Acute leukemia is a disease with a rapidly fatal outcome in the absence of effective treatment. In recent decades dramatic improvements in the treatment of acute leukemia have resulted in cure for some and an energetic search for similar progress for the remainder. Cure is expected for the majority of children and young adults with favorable prognostic factors and subsets of patients, such as those with acute promyelocytic leukemia (APL). Unfortunately, death from leukemia or its complications is the usual outcome for the majority of the 11,000 adults who are diagnosed each year. To foster development of new therapeutics for acute leukemia, we have reviewed data available for 6 recently approved products for leukemia and 20 large recent trials with the intention of suggesting efficient models for pre-trial planning and trial design and to create model pathways for licensure. Table I shows data for licensed products. The total number of patients enrolled ranged from 40 to 1106. The number of patients demonstrating the clinical effect that led to approval, which most often was complete hematologic response, ranged from 6 to 536.

Table II shows half of the published chemotherapy trials we reviewed. Enrollment ranged from 32 to 254, complete remission (CR) ranged from 11% to 84%, with no study showing a substantial increase in median disease free survival (DFS) or median overall survival (OS).

Both empiric evidence and statistical analysis of pivotal trials leading to approval have shown that, to obtain licensure, the intended clinical effect should be achieved in a minimum of 25 experimental subjects. We term this number the threshold of credibility. The design and size of studies required to establish the threshold of credibility depend upon the endpoint selected and the activity of the regimen. To achieve product approval the sponsor should plan to show that at least 25 subjects achieve complete remission or a meaningful increase in median disease free or overall survival. We will present data in support of this argument. Use of a statistically validated approach to trial design could shorten development time and conserve resources in addressing the urgent need for new therapies.

Table I. Recent FDA Approvals for Leukemia

AgentYearDisorderPhaseNo. of SubjectsNo. Response
Imatanib 2001 CML III 1106 536 
Arsenic Trioxide 2000 APL II 40 28 
Gemtuzumab 2000 AML II X 3 65, 40, 37 42 
Tretinoin 1995 APL II x 2 181, 64 54 
Teniposide 1992 ALL II X 2 16, 9 
Idamycin 1990 AML III X 4 130, 230, 214, 249 244 
AgentYearDisorderPhaseNo. of SubjectsNo. Response
Imatanib 2001 CML III 1106 536 
Arsenic Trioxide 2000 APL II 40 28 
Gemtuzumab 2000 AML II X 3 65, 40, 37 42 
Tretinoin 1995 APL II x 2 181, 64 54 
Teniposide 1992 ALL II X 2 16, 9 
Idamycin 1990 AML III X 4 130, 230, 214, 249 244 

Table II. Recent Large Chemotherapy Trials in AML

ReferencePhaseNo. SubjectsCR #(%)DFS (months)OS (months)
JCO, 2003; 21:1050
 
II 68 AML 7 (11) Not reported Not reported 
JCO 2003; 21:1722
 
II 34 10/18,3/11,0/5 No difference No difference 
Blood 2003; 102:2763
 
II 43 (2 months) Not reported 
Blood 2004; 103:479
 
II 254 63(50) v 48 (38) No difference Not reported 
Blood 2003; 102:4277
 
I & II 64 54 (84) Not reported 78% at 8 mos 
Ann Hemat 2003;82:231
 
II 46 24 (52) 12 Not reported 
Leuk Resch 2003; 27:893
 
II 32 9 (28) Not reported 5.3 
Ann Hemat 2000; 79:30
 
II 86 AML 46 (53) 12.5 no difference Not reported 
Blood 2001;98:548
 
III 169 not reported 10 vs 11 Not reported 
Blood 2002; 100:1224
 
II 120 28 (46) vs 23 (39) 7 vs 8  
ReferencePhaseNo. SubjectsCR #(%)DFS (months)OS (months)
JCO, 2003; 21:1050
 
II 68 AML 7 (11) Not reported Not reported 
JCO 2003; 21:1722
 
II 34 10/18,3/11,0/5 No difference No difference 
Blood 2003; 102:2763
 
II 43 (2 months) Not reported 
Blood 2004; 103:479
 
II 254 63(50) v 48 (38) No difference Not reported 
Blood 2003; 102:4277
 
I & II 64 54 (84) Not reported 78% at 8 mos 
Ann Hemat 2003;82:231
 
II 46 24 (52) 12 Not reported 
Leuk Resch 2003; 27:893
 
II 32 9 (28) Not reported 5.3 
Ann Hemat 2000; 79:30
 
II 86 AML 46 (53) 12.5 no difference Not reported 
Blood 2001;98:548
 
III 169 not reported 10 vs 11 Not reported 
Blood 2002; 100:1224
 
II 120 28 (46) vs 23 (39) 7 vs 8  

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