This presentation contains all the updated information regarding ongoing treatment protocol, HSCT, Antibiotic prophylaxis, upcoming targeted therapies related to AML

1. WELCOME TO SEMINAR
Presenters:
DR. RENESHA ISLAM
YEAR-4 RESIDENT (PHASE-B)
PAEDIATRIC HAEMATOLOGY & ONCOLOGY

2. 2
Case Scenerio
Shamim, 8years old boy is a
diagnosed case of AML now
receiving chemotherapy. His
uncle lives in abroad & during
counselling period, he shared his
views about treatment options in
abroad & asked us about the
availability of those options in
here.

3. Update
in management of
Acute Myeloid Leukaemia
3

4. Introduction
▧ Pediatric Acute Myeloid Leukemia (AML) is a
heterogeneous disease, accounts for approx. 20% of acute
leukemia cases in children & adolescents. It generally has
poor outcomes compared to childhood lymphoid leukemia.
▧ Decades of coordinated efforts through cooperative group
trials have improved our understanding of the unique
biology underlying pediatric AML & patient outcomes.
However, relapse remains frequent with limited available
treatment options.
4

5. Causes of Suboptimal Outcome
▧ Relapse rate:
5

6. Worldwide data
Complete remission
(CR) rates are high in
pediatric AML at
approx. 90%.
6
Event-free survival
(EFS) at 45% at 3
years.
Overall survival
(OS) suboptimal at
65%, at 3 years.
BSMMU PHO
2019-Till now: 88
patients.

7. Causes of Suboptimal Outcome
▧ Relapse rate: Higher. Nearly half of children will relapse.
Even in the low-risk genetic groups, relapse remains
common at up to 35%.
▧ Poor genetic features: children at the highest risk of relapse
related to poor genetic features have dismal outcomes
altogether and continue to require stem cell transplant
(SCT) to achieve cure, with only one in three surviving at 3
years.
7

8. Causes of Suboptimal Outcome
▧ Higher chance of infection.
▧ Slower advancement:
Due to a lack of drugs developed specifically for the pediatric
population and the challenges of evaluating novel agents for a
relatively rare disease.
▧ High intensity chemotherapy related:
-Short term & long term organ dysfunction.
8

9. Genetic risk classification
▧ Favorable risk genetics:
- t (8;21)
- Inv (16)
- CEBPA
- NPM1
9
▧ Non favorable/High risk
genetics:
- Monosomy 7
- Monosomy 5 or 5q deletions

10. 10

11. Updates in current/
ongoing therapy

12. Recent approaches
▧ The most recent Medical Research Council (MRC) trial
evaluated the addition of etoposide to Daunorubicin and
Cytarabine and reported no improvement in outcome for
patients randomized to receive Etoposide. Based on these
data, Etoposide will be removed from standard therapy in
the COG AAML1831 trial.
▧ New formulation of Liposomal Daunorubcin & Cytarabine
(CPX-351) provides a new hope.
12

13. Recent approaches
▧ The necessary number of consolidation cycles remains
unidentified till now. But most cooperative groups provide
an additional two to three cycles of intensive chemotherapy
to give a total of 3-5 cycles of chemotherapy.
▧ Although recent trials from the Japanese cooperative group
and MRC both demonstrated no change in survival with an
additional cycle of chemotherapy and the COG AAML1031
trial saw inferior outcomes for patients treated with 4 cycles
when compared with 5 on the prior trial.
13

14. 14
Recent approach to
prophylaxis

15. Recent approach to prophylaxis
▧ Anti-Bacterial prophylaxis: Levofloxacin. No to Oral
cephalosporins.
▧ Anti-Fungal prophylaxis: Fluconazole. Itraconazole,
Posaconazole, Liposomal amphotericin B for anti-mold
activity.
▧ Prophylaxis against P. jirovecii: Trimethoprim +
Sulphmethoxazole.
15

16. Recent approach to prophylaxis
▧ Anti-Viral prophylaxis: Acyclovir (Recurrent herpes simplex
reactivations).
▧ Vaccination: Influenza vaccination is recommended for
family members of pediatric AML patients.
▧ G-CSF has not been shown to influence the risk of
infectious complications or mortality in pediatric AML so its
routine use cannot be recommended.
16

17. Recent approach to Supportive care
▧ An exception may be made for AML of G-CSF patients with
sepsis and hemodynamic compromise.
▧ To mitigate Anthracycline related cardiotoxicity: Cardio
protective benefit of Dexrazoxane in pediatric AML without
a signal for increased relapse or toxicity, Dexrazoxane will
be incorporated as the standard of care in the next phase
III COG clinical trial.
17

18. Newer
treatment options

19. Newer Treatment Option
19
Epigenetic
modifiers
Novel
metabolic
pathway
inhibition
Immune
based
therapy
Others:
Such as
antagonist

20. Immune based therapy
▧ Drug-Antibody conjugates
▧ Chimeric antigen receptor T cell
Drug-Antibody conjugates
Regarded as targeted therapy which exploits cell surface
markers unique to cancer cells has been a significant
therapeutic advance in cancer treatment. In drug-antibody
conjugates, antibody targeting can deliver a drug, such as the
small molecule calicheamicin, directly to cells of interest.
20

21. 21

22. Gemtuzumab ozogamicin (GO)
▧ Here Calicheamicin is conjugated to an anti-CD33 antibody
& has potent antitumor effects on CD33-expressing cells,
found in a majority of AML cases.
▧ Lower doses can produce similar outcomes with less
treatment-related mortality.
▧ In both relapsed & upfront therapies, it improved EFS and
reduced relapse risk.
22

23. Gemtuzumab ozogamicin (GO)
▧ To maximize benefit while limiting toxicity by giving GO as
a single dose in induction, as this has been shown to have
the highest benefit & may reduce toxicity profiles.
▧ Children more likely to benefit from GO therapy include
those with FLT3-ITD mutations, KMT2A rearrangements,
single-nucleotide polymorphisms in ABCB1 and CD33, and
high CD33 expression,
23

24. Drug antibody conjugates
▧ Flotetuzumab:
-CD123/CD3 bi-specific dual-affinity retargeting antibody.
-Phase I trials for relapse/refractory AML.
 Nivolumab, Ipilimumab, Pembrolizumab:
-Anti-PD-1 antibody/checkpoint inhibitor.
-Phase I/II trials for relapse & refractory AML combined with
Azacitidine.
24

25. Chimeric antigen receptor T cell
▧ CD33 and CD123 are expressed in 90% & 75% of AML,
respectively, with less than 5% of cases being -ve for both.
▧ Due to concerns for on-target off-tumor effects, Both CD33
and CD123 directed CAR-T trials are currently underway in
pediatric studies for relapsed/refractory AML.
▧ Elzonris, Stemline gained FDA approval & currently under
COG trial both for monotherapy & in combination with
chemotherapy in pediatric patients(>2y).
25

26. 26

27. 27

28. Chimeric antigen receptor T cell
▧ CD123-targeting CAR-T:
-T cells genetically modified to target/kill CD123
expressing AML cells.
-Phase I trials for relapse & refractory AML.
▧ CD33-targeting CAR-T:
-T cells genetically modified to target/kill CD33 expressing
AML cell.
-Phase I trials for relapse & refractory AML.
28

29. Epigenetic modifiers
29
▧ The prevalence of epigenetic dysregulation in AML
development has led to a rising interest in targeting
epigenetic modifiers as part of therapy.
▧ Hypomethylating Agents
▧ Histone deacetylases (HDAC) inhibitors
▧ Utilized azacitidine (HMA) in combination with fludarabine
and cytarabine chemotherapy and achieved CR in 7/12
children with relapsed or refractory AML.

30. 30

31. HMA agents: Inhibits DNA methyl transferases
▧ Decitabine:
-Completed phase I trial for relapse/refractory AML.
Ongoing phase II trial with standard chemotherapy in
newly diagnosed AML.
▧ Azacitidine:
-Phase I/II trials for relapse/refractory AML.
-Phase II trial with standard chemotherapy in newly
diagnosed AML.
31

32. 32

33. HDAC inhibitors
▧ Vorinostat, Panobinostat:
-Inhibits histone deacetylase.
-Phase I trial for relapse & refractory AML.
▧ The effects of HDAC inhibitors are maximized when given
with other drugs such as HMAs & can be safely combined
with other agents in relapse regimens.
▧ Currently being investigated in relapsed pediatric AML.
33

34. Novel metabolic pathway inhibitors
▧ FLT3 Inhibitors
▧ BCL-2 Inhibitors
▧ Oxidative Phosphorylation Inhibitors
▧ Check point inhibitors
34

35. FLT3 inhibitors
▧ FLT3-mutated AML has been a specific disease subset of
interest due to the targetable nature of tyrosine kinases.
▧ There are at least 8 FLT3 inhibitors currently on the market
or under development, such as-
-Sorafenib
-Midostaurin
-Gilteritinib
-Quizartinib
-Crenolanib
35

36. 36

37. FLT3 inhibitors
▧ Midostaurin
-1st generation type I TKI
-Active against FLT3 and KIT mutations
-International: Phase II trials (Ongoing)
-blast percentages in relapsed/refractory AML when used as
a single agent regardless of FLT3 mutation status.
-Study demonstrated that standard chemotherapy (plus SCT)
plus Midostaurin prolonged survival & relapse risk compared
to chemotherapy & SCT alone.
37

38. FLT3 inhibitors
▧ Sorafenib
-1st-generation type II TKI
-Active against FLT3-ITD and FLT3-TKD mutations
-Completed phase III trials for high AR FLT3-ITD AML
-Preliminary results demonstrate that its addition, CR & EFS
& relapse risk in children with high AR FLT3-ITD.
▧ Quizartinib:
-2nd generation Type II TKI
-Phase I/II trials in relapse/refractory AML.
38

39. FLT3 inhibitors
▧ Gilteritinib:
-2nd generation type I TKI: active against FLT3 and AXL
-Study shows significantly prolonged survival when given as
monotherapy & combination with either azacitidine or
cytarabine & anthracyclines further potentiated anti-leukemic
effects.
▧ Crenolanib:
-Type I TKI
-Completed phase I trial in relapse/refractory leukemias.
39

40. BCL-2 inhibition
▧ BCL-2, an anti-apoptotic protein whose overexpression is a
mechanism of resistance in AML.
▧ Venetoclax:
-Initial studies demonstrated a CR of 70% when used in
combination with cytarabine with or without idarubicin.
-Preclinical studies also suggest that it works synergistically
with FLT3 inhibitors Midostaurin & Gilteritinib to induce
apoptosis in AML cells, and may provide another therapeutic
Avenue.
40

41. Oxidative Phosphorylation Inhibitors
▧ Atovaquone:
-Antibacterial and antimalarial medication.
-Mechanism of action:
-Phase I trial with standard chemotherapy & Pneumocystis
jiroveci prophylaxis.
41
..Inhibits oxidative phosphorylation
..Inhibiting STAT3 phosphorylation &
subsequent expression of STAT3 target genes
..induces apoptosis in AML cells
Prolonged
survival

42. Oxidative Phosphorylation Inhibitors
▧ Other agents:
-Metformin and lonidamine
-Identified as oxidative phosphorylation inhibitors with
anti-tumor effects in vitro.
42

43. E-Selectin inhibitors
▧ Majority of primary AML blasts express E-selectin ligand,
with increased expression in relapsed patients.
▧ Higher expression of E-selectin associated with relapsed
disease correlates with poor survival and high-risk disease in
AML.
▧ Study shows those with high expression of E-selectin ligand
demonstrated greater inhibition by Uproleselan and
significantly longer overall survival.
43

44. 44

45. Others: MDM2 antagonist
▧ Inactivation of wild-type p53 occurs in a majority of AML.
▧ Multiple mechanisms exist for the inactivation of p53. The
best-studied mechanism is by an overexpression of MDM2
(murine double minute 2).
▧ Its overexpression is reported in up to 50% of AML & in
addition, the overexpression of MDM2 is also associated
with shorter CR duration and event-free survival.
45

46. 46

47. MDM2 antagonist
▧ Idasanutlin:
-A second-generation Nutlin.
-More potency and less toxicity than early generation Nutlins.
-Study shows high anti-leukemic activity of Idasanutlin as a
single agent.
▧ Aileron:
-A dual MDM2/MDMX inhibitor.
-Ongoing Phase 1 trial in combination with Cytarabine.
47

48. Others: Targeting mutant TP53
▧ The most frequent genetic variation across all human
cancers is mutation of the tumor suppressor gene TP53.
▧ Despite its infrequent occurrence in pediatric population, it
is still associated with therapy-related myelodysplastic
syndrome (MDS)/AML, relapsed AML, & poor survival.
▧ Aprea Therapeutics (APR)-246, a methylated, small-
molecule derivative of PRIMA-1 (p53 re-activation and
induction of massive apoptosis) shows new hope.
48

49. 49

50. 50
Update of
HSCT in AML

51. Update of HSCT in AML
▧ Better overall and event free survival for those who
underwent blood and marrow transplant as a consolidation
therapy.
51
Stem Cell Transplantation (SCT) in Pediatric AML
Reporting 8 Years of Data From a CIBMTR Member
Centre, King Faisal Specialist Hospital and Research
Centre, Riaydh, Saudi Arabia.

52. Update of HSCT in AML
▧ Patients with favorable-risk AML are currently only offered
HSCT in second clinical remission.
▧ In contrast, patients with high-risk AML are nearly always
offered HSCT as consolidative therapy.
52
Impact of disease risk on efficacy of matched related
bone marrow transplantation for pediatric acute
myeloid leukemia: the Children’s Oncology Group.

53. Update of HSCT in AML: Definition of HR group
▧ Patients with complex cytogenetics
▧ Monosomy 7
▧ Monosomy 5
▧ Del (5)
▧ High allelic ratio FMS-like tyrosine kinase 3 (FLT3)/internal
tandem duplication (ITD) without good prognosis modifiers
▧ Those with poor response to induction therapy.
53
The role of matched sibling donor allogeneic SCT in pediatric
high-risk AML: results from the AML-BFM 98 study.

54. Take home message
▧ The outcomes in pediatric AML, while improved in recent
decades, remain suboptimal with high rates of relapse & few
options for therapy when initial treatment regimens fail.
▧ Genetic risk grouping has gone a long way to target the
intensity of therapy to those at the highest risk of relapse
and death.
▧ However, the heterogeneous nature of AML has left many
high risk genetic features unidentified until recently.
54

55. Take home message
▧ Additionally, challenges surrounding attainment of an MRD
negative complete remission using traditional
chemotherapy may limit the utility of this approach and
continue to highlight the need for additional treatment
options for such patients.
▧ Through ongoing collaboration, innovation, treatment
strategies will become more tailored to the underlying
genetics of the disease with resultant improvements in
outcome.
55

56. Thanks!
56