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                Reduced Intensity Conditioning Regimen for Bone Marrow Transplant in Children with Immune Deficiency: Managing Complications.

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Presentation on theme: "                Reduced Intensity Conditioning Regimen for Bone Marrow Transplant in Children with Immune Deficiency: Managing Complications."— Presentation transcript:

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 Children’s Hospital Medical Center Cincinnati, Ohio, USA

2 Cincinnati Children’s Hospital Medical Center

3 BMT for Immune Disorders SCID - 7 SCID - 7 NEMO – 4 NEMO – 4 CGD - 8 CGD - 8 CID - 8 CID - 8 WAS - 9 WAS - 9 HLH - 14 HLH - 14 XLP – 6 XLP – 6 Others (IPEX, LCH, ALPS) - 7 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 disorder caused by multiple genetic abnormalities affecting cytotoxic function abnormalities affecting cytotoxic function  XLP is an X-linked disorder caused by genetic abnormalities affecting T and NK genetic abnormalities affecting T and NK cells cells  HLH and XLP result in excessive and prolonged immune activation which is prolonged immune activation which is usually fatal usually fatal  HCT is the only curative therapy

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

7 Background  CONVENTIONAL APPROACH (Bu/Cy/+ VP-16)  CONVENTIONAL APPROACH (Bu/Cy/+ 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 Donor Matched 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 % rate of mortality by day 100 *Horne et al, BJM, 2006 *Horne et al, BJM, 2006 **Baker et al, ASH, 2006 **Baker et al, ASH, 2006

8 Background  CIBMTR Analysis, n=53, – high rate of early mortality:  CIBMTR Analysis, n=53, – high rate of early mortality: 35% by day % by day 100  GVHD, n=5  GVHD, n=5  Infection, n=8  Infection, n=8  Interstitial Pneumonitis, n=8  Interstitial Pneumonitis, n=8  Organ failure, n=6  Organ failure, n=6  Hemorrhage, n=3  Hemorrhage, n=3  Persistent disease, n=2  Persistent disease, n=2

9  Pilot data for use of RIC  Pilot data for use of RIC (Campath/Flu/Mel) (Campath/Flu/Mel) Great Ormond Street Hosp., UK Great Ormond Street Hosp., UK -12 pts, mixed diagnoses; 8 in clinical -12 pts, mixed diagnoses; 8 in clinical remission remission - 9 survive – 3 are mixed chimeras - 9 survive – 3 are mixed chimeras * Cooper et al, Blood, 2006 * Cooper et al, Blood, 2006 Background For The Use of Reduced Intensity Conditioning

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

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

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

13 Patient Characteristics – General DxGeneticsAge/GenderDonor HLHunknown8 yr/m7/8 URD marrow XLPSH2D1A1 yr/m6/8 URD marrow HLHunknown5 mo/m8/8 URD marrow HLHunknown10 yr/m8/8 URD marrow HLHunknown2 yr/m7/8 URD marrow XLPSH2D1A11 yr/m8/8 URD marrow HLHunknown1 yr/m7/8 URD marrow HLHPRF 14 mo/f8/8 MSD marrow XLPSH2D1A12 yr/m7/8 URD marrow HLHunknown16 yr/m8/8 MSD marrow

14 Patient Characteristics – General 2 DxGeneticsAge/GenderDonor XLPSH2D1A8 yr/m8/8 URD marrow HLHunknown12 yr/f8/8 URD marrow HLHunknown17 yr/f8/8 URD marrow HLHunknown30 mo/f8/8 MSD marrow HLHunknown2 yr/m8/8 MSD marrow HLHunknown3 mo/m8/8 MSD marrow XLPBIRC 411 yr/m8/8 URD marrow HLHunknown4 yr/m8/8 MSD marrow HLHunknown6 yr/m8/8 MSD marrow XLPBIRC 44 yr/m8/8 URD marrow

15 Patient Characteristics – Illness Related DxPre-HCT Complications Pre-HCT Viral Infections HLHLiver transplant *EBV XLPHLH, short gut, colostomyEBV HLHRefractory HLH (Campath salvage) HLH VZV HLH EBV, CMV XLPLymphoma x 2 HLH Liver failure (Campath salvage) XLPLymphoma and HLH HLHALL * Alpha 1 antitrypsin deficiency

16 Patient Characteristics – Illness Related 2 DxPre-HCT Complications Pre-HCT Viral Infections XLPSeizures, hepatitis, PCPCMV, HHV6 lung HLHEBV HLHSplenic ruptureEBV HLH Liver failure, ICU pleural effusionCMV HLHSeizures, CNS +, thrombosis EBV (gi and donor) HLHCMV XLP Liver transplant * EBV, CMV, Fungus (BAL) HLH Seizures, CNS +CMV XLPAutoimmune hepatitis * Cryptogenic cirrhosis

17 Post HCT Patient Outcomes Pt Organ Toxicity/ ComplicationsInitial GvHDSurvival 1 Auto-immune cytopenias0 30 months 2─0 28 months 3─0 4─Gr 1 skin26 months 5CMV viremiaGr 1 skin25 months 6─023 months 7─0 Died at 9 months 8─020 months 9─018months 10─Gr 3 skin17months

18 Post HCT Patient Outcomes 2 Pt Organ Toxicity/ ComplicationsInitial GvHDSurvival 11─014 months 12Toxo Retinitits014 months 13─013 months 14─013 months 15─011 months 16CMV viremia011 months 17─08 months 18─06 months 19 Aspiration Pneumonia04 months 20─04 months

19 Post HCT Patient Outcomes Patient Engraftment Nadir/CurrentDLI GvHD Post DLI 140/60 % at 5 months─ 276/89 %── 354/100 % at 6 months─ 439/100 %at 4.5 monthsGI (Gr III) 50.2/100 % at 3 monthsSkin and GI (Gr III) 698/100 %── 714/99% at 2 monthsSkin (Gr III) 840/57 % at 6 months─ 977/81 %── 10100/100 %──

20 Post HCT Patient Outcomes 2 Patient Engraftment Nadir/CurrentDLI GvHD Post DLI 11100/100 %── 1236/56 %at 6 months─ 139/100 % at 4 monthsSkin (Gr II) 1473/85 %── 1517/21 % at 3 months─ 1651/63%at 8 months─ 1782/88% ── 1899/99 %── 1999/99 %── 2038/42 %at 2 months─

21 Post RIC HCT Engraftment Trends Over Time NO DLI, N=4 (3 XLP, 1 HLH)

22 Post RIC HCT Engraftment Trends Over Time N=4 (arrow= initiation of DLI)

23 Post RIC HCT Engraftment Trends Over Time N=4

24 Outcomes Summary - CCHMC Experience Engraftment: total range % donor  10/14 HLH patients with failure to maintain engraftment received donor maintain engraftment received donor lymphocyte infusions (DLI) lymphocyte infusions (DLI)  1/6 XLP patients received DLI

25 Outcomes Summary CCHMC Experience  GvH skin - - 1/20 grade 3 without DLI - 1/20 grade 3 without DLI - 3/20 grade 2-3 post DLI - 3/20 grade 2-3 post DLI  GI GvH - 2/20 with grade 3 post DLI - 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 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 and Secretarial Support


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