This document summarizes recent advances in therapy for acute lymphoblastic leukemia (ALL) in young adults. It discusses how overall survival rates for ALL are much poorer in adults compared to children. Recent developments discussed include new cytotoxic agents approved for relapsed/refractory ALL, as well as antibody-based therapies targeting antigens like CD19, CD20, CD22, and CD52. Promising results are shown for therapies like inotuzumab ozogamicin, blinatumomab, and chimeric antigen receptor (CAR) T-cell therapies. CAR T-cell therapies in particular achieved high rates of remission and minimal residual disease negative complete remission in trials for relapsed/refractory ALL
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Updates in acute lymphoblastic leukemia therapy in young adults
1.
2. Updates in
ALL therapy
in young adults
:Presented by
Marwa Mahmoud Khalifa
Facultyof Medicine,AlexandriaUniversity
3.
4. Acute lymphoblastic leukemia (ALL) is the most
common malignancy diagnosed in children.
Overall survival exceeds 85%
5. :For adults
Overall survival is quite poor (30% to 40%)
CR2 rates are 50% at best.
Patients achieving CR2, remissions not sustained.
With each subsequent relapse, achieving remission is
harder and long-term survival is extremely poor.
Maude et al. American Society of Hematology.2015;125 :4017-23
6. Refractory ALL is also challenging, with long-term
survival close to 30%.
A variety of treatment regimens have been developed
for R/R ALL with remission rates ~ 30%.
Maude et al. American Society of Hematology.2015;125 :4017-23
7. Three recent cytotoxic agents have been
approved for patients with R/R ALL, clofarabine,
nelarabine, and liposomal–vincristine,
demonstrating respective CR rates in adult
patients of 17%, 31%, and 20%.
Daniel J. DeAngelo. American Society of Hematology.2015; 400-5
8. Recent advances in treatment in ALL
Recent years have seen a surge in antibody-based therapies
for B-ALL, primarily targeted against CD19, CD20, CD22,
andCD52.
Another strategy involves the use of chimeric antigen
receptor (CAR) T cells with promising results in R/R setting.
Jabbour E. Blood. 2015; 125: 4010-4016
DeAngelo D. American Society of Hematology. 2015:400-5
10. Wei et al. Journal of Hematology & Oncology (2017) 10:150
11. Rituximab
Chimeric anti-CD20 antibody
One of the first monoclonal antibodies that was
evaluated in combination with chemotherapy for
patients with B -ALL.
Wei et al. Journal of Hematology & Oncology (2017) 10:150
N Papadantonakis. Ther Adv Hematol. 2016, Vol. 7(5) 252–69
12. MD Anderson Cancer Center
97 patients with de novo CD20-positive ,
Ph -ve B-ALL treated with 8 doses of
rituximab (375 mg/m2/dose) combined with
hyper-CVAD
improved 3-year CRD
lower relapse rate
improved OS in patients <60 years
Wei et al. Journal of Hematology & Oncology (2017) 10:150
N Papadantonakis. Ther Adv Hematol. 2016, Vol. 7(5) 252–69
13. German ALL study group
263 patients CD20-positive B- ALL patients
(15-55 years) received 8 doses of rituximab with
chemotherapy during induction and consolidation.
no improvement in the CR rate
MRD-negative status higher in patients who
received rituximab
improvement in the 3-year CRD and OS rates
Wei et al. Journal of Hematology & Oncology (2017) 10:150
N Papadantonakis. Ther Adv Hematol. 2016, Vol. 7(5) 252–69
14. Ofatumumab
Humanized, anti-CD20 antibody
Ofatumumab combined with hyper-CVAD
in 25 adult patients with de novo ALL
CD20-positive
CR and MRD-negative rate both 96% ,
1-year DFS and OS are 94% and 92%
Wei et al. Journal of Hematology & Oncology (2017) 10:150
N Papadantonakis. Ther Adv Hematol. 2016, Vol. 7(5) 252–69
15. Blinatumomab
Bispecific monoclonal antibody that enables
CD3-positive T cells to recognize and
eliminate CD19-positive ALL blasts
Kantarjian H. N Engl J Med 2017; 376(9) 836-47
16. Kantarjian H. N Engl J Med 2017; 376(9) 836-47
Randomized
phase 3 trial
Open-label
Adults (≥18 years)
Ph-negative R/R B-ALL
Secondary end points : CR, EFS, DCR, MRD remission
Primary end point OS
treatment with either
blinatumomab (n =271) or
standard chemotherapy (n =134)
17.
18. Inotuzumab Ozogamicin
A monoclonal antibody (mAb) targeting CD22,
linked to a cytotoxic agent.
On binding to the CD22 antigen on malignant
B – cells, it is absorbed into the cell, at which
the cytotoxic agent calicheamicin is released
to destroy the cell.
Kantarjian HM et al. N Engl J Med.2016; 375(8) 740-53
19. INO-VATE trial
Open-label, randomized, phase 3 trial
Patients ≥ 18years
R/R, CD22-positive, (Ph)–positive or –negative
ALL
Kantarjian HM et al. N Engl J Med.2016; 375(8) 740-53
inotuzumab ozogamicin
(0.8 mg on day 1 of each
cycle and 0.5 mg on days 8
and 15 for up to 6 cycles)
The investigator’s
choice of standard
therapy
20. INO-VATE trial cont.
Primary end points were CR & OS
Secondary end points included safety
measures, duration of remission,
progression-free survival and rate of
subsequent stem-cell transplantation
Kantarjian HM et al. N Engl J Med.2016; 375(8) 740-53
21.
22.
23. Epratuzumab
Humanized anti-CD22 antibody
Southwest Oncology Group evaluated
epratuzumab combined with clofarabine plus
cytarabine in 31 relapsed adult patients
response rate (52%) significantly higher than
clofarabine/cytarabine alone (17%)
Wei et al. Journal of Hematology & Oncology (2017) 10:150
N Papadantonakis. Ther Adv Hematol. 2016, Vol. 7(5) 252–69
24. Alemtuzumab
Alemtuzumab is a fully humanized
monoclonal antibody against CD52
CD52, an antigen involved in T cell activation,
is expressed in 70% of T ALL and pre-B ALL.
In a phase I trial, 24 pts with de novo ALL in
CR1 (Median age was 37 years) median
OS was 55 months and DFS was 53 months
Wei et al. Journal of Hematology & Oncology (2017) 10:150
N Papadantonakis. Ther Adv Hematol. 2016, Vol. 7(5) 252–69
25. CAR-T cells
(Chimeric Antigen Receptor-T cells)
Genetically modified autologous T lymphocytes
collected by apheresis, engineered to express
an antigen binding domain.
In ALL, the majority of CAR-T constructs have
used a CD-19 antibody to target CD-19
expressing cells.
Maude et al. American Society of Hematology.2015;125 :4017-23
N Papadantonakis. Ther Adv Hematol. 2016, Vol. 7(5) 252–69
Wei et al. Journal of Hematology & Oncology (2017) 10:150
26. Maude et al. American Society of Hematology.2015;125 :4017-23
27. OSMRD (-)CRPatients
76%83%84%
44 adults with
R/R ALL
including Ph(+)
Memorial Sloan
Kettering
Cancer Center
78%94%94%
53 children and
young adults
with R/R ALL
University of
Pennsylvania
34.7 %90 %60.8 %
51 children and
young adults
with R/R ALL
National
Cancer
Institute
Wei et al. Journal of Hematology & Oncology (2017) 10:150
28. Side effects
Cytokine release syndrome (CRS)
Neurotoxicities
B cell aplasia.
Immunomodulation (steroids and/or tocilizumab)
decreases the rates of severe CRS while preserving
high rates of MRD-negative CR
Kansagra A et al. Curr Hematol Malig Rep (2017) 12:187–196
Maude et al. American Society of Hematology.2015;125 :4017-23