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Winship Cancer Institute of Emory University Advances in the Management of MDS Martha L. Arellano, MD Associate Professor of Hematology/Oncology Winship Cancer Institute of Emory University Atlanta, GA Disclosures 1 Objectives Introduction

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Winship Cancer Institute of Emory University

Advances in the Management of MDS Martha L. Arellano, MD

Associate Professor of Hematology/Oncology Winship Cancer Institute of Emory University Atlanta, GA

Disclosures

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Objectives

  • Introduction
  • Describe the clinical presentation and diagnostic

evaluation of MDS

  • Discuss updates in the classification of MDS and

tools to assess disease risk in MDS

  • Summarize data from key clinical trials in MDS
  • Apply current prognostic scoring system in the

management of MDS

Myelodysplastic Syndromes (MDS)

  • A group of malignant stem cell disorders

characterized by ineffective hematopoiesis and variable risk of transformation to acute leukemia

  • Risk factors:

–Age

– Genetics – Environmental exposures – Prior therapy

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Impact of MDS

  • Incidence in the US estimated at 3.3:100,000
  • Median age at MDS diagnosis: 71‐76
  • Annual incidence estimated at 75:100,000

among persons > 65 years of age

  • Estimated that 25% will progress to AML

CR Cogle etal. Blood 2011; Ma et al. Cancer 2007

Age‐specific Incidence

Williamson PJ, et al. Br J Haematol. 1994

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Clinical Presentation

Ineffective hematopoiesis Dysplastic hematopoiesis Life‐threatening complications of MDS Progression to AML Increased apoptosis Cytokine suppression

  • f hematopoiesis

Abnormal marrow stromal cell‐cell Interactions Decreased apoptosis Additional mutations

Clinical Presentation

  • Asymptomatic
  • Cytopenia‐associated complications:

– Anemia: fatigue, ischemic complications – Neutropenia: infection – Thrombocytopenia: hemorrhage

  • B‐symptoms: fever, weight loss
  • Auto‐immune manifestations: skin,

neurological, other

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Disease Peripheral Blood findings Bone Marrow findings

RCUD, RA, RN, RT uni or bicytopenia, blasts <1%

*unilineage dysplasia, ≥ 10% of the cells, < 5% blasts, < 15% RS

RARS anemia, no blasts

> 15% RS, <5% blasts, erythroid dysplasia only

RCMD cytopenia(s), blasts < 1%, no auer rods, monocytes <1 × 109/L

dysplasia, > 10% cells of > 2 lineages, <5% blasts, no auer rods, +/‐ 15% RS

RAEB‐1 cytopenia(s), blasts < 5%, no auer rods, monocytes <1 × 109/L

uni or multilineage dysplasia, 5‐9% blasts, no auer rods

RAEB‐2 cytopenia(s), blasts 5‐19%, auer rods ±, monocytes < 1 × 109/L

uni or multilineage dysplasia, 10‐19% blasts, +/‐ auer rods

MDS‐U Cytopenias, < 1% blasts

dysplasia in <10% cells, accompanied by cytogenetic evidence of MDS, < 5% blasts

MDS with isolated del (5q) Anemia, platelets normal or increased, blasts < 1%

normal to ↑ megas with hypolobated nuclei, <5% blasts, no Auer rods, Isolated del5q

2008 WHO Classification of MDS

Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, Thiele J, Vardiman JW (Eds): Lyon 2008.

Recurring chromosomal abnormalities as presumptive evidence of MDS in the setting of persistent cytopenias without definitive dysplasia

Unbalanced abnormalities Balanced abnormalities −7 or del(7q) t(11;16)(q23;p13.3) −5 or del(5q) t(3;21)(q26.2;q22.1) i(17q) or t(17p) t(1;3)(p36.3;q21.1) −13 or del(13q) t(2;11)(p21;q23) del(11q) inv(3)(q21q26.2) del(12p) or t(12p) t(6;9)(p23;q34) del(9q) idic(X)(q13)

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Case

70 year old female evaluated for yearly physical examination

  • PMH: HTN, coronary disease
  • Medications: beta blocker, aspirin
  • WBC 5 x 109/L, 40% segs, no blasts, hgb 10 gm/dL, MCV

105, platelets 240 x 109/L

  • Work‐up unrevealing for specific etiology
  • BM Bx: possible dysplasia in < 5% cells, no increase in blasts,

chromosomes: deletion (7q) in 18 of 20 metaphases.

  • Dx: ???

Disease Peripheral Blood findings Bone Marrow findings

RCUD, RA, RN, RT uni or bicytopenia, blasts <1%

*unilineage dysplasia, ≥ 10% of the cells, < 5% blasts, < 15% RS

RARS anemia, no blasts

> 15% RS, <5% blasts erythroid dysplasia only

RCMD cytopenia(s), blasts < 1%, no auer rods, monocytes <1 × 109/L

dysplasia, > 10% cells of > 2 lineages, <5% blasts, no auer rods, +/‐ 15% RS

RAEB‐1 cytopenia(s), blasts < 5%, no auer rods, monocytes <1 × 109/L

uni or multilineage dysplasia, 5‐9% blasts, no auer rods

RAEB‐2 cytopenia(s), blasts 5‐19%, auer rods ±, monocytes < 1 × 109/L

uni or multilineage dysplasia, 10‐19% blasts, +/‐ auer rods

MDS‐U Cytopenias, < 1% blasts

dysplasia in <10% cells, accompanied by cytogenetic evidence of MDS, < 5% blasts

MDS with isolated del (5q) Anemia, platelets normal or increased, blasts < 1%

normal to ↑ megas with hypolobated nuclei, <5% blasts, no Auer rods, Isolated del5q

2008 WHO Classification of MDS

Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, Thiele J, Vardiman JW (Eds): Lyon 2008.

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MDS Prognosis

The International Prognostic Scoring System (IPSS) and WHO PSS (WPSS)

Greenberg, et al. Blood 89:2079‐88 (1997) Malcovati et al. JCO (2007) 25: 3503‐10

IPSS Score 0.5 1 1.5 2.0 % BM Blasts <5 5‐10 ‐‐ 11‐20 21‐30 Karyotype Good (nl, 5q‐, 20q‐, ‐Y) Intermediate (other) Poor (complex, abn. chr. 7) # cytopenias 0‐1 2‐3 Total Score Risk Group Median Survival (yrs) 25% Progression to AML, y Low 5.7 9.4 0.5 ‐ 1 Intermediate‐1 3.5 3.3 1.5 ‐ 2 Intermediate‐2 1.2 1.1 >2 High 0.4 0.2 WHO Score 1 2 3 category RA RARS, 5q‐ RCMD, RCMD‐RS RAEB‐1 RAEB‐2 Karyotype good intermediate poor ‐ RBC Transfusion? No Yes ‐ ‐

Risk groups: Very low 0; low 1; int 2; high 3‐4; very high 5‐6; OS 1‐8.6 years, AML 0.06‐0.94

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MD Anderson Lower‐Risk MDS Prognostic Scoring System

  • G. Garcia‐Manero et al. Leukemia 22, 538–543 (2008) R. Bejar. Hematology 2013

The Revised International Prognostic Scoring System (IPSS‐R)

Variable 0.5 1 1.5 2 3 4 CTG Very good ‐ Good ‐ Interm. Poor Very poor %BM blasts < 2% ‐ > 2 ‐ < 5% ‐ 5 ‐ 10% > 10% ‐ Hgb. > 10 ‐ 8 ‐ < 10 < 8 ‐ ‐ ‐ Platelets > 100 50 ‐ 99 < 50 ‐ ‐ ‐ ‐ ANC > 0.8 < 0.8 ‐ ‐ ‐ ‐ ‐ Cytogenetic (CTG) groupings:

  • Very good: ‐Y, del(11q)
  • Good: NL, del(5q), del(12p), del(20q), double including del (5q)
  • Intermediate: del(7q), +8, +19, i(17q), any other single or double clone
  • Poor: ‐7, inv(3)/t(3q)/del(3q), double incl. ‐7/del(7q)
  • Very poor: complex (> 3 abn)

Greenberg, et al. Blood 2012. 120: 2454‐2465

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MDS: IPSS‐R

Risk Category Risk Score

Very Low < 1.5 Low 2‐ 3 Intermediate 3.5 ‐ 4.5 High 5‐ 6 Very High > 6 N Very Low Low Interm. High Very High

Patients, % 7012 19 38 20 13 10

  • Med. Survival,

years (95% CI) 8.8 (7.8‐9.9) 5.3 (5.1‐5.7) 3 (2.7‐3.3) 1.6 (1.5‐1.7) 0.8 (0.7‐0.8) AML/25%, years NR (14.5‐NR) 10.8 (9.2‐NR) 3.2 (2.8‐4.4) 1.4 (1.1‐1.7) 0.73 (0.7‐0.9)

Greenberg, et al. Blood 2012. 120: 2454‐2465

Outcomes according to IPSS‐R

Survival AML‐free Survival

Greenberg, et al. Blood 2012. 120: 2454‐2465

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Frequency of Point Mutations in MDS and Association with Survival

  • R. Bejar et al. N Engl J Med 2011.

Hazard Ratio for Death

  • R. Bejar et al. N Engl J Med 2011.
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11 Overall Survival according to IPSS category and mutational status

  • R. Bejar et al. N Engl J Med 2011.

RISK REWARD

Treatment Options

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Goals of Therapy for MDS

  • Treatment selection: factors to consider

– Who is the patient (comorbidities, performance status) – Disease classification (risk, HLA‐DR type)

  • Lower risk disease

– Reduce transfusion requirement – Decrease infection risk – Improve quality of life?

  • Higher risk disease

– Prolong survival – Delay AML onset – Cure???

MDS: Treatment Options

  • Options:

– Supportive: transfusion, antibiotics, cytokines – Immune suppression (hypoplastic MDS, HLA‐DR15) – Chemotherapy (cytotoxic, HMT, IMIDs, newer/targeted agents) – Transplantation

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MDS Treatment: Cytokines and Imids

Agent Responses Comments rHEPO 25‐40%

  • Predictive model for response (7‐74%) using baseline epo

level (< 500) and RBC transfusion requirement (< 2 U) rHEPO + G‐CSF 40‐70%

  • Epo non‐responders may respond after addition of G‐CSF

Thrombopoietin mimetics 40‐65% platelet responses

  • Caution advised due to concern for AML, DVT, marrow

fibrosis Lenalidomide 43‐ 76% transfusion independence

  • Dose 10mg/day x 21‐28 days
  • Predictors of response (not consistently seen): 5q‐,

younger age, shorter MDS duration, lower transfusion needs, therapy‐related thrombocytopenia

Balleari et al. Ann Hematol 2005 Sekeres. Leukemia 2012 List et al. NEJM 2006

MDS Treatment: Immune suppression

Agent N Response Comments ATG 129 39 (30%; 12/39 CR) 18/74 ATG, 20/42 ATG/CSP, 1/13 CSP

  • 3 years median follow‐up of patients treated at

NIH, compared to 816 patients on BSC reported to the international myelodysplasia risk analysis workshop( IMRAW).

  • Younger age, int and low risk IPSS, HLA‐DR15+, ATG

+ CSP combination were associated with response.

ATG/CSP 88 (ATG 45 BSC 43) Hem response: ATG: 13/45 (29%) BSC: 4/43 (9%)

  • Ph III RCT of ATG/CSP vs. BSC
  • Crossover design (14 BSC subjects)
  • Therapy: ATG 15mg/kg/day x 5d; oral CSP x 180

days

  • Hem response:

‐P= 0.0156 for ATG/CSP; TFS/OS P= NS

Alemtuzumab 32 (31 eval) 21/31 (68% HI + CR)

  • Denovo MDS; selected based on probability of

responding to IST (age, HLA‐DR15 status, # mos. of red cell transfusion dependence)

  • Alem dose: 10mg/day IV x 10 days

Sloand et al. JCO 2008 Passweg et al. JCO 2011

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MDS Treatment: Hypomethylating agents

Response Aza (n=179) CC (n=179) p value

CR 17% 8% 0.02 PR 12% 4% 0.009 Any HI (major or minor) 49% 29% <0.0001 Time to AML (mos.) 15 (8.8‐27.6) 10.1 (3.9‐19.8) <0.0001 Overall Survival 24.5 15 0.0001

Fenaux, P et al. Lancet Oncology 2009; Lu¨bbert et al. JCO 2011

Response DEC (n= 119) BSC (n= 114) p value

CR 13% ‐ PR 6% ‐ Any HI (major or minor) 15% 2% ‐ Time to AML or death (mos.) 8.8 6.1 0.24 Progression free survival 6.6 3 0.004 Overall Survival 10.1 8.5 0.38

Response DEC (n= 89) BSC (n= 81) p value

CR 9% < 0.001 PR 8% Any HI (major or minor) 13% 7% Time to AML or death (mos.) 12.1 7.8 0.16 Overall Survival 14 14.9 0.636

MDS Treatment: Hypomethylating agents

Silverman et al. (CALGB) JCO 2002; Kantarjian et al. Cancer 2006

Response AZA (n= 99) BSC (n= 92) p value

CR 7% < 0.01 *PR 16% Any HI (major or minor) 37% 5% Time to AML or death (mos.) ^Overall Survival 20 14 0.10

*CR+PR+HI, P = 0.0001 ^ Landmark analysis after 6 mos. for pt crossed over early, late or AZA 11, 14, 18 (P = 0.03)

  • DEC dose: 15mg/m2 IV every 8 hrs for 3 days
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Multicenter Study of Decitabine Administered Daily for 5 Days Every 4 Weeks to Adults With MDS: The Alternative Dosing for Outpatient Treatment (ADOPT) Trial

Steensma et al. JCO 2009

Response type ITT (N= 99), % CR 17 marrrow CR 15 PR HI 18 SD 24 PD 10 Total response 74 Not assessable 15

  • Decitabine dose: 20mg/m2 IV daily for 5 days every 4 weeks.
  • 1‐year survival rate for patients treated with decitabine was 66%. Median OS was 19.4 months

(95% CI, 15 months to not estimable).

  • Median cycles: 5 (range 1‐17)

MDS Treatment: Transplantation

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Role of Cytoreduction in Transplant Candidates

  • Lower blast percentage (<5%) at time of transplantation,

associated with better post‐transplant outcomes?

  • B. Oran, ASH 2013. Abstr 731, Warlick et al. BBMT15:30‐38, 2009

Case

75 year old female evaluated for yearly physical examination; has been fatigued lately.

  • PMH: HTN, arthritis; FHx: NC
  • Medications: metoprolol, baby aspirin, prn

acetaminophen

  • WBC 2 x 109/L, 40% segs, no blasts, hgb 8 gm/dL,

platelets 150 x 109/L

  • Work‐up unrevealing for specific etiology
  • BM Bx: dysplasia in 10% of the cells, 9 blasts,

chromosomes: deletion (11q) in 18 of 20 metaphases.

  • Dx: ???
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Disease Peripheral Blood findings Bone Marrow findings

RCUD, RA, RN, RT uni or bicytopenia, blasts <1%

*unilineage dysplasia, ≥ 10% of the cells, < 5% blasts, < 15% RS

RARS anemia, no blasts

> 15% RS, <5% blasts erythroid dysplasia only

RCMD cytopenia(s), blasts < 1%, no auer rods, monocytes <1 × 109/L

dysplasia, > 10% cells of > 2 lineages, <5% blasts, no auer rods, +/‐ 15% RS

RAEB‐1 cytopenia(s), blasts < 5%, no auer rods, monocytes <1 × 109/L

uni or multilineage dysplasia, 5‐9% blasts, no auer rods

RAEB‐2 cytopenia(s), blasts 5‐19%, auer rods ±, monocytes < 1 × 109/L

uni or multilineage dysplasia, 10‐19% blasts, +/‐ auer rods

MDS‐U Cytopenias, < 1% blasts

dysplasia in <10% cells, accompanied by cytogenetic evidence of MDS, < 5% blasts

MDS with isolated del (5q) Anemia, platelets normal or increased, blasts < 1%

normal to ↑ megas with hypolobated nuclei, <5% blasts, no Auer rods, Isolated del5q

2008 WHO Classification of MDS

Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, Thiele J, Vardiman JW (Eds): Lyon 2008.

The Revised International Prognostic Scoring System (IPSS‐R)

CTG: Very good: ‐Y, del(11q); Good: NL, del(5q), del(12p), del(20q), double including del (5q); Interm: del(7q), +8, +19, i(17q), any other single or double clone, Poor: ‐7, inv(3)/t(3q)/del(3q), double including ‐7/del(7q); Very poor: complex (> 3 abn)

Greenberg, et al. Blood 2012. 120: 2454‐2465

Variable 0.5 1 1.5 2 3 4 CTG Very good ‐ Good ‐ Interm. Poor Very poor %BM blasts < 2% ‐ > 2 ‐ < 5% ‐ 5 ‐ 10% > 10% ‐ Hgb. > 10 ‐ 8 ‐ < 10 < 8 ‐ ‐ ‐ Platelets > 100 50 ‐ 99 < 50 ‐ ‐ ‐ ‐ ANC > 0.8 < 0.8 ‐ ‐ ‐ ‐ ‐

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MDS: IPSS‐R

Risk Category Risk Score

Very Low < 1.5 Low 2‐ 3 Intermediate 3.5 ‐ 4.5 High 5‐ 6 Very High > 6

Greenberg, et al. Blood 2012. 120: 2454‐2465

N Very Low Low Interm. High Very High

Patients, % 7012 19 38 20 13 10

  • Med. Survival,

years (95% CI) 8.8 (7.8‐9.9) 5.3 (5.1‐5.7) 3 (2.7‐3.3) 1.6 (1.5‐1.7) 0.8 (0.7‐0.8) AML/25%, years NR (14.5‐NR) 10.8 (9.2‐NR) 3.2 (2.8‐4.4) 1.4 (1.1‐1.7) 0.73 (0.7‐0.9)

Therapy?

  • ESA?
  • Observation?
  • Clinical trial?
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Case

  • Following 10 months of ESA after initial response…
  • WBC 1 x 109/L, 40% segs, 2% blasts, hgb 8 gm/dL,

platelets 100 x 109/L

  • BM bx: cellularity 80%, 12% blasts, Chromosomes: ‐

7, del (11q)

  • Therapy?

– HMT? – Clinical trial? – Transplantation?

MDS Tissue Acquisition Program Allogeneic Stem Cell Transplant > INT-2

Refractory to / unlikely to respond to ESA therapy; no prior HMA

Phase II Pfizer

B1371003;

LDAC ± Hedgehog Inhibitor Phase I /II Incyte

INCB4798 - 201;

INCB047986 (Age ≥ 60) Phase II Cyclacel CYC682-06; Sapacitabine

After HMA; with 10-30% marrow blasts ± prior HMA; with 10-19% marrow blasts

Phase I/II Prism PRI-724-201; PRI-724

Relapsed / Refractory

Phase II PROBLEMA Winship 2429 Thrombocytopenia, starting Amicar PK / PD Study, Starting Amicar Phase III GSK

TRC112121;

Azacitidine +/- Eltrombopag

Phase I MedImmune D4190C00007; MEDI4736 No prior HMA