Secondary AML and MDS - ALAN - July 6, 2021 Moshe Mittelman Tel Aviv, Israel - Acute Leukemia Advocates ...

Secondary AML and MDS
    ALAN – July 6, 2021

     Moshe Mittelman
      Tel Aviv, Israel

MM: Disclosures
 Research funding:
   Amgen; Celgene; Johnson & Johnson; Roche;
    Novartis; Gilead; Takeda
 Speakers’ bureau:
   Johnson & Johnson; Novartis
 Advisory boards:
   Pfizer; Amgen; Roche; Novartis; Takeda; Silence

What are we talking about ?
 Secondary (acute myeloid) leukemia
   A collective term used to describe
       a group of patients with acute myeloid leukemia (AML)
        or myelodysplastic syndrome (MDS) with a history of
        exposure:
         environmental, occupational, chemo, radiation, …

       Following hematologic disease (MDS)

 We will describe the spectrum starting with MDS and
  progressing to acute (myeloid) leukemia (AML)
                                                                3

1986: My trip began…

Heme-Onc Fellowship – GW – NIH (USA) 1986-1989

Sec AML / MDS: 60 sec (I)
 Bone marrow disease
 Wear & Tear problem
 Slowly progressive
 Wide spectrum
 Phases:
    (“Pre-MDS”)
    MDS
    Intermediate MDS-AML
    Acute leukemia (AML)

                                  5

MDS and AML: 60 sec (II)
• Myelodysplastic syndromes evolve into acute leukemia
• Age-related clonal hematopoietic stem cell disease(s)
• Ineffective hematopoiesis:
   • Abnormal differentiation, maturation, impaired apoptosis
• Genetic (Immune) basis + environmental exposure
• Involvement of the immune system
• Median age: 74 years
• Incidence increases with age (40–50/100 000 in > 70yr)
• Anemia (90%); Pancytopenia (50%)
• AML Transformation (20%-60%)
          Mittelman M Isr J Med Sci 1990;26:468; Malcovati L, Blood 2013;122:2943;
          Tefferi A, NEJM 2009;361:1872; Ades L Lancet 2014;383:2239;
           Garcia-Manero G, AJH 2020;95:1399; Cazzola NEJM 2020;383:1358

Sh.Y. (20th Century)
• 1983
   • 67 yo, lady, painter (dyes exposure)
   • weakness, macrocytic anemia
   • BM: mild dysplasia, 3% blasts, 5q-

• 1986
   • Blood (RBC) transfusions

• 1989
   • Pancytopenia, BM: 10% blasts
   • Low -dose Ara C:
      • One cycle - no reaction; intolerance

• 1990
   • Leukemic transformation
   • Course: chemo (7 + 3), died

LS (21st Century)
 2001: 82yo lady, hair stylist, asymp. anemia – FU

 2004: Mild weakness; BM: MDS, 3% Bl, 5q-, FU

 2005: Hb decline – transfusions- EPO- response !

 2007: Transfusions, Len, response for 26m

 2009: Pancytopenia; BM: 10% blasts, Aza – CR

 2011: Pancytopenia, bleeding, PLT 15k, eltrombopag

   Excellent PLT rise – survived brain bleeding !

 2013: AML – azacitidine – Complete remission

 2017: Deterioration, relapse, sepsis, died (98yr)

Epidemiology
   Age:
     8th decade
     Median – 74 yr

 Registries:
        25 new patients /100,000/yr

Etiology (Causes)
 Unknown

 Leukemogenic:
   Radiation
   Chemotherapy
     Alkylating agents
   Chemical: benzene, organic
   Drugs: chemo, NSAIDs, Chloramphenicol
   Viral (?)
 Genetic
 Multifactorial
 Diseases: PNH, AA

Distribution by Age and Gender (A. Carmi)
                Age at diagnosis

female
                                      Patients
 male

                    Age

When to suspect?

• Older patient (70+)
• Macrocytic anemia
   • Leukopenia, thrombocytopenia
• Other causes of anemia – excluded
   • Vitamin B12 deficiency, Folic acid, hemolysis
   • Hypothyroidism, liver disease, viral
• In younger people:
   • After chemotherapy
   • Secondary MDS

Recurrent Karyotypes in MDS (n=3856)

                 Schanz J et al - ASH 2009 abstract #2772

MDS: Genetic- Recurrently Mutated Genes
                (Malcovati L, Blood 2013; 122:2943; ELN 2014)

Gene         Frequency (%)                           References
SF3B1            25-30%        Yoshida, Nature 2011; Malcovati Blood 2011
TET2             20-25%        Delhommeau, NEJM 2009
RUNX1            10-20%        Chen CY, BJH 2007; Dicker, Leukemia 2010
ASXL1            10-15%        Bejar NEJM 2011; Thol F JCO 2011
SRSF2            10-15%        Yoshida, Nature 2011; Thol F , Blood 2012
TP53             5-10%         Bejar NEJM 2011; Padua RA, Leukemia 1998
U2AF1            5-10%         Yoshida, Nature 2011; Graubert NatGen 2011
NRAS/KRAS        5-10%         Dicker, Leukemia 2010; Paguett Blood 1993
DNMT3A             5%          Walter M, Leukemia 2011; Thol F Haematologica
ZRSR2              5%          Yoshida K, Nature 2011; Thol F, Blood 2012
EZH2               5%          Nikoloski G, Nat Gen 2010; Emst T, Nat Gen 2010
IDH1, IDH2        2-3%         Bejar R, NEJM 2011; Kosmider O, Leukemia 2010
ETV6               2%          Bejar R, NEJM 2011;
CBL               1-2%         Bejar R, NEJM 2011;
NPM1              1-2%         Bejar R, NEJM 2011; Dicker F, Leukemia 2010
JAK2              1-2%         Bejar R, NEJM 2011; Steensma DP, Blood 2005
SETBP1            1-2%         Piazza R, Nat Gen 2013;

Age Related Clonal Hematopoiesis
 Whole exome sequencing; peripheral blood; 17,182 persons
 Looked for somatic mutations in 160 “hematologic” genes
    Results;

        Rare mutations in < 40 yr
        70-79 yr: 9.5% with clonal mutations
        80-89 yr: 11.7%
        90-108 yr: 18.4%
        Common mutations: DNMT3A, TET2, ASXL1
        Somatic mutation was associated with increased risk of
           Hematologic cancer (HR 11.1)

           All -cause mortality (HR 1.4)

           Coronary dis. (HR 2.0); Ischemic stroke (HR 2.6)

                                     Jaiswal S et al. N Engl J Med 2014; 371: 2488

Evolution: From ICUS to AML
                          Steensma D et al., Blood, April 30, 2015
             Traditional ICUS                           MDS by WHO 2008
              No clonal        CHIP          CCUS        LR-MDS        HR-MDS             AML
                ICUS
Clonality          -             +             +             +             +               +
Dysplasia          -             -             -             +             ++              ++
Cytopen.          +              -             +             +             ++              ++
BM blasts       < 5%           < 5%          < 5%          < 5%          < 19%            > 20%
Risk          Very low       Very low       Low (?)       Low/Int         High            High
Treat         Obs/BSC       Observat.     Obs/BSC/      Obs/BSC/ HMA / SCT Chemo /
                                             GF         GF/Imids/I         HMA / SCT
                                                            ST
                                               -----------Clonal cytopenias-------------
 ICUS- Idiopathic cytopenia of undetermined significance; CCUS – Clonal cytopenia of US

  Age-related clonal hematopoiesis (ARCH) (Jaiswal S NEJM 2014;371:2488)

Clinical Picture
 General symptoms:
    Weakness
    Weight loss
    Fever
 Bone marrow failure:
    Anemia – weakness, fatigue
        Cardiovascular complications
   Low WBC – infections
   Low PLT - bleeding

                                        19

AL – Common Features: Clinical
 Symptoms/ complications:
    Non-specific – generalized (“B”)
    Hematologic – related to BM
        Anemia; Leukopenia; Leukocytosis; Low PLT
    Organ-related complications
    Treatment-related complications
    Generalized complications
 Untreated – rapid lethal course
 Treatment: Aggressive; Potential cure

AL - Complications
 Infections:
 Bacterial; fungal; viral; parasites; mycobacterial
 Metabolic:
    Fluid / electrolyte imbalance: Ca; K; Na; Mg
 Tumor lysis syndrome (TLS)
 Hyperleukocytosis; DIC
 Neutropenic enterocolitis
 Organ involvement:
    CNS; testicular; Renal; Eyes; any organ…

Impaired Quality of Life

Mobility

Self care

Usual activities

Pain / discomfort

Anxiety / depression

VAS – self rated health                        pinterest.com

EU: Impaired QoL vs Healthy

 p < 0.001,  p< 0.01,  p

Biology & Pathogenesis
 Environmental factors (leukemogenic)

    Radiation; Chemical (drugs, benzene); Viral

 Cytogenetics

 Genetic (instability); Epigenetics

 Immune system

 BM microenvironment (angiogenesis)

 Cytokines

 Predisposing disorders (MPN, PNH, AA)

 Multifactorial (host, external)

 Intracellular: apoptosis, clonal expansion

Bone Marrow Examination
 Biopsy
   A bone (marrow) sample
   A solid cylinder of tissue
   Findings: Structure; Cellularity; Foreign Islands
   Time frame: (5-10) days (Touch prep can bridge)
 Aspiration
   Liquid from the bone marrow
   Findings: single cell morphology
   Time frame: hours

MDS/AML Diagnosis: Based on BM
 Clinical picture
     Age;                                                                      Normal
     anemia; cytopenia
     MCV
 Exclude other reasons
 Bone marrow
 Aspirate; Biopsy
     Morphology
       Dysplasia,                                                                MDS
       Blast (20-30%) - AML
       Additional:
              R.sidero; Mono; Fibrosis

Tefferi A, NEJM 2009; 361: 1872; Malcovati L, Blood 2013; 122:2943; ELN 2014;
Arber DA, Blood 2016; 127: 2391; Weinberg OK, Semin Hematol 2019; 56: 15

BM in MDS: Several types of immature cells

Acute Leukemia: Blasts in BM & PB

AL Dg:

ELN - EUMDS Countries
Austria                   Reinhard Stauder
Czech Republic            Jaroslav Cermák
France                    Pierre Fenaux
Germany                   Ulrich Germing
Greece                    Argiris Symeonidis
Italy                     Luca Malcovati
Netherlands               Saskia Langemeijer
Romania                   Aurelia Tatic
Spain                     Guillermo Sanz
Sweden                    Eva Hellström-Lindberg
United Kingdom            David Bowen (Co-chair)
Denmark (2009)            Mette S. Holm
Portugal (2010)           Antonio Medina Almeida
Poland (2010)             Krzysztof Mądry
Israel (2012)             Moshe Mittelman
Serbia (2013)             Aleksandar Savic
Croatia (2013)            Njetočka Gredelj Šimec

Project Coordination      Theo de Witte (Chief Investigator & Chair)

Project Management                 Radboudumc Nijmegen, NL - Corine van Marrewijk
Data Management & Statistics       University of York, UK - Alex Smith

MDS Diagnosis (2013): Mandatory
 Exclude other reasons for cytopenia
 Peripheral Blood
    Dysplasia (1-3 lines), Blasts

 Bone marrow Aspirate:
    Dysplasia, Blast % (1-20%), Ring sideroblasts

 Bone marrow biopsy:
    Cellularity; CD 34+ Cells; Fibrosis

 Cytogenetics:
    Clonal abnormality ( G- Banding)

 (FISH, FCM, Molecular – Recommended)

                                           Malcovati L, Blood 2013; 122:2943; ELN 2014

Do all patients need BM for Diagnosis ?
BM exam – gold standard
But…
   Invasive; Painful
   Possible bleeding
     Low PLT

   Difficult for elderly
   Subjective interpretation

Can we diagnose w/o BME ?

A simple modle can dg/exclude MDS
Figure: MDS Predictive Modelling Dg
63

10.9                                     2.6

48                                       124
                                                                                shiny.york.ac.uk/mds
1.3                                      0.2

122                                      0.88

                              Green              Brown      Red

                                                                                   Oster HS Bl Adv 2021
Figure: The web application; ten variables are entered. For this patient, the
blue line in the red region predicts probable MDS (pMDS).

Can We Detect Pre-MDS ?
 Early detection
   Pre-disease states
       Tools:
         Genetic

         Digital; Big Data

Pre-MDS: Hb declines before MDS diagnosis
E-data (420 pts), CBC/yr > 3yr prior to MDS diagnosis

                    Joffe E et al, Hematol Oncol 2020;38:782

French-American-British Co-Operative Group, circa 1990
                                          David Galton,
                                            London
            Georges      Harvey        Marie-
 Daniel     Flandrin,   Gralnick,                               Claude S.
                                      Thérèse        John M.
Catovsky,     Paris     Bethesda    Daniel, Paris   Bennett,     Sultan,
 London                                             Rochester     Paris

                                                                                RIP:
                                                                            Sultan, 1992
                                                                            Galton, 2006

Prognostic Parameters
 Included in prognostic models:
    % blasts
    Cytogenetics
    Blood counts
 Not included (yet ?)
    Genetic mutations
    Age
    Co-morbidities
    Others ??

                                   39

MDS: FAB Classification
FAB Type   BM Blasts     Other     Incid.       Dyspo.
                        criteria

  RA        < 5%                   30%             +

 RARS       < 5%       R.Siderob   20%             +

 RAEB       5-20%                  20%            ++

CMML        1-20%       P.Mono     15%            ++

RAEB-t     21-30%      Auer rods   15%          ++/+++

                                            Bennett JM; BJH 1982

MDS Prognostic Classifications
 FAB: % blasts (+ morphology)
 International Prognostic Scoring System (IPSS)
    Prognostic parameters
      BM % blasts (+morphology)

      Cytogenetics: “good”; “bad”

      # Lineages affected

    Low-risk (LR); Intermediate -1: Lower risk
    Intermediate-2; High-risk;         Higher risk
 IPSS-R (revised; use #):
    Very low; Low; Intermediate; High; Very high

                Bennett JM, BJH 1982; Greenberg P, Blood 1997; 2012

MDS: Secondary MDS
 Following a muatgen for HL, Breast Ca…

    chemotherapy / radiotherapy exposure (1-10 yr)

 Younger age

 Hypocellular BM, fibrosis

 Cytogenetics: 90% abnormal (ch 5,7, 3q)

 Clinical:

    Advanced; Rapid course; Resistant; Leukemic

     transformation; Poor prognosis (

Management

MDS Treatment – General
 Treatment depends on:
   Disease status (IPSS/R)

       Lower risk MDS
           IPSS: Low risk; Intermediate-I
       Higher risk MDS
           IPSS: Intermediate-II; High risk
       Acute leukemia
   Patient

       Age; co-morbidities; functional
       QoL; Pt reported outcomes (PRO)

Evaluation of Treatment Response – Not B&W:
                   Response Criteria
 Acute Leukemia: CR (< 5% blasts)
 IWG 2000 / 2006:
    Complete response (CR)
    Marrow CR (mCR); (Partial R)
    Cytogenetic response (Cyt R)
    Hematologic improvement (HI)
      Erythroid (HI-E); Neutrophil; Platelet
 IWG 2018: HI-E - Erythroid response
    Transfusion burden:
      Non (0/16 wk), Low (3-7); High > 8
      Response: minor (50% less) or major (TI)

    Cheson BD, Blood 2000; Cheson BD 2006; Platzbecker U, Blood 2019

MDS EUROPE Guidelines (2019)

Treatment of Anemia

MDS Treatment for Anemia:
               RBC Transfusions- Still
~ 80% of MDS patients
  have a hemoglobin

RBC Transfusions in MDS/AML
 RBC-Transfusions – mostly used (50%)
 Complication: Iron overload
 No disease progression !
 Hb threshold ?
      Often Hb< 7 g/dl; but Individualize
 Hb target ? No target
 Transfusion frequency ? As needed (for the pt and doctor)
 Consider: Symptomatic benefit vs toxicity
Heptinstall K, Leuk Res 2007; 31 (Sup 1): 107; deSwart L, BJH 2015; Platzbecker U, Blood 2018; Nov 7;
Bowen D, Mittelman M, ELN-EUMDS Guidelines (2019; on line); deSwart L, Haematologica 2020

rHuEPO in MDS: Initial (Mittelman M et al. Blood 1992)
Patient        Age /     FAB      sEPO     Hb (g/dL)   Hb (g/dL)
              Gender              mU/mL     Week 0      Week 8
1.     ZS       82 M     RARS       300       8.0         8.2

2.     GA       79 M     RARS        -        7.8         8.0
3.     DG       79 F     RARS       550       7.9         8.0

4.     JL       75 F     RARS       480       8.1         7.7

5.     BB       74 F     RARS       660       8.3         8.0

6.     DA       78 F     RARS       600       8.1         8.0

7.     SB       73 F      RA        75        8.0        11.0
8.     GK       68 F     RARS        -        8.2         8.3

9.     SY       65 M     RARS        -        7.8         8.1

10. SM          59 F      RA       471        8.9         9.4
11.    AF       80 M      RA        500       7.3         6.9

12. MBB         68 F     CMML       400       8.0         7.8

13. IS          82 F      RA        96        7.4        11.9

Erythropoietin (ESA) in 2021

 First line (w/o RBC Transfusions)
 Effective
   Hb rise
   Fewer RBC transfused
   Improved QoL
 Safe
     Cazzola M, BJH 2003;122:386; Hellstrom E, BJH 1997:99;344;
     Gafter-Gvili A, Acta Oncol 2013;52:18; Mittelman M, Acta Haematol 1993;
     Mittelman M, Med Clin N Amer 1994;8:993–1009

EPO Non-Erythroid (immunologic) Effects

 Anti-neoplastic (myeloma)
 Mittelman M, PNAS 2001; Mittelman M, EJH 1994;
 Mittelman M, Acta Haem 1994
 Improved immune (T-Cell) functions
 Deshet-Unger N, Leuk Res 2017; Sagiv S, BJH 2006
 Decreased glucose level
  Dseshet-Unger N 2018;
  Oster H Acta Haem 2020
 Bone loss                                                                                      serum IL6

  Hiram-Bab S, FASEB J 2015                                                       16

                                                    serum concentration (pg/ml)
 Decreased IL-6
                                                                                  14
                                                                                  12
                                                                                  10
  Prutchi Sagiv S, BJH 2006                                                       8
                                                                                  6
                                                                                  4
                                                                                  2
                                                                                  0
                                                                                       healthy        MM     MM + Epo

Thalidomide is back

                      55

Lenalidomide
 Del (5q): MDS-004
    RRBC TI 56%; Cyto response 50%; 10mg
    Poor response in TP53 mutation
    AE: cytopenia, rash, GI, thrombosis
    No Leukemic transformation
 Non-del (5q): MDS-005
    239 pts; 27% (vs 3.5%)

List AF, NEJM 2005; 2006; Lian XY. Plos One 2016;11:e0165948;
Alemeida A, Leuk Lymph 2018; Saft L; Haematologica 2014; 99: 1041;
Fenaux P, Blood 2011; 118: 3765; Santini V, J Clin Oncol 2016; 34: 2988

Anemia: When ESA fail
 Luspatercept (ACE-536) - approved
     Activin analog; Sc / 3wk
     40% ORR (MEDALIST trial); COMMANDS ongoing
               Platzbecker U, Lancet Oncol. 2017; Fenaux NEJM 2020
 Oral Aza: 38% response
     Quazar (MDS-003) trial (Phase 3)
                 Garcia Manero G, JCO 2021
 Roxodustat:
     Oral HIF inhibitor; 38% response; trial ongoing
         Henry DH; ASH 2019; ASH 2020; Paper sub.
 Imetelstat: Telomerase inh.; 42% ORR; iMerge ongoing
         Steensma D, ASH 2018, Fenaux P, EHA 2019; Platzbecker U; EHA 2020

PLT Transfusions
 Indication – in active bleeding
 PLT transfusion – per local guidelines
 Consider “thrombostatics”
   Tranexamic acid
   Anti-fibrinolytic: Hexakapron

Malouf R Cochrane Database Syst Rev 2018 May 14; Vijenthira 2019
Bowen D, Mittelman M, ELN-EUMDS Guidelines 2019 (on line); Carraway 2020

Romiplostim (weekly injection)
 Phase I/II
    n=44; Response 46%
                       Kantarjian H et al. J Clin Oncol 2010;28:437
 Phase II:
    n=250; Stopped – AML ?
                                Giagounidis A et al. Cancer 2014;120:1838
 Longer FU (5yr) – safe
    Similar AML rate
              Kantarjian H et al. Lancet Haematol. 2018; 5(3):e117
 Commentary:
    Long FU but short exposure
                   Mittelman M, Lancet Haematol. 2018 Mar;5(3):e100

Eltrombopag (Tablet)
 In LR-MDS:
    Effective – 47%
                   Oliva E, Lancet Haematol 2017
 In HR-MDS:
    Single agent – ASPIRE Part I: 4/17
                 Mittelman M et al. Blood 2012;120:abst 3822
    ASPIRE II: Fewer events (54% vs 69%)
                   Mittelman M, Lancet Haematol. 2018 Jan;5(1):e34
    Combo: SUPPORT (Elt + Aza)
      Early terminated Dickinson M et al. Blood 2016;128 2018
      
 Development stopped !

Fewer Clinically Relevant Thrombocytopenic Events in
                 Eltrombopag Patients
                                               Eltrombopag           Placebo        Odds ratio
                                                                                                         P valuea
                                                   (N=98)             (N=47)         [95% CI]
  Mean CRTE (Weeks 5‒12)                            54%                69%              0.202
                                                                                                         0.0315
         [95% CI]                                 [43-64]            [57-80]        [0.047-0.867]

                                     CRTE Analysis Over Time; Generalized Linear Mixed Model
                         100

                         90
                               78                                                                         78
                         80                                                                74
      CRTE, % [95% CI]

                                    67    69      69   69       67             69                   68
                         70                                                          66
                                                                       60
                         60
                                    59            59            59     57                                 59
                         50    56         54                                         54             54
                                                       53
                         40                                                    48          48

                         30

                         20
                                    Placebo
                         10
                                    Eltrombopag
                          0
                               1    2     3       4    5        6      7       8     9     10       11    12
                                                                Weeks

                                                            Mittelman M et al, Lancet Haematol 2018                 62

TPO RA – Still Embargo ?
 “Negative” trials
    ROM; SUPPORT
 “Positive”
    Others (both agents; LR-MDS)
    Long-term FU – safe
    Real-life (GFM/ Elt) – Safe !
 Meta-analysis (n=2):
    No excess mortality !
 Conclusion ?
    Personal: Time to lift the embargo

 Fenaux 2017; Dodilet 2017; Oliva 2018; Kantarjian 2018;
 Mittelman 2018; 2019; Meng 2020; Comont 2021; Mittelman BJH 2021

Immunosuppressive Treatment –
             Still Alive
    A large int cohort, 15 centers,
    207 pts
    The common: ATG + pred (43%)
    ORR 48.8%
       11% CR; 30% RBC-TI
    Median OS 47.4 m
       Longer for pts with TI
       TI associated with hypocellular BM (< 20%)
       Horse ATG + CSA most effective
    Did not predict: Age, HLA-DR 15

Mittelman M Acta Haematol 2015; 134: 135; Stahl M, Blood Adv 2018; 2: 1765

RBC Transfusions Result in Iron Overload

  RBC     2u/month
  24u/yr 100u/4yr
                                         200–250 mg
  100 u - 20 g iron !!!                     iron

Sanz GF et al., Blood 74:395-408, 1989

Iron Overload
 Organ damage ? Yes
 Iron chelation - Effective:
    Retrospective (Hoeks M; Haematologica. 2020;105(3):640)
    TELESTO (Angelucci E, Ann Intern Med. 2020;172:513)
      Prospective; DFX vs Placebo; 221 pts;
      36% reduced events (1440d vs 1091d)
      No survival advantage
 Guidelines:
    Use iron chelation, when:
    > 25 RBC u; Ferritin>1000
                  Mittelman M; IMAJ 2008;10: 374

Overview of iron chelators

                Deferoxamine
Property                               Deferiprone (DFP)                Deferasirox
                    (DFO)
Usual dose      25–60 mg/kg/day           75 mg/kg/day                20–30 mg/kg/day

Route               s.c., i.v.                 p.o.                           p.o.
              8–12 h, 5 days/week         3 times daily                    once daily

Half-life          20–30 min                 3–4 h                           8–16 h

Excretion        Urinary, faecal            Urinary                          Faecal

Approved       Treatment of chronic    Thalassaemia major        Treatment of chronic iron
indications     iron overload due to                             overload due to frequent
              transfusion-dependent                                 blood transfusions
                      anaemias

                                                                Deferoxamine Prescribing Information.
                                                      Deferasirox Summary of Product Characteristics.
                                                      Deferiprone Summary of Product Characteristics.

Treatment

HR-MDS / AML Treatment: Principles
 Strategic decision:
    Treat the disease ?
    Or supportive treatment ?
 If anti-MDS/AML:
    Quite aggressive
        Chemotherapy
        Epigenetic (biologic) treatment
        Investigational
 Frame:
    Protocols
    Skilled team
    Facilities (intensive care)

                                           70

Azacitidine (Vidaza) – 1st line
                                                  (Aza 001 Trial): Response 50%; 2yr
                             100

                                                                                                Azacitidine (n=179)
                         80                                                                     CCR (n=179)

                         60                                                     24.5 months           18 pts & Int-1
Patients surviving (%)

                         40                   15.0 months

                         20

                                       p=0.0001
                         0
                                   0          5     10      15     20      25         30   35    40
                                                   Time from randomisation (months)

                                       Fenaux P, et al. Lancet Oncol 2009;10:223–32

HR MDS/AML: How can we do better ?

 HMA still, but:
    Better formulations: oral? Derivative ?
        Guadecitabine; Oral Aza
    Add-on: HMA (Aza) combinations
    Identify responding subgroups
    Minimize toxicity: infections; low PLT; supportive
 Other known: Lenalidomide
 Chemotherapy
 Stem cell transplant
 Novel agents / strategies

HMA: Identifying Responders –Personalized

 Females respond better to DAC
         DeZern AE, Leuk & Lymph 2017; 58: 1325

 TP53 mutation predicts response to DAC:
        Welch JS, NEJM 2016; 375: 2023; Chang CK, BJH 2017; 176: 600
   TP53 activator: APR (Sallman D JCO 2021; Cluzeau JCO 2021)
 TET2 loss/mutation identified responders
        Bejar R, Blood 2014; 124:2705; Santini V, Curr Opin Hem 2015; 22: 155

 NPM1 mut + DNMT3A WT: DAC Favorable outcomes
           Wu L, Br J Haematol. 2020 Apr 8. doi: 10.1111/bjh.16628

Infections on Aza
 Israel MDS Working Group:
    Retrospective, 184 pts on Aza
    16.5% infect, 75% admission; 20% fatal !
        Merkel D; Am J Hematol 2013; 88:130

  Infections more common
    In 7d > 5d cycle; In PLT < 20k
          Ofran Y; Clin Lymphoma Myeloma Leuk 2015; March

 Fungal infections
            Kim GYG; Am J Hematol. 2020 Apr

 Prophylaxis ?
    GFM: failed ? (Sebert M; MDS 2015)
    Ongoing Israel trial

SUPPORT (phase 3) – Aim: Minimize Aza Toxicity
                              Eltrombopag           Placebo
                             (+ Azacitidine)     (+ Azacitidine)
  Death, n (%)                   57 (32%)           51 (29%)
   Disease                          16%               12%
   Sepsis                           10%                7%
  AML , n (%)
   By investigators              27 (15%)            16 (9%)
   Central lab                   21 (12%)            10 (6%)

             The study was early terminated

              Dickinson M Blood 2018; 132:2629

Aza+ Combination: Vi-Len-01
 Azacitidine (Vidaza) & Lenalidomide
 Recruited – 27 pts (evaluable – 25)
 Overall response rate (ORR): 18/25 (72%)
   CR / mCR:                  9 pts (36%)
    Hematologic improvement (HI): 9 pts
      Ery 6; PLT 4; Neut 5

 Probable OS 12m
    Mittelman M et al; ASH 2013; Ann Hematol. 2016; 95:1811

Novel (I): Venetoclax (+HMA): The Winner ?

 Anti BCL-2, oral, tolerable
 Multicenter, phase 1b:145 pts, unfit AML,
    CR/Cri 73%; OS 17.5m
         DiNardo CD, Lancet Oncol 2018; 19: 216; Blood 2019; 133: 7
 V+HMA: ORR 59%
          Ball BJ, Blood Adv. 2020 Jul 14;4(13):2866
 RCT Phase 3 (AML): 14.7m (V+Aza) vs 9.6m
        DiNardo CD, NEJM 2020 Aug 13;383:617
 V+ HMA – standard (?), but low ORR !
         Azizi A, Leuk Lymphoma. 2020 Jun 16:1-8  .
 VERONA Trial: Phase 3, MDS, RCT, ongoing !

AML Treatment: Induction (I)
 ELN Guidelines (2010):
 Standard Approach (“Young”)
    7+3
        Cytarabine (Ara-C)
            100-200mg/m/d X 7 days
        Anthracycline
            Daunorubicin
               60-90 mg/m/d x 3 days, or

            Idarubicin 10-12 mg/m/d x 3 days

                                 Dohner H; Blood 2010

AML Treatment: Induction (II)
 Additional 3rd drug ? Novel
    Chemotherapy:
        Etoposide; Cladribine; Clofarabine
    Antibodies:
        Gemtuzumab-Ozogomycin (Mylotarg, Anti-CD33)
    Targeted:
        Anti-FLT3: Midostaurin
        Anti Bcl2: Venetoclax
        Anti IDH1,2

AML: Post Remission
 Conservative:
    Chemotherapy
        High-dose Ara-C (Cytarabine)
        Other chemo regimens
 Stem cell transplant (SCT)
    Allo-SCT (or auto)
    For high-risk
    “Young”
    Resistant/ relapse (RR)

Other Chemo for HR-MDS/AML
 Clofarabine: mostly studied (phase 2)
  Horikoshi A Chemotherapy 2013;59:152; Becker PS AJH 2015;90:295;
  Sellesag D Haematol 2017;102:e50; Buckley SA BJH 2015;170:349;
  Rudrapatna VK Leuk Res 2015;39:835; Roberts DA Leuk Res 2015;39:204;
  Jabbour E Cancer 2017; 123: 629
 Other: Benda+ Ida; Ida+cytarabine+Mylotarg
      Lionberger JM Br J Haematol 2014;166:375; de Witte T Ann Hematol
  2015;94:1981
 Aza similar to 7+3
        Othus M, Leukemia 2018; October 12

 CPX-351: Liposomal cyatabine / daunoribicin 5:1
         Lancet JE, J Clin Oncol 2018; 36: 26

Stem Cell Transplantation
 Basic idea: Replace the sick marrow
 Problems:
    HLA typing – rejection
    GVHD
    Conditioning – pancytopenia
    Veno-occlusive disease of the liver
 Indications: AL/MDS (high-risk)
 Allow aggressive chemo - ABMT
 Source: BM; Peripheral; Cord blood

SCT for HR-MDS/AML
 The only curable !!
 Questions:
   Who? High-risk
   When?
   Pre-SCT treatment ? If blasts > 10%
   HMA or Chemo ? Similar
   RIC or MAC ? Similar
   Post SCT maintenance / DLI ? For HR of relapse
 ELN Recommendations - summary
  Robin M, Leuk Res 2015; Della Porta MG, Leuk 2017; Nazha A, ASH 2018;
  Symeonidis A BJH 2015; Sohn SK Crit Rev Oncol Hematol 2015;
  Konuma T, Hematol Oncol 2018; Potter VT, Biol BMT 2016; Damaj G, JCO 2012;
  Kroger N, JCO 2017; deWitte T, Blood 2017

Novel (Targeted/ Biologic) Agents
 Abs: Mylotarg (A-CD33; Gemtuz-Ozogamicin); Anti-CD123
 Targeted molecules:
    Midostaurin – anti-FLT3; Venetoclax – anti-bcl2
    Rigosertib - RAS/MEK inhibitor
    Pevonedistat - NEDD8 activ. enzyme inhib. – “ubiquitin”
    Glasdegib - Hedgehog inhibitor; PO
    Selinexor (Etanexor): Oral nuclear export protein inh.
    APR 246 (Eprenetapopt) – TP53 activator
    IDH inhibitors: Enasidenib; Ivosidenib
 Immunotherapy
    Sabatolimab (MBG 453; Anti TIM-3 Ab)
 Future: CAR-T; Others
                                                               86

MDS/AML Treatment 2021: Summary
 LR-MDS
    RBC transfusions; ESA
     Luspatercept; Investigational
   PLT transfusions; Thrombomimetics (?)
 HR-MDS / AML
    Hypomethylating; (HMA + ?)
    Chemotherapy
    Stem Cell Transplant
   Novel / Investigational

Why Clinical Trials ?
 Novel (inaccessible) treatments
 Close follow up
 Free treatment
 Helps people / science
 All supervised / controlled

Sec AML & MDS - Summary
 Spectrum from pre-MDS through AML
 Usually elderly people
 Better understanding
 Early diagnosis
 Not a verdict !
 More effective treatments
 Future looks better !

                                      89

Young / Rich / Healthy

                         90

Thx to Collaborators and…
 TASMC (Ichilov) – Tel Aviv team
    Hematology team (I. Avivi)
    Howard Oster
    Study coordinators: N. Sagy, N.Goldsmidt
 Israel MDS Working Group
 European Leukemia Net (ELN)
 European MDS group
 Patients

“The drug has no side effects;
However, the price will make you dizzy”

From Tel Aviv