? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? 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
  

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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
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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
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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
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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
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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
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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
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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 - -

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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 -

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Post RIC HCT Engraftment Trends Over Time
NO DLI, N4 (3 XLP, 1 HLH)
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Post RIC HCT Engraftment Trends Over Time
N4 (arrow initiation of DLI)
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Post RIC HCT Engraftment Trends Over Time
N4
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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

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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

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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

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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?

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Acknowledgements and Appreciation

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