case 123 summary

Our case this week looked at a 44 year old gentleman with a new diagnosis of AML.

He presented with pancytopenia and blasts with auer rods on peripheral blood.

Investigations confirmed a diagnosis of AML.  PML – RARA was negative, and cell markers inkeeping with AML (CD33+, CD34+, CD13+, CD19+, CD56+, HLA-DR, CD17+, CD64+).  Cytogenetic and molecular studies showed t(8:21), C-KIT positive, FLT3 negative and NPM1 negative.  We decided to treat this patient initially with DA+myelotarg.

Initial investigations should include:

  • FBC
  • Clotting screen including fibrinogen and D-dimers
  •  Urea and electrolytes
  •  Liver function tests
  •  Urate
  •  CMV serology (in those patients who may be transplant candidates)
  •  HLA class 1 and 2 tissue typing for potential allogeneic stem cell
    transplant candidates
  • Marrow aspirate and trephine where possible for morphological
    assessment
  • Marrow EDTA sample for immunophenotyping
  • Marrow sample for cytogenetic and molecular analysis

 

Risk Stratification

A number of factors are known to affect prognosis of patients with AML including:

  1.  age
  2. peripheral white cell count
  3. marrow cytogenetics
  4. response to induction chemotherapy
  5. molecular studies

 

Cytogenetic abnormalities

  • Good risk:  t(8;21), inv(16), t(16;16), t(15;17)
  • Standard: Any patient not in either good or poor risk groups.
  • Poor risk: -5, -7, del(5q), abnormal (3q) or complex (5 or more abnormalities)..

 

Molecular markers

  • FLT3-ITD +, NPM1 – Poor Risk
  • FLT3-ITD +, NPM1+ Intermediate Risk
  • FLT3-ITD -, NPM1 – Intermediate Risk
  • FLT3-ITD -, NPM1 + Good Risk

 

Core binding factor

CBF in acute myeloid leukaemia represents 5-8% of all AMLs and has a relatively favourable prognosis.  In general CBF patients have a higher CR rate and an extended CR time. Therefore many centres may opt to treat with chemotherapy, rather than chemo + transplantation.

However the presence of C-KIT mutation ALONE is associated with a higher risk of relapse and shorter survival.  Studies have reported contradictory results with regards to prognostic significance of KIT mutation in combination with CBF.  Some studies suggest a decreased remission rate and survival whilst others suggest no effect of KIT mutation in CBF-AML.   It has also been proposed that C-KIT in AML patients with T(8:21) confers a poorer prognosis however no definite conclusions can be made in AML inv(16).

Treatment options may include

  • Trial
  • DA
  • DA+ myelotarg (as per NICE guidance in the UK)
  • DA+ midostaurin (if FLT3 positive)
  • CPX – (AML with previous MDS, AML with previous CMML, therapy associated-AML, AML with genetics consistent with MDS)
  • IHD inhibitors – (IHD1 ivosidenib, ID2 enasidenib)
  • Venetoclax (not currently available in UK)
  • Allogeneic stem cell transplant
  • TKI ???

 

There are no definitive answer to how all AML patients should be treated.  Individualised treatment plans are essential to improving outcomes in this population.  Below is a brief synopsis of treatments currently available/in trials with lots of references if anyone wants to do some further reading!

Myelotarg

NICE guidance for myelotarg

  • untreated de novo CD33+ AML
      • start with induction therapy when either the cytogenetic test confirms that the disease has favourable, intermediate or unknown cytogenetics (that is, because the test was unsuccessful) or when their cytogenetic test results are not yet available and
      • start with consolidation therapy when their cytogenetic test confirms that the disease has favourable, intermediate or unknown cytogenetics (because the test was unsuccessful)

 

Myelotarg has shown significant survival benefit for favourable and intermediate cytogenetic risk groups when assessed separately or together.  A consistent observation of myelotarg is a lack of benefit in patients with adverse risk. Therefore optimal use of myelotarg requires rapid identification of risk groups in order to allow avoidance of myelotarg in the adverse risk groups

Midostaurin

The addition of FLT3 inhibitor Midostaurin to treatment in patients who are FLT3 positive has been founds to improve 4 year overall survivial to 51% versus 44% in the group that recieved placebo.  Disease free survival has been reported at 26.7 months versus 15.5 months.

 

However either myelotarg or midostaurin can be chosen.  They cannot be used in combination and this once again highlights to need to clarify cytogenetic/molecular status before instigating treatment.

 

CPX

CPX is a dual drug liposomal encapsulation of cytarabine and daunorubicin.  Clinical studies have shown prolonged drug exposure and prolonged survival compared to DA 3+7, in older patients with newly diagnosed secondary AML.

This study included patients with the following diagnosis

  • therapy-related AML,
  • AML with a history of myelodysplastic syndrome [MDS] with and without prior hypomethylating agents,
  • AML with a history of chronic myelomonocytic leukemia [CMML],
  • de novo AML with MDS-related cytogenetic abnormalities

 

IDH inhibitors

IDH1 and IDH2 mutations are seen in approximately 15-20% of patients diagnosed with AML and these mutations are targeted by ivosidenib and enasidenib.  The mutations more frequently occur in patients of older age, with a normal karyotype and NPM1 mutation.  These treatment have been used so far in relapsed/refractory AML.  Enasidenib has been found to be effective salvage treatment inducing responses of approximately 40% of patients with IDH2 mutations.  There are ongoing phase 1/2 trials in newly diagnosed AML, which include these treatment upfront.

 

Venetoclax

Venetoclax has been approved in the United states by the FDA for use in combination with hypomethylating agents or low dose cytarabine as front line therapy for older patients with AML or those unfit for intensive treatment.  Venetoclax is a promising treatment for AML and to date has produced some deep and durable responses, with promising overall survival.  The challenges come with tumour lysis syndrome, continuation of treatment (i.e. do both treatments need to be continued lifelong), and predicting who will have a poor response to treatment

Dasatinib

Ongoing phase III trial currently.  Inital studies found acceptable toxicity and favourable outcomes with OS of 74.7%,

 

References

Prognostic Importance of C-KIT Mutations in Core Binding Factor Acute Myeloid Leukemia: A Systematic Review.
Ayatollahi H1, Shajiei A2, Sadeghian MH2, Sheikhi M3, Yazdandoust E2, Ghazanfarpour M4, Shams SF2, Shakeri S2.  Hematol Oncol Stem Cell Ther. 2017 Mar;10(1):1-7. doi: 10.1016/j.hemonc.2016.08.005. Epub 2016 Sep 3.
The importance of relative mutant level for evaluating impact on outcome of KIT, FLT3 and CBL mutations in core-binding factor acute myeloid leukemia.
Allen C1, Hills RK, Lamb K, Evans C, Tinsley S, Sellar R, O’Brien M, Yin JL, Burnett AK, Linch DC, Gale RE.  Leukemia. 2013 Sep;27(9):1891-901. doi: 10.1038/leu.2013.186. Epub 2013 Jun 20.
The Addition of Gemtuzumab Ozogamicin to Induction Chemotherapy in Acute Myeloid Leukaemia : An Individual Patient Data Meta-analysis of Randomised Trials in .  Lancet Oncol. 2014 August ; 15(9): 986–996. doi:10.1016/S1470-2045(14)70281-5.

Midostaurin plus Chemotherapy for Acute Myeloid Leukemia with a FLT3 Mutation
Richard M. Stone, M.D.,  et al. August 3, 2017
N Engl J Med 2017; 377:454-464

CPX-351 (cytarabine and daunorubicin) Liposome for Injection Versus Conventional Cytarabine Plus Daunorubicin in Older Patients With Newly Diagnosed Secondary Acute Myeloid Leukemia  Jeffrey E. Lancet et al.  Journal of Clinical Oncology 36, no. 26 (September 10, 2018) 2684-2692.
Stein EM, DiNardo CD, Fathi AT, et al: Ivosidenib or enasidenib combined with induction and consolidation chemotherapy in patients with newly diagnosed AML with an IDH1 or IDH2 mutation is safe, effective, and leads to MRD-negative complete remissions. 2018 ASH Annual Meeting & Exposition. Abstract 560. Presented December 3, 2018.
How we use venetoclax with hypomethylating agents for the treatment of newly diagnosed patients with acute myeloid leukemia.  Brian A. Jonas & Daniel A. Pollyea
Leukemia volume 33, pages2795–2804(2019)
Adding dasatinib to intensive treatment in core-binding factor acute myeloid leukemia-results of the AMLSG 11-08 trial.  Paschka P et al.  Leukemia. 2018 Jul;32(7):1621-1630. doi: 10.1038/s41375-018-0129-6. Epub 2018 Apr 17.

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