Table 4. Results of some recently... | American Society of Hematology

Table 4.

Results of some recently published targeted clinical trials in acute myeloid leukemia (AML).

Treatment approach	Reference	Patients	Treatment	Results	Interpretation/conclusion
Abbreviations: ATRA, all-trans retinoic acid; ATO, arsenic trioxide; GO, gemtuzumab ozogamicin; APL, acute promyelocytic leukemia; MDS, myelodysplastic syndrome
FLT3 inhibitor PKC412 (phase 2)	Stone et al, 2005⁷¹	20 FLT3 mutated refractory or relapsed AML pts	3 × 75 mg daily p.o. until toxicity or disease progression occurs	Clinical benefit: 70%  PR: 33%	Toxicity acceptable (2 pts fatal pulmonary events); promising for FLT3 mutant AML.
ATRA plus ATO in APL (+ GO)	Estey et al, 2006⁶³	25 pts with low-risk APL (leukocytes =10 × 10⁹/L); (leukocytes >10 × 10⁹/L)	Low-risk APL: induction: ATRA (45 mg/m² daily from d 1) post-remission: ATRA + ATO without chemotherapy up to 28 wks; MRD at 3 mos positive: + gemtuzumab ozogamicin (GO)High-risk APL: as low risk and always + 9 mg/m² GO d 1	Complete remission: low-risk APL: 96%  Relapses: 8%  Post-induction GO only in 3 high-risk pts necessary	ATRA plus ATO represents an alternative to chemotherapy in low-may improve outcome in high-risk APL.
FLT3 -antagonist tandutinib (MLN518) (phase 1)	DeAngelo et al, 2006⁷³	40 pts with refractory or relapsed AML/high-risk MDS; of these 8 FLT3 -mutated	2 × 50 – 2 × 700 mg daily p.o. (dose escalation)  maximum 12 mo	Antileukemic effects in 2/5 evaluable pts with FLT3-ITD; no effect in FLT3-wildtype	Tandutinib should be evaluated more extensively in pts with FLT3 -mutant AML.
Imatinib and low-dose cytarabine in older patients with c-KIT–positive AML/high-risk MDS (phase 2)	Heidel et al, 2007⁸¹	34 AML, 6 MDS; 38 pts evaluable; median age 73 years	Imatinib 600 mg daily p.o.  Cytarabine 10 mg s.c. daily days 1–21 every 28 d  Maximum 12 mo	Stable disease: 21%  Hematological response: 8%  2 year OS: 20%	Imatinib + low-dose cytarabine seems comparable to myelosuppressive therapy, but was not superior to low- dose Ara-C monotherapy; pts have to be selected better
Decitabine alone or in combination with valproic acid in AML (phase 1)	Blum et al, 2007⁹⁵	25 AML: at diagnosis (12) or relapse (13); 21 pts - evaluable; median age 70 y	Decitabine 20 mg/m² iv. d 1–10 alone or combination with dose escalating valproic acid d 5–21: 20–25 mg/d	Hematological response: 52%  CR: 19%	Low-dose decitabline seems safe and is encouraging in AML.  Additional valproic acid led to in encephalopathy relatively low doses.
Farnesyltransferase inhibitor tipifarnib in refractory or relapsed AML (phase 2)	Harousseau et al, 2007⁸⁹	252 pts: refractory (117), at relapse (135), median age 62 y	Tipifarnib 2 × 600 mg d1-21 p.o.; every 4 weeks  Treatment possible until progression or unacceptable toxicity  Dose reduction to 2 × 200 mg, or escalation to 2 × 900 mg possible	OR: 12%  CR: 4%  Median CR duration: 17.3 mo  Median survival of CR pts: 369 d	Tipifarnib was associated with prolonged survival in pts with refractory or relapsed AML. Higher response rate, however, requires combination with other active agents.
Farnesyltransferase inhibitor tipifarnib in untreated, poor-risk elderly AML (phase 2)	Lancet et al, 2007⁹⁰	158 elderly pts with poor-risk AML; median age 74 y	Tipifarnib 2 × 600 mg d 1–21 p.o.; rest period up to 42 d  before second course  maximum 4 cycles for responding pts	OR: 23%  CR: 14%  Median CR duration: 7.3 mo  Median survival of CR pts: 18 mo	Tipifarnib is active and well tolerated in older pts with poor-risk AML.  Responders might have a survival benefit.

Treatment approach	Reference	Patients	Treatment	Results	Interpretation/conclusion
Abbreviations: ATRA, all-trans retinoic acid; ATO, arsenic trioxide; GO, gemtuzumab ozogamicin; APL, acute promyelocytic leukemia; MDS, myelodysplastic syndrome
FLT3 inhibitor PKC412 (phase 2)	Stone et al, 2005⁷¹	20 FLT3 mutated refractory or relapsed AML pts	3 × 75 mg daily p.o. until toxicity or disease progression occurs	Clinical benefit: 70%  PR: 33%	Toxicity acceptable (2 pts fatal pulmonary events); promising for FLT3 mutant AML.
ATRA plus ATO in APL (+ GO)	Estey et al, 2006⁶³	25 pts with low-risk APL (leukocytes =10 × 10⁹/L); (leukocytes >10 × 10⁹/L)	Low-risk APL: induction: ATRA (45 mg/m² daily from d 1) post-remission: ATRA + ATO without chemotherapy up to 28 wks; MRD at 3 mos positive: + gemtuzumab ozogamicin (GO)High-risk APL: as low risk and always + 9 mg/m² GO d 1	Complete remission: low-risk APL: 96%  Relapses: 8%  Post-induction GO only in 3 high-risk pts necessary	ATRA plus ATO represents an alternative to chemotherapy in low-may improve outcome in high-risk APL.
FLT3 -antagonist tandutinib (MLN518) (phase 1)	DeAngelo et al, 2006⁷³	40 pts with refractory or relapsed AML/high-risk MDS; of these 8 FLT3 -mutated	2 × 50 – 2 × 700 mg daily p.o. (dose escalation)  maximum 12 mo	Antileukemic effects in 2/5 evaluable pts with FLT3-ITD; no effect in FLT3-wildtype	Tandutinib should be evaluated more extensively in pts with FLT3 -mutant AML.
Imatinib and low-dose cytarabine in older patients with c-KIT–positive AML/high-risk MDS (phase 2)	Heidel et al, 2007⁸¹	34 AML, 6 MDS; 38 pts evaluable; median age 73 years	Imatinib 600 mg daily p.o.  Cytarabine 10 mg s.c. daily days 1–21 every 28 d  Maximum 12 mo	Stable disease: 21%  Hematological response: 8%  2 year OS: 20%	Imatinib + low-dose cytarabine seems comparable to myelosuppressive therapy, but was not superior to low- dose Ara-C monotherapy; pts have to be selected better
Decitabine alone or in combination with valproic acid in AML (phase 1)	Blum et al, 2007⁹⁵	25 AML: at diagnosis (12) or relapse (13); 21 pts - evaluable; median age 70 y	Decitabine 20 mg/m² iv. d 1–10 alone or combination with dose escalating valproic acid d 5–21: 20–25 mg/d	Hematological response: 52%  CR: 19%	Low-dose decitabline seems safe and is encouraging in AML.  Additional valproic acid led to in encephalopathy relatively low doses.
Farnesyltransferase inhibitor tipifarnib in refractory or relapsed AML (phase 2)	Harousseau et al, 2007⁸⁹	252 pts: refractory (117), at relapse (135), median age 62 y	Tipifarnib 2 × 600 mg d1-21 p.o.; every 4 weeks  Treatment possible until progression or unacceptable toxicity  Dose reduction to 2 × 200 mg, or escalation to 2 × 900 mg possible	OR: 12%  CR: 4%  Median CR duration: 17.3 mo  Median survival of CR pts: 369 d	Tipifarnib was associated with prolonged survival in pts with refractory or relapsed AML. Higher response rate, however, requires combination with other active agents.
Farnesyltransferase inhibitor tipifarnib in untreated, poor-risk elderly AML (phase 2)	Lancet et al, 2007⁹⁰	158 elderly pts with poor-risk AML; median age 74 y	Tipifarnib 2 × 600 mg d 1–21 p.o.; rest period up to 42 d  before second course  maximum 4 cycles for responding pts	OR: 23%  CR: 14%  Median CR duration: 7.3 mo  Median survival of CR pts: 18 mo	Tipifarnib is active and well tolerated in older pts with poor-risk AML.  Responders might have a survival benefit.