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Use Pediatric Regimens for

Adolescents and Young Adults with

Acute Lymphoblastic Leukemia

Richard M. Stone MD

Chief of Staff

Lunder Professor of Leukemia

Department of Medical Oncology, Dana-Farber Cancer Institute

Professor of Medicine

Harvard Medical School

Boston, MA

Consulting relationships past three years:

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Advisory Board Member: AbbVie, AvenCell, BMS, Amgen, Cellarity, CTI BioPharma, CTI Pharma, Daiichi Sankyo, GSK, Hermavant, Kura Onc, Lava Therapeutics, Ligand Pharma, Redona Therapeutics, and Rigel.

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Consultant: ENSEM and Glycomimetics.

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Data and Safety Monitoring Board Member: Aptevo, Epizyme, Syntrix, and Takeda.

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Protocols on which I served as site PI (support to institution only): AbbVie

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Exploring Frontiers in Oncology: Advances and Innovation in Cancer Care and Research across Solid Tumors and Hematologic Malignancies

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Pediatric Regimens v HyperCVAD in AYA ALL patients

• AI Overview
• Learn more
• When comparing pediatric therapy to hyper-CVAD for treating Acute Lymphoblastic Leukemia (ALL), pediatric regimens are generally considered superior, offering better overall survival rates and potentially less severe side effects, especially for adolescents and young adults (AYAs) with ALL; this is because pediatric protocols are often more targeted and optimized for younger patients, incorporating higher doses of certain drugs like asparaginase, while minimizing potentially harmful toxicities associated with hyper-CVAD regimens. 

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Pediatric Regimens in AYA ALL patients Outline

• How folks thought of the Concept
• A Little bit of Legacy ( e.g C9111, E2906, Hyper-CVAD) data
• The Current Data
• The Future

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Problem: Poor Outcomes in ALL in Adults

1. Hunger. NEJM. 2015;373:1541. 2. Rowe. Blood. 2005;106:3760.

OS Among Children With ALL in Clinical Trials: �1968-2009¹

OS by Age Among Adults With Ph-Negative ALL

in ECOG E2993²

Yr

Patients (%)

Yr Since Diagnosis

Patients (%)

2000-2005 (N = 7835)�1995-1999 (N = 7287)�1989-1994 (N = 8200)�1983-1988 (N = 3711)�1978-1983 (N = 2984)�1975-1977 (N = 1313)�1972-1975 (N = 936)

2006-2009 (N = 6530)

1970-1972 (N = 499)

1968-1970 (N = 402)

0

1

2

3

4

5

100

75

50

25

0

0

2

4

6

8

10

ALL in Children: A Success Story

ALL in Adults: We Have a Problem!

One Size Does NOT Fit All!

100

75

50

25

0

<20 (n = 234)�20-29 (n = 301)�30-39 (n = 217)�40-49 (n = 163)�≥50 (n = 108)

45%

44%

34%

23%

15%

NOTE: In 1978 ASPARAGINASE intro

Outcomes in AYA Patients Improved With �Pediatric Regimens

• AYA patients with ALL have better outcomes when receiving pediatric-inspired regimens
• Reported by Stock et al in 2008 retrospective study of AYA patients aged 16-20 yr who received treatment on pediatric (CCG) or adult (CALGB) trials from 1988-2001
• Replicated by several groups

Stock. Blood. 2008;112:1646.

Pts at

Risk, n

CCG

CALGB

197�124

151�84

131�63

98�48

57�37

19�30

2�8

Pediatric Regimens Decrease CNS Relapse Rates �in AYA Patients

Stock. Blood. 2008;112:1646.

Comparison of Isolated CNS Relapses

0

Patients at Risk, n

Yr Followed

R-Hyper-CVAD

• CVAD = Cytoxan, vincristine, doxorubicin, dexamethasone
• ARA-C/MTX
• CNS prophylaxis with IT-MTX (# depends on risk stratification)
• POMP Maintenance until 2 years from diagnosis
• Rituximab (or biosimilar) added on day 1 of each cycle, if CD20 positive

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CVAD

Maintenance

Until 2 years from Dx

ARA-C/MTX

H Kantarjian et al., JCO 2000

Repeat sequence X 4 cycles

Addition of Rituximab Improves Outcome in �CD20 Positive Patients

Thomas et al., JCO 2010

Legacy adult regimen: CALGB 9111

Larson RA et al, Blood, 1998.

Definition of AYA Can Vary Depending on Trial

AYA definition is relatively loose

DeAngelo. Leukemia. 2015;19:526. Huguet. JCO. 2009;27:91. Ribera. JCO. 2008;26:1843.

Principles of Pediatric vs Adult ALL Regimens

• Multiple chemotherapy drugs
• More asparaginase and corticosteroids
• Less myelotoxic drug
• Anthracyclines
• Alkylating agents
• Better time and dose adherence
• Allo-BMT only for very high risk

Toxicity Profile in AYAs: Differences �In “Young” vs “Old”

Advani. Blood Adv. 2021;5:504.

Although tolerable, further dose intensification of pediatric regimens �may not be feasible �in most AYA patients

↑ALT

Febrile �neutropenia

Hyperglycemia

Pancreatitis

40

30

20

10

0

17.1%

27.7%

6.2%

30.9%

6.2%

20.2%

22.6%

39.4%

0.7%

5.3%

%

Hyperbilirubinemia

Asparaginase: A Magic Bullet!�Not always a bullet, not always magic

All proteins affected means cure comes at a price:

• Hypoalbuminemia
• Hyperglycemia
• Altered drug metabolism
• Coagulation disturbances
• Diabetes
• Organ toxicities

Aspartic acid

Plasma

Protein biosynthesis

Asparagine

Aspartic acid + ammonia

Asparagine synthetase

Asparagine

L-Asparaginase

H₂O

Malignant Lymphoblast

Glutamine

Glutamic acid

Ammonia

Asselin. Leuk Lymphoma. 2015;56:2273. Koprivnikar. Onco Targets Ther. 2017;10:1413. Patel. Leukemia. 2017;31:58. Gillette. J Pediatr. 1972;81:109.

Asparaginase Mechanism of Action

Asparaginase-Related Symptomatic Thrombosis (VTE)

• Rechallenging asparaginase with anticoagulation
• 70% received 85% of the intended doses of asparaginase
• EFS or OS no difference between patients with and without VTE
• Asparaginase safely administered with anticoagulation after VTE
• Anticoagulation prophylaxis: complex

Grace RF, et al. Br J Haematol. 2011;152:452-459.

Age was the only factor with statistical

significance in multivariate analysis

Why Do We Use Asparaginase?

P =.04

Protocol 77-01:

3-Drug Induction ± Weekly High-Dose ASNase¹

4-Drug Induction ± Intensive ASNase²

1. Courtesy of Steve Sallan, MD. 2. Clavell. NEJM. 1986;315:657.

EFS Probability

EFS (%)

100

80

60

40

20

0

0

1

2

3

4

5

6

Yr

Yr

P =.003

+ ASNase

- ASNase

Standard Risk

High Risk

Impact of Omitting Asparaginase Doses in ALL

• Erwinia ASNase as substitution was approved in 2011 for allergic reactions
• However, it has been intermittently unavailable because of drug supply issues
• Higher-risk patients who missed prescribed doses of ASNase altogether had 50%? increased risk of relapse

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Gupta. JCO. 2020;38:1897.

DFS of NCI High-Risk Patients on �COG AALL0232

Patients at Risk, n

Yr

DFS Probability

P = .0030

Erwinia

Not all doses

All doses

Overview of DFCI Consortium ALL AYA Protocols: Multicenter Studies

Induction

Consolidation

Maintenance

Until 2 yr from CR

CNS Prophylaxis

IT Chemo + XRT

Induction

Consolidation II

Maintenance

CNS

IT Chemo + XRT

Consolidation I

Until 2 yr from CR

DFCI 00-001 (PEDS) and DFCI 01-175 (ADULT)

DFCI 05-001 (PEDS) and 06-254 (ADULT)

E coli asparaginase (30 wk)

PEDIATRIC: PEG vs E coli asparaginase (30 wk)

ADULT: PEG asparaginase (30 wk)

Vrooman. JCO. 2013;31:1202. DeAngelo. Leukemia. 2015;23:526. DeAngelo. ASH 2015. Abstr 80.

Prognosis of AYA Patients Improved With �Pediatric Regimens

5-yr OS for patients 20-50 yr: 20% to 45%

E2993 “Adult” Protocol¹

DFCI “Pediatric” Protocol^2,3

5-yr OS for patients 20-50 yr: 60% to 70%

• 1. Rowe. Blood. 2005;106:3760. 2. Vrooman. JCO. 2013;31:1202. 3. DeAngelo. Leukemia. 2015;29:526.

OS by Age in Yr

OS (%)

Probability of OS

Yr

Yr

OS for Patients Achieving CR³

100

75

50

25

0

0

1

2

3

4

5

<20 (n = 234)�20-29 (n = 301)�30-39 (n = 217)�40-49 (n = 163)�≥50 (n = 108)

45%

44%

34%

23%

15%

Updated Results on DFCI Adult Consortium Trial (06-254): ASH 2023

• Total Pts N=152
• Median Age 28 yrs (18-51)
• Male 92 (60%)
• B-cell 102 (67%)
• T-cell 48 (32%)
• CNS-2/3 15 (10 %)
• Normal KT 42 (28%)

Valtis. ASH 2023. Abstr 4239.

OS (n = 152)

Improved Survival for AYA Patients: CALGB 10403

• 72% survival at 3 years

• Immunophenotype: B-cell vs T-cell

• Stock. Blood. 2019;133:1548.

OS

Mo

36-mo OS, %: 72.6 (95% CI: 67.6-78.1)�Event/N: 105/295

OS by Immunophenotype

OS ( %)

OS ( %)

Mo

74.0 (68.3-80.2)�68.0 (57.8-80.0)

B-cell

T-cell

36-Mo OS, %

(95% CI)

B-cell

T-cell

76/223

28/71

Event/N

CALGB 10403: Outcomes With Pediatric Regimen �in AYA Patients

36-mo OS, % (95% CI)

• 1. Stock. Blood. 2019;133:1548. 2. Stock. Blood. 2008;112:1646.

3-yr OS¹: 72%

3-yr EFS¹: 59%

CALGB OS²: 46%

OS (%)

EFS (%)

OS (%)

OS (%)

OS¹

EFS¹

OS by BMI¹

OS by Ph-Like Signature¹

36-mo OS, %: 72.6 (95% CI: 67.6-78.1)�Event/N: 105/295

36-mo OS, %: 59.3 (95% CI: 53.8-65.3)�Event/N: 139/295

Mo

Mo

Mo

Ph-like

HR: 1.92 (95% CI: 1.05-3.48)

Likelihood-ratio P =.0371

36-mo OS, % (95% CI)

BMI, kg/m²

Early MRD Eradication: CALGB 10403

3-yr DFS: 85%

3-yr DFS: 56%

• Stock. Blood. 2019;133:1548.

DFS by MRD Status

DFS (%)

*QT-PCR following induction.

Mo

Only 40% of patients are MRD negative early in treatment

HR: 0.25 (95% CI: 0.10-0.60; P = .0006)

Pediatric-Inspired Chemotherapy Regimen vs HCT: �Overall Survival

OS Probability (%)

Yr Since CR1

HR: 3.12 (95% CI: 1.99-4.90; P <0.0001)

Chemo (n = 107)

HCT (n = 422)

1

Seftel. Am J Hematol. 2016;91:322.

ON and Bone Fracture are Common Late Events

Osteonecrosis

Fracture

Surgery: 46%

54 events with information

100 events in 60 patients

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5-year CI: 17% (95% CI, 13-22%)

Median time to event: 1.6 years

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51 events in 40 patients

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5-year CI: 12% (95% CI, 9-16%)

Median time to event: 1.4 years

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Years from registration

Years from registration

Surgery: 33%

9 events with information

Valtis YK, et al. Blood Adv 2022.

BMI and Prognosis

Shimony et al. Blood Adv 2023

Anticoagulation

• Prophylaxis
• LMWH preferred
• hold Plts < 30K
• Check AT functional levels (replete if < 30%)
• Only during Asp therapy
• Hold for procedures
• Do not replete fibrinogen unless bleeding!

Ph- ALL: Incorporating Novel Agents

30

T-cell

ALL

CD3

CD19

ALL

CD22

Blinatumomab

Inotuzumab

ALL

Venetoclax

• Until recently, only option available for Ph- ALL was conventional chemotherapy.

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• Blinatumomab (2014) and inotuzumab ozogamicin (2017) approved for relapsed and refractory B-ALL.

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• Other novel agents being investigated for ALL, including venetoclax.

Phase 3 Alliance 041501 Trial (AYA ALL): �INO in Young Adults With Ph-negative B-Cell ALL

Eligibility

Previously untreated B-cell ALL

Patients ages 18-39.9 years

Presence of surface CD22+ lymphoblasts

Philadelphia negative cytogenetics

Initial run-in safety phase in 6-12 patients before randomized trial opens

https://clinicaltrials.gov/ct2/show/NCT03150693. Accessed November 21, 2017.

DeAngelo, ASH 2024

DeAngelo D, et al, # 308, ASH 2024.

Adverse Events

DeAngelo D, et al, # 308, ASH 2024.

EFS - �Stratified

3-yr EFS:

INO = 69%

Control = 67%

EFS table by arm

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DeAngelo D, et al, # 308, ASH 2024.

OS - �Stratified

3-yr OS:

INO = 80%

Control = 81%

DeAngelo D, et al, # 308, ASH 2024.

Overall Survival: A041501 vs C10403

OS = time from enrollment to deaths due to any causes

3-yr OS:

A041591 = 80%

C10403 = 73%

DeAngelo D, et al, # 308, ASH 2024.

Conclusions�

• A041501 did not meet the primary EFS endpoint for the addition of INO to the pediatric regimen CALGB 10403.
• These data provide compelling evidence for continued use of pediatric regimens in AYA patients.

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• INO may still be efficacious if late toxicity can be mitigated.
• A pilot study is planned that will decrease INO dose, add 2 cycles of blinatumomab and strict infectious prophylaxis guidelines.

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A041501 C10403

3-yr OS: 80% 73%

3-yr EFS: 69% 59%

Historical CALGB OS: 46%

DeAngelo D, et al, # 308, ASH 2024.

ECOG 1910

• n=224, Ph-negative B-ALL
• Median age, 51 years
• Men 50%, women 50%
• MRD-neg CR after chemotherapy (<0.01% leukemic cells in bone marrow by flow cytometry)

Litzow et al. N Eng J Med 2024;391:320

E1910 Regimen

ECOG 1910

Litzow et al. N Eng J Med 2024;391:320

Note: Rau R et al, ASH abst 1, 2024: Results of AALL0434 support the use of blina in children with non-favorable SR MRD neg disease

Pediatric Regimens v HyperCVAD in AYA ALL patients: �meta-analysis ( Su W… DeAngelo, Am J Hematol, in press)

• 46 primary publications of potential relevance-none randomized
• -ASP-containing regimens had statistically significant improvement in median OS (4 studies), 2-year OS (1 study), 3-year OS (3 studies), and 5-year OS (1 study) compared with hyper-CVAD.
• Pts treated with ASP-containing regimens had a significantly higher chance of achieving CR (random- and fixed-effects model: OR, 2.04 [95% CI: 1.31, 3.18]) and improved OS (random-effects model: HR, 1.76 [95% CI: 1.36, 2.29];

Another meta-analysis showed similar findings (Salama H, et al, Leuk Res 103: 2023)

Conclusions- Pedi-inspired v hyperCVAD for AYA ALL

• Comparing studies using each strategy in the same age group suggest pedi-inspired regimens lead to better EFS and OS outcomes than hyperCVAD
• Metanalyses suggest pedi-inspired regimens better
• Toxicities different but manageable
• Use of targeted therapy may improve results even further

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The End: questions?

Questions or need help?

Email: richard_stone@dfci.harvard.edu

Phone: 617-632-2214

Administrative Assistant: 617-632-2168

New Patients: 617-632-6028

Page: 617-632-3352 #42194