Advances in induction in Acute Lymphocytic Leukemia

RAYMONDWONG, MD
Hong Kong
• Consultant of the Department of Medicine & Therapeutics,
Prince of Wales Hospital
• Dr. Wong received his medical degree from the Chinese
University of Hong Kong and received his training in
Haematology, Internal Medicine as well as Clinical
Pharmacology and Therapeutics at the Prince of Wales
Hospital, Hong Kong. He also obtained his Doctor of Medicine
from the Chinese University of Hong Kong. He joined the
Prince of Wales Hospital Poison Treatment Centre since its
establishment in 2005 which is a tertiary referral centre for
the management of patients with poisoning. Dr. Wong has
published over 70 articles in peer-reviewed journals including
Blood, Circulation, JAMA and the New England Journal of
Medicine in various areas of haematology and therapeutics.

Acute Lymphocytic Leukemia: Best of 2014
Advances in Induction in ALL
Dr. Raymond Wong
Department of Medicine & Therapeutics
The Chinese University of Hong Kong
BTG 2015

Induction for ALL
• Cytotoxic chemotherapy regimens are currently the
standard of care in the induction phase of treatment
for adult ALL
• Several regimens are in use but none has been proven
more efficacious than the others in clinical trials
• Regardless of the induction regimen employed,
achieving CR prior to post-remission maintenance
therapy is highly predictive of OS

Induction for ALL
• During the past 20 years, development of risk-stratified,
multi-agent, multi-phase treatment regimens for pediatric
ALL patients has resulted in >95% patients achieving CR,
and 5-year EFS >80%
• Therapeutic regimens for adults with ALL has been less
effective, achieving OS of < 50%
• In the past decade, studies have shown that older
adolescents and young adults (aged 16-21 years) treated
with pediatric ALL regimens achieved improved outcomes

• A multicenter, phase 2 trial to assess the feasibility of treating
newly diagnosed ALL with the Dana-Farber Cancer Institute
(DFCI) Pediatric ALL Consortium regimen
• Between 2002 and 2008, 92 eligible patients aged 18–50 years
were enrolled at 13 participating centers
DeAngelo DJ, et al. Leukemia 2014

Patient demographics and disease characteristics

Therapy on DFCI Adult ALL Consortium
Protocol01–175

Results
• 78 patients
(85%)
achieved a CR
after 1 month
of intensive
induction
therapy

Results
• With a median follow-up of 4.5 years, 4-year DFS for the
patients achieving a CR was 69% (95% CI 56–78%)
• 4-year OS for all eligible patients was 67% (95% CI 56–76%)
OS PFS

Results
• The 4-year DFS for the 64 patients who achieved a CR and were
Ph−ve was 71% (95% CI, 58–81%)
• For all 74 Ph−ve patients the 4-year OS was 70% (95% CI 58–
79%)

Toxicity

Toxicity
• 72% of the patients who initiated the 30-week asparaginase
course were able to receive ≥ 26 doses (87% of targeted therapy),
similar to, although slightly lower than the proportion of
pediatric patients.
• The incidence of major asparaginase-related toxicities, such as
pancreatitis, and thrombosis was also similar to that reported in
older children

A pediatric-like treatment strategy for young adults
with de novo ALL is feasible, associated with tolerable
toxicity, and results in improved outcomes compared
with historical regimens in young adult patients with
ALL

IntensifiedChemotherapyfor Older Patientswith ALL
A phase II study from the DFCI ALL Consortium
• To determine the efficacy in patients 51-75 years old
with newly diagnosed ALL or lymphoblastic lymphoma
• Based on the DFCI ALL Consortium pediatric regimen:
• incorporation of clofarabine in consolidation
• adjustment to dose and scheduling of PEG asparaginase and
steroids
• prednisolone x 21 days for patients < 60 years old
• prednisolone x 7 days for patients ≥ 60 years old
• inclusion of stem cell transplant (SCT) for eligible patients
after induction and 1st consolidation
Fathi A T et al. Blood 2014;124:3714

• 30 patients enrolled, 29 evaluable
Status N (%)
Achieved CR 19 (66%)
Relapsed after remission 9
Undergone SCT 9
Refractory to induction therapy 3 (10%)
Discontinued treatment during induction due to toxicity 4 (14%)

• OS (by Kaplan-Meier) at 1 year = 62% (95% CI, 41-77%)

For evaluable patients with at
least 1 year of follow-up:
• Proportion surviving at 1
year = 16/26 = 61%
• Significantly higher than the
historical rate (33%)
OS for Ph+ and Ph- groups

• Most common grade 3/4 toxicities:
• transaminitis
• hyperbilirubinemia
• cytopenias
• hypophosphatemia
• hyperglycemia
• neutropenic fever
• liver injury  reduction of PEG-asparaginase dosage
• The data suggest that intensive multi-agent chemotherapy is
tolerable in older patients with ALL and can result in
improved outcomes when compared to historical data

Asparaginase in ALL
• An enzyme that deamidases serum asparagine,
depleting it from ALL lymphoblasts
• Several large randomized pediatric ALL trials reported
that higher cumulative doses of asparaginase result in
significantly improved outcomes
• In contrast, large adult ALL clinical trials generally
involve no asparaginase or use it in only one to two
post-remission cycles, considering its potential higher
toxicity

• To study a pegaspargase dosing strategy based on its
pharmacokinetic characteristics in adults aged 18 to 57 years with
newly diagnosed ALL treated with the adult ALL BFM protocol and
included 6 doses of IV pegaspargase at 2,000 IU/m2 per dose
• Intervals between doses were longer than 4 weeks and rationally
synchronized with other chemotherapy drugs to prevent overlapping
toxicities
Douver D, et al. JCO 2014

Patient Demographic and Clinical Characteristics
Douver D, et
al. JCO 2014

Results
Minimal enzymatic activity of 0.2 IU/mL for complete asparagine deamidation

Results
• 49/51 patients (96%) achieved CR, 2 had resistant disease
• CR was achieved in 48 patients (98%) after induction phase 1
(at 4 weeks)
• Among the 40 Ph-negative patients, 39 (98%) achieved CR, all
by 4 weeks
All patients (N=51) Ph-ve ALL (N = 40)
7-year OS 51% 58%
7-year DFS 58% 58%

Asparaginase-Related Toxicity
• 23 patients (45%)
received all 6
pegaspargase doses
received ≥3 doses
discontinued
pegaspargase after
prohibitive toxicity
• pancreatitis
• severe allergy

Ph+ ALL
• Until recently, Ph+ ALL was associated with a poor
prognosis (5-year OS, 10%–20%), with the greatest
hope for success via allogeneic HSCT
• Combination of cytotoxic chemotherapy with TKIs is
effective in the treatment of Ph+ ALL
• Imatinib and dasatinib have been approved for use in
Ph+ ALL

Phase II Study of Combinationof Hyper-CVAD+
Ponatinib in Frontline Therapy of Ph+ ALL
• Patients with newly diagnosed Ph+ ALL received 8
cycles of hyper-CVAD alternating with high dose MTX
and cytarabine every 21 days
• Ponatinib was given at 45mg daily po for days 1-14 of
cycle 1 then continuously for cycle 2-8
• Patients in CR received maintenance with ponatinib
45mg daily, vincristine and prednisolone monthly for 2
years followed by ponatinib indefinitely
Jabbour E, et al. Blood 2014;124:2289

• 34 patients with untreated Ph+ ALL and 3 patients
treated with 1 previous course received a median of 6
cycles (range 2-8)
• 10 patients are receiving maintenance in CR
• 3 patents have completed maintenance and are
receiving TKI alone

• All patients (N = 37) achieved CR after cycle 1
• 32 patients with cytogenetic analysis at baseline
• 30 (94%) achieved CCyR after 1 cycle
• 1 had mCyR
• 1 had no CG analysis at CR
• 35 patients (95%) achieved MMR and 26 (70%) CMR
• Median time to MMR and CMR were 3 and 10 week
• MRD is negative in 35/36 evaluable patients (97%)
• 9 (24%) received allo-BMT after a median of 4 cycles

Grade ≥ 3 toxicity N (%)
Infections during induction 18 (49%)
Increased LFT 12 (32%)
Thrombotic events 3 (8%)
Myocardial infarction 3 (8%)
Skin rash 4 (11%)
Pancreatitis 6 (16%)

• With a median FU of 18 months (9 - 31), 31 patients
are alive
• Causes of death:
• unrelated cardiac event after off therapy and was on imatinib
• multi-organ failure (C2D13)
• NSTEMI (CsD41)
• potential MI (C4D42)
• head injury sustained after a fall (C4D13)
• sepsis post allo-BMT

• At the last follow-up,
• 8 patients (19%) are alive post allo-BMT
• 14 patients on ponatinib 15mg daily
• 1 patient on ponatinib 30mg daily
• 7 patients were switched to dasatinib
• 2 patient were switched to imatinib/nilotinib (1 each)
• 1 year PFS and OS were 96% and 86% respectively
• The combination of hyperCVAD with ponatinib is
highly effective in patients with Ph+ ALL
Jabbou E, et al. Blood 2014;124:2289

Potential targeted agents for ALL
Mackenzie A et al. Blood and Lymphatic Cancer: Targets and Therapy 2012

• Phase 1 study with 2 parts: decitabine alone or in combination
with Hyper-CVAD
• Decitabine was given IV at doses of 10–120 mg/m2 per day for
5 days
Benton CB, et al. BJH 2014

Decitabine +/- Hyper-CVAD

• Decitabine was tolerated at all doses administered
• Grade 3 or 4 toxic effects included non-life-
threatening hepatotoxicity and hyperglycemia.
• Induction of DNA hypomethylation was observed at
doses of decitabine up to 80 mg/m2
• Decitabine +/- Hyper-CVAD is safe and has clinical
activity in patients with advanced ALL

• To investigate the tolerability and efficacy of decitabine and
vorinostat plus chemotherapy in relapse/refractory ALL
Burke MJ, et al. 2014

Patient Characteristics
• Median age = 16 (range, 3–54) years
• All patients had a prior BM relapse, with 5 relapsing after
allogeneic transplant

Response
• Of the 13 eligible patients
• 4 (31%) achieved CR without platelet recovery (CRp)
• 2 (15%) partial response (PR)
• 1 (8%) stable disease (SD)
• 1 (8%) progressive disease (PD)
• 2 (15%) deaths on study
• 3 (23%) did not have end of therapy evaluations
• Overall response rate = 46.2% (CRp + PR)

Response

Results
• The most common
non-hematological
toxicities possibly
related to decitabine
or vorinostat were:
• infection with
neutropenia (grade 3;
n = 4)
• fever/neutropenia
(grade 3, n = 4; grade
4, n= 1)

• Decitabine and vorinostat followed by re-induction
chemotherapy was tolerable and demonstrated
clinical benefit in relapsed patients with ALL
• Methylation differences were identified between
responders and non-responders indicating inter-
patient variation, which could impact clinical outcome

Summary
• New approaches are needed to improve the cure rate for
adult patients with ALL
• Pediatric-inspired regimens have been shown to be
feasible with promising results in older patients but more
clinical trials are needed to confirm their benefits and
toxicities
• Improved understanding of the molecular pathways,
development of more precisely targeted agents and
incorporation of these novel agents into frontline
induction therapy may further improve the outcomes

Advances in induction in Acute Lymphocytic Leukemia

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