Baseline characteristics
A total of 56 adult AML patients with a median age of 66.5 (range 34 - 83) years were included in this analysis. Table 1 provides information about morphology, AML-type and genetics including risk stratification.
48.2% (n = 27) presented with de novo AML, 51.8% (n = 29) with secondary AML (sAML) including one patient with treatment association (Table 1). The median time of myelodysplastic syndrome (MDS) diagnosis to sAML development was 11.7 (1.7 – 156.4) months (data not shown).
Eastern Cooperative Oncology Group (ECOG) performance status rated 31 patients (55.3%) as 0 - 1 and 25 patients (44.6%) as 2 - 3, respectively.
Cytogenetic risk profiling was performed for 55 of 56 patients (98.2%) and resulted in favorable, intermediate and adverse risk in 0 (0%), 34 (60.7%) and 21 (37.5%), respectively. Data for molecular aberrations were available in 54 of 56 (96.4%) AML patients. Risk stratification according to the current ELN criteria 2017 showed a distribution in favorable, intermediate and adverse risk in 5 (8.9%), 17 (30.3%) and 32 (57.1%) of patients, respectively (Table 1). Further characteristics of those patients who received alloHSCT (39.3%, n = 22) are summarized in Table S1.
Treatment characteristics
Treatment intentions are illustrated in the CONSORT diagram (Figure 1) and detailed information is provided in Table 2.
Table 2
Treatment characteristics
Treatment cohorts, n (%)
|
|
VEN first-line, palliative
|
17 (30.4)
|
VEN >1 line, palliative
|
17 (30.4)
|
VEN at relapse post-alloHSCT
|
15 (26.7)
|
VEN as salvage prior to alloHSCT
|
7 (12.5)
|
Remission status prior to VEN, n (%)
|
|
Progressive disease
|
50 (89.2)
|
Partial remission
|
4 (7.1)
|
Complete remission
|
1 (1.8)
|
Stable disease
|
1 (1.8)
|
refractory to any line prior VEN
|
24/40 (60)
|
Lines prior to VEN, median (range)
|
1.5 (0-8)
|
Combination with VEN, n (%)
|
|
Decitabine
|
22 (39.3)
|
5-Azacitidine
|
28 (50)
|
LDAC
|
2 (3.6)
|
More than one
|
4 (7.1)
|
Cycles VEN applied, median (range)
|
3 (1-18)
|
Dosing
|
|
Months of VEN treatment, median (range)
|
3.4 (0.6-22.1)
|
Total amount applied in mg, median (range)
|
13920 (640- 106720)
|
Mean dosage of VEN in mg (range)
|
149 (20.9 – 362,5)
|
Concurrent azole application, n (%)
|
48/56 (85.7)
|
Posaconazole
|
23 (47.9)
|
Fluconazole
|
11 (22.9)
|
Isavuconazole
|
9 (18.7)
|
more than one azole
|
5 (10.4)
|
VEN interruption, n (%)
|
16 (28.6)
|
due to neutropenia
|
15 (93.7)
|
due to nausea
|
1 (6.2)
|
CR achieved before VEN, median (range)
|
1 (0-4)
|
PR achieved before VEN, median (range)
|
0.5 (0-4)
|
Prior treatment lines before VEN, n
|
|
HMA
|
22
|
LDAC
|
8
|
Consolidation chemotherapy
|
14
|
Induction/reinduction
|
44
|
alloHSCT
|
15
|
TKI
|
6
|
Other
|
9
|
Treatment lines post VEN, n
|
18/56
|
alloHSCT
|
7
|
Quizartinib
|
1
|
LDAC
|
7
|
Second VEN application
|
2
|
clinical trial
|
1
|
Abbreviations: VEN Venetoclax; alloHSCT allogeneic stem cell transplantation; LDAC low dose cytarabine; HMA hypomethylating agents; CR complete remission, PR partial remission, TKI tyrosine kinase inhibitor
For first-line therapy VEN was applied in 18 AML patients, 23 patients received VEN as subsequent therapy (r/r AML without prior alloHSCT). A third subgroup was treated with VEN due to disease relapse following alloHSCT (n = 15). Of note, 7 patients were successfully transitioned to alloHSCT after VEN treatment.
The majority of patients received VEN in combination with a HMA agent backbone, including 22 (39.3%) decitabine and 28 (50%) AZA (Table 2).
Median time of VEN treatment was 3.4 (0.6 – 22.1) months with a median application of 3 (1 - 18) treatment cycles (28 days). The overall mean drug dosage was 149 (20.9 - 362.5) mg. In 85.7% of all patients concurrent azole medication was applicated (posaconazole 47.9%, fluconazole 22.9% and isavuconazole 18.7%). Interruption of treatment was necessary in 16 patients (28.6%) due to grade 4 neutropenia (93.7%).
24 of 40 patients (60%) were refractory to any treatment line prior to VEN. In median one CR (range 0 - 4) with a median of 1.5 (range 0 - 8) therapy lines could be achieved prior to initiation of VEN treatment. Information on prior or subsequent treatment regimens to VEN is indicated in Table 2. Importantly, except for 3 patients receiving alloHSCT, no response to further treatment approaches after VEN could be achieved.
Response to VEN treatment
Subgroup analyses with respect to treatment intention showed a median OS starting at VEN treatment initiation of 13.3 (2.2 - 20.5) months, 5.0 (0.8 - 24.3) months, 4.0 (1.5 - 22.1) months for first-line treatment, subsequent line treatment and post-alloHSCT, respectively (Figure 2A, B). Of note, survival rates for patients who received VEN prior to alloHSCT were calculated separately with a median OS of 11.5 (10.4 - 22.3) months (Figure S1, C).
Patients who achieved CRc on VEN treatment had a median OS of 20.8 (2.5 - 24.3) months and PFS of 20.5 (2.6 – 24.3) months, respectively (Figure 2C, D).
For the whole cohort, OS starting at AML diagnosis was 18.7 (2.8 – 125.3) months and not reached in patients who received CRc (2 - year OS: 63%) (Figure S1 A, B).
An ORR of 51.8% was achieved for the whole population (data not shown). In detail, ORR of 61.1% was seen when VEN was applied as first-line treatment, 52.2 % for subsequent line treatment and 42.8% at relapse post-alloHSCT (Figure 3). Median time to first response for patients achieving CRc was 2.7 (1.4 – 16.2) months.
With respect to genetic subgroups no difference in survival since VEN initiation was seen for cytogenetic (intermediate vs. high-risk) and ELN risk groups (favorable + intermediate vs. high-risk) (Figure 4A, B): 6.4 (2.2 - 24.3) months for intermediate vs. 4.9 (1.1 - 20.8) months for high-risk cytogenetics (p = 0.598) and 6.4 (1.1 - 22.2) months vs. 5.0 (2.2 - 24.3) months for ELN high-risk vs. favorable + intermediate, respectively (p = 0.565).
Analysis of distinct molecular subgroups revealed that patients harboring FLT3-ITD mutation (16%, n = 9) had a significantly reduced median OS of 3.4 (1.9 - 8.0) months compared to 10.4 (0.8 - 24.3) months for those without an activating FLT3-ITD mutation (HR 3.59, 95% CI 0.94 - 13.72, p = 0.001). FLT3-ITD positive AML showed an ORR to VEN of only 22.2% while one third exhibited PD on treatment (data not shown).
In contrast, patients with NPM1, IDH1, or IDH2 mutations without co-occurring FLT3-ITD mutations showed an increased sensitivity to VEN-based therapy: 11.2 (5 - 24.3) months versus 5.0 (0.8 - 22.1), respectively (HR 0.53, 95% CI 0.23 – 1.21, p = 0.131).
Furthermore, assessment of blood count and transfusion (in-) dependence was performed. As demonstrated in Table 3, median count for platelets was 12 x 109/l (12 - 317) and 42.5 x 109/l (12 - 280) on days 0 and 100 of treatment, respectively. Transfusion dependence for platelets was decreasing from 62.9% to 47.2% and for red blood cells (RBC) from 75.9% to 55.5% during the first 100 days of treatment. Median neutrophil count was 0.39 x 109/l (range 0.1 - 12.5) and 0.2 x 109/l (range 0.1 - 3.8) at days 0 and 100 of treatment, respectively. On day 60, 17 of 49 patients (36%) showed an increase of the neutrophil count compared to baseline value.
Table 3
Development of blood count and requirement for transfusions under Venetoclax treatment.
|
platelets d0 (54 pts)
|
platelets d60 (49 pts)
|
platelets d100 (36 pts)
|
Median count (range) in 109/l
|
12 (12-317)
|
12 (12-349)
|
42.5 (12-280)
|
Pts with requirement for transfusion
|
34 (62.9%)
|
27 (55.1%)
|
17 (47.2%)
|
Pts lost requirement for transfusion to baseline
|
|
10
|
+ 1
|
|
RBC d0 (54 pts)
|
RBC d60 (49 pts)
|
RBC d100 (36 pts)
|
Median count (range) in 109/l
|
4.5 (4.5-8)
|
4.5 (4.5-7.3)
|
4.5 (4.5-8.3)
|
Pts with requirement for transfusion
|
41 (75.9%)
|
36 (73.4%)
|
20 (55.5%)
|
Pts lost requirement for transfusion to baseline
|
|
7
|
+ 1
|
|
ANC d0 (52 pts)
|
ANC d60 (47 pts)
|
ANC d100 (34 pts)
|
Median count (range) in 109/l
|
0.39 (0.1-12.5)
|
0.2 (0.1-4.3)
|
0.2 (0.1-3.8)
|
Pts with increase of neutrophiles compared to baseline
|
|
17
|
+ 3
|
Abbreviations: pts patients; d days; ANC absolute neutrophiles count; RBC red blood count
Response and survival depending on VEN dosage
The median of the mean VEN dosage of the whole cohort was 149 mg/d (20.9 – 362.5) with a median treatment duration of 105 (18 – 674) days (Table 2).
To uncover a potential impact of VEN dosing on survival or response rates, patients with a mean daily dose of VEN £100 mg (n = 22) were compared to those with > 100 mg (n = 34). Kaplan Meier analysis demonstrates a median survival of 6.4 (1.5 – 17.7) months and 8.1 (1.1 - 24.3) months for patients having received a mean daily dose of £100 mg and >100 mg, respectively (p=0.357) (Figure 5A). Doses of > 100 mg showed an increased ORR (55.9%) compared with patients receiving £100 mg mean dosage (45.5%). Progressive disease while on VEN treatment was noted in 22.3 % and 8.9% comparing the cohorts of £100 mg and >100 mg, respectively (Figure 5B).
Toxicity assessment
Most frequent grade 3 and 4 side effects were hematologic with neutropenia, thrombocytopenia, and anemia (44.6%, 14.5%, 12% respectively) (Figure 6). Grade 3 renal insufficiency occurred in 3 patients (5.3%) including two cases of tumor lysis syndrome. One patient suffered from severe retinal bleeding, another patient from dysesthesia und body aches. Common adverse events are summarized in Figure 6. Non-relapse mortality rate was 8.9% (5/56 patients) and early deaths till day 30 since treatment start occurred in 3.5% (2/56 patients).