challenging cases in the elderly — Neil Rabin

Report
CPC vignettes – challenging cases in the
elderly
Dr Neil Rabin
Consultant Haematologist
University College London Hospital
& North Middlesex University Hospital
Case 1: William
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70 year old retired biomedical scientist
June 2007: weight loss and fatigue
IgG lambda pp 44g/L, BJP negative
Hypercalcaemia with normal renal function
BM 80-90% plasma cells
SS: multiple lytic lesions
Cytogenetic – FISH - normal
ISS stage: 2
• PMHx – Asthma, investigated for SVTs
• PHx - Ex smoker. PS = 0. Active lifestyle.
Case 1: William
• Diagnosed with symptomatic myeloma (age 70)
• Treated with Cyclophosphamide Dexamethasone
Thalidomide (CTD) for 4 months at local hospital
• PP falls from 44g/L to 13 g/L (partial response)
• Echocardiogram – normal
• Creatinine clearance – normal
How would you treat him ?
Case 1: William
Decision – what treatment now?
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Continue CTD to maximal response
Switch to salvage treatment (Velcade based)
Proceed to ASCT
Other
Case 1: William
CVD
CDT M200 THALIDOMIDE
50
Serum paraprotein (g/L)
45
40
35
Retro-orbital
Plasmacytoma
30
25
20
15
10
5
-
10
20
30
40
50
Time (months)
60
70
80
90
100
Stratification of treatment by age
Myeloma IX: AGE DISTRIBUTION BY PATHWAY
150
120
INTENSIVE
NON-INTENSIVE
90
60
30
40
50
60
70
80
AGE
ASCT-eligible
Not eligible
?
67.4% of patients entered into Intensive arm proceeded to ASCT
90
How do we decide if a patient is for
intensive
therapy (ASCT eligible) ?
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Age
Performance status
Organ Function
Disease biology
Adequate stem cells
Patient choice
Transplantation in the elderly
•ASCT performed at UCLH from 1993 →2010
•338 patients
•Median age 57 years (range 34-71)
•40 patients >65 years
Maciocioa P, unpublished data
Facon T. et al. Lancet; 370:1209-1218, 2007
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IFM 99-06 trial
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MPT vs MP vs M100
Age 65-75
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Improvement in
PFS/OS with MPT vs
MP/M100
Case 2: Jennifer
• 69 year old retired elderly
care nurse
• Anaemia last 2 years
• PMHx -↑BP
• Fall going down the
stairs at home
• PHx – previously active,
current PS = 2
Case 2: Jennifer
• CT fracture through lytic lesion with extraosseous tumour
• Biopsy lytic lesion = plasma cell neoplasm
• MRI: multiple lytic lesions vertebrae, sacrum, femora,
fractures T6, L1, L5, small paravertebral mass at T6
• Haemoglobin 9 g/dL, Creatinine 107 umol/L, Calcium
normal
• IgD lambda PP 12 g/L + Lambda LC
• Urinary BJP 2.72 g/L
• BM 80-90% plasma cells
• ISS stage 3 (beta-2 m 7.7mg/L)
• Cytogenetic – FISH failed
Case 2: Jennifer
Decision – what initial treatment?
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Aim for induction treatment prior to ASCT
MPV
CTDa or MPT
Clinical trial
Case 2: Jennifer
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Decision for non-intensive treatment
Declined clinical trial entry
Treated with MPV November 2012
Intra-medullary nail inserted November 2012
Single fraction radiotherapy to humerus
Completed 8 cycles – achieving CR
Lambda LC
15,571 mg/l pre-cycle 1
3,274 mg/l pre-cycle 2
SFLC normal from cycle 4 onward
“Velcade eyes” cycle 6
VISTA study: VMP vs MP
VMP
Cycles 1-4
Bortezomib 1.3 mg/m2 IV: days 1,4,8,11,22,25,29,32
Melphalan 9 mg/m2 and Prednisone 60 mg/m2 days 1-4
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Cycles 5-9
Bortezomib 1.3 mg/m2 IV: days 1,8,22,29
Melphalan 9 mg/m2 and Prednisone 60 mg/m2 days 1-4
9 x 6-week cycles (54 weeks) in both arms
MP
Cycles 1-9
Melphalan 9 mg/m2 and Prednisone 60 mg/m2 days 1-4
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Primary Endpoint: TTP
Secondary Endpoints: CR rate, ORR, TTR, DOR, PFS, TNT, OS, QoL
(PRO)
San Miguel et al. N Engl J Med 2008;359:906–17
VISTA: Updated Survival
13.3 months OS benefit
San Miguel J F et al. JCO 2013
Case 3: Ruth
• 68 year old retired secretary
• PMHx – 2005: invasive ductal breast ca – treated with
lumpectomy, RT, tamoxifem / arimidex
• 2008: Anaemia, Back pain, Epistaxis
• IgG lambda PP 82 g/L, BJP 0.74g/L
• BM 80% plasma cells
• SS: multiple lytic lesions
• Cytogenetic – FISH – t(4:14)
• ISS stage: 2
Treatment Options
1.
2.
Intensive: not fit
Non-Intensive
a) Clinical Trial: ineligible
b) NICE approved:
1. CTDa
2. MPT
3. VMP (if unable to receive thalidomide based regimen)
c) Others:
1. M&P
2. Cyclo Dex
Case 3
Case 3: Ruth
• MPT x 3
– Bowel disturbance, neutropaenia
– MR (PP 82 → 56 g/L)
• VMP x 8
– Biweekly to weekly bortezomib
– Weekly bortezomib at 1.3 mg/m2→ 1mg/m2
(progressive PN)
– VGPR (PP 56 → 4 g/L)
• Relapsed 2 years later (2010):
• Lenalidomide and Dex x 4
– PD on treatment (pp 36 → 65 g/L)
Case 3: Ruth
Decision – what treatment now?
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Velcade re-treatment
Bendamustine
Clinical trial
Other
Overview: Case [t(4;14)] 2008 - 2012
NICE approved
MPT
VMP
1st Line
1st Line
Clinical Trials
RD
2nd Line
Velcade
&
Panobinostat
MUK 1
3rd Line
4th Line
ADMYRE
FOCUS
5th Line
6th Line
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Treatment Line
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Case 4: John
• 76 year old Afro-Caribbean retired builder
• 6 month history of exertional dyspnoea and marked
peripheral oedema
• Repeat admissions to hospital
• PMHx – Diabetes / ↑BP / ↑Cholesterol / Atrial fibrillation
• Echocardiogram – 30% LVEF, severe concentric LVH
• Lambda LC noted in serum and urine
– Kappa FLC 11 mg/L, lambda FLC 864 mg/L
– Haemoglobin / Creatinine / Calcium - normal
• Bone marrow – 75% plasma cells
• Skeletal survey normal
Case 4: John
Decision – what is the likely
diagnosis?
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Symptomatic myeloma
AL cardiac amyloidosis
Cardiac failure (unrelated)
Other
Case 4: John
• Referred to National Amyloidosis Centre
– Echocardiogram characteristic of amyloid
IVSd 1.9 cm, moderate to severely impaired LV
systolic function, grade 2 diastolic dysfunction.
– ECG showed atrial flutter, variable AV block,↓ QRS
– Troponin-t 0.1 ng/mL (normal), NT pro BNP 430 pmol/L
– No visceral amyloid detected on SAP scintography
• Differential diagnosis of
– AL amyloid
– Senile cardiac amyloid with co-existent myeloma
– Hereditary cardiac amyloid with co-existent myeloma
Case 4: John
Endocardial biopsy
stained with Congo Red
Endocardial biopsy
showing apple-green birefringence
in polarised light
Lydia Lee et al, BJHM, Nov 2011
Positive immunohistochemical
staining for transthyretin
Case 4: John
• Hereditary cardiac amyloid (TTR variant)
– Reviewed regularly at the NAC and local cardiologist
– Cardiac medication (Enalapril, Digoxin and
Furosemide) adjusted. Anti-coagulated for mural
thrombus
– Cardiac function remained stable for 2 years (NYHA II)
– Treatment – low salt diet, fluid management, diuretics
• Myeloma
– Declined chemotherapy (? initial treatment needed)
– Inappropriate to treat for AL cardiac amyloid
• Died 2 years later
Cardiac amyloid
• Deposition of amyloid fibrils (cardiac and other tissues)
• Common findings
– Low amplitude QRS complexes (<1mV in pre-cordial
leads or <0.5mV in all limb leads)
– Pseudoinfarction pattern (Q waves in consecutive
leads)
– Conduction delays + arrhythmias (commonly AF)
– LV wall thickening in the absence of hypertension
• AL amyloid (associated with a plasma cell clone)
• Senile systemic amyloid (wild type transthyretin)
• Hereditary cardiac amyloid (ATTR)
Hereditary cardiac amyloid (TTR)
4 % Afro-Caribbeans Val122Ile
Variable penetrance
Presents in the 7th decade
Cardiac failure / arrythmia
Resistant to diuretics / ACE i
Gilmore et al, Heart 1999
Diagnosis based on
-Finding of cardiac amyloid
-Mutation in TTR gene
Occasionally cardiac biopsy
Case 5: Joan
• 86 year old artist
• Referred to general haematology clinic with normocytic
anaemia (Hb 9.8 g/dL) developed previous 2 years
• Symptom - fatigue, and exertional chest pain
• IgG kappa PP 16 g/L, no BJP, normal SFLC ratio
• Creatinine, Calcium - normal
• BM 20% plasma cells
• SS: no lytic lesions
• Cytogenetic – FISH – 1q gain
• ISS stage: 1
• PMHx - ↑BP, Hiatus hernia, previous Cystitis
• PHx - Lives alone, independent with ADL
Case 5: Joan
Decision – how would you treat?
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Observation only
Treatment for anaemia alone
Systemic chemotherapy
Other
Case 5: Joan
• Adopted watchful waiting
– Reviewed by cardiologist – normal myocardial
perfusion scan
– Erythropoetin, rise in haemaglobin → 11 g/L
– Bisphosphonates (absence of bone disease)
• Observed for 9 months
Asymptomatic
• Presented with acute lower back pain
– Lower back pain whilst gardening
– Plain x-rays showed fractures T12, L4 and L5
– Paraprotein increase from 16g/L → 24 g/L
Case 5: Joan
How would you treat her ?
Case 5: Joan
Decision – how would you treat her?
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Systemic chemotherapy + Analgesia
Systemic chemotherapy + Radiotherapy
Systemic chemotherapy + Vertebral augmentation
Other
Case 5:Joan
• Admitted for pain control
– Treated with long acting and short acting opiate
analgesia
– Received palliative RT to lumbar spine (8Gy)
– Started on Cyclophosphamide po weekly, and
Dexamethasone 20mg daily for 4 days / month
• Discharged when mobility improved
• Ongoing problems with pain
– Multiple level kyphoplasty at Royal National
Orthopaedic Hospital (Sean Molloy)
– Very good symptomatic benefit
– Support from palliative care team, and liaison with
primary care
Case 5: Joan
Velcade Dex
Cyclo Dex
Weekly sc, Velcade
Dose reduced to 1 mg/m2
from cycle 3
Completed 8 cycles
No sig. Rx toxicity
RT K’plasty
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Serum paraprotein (g/L)
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25
Progressed within 3 months
completing Velcade
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Time (months)
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Case 6: Arthur
• 97 year old
• Known diagnosis of Alzheimer’s disease
– Mobile with a Zimmer Frame
– Lives at home with carers – washing/cooking/cleaning
– Memantadine.
• PMHx - ↑BP, GORD, BPH
• 2012: 6 week history
– Confusion
– Lower back pain
– Bed bound
Case 6: Arthur
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IgG kappa pp 14g/L, BJP – faint band
Haemoglobin 11 g/dL
Hypercalcaemia
Creatinine 120 umol/L (eGFR 50 ml/min)
BM 40% plasma cells
SS: Fracture L4/L5, lytic lesion pelvis/femur
Cytogenetic – FISH – 17p del
ISS stage: 2
Diagnosed with symptomatic myeloma
Case 6: Arthur
Decision – how would you treat?
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Analgesia + Bisphosphonate treatment
+ Radiotherapy
+ Dexamethasone
+ Systemic chemotherapy
Case 6: Arthur
• Pain control
– Palliative care input
– Opiate analgesia
• Treatment
– Dexamethasone (low dose). Decision not systemic RX
– Bisphophonate
– Radiotherapy to lumbar spine and left ilium
• Discharged home, returned to previous baseline
– Re-instituted package of care
– Community palliative care input
– Haematology day unit
Case 6: Arthur
• Well for 3 months
• Decline mobility
– Pain weight bearing right leg. Unable to mobilise
• Re-assessed
– Radiotherapy – right femur + sacrum (symptom better)
– Systemic chemotherapy
• ? Imid based (need for anticoagulation)
• ? Proteosome inhibitor (able to visit hospital)
– Velcade sc weekly at 1mg/m2, with Dex (10mg 2/7)
• PP 14 → < 3g/L (VGPR). Received 4 cycles, stop.
• No treatment emergent problems
• Stable for 9 months → RIP
Frail elderly patient
• Dependent on co-morbidities – more likely > 75 yrs.
• Assessments of frailty / co-morbidities
– Comprehensive geriatric assessment (CGA)
– Cumulative illness rating scale (CIRS-G)
• Important to note the impact of disease on performance
status
• Ability to benefit from novel agents
• Modification of treatment dose and schedule
• Balance goal of depth of response with minimising
toxicities
PALUMBO ET AL< BLOOD, 27 OCTOBER 2011 VOLUME 118, NUMBER 17
Summary
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Fit elderly should be treated as any other patient
Dependent on co-morbidities – more likely > 75 yrs.
Assessments of frailty / co-morbidities
Important to note the impact of disease on performance
status
Ability to benefit from novel agents
Modification of treatment dose and schedule
Balance goal of depth of response with minimising
toxicities
Consider other causes for co-existent medical problems
UCLH
• Clinical team
Kwee Yong / Shirley D’Sa / Ali Rismani / Rakesh Popat
Jaimal Kothari / Dean Smith / Laura Percy / Lydia Lee
• Clinical Nurse Specialists
Aviva Cerner / Samantha Darby
Jude Dorman
• Clinical Trials
Janet Lyons – Lewis / Diane Gowers
North Middlesex
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Clinical Nurse Specialist
Millicent Blake – McCoy
Clinical Trials
Christy Griffin-Pritchard

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