Technology Assessment: Report on the Relative Efficacy of Oral Cancer Therapy for Medicare Beneficiaries Versus Currently Covered Therapy, Part 3. Imatinib for Chronic Myeloid Leukemia (CML). Table 13

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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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