Updates in acute lymphoblastic leukemia therapy in young adults

2. Updates in
ALL therapy
in young adults
:Presented by
Marwa Mahmoud Khalifa
Facultyof Medicine,AlexandriaUniversity

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

9. DrugsExpression
Blinatumomab,
SGN19a(denintuzumab) ,
SAR3419(Coltuximab
ravtansine) ,
Combotox
>95%CD19
Rituximab, Ofatumumab20%CD20
Epratuzumab,
Inotuzumab, Combotox,
BL22, HA22
>90%CD22
Alemtuzumab70%CD52

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)

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

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