? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? Reduced Intensity Conditioning Regimen for Bone Marrow Transplant in Children with Immune Deficiency: Managing Complications and Improving Outcomes ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? - PowerPoint PPT Presentation

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? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? Reduced Intensity Conditioning Regimen for Bone Marrow Transplant in Children with Immune Deficiency: Managing Complications and Improving Outcomes ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ?

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Reduced Intensity Conditioning Regimen for Bone Marrow Transplant in Children ... Cryptogenic cirrhosis. Autoimmune hepatitis. XLP. CMV. Seizures, CNS HLH. HLH ... – PowerPoint PPT presentation

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Title: ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? Reduced Intensity Conditioning Regimen for Bone Marrow Transplant in Children with Immune Deficiency: Managing Complications and Improving Outcomes ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ?


1
? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? Reduced
Intensity Conditioning Regimen for Bone Marrow
Transplant in Children with Immune Deficiency
Managing Complications and Improving Outcomes ?
? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ?
  • Presented by Gretchen Vaughn, RN, MSN, CPNP
  • Immunology / Bone Marrow Transplant Nurse
    Practitioner
  • Cincinnati Childrens Hospital Medical Center
  • Cincinnati, Ohio, USA

2
Cincinnati Childrens Hospital Medical Center
3
BMT for Immune Disorders 2006-2008
  • SCID - 7
  • NEMO 4
  • CGD - 8
  • CID - 8
  • WAS - 9
  • HLH - 14
  • XLP 6
  • Others (IPEX, LCH, ALPS) - 7

4
Hemophagocytic Lymphohistiocytosis
  • ? HLH is a condition of abnormal cytotoxic
    functions which result in excessive and prolonged
    immune activation, usually fatal if untreated
  • ? There are many genetic causes of HLH
  • Familial HLH PRF1, Munc 13-4, STX-11
  • XLP SH2D1A, BIRC4
  • ? HCT is the only cure for these disorders

5
Background
  • ? HLH is an autosomal recessive
  • disorder caused by multiple genetic
  • abnormalities affecting cytotoxic function
  • ? XLP is an X-linked disorder caused by
  • genetic abnormalities affecting T and NK
  • cells
  • ? HLH and XLP result in excessive and
  • prolonged immune activation which is
  • usually fatal
  • ? HCT is the only curative therapy

6
Background
  • ? Results of conventional myeloablative
  • chemotherapy pre-HCT for HLH are suboptimal
  • ? Patients with active disease at the
  • time of HCT fare poorly
  • ? Early treatment related mortality (as
  • defined by death within 100 days of
  • transplant) is a major cause of treatment
  • failure

7
Background
  • ? CONVENTIONAL APPROACH (Bu/Cy/ VP-16)
  • ? HLH94, n108
  • - 70 DFS at 5 years with Matched
    Sibling and
  • Matched Unrelated Donor
  • - 50 DFS at 5 years with
    Mismatched Unrelated Donor
  • - Most fatalities occurred within
    the first 100 days
  • ? CIBMTR Analysis, n53
  • - 35 rate of mortality by day 100


  • Horne et al, BJM,
    2006

  • Baker et al, ASH, 2006

8
Background
  • ? CIBMTR Analysis, n53, high rate of
    early mortality
  • 35 by day 100
  • ? GVHD, n5
  • ? Infection, n8
  • ? Interstitial Pneumonitis, n8
  • ? Organ failure, n6
  • ? Hemorrhage, n3
  • ? Persistent disease, n2

9
Background For The Use of Reduced Intensity
Conditioning
  • ? Pilot data for use of RIC
  • (Campath/Flu/Mel)
  • Great Ormond Street Hosp., UK
  • -12 pts, mixed diagnoses 8 in
    clinical
  • remission
  • - 9 survive 3 are mixed chimeras

  • Cooper et al, Blood, 2006

10
CCHMC Therapy HCT in Non-malignant Disease
Using RIC Preparatory Regimen with Campath 1H,
Fludarabine and Melphalan
  • ? Eligibility Criteria
  • ? Diagnosis of HLH or Related Genetic
    Disorder
  • at high risk for HLH reaction,
    e.g. XLP,
  • Chediak Higashi syndrome
  • ? Systemic and CNS remission at the
    time of HCT
  • ? No active life-threatening
    infections
  • ? Availability of 6/8 or gt matched
    donor
  • ? Adequate pulmonary, liver and renal
    function

11
Treatment
  • ? Campath 1-H subQ or IV on 4 consecutive
    days, -11 to -8,
  • - doses revised October, 07
  • - timing for matched sibs changed May, 2008 to
    start day -22
  • ? Fludarabine 30 mg/M2 IV on 5
    consecutive days, -7 to -3
  • ? Melphalan 140 mg/M2 IV once, on day
    -2
  • ? GvHD Prophylaxis CsA/FK506 and steroids
  • Doses adjusted per kg if patient lt 10 kg

12
Treatment
  • ? Campath 1-H subQ or IV on 4 consecutive
    days proximal
  • - doses revised October, 07
  • - timing changed May, 2008 to start day -22
    distal as an option
  • ? Fludarabine 30 mg/m2 IV on 5
    consecutive days, -8 to -4
  • ? Melphalan 140 mg/m2 IV once, on day
    -3
  • ? GvHD Prophylaxis CsA/FK506 and steroids
    1mg/kg/day
  • Doses adjusted per kg if patient lt 10 kg

13
Patient Characteristics General
Dx Genetics Age/Gender Donor
HLH unknown 8 yr/m 7/8 URD marrow
XLP SH2D1A 1 yr/m 6/8 URD marrow
HLH unknown 5 mo/m 8/8 URD marrow
HLH unknown 10 yr/m 8/8 URD marrow
HLH unknown 2 yr/m 7/8 URD marrow
XLP SH2D1A 11 yr/m 8/8 URD marrow
HLH unknown 1 yr/m 7/8 URD marrow
HLH PRF 1 4 mo/f 8/8 MSD marrow
XLP SH2D1A 12 yr/m 7/8 URD marrow
HLH unknown 16 yr/m 8/8 MSD marrow
14
Patient Characteristics General 2
Dx Genetics Age/Gender Donor
XLP SH2D1A 8 yr/m 8/8 URD marrow
HLH unknown 12 yr/f 8/8 URD marrow
HLH unknown 17 yr/f 8/8 URD marrow
HLH unknown 30 mo/f 8/8 MSD marrow
HLH unknown 2 yr/m 8/8 MSD marrow
HLH unknown 3 mo/m 8/8 MSD marrow
XLP BIRC 4 11 yr/m 8/8 URD marrow
HLH unknown 4 yr/m 8/8 MSD marrow
HLH unknown 6 yr/m 8/8 MSD marrow
XLP BIRC 4 4 yr/m 8/8 URD marrow
15
Patient Characteristics Illness Related
Dx Pre-HCT Complications Pre-HCT Viral Infections
HLH Liver transplant EBV
XLP HLH, short gut, colostomy EBV
HLH Refractory HLH (Campath salvage)  
HLH   VZV
HLH   EBV, CMV
XLP Lymphoma x 2  
HLH    
HLH Liver failure (Campath salvage)  
XLP Lymphoma and HLH  
HLH ALL  
Alpha 1 antitrypsin deficiency Alpha 1 antitrypsin deficiency Alpha 1 antitrypsin deficiency
16
Patient Characteristics Illness Related 2
Dx Pre-HCT Complications Pre-HCT Viral Infections
XLP Seizures, hepatitis, PCP CMV, HHV6 lung
HLH EBV
HLH Splenic rupture EBV
HLH  Liver failure, ICU pleural effusion CMV
HLH Seizures, CNS , thrombosis  EBV (gi and donor)
HLH CMV 
XLP  Liver transplant EBV, CMV, Fungus (BAL) 
HLH  
HLH Seizures, CNS CMV 
XLP Autoimmune hepatitis  
Cryptogenic cirrhosis Cryptogenic cirrhosis Cryptogenic cirrhosis
17
Post HCT Patient Outcomes
Pt Organ Toxicity/ Complications Initial GvHD Survival
1 Auto-immune cytopenias 0 30 months
2 - 0 28 months
3 - 0 28 months
4 - Gr 1 skin 26 months
5 CMV viremia Gr 1 skin 25 months
6 - 0 23 months
7 - 0 Died at 9 months
8 - 0 20 months
9 - 0 18months
10 - Gr 3 skin 17months
18
Post HCT Patient Outcomes 2
Pt Organ Toxicity/ Complications Initial GvHD Survival
11 - 0 14 months
12 Toxo Retinitits 0 14 months
13 - 0 13 months
14 - 0 13 months
15 - 0 11 months
16 CMV viremia 0 11 months
17 - 0 8 months
18 - 0 6 months
19 Aspiration Pneumonia 0 4 months
20 - 0 4 months
19
Post HCT Patient Outcomes
Patient Engraftment Nadir/Current DLI GvHD Post DLI
1 40/60 at 5 months -
2 76/89 - -
3 54/100 at 6 months -
4 39/100 at 4.5 months GI (Gr III)
5 0.2/100 at 3 months Skin and GI (Gr III)
6 98/100 - -
7 14/99 at 2 months Skin (Gr III)
8 40/57 at 6 months -
9 77/81 - -
10 100/100 - -

20
Post HCT Patient Outcomes 2
Patient Engraftment Nadir/Current DLI GvHD Post DLI
11 100/100 - -
12 36/56 at 6 months -
13 9/100 at 4 months Skin (Gr II)
14 73/85 - -
15 17/21 at 3 months -
16 51/63 at 8 months -
17 82/88 - -
18 99/99 - -
19 99/99 - -
20 38/42 at 2 months -

21
Post RIC HCT Engraftment Trends Over Time
NO DLI, N4 (3 XLP, 1 HLH)
22
Post RIC HCT Engraftment Trends Over Time
N4 (arrow initiation of DLI)
23
Post RIC HCT Engraftment Trends Over Time
N4
24
Outcomes Summary - CCHMC Experience
  • Engraftment total range 21-100 donor
  • ? 10/14 HLH patients with failure to
  • maintain engraftment received donor
  • lymphocyte infusions (DLI)
  • ? 1/6 XLP patients received DLI

25
Outcomes Summary CCHMC Experience
  • ? GvH skin -
  • - 1/20 grade 3 without DLI
  • - 3/20 grade 2-3 post DLI
  • ? GI GvH
  • - 2/20 with grade 3 post DLI

26
Outcomes Summary CCHMC Experience
  • ? Minimal organ toxicity for all
  • ? Survival 19/20 alive 4-30 months
  • post transplant
  • ? Immune reconstitution 1 year post
  • - most patients have normal T cell numbers
    and function (mitogens)
  • - most patients remain on IVIG replacement
    with good progress toward B cell reconstitution

27
Future Implications
  • ? Long term monitoring of donor versus recipient
    lymphocyte populations is needed as well as
    determination of functional engraftment
  • ? How much engraftment is enough?

28
Acknowledgements and Appreciation
  • ? Alexandra Filipovich, MD
  • ? Jack Bleesing, MD
  • ? Michael Jordan, MD
  • ? Rebecca Marsh, MD
  • ? Nursing Colleagues, Data Managers,
  • and Secretarial Support

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