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Report on the Relative Efficacy of Oral Cancer Therapy for Medicare Beneficiaries Versus Currently Covered Therapy

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Table 11. Tumor Characteristics Predictive of Disease Response or Survival: Group 1A—DNA Factors at the Start of Imatinib Therapy

Prognostic factor Studies indicating an association and quality Strength of association with tumor response Strength of association with survival
% of Ph+ metaphases at the start of therapy Cortes, Talpaz, et al., 20031
(Quality = 6/6)
CP & AP
Relationship to Major CR:
Ph+ <90%: N= 295 91%
   p<0.0001
Ph+ >90%: N = 270 54%
Relationship to survival:
Ph+ <90% N= 295 96%
   p=0.08
Ph+ >90% N = 270 81%
Kantarjian, Sawyers, et al.,20022
(Quality = 6/6)
CP-IFN-r
Relationship to Major CR:
Ph+ <90%: N= 55 89%
   p<0.001
Ph+ >90%: N = 378 56%
 
Marin, Goldman, et al., 200374
(Quality 1/5)
CP-IFN-r
Predictor of response to I at 800 mg (when resistant to I at 400 mg):
Ph+ < 100%: N=18 28% CCR, 16% MCR + minorCR
Ph+ = 100%: N=18 0% CCR, 6% MCR + minorCR
   p<0.05
 
Marin, Marktel, Bua, et al., 200375
(Quality 2/5)
CP-IFN-r
Relationship to CCR:
Ph+ < 100%: N= 20 80%
   p=<0.0001
Ph+ = 100%: N = 122 21%
Relationship to OS:
Ph+ < 100%: N= 20 100%
   p=<0.02
Ph+ = 100%: N = 122 68%
O'Dwyer, 200496
(Quality 2/5)
CP-IFN-r
Relationship to hematologic relapse:
Ph+ <99%: N= 20 2%
  p=0.2478
Ph+ = 99%+: N = 118 17%
 
Clonal evolution (AP and BP/BC) Kantarjian, Cortes, 200290
(Quality 5/6) BP
Relationship to Major CR:
None: N = 28 64%
   p=0.15
Clonal evolution: N = 43 47%
None: N = 28 median survival = 7.5 mo
Clonal evolution: N = 43 median survival = 4.5 mo
   p=0.49
Sawyers, 20023
(Quality 5/6) BP
  None: N = 67 median survival = 10.5 mo
Clonal evolution: N = 111 median survival = 5.5 mo
   p=0.003
Sureda, 20034
(Quality 4/5) BC
  Ph+ only: N= 18 1-yr OS = 57% (SD 18%)
Clonal evolution: N = 12 1-yr OS = 0%
   p=0.0043
Talpaz, 200287
(Quality 5/6) AP
Relationship to disease progression:
None: N = 100 38%
   p=0.086
Clonal evolution: N = 60 50%
 
Cyotgenetic clonal evolution (likely overlapping patient populations) Braziel, 200267
(Quality = 3/6)
CP-IFN-r
Presence or absence of clonal evolution not related to response (3 of 19 pts with complex cyto—were distributed among three response groups)  
Cortes, Talpaz, et al., 20031
(Quality = 6/6)
CP
Relationship to Major CR:
None: N= 295 65%
   p=0.1
Clonal evolution: N = 270 54%
Relationship to survival:
None: N= 295 92%
   p=0.002
Clonal evolution: N = 270 77%
El-Zimaity, 200497
(Quality = 3/6)
CP & AP
Shorter duration of response
RR 4.34 (SE 0.47)
   p=0.002
 
Kantarjian, Sawyers, et al.,20022
(Quality = 6/6) BP
Relationship to Major CR:
None: N = 379 61%
   p=0.18
Clonal evolution: N = 54 52%
 
Karntarjian, Talpaz, et al., 200270
(Quality 5/5)
CP-IFN-r
Relationship to Major CR:
None: N= 222 65%
   p=0.02
Clonal evolution: N = 27 41%
Relationship to survival:
None: N= 222 98%
   p<0.01
Clonal evolution: N = 27 84%
Kantarjian, O'Brien, 2004
Kantarjian, 2004151
(Quality 5/6)
CP-IFN-r
  None: 2 yr survival = 87%
4 yr survival = 66%
Clonal evolution: 2 yr survival = 66%
4 yr survival = 55%
   p=0.05
Kantarjian, O'Brien, 200398
(Quality 3/6)
CP-new diagnosis
  Relationship to estimated 5-yr survival:
None: N= 779 66%
   p=0.95
Clonal evolution: N = 58 65%
(only 187 received I; others = IFN)
Karntarjian, Cortes, et al., 200472
(Quality 5/6)
CP-IFN-r
  Relationship between baseline clonal evolution and 4-yr survival:
None: N= 237 88%
   p=0.007
Clonal evolution: N = 24 69%
Marin, Marktel, et al., 200375
(Quality 2/5)
CP
Relationship to CCR:
None: N= 24 33%
   p=0.41
Clonal evolution: N = 31 24%
Relationship to OS:
None: N= 111 81%
   p<0.0001
Clonal evolution: N = 31 32%
Marktel, 200399
(Quality 5/6)
CP-IFN-r
Relationship to PFS at 18 mos:
None: N= 50 94%
   p<0.0001
Clonal evolution: N = 10 34%
Confirmed in multivariate model (RR 14.8, CI 2.8-76.6)
 
O'Dwyer, 200496
(Quality 2/5)
CP-IFN-r
Relationship to hematologic relapse:
None: N= 119 9%
   p<0.0001
Clonal evolution: N = 22 50%
HR 4.912 (CI 1.944-12.409)
 
CD34+ cells in the bone marrow *Marin, 2004100
(Quality*)
CP
Relationship to PFS:
CD34+ % of BM cells <2% (N=44)—PFS @ 3-yr = 77%
CD34+ % of BM cells >2% (N=14)—PFS @ 3-yr = 36%
   p=0.006
 
*Elliot, 2004101
(Quality*) phase unclear
CD34+ cells/10hpf predicts CCR  
Variant Ph translocations El-Zimaity, 200497
(Quality = 3/6)
CP & AP
Shorter duration of response
RR 1.33 (SE 0.76)
   p=0.71
 
Chromosome 9 deletions Huntly, 200351
(Quality = 2/6)
CP-new diagnosis, AP, BP
Progression free survival for CP patients with (N = 35) and those without deletions (N=172) is significantly different; those with deletions did worse.
   p=0.02

Progression free survival for AP + BP patients with (N = 15) and those without deletions (N=106) is significantly different; those with deletions did worse.
   p=0.02
Overall survival for patients with (n = 54) and those without deletions (n=297) not significantly different; median followup 48 months.
   p=0.18
Genes known to be related to apoptosis and drug resistance in leukemia cells Lange, 2003102
(Quality 4/6) BC
8 candidate genes studied via Q-RT-PCR; when compared to healthy controls, BCL-XL, MDR-1, BAX, MRP-1 and survivin is overexpressed in BC (all p<0.05)
MDM-2 is underexpressed
   (p=0.001)

The only candidate gene correlated with tumor response was MRP-1 (med <24 10/16 responses, >24 5/21, p=0.018; multivariate model OR of no response with high MRP-1 = 14.4
   (p=0.011)
 
Genomic microarrays McLean103
(Quality 5/6)
CP
Used microarray technology to evaluate the signature of >1000 genes and develop a genomic expression profile that is characteristic of CR in CP-CML

Pt met ideal microarray profile:
OR for CCR = 200 (19-3096; N=66)
OR for MCR = 19.9 (6-67; N=90)
 

Abbreviations: * = abstract; AP = Accelerated phase; BC = Blast crisis; BM = bone marrow; BP = Blastic phase; CI = 95% confidence interval; CML = Chronic myelogenous leukemia; CP = chronic phase; CR = cytogenetic response; CCR = complete cytogenetic response; cyto = cytogenetics; hpf = high powered fields; HR = Hazard Ratio; I = Imatinib; IFN = Interferon; M = Male; MCR = major molecular response; N = Number; NR = not reported; OR = Odds ratio; OS = Overall Survival; PFS = progression-free survival; Ph+ = Philadelphia chromosome positive; pt(s)=patient(s); RR = relative risk.

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