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Table 10. Adverse Effects of Thalidomide—Studies of Specific Adverse Effects

Study ID

Thalidomide Dose Daily
[Median length of followup]

No. of Patients, Age, Sex, additional MM characteristics

N

Adverse Effects

Other

*Anaissie, 2004 (ASH 3467)114

Quality*

Thal dose not specified, randomization to receive thal or not after Dex-containing chemo ASCT, consolidation and IFN
[33 mo, 5-114]

553

553

9% Avascular necrosis (AVN) of femoral head

Among thal treated pts, prevalence similar to control group (8% vs. 10%; p=0.58)

Median time to onset of AVN of femoral head 12 mo (2-41)

Risk factors:
   Cumulative Dex dose (p=0.0006; OR 1.028; 95% CI 1.012-1.044) per Dex 40 mg
   Male gender (p=0.009; OR 0.390; 95%CI 0.192-0.790)
   Younger age (p-0.0122; OR 0.961, 95% CI 0.934-0.991/year)

FDG-PET failed to detect abnormal uptake

Badros, 2002115

Quality 2/5

200-800 mg ± chemo
[Median f/u NS]

343

174=MM treated in prior clinical trial
169=relapsed MM
Age & gender not specified

174

92 chemo +Thal; 82 chemo
169 Thal relapsed MM

Chemo + Thal=92:
   20% TSH > 5
   7% TSH >10

Chemo only=82:
   7% TSH >5
   0% TSH >10

Thal=169:
   22% TSH >5
   14% TSH >10

Conclusion=subclinical hypothyroidism occurred more frequently with Thal

Bowcock, 2001116

Quality 0/5

Mean dose 150 mg
[5 mo]

23

65.6 yr=avg age for thromboembolism (TE) pts
Gender not specified
relapsed, resistant
Historical control group=18 pts with relapsed, resistant MM who had not received thal (age, gender not specified)

23
18

5 DVT

2 Cerebral TE (1=TIAs)
1 Cerebral TE (TIAs)

Conclusion=TE more common on thal

Fahdi, 2004117

Quality 4/6

Combo chemo VAD/PAC then randomized to placebo vs. Thal
Induction=400 mg
Maintenance=200 mg q other day x 1 yr then 100 mg/d
[Median f/u NS]

200
50 yr ± 3 yr

Gender not stated
newly diagnosed

200

Placebo=104
Thal=96

Bradycardia:
   Baseline=9.1%
   4-12 weeks=8.3%
   Baseline=9.4%
   4-12 weeks=38.8%

Thal: Overall 53% developed bradycardia; (4.8% required pacemaker)

Bradycardia defined as 30-60 beats/min.

TSH, cardiac history, diabetes, & renal function were equivalent between groups

Hall, 2003118

Quality 1/5

200-800 mg
Group 1 (Indolent) & Group 2 (refractory)

40

Age & gender not specified (Thal only: Group 1 Indolent=19 & Group 2 refractory=31)

Group 1=19
Group 2=31

Minor =14
Moderate=8
Severe (exfoliative)=1

Minor derm toxicity=rash that didn't require change in thal schedule.

Mod=altered in schedule or dose.

Severe=discontinued drug due to rash

200-400 mg
+ Dex 40 mgx4d on D1, 9, 17 on odd-numbered cycles and D1 on even-numbered cycles
[Median f/u NS]

Thal/Dex 37

Age & gender not specified
Newly diagnosed

37

Minor=5
Moderate=8
Severe=3
   Toxic necrolysis=1
   Erythema multiforme=1
   Exfoliative=1

Onset of skin reactions from 1st mo until after 4 mo after Thal begun

3 pts ↓ Thal until rash resolved.
5 pts interrupted Thal due to adverse reactions; resumed at lower doses.
3 stopped Thal

Hattori, 200445

Quality 4/5

200-400 mg
Dose reductions + G-CSF for neutropenia
[Median f/u NS]

44
55.9 yr (30-70)
58% M

Relapsed refractory

44

 

11% d/c Thal due to grade 4 cytopenia

25% had ≥ 50% drop in neutrophils (w/ lower hgb, platelets, & BM plasma cells than in nonneut. pts)

11%=concomitant thrombocytopenia; Nadir=3-8 wk

"Dose reduction and exogenous GCSF usually ameliorated neutropenia"

*Singh, 2004 (ASCO 3142)119

Quality*

Thal dose NS
[Median f/u NS]

257

235 cases reviewed from FDA representing reports from clinical practice and compared to clinical trials reports in the medical literature (n=22)
Includes information about completeness of age, gender, dose, etc. in study but not reported in abstract

166

Clinical practice reports
Clinical trial reports N=69

 

Case Report Information: In comparison with reports from clinical practice settings (n=166), clinical trial reports (n=69) had higher rates of inclusion of information on: thalidomide administration dates (77% vs. 32%), DVT/PE onset date (62% vs. 23%), no of days from thal administration to DVT/PE (52% vs. 17%), and DVT/PE treatment (76% vs. 42%)
[p <.0001 for each comparison]

*Spencer, 2004 (ASCO 6655)120

Quality*

Thal 200 mg + Zoledronic acid (ZA) 4 mg IV q 28d +Prednisolone 50 mg qod
As post—SCT maintenance
[Median f/u NS]

83

Age & gender well-matched but specifics not included
12 mo post-ASCT non-progressive MM
Randomized to zoledronic acid ± Thal

83 enrolled

40 ZA/Thal
43 ZA alone

Higher creatinine levels (i.e. renal dysfunction) associated with:
   Male gender + pre-ASCT B2M >4 mg/L (p<0.001)
   But not cumulative ZA dose—NS
   Or presence of thal—NS

No evidence of PK interaction Thal to ZA.

*Tosi, 2004 (ASH 4898)77

Quality*

Likely includes pts presented in report below

n=34 on Thal 200 + Dex 40 d1-4 even cycles & d1-4, 9-12, 17-20 odd cycles
Followed by cyclophosphamide 7 g/m2 + G-CSF; then auto PBSCT.
n=40 on Thal 200 mg + Dex 40 mg d1-4 q mo
[Median f/u NS]

74

>8 mo Thal/Dex treatment
34=newly diagnosed symptomatic MM
55 yr
52% M
40=pretreated
(14 relapsed or
26 progressive)
61 yr
68% M

74

Neurotoxicity

Newly diagnosed=74%
   Grade I=57%
   Grade III=0%

Pretreated=75%
   Grade II=32.5%
   Grade III=27.5%

Not related to sex, M protein isotype or daily Thal dose

Grades II + III correlated to longer disease duration ("significant")

Tosi, 2005121

Quality 4/6

Likely second report of the pretreated pts presented in report above

100-400 mg
Some (N NS) received dex 40mg/d x4d q4 wks
Eligibility criteria=on thal for > 1 year

40
61.5 yr (34-78)
68% M

Stage III=90%
Previous SCT=55%
Previous conventional chemo=38%
IgG=68%
IgA=17%
B-J protein=12%
Non-secretory=NS

40

Goal=evaluation of toxicity I pts exposed to long-term thal

Median tx duration=15 mo (12-44)

Sub-clinical hypothyroidism=3%
Sinus bradycardia=6%
Peripheral neuropathy=75%

Grade 1:
   6 months=35%
   12 months=15%

Grade 2:
   6 months=18%
   12 months=33%

Grade 3:
   6 months=0%
   12 months=28%

Med time to onset of sx=11 mo (5-13)

Electrophysiologic evaluation tested in all with Grade >1 neurotoxicity revealed sensory axonal polyneuropathy=100%

Pts with longer time from diagnosis to onset of thal with higher risk of toxicity (p=0.01) but this was not related to the prior therapies used

Zangari, 2001122

Quality 0/5

400 mg (see Total Therapy II program Barlogie, 2002109)
Pts randomized to thal or not within Total Therapy II
[Median f/u not stated]

100 randomized
56 (32-71)
67% M

6 with previous DVT o/w equal distribution of risk factors (doesn't state which groups 6 previous DVT were in)

DVT confirmed by Doppler ultrasound or venography

Thal=50
No thal=50

 

DVT=14/50 (28%)
DVT=2/50 (4%); p=0.002

Median time from start of thal to diagnosis of DVT=42.5d (7-93d)

Zangari, Saghafifar, et al., 2002123

Quality 0/6

400 mg (see Total Therapy II program Barlogie, 2002109)
Pts randomized to thal or not within Total Therapy II
[Median f/u not stated]

62 randomized
61 (33-76)
58% M

3 with previous DVT o/w equal distribution of risk factors (doesn't state which groups 6 previous DVT were in)
Incidence of APC resistance in absence of Factor V Leiden mutation 23%, 8/30 thal pts and 6/32 no thal pts
DVT confirmed by Doppler ultrasound or venography

Thal=30
No thal=32

 

DVT=11/30 (37%)
DVT=1/32 (1%); p=0.002

Median time from start of thal to diagnosis of DVT=42.5d (7-93d)

Pts with APC resistance on thal with highest likelihood of developing DVT (50%) and developing early DVTs (p=0.04)

Zangari, Siegel, et al., 2002124

Quality2/6

400 mg
Pts enrolled in 2 different Phase III studies —
Total Therapy II using DT-PACE (see Total Therapy II program Barlogie, 2002109) and study with relapsed patients after autoSCT that used DCEP-T which is the same combination of agents minus doxorubicin
[Median f/u NS]

232

DT-PACE: Med age=60
Gender not stated
Serum M protein=1.7 g/dL

DCEP-T:
Med age=58
Gender not stated
Serum M protein=0.01 g/dL
DVT confirmed by Doppler ultrasound or venography

DT-PACE Thal including doxorubicin=192
DCEP-T (Thal)=40

 

DVT=1/40 (2.5%)
DVT=31/192 (16%); p=0.02
DT-PACE with shorter time to develop DVT (p=0.04)

Pts with chromosome 11 abnormalities developed DVT more frequently than those without them (23% vs. 11%, p=0.04)

In addition to doxorubicin, risk factors (RF) determined to be age >60 and chromosome 11 abnormalities

Cumulative incidence of DVT on thal:
   No doxo, No RF 3%
   Doxo, No RF 12%
   Doxo, 1 RF 23%
   Doxo 2 RF 46%

*Zangari, Barlogie, Lee, et al., 2004 (ASH 4914)125

Quality*

Thal dose NS
DVT in Thal regimens where bortezomib (V) is added or not added to Dex & Doxorubicin without anticoagulation (VDT-PACE vs. DT-PACE)
[Median f/u NS]

24

Age & gender not specified

24 pts

Received 98 cycles DTPACE
69 cycles VDTPACE

10% DVTs in these pts

0% thromboembolic events reported in these pts

Historical reports of DVT in Thal/Dex=12-16%

 

Zangari, 2004126

Quality 6/6

400 mg (see Total Therapy II program Barlogie, 2002109)
Pts randomized to thal or not within Total Therapy II
Cohort 1=221 pts—no anticoagulation with n=87 randomized to thal
Cohort 2=35 pts all on thal and received low dose warfarin
Cohort 3=130 with pts randomized to thal (n=68) receiving enoxaparin 40mg sc daily
[22 mos]

386
Age 65 yr=18%
62% M

Prior chemotherapy=15%
IgG=NS
IgA=21%
B-J protein=NS
Non-secretory=NS
Known risk factors for DVT similar across groups
Cohorts similar except Cohort 3 with significantly more pts with high LDH >190 IU/l, >50% plasma cells in BM, and platelet count <150 x 109/l

386

Cohort 1=221
Thal=87
No thal=134
Cohort 2=35 (all thal)
Cohort 3=130
Thal=68
No thal=62

Cohort 1 DVT incidence:
   Thal=30%
   No thal=4%
   p=0.0001
   OR DVT=4.3 (CI 2.09-8.65)

Cohort 2: Incidence of DVT similar with and without warfarin 1 mg/d (p=0.07)

Cohort 3 DVT incidence:
   Thal + enoxaparin=15%
   No thal=15%
   p=0.81

All DVTs occurred within 15 months of starting thal

No relationship between DVT and paraprotein response

Abbreviations: *=abstract, ASCT=Autologous stem cell transplant, CI=Confidence Intervals, CR=Complete Response, CT=consolidation therapy, DTPACE=combination chemotherapy including Dex/Thal/Cisplatin/Doxorubicin/Cyclophosphamide/Etoposide, EFS=event free survival, HDT=high dose therapy, IFN=Interferon, Near CR=+IFE only, NS=not stated, OS=overall survival, pt(s)=patient(s), SCT=stem cell transplant, UTD=unable to determine, VAD=standard chemotherapy including Vincristine/Doxorubicin/Dexamethasone

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