MYELODYSPLASTIC

SYNDROME

Vivienne Fairley

Clinical Nurse Specialist

Sheffield

MDS

INCIDENCE 1/100,000/YEAR

3,250/YEAR

MEDIAN AGE 70

MDS

HYPO OR HYPERCELLULAR BONE MARROW

BLOOD CYTOPENIAS (EARLY STAGES DUE TO APOPTOSIS)

INEFFECTIVE BLOOD PRODUCTION

ALL 3 LINES CAN BE AFFECTED

PRODUCE CELLS THAT HAVE LOST THEIR ABILITY TO DIFFERENTIATE

PREMALIGNANT

PRIMARY OR SECONDARY(60-70% NO CAUSATIVE FACTOR)

SIGNS AND SYMPTOMS

BONE MARROW FAILURE- anaemia, bleeding, frequent infections

SPLENOMEGALY – CMML

~50% ASYMPTOMATIC AND HAVE AN INCIDENTAL FINDING

DIAGNOSIS FULL BLOOD COUNT AND FILM

?BONE MARROW ASPIRATE AND TREPHINE( 5-19% BLAST CELLS AND DYSPLASTIC FEATURES IN >10% CELLS)

?CYTOGENETICS

RULE OUT OTHER CAUSES(MEGALOBLASTIC ANAEMIA, HIV, ALCOHOLISM, RECENT CHEMOTHERAPY, SEVERE

CONCOMMITANT ILLNESS)

PNH CLONAL STUDIES

FULL HISTORY

FAMILY HISTORY MDS/AML

FERRITIN, FOLATE, B12

MDS

VARYING CLINICAL CONDITION – INDOLENT TO AGGRESSIVE

RA(REFRACTORY ANAEMIA) – PROLONGED CLINICAL COURSE LOW RISK PROGRESSION TO AML

RAEB(refractory anaemia with excess blasts) – SHORT CLINICAL COURSE MORE LIKELY TO TRANFORM TO AML

WHO CLASSIFICATION OF MDS

DISEASE BLOOD BONE MARROW

REFRACTORY ANAEMIA(RA) ANAEMIA

NO OR RARE BLASTS

ERYTHROID DYSPLASIA ONLY, 10% CELLS IN 2 OR MORE MYELOID LINES, 10% CELLS IN 2 OR MORE MYELOID LINES, 15% RINGED SIDEROBLASTS

REFRACTORY ANAEMIA WITH EXCESS BLASTS 1(RAEB-1)

CYTOPENIAS

MDS

IPSS SCORE BASED ON CYTOPENIAS, CYTOGENETICS AND BLAST PERCENTAGE

AGE

NEW WHO SCORE TAKING INTO ACCOUNT TRANSFUSION REQUIREMENTS

IPSS-R

0 1 1.5 1.5 2.5 3.5 5

cytogenetics Very good good int poor Very poor

blasts /- 10 /- 100 /-0.8

PROGNOSTIC RISK

GROUPS/SCORES

1. Very low 0-2

2. Good >2-3.5

3. Intermediate >3.5-5

4. High >5-6

5. Very high >6

For consideration of age (age in years-70)x 0.04, add result to sum of other variables

IPSS-R: PROGNOSTIC SUBGROUP CLINICAL

OUTCOMES( median in years)

1

Very low

2

Good

3

Intermediate

4

Poor

5

Very high

OS

(overall survival)

8.7 5.3 3.0 1.6 0.8

AML

25%

NR 10.7 4.0 1.4 0.8

CATEGORIES AND SURVIVAL

SUBTYPE % CASES SURVIVAL MONTHS

RA 8 69

RCMD 24 33

RARS 11 69

RAEB-1 21 18

RAEB-2 18 10

5q- 3 116

RCMDRS 15 32

PROGNOSTIC FACTORS

GOOD – YOUNGER, NORMAL OR MODERATELY LOW NEUTOPHILS AND PLATELETS, LOW BLASTS IN BONE MARROW, NO BLASTS IN PERIPHERAL BLOOD, NO AUER RODS OR RINGED SIDEROBLASTS, NORMAL OR MIXED KARYOTYPE WITHOUT COMPLEX CYTOGENETICS, NO LEUKAEMIC GROWTH PATTERN IN CULTURE

POOR –ADVANCED AGE, SEVERE NEUTROPENIA AND THROMBOCYTOPENIA, BLASTS IN PERIPHERAL BLOOD, ABOVE 20% BLASTS IN BONE MARROW, AUER RODS, ABNORMAL OR COMPLEX KARYOTYPE, LEUKAEMIC GROWTH PATTERN IN CULTURE

LOW RISK DISEASE

APPROX 2/3 HAVE LOW RISK DISEASE – LOW – INT-1 IPSS SCORE BUT CAN HAVE A POOR PROGNOSIS

EXISTING TOOLS DO NOT DIFFERENTIATE FOR THIS

DECREASED SURVIVAL IF PLATELETS 60, UNFAVOURABLE CYTOGENETICS, Hb4-10%

30% PROGRESS TO AML

TREATMENT TRIALS

TRANSPLANT

GROWTH FACTORS

SUPPORTIVE

REVLIMID(5q-)70% CYTOGENETIC RESPONSE

LOW DOSE ARA-C

HYDROXYCARBAMIDE

5 AZACITADINE

CHEMOTHERAPY

IRON CHELATION

TREATMENT - TRIALS

INTENSIVE TREATMENT POTENTIALLY LEADING TO TRANSPLANT

MUST BE HIGH RISK MDS WITH >10% BLASTS IN BONE MARROW

UNDER 60 – AML 17

OVER 60 – NO CURRENT TRIAL AVAILABLE

TREATMENT

CHEMOTHERAPY

STANDARD TREATMENT OFF TRIAL DA 3+10

LOW DOSE S/C CYTARABINE

HYDROXYCARBAMIDE

TREATMENT 5-AZACITADINE

EXERT AN ANTICANCER EFFECT BY CAUSING DNA DEMETHYLATION OR HYPOMETHYLATION IN ABNORMAL MARROW CELLS

RESTORE NORMAL FUNCTION TO THE TUMOUR SUPPRESSOR GENES RESPONSIBLE FOR REGULATING CELL DIFFERENTIATION AND GROWTH

RETARDS THE PROGRESSION OF MDS TO AML

COMPARED TO BEST SUPPORTIVE CARE 5-AZA HAD A 60% LONGER TIME TO PROGREESION TO AML AND AN IMPROVEMENT IN QUALITY OF LIFE, BUT NO SURVIVAL BENEFIT

PHASE III TRIAL 5-AZA INCREASED OS AND 2 YEAR SURVIVAL DOUBLED COMPARED TO CONVENTIONAL THERAPY

TREATMENT 75MG/M2(CAN BE INCREASED IF TOLERATED) S/C FOR 7 DAYS EVERY 4 WEEKS

MAIN SIDE EFFECTS – INJECTION SITE INFLAMMATION, INITIAL LOWREING OF BLOOD COUNTS

TREATMENT LENALIDOMIDE

THOUGHT TO INTERFERE WITH THE IMMUNE SYSTEM AND ACTS ON ANGIOGENESIS

IN-VIVO HAS DIRECT ANTI-TUMOUR EFFECTS, INHIBITS THE MICRO-ENVIRONMENT SUPPORT FOR TUMOUR CELLS AND HAS AN IMMUNOMODULATORY ROLE

IN-VITRO INDUCES TUMOUR CELL APOPTOSIS DIRECTLY, AND INDIRECTLY INHIBITS BONE MARROW STROMAL CELL SUPPORT, ANTI-ANGIOGENIC AND ANTIOSTEROCLASTIC EFFECTS

ON TRIAL 63% OF PATIENTS ACHIEVED RBC INDEPENDENCE ACCOMPANIED BY A MEDIAN INCREASE OF 5.8G/Dl Hb

MAJOR CYTOGENETIC RESPONSE 44% MINOR 24% 10MG PO FOR 21 28 DAYS AS LONG AS EFFECTIVE INCREASED RISK OF PROGRESSING TO AML RESPONSE AROUND~2 YEARS

TREATMENT

ATG

ANTI-LYMPHOCYTE GLOBULIN

USED IN CONJUNCTION WITH CYCLOSPORIN

HYPOPLASTIC MDS ? AUTO-IMMUNE COMPONENT

5 DAYS ATG WITH ~6 MONTHS CYCLOSPORIN

TREATMENT

GROWTH FACTORS G-CSF AND EPO

EFFECTIVENES OF EPO~ 30% IN MDS

PHASE II STUDY SHOWED A RESPONSE OF 60% IN LOW RISK IPSS WITH SERUM EPO LEVELS

TREATMENT

SUPPORTIVE

G-CSF

BLOOD/PLATELET TRANSFUSIONS

PREVENTATIVE ANTIMICROBIALS

NURSE LED CLINICS

HOME VISITS

DECISIONS RE TREATMENT

TREATMENT IRON CHELATION

RECOMMENDATIONS FOR IRON CHELATION BASED ON LIMITED DATA

EVIDENCE SUGGESTS THAT IRON OVERLOAD CAN LEAD TO ORGAN FAILURE AND MORBIDITY

IN THE BONE MARROW IT MAY ADD TO EARLY CELLULAR APOPTOSIS CONTROLLED BY MICROENVIRONMENT

TRIAL OF 170 PATIENTS WITH MDS 76 RECEIVED CHELATION – OS 115 MONTHS VS 51 IN NON CHELATED

SHOULD BE CONSIDERED WHEN A PATIENT HAS RECEIVED 5G OF IRON( APPROX 25 UNITS OF RED CELLS)

ONLY IN PATIENTS REQUIRING LONG TERM TRANSFUSION THERAPY WITH LIFE EXPECTANCY OF 2-4+ YEARS

TWO MAIN METHODS – SUB-CUTANEOUS – DESFERRIOXAMINE(DESFERRAL) AND ORAL DEFERASIROX(EX-JADE)

TREATMENT IRON CHELATION

DESFERRAL S/C OVER 12 HOURS UP TO 5 DAYS EACH WEEK INFUSORS OR SYRINGE DRIVERS EXCRETED RENALLY( CAUTION IN RENAL

INSUFFICIENCY) INCREASED RISK OF YERSINIA INFECTIONS NEED YEARLY EYE/HEARING TESTS NEED TO REDUCE DOSE WHEN FERRITIN LEVELS

FALL BELOW 1000ug/L( normal range 22-322ug/L)

VITAMIN C ENHANCES SECRETION SIDE EFFECTS – PAIN, SWELLING,

INFLAMMATION AT INJECTION SITE, VERY RARE ANAPHYLAXIS, DIZZINESS

TREATMENT IRON CHELATION

EX-JADE

ORAL PREPARATION ONCE DAILY DOSING

½ LIFE 8-16 HOURS

FAECALLY ELIMINATED

TAKEN ON AN EMPTY STOMACH 30MINS BEFORE FOOD

NEED REGULAR U+E BLOOD TEST

SIDE EFFECTS – ALLERGIC REACTIONS, NAUSEA, WORSENING RENAL/LIVER FUNCTION, RASH, FLU-LIKE SYMPTOMS, DIARRHOEA

? TO CHELATE

COMPLICATIONS OF IRON OVERLOAD DEVELOP AFTER MANY YEARS OF TARGET ORGAN EXPOSURE

MORE THAN 85% PATIENTS ARE DIAGNOSED OVER THE AGE OF 60 WITH 3 YEAR SURVIVAL BEING 35%

MDS IN A LOW RISK CATEGORY BUT REQUIRING TRANSFUSIONS OFTEN ASSOCIATED WITH INFERIOR OS AND LEUKAEMIA FREE SURVIVAL

SERUM FERRITIN USED AS A MARKER OF IRON OVERLOAD CORRELATES WITH TRANSFUSION LOAD – DIFFICULT TO DECIPHER ITS INDEPENDENT PROGNOSTIC VALUE

MYOCARDIAL OR HEPATIC IRON DEPOSITION SELDOM CITED AS A CAUSE OF DEATH IN MDS

SUPPORTIVE CARE INFORMATION, EDUCATION MDM SURVIVORSHIP HOLISTIC ASSESSMENT FERTILITY LEUKAEMIA CARE, WILLOW FOUNDATION KEYWORKER NURSE LED CLINIC HOME VISITS DN/ MACMILLAN DLA/AA/MACMILLAN GRANTS DIETETIC/OT/PT/SW SUPPORT GROUPS(MDS UK PATIENT SUPPORT GROUP, LOCAL GROUP)

READING LIST

HEALTHLIBRARY.EPRET.COM

EMEDICINE

NORTH TRENT HAEMATO-ONCOLOGY NETWORK GUIDELINES VERSION 1 FEBRUARY 2007

GARCIA-MANERO ET AL 2008; A PROGNOSTIC SCORE FOR PATIENTS WITH LOWER RISK MDS LEUKAEMIA 22(3) 538-543

SCHMID ET AL 2009; EX-JADE IS EFFECTIVE AND WELL TOLERATED IN CHELATION NAÏVE AND PREVIOUSLY CHELATED PATIENTS IN TRANSFUSION DEPENDANT MDS BLOOD 111(22)

LIST ET AL 2009; 2 YEAR ANALYSIS OF EFFICACY OF DESFERRIOX TREATMENT IN MDS BLOOD 114(22)

FOX ET AL 2009; MATCHED PAIR ANALYSIS OF 186 MDS PATIENTS RECEIVING CHELATION THERAPY OR TRANSFUSION THERAPY ONLY BLOOD 114(22)

TEFFERI ET AL 2009; IRON CHELATION THERAPY IN MDS- CUI BONO LEUKAEMIA 23 1373

MALCOVATI ET AL 2005; PROGNOSTIC FACTORS AND LIFE EXPECTANCY IN MDS CLASSIFIED ACCORDING TO WHO CRITERIA J CLIN ONCOL 23 7594-7603

FENAUX ET AL 2007;AZACITADINE TREATMENT PROLONGS OVERALL SURVIVAL IN HIGHER RISK MDS PATIENTS COMPARED WITH CONVENTIONAL CARE REGIMENS ASH ANNUAL MEETING ABSTRACTS 110 817

LIST ET AL 2006; LENALIDOMIDE IN THE MDS SYNDROME WITH CHROMOSOME 5q DELETION N ENG J MED 355 1456-1465

GREENBERG ET AL 1989; INTERNATIONAL SCORING SYSTEM FOR EVALUATING PROGNOSIS IN MDS BLOOD (6) 2079-88

LIST ET AL 2005; EFFICACY OF LENALIDOMIDE IN MDS N ENG J MED (6) 549-57

SILVERMAN ET AL 2006; FURTHER ANALYSIS OF TRIALS WITH AZACITADINE IN PATIENTS WITH MDS J CLIN ONCOL 24(24) 3895-903

READING LIST

VARDIMAN 2006: HAEMATOPATHOLOGICAL CONCEPTS AND CONTROVERSIES IN THE DIAGNOSIS OF MDS HAEMATOLOGY AMERICAN SOCIETY OF HAEMATOLOGY 199-204

AUL ET AL : EMERGING TREATMENT OPTIONS FOR ADULT MDS: A CLINICAL PERSPECTIVE MDS FOUNDATION INC

FENAUX ET AL 2006; TREATMENT OF THE 5q- SYNDROME AMERICAN SOCIETY OF HAEMATOLOGY 192-198

DE WITTE ET AL 2007: AUTOLOGOUS AND ALLOGENEIC STEM CELL TRANSPLANTATION FOR MDS BLOOD REVIEWS 21 49-59

BENNETT 2008; CONSENSUS STATEMENT ON IRON OVERLOAD IN MDS AMERICAN JOURNAL OF HAEMATOLOGY 1-4