Retinoic acid and arsenic trioxide in the treatment of acute promyelocytic leukemia: current perspectives

Figures & data

Table 1 Risk stratification in APL

Sanz risk category	WCC (×10^9/L)	Platelet count (×10^9/L)
Low	≤10	>40
Intermediate	≤10	≤40
High	>10

Abbreviations: APL, acute promyelocytic leukemia; WCC, white cell count.

Figure 1 Comparison of OS in the ALLG APML4 and ALLG APML3 trials.

Note: Figure was provided courtesy of H Iland (APML4 principal investigator) from the Australasian Leukaemia and Lymphoma Group APML4 Statistical Report (June 2013) by Collins M, Di Iulio J, and Beresford J (unpublished).
Abbreviations: OS, overall survival; ALLG, Australasian Leukaemia and Lymphoma Group; HR, hazard ratio; CI, confidence interval; ATRA, all trans-retinoic acid.

Figure 2 Comparison of DFS in the ALLG APML4 and ALLG APML3 trials.

Note: Figure was provided courtesy of H Iland (APML4 principal investigator) from the Australasian Leukaemia and Lymphoma Group APML4 Statistical Report (June 2013) by Collins M, Di Iulio J, and Beresford J (unpublished).
Abbreviations: DFS, disease-free survival; ALLG, Australasian Leukaemia and Lymphoma Group; HR, hazard ratio; CI, confidence interval; HCR, hematological complete remission.

Figure 3 Estimated Kaplan–Meier curve for freedom from relapse from documented hematological CR in the APML4 trial, stratified by Sanz risk category.

Note: Figure was provided courtesy of H Iland (APML4 principal investigator) from the Australasian Leukaemia and Lymphoma Group APML4 Statistical Report (June 2013) by Collins M, Di Iulio J, and Beresford J (unpublished).
Abbreviations: CR, complete remission; HCR, hematological complete remission.

Table 2 Results of recent ATO-inclusive trials

Risk category	Protocol (published trial analysis period)	Median follow-up (years)	No	Age restriction (years)	CR	ED	CIR	Death in CR	DFS	EFS	OS	Therapy-related neoplasm
Low-intermediate risk	APL0406^Citation142 ATRA-ATO (4-yr)	3.4	127	18–71	100%	0%	1.9%	0.8%	ns	97.3%	99.2%	0
	APL0406 ATRA-Ida (4-yr)	3.4	132	18–71	97%	3%	13.9%	3.7%	ns	80%	92.6%	2
	UK AML17^Citation40 ATRA-ATO ± GO (4-yr)	2.5	86	≥16	94% (all risk groups)	4%	1%a,c 0%b,c	2%c	97%a 98%b	92%	95%d	0
	UK-AML17 ATRA-Ida (4-yr)	2.5	92	≥16	89% (all risk groups)	6%	18%a 27%b	1%c	78%a 70%b	71%	90%c	1-risk group ns
	MD Anderson^Citation139 ATRA/ATO ± GO (3-yr)	1.9	56	ns	95%	3.6%	0%	4% of all patients	ns	89%e	89%e	ns
	North American Intergroup C9710^Citation36 No ATO in Consolidation (3-yr)	2.4	144	≥15	93%–94%	4%	ns	ns	77%e	71%e	ns	ns
	North American IntergroupC9710 ATO in consolidation (3-yr)	2.4	189	≥15	93%–94%	4%	ns	ns	90%e	84%e	ns	ns
	APML4^Citation41 ATRA-ATO-Ida (5-yr)	4.2	101	>1	96%	2%	5%	0%	96%	92%	96%	ns
High-risk	UK AML17^Citation40 ATRA-ATO (4-yr)	2.5	30	≥16	ns	ns	ns	2%c	ns	87%f	87%d	ns
	UK AML17 ATRA-Ida (4-yr)	2.5	27	≥16	ns	ns	ns	1%c	ns	64%f	84%d	ns
	MD Anderson^Citation139 ATRA/ATO ± GO (3-yr)	1.9	26	ns	81%	19%	11%	4% of all patients	ns	65%e	75%e	ns
	North American Intergroup C9710^Citation36 No ATO (3-yr)	2.4	58	≥15	71%	20%	ns	ns	46%e	39%e	ns	ns
	North American Intergroup C9710 ATO consolidation (3-yr)	2.4	55	≥15	71%	20%	ns	ns	87%e	64%e	ns	ns
	APML4^Citation41 ATRA-ATO-Ida (5-yr)	4.2	23	>1	88%	8.7%	5%	0%	95%	83%	87%	ns

Notes:

a Morphological,

b molecular,

c difference between high and low-intermediate risk not given,

d no significant difference in OS between ATRA-ATO and ATRA/Ida therapy within risk groups,

e estimated from published survival curves (data not given),

f no significant difference in EFS between ATRA-ATO and ATRA/Ida in high-risk patients. The year given in parentheses is the time-point at which the survival endpoints were analyzed.

Abbreviations: ATO, arsenic trioxide; CR, complete remission; CIR, cumulative incidence of relapse; DFS, disease-free survival; ED, early death; EFS, event-free survival; OS, overall survival; ATRA, all trans-retinoic acid; ns, not specified; Ida, idarubicin; GO, gemtuzumab ozogamicin.

Table 3 Commonly employed current treatment regimens in APL, stratified by risk category

Protocol	Induction	Consolidation	Maintenance
Low-intermediate risk
APL0406^Citation39	ATRA 45 mg/m^2/d PO + ATO 0.15 mg/kg/d IV until CR (max 60 days)	ATRA 45 mg/m^2/d PO for 14 days then rest for 14 days ×7 cycles + ATO 0.15 mg/kg/d IV for 5 days per week for 4 weeks then rest for 4 weeks ×4 cycles	Nil
LPA2005^Citation37	ATRA 45 mg/m^2/d POc + ATO 0.15 mg/kg/d IV until CR (max 60 days)	1. ATRA 45 mg/m^2/d PO d1–15 + Idarubicin 5^low/7^int mg/m^2/d d1–4 2. ATRA 45 mg/m^2/d PO d1–15 + MTZ 10 mg/m^2/d d1–3 3. ATRA 45 mg/m^2/d PO d1–15 + Idarubicin 12 mg/m^2/d d1^low or d1–2^int	ATRA 45 mg/m^2/day PO d1–15 every 90 days MTX 15 mg/m^2/wk IM d15–90 6-MP 50 mg/m^2/wk PO d15–90 for 2 years
High risk
APML4^Citation38	ATRA 45 mg/m^2/day PO d1–36 ATO 0.15 mg/kg/day IV d9–36 Idarubicin 6–12 mg/m^2 d2, 4, 6, 8a,b	1. ATRA 45 mg/m^2/d PO days 1–28 + ATO 0.15 mg/kg/d IV d1–28 2. ATRA 45 mg/m^2/d PO d1–7, 15–21 and 29–35 + ATO 0.15 mg/kg/d IV for 5 days per week for 5 weeks	ATRA 45 mg/m^2/day PO d1–14 every 90 days MTX 5–15 mg/m^2/wk PO d15–90 6-MP 50–90 mg/m^2/wk PO d15–90 ×8 cycles
Study C9710^Citation36	ATRA 45 mg/m^2/d PO until CR (max 90 days) + Cytarabine 200 mg/m^2 d3–9 + DNR 50 mg/m^2 d3–6	1. ATO 0.15 mg/kg/d IV for 5 days per week for 5 weeks ×2 cycles 2. ATRA mg/m^2/d PO days 1–7 + DNR 50 mg/m^2 d1–3 ×2 cycles	ATRA mg/m^2/d PO days 1–7 repeated on alternate weeks MTX 20 mg/m^2/wk PO 6-MP 60 mg/m^2/d PO for 1 year
APL2000^Citation96	ATRA 45 mg/m^2/d PO until CR + Cytarabine 200 mg/m^2 d1–7 + DNR 60 mg/m^2 d1–3	1. DNR 60 mg/m^2/d d1–3 + Cytarabine 200 mg/m^2/d d1–7 2. DNR 45 mg/m^2/d d1–3 + Cytarabine 2 g/m^2/12 h d1–5 (50 years) or Cytarabine 1.5 g/m^2/12 h d1–5 (50–60 years) + 5 doses of MTX 15 mg/Cytarabine 50 mg given IT	ATRA 45 mg/m^2/day POd1–15 every 90 days MTX 15 mg/m^2/wk PO d15–90 6-MP 50 mg/m^2/wk PO d15–90 for 2 years
LPA2005^Citation37	ATRA 45 mg/m^2/d POc until CR + Idarubicin 12 mg/m^2/d d2, 4, 6, 8d	1. ATRA 45 mg/m^2/d PO d1–15 + Idarubicin 5 mg/m^2/d d1–4 + Cytarabine 1 g/m^2/d d1–4e 2. ATRA 45 mg/m^2/d PO + MTZ 10 mg/m^2/d d1–5 3. ATRA 45 mg/m^2/d PO + Idarubicin 12 mg/m^2/d d1 + Cytarabine 150 mg/m^2/8h d1–4	ATRA 45 mg/m^2/day PO d1–15 every 90 days MTX 15 mg/m^2/wk IM d15–90 6-MP 50 mg/m^2/wk PO d15–90 for 2 years

Notes:

a Age adjusted; 1–60 years, 12 mg/m²; 61–70 years, 9 mg/m²; >70 years, 6 mg/m².

b Prednisolone 1 mg/kg/day PO on d1–10 or until WCC <1×10⁹/L.

c ATRA 25 mg/m²/d if ≤20 years.

d If >70 years Idarubicin 12 mg/m² d8 omitted.

e If >60 years no Cytarabine given in consolidation and Idarubicin dose as per intermediate risk patients described in LPA2005 low-int risk protocol.

Abbreviations: Low, low risk patients; Int, intermediate risk patients; MTX, Methotrexate; 6-MP, Mercaptopurine; DNR, Daunorubicin; MTZ, Mitoxantrone; IT, intrathecal; IM, intramuscular; IV, intravenous; PO, per os (orally).

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