Simposio AA & MDS International Foundation: Manejo de Anemia Aplásica Severa - Dr. Rodrigo Calado

VII CONGRESO PERUANO DE HEMATOLOGÍA Lima, 20-22 Octubre, 2016

MANAGEMENT OF SEVERE APLASTIC ANEMIA

Rodrigo T. Calado, MD/PhD Associate Professor of Medicine, Hematology Ribeirão Preto School of Medicine University of São Paulo

TREATMENT OF REFRACTORY SAA Era Drug 1960s corticosteroids 1970s ATGs 1980s h-ATG plus CSA 1990s salvage ATG ≅ 75-90% overall response

Failure due to: • Insufficient immunosuppression • ↓ stem cell reserve • non-immune disease

Survival probability

• • • • •

Response ~10% (occasional) 40-50% 60-70% 30-70% (refractory cases) 1.0

Improvement in survival refractory SAA

0.8

2002-2008; OS = 57% 0.6

0.4

96-2002; OS = 35%

0.2 Non-responders to IST (N=174)

89-1996; OS = 23%

P<0.001

0 0

2

4

6

Time (years)

8

INSUFFICIENT IMMUNOSUPPRESSIVE THERAPY

Horse-ATG IS SUPERIOR FOR THE TREATMENT OF SEVERE APLASTIC ANEMIA Response

h-ATG

r-ATG

p value

3 months

37/60 (62%)

20/60 (33%)

0.002

6 months

41/60 (68%)

22/60 (37%)

< 0.001

Not censored for HSCT

100

100

80

80

Survival (%)

Survival (%)

Censored for HSCT

60 40 20

60 40 20

h-ATG r-ATG

0

h-ATG r-ATG

0 0

500

1,000

1,500

Time (days)

2,000

0

500

1,000

1,500

2,000

Time (days) Scheinberg P, et al. NEJM 2011;365:430-8

1.00

Horse-ATG IS SUPERIOR FOR SAA: BONE STUDY

0.50

0.75

USP Ribeirão Preto INCa Rio de Janeiro UFPR Curitiba UFBA Salvador UNICAMP Campinas ABP São Paulo

0.25

Logrank Test < 0.05

0.00

HORSE ATG RABBIT ATG 0

Number at risk HORSE 85 RABBIT 170

500

1000 time(days)

1500

2000

75 107

73 75

68 39

60 21

JP Garrahan Buenos Aires

Clé DV et al, unpublished

FURTHER IMMUNOSUPPRESSION: MESENCHYMAL CELLS No addi4onal benefit added to second line r-ATG + CSA + mesenchymal stromal cells2

r-ATG + CSA1 100

100 75 OS:70%

OS (%)

OS (%)

75

50 25 0

OS:71%

50 25

0

250

500

Time (days)

750

1,000

0

0

180 360 540 720 900 1,080

Time (days) Scheinberg et al. Br J Haematol. 2006 Clé et al. Cytotherapy 2015

Patients treated <1999

IMMUNOSUPPRESSION VS. BONE MARROW TRANSPLANT FOR SAA

Fig. 3 Comparison of IST versus BMT The>advantage of IST is no longer Yearin< patients 1999 aged 21–40 years, before (Fig. 3a) or ≥ 1999 (Fig. 3b).

Year 1999 Patients age (years) a in the last decade b seen

Univariate analysis

IS; n=750

62%

7 6% Dx Tx (days) <100 BMT; n= 636 Interval 76 %, whereas the IST group has remained at the same surTreatment vival (62 versus 65 %).

Severity n=241patients aged Figure 4 shows survival of theIS;older over of SAA 65% 40 years: no significant difference between IST and BMT before 1999 (Fig. 4a), but a significant survival advantage Patients treated ≥1999 for IST over BMT in the most recent period (Fig. 4b).Patients age (years)

0–20

≥10

IST vSA

Figure 2 depicts the actuarial 10-year survival for patients 58% aged 1–20 years, treated first-line withn=either BMT; 669 IST or BMT in the two time periods: both curves (Fig. 2a, b) show higher early mortality in the BMT group, which is compen0–20 sated by higher late mortality in the IST group. The probP=0.6 P=0.002 ability of being alive at 10 years in the period ≥1999 is Multivariate analysis on survival Interval Dx Tx (days) <100 really identical in both groups.

Treatment IST Figure 3 outlines survival for patients aged 21–40 years A multivariate Cox on survival was run with the following vSA Severity of SAA in the 2 time periods. In the earlier period, there is a clear variables: age (0–20, 21–40, >40 years); interval diagnosis advantage for patients receiving IST at all time points transplant (Dx-Tx) (<100 days; ≥100 days), first-line treat(Fig. 3a). If one compares this results with the most recent ment (IST, BMT), year of treatment (>1999; ≥1999); and Fig. 3 Comparison of IST versus BMT in patients aged 21–40 years, before (Fig. 3a) or ≥ 1999 (Fig. 3b). The advantage of IST is no longer decade (Fig. 3b), there is now no difference due to the sigseverity of the disease (<0.20; 0.21–0.5; >0.5 × 10^9/L seen in the last decade nificant improvement of the transplant group, from 58 to neutrophils). Results are shown in treatment Table 2. was entered as a categorical variaWhen year of

> 40 YEARS

< 20 YEARS

Univariate analysis

13

Figure 2 depicts the actuarial 10-year survival for patients aged 1–20 years, treated first-line with either IST or BMT in the two time periods: both curves (Fig. 2a, b) show higher early mortality in the BMT group, which is compensated by higher late mortality in the IST group. The probability of being alive at 10 years in the period ≥1999 is really identical in both groups.

Figure 3 outlines survival for patients aged 21–40 years in the 2 time periods. In the earlier period, there is a clear advantage for patients receiving IST at all time points (Fig. 3a). If one compares this results with the most recent decade (Fig. 3b), there is now no difference due to the significant improvement of the transplant group, from 58 to

20-40 YEARS

ble IST (<1999; this proved highly 76 %, whereas the group≥1999), has remained at the same sur-significant, with a RR vival (62 versusof 65death %). of 0.69 for patients treated in the most recent period.

Other positive predictors of survival were a less severe disFigure 4 shows survival of the older patients aged over 40 years: no significant difference ISTtreatment and BMT (<100 days). Similar ease, younger age,between and early before 1999 (Fig. 4a), but a significant survival advantage for IST over BMT in the most recent period (Fig. 4b).

Multivariate analysis on survival A multivariate Cox on survival was run with the following variables: age (0–20, 21–40, >40 years); interval diagnosis transplant (Dx-Tx) (<100 days; ≥100 days), first-line treatment (IST, BMT), year of treatment (>1999; ≥1999); and severity of the disease (<0.20; 0.21–0.5; >0.5 × 10^9/L neutrophils). Results are shown in Table 2.

13 Bacigalupo A et al, Int J Hematol 2016

REDUCED STEM CELL RESERVE

Patients

DOES FAILURE TO RESPOND TO IST REFLECT ONLY RESIDUAL STEM CELL NUMBERS?

Lower limit of accurate in vitro assays ↑ Probability of failure

↑ Probability of recovery

(Correlation with blood counts, age)

Stem cell number

Young NS. Hematology ASH Educ Program 2013

Eltrombopag

§ 2nd-genera[on, small-molecule TPO agonist § Orally administered non-pep[de § FDA accelerated approval in 2008 for treatment of chronic ITP § FDA approval for refractory SAA in August 2014 Courtesy of Dr. D. Townsley, NIH

A RANDOMIZED TRIAL OF ELTROMBOPAG IN REFRACTORY SAA

§ 44% (11/25) response rate § Trilineage responses observed § Transfusion independence § Well tolerated Olnes MJ, et al. N Engl J Med. 2012;367:11-9.

ELTROMBOPAG FOR REFRACTORY APLASTIC ANEMIA Treatment plan • SAA with plts < 30K/uL • Refractory to IST

Eltrombopag 50 mg daily

Dose escala]on every 2 weeks to 150 mg daily

Hematologic response a`er 12 weeks

Con]nue eltrombopag un]l robust response or no further improvement (extension study)

Hematologic Response Criteria • Platelets: >20K/uL increase, or transfusion-independence • RBCs: >1.5 g/dL increase in Hb, or least 50% transfusion reduction • ANC: >100% increase if severe neutropenia, or >500/uL increase Olnes MJ, et al. N Engl J Med. 2012;367:11-9.

RESPONSE SUMMARY OF EXPANDED COHORT

Median follow-up: 9 months (range 3–47)

44 patients enrolled 11 patient patient ineligible; not treated ineligible, not treated

17 responders (40%) § 11 PLT responses § 4 erythroid responses − additional 7 at > 16 weeks

§ 8 neutrophil responses

43 evaluable patients

26 non-responders § 2 responded > 16 weeks § 1 died of progression

− additional 3 at

§ 3 deaths from sepsis

> 16 weeks

§ 6 clonal evolution Desmond R, et al. Blood. 2014;123:1818-25.

LINEAGE CHARACTERISTICS OF RESPONSES 12-week primary end-point

1

6 3

Best response at follow-up

2

3

2

1

7

4

4

2

PLTs Neutrophils Hb Desmond R, et al. Blood. 2014;123:1818-25.

BM CELLULARITY AT 1 YEAR Pretreatment

Post-treatment

Pretreatment

Post-treatment

Pretreatment

Post-treatment

Pretreatment

Post-treatment

Olnes MJ, et al. N Engl J Med. 2012;367:11-9

EXTENDED DOSING OF ELTROMBOPAG FOR rSAA Responder - platelets

Patients #

16

16

11

8

3

2

Winkler T et al, unpublished

EXTENDED DOSING OF ELTROMBOPAG FOR rSAA Responderâ&#x20AC;&#x201C; hemoglobin

Patients #

16

16

11

8

3

2

Winkler T et al, unpublished

EXTENDED DOSING OF ELTROMBOPAG FOR rSAA Responder â&#x20AC;&#x201C; neutrophils

Patients #

16

16

11

8

3

2

Winkler T et al, unpublished

EXTENDED DOSING OF ELTROMBOPAG FOR rSAA Can EPAG administra]on be discon]nued ?

• • • •

16/36 on EPAG extension 1/16 early relapse (8 month) 2/16 alterna[ve Rx Eltrombopag stopped • 9 robust response

Stopping criteria:

Robust response (RB): • Platelets >50,000/ul • Hb >10 g/dL • Neutrophils >1,000/ul or • stable counts (ST) but not SAA

• Median [me to robust 15 months (range 7-27m) • Relapse: (n=2) • 1 at [me of influenza -> addi[onal 3m on EPAG -> RB – off drug • 1 ajer CSA stop -> slow taper-> count recovery

Winkler T et al, unpublished

EXTENDED DOSING OF ELTROMBOPAG FOR rSAA CBC a`er EPAG discon]ua]on platelets

Patients #

9

7

Neutrophil

2

hemoglobin Median increase from basline:

platelets: 47000 k/ul ANC:1.21k/ul Hgb:3.7 g/dl Winkler T et al, unpublished

EXTENDED DOSING OF ELTROMBOPAG FOR rSAA Can EPAG administra]on be discon]nued ?

Patient 1

Baseline

39 mo

6 mo off drug

33 mo

6 mo off drug

Patient 2

Baseline

Winkler T et al, unpublished

EXTENDED DOSING OF ELTROMBOPAG FOR rSAA Clonal evolu]on Age

Baseline

Clone

Time on EPAG (months)

30

46XX[20]

46XXdel(13)q[17]/ 46XX[3]

3

N

Sepsis, died

47

46XY[20]

46,XX,inv(3)(q12q27)[3]/ 46,XX[17]

3

N

46 XY, Stable counts

54

46XY[20]

47,XX,+6[7]/ 46,XX[13]

3

N

EPAG for MDS, response

67

No metaphases

MDS/AML

3

N/A

Sepsis, died

30

46XX[20]

46,XX,del(7)(q22q34)[18] /46,XX[2]

3

Y

MUD, died, TRM

26

46XY[20]

45,XY,-7[14]/ 46,XY[6]

6

Y

MUD

Clonal evolu]on at 6 months 6/36 =17%, Time ďŹ rst IST to evolu]on 24 months ( 12-200)

Dysplasia

Follow up

Winkler T et al, unpublished

EXTENDED DOSING OF ELTROMBOPAG FOR rSAA Toxici]es • No grade 4 or 5 adverse events aoributable to drug • No significant increase in marrow re[culin

• No dose adjustments due to transamini[s

Winkler T et al, unpublished

ELTROMBOPAG ADDED TO IST AS FIRST-LINE TREATMENT Hematologic response hATG Day 1 to 4

3 months

6 months

CSAÃ&#x2014;6 months

Cohort 1 Cohort 2 Cohort 3

Eltrombopag 150 mg Day 14 to 6 months Eltrombopag 150 mg Day 14 to 3 months

5 year follow-up

Eltrombopag 150 mg Day 1 to 6 months

clinicaltrials.gov NCT01623167 Oral presentation at ASH 2015; Townsley DM et al. Blood 2015;126:LBA-2

ELTROMBOPAG ADDED TO IST AS FIRST-LINE TREATMENT Study endpoints • Primary endpoints – Complete response (CR) rate at 6 months – Toxicity

• Secondary endpoints – Overall response (OR) and par[al response (PR) – Survival, clonal evolu[on, relapse CR = ANC ≥1 x109/L, hemoglobin ≥10 g/dL and platelets ≥100 x109/L PR = Blood counts no longer meeting criteria for SAA or CR

clinicaltrials.gov NCT01623167 Oral presentation at ASH 2015; Townsley DM et al. Blood 2015;126:LBA-2

ELTROMBOPAG ADDED TO IST INCREASES RESPONSE RATES Cohort 1 N=30

Cohort 2 N=31

Cohort 3 N=31

N (%)

N (%)

N (%)

OR

23 (77)

24 (77)

23/25 (92)

CR

5 (17)

8 (26)

11/25 (44)

OR

24 (80)

27 (87)

19/20 (95)

CR

10 (33)

8 (26)

12/20 (60)

Historic IST response rates 3 months

6 months

OR

57–62%

62–68%

CR

7–10%

10–15%

3 months

6 months

OR = 84% (51/61) P=0.013* (95% CI, 71–91%)

OR = overall response (blood counts no longer meeting criteria for SAA) CR = complete response (ANC ≥1x109/L, hemoglobin ≥10 g/dL, and platelets ≥100x109/L)

clinicaltrials.gov NCT01623167 Oral presentation at ASH 2015; Townsley DM et al. Blood 2015;126:LBA-2

CLONAL EVOLUTION IN REFRACTORY AA ON ELTROMBOPAG Age (years)

Response

Time to evolu]on

Cytogene]cs

68

CR

3 months

46, XX, del(13)(q12q22)[cp3]/ 46,XX[17]

No

Cytogene[cs normalized none detected

39

CR

30 months

48,XX +6 +15 [2]/46,XX[18]

No

Stable DNMT3A (3%)

64

PR

3 months

45,XX,t(3;3)(q21;q26),-7[3]/ 46, XX[17]

Yes

AML/HSCT, death none detected (RTEL1)

72

PR/ Relapse

30 months

45, XY,-7[20]

Yes

ASXL1 (24%) Stable RUNX1 (12%)

48

CR/ Relapse

6m

46,XX,del (7)(p13p15)[3]/46,XX[19]

No

DNMT3A (15%) HSCT

61

PR

6m

45,XX,-7[7]/46,XX[16]

Yes

none detected Proceeding to HSCT

16

NR

3m

45,XY,-7[6]/46,XY[14]

No

HSCT none detected (RTEL1)

VAF, variant allele frequency

MDS/AML soma]c gene BM dysplasia Outcome muta]ons (VAF)

Dumitriu B et al. Blood 2015;125:706â&#x20AC;&#x201C;709; Oral presenta[on at ASH 2015; Townsley DM et al. Blood 2015;126:LBA-2

clinicaltrials.gov NCT01623167 Oral presentation at ASH 2015; Townsley DM et al. Blood 2015;126:LBA-2

ELTROMBOPAG ADDED TO IST IMPROVES OVERALL SURVIVAL Censored for HSCT

Not censored for HSCT

100

100 99%

Survival (%)

97% Median follow-up 18 months (range 1 â&#x20AC;&#x201C; 42 months)

50

50

0

0 0

500

1000

1500

0

500

Time (days) No. at risk:

92

69

49

26

12

1000

1500

Time (days) 1

92

69

49

26

11

1

clinicaltrials.gov NCT01623167 Oral presentation at ASH 2015; Townsley DM et al. Blood 2015;126:LBA-2

INSIGHTS INTO SAA PATHOPHYSIOLOGY Immune attack Eltrombopag therapy

↑ Probability of failure

↑ Probability of recovery

Stem cell number

ELTROMBOPAG ADDED TO IST AS FIRST-LINE TREATMENT FOR SAA Study designed by the BONE group Hematologic response FPFV 01/2017

3 months

6 months

12 months

CSAĂ&#x2014;12 months Eltrombopag 150 mg Day 0 to 6 months

5 year follow-up

Phase II, open label, single-arm trial to assess efficacy and safety of eltrombopag combined with CSA as first-line therapy in patients with SAA

Primary endpoints: OR rate at 6 months Secondary endpoints: OR rate at 3 and 12 months, survival and safety Overall hematologic response (OR) = complete response (CR) plus partial response (PR)

CETB115 2403

NON-IMMUNE MECHANISM

TELOMERES AND HUMAN DISEASE • Muta[ons in TERT, TERC, TINF2, RTEL1, DKC1, TCAB1...

• Dyskeratosis congenita is the typical telomere disease • Very short telomeres

Aplas[c anemia

• Fogarty et al. Lancet, 2003 • Yamaguchi et al. NEJM, 2005

Pulmonary fibrosis

Liver disease

• Tsakiri et al. PNAS, 2007 • El-Chemaly et al. Chest, 2010

• Calado et al. PLoS, 2009 • Calado et al. Hepatology, 2011 • Hartmann et al. Hepatology, 2011

ANDROGEN THERAPY FOR APLASTIC ANEMIA

Hematocrit

48%

16%

May/90

Feb/92

SEX HORMONES INCREASE TELOMERASE ACTIVITY IN CULTURED HUMAN LYMPHOCYTES 900 (n=10)

TPG units

600

300

0

0

0.5 5μM

R1881

0 5μM

0 5μM

0 1μM

19-NT

6β-HT

Estradiol

Androgens Calado et al, Blood 2009

DANAZOL FOR TELOMEROPATHY PATIENTS: Study Design • Danazol 800 mg/day was given for 24 months • 27 pa[ents with telomere diseases, short telomeres ± muta[ons were enrolled • 10 with TERT muta[on; 7 with TERC, 3 with DKC1, 1 with RTEL1; 6 unknown • 12 pa[ents were evaluable for primary endpoint: • 12/27 met response criteria at 2 years • 11/12 showed telomere elonga[on • 10/12 showed hematologic response at 2 years • 10 pa[ents withdrew before 2 years (5 toxicity, 2 alterna[ve therapy, 1 disease progression, 2 no stated reason) • 5 pa[ents with missing data due to study halted early Townsley et al, NEJM 2016

All evaluable patients had improvement in telomere attrition on danazol. Sign

telomere elongation was observed at 6, 12, and 24 months after starting dana DANAZOL FOR TELOMEROPATHY PATIENTS: compared with time 0 (Table 2). When danazol was stopped at 24 months, a Primary Endpoint: Telomere AFri4on telomere length was observed at 30 and 36 months. All available data points in this analysis.

Townsley et al, NEJM 2016

DANAZOL FOR TELOMEROPATHY PATIENTS: Hematologic Response 150

ARC (k/μL)

Hemoglobin (g/dL)

15

10

5

0

Danazol!

0 mo

6 mo

12 mo

24 mo

36 mo

Danazol!

0 mo

6 mo

12 mo

24 mo

36 mo

24 mo

36 mo

150

Platelets (k/μL)

4000

ANC (/μL)

50

0

5000

3000 2000 1000 0

100

Danazol!

0 mo

6 mo

12 mo

24 mo

36 mo

100

50

0

Danazol!

0 mo

6 mo

12 mo

Townsley et al, NEJM 2016

NANDROLONE FOR TELOMEROPATHIES “Nandrolone for GeneEc Marrow and Lung Disorders”

Nandrolone 5mg/kg every 2 weeks x 2 yrs for pa[ents with short telomeres +/- muta[ons

Phase I/II design, N=20

Primary endpoint: telomere aori[on Secondary clinical endpoints: toxicity (especially hepa[c) efficacy (blood counts and pulmonary func[on)

RECRUITING PATIENTS! ClinicalTrials.gov identifier: NCT02055456

20"

5"

18"

4,5"

16"

4"

14"

3,5"

12"

3"

ANC$

Hemoglobin*(g/dL)*

NANDROLONE FOR TELOMEROPATHIES

10" 8"

2"

6"

1,5"

4"

1"

2"

0,5"

0"

0"

Pre"

6m"

12m"

18m"

80"

Pre"

6m"

12m"

18m"

Pre"

6m"

12m"

18m"

250"

70"

200"

60"

Platelets'(/uL)'

Re#culocytes+(k/uL)+

2,5"

50" 40" 30" 20"

150"

100"

50"

10" 0"

Pre"

6m"

12m"

18m"

0"

Clé et al. unpublished

Translational Hematology Lab

Support

Translational Hematology Lab Diego Clé Barbara Santana Raquel Alves Paiva Gustavo Borges Renan Carvalho Flávia Donaires Lilian Figueiredo Fernanda Gutierrez Marcos Oltramari Pedro Prata André Santos João Paulo Silva Florencia Tellechea Leonardo Zanelatto

BONE: Brazilian Marrow Failure Network Phillip Scheinberg Diego Clé Larissa Medeiros Michel Michels Elias Aoa Marco Salvino Sara Ollala Saad Rodrigo Calado

NHLBI: Neal Young Phillip Scheinberg James Cooper Thomas Winkler