Autologous Stem Cell Transplantation for Multiple Sclerosis Richard A. Nash Colorado Blood Cancer Institute Denver, CO University of Louisville April 9, 2016

Background: Multiple Sclerosis • MS is an immune-mediated disease of the CNS (brain and spinal cord) causing multiple demyelinating lesions and neuronal/axonal loss. • Major cause of disability among young adults. • Clinical course: – Relapsing-remitting (inflammatory) – Secondary Progressive (inflammatory/degenerative)

Focal White Matter Lesions: T1, T2 and Gadolinium-Enhancing T1

T2

Gd-enhancement on T1 scan with accompanying new T2 lesion

T1

T2

2 months post: no Gdenhancement on T1 scan but T2 lesion persists

Expanded Disability Status Scale Increasing Disease Burden

Level of Disability

Death due to MS

Normal neurologic exam

0

No disability

1

Minimal disability

2

Moderate disability

3

Ambulatory with unilateral Wheelchair Ambulatory assistance Fully 100 m ambulatory without aid 200 m with severe disability

4

5

6

7

Helpless Bedridden

8

9

10

EDSS Score Kurtzke JF. Neurology. 1983;33:1444-1452.

Outcomes after HDIT and autologous HCT for advanced MS Bowen et al, BMT, 2012

Figure 1

Long-term results of stem cell transplantation for MS: a single-center experience. Fassas A; Kimiskidis VK; Sakellari I; Kapinas K; Anagnostopoulos A; Tsimourtou V; Sotirakoglou K; Kazis A Neurology. 76(12):1066-70, 2011 Mar 22. DOI: 10.1212/WNL.0b013e318211c537

Figure 1 Progression-free survival by pretransplant MRI activity (presence of gadolinium-enhancing, new, or enlarging T2 lesions). Data were available in 20 patients with secondary progressive (n= 15) and relapsing (n= 5) multiple sclerosis (MS) types, and in 10 patients with primary progressive MS: 44% at 15 years for patients with active lesions on MRI vs 10% for those without; p= 0.01. The difference also appears significant for the group of secondary progressive/relapsing MS (upper right) but not for primary progressive disease (lower right). ©2011 American Academy of Neurology.

2

Five-Year Outcomes of Halt-MS: High-Dose Immunosuppressive Therapy and Autologous Hematopoietic Cell Transplantation for Severe Relapsing-Remitting Multiple Sclerosis Richard A. Nash, MD University of Louisville, 04/09/2016

Immune Tolerance Network, ITN033AI DAIT, NIAID, NIH, USA

HALT MS: Study Overview

• Hypothesis: Intensive immunosuppressive therapy supported by autologous hematopoietic cell infusion will arrest disease activity in individuals with poor-risk MS. • Study design: Prospective, open-label, single-arm, multicenter Phase II clinical trial. • Primary Objective: To determine the 5-year durability of disease stabilization in MS subjects after HDIT and autologous HCT. Interim analysis was done at 3 years.

Previous Publication

• High-Dose Immunosuppressive Therapy and Autologous Hematopoietic Stem Cell Transplantation for Relapsing-Remitting Multiple Sclerosis (HALT-MS) A 3 Year Interim Report JAMA Neurology 72 (2):159-169, February, 2015

Primary Endpoint

Event-free survival during the 5 years after high-dose therapy. Composite endpoint for event-free survival includes one or more of the following: a) Relapse •

New neurological S/S persisting > 48 hrs

b) MRI abnormalities (>12 months post-tx) ≥ 2 or more independent MS lesions

•

c) Progression in disability (> 6 months post-tx) •

≥ 1.0 EDSS confirmed > 3 months later

d) Mortality

Eligibility

1. 2. 3. 4. 5. 6. 7.

Age: 18- 60 years, inclusive. Diagnosis of MS using McDonald Criteria. MS duration < 15 yrs from diagnosis. RRMS with cumulative disability or PRMS. EDSS 3.0 – 5.5 T2 abnormalities on MRI consistent with MS. 2 or more relapses within 18 months on therapy with EDSS increase > 0.5, or 1 relapse on therapy with EDSS increase > 1.0 and 1 separate event with gadolinium-enhancing lesions (brain or spinal cord) on MRI. 8. Approval by MS Review Panel.

Patient Characteristics (n=25) Age at Mobilization (years), median (range) Gender (F/M)

37 (26 – 52) 17/8

Baseline EDSS, median (range)

4.5 (3.0 – 5.5)

Disease Duration (years), median (range)

4.9 (0.6 – 12.0)

Prior therapy (n): Interferon Beta-1A

22

Interferon Beta-1B

1

Copaxone

18

Mitoxantrone

8

Natalizumab

6

Other

11

PBSC Mobilization with G-CSF

Day 0

1

2

3

4

5

Prednisone* (1 mg/kg/day) X x10 days

X

X

X

X

X

→

G-CSF (16 µg/kg/day)

X

X

X

X

X

→

X

X

→

Leukapheresis

CD34 selection with Baxter Isolex 300i system: > 2.0 x 106 CD34 positive cells/kg required for transplant.

Collection of Hematopoietic Stem Cells and Engraftment after Transplant Number of collections:

Collection # 1 2 3

Patient (n) 5 15 5

One patient failed mobilization with G-CSF/prednisone and required mobilization with Cy. All patients collected >2.0 x106 CD34-selected cells/kg (n=25). No delayed engraftment events were observed.

High-Dose Immunosuppressive Therapy Regimen (BEAM + ATG) HDIT Day -6 -5 -4 -3 -2 -1 0

BCNU 300 mg/m2 IV VP-16 100 mg/m2 bid IV; Ara C 100 mg/m2 bid IV VP-16 100 mg/m2 bid IV; Ara C 100 mg/m2 bid IV VP-16 100 mg/m2 bid IV; Ara C 100 mg/m2 bid IV VP-16 100 mg/m2 bid IV; Ara C 100 mg/m2 bid IV rATG 2.5 mg/kg IV Melphalan 140 mg/m2 IV; rATG 2.5 mg/kg IV CD34+ HSC infusion

Post-transplant G-CSF from Day +5 until ANC >500/uL. Prednisone 0.5 mg/kg/day from Day +7-21 then taper over 2 weeks.

Adverse Events • AE grade 2 and above were recorded EXCEPT during the peri-transplant period (from the start of conditioning until Day 60 after transplant) when only grade 3 and above were recorded. • Total Adverse Events: 399 among 25 patients • Total Serious Adverse Events: 66 among 16 patients AE Start Time Prior to Year 3

Year 3 and Beyond

Grade 1 or 2

145

18

Grade 3

124

14

Grade 4

94

0

Grade 5

1

2

Severity*

*one ungraded pregnancy AE is not included in table

Non-hematopoietic and Non-GI Adverse Events after High-Dose Immunosuppressive Therapy (Gr 4 and 5 NCI CTC) Patients (n)

Events (n)

Grade

Event

4

Manic Depression/Suicide Attempt/Respiratory Failure

1

3

Suicide attempt

1

1

Respiratory arrest/failure

1

1

Hypokalemia

1

1

Pulmonary Embolism (HIT)

1

1

Hyperuricemia

1

1

Increased ALT

1

1

MS Progression at >2 years

1

1

Anoxic encephalopathy at >3 years

1

1

Cardio-respiratory arrest at >4 years

1

1

5

Primary Endpoint: Event-Free Survival

5 year EFS: 69.2% (90% CI: 50.2%, 82.1%) Number of Primary Endpoint Events

7

EDSS increase > 0.5

2

Clinical relapse

3

MRI criteria

2

Death

0

Primary and Subsequent Endpoints • Primary endpoint events AND subsequent endpoints are captured in the clinical database Subject ID

Endpoint Event Date/Month

Endpoint Met

203102 2031034

12NOV2010/45.5

MRI criteria

23FEB2009/18.9 21MAR2010/31.8

EDSS increase > 0.5 Death

2031068

17JAN2012/48.4

MRI criteria

2031111

06OCT2010/22.2

Clinical relapse

2031144

23FEB2010/5.1 16SEP2010/11.9 03AUG2013/46.5

Clinical relapse MRI criteria Death

2031158

15NOV2012/32.6 03MAY2011/15.2 26JUL2014/54.1

Clinical relapse EDSS increase > 0.5 Death

2109025

Relapse-Free Survival

5 year RFS: 86.9% (90% CI: 69.5, 94.7)

Note: Upon meeting primary endpoint, a participant is not censored from further events in the remaining components.

MRI Activity-Free Survival

5 year MAFS: 86.3% (90% CI: 68.1%, 94.5%)

Note: Upon meeting primary endpoint, a participant is not censored from further events in the remaining components. The MRI event that occurred at 11.9 months was not a primary endpoint event, but rather an event that occurred subsequently after the subject met primary endpoint via clinical relapse at 5.1 months

Disease Progression-Free Survival

5 year DPFS: 91.3% (90% CI: 74.7%, 97.2%)

Note: Upon meeting primary endpoint, a participant is not censored from further events in the remaining components.

Overall Survival

5 year OS: 86.3% (90% CI: 68.3, 94.5)

Note: Upon meeting the primary endpoint, a participant is not censored from further events in the remaining components. In each of the 3 deaths, the subject previously met primary endpoint via another criterion.

Change in EDSS

Change in MSFC Total Score and Summary of Components MSFC Score

PASAT, % correct

9-hole Peg Test (avg. of both hands)

Time 25-foot walk

Change in MSIS-29

Changes in Gadolinium Enhancing Lesions

Change from Baseline in T1 and T2 Lesion Volume

Percent Change in Brain Volume from Screening

Conclusions 1. High-dose immunosuppressive therapy was welltolerated with few serious early complications. 2. High-dose immunosuppressive therapy was highly effective for inducing sustained remissions of highly active RRMS through Year 5. No diseasemodifying therapy was administered after transplant unless the subject experienced relapse or increase in EDSS. 3. EDSS was improved at Year 1 and sustained through Year 5. 4. Brain volume stabilized at Year 3 through Year 5.

Investigators (HALT MS; ITN033AI) Neurology Investigators •Jim Bowen - Swedish Neuroscience Inst •George Kraft - UW •Annette Wundes - UW •George Hutton - Baylor •Michael Racke – OSU

Transplant Physicians •Steve Devine – OSU •Uday Popat - MD Anderson •George Georges - UW/FHCRC

Consultant Neurologists •Paolo Muraro - Imperial College •Harry Openshaw - COH •Olaf Stuve - UTSW •Doug Arnold - McGill

Study Monitors •Linda Griffith - NIAID/NIH •Peter Sayre – ITN Statisticians •Kaitlyn McConville – Rho •James Rochon - Rho

National Institute of Allergy & Infectious Diseases

Supported and conducted by Immune Tolerance Network (ITN), and sponsored by NIAID, NIH, Bethesda, MD USA

Autologous HSCT for Multiple Sclerosis (ASTIMS): A randomized phase II study

Therapy Mobilization Cyclophosphamide 4 g/m2 + G-CSF HDIT BEAM + rATG 7.5 mg/kg vs Mitoxantrone 20 mg monthly x6 months

Neurology 2015;84:981–988

ASTIMS: Baseline characteristics

2

Neurology 2015;84:981–988

ASTIMS: Cumulative T2 lesions over 4 years

2

Autologous HSCT for Multiple Sclerosis (ASTIMS): A randomized phase II study

Annualized relapse rate

Autologous HSCT 0.19

Mitoxantrone 0.60

Progression

57%

EDSS

No difference

48%

p value 0.026 0.50

Association of Autologous HSCT with Neurological Disability in Patients with RRMS Treatment Mobilization: Cyclophosphamide 2 g/m2 + G-CSF Conditioning: Cyclophosphamide 200 mg/kg + rATG (129 pts) or alemtuzumab (22 pts) Alemtuzumab- 22.7% ITP/hypothyroidism/hyperthyroidism Treatment related mortality: 0%

Burt et al, JAMA. 2015;313(3):275-284.

Association of Nonmyeloablative HSCT With Neurological Disability in Patients With RRMS: Baseline Demographics (n=145)

Sex

Men Women Type of MS RRMS Secondary Age, yrs 18-25 26-35 36-45 46-60 Tx before HSCT2-3 treatm 4-5 treatm >6 treatm Base disability 6 EDSS JAMA. 2015;313(3):275284.

60 85 118 27 11 55 56 23 86 52 7 66 61 18

Association of Nonmyeloablative Hematopoietic Stem Cell Transplantation With Neurological Disability in Patients With RRMS: Neurological Disability Before and After Hematopoietic Stem Cell Transplantation

JAMA. 2015;313(3):275-284.

Association of Nonmyeloablative Hematopoietic Stem Cell Transplantation With Neurological Disability in Patients With RRMS: Survival

JAMA. 2015;313(3):275-284.

Effect of HDIT and Autologous HSCT on Outcomes: Neurological Rating Scale, MS Functional Composite and SF 36 Composite (total)

Before

6m

1 yr

2 yr

3 yr

4 yr

5 yr

NRS (n)

143

119

111

78

56

34

25

Median

74

83

85

88

90.5

87.5

85

p