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Comparison of toxicities in young adults with ALL in CALGB 10403 and COG AALL0232

Mar 2, 2021
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Superior outcomes have been reported in retrospective studies of pediatric-inspired regimens in young adults with acute lymphoblastic leukemia (ALL) compared with conventional adult regimens. However, little is known about potential toxicities that might result from using these protocols in a young adult population.

The CALGB 10403 study (NCT00558519) was designed to prospectively investigate the use of these pediatric regimens by hematologists/oncologists in adolescents and young adults (AYAs) aged 16–39 years by comparison with the same treatment arm of the Children’s Oncology Group (COG) AALL0232 trial (NCT00075725). Furthermore, it aimed to identify any treatment-related toxicities that may affect potential use in this patient population. Comparison of adverse event (AE) profiles between the two studies was published in Blood Advances1 and we summarize the key results here.

Study design

Overall, 318 AYAs aged 18–39 years with newly diagnosed B- or T-precursor ALL were enrolled in CALGB 10403.1 Eligibility criteria included no prior ALL treatment, with one dose of intrathecal chemotherapy permitted prior to registration. The treatment schedule, which is now standard of care, is laid out in Table 1.

Table 1. Treatment schedule for adolescents and young adults with acute lymphoblastic leukemia in CALGB 104031,2

Course

Drug

Remission induction

 

Allopurinol: 300 mg/day until reduction of peripheral blasts and extramedullary disease

Intrathecal cytarabine: 70 mg on Day 1

Prednisolone: 60 mg/m2/day on Days 1–28

Vincristine: 1.5 mg/m2 on Days 1, 8, 15, and 22

Daunorubicin: 25 mg/m2 IV on Days 1, 8, 15, and 22

Pegasparaginase: 2,500 IU/m2 on Day 4

Intrathecal methotrexate: 15 mg on Days 8 and 29

Extended remission induction (if required)

Prednisolone: 60 mg/m2/day on Days 1–14

Daunorubicin: 25 mg/m2 on Day 1

Vincristine: 1.5 mg/m2 on Days 1 and 8

Pegasparaginase: 2,500 IU/m2 on Day 4

Remission consolidation

Cyclophosphamide: 1,000 mg/m2 on Days 1 and 29

Cytarabine: 75 mg/m2 on Days 1–4, 8–11, 29–32, and 36–39

6-Mercaptopurine: 60 mg/m2 on Days 1–14 and 29–42

Vincristine: 1.5 mg/m2 on Days 15, 22, 43, and 50

Pegasparaginase: 2,500 IU/m2 on Days 15 and 43

Intrathecal methotrexate: 15 mg on Days 1, 8, 15, and 22

Interim maintenance

Methotrexate: starting dose 100 mg/m2, escalate by 50 mg/m2/dose on Days 1, 11, 21, 31, and 41

Vincristine: 1.5 mg/m2 on Days 1, 11, 21, 31, and 41

Pegasparaginase: 2,500 IU/m2 on Days 2 and 22

Intrathecal methotrexate: 15 mg on Days 1 and 31

Delayed intensification

 

Vincristine: 1.5 mg/m2 on Days 1, 8, 15, 43, and 50

Dexamethasone: 10 mg/m2 on Days 1–7 and 15–21

Doxorubicin: 25 mg/m2 on Days 1, 8, and 15

Pegasparaginase: 2,500 IU/m2 on Days 4, 5, or 6, and 43

Cyclophosphamide: 1,000 mg/m2 on Day 29

Cytarabine: 75 mg/m2 on Days 29–32 and 36–39

Thioguanine: 60 mg/m2/day on Days 29–42

Intrathecal methotrexate: 15 mg on Days 1, 29, and 36

Maintenance

Vincristine: 1.5 mg/m2 on Days 1, 29, and 57

Dexamethasone: 6 mg/m2/day every 4 weeks on Days 1–5, 29–33, and 57–61

6-Mercaptopurine: 75 mg/m2/day on Days 1–84

Intrathecal methotrexate: 15 mg on Day 1, and on Day 29 of the first four maintenance courses

Oral methotrexate: 20 mg/m2 weekly on Days 8, 15, 22, 29, 36, 43, 50, 57, 64, 71, and 78

These AYAs were compared with patients randomized to the PC (prednisone during induction and Capizzi methotrexate/pegaspargase during interim maintenance) arm of COG AALL0232 (n = 158), of which 146 were aged 16–21 years and 12 were aged 22–30 years.3 Of note, slow responders in COG AALL0232 who had received an extra 4 months of intensive therapy compared with those in CALGB 10403 were included, although any AEs that arose during the additional months of therapy were not.

Results

Median age was 24 years in CALGB 10403 vs 17 years for AYAs in COG AALL0232, and overall:

  • 33% vs 92% of patients were aged 16–21 years
  • 45% vs 8% of patients were aged 22–30 years
  • 22% vs 0% of patients were aged 31–39 years (p < 0.001)
  • 61% of patients were male
  • 75%, 10%, and 15% of patients were White, African American, and Hispanic, respectively

Remission induction toxicities

Table 2 shows Grade 3–4 AEs that occurred during the induction course of both trials. Rates of hyperglycemia, transaminase elevation, hyperbilirubinemia, and febrile neutropenia were higher in CALGB 10403 compared with COG AALL0232. Notably, induction mortality rates were low, at 3.1% in CALGB 10403 and 1.3% in COG AALL0232 (p = 0.034).

Table 2. Grade 3–4 AEs in CALGB 10403 and the comparison arm of COG AALL02322

AE, adverse event; ALT, alanine aminotransferase; AST, aspartate aminotransferase.
*Assessed by χ2 or Fisher’s exact test, and statistical significance is indicated in bold.

AE, %

CALGB 10403
(n = 289)

COG AALL0232
(n = 158)

p value*

Hyperglycemia

31.1

22.8

0.06

AST

12.8

5.7

0.02

ALT

28.7

17.7

0.01

Hyperbilirubinemia

19.0

7.0

<0.001

Anaphylaxis

1.4

0.6

0.66

Pancreatitis

2.8

1.3

0.51

Thrombosis

5.2

1.9

0.13

Febrile neutropenia

23.9

5.7

<0.001

Infection

24.6

22.8

0.67

Postremission therapy toxicities

Grade 3–4 AEs reported during postremission treatment are listed in Table 3. Key points were:

  • Rates of infections were higher in COG AALL0232 vs CALGB 10403, despite being similar during induction.
  • Rates of febrile neutropenia, which were higher in CALGB 10403 during induction therapy, were similar to COG AALL0232 postinduction.
  • Mucositis occurred more frequently during interim maintenance with methotrexate and pegaspargase in COG AALL0232 (16.5%) compared with CALGB 10403 (9.1%; p = 0.037).
  • Higher rates of decreased fibrinogen, thrombotic events, elevated transaminase levels, pancreatitis, and encephalopathy were reported in CALGB 10403 compared with COG AALL0232.
  • Grade 3–4 hypersensitivity reactions requiring discontinuation of pegaspargase were more common in COG AALL0232 (14.6%) compared with CALGB 10403. However, CALGB 10403 included a protocol amendment requiring premedication for pegasparagase with corticosteroids, acetaminophen, and diphenhydramine, which resulted in a reduction in grade 3–4 hypersensitivity reactions from 10% to 4%, whereas no premedication was stipulated in CALGB 10403.
  • Postremission mortality events were low in both studies (1.3% in CALGB 10403 vs 0.8% in COG AALL0232; p = 0.064).

Table 3. Grade 3–4 AEs during postremission therapy in CALGB 10403 and the comparison arm of COG AALL02322

AE, adverse event; ALT, alanine aminotransferase; AST, aspartate aminotransferase; CNS, central nervous system.
*Assessed by χ2 or Fisher’s exact test, and statistical significance is indicated in bold.

AE, %

CALGB 10403
(n = 238)

COG AALL0232
(n = 149)

p value*

Allergic reaction

0

2.0

0.056

Anaphylaxis

12.6

17.5

0.19

Coagulation abnormalities

 

 

 

              Decreased fibrinogen

12.2

1.3

<0.001

              Prothrombin time

0.4

0.7

1

              Partial thromboplastin time

5.0

0.7

0.02

              Disseminated intravascular coagulation

0

1.3

0.15

              CNS hemorrhage

0.8

0

0.53

              Thrombosis

10.1

2.0

0.002

Hepatic

 

 

 

              AST

34.0

17.5

0.004

              ALT

55.5

35.6

0.001

              Hyperbilirubinemia

15.6

16.1

0.88

Pancreatitis

8.0

2.7

0.045

Bone

 

 

 

              Fracture

0.8

0.7

1

              Osteonecrosis

3.4

2.7

0.77

Hyperglycemia

19.3

10.7

0.025

Neurologic

 

 

 

              Confusion

1.7

0.7

0.65

              Encephalopathy

0

4.7

0.001

              Motor neuropathy

6.3

14.8

0.006

              Sensory neuropathy

18.5

10.1

0.025

              Seizure

3.4

0

0.026

              Dysphasia

2.9

4.0

0.56

              Somnolence

1.3

1.3

1

Febrile neutropenia

49.2

40.9

0.11

Infection

38.7

55.0

0.002

Toxicities according to age and BMI

There was no evidence of an association between increasing frequency of toxicities and age. However, there were differences in toxicity rates between both studies:

  • During induction, there were more Grade 3–4 events of hyperglycemia, hyperbilirubinemia, transaminase elevation, pancreatitis, and febrile neutropenia in patients aged 16–21 years in CALGB 10403 compared with COG AALL0232.
  • During postremission therapy, Grade 3–4 transaminase elevation, decreased fibrinogen, pancreatitis, partial thromboplastin time, seizures, and thrombosis all occurred more frequently in CALGB 10403 compared with COG AALL0232 in patients aged 16–21 years.

Analysis of age as a continuous variable revealed a correlation between increased age and decreased fibrinogen in both induction (odds ratio [OR], 1.10; p < 0.0001) and postremission therapy (OR, 1.111; p = 0.0002), and with elevated alanine aminotransferase during induction (OR, 1.037; p = 0.039) and postremission therapy (OR, 1.045; p = 0.011).

Overall, median body mass index (BMI) was higher in CALGB 10403 than COG AALL0232 (p = 0.056), with a higher proportion of patients with a BMI ≥30 kg/m2 in CALGB 10403 (30%) than COG AALL0232 (19%).

  • In both studies, patients with a BMI <30 kg/m2 had a lower frequency of Grade 3–5 toxicities (p = 0.002 in COG AALL0232).
  • In CALGB 10403, patients with a BMI ≥40 kg/m2 had the highest rate of Grade 3–5 toxicities.
  • During induction treatment, patients with a higher BMI experienced more Grade 3–4 toxicities than those with a lower BMI across both trials.

Treatment delays and completion

There was a trend towards more delays in treatment (start of induction to start of maintenance) due to Grade 3–4 liver function or pancreatitis events in CALGB 10403 compared with COG AALL0232 (p = 0.051).

It was also noted that there was a high dropout rate in CALGB 10403, with only 39% patients completing treatment compared with 57% AYAs in COG AALL0232. Interestingly, 74% of patients aged <18 years in COG AALL0232 completed treatment. However, there was no correlation between increased rate of Grade 3–4 toxicities and not completing treatment.

Conclusion

This comparison found that use of a pediatric chemotherapy regimen for ALL in an AYA population is effective and tolerable. There was an increase in some toxicities during induction therapy (hyperglycemia, hepatic toxicity, and febrile neutropenia) in the adult trial compared with the same treatment arm of the pediatric trial, but not to an extent that they limited or significantly delayed treatment. Furthermore, data also showed a clear association between toxicity and increased BMI, which might explain increased liver and pancreas-related side effects during induction and postremission therapy in CALGB 10403, given the higher frequency of participants with a high BMI in this trial. Also, treatment of older AYA patients increased the risk of developing low fibrinogen and elevated alanine aminotransferase levels. Notably, treatment-related mortality was similarly low in both study populations.

The authors noted that the results were limited by the high dropout rate, which they suggested may be due to clinicians switching patients to non-protocol treatments in addition to employment, education, and relationship challenges faced in young adulthood affecting adherence to long and intense clinical trials. Looking ahead, not only is it important for hematologists/oncologists who treat AYAs to gain familiarity with these pediatric regimens, but it is also likely that combining new frontline immune targeting agents with traditional chemotherapy regimens will enable treatment modifications to reduce toxicity.

  1. Stock W, Luger SM, Advani AS, et al. A pediatric regimen for older adolescents and young adults with acute lymphoblastic leukemia: results of CALGB 10403. Blood. 2019;133(14):1548-1559. DOI: 1182/blood-2018-10-881961
  2. Advani AS, Larsen E, Laumann K, et al. Comparison of CALGB 10403 (Alliance) and COG AALL0232 toxicity results in young adults with acute lymphoblastic leukemia. Blood Adv. 2021;5(2):504-512. DOI: 1182/bloodadvances.2020002439Top of Form
  3. Larsen EC, Devidas M, Chen S, et al. Dexamethasone and high-dose methotrexate improve outcome for children and young adults with high-risk B-acute lymphoblastic leukemia: A report from Children’s Oncology Group Study AALL0232. J Clin Oncol. 2016;34(20):2380-2388. DOI: 1200/JCO.2015.62.4544

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