Reduced Intensity Conditioning Reduced Intensity Conditioning Regimen for Bone Marrow Transplant Regimen for Bone Marrow Transplant in Children with Immune Deficiency: in Children with Immune Deficiency: Managing Complications and Managing Complications and Improving Outcomes Improving Outcomes Presented by Gretchen Vaughn, RN, MSN, CPNP Presented by Gretchen Vaughn, RN, MSN, CPNP Immunology / Bone Marrow Transplant Nurse Practitioner Immunology / Bone Marrow Transplant Nurse Practitioner Cincinnati Children’s Hospital Medical Center Cincinnati Children’s Hospital Medical Center Cincinnati, Ohio, USA Cincinnati, Ohio, USA
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Reduced Intensity Conditioning Regimen for Bone Marrow Transplant in Children with Immune Deficiency: Managing Complications.
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Regimen for Bone Marrow Regimen for Bone Marrow Transplant in Children with Immune Transplant in Children with Immune Deficiency: Managing Complications Deficiency: Managing Complications
and Improving Outcomesand Improving Outcomes
Presented by Gretchen Vaughn, RN, MSN, CPNPPresented by Gretchen Vaughn, RN, MSN, CPNPImmunology / Bone Marrow Transplant Nurse Immunology / Bone Marrow Transplant Nurse
PractitionerPractitionerCincinnati Children’s Hospital Medical CenterCincinnati Children’s Hospital Medical CenterCincinnati, Ohio, USACincinnati, Ohio, USA
Cincinnati Children’s Cincinnati Children’s Hospital Medical Hospital Medical CenterCenter
BMT for Immune BMT for Immune Disorders 2006-2008Disorders 2006-2008
HLH: is a condition of abnormal HLH: is a condition of abnormal cytotoxic functions which result in cytotoxic functions which result in excessive and prolonged immune excessive and prolonged immune activation, usually fatal if untreated activation, usually fatal if untreated
There are many genetic causes of HLHThere are many genetic causes of HLHFamilial HLH: Familial HLH: PRF1, Munc 13-4, STX-11PRF1, Munc 13-4, STX-11XLP: XLP: SH2D1A, BIRC4SH2D1A, BIRC4
HCT is the only cure for these disordersHCT is the only cure for these disorders
BackgroundBackground
Results of Results of ‘conventional’‘conventional’ myeloablative myeloablative chemotherapy pre-HCT for HLH chemotherapy pre-HCT for HLH are are
suboptimalsuboptimal
Patients with active diseasePatients with active disease at the at the time of HCT fare poorlytime of HCT fare poorly
Early treatment related mortality (as Early treatment related mortality (as defined by death within 100 days of defined by death within 100 days of transplant) is a transplant) is a majormajor cause of treatment cause of treatment failurefailure
HLH94, n=108 *HLH94, n=108 * -- 70% DFS at 5 years with Matched Sibling and 70% DFS at 5 years with Matched Sibling and Matched Unrelated DonorMatched Unrelated Donor -- 50% DFS at 5 years with Mismatched Unrelated Donor 50% DFS at 5 years with Mismatched Unrelated Donor -- Most fatalities occurred within the first 100 days Most fatalities occurred within the first 100 days
CIBMTR Analysis, n=53**CIBMTR Analysis, n=53** -- 35% rate of mortality by day 100 35% rate of mortality by day 100
*Horne et al, BJM, *Horne et al, BJM, 20062006
**Baker et al, ASH, **Baker et al, ASH, 2006 2006
Pilot data for use of RIC Pilot data for use of RIC (Campath/Flu/Mel)(Campath/Flu/Mel) Great Ormond Street Hosp., UKGreat Ormond Street Hosp., UK --12 pts, mixed diagnoses; 8 in 12 pts, mixed diagnoses; 8 in
clinical clinical remissionremission - - 9 survive – 3 are mixed chimeras9 survive – 3 are mixed chimeras * * Cooper et al, Blood, 2006Cooper et al, Blood, 2006
Background For The Use of Background For The Use of Reduced Intensity Reduced Intensity
ConditioningConditioning
TreatmentTreatment
Campath 1-HCampath 1-H**: subQ or IV on 4 consecutive days : subQ or IV on 4 consecutive days “proximal” “proximal”
- - doses revised October, 07; doses revised October, 07; -- timing changed May, 2008 to start day -22 “distal” as an timing changed May, 2008 to start day -22 “distal” as an
optionoption
FludarabineFludarabine**: 30 mg/m2 IV on 5 consecutive days, -8 to : 30 mg/m2 IV on 5 consecutive days, -8 to -4-4
MelphalanMelphalan**: 140 mg/m2 IV once, on day -3 : 140 mg/m2 IV once, on day -3
GvHD Prophylaxis: CsA/FK506 and steroids 1mg/kg/dayGvHD Prophylaxis: CsA/FK506 and steroids 1mg/kg/day ** Doses adjusted per kg if patient < 10 kgDoses adjusted per kg if patient < 10 kg
Patient Characteristics – Patient Characteristics – General 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
Patient Characteristics – Patient Characteristics – General 2General 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
Post HCT Patient Post HCT Patient OutcomesOutcomes
Pt
Organ
Toxicity/Complications Initial GvHD Survival
1Auto-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 ─ 0Died at
9 months
8 ─ 0 20 months
9 ─ 0 18months
10 ─ Gr 3 skin 17months
Post HCT Patient Post HCT Patient Outcomes 2Outcomes 2
Pt
OrganToxicity/
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
19Aspiration Pneumonia 0 4 months
20 ─ 0 4 months
Post HCT Patient OutcomesPost 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 % ─ ─
Post HCT Patient Outcomes Post HCT Patient Outcomes 22
Minimal organ toxicity for allMinimal organ toxicity for all Survival – 19/20 alive 4-30 months Survival – 19/20 alive 4-30 months post transplantpost transplant Immune reconstitution – 1 year post: Immune reconstitution – 1 year post:
- most patients have normal T cell - most patients have normal T cell numbers and function (mitogens)numbers and function (mitogens)- most patients remain on IVIG - most patients remain on IVIG replacement with good progress replacement with good progress toward B cell reconstitutiontoward B cell reconstitution
Future ImplicationsFuture Implications
Long term monitoring of donor Long term monitoring of donor versus recipient lymphocyte versus recipient lymphocyte populations is needed as well as populations is needed as well as determination of “functional determination of “functional engraftment”engraftment”
How much engraftment is enough? How much engraftment is enough?
Acknowledgements and Acknowledgements and AppreciationAppreciation
Alexandra Filipovich, MDAlexandra Filipovich, MD Jack Bleesing, MDJack Bleesing, MD Michael Jordan, MDMichael Jordan, MD Rebecca Marsh, MDRebecca Marsh, MD Nursing Colleagues, Data Managers, Nursing Colleagues, Data Managers,