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 11

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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
CD34+ cells in the bone marrow	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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