Table 4. Randomized Trials Comparing... | American Society of Hematology

Table 4.

Randomized Trials Comparing IFN- With Chemotherapy in the Treatment of CML

Authors, Year	Population Description	No.Randomized	Rx^4-150	Med f/u (mo)	Outcomes
					Hematologic Response^4-151		Cytogenetic Response^‡		Survival % (CI)
					CHR %	PHR %	CCyR %	PCyR %	5-yr (CI)	Med (mo)
Hehlmann et al,⁹ 1994	CP-Ph or bcr/abl+, med age = 47-49, newly diagnosed (mo from dx NR), symptomatic, <30% blasts + promyelocytes in peripheral blood, none with prior treatment	133 186 194	rIFN-α BUS HU	35 34 41	31^NS 23^NS 39^NS	52^NS 69^NS 51^NS	5 0 1	2 1 1	59 (48-70)^4-153 32 (24-40) 44 (36-53)	66 45 56
Italian Cooperative Group,²² 1994	CP-Ph+, med age = 47-49, <6 mo (med) from dx, no disorder that could influence evaluation of rx or tox or nonhematologic involvement. <10% blasts in peripheral blood, 10% to 16% with prior treatment	218 104	rIFN-α HU, BUS	68	CHR + PHR = 45% (3 mo), 62% (8 mo)^NS CHR + PHR = 46% (3 mo), 53% (8 mo)^NS		8 0	11 1	50% 29 (17-41)	72 52
Allan et al,²⁶ 1995	CP, ≥92% Ph+, med age NR, mo from dx, no pts with platelets, NR <50,000 μL or other severe disease, 6% with prior treatment	293 294	rIFN-α HU, BUS	NR	WBC <5,000/μL in 18% <10,000/μL in 31%; 10,000-30,000/μL in 13% NR		6 0	4 3	52 (45-59) 34 (27-42)	61 41
Ohnishi et al,¹⁰ 1995	CP-Ph+, age 20-70 eligible, med age and mo from dx NR, newly diagnosed, no serious hem disease, no other neoplasms, 0-2	80	rIFN-α	50	39^NS	39^NS	9^NS	8^NS	54	NR
	ECOG status, BMT pts censored, prior rx NR	79	BUS		54	43	3	3	32	NR
Benelux CML Study Group,²⁷ 1998	CP-Ph/bcr-abl, med age = 56, 2-3 mo from dx, newly diagnosed, none with prior treatment	100 95	rIFN-α + HU HU	51	62 38	NR NR	9 0	7 2	NR NR	64 NS 68
Broustet et al,⁵⁶ 1991	CP-Ph+, mean age = 57, <3 mo (med) from dx, pts eligible for BMT excluded, some with prior treatment	30 28	rIFN-α HU	NR	53 82	NR NR	7 0	30 7	NR NR	NR NR

Authors, Year	Population Description	No.Randomized	Rx^4-150	Med f/u (mo)	Outcomes
					Hematologic Response^4-151		Cytogenetic Response^‡		Survival % (CI)
					CHR %	PHR %	CCyR %	PCyR %	5-yr (CI)	Med (mo)
Hehlmann et al,⁹ 1994	CP-Ph or bcr/abl+, med age = 47-49, newly diagnosed (mo from dx NR), symptomatic, <30% blasts + promyelocytes in peripheral blood, none with prior treatment	133 186 194	rIFN-α BUS HU	35 34 41	31^NS 23^NS 39^NS	52^NS 69^NS 51^NS	5 0 1	2 1 1	59 (48-70)^4-153 32 (24-40) 44 (36-53)	66 45 56
Italian Cooperative Group,²² 1994	CP-Ph+, med age = 47-49, <6 mo (med) from dx, no disorder that could influence evaluation of rx or tox or nonhematologic involvement. <10% blasts in peripheral blood, 10% to 16% with prior treatment	218 104	rIFN-α HU, BUS	68	CHR + PHR = 45% (3 mo), 62% (8 mo)^NS CHR + PHR = 46% (3 mo), 53% (8 mo)^NS		8 0	11 1	50% 29 (17-41)	72 52
Allan et al,²⁶ 1995	CP, ≥92% Ph+, med age NR, mo from dx, no pts with platelets, NR <50,000 μL or other severe disease, 6% with prior treatment	293 294	rIFN-α HU, BUS	NR	WBC <5,000/μL in 18% <10,000/μL in 31%; 10,000-30,000/μL in 13% NR		6 0	4 3	52 (45-59) 34 (27-42)	61 41
Ohnishi et al,¹⁰ 1995	CP-Ph+, age 20-70 eligible, med age and mo from dx NR, newly diagnosed, no serious hem disease, no other neoplasms, 0-2	80	rIFN-α	50	39^NS	39^NS	9^NS	8^NS	54	NR
	ECOG status, BMT pts censored, prior rx NR	79	BUS		54	43	3	3	32	NR
Benelux CML Study Group,²⁷ 1998	CP-Ph/bcr-abl, med age = 56, 2-3 mo from dx, newly diagnosed, none with prior treatment	100 95	rIFN-α + HU HU	51	62 38	NR NR	9 0	7 2	NR NR	64 NS 68
Broustet et al,⁵⁶ 1991	CP-Ph+, mean age = 57, <3 mo (med) from dx, pts eligible for BMT excluded, some with prior treatment	30 28	rIFN-α HU	NR	53 82	NR NR	7 0	30 7	NR NR	NR NR

Abbreviations: CCyR, complete cytogenetic response; PCyR, partial cytogenetic response; CHR, complete hematologic response; PHR, partial hematologic response; CI, confidence interval; CP, chronic phase; dx, diagnosis; f-u, follow-up period (mo); hem, hematologic; med, median; NR, not reported; NS, not statistically significant; pts, patients; rx, treatment; tox, toxicity.

F4-150

Treatment regimens: $\underset{̲}{Hehlmann et al :}$ rIFN-α = 5 MU/m²/d maximized to achieve WBC count 2,000-4,000/μL and hem remission; average dose of 3.5 MU/m²/d by 12 mo, 3 MU/m²/d by 30 mo; discontinued within 3 mo if no response; reduced for tox. HU = 40 mg/kg/d continuously to achieve normal WBC count; BUS = 0.1 mg/kg/d intermittently. 90 patients censored for BMT. $\underset{̲}{Italian Group :}$ 2:1 randomization, rIFN-α = 3 MU/d × 2 wk, then 6 MU/d × 2 wk, then 6 MU/d × 2 week, then 9 MU/d; increased by 25% to 50% after 8 mo if no complete response. At 14 mo dose reduced to 3 MU TIW if no response. Chemo added if no hem response, patient refusal, BMT. Median dose = 4.3 MU/d; HU or BUS dose deferred to clinician (treatment mandatory if WBC >30,000/μL, platelets >750,000/μL, or splenomegaly). $\underset{̲}{Allan et al :}$ Induction with HU (1.5 g/d), BUS (continuous 4 mg/d or intermittent 50-100 mg/d), or BUS (2 mg/d) + thioguanine (80 mg/d) “by randomization or physician’s choice,” then randomized “at diagnosis or at this point” to maintenance rIFN-α (3 MU/d × 3 wk, increased to 6, 9, or 12 MU as tolerated to achieve WBC count of 2,000-5,000/μL) or conventional chemo (continued induction agent “until therapy became ineffective,” physician free to adjust dose to achieve WBC count 5,000-20,000/μL). Induction agent added for rIFN-α patients with poor results. $\underset{̲}{Ohnishi et al :}$ rIFN-α = 3 MU/d × 3 d, then 9 MU/d × 4 wk, increased to 12 MU/d (later, 18 MU/d) × 4 wk if WBC count not reduced by 25%, maintenance to achieve normal WBC count and platelets; BU = 6 mg/d, reduced to 4 mg/d when WBC count <50,000/μL, continued for 4-12 wk until WBC count reduced by 25%, then reduced to 1-2 mg/d with adjustment to achieve normal WBC count. $\underset{̲}{Benelux :}$ rIFN-α = 3 MU/d (average of 2.14) + HU as needed; HU dose NR. $\underset{̲}{Broustet et al :}$ IFN = 4 MU/d maintained until disease progression; HU = dose to achieve WBC count 4,000-10,000/μL.

F4-151

Generally based on M.D. Anderson criteria, but details of definition vary across studies. M.D. Anderson criteria: CHR = WBC count, platelet count and differential normal (no immature forms) and disappearance of symptoms/signs (including palpable splenomegaly); PHR = decrease in WBC count to <50% of pretreatment level and <20,000/μL or normalization of WBC count with persistent splenomegaly or immature peripheral blood cells. $\underset{̲}{Italian Cooperative Group :}$ CHR = hemoglobin >110 g/L, platelets <500,000 μL, WBC <10,000 μL, normal diff, nonpalpable spleen; PHR = hemoglobin 90-110 g/L, platelets >500,000/μL, WBC count 10,000-50,000 μL, differential with 1% to 5% immature cells, palpable spleen.

‡

Generally based on M.D. Anderson criteria and percentage of Ph+ metaphases on most favorable karyotype: CCyR = 0% Ph+ metaphases, PCyR = 5-34% Ph+. $\underset{̲}{Hehlmann et al :}$ PCyR (described as “major and minor” = 1% to 65%; results for “major” not reported separately); cytogenetic results reported only for 63% of patients who underwent 2 tests (conducted twice/yr). $\underset{̲}{Italian Cooperative Group :}$ CCyR = 0%, PCyR (described as “major”) = 1% to 33%; only 78% of rIFN-α and 80% of control assessed for cytogenetic response. $\underset{̲}{Allan et al :}$ PCyR (“major”) = 1% to 34%, cytogenetics reported for 92% of rIFN-α pts, 89% of controls. $\underset{̲}{Broustet et al :}$ PCyR = 1% to 75%.

F4-153

rIFN-α v BUS statistically significant (P = .008): rIFN-α v HU not significant (P = .44).

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