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JOURNAL PRESENTATION

Dr. Nasrin Akhter

Resident (Phase B)

Department of Haematology,

BSMMU

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Case summary

Mrs. X , 32 year-old otherwise healthy woman diagnosed as AML

presented with fever and bleeding manifestations by BMS, flow cytometry.

Initial analyses not identified any taragatable mutation

She received induction with cytarabine (100mg/m2) plus daunorubicin (60 mg/m2) and bone marrow 1 month after treatment demonstrated an MRD –ve.

She elected not to pursue allogeneic HCT and received 3 cycles of consolidation therapy with HiDAC. After 3 cycle of consolidation MRD was negative.

7months after completing consolidation, she presented with bleeding manifestation with hyperleukocytosis, thrombocytopenia.

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What can be the approach to this patient?

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�� First Published: 10TH June, 2020 on ASH Publications�� Authors: Susan DeWolf (Memorial Sloan Kettering Cancer Center, NY)�� Martin S. Tallman (Weill Cornell Medical College, NY)�

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Introduction

  • Treatment of relapsed or refractory AML has presented challenges for hematologists for decades.

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  • More then 10,000 of the 20,000 new patients with AML in the US each year die of their disease.

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  • Outcomes are consistently disappointing with 5-year OS rates of ∼10%.

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  • AlloHSCT at the time of second CR remains the only reliable option with curative potential ( Three-to-five-year OS 15%-25%)

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Introduction

  • Recent approval of several new agents has transformed treatment paradigms.

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  • Through illustrative cases, will describe approaches reliying on specific disease biology, age, fitness to tolerate intensive chemotherapy, remission duration and presence of a targetable mutation to guide treatment.

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Definitions

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  • Precise definitions of relapsed and refractory disease are important in an effort to promulgate uniform terminology.

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  • In the past, some argued that 1 cycle should include high-dose cytarabine (HiDAC), given the ability of HiDAC to overcome resistance to standard-dose cytarabine.

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  • PRD, also known as PIF:

​

​

​

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  • For targeted therapy, to define treatment failure is an even greater challenge:

state of persistent leukemia with ˃5% blasts

after at least 2

cycles of intensive induction therapy

median time to remission is typically over 2 months

patients can respond after even 4 to 6 months

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Relapsed disease falls into 2 main categories:�

Clear morphologic relapse, which may be in the bone marrow or extramedullary.

The emergence of MRD after initial clearance

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Table 1. Definitions of relapsed and refractory AML

Category

Definition

PIF (PRD)

Lack of CR or CRi following at least 2 cycles of intensive chemotherapy

​

Hematologic relapse

Detection of ˃5% blasts in the BM,

identification of circulating blasts, or

emergence of extramedullary disease

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MRD

Detection of MRD defined by molecular

techniques or multiparameter flow

cytometry after an MRD-negative CR

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Prognostic factors

Factors that play a role in a patient’s clinical course :

Duration of first complete Remission

Age

Cytogenetics at diagnosis

Molecular features e.g. FLT3–(ITD) mutation status

History of prior allogeneic HCT

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Patient 1: Early relapsed AML in a young patient

30 year-old woman presented with cervical lymphadenopathy diagnosed as AML by BMS and flow cytometry who relapsed only 2 months after intensive induction and consolidation chemotherapy.

Initial analyses identified a DNMT3A mutation

She received induction with cytarabine plus daunorubicin (90 mg/m2) & bone marrow 1 month after treatment demonstrated an MRD –ve.

She elected not to pursue alloHCT and received 4 cycles of consolidation therapy with HiDAC.

2 months after completing consolidation, her cervical adenopathy returned and bone marrow studies revealed 55% blasts with the same phenotype and mutation profile as her original disease.

She was swiftly reinduced with MEC leading to a second morphologic CR with evidence of MRD -ve by flow cytometry

She proceeded to allo HCT from a matched unrelated donor with an ablative conditioning regimen and remains in CR 1 year after transplant without MRD.

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Early relapsed AML in a young patient

  • Specific reinduction choice guided by prior treatment history and side-effect profile.

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  • Regimens frequently consider are MEC,FLAGIDA, HiDAC.

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  • The efficacy of these regimens and similar variations is consistently relatively disappointing with CR rates ranging from 20% to 65% with a median duration of response typically 1 year.

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Early relapsed AML in a young patient

  • Studies in consolidation suggesting that lower doses of cytarabine (1.5-2 g/m2) appear equally effective and less toxic than classical HiDAC.
  • Other prefer regimens with cladribine (cladribine/araC/mitoxantrone/G-CSF) or clofarabine (clofarabine/cytarabine/G-CSF).
  • However, these regimens have yielded similarly relatively poor outcomes despite their initial promise.

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Implications of a FLT3 mutation

  • Somatic FLT3 mutation is identified in nearly 30% of AML patients.

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  • From the ADMIRAL study, a phase 3 trial investigating the potent FLT3 inhibitor gilteritinib in primary refractory or first relapse FLT3-mutated AML approved by the US FDA in November 2018.

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  • Gilteritinib monotherapy resulted in a median OS of 9.3 months compared with 5.6 months in the reinduction chemotherapy (low-dose cytarabine, azacitidine, MEC or FLAG-IDA) arm. �

7.1 months

4.3 months

high FLT3-ITD allelic ratios

10.8 months

8.9 months

NPM1 and DNMT3A

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Patient 2: PIF in a patient with AML

52-year-old man presented with shortness of breath and anemia diagnosed as AML by bone marrow biopsy with inversion(3) by cytogenetics

He initially received cytarabine-plus daunorubicin induction with persistence of over 70% blasts.

Then he received classical HiDAC, but had 33% blasts on follow up marrow evaluation.

After failing a clinical trial, he received reinduction with MEC followed again by progression of disease.

Finally, 8 months after diagnosis, he received 2 cycles of azacitidine and venetoclax & achieved a morphologic CR though with MRD by flow cytometry.

He proceeded to allogeneic HCT and remained disease-free for over 2 years.

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PIF AML

  • combining the oral BCL-2 inhibitor venetoclax with HMAs or LoDAC would have been our first choice.

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  • The regimen is typically well tolerated, rapid clinical response, not limited to patients with a specific mutation and often can be given outpatient.

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  • Single agent ventoclax has response rate 19% in RR AML whereas combination RR 70% in newly diagnosed older AML.

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PIF AML

  • Reduction of duration of venetoclax dosing from 28 days to 21 or even 14 days because of prolonged count recovery.

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  • Allogeneic HCT after 1 to 2 cycles of therapy, ideally when morphologic CR is achieved.

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  • If transplant is not the intended course, we continue HMA plus venetoclax indefinitely.

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Relapse following allogeneic HCT

clinical trials

Anti CD33 gemtuzumab

HMAs

donor lymphocyte infusion(DLI)

second transplant from a new donor

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Patient3 : Relapsed IDH1 AML in the older patient

An 86-year-old woman was originally treated with azacitidine for AML diagnosed by bone marrow biopsy identified 64% blasts with cytogenetics notable for a 5q deletion.

She enjoyed 2 years of excellent response with an improvement in her peripheral blood counts until a bone marrow evaluation detected 30% to 40% blasts along with worsening pancytopenia.

Complete molecular evaluation led to discovery of an IDH1 mutation, prompting the initiation of ivosidenib,

Within weeks her peripheral blood counts began to improve.

She continues without evidence of recurrent disease on ivosidenib for over a year following relapse..

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Relapsed IDH mutated AML

  • This case underscores the importance of a complete molecular investigation at the time of relapse.

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  • We always check for IDH andFLT3 mutation status,comprehensive panel of mutations by next-generation sequencing.

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Relapsed IDH mutated AML

  • Ivosidenib and enasidenib are novel oral agents targeting IDH1 and IDH2 respectively and are included in the 2019 NCCN guidelines for relapsed or refractory patients.
  • ivosidenib’s identified a CR rate among RR patients 21.6% with a median CR duration of 9.3 months.
  • The outcome of enasidenib is similarly encouraging .

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Relapsed IDH mutated AML

  • Both are associated with a risk of IDH differentiation syndrome.

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  • Steroids are typically effective.

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  • We temporarily interrupt targeted therapy if the presentation requires hospitalization or if severe symptoms persist for 48 hours after steroids.

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Relapsed IDH mutated AML

  • As the median time to CR is over 2 months for ivosidenib & enasidenib they continue treatment as long as patients appear to be deriving some clinical benefit before changing
  • In many parts of the world, IDH inhibitors are not available.
  • Therefore, IDH-mutated relapsed or refractory patients, consider HMA or LoDAC plus venetoclax.

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Relapsed IDH mutated AML

  • If venetoclax is not available, consider HMA alone or best supportive care

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  • Approved in Japan, quizartinib is apotent FLT3 inhibitor found to be superior as a single agent to chemotherapy in the phase 3 QuANTUM-R trial in the relapsed or refractory setting

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New targeted therapeutics in current clinical use for relapsed or refractory AML

Agent

Target

​

CR1CRh/CRi/CRp %

(CR %)

​

Median

survival,

mo

Approved population

​

FDA

Approval status

​

Reference for

FDA-approved

indication and

support for use

in the

unapproved

setting

​

Giltertinib

FLT3

34(21.1)

9.3

FLT3-mutated R/R AML

2017

6

Enasedinib

IDH2

26.6(20.2)

9.3

IDH2-mutated R/R AML

2017

18

Ivosidenib

IDH1

30.4(21.6)

8.8

IDH1-mutated R/R or

untreated AML

2018

19

GO

CD33

33(26)

8.4

CD33 untreated or

R/R AML in adults or

pediatric patients 2 y

or older

2017

101

HMA/LoAC + Venetoclax

BCL2

67(54),54(26) untreated

17.5, 10.1

Untreated AML in patients

75 y and older unfit for

chemotherapy

2018

16,16,68-74

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If you have built castles in the air, your work need not be lost; that is where they should be. Now put the foundations under them.

—HENRY DAVID THOREAU

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Guiding principles for relapsed or refractory AML

1. Enroll patients on clinical trials, when available

2.Perform molecular testing to identify potential for targeted therapy and drug development

3. Decipher mechanisms of treatment resistance

4. Avoid reinduction attempts with multiple sequential courses of intensive cytotoxic chemotherapy

5. Ensure appropriate patients proceed to allogeneic HCT, ideally when patients are MRD- negative.

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