WELCOME TO JOURNAL CLUB

Presented by 

Dr. Mim Zarrine Tasnime 

Phase B Resident, Haematology

Objective 

• To know pros & cons of the targeted therapies that we used in AML 

SUMMARY

• AML is an aggressive hematologic malignancy often characterized by specific genomic alterations.
• Cytogenetic and molecular aberrations are the most important factors in determining response to chemotherapy as well as long-term outcome.
• Molecular-targeted therapy has had a significant impact on clinical practice, especially for patients with specific genomic abnormalities.

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OVERVIEW OF CURRENTLY APPROVED DRUGS IN AML

This Photo by Unknown author is licensed under CC BY-NC.

Mechanism of action of the approved targeted therapies

Arsenic trioxide 

INDICATION

Targeting PML/rara

Adverse effect

• Associated with a higher frequency of grade 3 or 4 hepatic toxicity
• Differentiation syndrome.
• QT Prolongation in ECG
• Neuropathy.

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OUTCOME 

• CR rate: 92% 
• 2-year EFS rate of 97 vs 86% 

(P = 002);

CIR after 50 months 19% after ATO/ATRA vs 13.9% after CTX + ATRA.

Gemtuzumab ozagamicin

• Anti-CD33 monoclonal antibody conjugated with calicheamicin.
• A  highly cytotoxic antibiotic.
• Recommended Dose : 
•  During induction :3 mg/m2 (capped at one vial) on days 1, 4, 7 with DA 3+7
• During consolidation :3mg/m2 on day 1 with cytarabine 1mg/m2 12 hourly over 2 hours from day 1 to 4.
• Should not be given during second induction therapy

indication

• Newly diagnosed CD33+ adult AML in combination with CTX (7 + 3)
• Relapsed/refractory CD33 + adult AML 
• Paediatric patients ≥2 years
• High risk APL along with ATO-ATRA

outcome

• Newly diagnosed: CTX (7 + 3)+ GO vs CTX alone: median EFS 156 vs 97 months (HR: 0.58; P = 0.0003)
• GO vs BSC: median OS 49 vs 3.6 months (HR: 0.69; P = 0.005)
• Relapsed/refractory: ORR 33.3%, CR rate 26.3%; median OS 8.4 months

Cpx-351

• Newly diagnosed t-AML or AML-MRC
• Liposomal cytarabine and daunorubicin at a fixed 5:1 molar ratio.
• More effective delivery to the malignant cells while sparing cardiac and other  non-hematopoietic tissues.
• Enhancing efficacy and reducing toxicity.

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Targeting flt3 mutation

MIDOSTAURIN

• Approved oral TKI. 
• Recommended dose :
• Both during induction & consolidation : 50 mg twice daily on days 8–21.
• After CR as single agent maintenance therapy 50mg twice daily until relapse for up to 12 cycles of  28 days each.
•  In patients receiving an Allo-HCT, midostaurin should be discontinued 48 h prior to the conditioning regimen.

indication

• Newly diagnosed FLT3-ITD or FLT3-TKDmutated AML in combination with standard CTX (7 + 3)
• Single-agent maintenance after intensive CTX (EMA only)

Adverse effect 

• febrile neutropenia,
• nausea, 
• exfoliative dermatitis, 
• vomiting, 
• headache,
• petechiae, and 
• pyrexia. 

outcome

• CTX (induction: 7 + 3, consolidation: HiDAC) + midostaurin vs CTX alone: median OS 74.7 vs 25.6 months (HR: 0.78; P = 0.009)

Gilteritinib

• It  is a novel, highly selective, potent oral FLT3 inhibitor with activity against ITD and TKD mutations.
• Most common adverse effect Differentiation syndrome.
• Used in Relapsed/refractory FLT3-ITD or TKD mutated AML

Targeting idh1 & idh2 mutation

IVOSIDENIB

• Indication:
• Newly diagnosed IDH1 mutated AML patients ≥75 years or ineligible for intensive CTX or 
• Relapsed/refractory IDH1 mutated AML.
• Recommended dose : 500mg daily orally in 28-day cycles.

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Adverse effect

• prolongation of the QT interval
•  DS
• Anaemia , thrombocytopenia 
•  Leukocytosis

ENASIDENIB

• Used in Relapsed/refractory IDH2 mutated AML.
• Recommended dose: 100 mg orally once daily until disease progression or unacceptable toxicity.
• Adverse effect :
• Grade 3/4 hyperbilirubinemia
• IDH-inhibitor-associated DS

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Targeting Anti-Apoptotic BCL-2

BCL-2 family regulates the mitochondrial apoptotic

pathway by controlling mitochondrial outer membrane permeabilization (MOMP)

and the release of cytochrome c

VENETOCLAX

• Indication : Newly diagnosed AML in patients ≥75 years or ineligible for intensive CTX in combination with + HMA or LDAC
• Dose : 400mg/daily day 1 to day 28 + Azacitidine 75 mg/m2 subcutaneously or intravenously on days 1 through 7 every 28-day cycle.
• It is BCL-2 Inhibitor

Adverse effect

• Nausea
• thrombocytopenia  
• neutropenia
• febrile neutropenia 

Outcome 

• Azacitidine + venetoclax vs
• azacitidine alone: median OS 14.7
• vs 9.6 months (HR: 0.66;
• P < 0.001)

Glasdegrib 

• Indication : Newly diagnosed AML in patients ≥75 years or ineligible for intensive CTX in combination with LDAC.
• Dose : 100mg once daily + DA 3+7 or Azacitidine.
• It is a selective small-molecule inhibitor which binds to the smoothened receptor, thereby regulating the Hedgehog pathway, which plays critical signaling roles in embryogenesis and stem cell maintenance.

Oral Azacitidine CC-486

• Oral formulation of Azacitidine.
• Indication : Maintenance, patients in CR/CRi post intensive CTX
• Dose : 300mg oncer daily for 14 days per 28-day cycle.
• Assessment of remission status on the basis of bone marrow and peripheral blood examination was performed every three cycles during the first 24 cycles, at cycles 30 and 36, and as clinically indicated.

Adverse effect

• Gastrointestinal symptoms, which were controllable with antiemetics and antidiarrhoeal agents, and 
• Neutropenia  manageable with haematopoietic growth factors support.

Outcome 

• CC-486 vs placebo: median OS 24.7 vs 14.8 months (P < 0.001)

Future directions

• Currently, there are clinical trials ongoing 
• Evaluating triple combinations of venetoclax + HMAs and IDH inhibitors or other investigational products.
• Evaluating venetoclax and intensive chemotherapy in younger newly diagnosed AML patients, e.g. FLAG-IDA  or cladribine/idarubicine cytarabine are ongoing and preliminary results are promising with a composite CR rate of 90% including a MRD negativity rate by flow cytometry of 96%.

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• In TP53-mutated MDS or AML, APR- 246(eprenetapopt), a novel, first-in-class, small molecule, in combination with azacitidine.
• Additionally, novel doublet and triplet therapy with venetoclax and azacitidine in combination with APR-246 as post-transplant maintenance is being investigated.
• Finally, antibody-based immunotherapy for AML, such as the dual-affinity re-targeting inhibitor flotetuzumab (CD123 X CD3) or cusatuzumab (anti-CD70 antibody) in combination with azacytidine,

• Several trials of gilteritinib are under way,
• including a trial of gilteritinib versus placebo as maintenance therapy after consolidation (NCT02927262) or after allo-HCT in patients with FLT3-ITD mutations (NCT02997202)
• combining gilteritinib with atezolizumab (NCT03730012) and venetoclax (NCT03625505) 
• gilteritinib in combination with induction and consolidation therapy in patients with newly diagnosed AML in patients with relapsed/refractory AML

Take home massage

• Outcome of targeted therapy is really stratifying 
• In future with the targeted therapy there will be maintenance therapy for AML which will lead to decrease both the mortality rate & relapse rate of AML.