Maintenace therapy in acute myeloid leukaemia

Presenter

Dr.Sharup Chandra Poddar

Resident

Phase –B

Haematology

BSMMU

• Acute myeloid leukemia (AML) is characterized by infiltration of the bone marrow (BM), blood, and other tissues by proliferative, clonal, poorly differentiated myeloid cells.
• Intensive induction chemotherapy (IC) is standard of care for patients with newly diagnosed AML (ND-AML) who are fit to receive it.

• Most patients with intermediate- or high-risk AML either relapse or do not achieve a remission without allogeneic hematopoietic cell transplantation (allo-HCT).
• Moreover, a significant proportion of patients are not eligible for allo-HCT consolidation due to lack of an acceptable donor or to comorbid condition.

Morphologic complete remission (CR) is defined

• < 5% blasts in BM
• Absence of circulating blasts in PBF
• Absence of extramedullary disease
• Hematologic recovery

( ANC ≥ 1000/μL and platelet count ≥100,000/μL in PBF) .

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Prognostic factors impacting the likelihood of attaining CR include patient

• Age
• General health ( comorbidities and performance status),
• Disease characteristics ( genetic profile).

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Morphologic CR with IC in AML

• 60 to 80% aged ≤60 years
• 40–60% in selected patients aged >60 years
• Newer regimens have shown overall response rates

(ORR= CR + Cri) of >60% in patients aged ≥65 year.

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• AML relapse is defined by the reappearance of ≥5% myeloblasts in the BM not attributable to BM regeneration after consolidation therapy or to any other cause .
• AML relapse occurs from the expansion of a dominant or secondary clone that survives therapy and may gain additional mutations and/or epigenetic modifications
• . In 10–15% of cases, relapse is caused by a clone that carries mutations induced by cytotoxic chemotherapy that were not detected in the initial tumor (therapy-related AML) .

• Relapse rates range from ~30–35% in younger patients with favorable risk factors to ~80% in older patients with adverse risk factors.

• There has long been interest in utilizing lower-intensity treatments as remission maintenance therapies for patients with AML who achieve remission after IC or HCT in an effort to prolong remission duration and improve survival .
• However, post-remission maintenance therapy in AML has been controversial based on disappointing results from early trials in this setting.
• Though some studies have shown maintenance therapy is associated with prolonged RFS or disease-free survival (DFS) robust evidence of improved OS has been lacking.
• Consequently, the demonstration of significantly prolonged OS and RFS with CC-486, an oral hypomethylating agent, as maintenance therapy in the phase III, placebo-controlled QUAZAR AML-001 trial in patients aged ≥55 years who had achieved a first CR or CRi after IC represents a major therapeutic advance.
• Based on results of QUAZAR AML-001, CC486 was approved in August 2020 for continued treatment of adult patients with AML who achieved first CR or CRi following intensive IC and who are not considered candidates for HCT .
• Though maintenance therapies have become standard treatment for nearly all patients with acute lymphoblastic leukemia [34] and chronic myeloid leukemia (eg, imatinib/dasatinib) [35], and acute promyelocytic leukemia (APL) (eg, all-trans retinoic acid) there is no standard of care for AML remission maintenance.

• A primary goal of maintenance therapy is to eradicate residual leukemic cells in the BM, eliminating MRD and potentially reducing the risk of relapse [13]. Therapeutic approaches for patients in remission have generally involved three main strategies: consolidation chemotherapy comprising additional cycles of high-dose cytarabine (HiDAC), or multi-agent combinations such as cytarabine along with an anthracycline with or without other purine analogs such as cladribine or fludarabine [37]; high-dose or reduced intensity chemotherapy (conditioning) followed by consolidation with allo-HCT; and prolonged, ongoing cycles of lowerintensity treatments (eg, hypomethylating agents) following IC or allo

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Why maintenance therapy is important ?

• To induce prolong remission
• To prevent relapse
• To increase OS

Candidates for maintenance therapy

Patients with intermediate or adverse risk disease :

• Who received prior IC and now in remission
• Completed no consolidation , some consolidation or a recomented course of consolidation and
• No allogenic stem cell transplant is planned

=Oral azacitidine 300 mg daily on days 1-14 of each 28 days cycle until progression or unacceptable toxicity

• Post allogenic stem cell transplant,in remission,and h/o FLT3-ITD
• =FLT3 inhibitor maintenance -sorafenib

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Recommended maintenance therapy for AML

Oral azacitidine 300 mg daily

Dose :on days 1-14 of each 28 days cycle

Duration : until progression or unacceptable toxicity

• Monitoring :1-3 mo 2years, 3-6 mo upto 5 years .

by ,CBC and plt BM if CBC shows abnormality or cytopenia

Post allogenic stem cell transplant,in remission,and h/o FLT3-ITD

FLT3 inhibitor maintenance -sorafenib

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Recommended maintenance for APL

• ATRA 45mg/m2/daily 15 days every 3 months
• 6- MP 60mg/m2/daily
• MTX 20mg/m2 /weekly
• Route : oral
• Duration : 2 years
• Monitoring: RT-PCR 3 monthly for first 2 years then 3-6 monthly for next 3 years.

Trials including maintenance therapy after IC

• Chemotherapy :
• Low dose ara –c
• TAD (thioguanine, ARA-C and daunorubicin)
• Hypomethylating agents:
• 5- azacytidine
• Decitabine

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• Immunotherapy

Interferon and interleukin-2

Lenalidomide

Gemtuzumab Ozogamicin

Immune checkpoint inhibitor

• Small molecules
• FLT3-inhibitors
• Isocitrate dehydrogenase (IDH) inhibitors
• BCL-2 inhibitor

• TRIALS INCLUDING MAINTENANCE THERAPY AFTER TRANSPLANT IN PATIENTS WITH AML
• HMAs agent
• Lenalidomide
• FLT3-inhibitors