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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 13. Tumor Characteristics Predictive of Disease Response or Survival: Group 2—Production of the RNA Message

Prognostic factor Studies indicating an association and quality Strength of association with tumor response
Molecular response as a marker of tumor response Paschka, 200310
(Quality = 4/6)
CP-IFN-r
Best individual molecular ratios in patients who achieved a MCR and subsequently relapsed were significantly higher than that of patients who remained in CCR, median f/u 13 mo
   (p=0.0017)
BCR-ABL/ABL Median
     All pts = 0.086 (0-3.9)
     Relapse = 1.4 (0.013-7.8)
     Continuous CCR = 0.071 (0-3.9)
     All pt who achieved median ratio <0.1% are in CCR
Müller, 2003104
(Quality 5/6)
CP-new diagnosis
Median BCR-ABL/ABL ratio at start of I (N=98) was 51% (1-210%)

Median for CR pts (N=85): 0.067% (0-5.7%)
Median for PR pts (N=5): 1.4% (0.18-11%)
Median for MinorR pts (N=7): 27% (6-69%)
Median for pts in NR (N=2): 42% (38-45%)

Hughes, 200311
(Quality 6/6)
CP- new diagnosis
Relationship between CCR and reduction in level of transcripts:
     I-treated in CCR (N=333): 2.5 log reduction
     IFN+cytarabine in CCR (N=37): 2.2 log reduction
   p=0.036
Merx, 2002105
(Quality = 5/5)
CP-IFN-r
Median BCR-ABL/ABL ratio at start of I (N=120) was 67% (0.01-100%)
Median for CR pts (N=50): 0.85% (0.018-21%)
Median for PR pts (N=42): 6.7% (0.5-94%)
Median for Minor R pts (N=33): 45% (6-100%)
Median for NR pts (N=50): 46% (6-100%)

CR to PR (p < 0.0001)
PR and MinorR (p < 0.0001),
MinorR and NR (p NS)

Rosti, 20048
(Quality 4/5)
CP-IFN-r
>2 log reduction in the BCR-ABL/B2 microglobulin transcript ratio in 76/85 (89%) pt in CCR with I and 0/23 (0%) pt in PCR
Stentoft, 20017
(Quality 4/5)
AP & CP
Longitudinal plots of BCR-ABL transcripts derived from blood and bone marrow samples correlate (i.e. peripheral blood assessments are adequate)
On plots, 1 log reduction in BCR-ABL transcript levels correlate with CCR (strength of association not given)
Wu, 20026
(Quality 3/5)
CP, AP & BC
Longitudinal plots of BCR-ABL transcript copy numbers correlate with cytogenetic response
*Cortes, Talpaz, O'Brien, Giles, et al., 20045
(Quality*)
CP-new diagnosis
Relationship between increasing transcript levels and relapse at 24 mos:
     <0.05 increase-0/44 (0%) loss of CCR 0.05-1 increase-6/33 (18%)
     >1-5/11 (45%)
   p=0.0001
Moravcova, 20049
(Quality 3/6)
CP-IFN-r
6/11 CP pts achieved CCR with rapid decrease in transcript 18-2600 fold at 6 mo, and 37-12500 fold at 12 mo; no BP or AP pt (0/8) showed this trend
Karntarjian, Talpaz, et al., 200412
(Quality = 5/5)
CP-IFN-r
If BCR-ABL/ABL is <0.05%, then all pt (N=71) had a CCR and none relapsed by 10 mo median f/u
Prognostic value of baseline transcript levels Müller, 2003104
(Quality 5/6)
CP-new diagnosis
Median BCR-ABL/ABL ratio at start of I (n=98) was 51% (1-210%)
Response to I was independent of BCR-ABL level at start of therapy
Hochhaus, 200255
(Quality = 3/6)
CP
Relationship between presence of higher ratio and resistance expressed as the ration of BCR-ABL/G6PD:
Prior to Imatinib - 4.6 %
With Imatinib resistance - 6.0% p=NS
Wu, 20026
(Quality 3/5)
CP, AP & BC
BCR-ABL copy number at baseline was not significantly different among I treated patients who ultimately did or did not have cytogenetic response)
   (p=0.09)
Prognostic value of transcript trends while on imatinib treatment Branford, 200333
(Quality = 5/6)
CP-new diagnosis
Among I-treated pts (n=28), median log reduction is associated with MMR at 24 mo
  • Med log reduction > 2 versus < 2 at 3mo (100% vs. 54%; p<0.001 by K-M).
  • Med log reduction > 2 versus < 2 at 6 mo (86% vs. 0%; p<0.001 by K-M) and incidence of progression.
  • Med log reduction <2 versus > 2 at 6 mo (56% vs 4%; p=0.002 by K-M).
Hughes, 200335
(Quality = 6/6)
11 CP-new diagnosis
Relationship between >3 log reduction@ 12 mo & being progression free @ 24 mo:
     >3 log reduction @ 12 mo: 100%
     < 3 log reduction: 95%
     no CCR: 85%
   p=<0.001

Relationship between >3 log reduction and CCR:
>3 log reduction at 6 months:
     I-treated in CCR: 42%
     IFN+cytarabine in CCR: 13%
   p=0.03
>3 log reduction at 12 months:
     I-treated in CCR: 57%
     IFN+cytarabine in CCR: 24%
   p=0.003

Rosti, 20048
(Quality 4/5)
CP-IFN-r
Median transcript level in pt who reached CCR in <6 mo after start of I:
   Baseline 0.2330
   3 mo 0.0039
   6 mo 0.0003
   12 mo 0.0005
   24 mo 0.0001

Median transcript level in pt who reached CCR in 9-12 mo after start of I:
   Baseline 0.2490
   3 mo 0.0213
   6 mo 0.0046
   12 mo 0.0034
   24 mo 0.0002
Müller, 2003104
(Quality 5/6)
CP-new diagnosis
After 3 mo, CCR within the first year could be predicted using the ratio BCR-ABL/ABL (p=0.0026) or BCR-ABL/G6PD (p=0.0074).

Empirically derived statistical cutoff point for best prediction of CCR after 12 mo was a ratio BCR-ABL/ABL of 10% at 3 months with a positive predictive value of 71% and a negative predictive value of 82%.

Empirically derived statistical cutoff point for best prediction of CCR after 12 mo was a reduction of the ratio BCR-ABL/G6PD of 0.3 log after 3 mo with a positive predictive value of 76% and a negative predictive value of 80%, respectively.
*Müller, 2004106
(Quality*)
CP, AP & BC
BCR-ABL/ABL ratios after 12mo were lower in I pts in CCR than I pts with subsequent relapse (0.18-0.60%, p=0.04)

In n=132 pt from the IRIS study, no pt with BCR-ABL/ABL <0.12% (>3 log reduction) after 12 mo relapsed
*Branford, 200432
(Quality*)
CP
BCR-ABL levels do not appear to decrease substantially after 24 mo on I (see efficacy table, IRIS trial)
*Cortes, Talpaz, O'Brien, Giles, et al., 20045
(Quality*)
CP-new diagnosis
Relationship between 1 log reduction in transcript levels after 3 mo and 3 log reduction at 24 mo:
     >1 log: 90%
     <1 log: 55%
   p=0.0002
*Press, 2004107
(Quality*)
CP
Relationship between >2 log reduction in transcripts at time of CCR and relapse over 29 mo median f/u
     >2 log reduction - 3/10 (10%) relapsed
     <2 log reduction - 22/49 (45%) relapsed
          OR 7.1 (CI 1.9-26)
Wang, 200348
(Quality 2/5)
All phases and relapse states including after allogeneic SCT
Relationship to PFS at 500 days estimated from K-M:
     BCR-ABL/ABL ratio @ 4 wk <50% - 100%
     BCR-ABL/ABL ratio @ 4 wk >50% - 45%
   p=0.01

     BCR-ABL/ABL ratio @ 3 mo <10% - 100%
     BCR-ABL/ABL ratio @ 3 mo >10% - 38%
   p=0.003
Wu, 20026
(Quality 3/5)
CP, AP & BC

Merx, 2002105
(Quality = 5/5)
CP-IFN-r
BCR-ABL copy number at 3mos was significantly reduced among I treated patients who had a cytogenetic response (p=0.02) and this trend increased with time (p=0.04 at 6 mo, p=0.005 at 9 mo, and p=0.0008 at 12 mo)

Median BCR-ABL/ABL ratio at start of I (n=120) was 67% (0.01-100%)
Median for CR pts (n=50): 0.85% (0.018-21%)
Median for PR pts (n=42): 6.7% (0.5-94%)
Median for Minor R pts (n=33): 45% (6-100%)
Median for NR pts (n=50): 46% (6-100%)

CR to PR (p < 0.0001)
PR and MinorR (p < 0.0001),
MinorR and NR (p NS)

Probability of MCR after 6 mo was higher when ratio <20% at 2 mo (p=0.007)

Abbreviations: *= abstract; AP = Accelerated phase; BP = Blastic phase; CI = 95% confidence interval; CML = Chronic myelogenous leukemia; CP = chronic phase; CR = cytogenetic response; CCR = complete cytogenetic response; f/u = followup; I = Imatinib; IFN = Interferon; K-M = Kaplan-Meier; M = Male; MMR = major molecular response; NR = no response; NS = not significant; OR = Odds ratio; OS = Overall Survival; PCR = polymerase chain reaction; PFS = progression-free survival; PR = partial response; pt(s)=patient(s); RR = relative risk; SCT = Stem cell transplant

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