Page 62 - 2021_06-Haematologica-web

M.B. Geyer et al.
eridemia were common (each observed in 59% of patients). Grade 3-4 hyperbilirubinemia was significantly more common in patients aged 40-60 years versus 18-39 years (44% vs. 10%, P=0.025); a non-significant trend toward greater risk of grade 3-4 hyperbilirubinemia was observed in patients with body mass index (BMI) ≥30 ver- sus <30 kg/m2 at treatment initiation (50% vs. 17%, P=0.087). Incidence of grade 3-4 transaminitis, hyper- triglyceridemia, hyperglycemia, hypofibrinogenemia, pancreatitis, and thromboembolic events otherwise did not significantly differ by age (18-39 years vs. 40-60 years), BMI (≥30 kg/m2 vs. <30 kg/m2), or sex.
Nine of the ten patients experiencing grade 3-4 hyper- bilirubinemia following pegaspargase during induction I resumed pegaspargase at the dose and schedule per pro- tocol; eight of nine patients resuming pegaspargase did not experience recurrent grade 3-4 hyperbilirubinemia. In four patients, Erwinia asparaginase was substituted for pegaspargase due to hypersensitivity associated with pegaspargase infusion.
Other non-hematologic adverse events and febrile neu- tropenia definitely, probably, or possibly related to proto- col therapy are detailed in the Online Supplementary Table S7. Association of pegaspargase with treatment delays is summarized in the Online Supplementary Results.
Subsequent therapy and relapse
The patient with T-ALL who was withdrawn from study after exhibiting persistent disease following induc- tion I received second-line chemotherapy off-protocol with nelarabine, etoposide, and cyclophosphamide, and subsequently underwent alloHCT. Ten additional patients receiving protocol therapy underwent alloHCT in CR1. Rationale for alloHCT in CR1 was as follows: persistent MRD following course II of induction (n=3), Ph-like ALL (n=1), unfavorable cytogenetic features including t(4;11) (n=1) or evidence of clonal evolution (n=1), or physician preference (n=4).
Of 38 patients achieving CR/CRi on protocol, ten subse- quently experienced relapse (BM, n=4; CNS only, n=2; combined BM and CNS, n=1; combined BM and other extramedullary sites, n=1; testis, n=1; cortical bone, n=1); median time to relapse from start of therapy was 15.4 months (range, 5.4-40.4) in these ten patients. Six patients underwent alloHCT following relapse, including one patient who had relapsed following first alloHCT in CR1.
Survivaloutcomes
Two patients died in CR1 during re-induction I due to complications of sepsis (n=1) or multi-organ system fail- ure (n=1), aged 55 and 47 years, respectively, at the time of death. At median follow-up of 38.6 months among sur- viving patients (range, 1.8-57.8), 3-year OS is 76.4% (95% Confidence Interval [CI]: 63.3-92.3) and 3-year EFS is 67.8% (95% CI: 53.4-86.0), as summarized in Figure 1A and B. Three-year cumulative incidence of relapse (CIR, with death in CR as competing event) is 25.3% (95% CI: 11.4-42.0). Superior OS and EFS were observed among patients aged 18-39 years versus 40-60 years at the start of therapy (3-year OS: 88.2 vs. 61.9%, P=0.03 and 3-year EFS: 85.0% vs. 48.6%, P=0.05, respectively, Figure 1C and D). OS and EFS did not differ significantly with respect to B-cell versus T-cell lineage (3-year OS: 78.7% vs. 71.6%, P=0.8, and 3-year EFS: 71.8% vs. 58.7%, P=0.7, respec- tively). In this small study, significant differences were not observed in OS, DFS, or CIR between the 10 patients undergoing alloHCT after achieving CR1 with protocol therapy and the 27 evaluable patients not undergoing alloHCT in CR1 (3-year OS: 100% vs. 70.7%, P=0.3; 3- year DFS: 88.9% vs. 62.5%, P=0.09; 3-year CIR: 11.1% vs. 29.8%, P=0.197).
Among the patients with ALL achieving MRD-negative CR versus MRD-positive CR/CRi (central review) follow- ing induction 1, there was no difference in OS or DFS measured from time of post-induction I disease assess- ment (3-year OS: 75.0% vs. 80.8%, P=0.8, and 3-year DFS: 75.0% vs. 68.8%, P=0.5). Twelve patients with ALL who were in MRD-positive CR/CRi following induction I subsequently achieved MRD negativity following induction II (MRD converter group) and seven patients with ALL were confirmed to be in MRD-negative CR fol- lowing both induction I and induction II (early MRD neg- ativity group). The MRD converter and early MRD nega- tivity groups achieved 3-year DFS 56.2% and 71.4%, respectively, P=0.7, and 3-year OS 90.9% and 71.4%, P=0.5, respectively, as measured from time of post-induc- tion II disease assessment. The small number of patients with MRD positivity post-induction II (n=4) also pre- cludes meaningful comparison of this group with those exhibiting MRD negativity post-induction II; these patients are described in the Online Supplementary Table S8. All patients with MRD positivity post-induction II underwent alloHCT (CR1, n=3; CR2, n=1) following sub- sequent therapy and three are in ongoing CR.
Table 4. Selected grade 3-4 toxicities possibly, probably, or definitely attributed to pegaspargase.
Toxicity All patients (N=39)
Grade 3 Grade 4 Total
Grade 3-4
Patients aged 40-60 years (N=18) Grade 3 Grade 4 Total
Grade 3-4
N%N%N%N%N%N% Hypofibrinogenemia 21 54 2 5 23 59 10 56 0 0 10 56 Hypertriglyceridemia 11 28 12 31 23 59 4 22 6 33 10 56 Transaminitis 15 38 1 3 16 41 9 50 1 6 10 56 Hyperglycemia 8 21 4 10 12 31 4 22 2 11 6 33 Hyperbilirubinemia 5 13 5 13 10 26 3 17 5 28 8 44 Pancreatitis 130013000000
Thromboembolicevents 1 3 0 0 1 3 1 6 0 0 1 6
ALL: acute lymphoblastic leukemia.
2090
haematologica | 2021; 106(8)