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N.K.A. van Eijkelenburg et al.
Safety and tolerability
Initial dose-escalation was halted at DL3 because of DLTs (3 Grade 3 pulmonary fungal infections (aspergillo- sis); 1 Grade 3 non-fungal pulmonary infection). An amendment was issued to repeat cohort 3 after adding screening for subclinical fungal infections, and only one DLT in 6 patients was noted (Grade 3 pulmonary candida infection), hence escalation to DL4 was pursued. In DL4 only one DLT was noted (Grade 4 septicemia). As DL4 was considered safe, this dose-level was expanded to 10 patients. Subsequently, DL5 was opened for patients with early 1st relapse without prior SCT. At DL5, 2 of 5 patients experienced DLT (1 Grade 3 pseudomonas aeruginosa celluli- tis and 1 Grade 3 Gram-negative septicemia), and DL5 was closed therafter (Table 3). Of note, the use of prophy- lactic antibacterial, antifungals, and antiviral agents was recommended according to each institution’s guidelines. Twenty-eight of 34 patients received anti-fungal prophy- laxis with azoles (either itraconazole, voriconazole or flu- conazole); 17 of 34 patients were on prophylactic treat- ment with amphotericin B. Hence 11 of 34 patients received both azole prophylaxis as well as amphotericin B.
In total, 34 SAEs were reported, mostly consisting of febrile neutropenia (n=18), documented infections (n=9), or gastrointestinal SAEs (n=3) (Online Supplementary Table S3). Non-hematologic AEs related to the first cycle of
Table 3. Non-hematologic adverse events in the first treatment cycle. AEs
study treatment are summarized in Table 3. Overall, the most common treatment-related AEs were gastrointesti- nal, pain and infection. These non-hematologic AEs were mild (Grade 1-2) in most patients. In 2 patients, acute renal failure was reported, one in combination with a tumor lysis syndrome. Another patient had a capillary leak syn- drome with ascites and reduced diuresis. Hematologic AEs occurred frequently and mostly concerned Grade 3-4 myelosuppression, not resulting in DLTs (data not shown).
Overall, 21 patients died: 2 as the result of an AE (one multi-organ failure secondary to febrile neutropenia, 1 hypoxia and respiratory and cardiovascular failure); 15 deaths were due to progressive leukemia following other treatment attempts in some but not all patients. The remaining 4 deaths were: SCT procedure related (n=2), lung toxicity after allogeneic transplantation with cytomegalovirus (CMV) reactivation (n=1), and invasive aspergillosis (n=1).
Efficacy
Of 31 evaluable patients, the ORR was 68% after the 1st cycle of treatment, including 5 (16%) patients with CR, 15 (48%) patients with CR with incomplete blood count recovery (CRi), and 1 patient with a partial response (PR) (3%). Overall response rate (ORR) differed according to disease phase: 87% in 15 patients with early 1st relapse;
AE term
Gastrointestinal
Pain
Infection
Metabolic/laboratory
Skin/dermatological
Constitutional symptoms
Pulmonary/upper respiratory
Cardiac problems including arrhythmia
Neurology (or ocular/visual)
Allergy/immunology
Total
All grades, n (%)
114 (24)
62(13) 61(13) 46(10) 34(7) 2(5) 19(4) 13(3) 10(7) 8(2)
Grade 1-2 n (%)
96(29)
54(17) 9(3) 37(11) 31(9) 22(7) 13(4) 8(2) 14(3) 7(2) -
Grade 3-4 n (%)
AEs
Patients
27(79)
16(47) 8(24) 8(24) 24(71) 11(32) 9(27) 7(21) 11(32) 6(18) -
Patients with DLT (n)
1
0 4
1
1
2
AEs
18(13)
8(6) 52(36) 9(6) 3(2) 2(1) 6(4) 5(3) 3(2) 1(<1) 5(3)
Patients
14(41)
7(21) 27(79) 5(15) 3(9) 2(6) 3(9) 4(12) 3(9) 1(3) 4(12)
Others (renal/genitourinary/vascular/syndromes) 5(1)
DLTs Dose level
Dose level 1
Dose level 2 Dose level 3A
Dose level 3B
Dose level 4
Dose level 5
Total patients per dose level (n)
4
3 6
6
10
5
Details about DLTs
Gr 3 Streptococcal infection
None
Gr 3 Pulmonary infection including 3 fungal infections/ aspergillosis
Gr 3 Pulmonary infection:
fungal infection / candida albicans Gr 3 Sepsis
Gr 3 Cellulitis infection (pseudomonas) Gr 3 Sepsis
AE: adverse events; DLT: dose-limiting toxicities; Gr: grade; n: number.
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haematologica | 2018; 103(9)