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Pediatric-inspired ALL therapy in adults age 18-60
one continued protocol therapy and achieved CR follow- ing induction II and the other was removed from study after induction I at the discretion of the investigator to pur- sue alternative therapy (representing the single patient who did not achieve CR/CRi on study). One patient was not evaluable for response post-induction I due to incom- plete restaging; this patient continued protocol therapy and was confirmed to be in CR following induction II. No patients died during induction I or II.
Central evaluation for MRD in BM was performed in 26
Table 2. Patient demographics and clinical characteristics.
of 31 patients with ALL (i.e., not LBL) on day 15 of induc- tion I; at that time, five of 26 (19%) of patients had achieved MRD negativity. The proportion of patients with ALL exhibiting BM MRD negativity on central review increased following induction I (nine of 27, 33%) and induction II (20 of 24, 83%). Patients with LBL and low- level BM involvement at diagnosis are not included in the aforementioned analysis. However, four of four patients with low-level BM involvement by LBL exhibited MRD negativity in the BM on day 15 of induction I. Local MRD data are summarized in the Online Supplementary Results.
Pegaspargase administration, enzymatic activity, and immunogenicity
All treated patients received at least one dose of pegas- pargase, and the median number of doses received was three (range, 1-6). Reasons for receipt of <6 total doses of pegaspargase are summarized in the Online Supplementary Table S4. Asparaginase enzymatic activity as measured 7 days post-pegaspargase is summarized in Online Supplementary Table S3. All activity levels obtained 7 days following a full dose of pegaspargase (i.e., excluding those with immediate hypersensitivity) were >0.1 IU/mL (mini- mum observed level 0.34 IU/mL). In two patients with immediate hypersensitivity to pegaspargase who received 5 and 15 minutes of the infusion, activity levels 7 days post-pegaspargase were <0.013 and 0.028 IU/mL, respec- tively. Enzymatic activity appeared similar in patients ageg 40-60 years versus 18-39 years (Online Supplementary Table S5).
In 19 patients, 75 plasma samples were screened for anti- bodies specific to Oncaspar® and polyethylene glycol (PEG; see the Online Supplementary Methods). Inhibition with Oncaspar® showed ten confirmed positive samples and specific inhibition with 5 kDa PEG showed six con- firmed positive samples; these confirmed results were from four patients and are summarized in the Online Supplementary Table S6. Despite the presence of antibodies, asparaginase activity levels were >0.1 IU/mL (minimum 0.34 IU/mL) 7 days post-pegaspargase in all instances in which the full dose of pegaspargase was administered (i.e., not terminated early due to hypersensitivity).
Pegaspargase toxicity
Selected grade 3-4 toxicities of pegaspargase in all patients and in those aged 40-60 years at treatment initi- ation are summarized in the Online Supplementary Table S4. Grade 3-4 hypofibrinogenemia and hypertriglyc-
Table 3. Serum asparaginase enzymatic activity post-polyethylene glycol.
Characteristic
Age at start of induction, years Median
Range
Sex Male
Female
Lineage and presentation B cell
B-cell ALL
B-cell LBL T cell
T-cell ALL
T-cell LBL
ETP immunophenotype Non-ETP
ETP status indeterminate
Cytogenetics Unfavorable
Intermediate
Favorable
Not prognostically classified Not evaluable
ALL subgroup only Unfavorable Intermediate Favorable
Not prognostically classified
Not evaluable
CNS disease (CNS-2/3 CSF or parenchymal brain involvement) at diagnosis
Yes No
Unequivocal extramedullary disease at diagnosis
Yes
No
Pegaspargase doses received Median
Range
AlloHCT in CR1* Yes
No
All Patients Aged 40-60 years (N=39) (N=18)
N%N%
38.7 50.9 20.2-60.4 43.6-60.4
30 77
9 23
27 69 24 62 38
14
4
12 12 0 6 3 3 2 4 0
3 3 0 4 8
3 1 0 4 7
0 18
7
11
78
22
67 67 0 33 17 17 11 22 0
17 17 0 22 44
17 6 0 22 39
0 100
39
61
12 7 5 5 6 1
5 9 2 8 15
5 4 2 7 13
3 36
16
23
3 1-6
31 18 13 13 15 3
13 23 5 21 38
13 10 5 18 33
8 92
41
59
Time point in treatment
Induction I
Induction Phase II Intensification I Re-induction I Intensification II Re-induction II All Phases
Samples Serum asparaginase (N) enzymatic activity 7 days
post-PEG (IU/mL) Mean SD
2 1-6
15 0.787
14 0.881
6 0.989
7 0.852
10 1.057
7 1.087
59 0.919
0.238
0.234 0.149 0.238 0.190 0.145 0.233
11 28 3 17
28 72 15 83
*Includes patients known to have undergone allogeneic hematopoietic cell trans- plantation (alloHCT) in first complete response. ALL: acute lymphoblastic leukemia; LBL: lymphoblastic lymphoma; ETP: early T-precursor phenotype (CD1a-, CD8-, CD5dim/-, with expression of one or more stem cell or myeloid antigens, e.g., CD11b, CD13, CD33, CD34, CD117, HLA-DR); cytogenetic risk group classification per criteria used in the CALGB 19802 study,are summarized in the Online Supplementary Table S3; CNS: central nervous system; CSF: cerebrospinal fluid.
PEG: polyethylene glycol; SD: standard deviation.
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