Presented by Gretchen Vaughn, RN, MSN, CPNP Immunology / Bone Marrow Transplant Nurse Practitioner

Reduced Intensity Conditioning Reduced Intensity Conditioning

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

SCID - 7SCID - 7 NEMO – 4 NEMO – 4 CGD - 8CGD - 8 CID - 8CID - 8 WAS - 9WAS - 9 HLH - 14HLH - 14 XLP – 6XLP – 6 Others (IPEX, LCH, ALPS) - 7Others (IPEX, LCH, ALPS) - 7

Hemophagocytic Hemophagocytic LymphohistiocytosisLymphohistiocytosis

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

BackgroundBackground

CONVENTIONAL APPROACH (Bu/Cy/CONVENTIONAL APPROACH (Bu/Cy/++ VP-16) VP-16)

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 PRF 1 4 mo/f 8/8 MSD marrow


HLH unknown 16 yr/m 8/8 MSD marrow

Patient Characteristics – Patient Characteristics – General 2General 2

Dx Genetics Age/Gender Donor


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 3 mo/m 8/8 MSD marrow

XLP BIRC 4 11 yr/m 8/8 URD 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

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 ─

Outcomes Summary - Outcomes Summary - CCHMC ExperienceCCHMC Experience

Engraftment: total range 21-100% Engraftment: total range 21-100% donordonor

10/14 HLH patients with failure to 10/14 HLH patients with failure to

maintain engraftment received maintain engraftment received donor donor

lymphocyte infusions (DLI)lymphocyte infusions (DLI) 1/6 XLP patients received DLI1/6 XLP patients received DLI

Outcomes Summary Outcomes Summary CCHMC ExperienceCCHMC Experience

GvH skin - GvH skin -

- - 1/20 grade 3 without DLI1/20 grade 3 without DLI

-- 3/20 grade 2-3 post DLI 3/20 grade 2-3 post DLI

GI GvH GI GvH

- - 2/20 with grade 3 post DLI2/20 with grade 3 post DLI

Outcomes Summary Outcomes Summary CCHMC ExperienceCCHMC Experience

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,

and Secretarial Supportand Secretarial Support

Presented by Gretchen Vaughn, RN, MSN, CPNP Immunology / Bone Marrow Transplant Nurse Practitioner

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