage of bone marrow blasts, or progression to a more advanced MDS
	FAB subtype than pretreatment
Relapse after CR or PR	At least 1 of the following:
	Return to pretreatment bone marrow blast percentage
	Decrement of ≥50% from maximum remission/response levels in granulocytes or platelets
	Reduction in Hgb concentration by 1.5g/dL or transfusion dependence
Cytogenetic response	Complete
	Disappearance of the chromosomal abnormality without appearance of new ones
	Partial
	At least 50% reduction of the chromosomal abnormality
Survival	Endpoints:
	Overall: death from any cause
	Event free: failure or death from any cause
	PFS: disease progression or death from MDS
	DFS: time to relapse
	Cause-specific death: death related to MDS

Deletions to IWG response criteria are not shown. To convert hemoglobin from grams per deciliter to grams per liter, multiply grams per deciliter by 10. Abbreviations: MDS, myelodysplastic syndromes; Hgb, hemoglobin; CR, complete remission; HI, hematologic improvement PR, partial remission; FAB, French-American-British; AML, acute myeloid leukemia; PFS, progression-free survival; DFS, disease-free survival. Dysplastic changes should consider the normal range of dysplastic changes (modification). ∗Modification to IWG response criteria.

Table 6.

Proposed modified International Working Group response criteria for hematologic improvement

Hematologic improvement	Response criteria (responses must last at least 8 wk)∗
Erythroid response (pretreatment, ＜11g/dL)	Hgb increase by ≥1.5g/dL
	Relevant reduction of units of RBC transfusions by an absolute number of at least 4 RBC transfusions/8 wk compared with the pretreatment transfusion number in the previous 8 wk. Only RBC transfusions given for a Hgb of ≤9.0g/dL pretreatment will count in the RBC transfusion response evaluation∗
Platelet response (pretreatment, ＜100×10⁹/L)	Absolute increase of ≥30×10⁹/L for patients starting with ＞20×10⁹/L platelets
	Increase from ＜20×10⁹/L to ＞20×10⁹/L and by at least 100%∗
Neutrophil response (pretreatment, ＜1.0×10⁹/L)	At least 100% increase and an absolute increase ＞0.5×10⁹/L∗
Progression or relapse after HI	At least 1 of the following:
	At least 50% decrement from maximum response levels in granulocytes or platelets
	Reduction in Hgb by ≥1.5g/dL
	Transfusion dependence

Deletions to the IWG response criteria are not shown. To convert hemoglobin levels from grams per deciliter to grams per liter, multiply grams per deciliter by 10. Abbreviations: Hgb, hemoglobin; RBC, red blood cell; HI, hematologic improvement. Pretreatment counts averages of at least 2 measurements (not influenced by transfusions) ≥1 week apart (modification). Modification to IWG response criteria. ∗In the absence of another explanation, such as acute infection, repeated courses of chemotherapy (modification), gastrointestinal bleeding, hemolysis, and so forth. It is recommended that the 2 kinds of erythroid and platelet responses be reported overall as well as by the individual response pattern.

Table 7.

Remission rates according to the International Working Group response criteria

						IWG response
Treatement	No. patient	IPSS (%)				% hematologic response			Median survival, mo	%HI-major
Treatement	No. patient	Low	Int1	Int2	High	Overall	CR	PR	Median survival, mo	%HI-major
Azacitidine	99	5	53	23	17	11	10	1	20	36 (+minor
Decitabine	89		31	43	26	17	9	8	22.3/13.3	13
Tipifarnib	82		17	39	44	12	7	5	11.9	22
Arsenic	101	NA	39	NA	61	1	1	0	NA	20

Abbreviations: IWG, International Working Group; IPSS, International Prognostic Scoring System; CR, complete remission PR, partial remission; HI, hematologic improvement; Int1, IPSS intermediate-1; Int2, IPSS intermediate-2; TTL, time to leuke mia; NA, not available.

Table 8.

CCC classification of childhood MDS

Category - etiology of the MDS

Idiopathic disease

Treatment related disease

Syndrome related disease

Cytology - morphologic features of BM and PB

Refractory cytopenia with ringed sideroblasts

Refractory cytopenia

Refractory cytopenia with dysplasia

Refractory cytopenia with excess blasts (5∼29% blasts

Refractory cytopenia with dysplasia and excess blasts

Cytogenetics

Normal cytogenetics

Abnormal cytogenetics

Cytogenetics unknown

Table 9.

Pediatric WHO classification

Myelodysplastic/Myeloproliferative disease

Juvenile myelomonocytic leukemia (JMML)

Chronic myelomonocytic leukemia (CMML) (secondary only)

BCR-ABL-negative chronic myeloid leukemia (Ph-CML)

Down syndrome (DS) disease

Transient abnormal myelopoiesis (TAM)

Myeloid leukemia of DS

Myelodysplastic syndrome (MDS)

Refractory cytopenia (RC)

Refractory anemia with excess blasts (RAEB)

RAEB in transformation (RAEB-t)

Table 10.

Diagnostic criteria for juvenile myelomonocytic leukemia

I. Clinical and hematological features (all 3 features mandatory)

Peripheral blood monocyte count >1×109/L

Blast percentage in PB and BM<20%

Splenomegaly

II. Oncogenetic studies (1 parameter sufficient)

Somatic mutation in PTPN11 or RAS

NF1 mutation or clinical diagnosis of NF1

Monosomy 7

III. 1. In the absence of 1 parameter listed under II, the following criteria have to be fulfilled

Absence of Ph' chromosome (bcr/abl rearrangement) (mandatory)

2. And at least two of the following criteria

Spontaneous growth or GM-CSF hypersensitivity in colony assay

HgF increased for age

Myeloid precursors on PB smear

White blood count >10×10⁹/L

Clonal abnormality besides monosomy 7

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