Updates in Myelodysplastic Syndromes - Michael Keng, MD Assistant Professor of Medicine March 22, 2019 - UVA School of Medicine

Updates in
   Myelodysplastic Syndromes

Updates in Hematology and Hematologic Malignancies – 2019
                   University of Virginia
                    Charlottesville, VA

               Michael Keng, MD
        Assistant Professor of Medicine
                March 22, 2019

Disclosures

    Agios – Advisory Board

Question

 75F went to her PCP for fatigue x 8 months. CBC
 reveals Hg 11, MCV 103, Platelets 125K. Blood smear
 and nutritional studies normal. No inciting
 medications. BMBX reveals 30% cellularity, rare
 dysplastic megakaryocytes 6%, no blasts or fibrosis.
 Normal cytogenetics and NGS panel.

 What is the next step in treatment:
 A. Observation
 B. Repeat BMBX
 C. TPO agonist
 D. Lenalidomide
 E. Azacitidine

Question
 75F went to her PCP for fatigue x 8 months. CBC
 reveals Hg 11, MCV 103, Platelets 125K. Blood smear
 and nutritional studies normal. No inciting medications.
 BMBX reveals 30% cellularity, rare dysplastic
 megakaryocytes 6%, no blasts or fibrosis. Normal
 cytogenetics and NGS panel reveals DNMT3A R882H
 mutation at 18% variant allele frequency (VAF).

 What is the next step in treatment:
 A. Observation
 B. Repeat BMBX
 C. TPO agonist
 D. Lenalidomide
 E. Azacitidine

MDS: Diagnosis

  Cytopenia(s):                                         MDS “decisive” criteria:
                                             • >10% dysplastic cells in 1 or more lineages,
  • Hb

MDS: CHIP

            Steensma et al Mayo Clin Proc 2015; 90(7):969-983.

MDS: CHIP

            Adapted: NCCN – MDS 2.2019.

MDS: CHIP

            Steensma et al Mayo Clin Proc 2015; 90(7):969-983.

MDS: CHIP

   “Watchful” waiting
   Do NOT have disease, but a
    condition with a risk factor

   Reducing the Clone

MDS: CHIP

   Cardiovascular Risk
      Myocardial Infarction
      Stroke

      Reducing the risk – follow American
       Heart Association lifestyle guidelines

MDS: CHIP

   CHIP Clinic at UVA
  Heme/Onc
  Genetics
  Cardiology

MDS: Lower Risk

 MEDALIST Trial – Phase 3, Randomized, Double-Blind,
 Placebo-Controlled Study of Luspatercept to Treat
 Patients with Very Low-, Low-, or Intermediate-Risk
 MDS Associated Anemia with Ringed Sideroblasts Who
 Require RBC Transfusions

                                        List A, et al. ASH 2018. Abstract 001.

MDS: Lower Risk

 MEDALIST Trial – Study Endpoints

 Primary Endpoint:
 RBC Transfusion Independence ≥ 8 weeks

 Secondary Endpoint:
 RBC Transfusion Independence ≥ 12 weeks

 Additional Endpoints:
 Duration of Response
 Hb Change from Baseline

                                          List A, et al. ASH 2018. Abstract 001.

MDS: Lower Risk

                  List A, et al. ASH 2018. Abstract 001.

MDS: Lower Risk

                  List A, et al. ASH 2018. Abstract 001.

MDS: Lower Risk

                  List A, et al. ASH 2018. Abstract 001.

MDS: Lower Risk

                  List A, et al. ASH 2018. Abstract 001.

MDS: Lower Risk

                  List A, et al. ASH 2018. Abstract 001.

MDS: Lower Risk

                  List A, et al. ASH 2018. Abstract 001.

MDS: Lower Risk

                  List A, et al. ASH 2018. Abstract 001.

MDS: Lower Risk

 MEDALIST Trial – Conclusions
  In lower-risk, RS-positive MDS, luspatercept
   resulted in RBC-TI, major RBC transfusion
   reduction, and hemoglobin increase
  Erythroid responses are durable
  Well tolerated
  Potential new therapy

                                          List A, et al. ASH 2018. Abstract 001.

Question

 70M with MDS-EB2, trisomy 8, and 8% BM blasts.
 Treatment with azacitidine (75mg/m2 x 5 days) for 3
 cycles. Patient complains of fatigue and CBC (WBC
 1.5, ANC 0.5, Hg 8, Platelets 50K), all worse than prior
 to start of treatment.
 What is the next step:
 A. Stop therapy and perform BMB
 B. Continue azacitidine
 C. Continue azacitidine & increase treatment intervals
 D. Continue azacitidine & add GCSF
 E. Continue azacitidine & add TPO agonists
 F. Continue azacitidine & add GCSF and TPO agonists
 G. Switch to decitabine
 H. Switch to another agent

Question

 70M with MDS-EB2 and treated with azacitidine for 16
 cycles. BMBX after 7 cycles revealed CR. Patient now
 complains of fatigue and CBC (WBC 2.5, ANC 1.1, Hg
 7, Platelets 90K). BMBX now reveals 17% blasts, TP53
 and ASXL1 mutations, and complex cytogenetics
 (trisomy 8, del5q, del 7). He had and continues to
 decline SCT. What is the next step:
 A. Hospice
 B. Continue azacitidine
 C. Continue azacitidine, but add venetoclax
 D. Lenalidomide
 E. CPX-351
 F. Switch to decitabine
 G. Clinical Trial

MDS: Higher Risk
                     Why Is Time Required?
                  Consider What is Happening…
                                                          ANC (Neutrophil Granulocytes)
                                             3.2                                                     100%

  Early toxicities may be                    2.7                                                     80%

                                ANC, 109/L
      difficult and/or                       2.2       ANC ref. value                                60%
   discouraging for the                      1.7                                                     40%
           patient
                                             1.2                                                     20%

                                             0.7                                                     0%
                                                   1       6         11        16           21
                                                                 Treatment, weeks

                                                                                  ANC Mean ± 97.5 CI

                                                                 Sekeres MA, List AF. Clin Leuk. 2008;2:28-33.

MDS: Higher Risk

    Timing of Evaluation
    Definition of Resistance
    Prediction of Response after HMA
     Failure

MDS: Higher Risk

                                                                   Median OS 5.6 months
Percent Overall Survival

                                                                      at HMA failure
                                                                       for HR MDS

                                                                    N=435

                           Time Since Azacitidine Failure (days)

                                                                            Prebet et al. JCO 2011;29:3322

MDS: Higher Risk

      Performance Status (PS

MDS: Higher Risk

    IPSS-R Lower Risk
        Rechallenge with ESAs
        TPO Mimetics
        Lenalidomide
        Clinical Trial
           Luspatercept
           Guadecitabine
           Spliceosome Inhibitors

MDS: Higher Risk

  IPSS-R Higher Risk
       SCT
       Low Dose Chemotherapy
       CPX-351
       Clinical Trial
           Targeted Therapy (Enasidenib, Ivosidenib)
           Non-Targeted Therapy (Rigosertib, Venetoclax)
           Combination Therapy (HMA + )
           Second Generation HMA
           Immunotherapy (Ipilumumab, Nivolumab,
            Pembrolizumab)

MDS: Higher Risk

 ETCTN Trial 10026 - Ipilimumab and Decitabine
 - Relapsed MDS patients with 5% blasts or greater
        After allogeneic stem cell transplant
                       OR
        After 4 cycles of hypomethylating agent

MDS: Higher Risk

   Phase III ONTIME: Rigosertib: PLK and PI3K inhibitor; a novel synthetic
   benzyl styryl sulfone that is cytotoxic against a variety of human tumor cell
   lines

                                                                      Wk 16
                         Stratified by blast %
                     (5% to 19% vs 20% to 30%)
 Patients with higher-risk
   MDS (FAB, RAEB/t,                     Rigosertib (ON 01910.Na) + BSC               Continue
          CMML),                              1800 mg/d x 3 days q2w                  treatment q4w until
 relapsed/refractory after
                                                     (n = 180)                        progression
 azacitidine or decitabine
    (planned N = 270)
                                          Best Supportive Care
                                          LoDAC, hydrea, GFs
                                                (n = 90)

   •   Primary endpoint: OS (HR: 0.62)
   •   Secondary endpoints: IWG response, transformation to AML, infection,
       bleeding, QoL

                                                               Garcia-Manero et al. Lancet Oncology; 2016;17:496-508

MDS: Higher Risk

                   Garcia-Manero et al. Lancet Oncology; 2016;17:496-508

MDS: Higher Risk

             INSPIRE - Rigosertib

MDS: Higher Risk

  BCL-2 Inhibitor - Venetoclax
   - Current studies in both treatment naïve and HMA
  failure settings

  New Hypomethylating Agents
  - Guadecitabine (SGI-110, oral)
  - CC486 (oral form of azacitidine)
  - Cedazurine (ASTX727, orally fixed-dose combination
  of decitabine and a cytidine deaminase inhibitor)

  Imetelstat (telomerase inhibitor)
  - studied in myeloproliferative neoplasms and
  transfusion independence rates were ~30%

MDS: Higher Risk

                    Other Targets
 • IDH 1 and 2 – Ivosidenib and Enasidenib
 • HIF – Roxadustat
 • Need targets for TP53
    • Decitabine – 10 day regimen
    • APR-246, a TP53 modulator

MDS: Future Direction

            We have to do BETTER.

MDS and AML: Clinical
Trials at UVA
   Upfront – Unfit for Intensive Chemotherapy
      Azacitidine and Pracinostat (AML)
      BST-236 (conjugate of cytarabine and asparagine)
      Azacitidine and Pevonedistat (MDS, CMML, low blast AML)
   Upfront – Intensive Chemotherapy
      7+3 and Crenolanib (AML)
   Relapsed/Refractory
        MEC and Lenalidomide (AML)
        HAM/Ida-FLAG and Crenolanib (AML)
        Ipilimumab and Decitabine (AML/MDS)
        Rigosertib (MDS)
   Post-SCT
      Gilteritinib as maintenance post-SCT
   Myelofibrosis
      Ictacitinib (Post ruxolitinib failure)

Thanks!
  University of Virginia Leukemia/MDS Program
Karen Ballen, MD                     Veronica Brill, MSN, RN, NEA-BC
Kelly Davidson, MD                   Lisa Huntsinger, MSN, RN, CCRN
John J. Densmore, MD, PhD            Elizabeth Daniels, MSN, RN
                                     Katie Ruefer, BSN, RN, PCCN
Michael G. Douvas, MD
                                     Tanya Thomas, BSN, BA, RN, OCN
Laahn Foster, MD                     Devon Bloxsom, RN
Francine Garrett-Bakelman, MD, PhD   Lauren Kramer, RN
Michael K. Keng, MD                  Holly Mellott, RN
Tamila L Kindwall-Keller, DO         Mary Souder, RN
                                     Amy Morris, PharmD
Hillary Maitland, MD
                                     Amelia Hodson, RN
Louise Man, MD                       Kimberly Underwood, BA
Craig Portell, MD                    Megan Healy, BA
Indumathy Varadarajan, MD            Cory Caldwell, RN
Leonid Volodin, MBBS
Michael E. Williams, MD
Thomas P. Loughran, Jr.,MD
Daniel Reed, MD
Kimberly Leake, FNP, MSN, RN

                                 And Our Patients & Families!!!

Contact Information
Appointments or Referrals:
      434-924-9333

       Office:
    434-924-4257
  mk2pv@virginia.edu