myelodysplastic syndrome · myelodysplastic syndrome author: pre-installed created date: 11/28/2017...
TRANSCRIPT
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MYELODYSPLASTIC
SYNDROME
Vivienne Fairley
Clinical Nurse Specialist
Sheffield
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MDS
INCIDENCE 1/100,000/YEAR
3,250/YEAR
MEDIAN AGE 70
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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)
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SIGNS AND SYMPTOMS
BONE MARROW FAILURE- anaemia, bleeding, frequent infections
SPLENOMEGALY – CMML
~50% ASYMPTOMATIC AND HAVE AN INCIDENTAL FINDING
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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
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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
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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
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MDS
IPSS SCORE BASED ON CYTOPENIAS, CYTOGENETICS AND BLAST PERCENTAGE
AGE
NEW WHO SCORE TAKING INTO ACCOUNT TRANSFUSION REQUIREMENTS
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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
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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
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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
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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
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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
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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
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TREATMENT TRIALS
TRANSPLANT
GROWTH FACTORS
SUPPORTIVE
REVLIMID(5q-)70% CYTOGENETIC RESPONSE
LOW DOSE ARA-C
HYDROXYCARBAMIDE
5 AZACITADINE
CHEMOTHERAPY
IRON CHELATION
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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
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TREATMENT
CHEMOTHERAPY
STANDARD TREATMENT OFF TRIAL DA 3+10
LOW DOSE S/C CYTARABINE
HYDROXYCARBAMIDE
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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
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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
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TREATMENT
ATG
ANTI-LYMPHOCYTE GLOBULIN
USED IN CONJUNCTION WITH CYCLOSPORIN
HYPOPLASTIC MDS ? AUTO-IMMUNE COMPONENT
5 DAYS ATG WITH ~6 MONTHS CYCLOSPORIN
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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
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TREATMENT
SUPPORTIVE
G-CSF
BLOOD/PLATELET TRANSFUSIONS
PREVENTATIVE ANTIMICROBIALS
NURSE LED CLINICS
HOME VISITS
DECISIONS RE TREATMENT
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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)
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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
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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
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? 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
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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)
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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
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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