Acute Lymphoblastic Leukemia in AYA

Chi-kong LI, MD

Department of Paediatrics

The Chinese University of Hong Kong,

Prince of Wales Hospital and Hong Kong Children’s Hospital

Improved overall survival of children with acute lymphoblastic leukaemiatreated on cooperative group trials

US Children’s Oncology GroupHong Kong Ped Haem/Onc Study Group

DEFINITION OF AGE FOR AYA

• The United Kingdom (UK) defines teenagers and young adults as those aged 15–24 years

• In the EUROCARE (a European multinational project to examine cancer survival) study, AYA was defined as those aged between 15 and 24 years

• The Canadian Cancer Society defines AYA as those aged between 15 and 29 years.

• USA AYA definitions:• SEER 16-29 years

• National Cancer Institute 15-39 years

• Children’s Oncology Group 15-29 years

• WHO defined adolescent 10-19 years

• In Asian countries, there is no official definition for AYA age ranges in many Asia countries

Geiger AM, Castellino SM. Delineating the age ranges used to define adolescents and young adults. J Clin Oncol. 2011 Jun 1;29(16):e492-3.

Increasing trend of Adolescents and Young Adults With ALL

JAMA Oncol. 2018;4(5):725-734. doi:10.1001/jamaoncol.2017.5305

The age range of the AYAs was 15 to 39 years. Average percentage change (APC) represents the

mean percentage change of logarithmic values, with APC values and P values for incidence

provided by SEER and calculated by us for new case numbers.

Five year Relative Survival Rate of Patients with ALL by Single

Year of age at diagnosis, 2000 to 2007. Survival Cliff

JAMA Oncol. 2018;4(5):725-734.

Data A, Included is joinpoint analysis that created linear regressions for ages 1 to 17 years and 20 to 68 years

and associated statistical variables.

B, The pediatric age-dependent survival trend in A is extrapolated into the adult age range..

JAMA Oncol. 2018;4(5):725-734. doi:10.1001/jamaoncol.2017.5305

Pediatric and Adult Therapy Regimen Outcomes

in AYAs With ALL or LBL

JAMA Oncol. 2018;4(5):725-734. doi:10.1001/jamaoncol.2017.5305

Pediatric and Adult Therapy Regimen Outcomes

in AYAs With ALL or LBL

AYA treated by pediatric or adult based regimens

• All but 2 of 25 published comparisons of outcomes with pediatric and adult regimens for ALL and LBL in AYAs and 1 meta-analysis favor the pediatric regimen

• at least 160 phase 3 trials in the United States, the pediatric regimens have become far more complex than most adult regimens.

• Asparaginase, a critical component of the pediatric regimens, is more difficult to administer to AYAs (and older patients) but nonetheless has a favorable benefit to toxicity ratio for AYAs.

• A dramatic reduction in outcome of ALL and LBL during the AYA years (the "survival cliff") is coincident with similar reductions in proportions of AYAs referred to academic centers and enrolled on clinical trials (the "accrual cliff" and "referral cliff").

JAMA Oncol. 2018;4(5):725-734.

doi:10.1001/jamaoncol.2017.5305

Children’s Cancer Group and Pediatric Oncology Group Phase 3 Randomized

Trials in Adolescents and Young Adults With Acute Lymphoblastic Leukemia.

Prevalence of ALL genetic subtypes across age groups

Roberts, K. G. & Mullighan, C. G. (2015) Genomics in acute lymphoblastic leukaemia: insights

and treatment implicationsNat. Rev. Clin. Oncol. doi:10.1038/nrclinonc.2015.38

Children standard risk

ChildrenHigh Risk

Outcomes of children,

adolescents, and young

adults with Ph-like ALL. (A)

Patients with Ph-like ALL

have an inferior outcome

compared with patients

with non–Ph-like patients

treated on AALL0232.

Thai Hoa Tran, and Mignon L. Loh Hematology 2016;2016:561-566

Adult oncology center treating ALL according to pediatric protocol?

• Acceptance of adopting a paediatric protocol for young adults by adult oncologist/hematologist?

• Practical difficulties in adopting:

Paediatric protocols associated with higher chemo intensity in adults:

• Longer hospital stay in the busy adult oncology wards

• Short of in-patient beds

• Intolerance of some chemotherapeutic agents, e.g. asparaginase

• Prefer performing allogeneic Stem cell transplant as ‘curative’ treatment

• Complicated treatment protocols

• Frontline staff may not be able to follow, poor compliance,

• Prone to have medication errors

Blood 2018;132:351-356.

Asparaginase• Pediatric trials showed superior outcome in patients treated with asparaginase:

• RCT trials in children with ALL, the asparaginase-containing regimen had 34% higher 10-year to 20-year overall survival,

• Asparaginase causes more hepatic dysfunction, pancreatitis, and coagulopathies in AYAs than in younger patients.

• A lower dose and longer intervals between doses of asparaginase prevent drug-limiting hyperbilirubinemia.

• Several review articles offer practical guidelines for prevention and management of asparaginase toxicities in AYAs.

• The benefit to toxicity ratio of asparaginase in AYAs with ALL or LBL is favorable.

Adult ALL trials: experience with Asp.• significant benefit from asparaginase in a Cancer and Leukemia Group B trial, the 22

patients who had less asparagine depletion had a lower overall survival (hazard ratio [HR], 2.37; P = .002) and disease-free survival (HR, 2.21; P = .01) than 63 patients who did achieve asparagine depletion.

• In a multi-institutional study, 60 of 95 adult patients with T-cell ALL or T-cell LBL, those who received asparaginase had statistically improved relapse-free survival (HR, 2.65; P = .01) and overall survival (HR, 2.30; P = .02), even after adjusting for other variables.

• Overall survival was greater in asparaginase-treated patients younger than 40 years (HR, 3.4; 95% CI, 1.2-9.5) than in older adults.

• In another multi-institutional study, 61 adults with early T-cell precursor ALL had a statistically significant better progression-free survival and overall survival if they received asparaginase.

Wetzeler M. Blood 2007;109:4264, Borate U. Blood 2015;126:4869

Pediatric inspired or pediatric protocol in AYA:

• Increasing toxicities with age reported in almost all cohorts of patients treated with fully pediatric or pediatric-like approaches

• Increase in thrombosis according to age

• Pancreatitis incidence depends on the intensity of asp. use, more common in older children and adolescents, global rates 2.3% to 7% in large cohorts. Its odds ratio was comparable for patients age 10-17 and 17-45 years vs age 1 to 9 years in NOPHO 2008 (2.2 and 2.4, respectively; P = not significant).

• incidence of hypersensitivity to Pegasp lower in adults compared with children included in the NOPHO 2008 and the Dana-Farber Cancer Institute studies

• The risk of developing avascular osteonecrosis maximum in teenagers and decreases in young adults. AVN incidence in the NOPHO 2008 study was 1.5% for patients age 1 to 9 years, 13.4% for age 10 to 17 years, and 8.5% for age >18 years.

Blood. 2018 Jul 26;132(4):351-361.

Hematopoietic Stem Cell Transplant

• With the notable exception of Ph chromosome–positive ALL, pediatric regimens have not required allogeneic HSCT. (<5-10% in CR1)

• In contrast, many adult patients with ALL treated on an adult regimen receive HSCT during initial remission if they have a matched, available donor.

• To avoid the toxicities, late adverse effects, and financial cost of HSCT, thus substantially favors the pediatric regimen.

• Another factor favoring the pediatric regimen • young AYA recipients are more susceptible to allogeneic HSCT-induced acute

graft-vs-host disease than either younger or older patients.

Wendy Stock et al. Blood 2019;133:1548-1559

Adult ALL treated by a Pediatric Based study:3 US cooperative groups: CALGB, ECOG, SWOG

Treatment schema for

CALGB 10403.

*Maintenance therapy

consisted of 12-week

courses continuing

until 3 years from

initiation of interim

maintenance for male

and 2 years for female(A COG HR arm protocol)

A pediatric regimen for older adolescents and young adults with acute lymphoblastic leukemia: results of CALGB 10403

Wendy Stock et al. Blood 2019;133:1548-1559

A pediatric regimen for older adolescents and young adults with acute lymphoblastic leukemia: results of CALGB 10403

318 patients :• 263 patients

(89%) achieved CR

• 9 deaths (3%) during induction therapy.

• 6 treatment related (2 sepsis, 2 hepatic failure, 2 cardiac).

• 20 underwent allo HSCT in CR1,; 3 had t(4;11).

3 yr OS 73%

3 yr EFS 59%

3 yr DFS 48%

Wendy Stock et al. Blood 2019;133:1548-1559

Adverse factors to survival:High BMIPh-likeMRD positivity

Markedly improved outcomes and acceptable toxicity in adolescents and young adults with acute lymphoblastic leukemia following treatment with a pediatric protocol: a phase II study by the Japan Adult Leukemia Study Group.

• The ALL202-U protocol to examine the efficacy and feasibility of a pediatric protocol in adolescents and young adults (AYAs) with BCR-ABL-negative ALL.

• Patients aged 15-24 years (n=139) were treated with same protocol used for pediatric B-ALL.

• The primary objective of this study was to assess DFS rate and its secondary aims were to assess toxicity, the CR rate and OS rate.

• The CR rate was 94%, The 5-year DFS and OS rates were 67% and 73% respectively.

• Severe adverse events were observed at a frequency that was similar to or lower than that in children treated with the same protocol.

Blood Cancer J. 2014 Oct 17;4:e252

Where Should an AYA With ALL Be Treated?• Optimally, AYAs with ALL should be referred to a center with an available

clinical trial.

• the challenges faced by adult-treating oncologists in transitioning to a pediatric regimen require pediatric oncologists and their staffs and the cooperative groups to educate, train, and provide close support to their medical oncology colleagues.

• Ideally, an AYA patient with ALL should be co-managed by the pediatric and adult services and, in certain circumstances, be transferred to a pediatric or AYA oncology service.

• Ultimately, an AYA oncology discipline with specific training, including fellowship programs, may provide a sufficient number of AYA oncologists to optimize management of a complex pediatric regimen.

Location of Care: adopting ped regimen?

• The effect of adopting pediatric protocols in AYA with ALL in pediatric vs adult centers: An IMPACT Cohort study• The Initiative to Maximize Progress in Adolescent and Young Adult Cancer

(IMPACT) study collected detailed patient, disease, treatment, and outcome data on all AYA aged 15‐21 years diagnosed in Ontario, Canada between 1992 and 2011

• LOC was categorized as pediatric vs adult center, based on the institution that delivered the first 3 months of chemotherapy.

• For treatment protocol, AYA treated at pediatric centers were categorized as having been treated with pediatric–based protocols,

• AYA treated at adult centers were categorized as having received pediatric–based vs adult–based protocols using three data sources.

Gupta S. Cancer Med. 2019 Mar 26. doi: 10.1002/cam4.2096.

Patients: Ontario, Canada

• 275 AYA with ALL, 152 (55.3%) treated in adult centers.

• Adult center AYA were treated at 17 institutions. The five largest adult centers accounted for 81.6% of such patients overall, and 46/59 (78.0%) in the late time period (2006‐2011).

• AYA at pediatric centers far more likely to be registered on clinical trials [86/123 (69.9%) vs 7/152 (4.6%); P < 0.001]

• AYA at pediatric centers were no more likely to undergo stem cell transplant in first remission [18/123 (14.6%) vs 24/152 (15.8%); P = 0.79].

outcome

• Of the 152 AYA treated at adult centers, 46 (30.3%) were treated using pediatric–based protocols.

• Of 59 patients treated during the late time period (2006‐2011), 39 (66.1%) were treated using pediatric–based protocols.

• The 5 year EFS for AYA treated in pediatric centers was 72.4% ± 4.0% vs 56.6% ± 4.0% in AYA treated in adult centers (P = 0.03).

• 5‐year OS was 82.1% ± 3.5% vs 63.8% ± 3.9% (P < 0.001)

• LOC–based disparities persisted over time, the 5‐year OS for patients treated in the latest time period was 90.9% ± 4.3% for those AYA treated in pediatric centers vs 72.9% ± 5.8% for those treated in adult centers (P = 0.02).

The effect of adopting pediatric protocols in adolescents and young adults with acute

lymphoblastic leukemia in pediatric vs adult centers: An IMPACT Cohort study

Gupta S. Cancer Med. 2019 Mar 26. doi: 10.1002/cam4.2096.

• Induction deaths did not differ between AYA at pediatric vs adult centers (<2% in both; P = 0.44).

• The 2‐year cumulative incidence of TRM was 5.6% ± 2.1% for pediatric center AYA vs 5.9% ± 1.9% for adult center AYA (P = 0.95).

• Restricted to AYA diagnosed in the late period, the pediatric vs adult 2‐year TRM was 2.3% ± 2.3% vs 3.4% ± 2.4% (P = 0.88).

Hong Kong experience of adolescents with ALL

• From 1993 to 2018: total 879 subjects recruited into ALL trials

Protocol No. of cases >12 yrs >15 yrs

ALL93 152 18 1

ALL97 171 26 7

ALL2002 169 33 13

ALL2008 221 52 22

ALL2015 128 14 5

EsPhALL 7 2 2Interfant 99 11 - -

Interfant 06 20 - -

Total No. 879 145 (16.5%) 50 (5.7%)

>12 yrs >15 yrs

No. 145 50

Age range 12.03 – 18.56 15.13 – 18.56

median 14.47 16.25

B cell 105 36

T cell 37(25%) 14 (28%)

HSCT 24 (CR1 12, >CR2 12) 11 (CR1 7, >CR2 4)

At 5 years

OS 77.9% (4) 75.3% (6)

EFS 77.1% (4) 73.2% (6)

HKPHOSG: Overall survival of patients with ALL > 12 years, or > 15 years of age

77.9%

75.3%

Factors contributing to difference in outcome• adherence to dose intensity and differences in psychosocial care.

• AYA are at higher risk of toxicity, including VCR and Asp, pediatric oncologists may be more comfortable with continuing intensive treatment and maintaining dose intensity in the face of such toxicity.

• Dose reductions of these agents may have contributed to outcome differences. In the DFCI Protocol 91‐01, patients who tolerated <25 weeks of asparaginase had a significantly inferior EFS (73% ± 7% vs 90% ± 2%; P < 0.1

• AYA have been shown to have lower rates of medication adherence as compared to younger children. Rates of 6‐MP nonadherence of >5% have been associated with a threefold increase in the risk of relapse.

• Given lower patient volumes in pediatric centers, AYA at risk of nonadherence may be more easily identified and referred to the appropriate psychosocial supports

Collaboration with pediatric oncologists• The challenge of the pediatric regimen to adult oncologists: becoming

knowledgeable and comfortable with the complexity of pediatric regimen.•

• Adult-treating oncologists benefit from the collaboration with and support of pediatric oncologists and their staff in applying a pediatric regimen, as well as from organizational modifications of their ambulatory clinics to support effective and manageable delivery of the pediatric regimen.

• Comparison of the mortality rate of pediatric and young AYA patients treated at Children’s Oncology Group (COG) vs non-COG institutions. • The mean death rates in the non-COG centers were almost twice the death rate

within 1 year after diagnosis and increasingly worse from 5 to 9 years after diagnosis. • The AYAs treated at specialty or NCI-designated cancer centers likely have improved

outcomes due to the familiarity of these centers with ALL management in this age group.

National Comprehensive Cancer Network NCCN Guidelines for AYA with ALL• Since 2012, the NCCN has recommended

• either a clinical trial or pediatric-inspired regimen for newly diagnosed Phchromosome-negative ALL in AYAs.

• In 2016, the NCCN added hyper-CVAD plus rituximab to its AYA ALL guidelines but specified that it was for CD20-positive ALL only• and that the pediatric regimens for all forms of Ph chromosome-negative ALL were

“preferred.”

• In 2017, the guidelines expanded hyper-CVAD to all Ph chromosome-negative AYAs and added a pediatric-inspired University of Southern California regimen, • with the specification that both were based on data from single institutions as

opposed to the pediatric regimens that were based on data from multi-institutional or cooperative group studies.

Bleyer A. J Natl Compr Canc Netw. 2012 Sep;10(9):1065-71, https://www.nccn.org/

New treatment

• 3rd generation TKI for Ph+ ALL

• Immunotherapy with better control and less HSCT?• Blinatumomab

• Inotuzumab ozogamicin

• CART THERAPY

Conclusions and Recommendations

• the development of protocols to address important treatment issues and subgroups in AYA with ALL is necessary

• The survival cliff and accrual cliff and other data provide the rationale to treat AYAs with newly diagnosed ALL on either a pediatric-inspired regimen or an approved national clinical trial designed for this patient group, referral to a specialized center with access to these trials should be arranged.

• Outcome should include better quality of life during and after therapy, as indicated by hospitalization time, readmission for treatment complications, and late adverse effects, such as infertility and second malignant neoplasms.

Thank you谢谢