Disclosures. I have no disclosures.

Transcription

1 Not Your Own Marrow Jenni Krajewski, MD Clinical Assistant Professor, Rutgers New Jersey Medical School Attending Physician, Pediatric Blood and Marrow Transplantation The Institute for Pediatric Cancer and Blood Disorders Hackensack University Medical Center

2 Disclosures I have no disclosures.

3 Objectives 1) Discuss the indications for bone marrow transplant in nonmalignant diseases 2) Summarize the long term outcomes in stem cell transplant survivors

4 Transplant basics Two types of transplant Autologous Allogeneic 3 donor sources Bone marrow Peripheral blood stem cells (PBSC) Umbilical Cord Blood (UCB)

5 Transplant basics HLA-matching (allogeneic) Matched (6/6 or 10/10) Mismatched Haploidentical (3/6 or 5/10) Two general types of conditioning Myeloablative (MAB) Reduced Intensity (RIC)

6 Transplant Indications Malignant Leukemia (allogeneic) Lymphoma (autologous, allogeneic) CNS tumors (autologous) Solid tumors (autologous)

7 Transplant Indications Non-malignant (allogeneic) Hemoglobinopathies Immunodeficiencies Metabolic disorders Bone marrow failure

8 Transplant Complications Graft vs. Host Disease (GVHD) Graft failure Infections Long-term complications (Sterility, endocrine issues, etc)

9 Hemoglobinopathies Sickle cell anemia (Hb SS, SC, SBthal) Thalassemia

10 Sickle Cell Anemia First transplant done in 1984 in a patient who had AML & sickle cell anemia (Johnson et al, NEJM 1984) Began doing MAB transplants from sibling donors in mid-1990 s Largest cohort reported in 2007 showed an overall survival (OS) of 93% & event-free survival (EFS) of 86% (Bernaudin et al, Blood 2007) EFS was increased to 95% after 2000 by addition of ATG

11 Sickle Cell Anemia Because of these results, the National Marrow Donor Program (NMDP) recently endorsed matched sibling transplants as a standard of care for sickle cell disease In our open protocol recruiting patients at Hackensack, having a sibling donor makes you eligible for transplant as soon as you turn 2 (meaning you don t have to have had any sickle cell complications) Using a RIC regimen, hoping to minimize transplant complications and preserve fertility Unfortunately, only about 15-20% of sickle cell patients will have a matched sibling who doesn t also have sickle cell disease

12 Sickle Cell Anemia So how can we make this potential cure available to more patients? Use unrelated donors Higher risk of transplant complications, especially with MAB conditioning Use umbilical cord blood Higher risk of rejection, especially with RIC Use haploidentical donors Almost every patient should have one of these Much higher risk of transplant complications

13 Sickle Cell Anemia Unrelated donors Unfortunately, only 20-25% of sickle cell patients will have an matched unrelated donor in the registry Allowing for 1 mismatch in the HLA typing increases the donor pool, but also increases the risk for transplant complications Currently a national unrelated donor trial is nearing completion for 8/8 MUD, and results should be available soon At Hackensack, we offer unrelated donor transplants to patients with severe sickle cell complications on a RIC regimen One patient received a 9/10 MUD, and has been cured of her sickle cell disease Unfortunately, a second patient who received a 10/10 MUD died from complications due to severe GVHD

14 Sickle Cell Anemia UCB UCB results have been disappointing for sickle cell disease Ruggeri et al. examined the efficacy of unrelated UCB transplantation in children with SCD (n =16) OS and DFS were 94% and 50%. The 2-year probability of DFS was 45% in patients who received grafts with nucleated cell dose >5 10^7/kg but only 13% with lower cell doses. Primary graft failure was the predominant cause of treatment failure occurring in 7 patients with SCD These results suggest that only UCB units containing an expected infused nucleated cell dose >5 107/kg should be considered for transplantation for hemoglobinopathies which further limits the available UCB units for this population of patients The national trial had to close their UCB arm early due to a high rate of graft failure Our trial at Hackensack only allows the use of UCB if a single or double cord blood unit can be found that has a cell dose >5* 10^7/kg

15 Sickle Cell Anemia Haploidentical donors Not yet routinely done in children with sickle cell disease There are a few national trials being done to investigate this currently

16 Immunodeficiencies Severe Combined Immunodeficiency (SCID) Primary T cell immunodeficiencies Wiscott-Aldrich Syndrome (eczema, T cell immunodeficiency, thrombocytopenia)

17 SCID Absence of T & B cell responses All have absence of T cells & T cell function Most have absence of NK cells and B cells as well Multiple genetic causes Most common are X-linked ADA deficiency is autosomal recessive Patients typically present around 3-6 months of age with opportunistic infections as maternal immunity decreases

18 SCID First successful allogeneic SCT was in a patient with SCID in 1968 If patient does not have any maternal T cell engraftment, often don t need to use a conditioning regimen Matched sibling is the preferred donor source Long term survival of >80% in all studies published in last 20 years Matched sibling transplants do not require GVHD prophylaxis as the incidence of GVHD is extremely low

19 SCID For patients without sibling donors, options include T cell depleted haploidentical transplants, MUD, or UCB All have survival rates between 60-80%, depending on the study T cell depleted transplants have a lower incidence of GVHD, but delayed immune reconstitution MUD transplants have a higher incidence of GVHD UCB have a higher incidence of graft failure Myers et al (Blood 2002) found that patients transplanted before 28 days of age had better long-term survival than those transplanted later in life (21/22 vs. 51/67) Buckley et al (J Allergy Clin Immun 2012) found that patients transplanted before 3.5 months of age had better OS

20 SCID newborn screening Currently 18 states include SCID as part of newborn screening NJ just started screening for SCID in 2/2014 Analyze the number of TRECs (T-cell receptor excision circles) in the blood spot collected after birth If the TRECs are low (generally <25), the infant is referred for further work-up In California, survival of their neonates with SCID diagnosed on NBS is 93% (Kwan et al J Allergy Clin Immun 2013)

21 SCID projected incidence in NJ California NJ N 993, ,000 TREC < (<0.1%) 100 Second DBS 806 (0.08%) 80 Cell Flow 116 (0.016%) 16 TCL 50 (0.005%) 5 SCID 15 (1/66, 250) 2

22 Immunodeficiency work-up CBC, diff and retic Full chemistry and GGTP Type and cross Lymphocyte phenotyping (T + B + NK) (HUMC) Immunoglobulin levels (IgG, IgA, IgM, IgE) Isohemagglutinin titers Tetanus ab, diphtheria ab, pneumococcal ab (in immunized patients) Lymphocyte proliferation to antigens and mitogens (Mayo-TCIPF) NK function (Cincinnati) T TCR V beta repertoire (Cincinnati) Trec testing (Mayo TREC) Mutation analysis (Correlagen, ) Maternal chimerism (donor/host STR sample or FISH XY pt. and mother ) ADA level (Mayo ADA) PNP level (Herschfield Lab at Duke) Viral studies: HLA typing of patient, siblings and parents CT scan of chest thymic shadow Fibroblast and Fibroblast DNA (UMDNJ)

23 Indications for Hematopoietic Stem Cell Transplants for Age 20yrs, in the U.S., Allogeneic (Total N=1,479) Autologous (Total N=782) Other Cancer ALL AML Aplastic Anemia MDS/MPS HD NHL CML Other Leuk Non- Malig Disease Pasquini MC, Wang Z. Current use and outcome of hematopoietic stem cell transplantation: CIBMTR Summary Slides, 2012

24 Allogeneic Transplants for Age 20yrs, Registered with the CIBMTR, by Donor Type and Graft Source - 5,000 4,500 4,000 Related BM/PB Unrelated BM/PB Unrelated CB 3,500 3,000 2,500 2,000 1,500 1, Pasquini MC, Wang Z. Current use and outcome of hematopoietic stem cell transplantation: CIBMTR Summary Slides, 2012

25 General cure rates & incidence of transplant survivors The cure rate for most patients undergoing transplant ranges from 20% to 95% Large variation based on diagnosis, but almost all diagnoses have improved survival over that seen 2 decades ago Because of this, far more patients will be long term survivors

26 Long-term follow-up Referral to a long-term follow-up clinic is very important Hackensack has the Cure & Beyond program, which follows patients who are 2 years or more from transplant without active transplant issues Develop a summary for the patient and PMD regarding treatment regimen, including doses of chemo & radiation Follow patient for medical and non-medical post-treatment issues

27 Long-term follow-up For a great comprehensive review, visit Guidelines developed by a consensus group through the Children s Oncology Group, last version 3 released in 2008 Akron Children s Hospital also released a website and an application detailing guidelines for cancer survivors in Jan Good for patients and medical providers

28 Long-term follow-up Common late effects Cardiac toxicity Particularly for those patients receiving anthracyclines & radiation to the chest Pulmonary Particularly for those patients receiving Busulfan, Bleomycin, or radiation to the lungs Endocrine Reproductive Particularly for those patients receiving alkylating agents and radiation to the abdomen Non-reproductive Particularly for patient receiving brain radiation or long term steroid use Secondary malignancies Particularly for those patients receiving Etoposide or radiation therapy

29 Conclusion As we get better at managing transplant complications, more patients will be transplant survivors Especially since more patients with non-malignant diseases will likely come to transplant more often Areas of improvement for the future Managing, or better yet predicting, which patients will develop severe refractory GVHD Preventing infections Using less intense regimens to achieve similar disease cure rates with fewer long-term toxicities

30 Thank you! Questions? Comments?