WELCOME TO TODAY'S CLINICAL GRAND ROUNDS, WHICH IS THE LAST OFFICIAL GRAND ROUNDS OF THE ACADEMIC SEASON. WE'LL START IN AUGUST WITH GRAND ROUNDS FOR A TOPIC FOR GRADUATE MEDICAL. TODAY WE HAVE TWO SPEAKERS FROM THE NATIONAL HEART LUNG AND BLOOD INSTITUTE WITH THEIR RESEARCH AND SICKLE CELL DISEASE. OUR FIRST SPEAKER IS COURTNEY FITZHUGH IN THE HEMATOLOGY BRANCH OF THE NATIONAL HEART AND LUNG INSTATE. COURTNEY EARNED HER MEDICAL DEGREE FROM THE UNIVERSITY OF CALIFORNIA SAN FRANCISCO SCHOOL OF MEDICINE IN 2001. DURING MEDICAL SCHOOL SHE SPENT ONE YEAR AT NIH IN THE RESEARCH CLINICAL PROGRAM WHILE WORKING ON AN ANIMAL MODEL OF TRANSPLANTATION FOR SICKLE CELL DISEASE. SHE COMPLETED AT DUKE UNIVERSITY MEDICAL CENTER IN 2005. DR. FITZHUGH COMPLETED FELLOWSHIP ADULT HEMATOLOGY IN HEMATOLOGY ONCOLOGY AT THE NATIONAL INSTITUTES OF JOHNS HOPKINS HOSPITAL. SHE'S BOARD CERTIFIED. SINCE COMPLETING HER FELLOWSHIP DR. FITZHUGH HAS FOCUSED HER RESEARCH ON CLINICAL RESEARCH PROJECTS INVOLVING BONE MARROW TRANSPLANTATION AND OTHER TREATMENTS FOR PATIENTS WITH SICKLE CELL DISEASE. DR. FITZHUGH HAS SERVED ON THE PEDIATRIC ONCOLOGY BRANCH AS THE REPRESENTATIVE ON THE CLINICAL FELLOWS COMMITTEE. MEMBER OF THE CLINICAL CENTER ETHICS COMMITTEE AND REPRESENTATIVE FOR NHLBI AND A MEMBER OF THE AMERICAN SOCIETY OF HEMATOLOGY. OUR SECOND SPEAKER IS DR. MATTHEW HSIEH, A STAFF COLLISION FOR THE HEMATOLOGY BRANCH OF NHLBI. DR. HSIEH EARNED HIS MEDICAL DEGREE FROM VERMONT IN BURLINGTON IN 1988. HE COMPLETED AN INTERNAL RESIDENCY AT BROWN UNIVERSITY AFFILIATE HOSPITAL IN 2001. DR. HSIEH COMPLETED A COMBINED FELLOWSHIP IN HEMATOLOGY AND ONCOLOGY AT THE NIH IN 2005 AND COMPLETED A CLINICAL RESEARCH SCHOLARSHIP IN HEMATOLOGY IN THE IN 2006. DR. HSIEH IS A MEMBER OF THE AMERICAN SOCIETY OF HEMATOLOGY AND THE AMERICAN SOCIETY OF BONE MARROW TRANSPLANTATION. HE RECEIVED THE NHLBI ENVIRONMENT AWARD IN 2013 FOR IMPROVING PERFORMANCE EVALUATION TO STAFF CLINICIANS. LET'S BEGIN BY WELCOMING DR. FITZHUGH WHO WILL ADDRESS PREVENTION OF ORGAN DAMAGE MORTALITY IN SICKLE CELL DISEASE. [APPLAUSE] >> GOOD AFTERNOON. THANK YOU FOR THE INTRODUCTION AND THANK YOU FOR INVITING ME TO GIVE THIS PRESENTATION. I HAVE NO FINANCIAL DISCLOSURES TO REPORT. I WILL BE DISCUSSING THE OFF LABELED USE OF HYDROXY IN PEDIATRIC PATIENT WITH HOMOZYGOUS SICKLE CELL DISEASE. THE FIRST OBJECTIVE WILL BE TO DESCRIBE THE MOST RECENT RISK FACTORS FOR EARLY MORTALITY IN ADULT PATIENTS WITH SICKLE CELL DISEASE. BASED ON CURRENT DATA DISCUSS THE POTENTIAL TO PREVENTED OR DECREASE ORGAN DAMAGE AND IMPROVE SURVIVAL IN MEASURES WITH HOMOZYGOUS SICKLE CELL DISEASE. SICKLE CELL DISEASE WAS FIRST REPORTED MORE THAN 100 YEARS AGO. LATER IT WAS FOUND TO BE CAUSED BY A SINGLE SUBSTITUTION AS A SINGLE SUBSTITUTION AT POSITION 6 OF B GLOBIN CHAIN. THIS IS UPON OXYGENATION AND OCCLUSION OF THE MICRO VASCULATURE. THIS LEADS TO MANY DIFFERENT COMPLICATIONS. THIS IS RECURRENT CRISES, ACUTE CHEST SYNDROME, STROKE, PRIAPISM AND NEPHROPATHY -- RECORD IN 2007, 232 PATIENTS WHO ARE AT LEAST 16 YEARS OF AGE WHO COMPLETED A PAIN DIARY FOR UP TO SIX MONTHS. AND HE FOUND THAT PAIN WAS REPORTED ON A MAJOR OF DAYS. SO 38% OF THE PAGES OR 38% OF THE DAYS PATIENTS REPORTED CHRONIC PAIN, 12.5 PERCENT OF THE DAY PATIENTS HAD PAINFUL CRISES THAT WERE TREATED AT HOME. AND THREE.5 PERCENT OF THE DAY WAS ACTUALLY PRESENTED TO THE EMERGENCY ROOM OR HOSPITAL FOR ADMISSION. PAIN IS THE MORE COMMON EVENT FOR PATIENTS WITH SICKLE CELL DISEASE. THE STUDY OF SICKLE CELL DISEASE RECORD IN 1994, MORE THAN 3700 PATIENTS THAT THEY FOLLOWED FROM BIRTH TO 66 YEARS OF AGE. THEY REPORTED A MEDIAN AGING DEBT OF 42 YEARS FOR MEN AND 48 YEARS FOR MEN WITH HOMOZYGOUS SICKLE CELL DISEASE AND THIS IS 25 OR 30 YEARS WITH THE GENERAL BLACK POPULATION WITH SICKLE DISEASE AND DAISHZ DIED PREMATURELY. 64% OF THE DEATHS OCCURRED IN PATIENTS WITHOUT CLINICAL EVIDENCE OF END ORGAN DAMAGE BUT 18% DIDN'T HAVE ORGAN DYSFUNCTION. CHRONIC RENAL FAILURE, CONGESTIVE HEART FAILURE AND DEBILL DATING STROKE. OF THE STUDY REPORTED MORE RECENTLY WAS REPORTED BY INVESTIGATORS AT UNIVERSITY OF SOUTHERN CALIFORNIA MORE THAN 1,000 PATIENTS OVER A 40 YEAR PERIOD AND FOR PATIENTS WHO ARE LESS THAN 20 YEARS OF AGE, MOST COMMON CAUSE OF DEATH WAS INFECTION RELATED AND ONLY 13% OF THE PATIENTS HAD IRREVERSIBLE ORGAN DAMAGE AT THE TIME OF DEATH. WHILE PATIENTS WHO ARE AT LEAST 20 YEARS OF AGE, 42% OF THEM HAD IRREVERSIBLE ORGAN DAMAGE INCLUDING ONE KIDNEY AND/OR LIVER DAMAGE. WHAT OTHER RISK FACTORS FOR EARLY DEATH IN PATIENTS WITH SICKLE CELL DISEASE. STUDIES REPORTED THAT SIGNIFICANT HERE DECREASED OR DISEASED PATIENTS THAT FIELD HEMOGLOBIN AND HIGH WHITE COUNT IS INDEPENDENTLY ASSOCIATED WITH EARLY MORTALITY AND THEY ALSO REPORTED THAT RENAL FAILURE WAS ASSOCIATED WITH EARLY MORTALITY. THIS IS CONFIRMED BY A LATER STUDY THAT SHOWED PATIENTS WITH RENAL FAILURE DIED EARLIER AS COMPARED TO PATIENTS WHO DID NOT HAVE RENAL FAILURE. SO THE NIH INVESTIGATORS WANTED TO KNOW WHETHER THE HEMO LYTIC PHENOTYPE WAS A RISK FACTOR FOR EARLY DEATH IN PATIENTS WITH SICKLE CELL DISEASE. THEY DIVIDED THEM IN TWO DIFFERENT GROUPS WHETHER THEY HAD THE HIGHEST LDH OR LOW LDH. IT WAS CORRELATED WITH HEMOGLOBIN LEVEL AND LDH WAS UP BECAUSE OF -- AND THESE PATIENTS WERE MORE LIKELY TO HAVE A HIGHER HEMOGLOBIN AND A LOWER LDH. ALSO THEY REPORTED THAT PATIENTS WITH THE HIGHEST LDH WITH REDUCED SURVIVAL, HOWEVER AGAIN THE PATIENTS WITH HEMATOMA GOINGEN DISEASE WERE MORE LIKELY TO HAVE A LOWER LDH AND ALSO WERE MORE LIKEN TO LIVE LONGER. SO OUR HIGH LDH EXCESSIVE MORTALITY DUE TO INCREASED HUH MALL SIST I'LL DISCUSS THAT LATER. WHY DO OUR MEASURES WITH SICKLE CELL DISEASE DIE. TWO, DOES HIGH ROXY UREA IMPROVE ORGAN DYSFUNCTION AND DOES IT IMPROVE SURVIVAL. WHY DO OUR PATIENTS WITH SICKLE CELL DISEASE DIE. REQUESTS FOR MEDICAL RECORDS WERE SENT TO ALL HOSPITALS WHERE PATIENTS DIED. CAUSES OF DEATH WERE BY TWO INVESTIGATORS INDEPENDENTLY, DR. MATTHEW -- BASED ON DEATH CERTIFICATES, MEDICAL RECORDS AND AUTOPSY REPORTS WERE AVAILABLE. LABORATORY STUDIES AND NEPHROCARDIOGRAMS WERE EVALUATED AT THE TIME OF THE STUDY AND MOST RECENT FOLLOW UP. VARIOUS TESTS AND LOGISTIC REGRESSION ANALYSIS WERE PERFORMED TO DETERMINE WHICH FACTORS MAY BE ASSOCIATED WITH DEATH. 518 PATIENTS WITH SICKLE CELL DISEASE WERE ENROLLED BETWEEN JANUARY 2001 AND MARCH 2010 AND THE SCREEN STUDY BEING RUN BY DR. JAMES TAYLOR. THE MAJORITY OF PATIENTS RECEIVED PRIMARY CARE AT OUTSIDE INSTITUTIONS. 82 PATIENTS OR 16% OF THEM DIED AND THE MEAN DURATION OF FOLLOW UP WAS THREE AND-A-HALF YEARS FOR LIVING AND TWO AND-A-HALF YEARS FOR DISEASED PATIENTS. PATIENTS DIED AT 25 HOSPITALS AND MEDICAL RECORDS WERE REQUESTED. MEDICAL RECORDS WERE RECEIVED FROM 10 HOSPITALS FOR 29 PATIENTS. DEATH CERTIFICATES WERE AVAILABLE FOR ABOUT THREE QUARTERS OF THE PATIENTS, AND AUTOPSY REPORTS WERE AVAILABLE FOR ABOUT A THIRD OF THE PATIENTS. IF YOU LOOK AT ALL THE PATIENTS FROM THE STUDY AT THAT TIME, THE MEDIAN AGE AT THE TIME OF ENROLLMENT AT THE TIME OF THE STUDY WAS 35 YEARS. EQUAL DISTRIBUTION OF MALE AND FAME PATIENTS AND THE GREAT MAJORITY OF THE PATIENTS HAD HOMOZYGOUS SICKLE CELL DISEASE -- FOLLOWED BY PATIENTS HAVE HEMOGLOBIN SC DISEASE. WE FOUND THE DEATH OF OUR PATIENTS WAS 44 YEARS WHICH IS NOT SIGNIFICANTLY DIFFERENT FROM THE RESULTS REPORTED 20 YEARS EARLIER BUT PATIENTS CONTINUED TO DIE PREMATURINGLY. THE MOST COMMON CAUSE OF DEATH WAS PULL MARRY ETIOLOGY FOLLOWED BY SICKLE CELL CRISES. THE CAUSE OF DEATH WAS LISTED AS SICKLE CELL DISEASE ALTHOUGH THAT'S NOT TRULY CAUSE 06 DEATH. THERE WAS CARDIAC AND INFECTION ETIOLOGY AND THE CAUSE OF DEATH WAS UNKNOWN IN ABOUT A QUARTER OF THE PATIENTS. SUBSEQUENT ANALYSIS WILL ONLY INCLUDE PATIENTS WITH HEMOGLOBIN SS DISEASE AND THAT'S BECAUSE WE WANTED TO STUDY A PHENOTYPE AND CONFORM THE VARIABLES INCLUDING LOWER LDH, HIGHER HEMOGLOBIN, A LONGER SURVIVE IN PATIENTS WITH HEMATOMA GOINGEN SC DISEASE. SO SIMILAR TO THE PREVIOUS STUDY THAT I REPORTED, DISEASED PATIENTS HAD A SIGNIFICANT HIGHER WHITE CELL COUNT AND SIGNIFICANT LOWER HEMOGLOBIN AS YOU CAN SEE HERE. THESE PATIENTS ALSO HAD A HIGHER LDH. HOWEVER, THERE'S NO SIGNIFICANT DIFFERENCE IN HEMOGLOBIN -- COUNT OR -- THEREFORE THE HIGHER LDH IN OUR PATIENTS IS NOT DUE TO HUH MALL SUS. WE LOOKED AT ORGAN FUNCTION PARAMETERS AND WE FOUND DISEASED PATIENTS HAD A SIGNIFICANTLY ELEVATED -- MORE LIVER DAMAGE, SIGNIFICANTLY HIGHER CREATININE AND -- AND A SIGNIFICANT HIGHER -- SUGGESTING MORE CARDIO PULMONARY ABNORMALITIES. THE HIGHER LDH REFLECT INCREASED ORGAN DAMAGE IN OUR DISEASED PATIENTS AND NOT HEMOLYSIS. THIS IS CONFIRMED BY REGRESSION WHERE WE FOUND THAT ELEVATED ALKALINE -- ELEVATED BILIRUBIN AND ELEVATED VELOCITY AS WELL AS DECREASED -- WERE INDEPENDENTLY ASSOCIATED WITH DEATH. THE ORGAN DAMAGE AND DYSFUNCTION LEADS TO EARLY MORTALITY IN OUR PATIENTS. SO THE NEXT QUESTION DOES HYDROXY UREA -- WHILE IT HAS MULTIPLE PROPOSED MECHANISM THE MAIN BENEFICIAL EFFECT IS HEMAGLOBINNEN INDUCTION. YOU CAN SEE WITHOUT HYDROXY UREA OXYGENATED STATE THE BLOOD CELL IS ROUND AND EASILY FORMABLE -- AND THIS LEADS TO A RIDGED SICKLE RED CELL. HOWEVER IN THE PRESENCE OF HYDROXY UREA HEMOGLOBIN INCREASED AND DECREASES HEMOGLOBIN POLYMERIZATION AND SO UNDER DEOXYGENATED PRESENCE THE CELL REMAINS ROUND AND EASILY DEFORMABLE. THE PACKAGE INSERTS RECOMMEND STARTING HYDROXY UREA -- AND THEN TITRATING THE DOSE EVERY EIGHT WEEKS FOR A MAXIMUM DOSE OF 35 MILL GRAMS PER DAY -- THAT'S BECAUSE NEUTROPENIA IS TOXICITY WITH HYDROXY UREA. SO IN 1995, THE MULTICENTER STUDY OF HYDROXY UREA OR IN THE STATE TRIAL WAS REPORTED AND THIS IS A STUDY WHERE PATIENTS WITH SICKLE CELL ANEMIA WERE RANDOMIZED TO RECEIVE -- OR PLACEBO AND THE STUDY WAS STOPPED EARLIER BECAUSE PATIENTS WHO TOOK IT HAD SIGNIFICANTLY DECEASED -- AND ACUTE TEST SYNDROME AND A SIGNIFICANTLY HIGHER HEMOGLOBIN AND THEY ALSO HAD A DECREASED TRANSFUSION REQUIREMENT. BASED ON THIS STUDY IT WAS FDA APPROVED FOR PATIENTS WITH SICKLE CELL ANEMIA IN 1998. THE NEXT QUESTION IS DOES HYDROXY UREA IMPROVE ORGAN FUNCTION. THIS IS A STUDY WHERE 193 HOMOZYGOUS SICKLE CELL DISEASE WERE AT A FIXED DOSE OF 20 MILLIGRAMS VERSUS PLACEBO FOR TWO YEARS. THE PRIMARY END POINTS WERE SPLENIC FUNCTION AND GFR BY RADIONUCLIDE STUDIES -- IN PATIENTS TREATED AS COMPARED TO THE CONTROL. SO FIXED CONTROL DOES NOT IMPROVE FUNCTION IN MEASURES WITH SICKLE CELL ANEMIA. ANOTHER STUDY THAT LOOKED AT ACUTE PATIENTS WHO WERE 21-27 YEARS OF AGE WITH FUNCTIONAL -- AND THESE PATIENTS WERE ACTUALLY STARTED AT THE RECOMMENDED DOSE AND TITRATED TO MAXIMUM TOLERATED DOSE. SO THE FIELD LEVELS INCREASED FROM 4 TO 7 PERCENT TO HIGH AS -- AFTER STARTING IT IT WAS DETECTED IN BOTH PATIENTS AND THIS IS THE NORMALIZATION OF THE PITTED RED BLOOD CELLS, SPLENIC UPTAKE ON LIVER SPLEEN SCAN AND PEOPLE WITH LARGE SPLEENS -- THIS IS CONFIRMED WITH TWO LARGER PEDIATRIC STUDIES. THE FIRST WERE 43 CHILDREN HAD LIVER SPLEEN SCANS AND AFTER TAKING HYDROXY UREA -- AFTER TWO AND-A-HALF YEARS 14% OF THE KIDS HAD RECOVERED COMPLETELY WITH SPLENIC FUNCTION. YOU CAN SEE HERE BEFORE HYDROXY UREA THERE WAS NO UPTAKE AND AFTER THERE WAS EVIDENCE. ANOTHER STUDY LOOKED AT 36 CHILDREN WHO HAD LIVER SPLEEN SCANS THREE YEARS AFTER TAKE AND THEY FOUND THAT HEMOGLOBIN LEVELS OF 25% WERE MORE LIKELY TO BE ASSOCIATED WITH -- COMPARED TO 14% -- DOSING REVERSE ORGAN FUNCTIONS IN CASES WITH SICKLE CELL ANEMIA. WE WANTED TO KNOW HOW MANY OF OUR PATIENTS TAKE HYDROXY UREA AND WHAT IS THEIR DOSE. THIS IS A HARD QUESTION BECAUSE THIS IS A RETROSPECTIVE ANALYSIS AND DR. -- WAS HELPFUL IN ANSWERING THIS QUESTION. SO THERE WERE 46,000 CLINICAL NOTES -- 23,000 NOTES CON TAINED THE WORD HYDROXY UREA. HE OBTAINED THE DOSES WHERE POSSIBLE AND DATA QUERY FOR PATIENT WEIGHT, MCV VALUES AND HEALED HEMOGLOBIN LEVELS. THE REASON WE WERE INTERESTED IN MCV IS THEY HAVE VOLUME INCREASES IN PATIENTS WHO TAKE HYDROXY UREA. THE HEMOGLOBIN WAS 10% AND PATIENTS WEREN'T ASSIGNED TO THE -- GROUP -- AND DRUG DOSAGES. SO WE FOUND THAT WE DID A PRETTY GOOD JOB OF ASSIGNING PATIENTS TO HYDROXY UREA OR NOT BECAUSE THOSE HAD A HIGHER FIELD OF HEMOGLOBIN AND SIGNIFICANTLY HIGHER MCV. WE FOUND THAT PATIENTS HAD A MEAN COUNT OF 4.9 AND ALSO THERE WAS NO SIGNIFICANT DIFFERENCE IN THE HEMOGLOBIN LEVELS BETWEEN THE TWO GROUPS. SO THAT SUGGESTED THAT WHILE THE PATIENT HAD TAKEN HYDROXY UREA BUT THE DOSE IS NOT CLOSE TO THE MAXIMUM TOLERATED DOSE. WE FOUND THAT TWO THIRDS OF THE PATIENTS HAD EVER BEEN TREATED WITH HYDROXY UREA, AND THAT THE MEDIAN HYDROXY UREA DOSE WAS 19 AND-A-HALF MILLIGRAMS KILOGRAMS PER DAY. OF THE PATIENTS WHO TOOK IT ONLY TWO THIRDS OF THEM WERE ON THE RECOMMENDED DOSE, AND 18% OF THE PATIENTS WERE ON A DOSE LESS THAN 15 MILLIGRAMS PER KILOGRAM MARIE DAY. AND IF YOU LOOK AT ALL THE PATIENTS TAKING HYDROXY UREA THE HEMOGLOBIN LEVELS SEEN IN THAT GROUP WERE AT A MEAN OF 17%. SO WHEN WE DIVIDED THE PATIENTS IN THESE GROUPS BASED ON WHETHER THEY HAD EVER TAKEN HYDROXY UREA OR NOT, THERE WAS NO SIGNIFICANT DIFFERENCE IN ANY OF THESE ORGAN FUNCTION PARAMETERS. SO THERE'S NO SIGNIFICANT IMPROVEMENT IN ORGAN FUNCTIONS BASED SIMPLY ON HYDROXY UREA STATUS. WHAT ABOUT PATIENTS LOOKING AT FIELD HEMOGLOBIN RESPONSE. THE PATIENTS WERE DIVIDED ON GROUPS BASED ON WHETHER THEY HAD THE HIGHEST OR LOW HE IS LEVELS. THE PATIENTS WITH THE HIGHEST LEVELS HAD A DOSE OF 24 MILLIGRAMS COMPARED TO 19 IN ALL OF THE PATIENTS WHO TOOK IT AND THE HEMOGLOBIN WAS 26% COMPARED TO -- COMPARED TO ALL THE PATIENTS WHO TOOK HYDROXY UREA. THE PEOPLE WITH THE -- YOU CAN SEE THAT THERE WAS LESS EVIDENCE OF LIVER DAMAGE, LESS EVIDENCE OF RENAL DAMAGE AND THE -- IS SIGNIFICANTLY HIGHER. SICKLE CELL PATIENTS WITH HIGHER HEMOGLOBIN HAD THE BEST FUNCTION. TWO LONG STORM STUDIES PROVES -- ONE WAS A 17.5 YEAR FOLLOW UP. WHILE 43% OF THE ORIGINAL COHORT DIED THERE WAS DECREASED MORTALITY WITH LONG TERM HYDROXY UREA EXPOSURE. ANOTHER STUDY WITH 330 PATIENTS MOST OF THEM HAD HEMOGLOBIN -- BUT 34 OF THEME HAD HEMOGLOBIN SS DISEASE. THE PROBABILITY, ALL THESE PATIENTS FOR UP TO 17 YEARS AND THE PROBABILITY OF 10 YEAR SURVIVAL WAS HIGHER IN PATIENTS WHO WERE ADMINISTERED HYDROXYUREA. IT'S IMPORTANT TO KNOW IN TWO STUDIES THE PATIENTS WERE STARTED ON THE RECOMMENDED DOSE AND THE DOSE WAS TITRATED FOR THE MAXIMUM TOLERATED DOSE. THERE ARE MULTIPLE STUDIES THAT HAVE BEEN PUBLISHED IN THE UNITED STATES AND IN FRANCE THAT HAS SHOWN IN THE POST HYDROXY UREA PATIENTS CONTINUED TO DIE EARLY AS EARLY AS 32 TO 40. THIS LAST STUDY PERFORMED BY THE HOPKINS GROUP LOOKED AT THE MORTALITY RATE FOR OVER 16,000 PEOPLE IN THE UNITED STATES WITH SICKLE CELL DISEASE AND YOU LOOK AT THE MORTALITY RATE FROM 79 TO 2005 AND THEY COMPARED THE PERIOD BETWEEN 1992 AND 1998 BEFORE FDA APPROVAL TO THE PERIOD OF 1999 TO 2005. AND THEY DID NOT FIND ANY SIGNIFICANT CHANGE IN MORTALITY RATE AND IF ANYTHING IT LOOKS LIKE THE MORTALITY RATE IN ADULTS IS GOING UP OVER TIME RATHER THAN DOWN. THE TWO STUDIES I LOOKED AT THE PROVIDERS HYDROXY UREA PRESCRIPTION PATTERNS AND THEY FOUND THE FIRST STUDIES LOOKED AT 48 ADULT SICKLE CELL PROVIDERS THAT RESPONDED TO A QUESTIONNAIRE. ANY RECOMMENDATIONS ON HYDROXY UREA USE AND 76% AGREED WITH THE RECOMMENDATION. HOWEVER 45% PRESCRIBED IT TO ELIGIBLE PATIENTS. THE SECOND STUDY HAD 1 6 POSITIONS OF SICKLE CELL PATIENTS WHO RESPONDED TO A QUESTIONNAIRE. AND THEY FOUND THAT 45% OF THEM PRESCRIBED HYDROXY YOU'RE JAW TO LESS THAN 10% OF THEIR PATIENTS. ONLY A MINORITY OF ADULT PROVIDERS PROVIDE HYDROXY UREA TO HIGH LEVEL PATIENTS. WHEN I LOOKED MOST CLOSELY AT THESE STUDIES I FOUND THE MINORITY OF PATIENTS WERE ACTUALLY PRESCRIBED HYDROXY UREA OR TOOK HYDROXY UREA. SO WHEN WE LOOK BACK AT OUR STUDY WE FOUND THERE WAS NO SIGNIFICANT DIFFERENCE IN ARE SURVIVAL WHEN LOOKING AT HYDROXY UREA STATUS. HOWEVER THE HIGHER DOSE WAS SIGNIFICANTLY ASSOCIATED WITH SURVIVAL. AND THE HYDROXY UREA DOSES ASSOCIATED WITH SURVIVAL WAS CONFIRMED BY A MULTIVARIATE ANALYSIS. COMPARING THEM FROM THE HIGHEST TO THE LOWEST, THE PEOPLE WITH THE HIGHEST LEVELS WERE MORE LIKELY TO SURVIVE. SO IN CONCLUSION, WHY DO OUR PATIENTS WITH SICKLE CELL DISEASE DIE FROM ORGAN DAMAGE. DOES HYDROXY UREA IMPROVE ORGAN FUNCTIONS. YES, IF DOSED PROPERLY. DOES HYDROXY UREA IMPROVE SURVIVAL. YES -- AND RESPONSE IS OPTIMIZED. SO IN THE FUTURE I'LL BE WORKING ON STUDIES TO MAXIMIZE INDEDUCTIONS TO PREVENT RED BLOOD CELL SICKLING BY DOSING AND WITH OR WITHOUT OTHER FIELD HEMOGLOBIN AND I BELIEVE THAT WILL HELP TO DECREASE ORGAN DAMAGE AND ESSENTIALLY DECREASE EARLY MORTALITY IN PATIENTS WITH SICKLE CELL DISEASE. I WOULD LIKE TO THANK THE PATIENTS AND THEIR FAMILIES. DR. -- HAS BEEN MY MENTOR FOR MANY YEARS AND MATTHEW HSIEH AND -- AND HIS GROUP AS WELL AS THE STUDENTS WHO HAVE BEEN WORKING WITH US. DR. MICHAEL -- HELPED WITH HYDROXY UREA DOSING -- MEDICINE BRANCH, THE CLINICAL STAFF OF THE CRC AND LAST BUT NOT LEAST -- OR PREVIOUSLY THE CRTP BECAUSE IT ALLOWED ME TO COME HERE AS A MEDICAL STUDENT AND I'VE HAD A WONDERFUL EXPERIENCE WHICH WAS THE MAIN REASON I WANTED TO COME BACK HERE. [APPLAUSE] >> A GREAT INTRODUCTION. I HOPE YOU LEARNED A LOT FROM DR. FITZHUGH ABOUT HYDROXY UREA. RIGHT NOW I WOULD LIKE TO TALK ABOUT ANOTHER TREATMENT FOR SICKLE CELL DISEASE WHICH IS CALLED -- AND WE'RE REALLY GRATEFUL FOR THIS OPPORTUNITY TO PRESENT OUR WORK ON SOMETHING THAT I WORKED ON PRETTY HARD FOR THE LAST SEVERAL YEARS. I'M VERY EXCITED TO PRESENT TO YOU GUYS OUR RESULTS. I ALSO HAVE NO FINANCIAL DISCLOSURE AND OFF LABEL USE WILL BE DISCUSSED DURING THIS HALF OF THE TALK. I HOPE BY THE END OF THE -- I CAN SHOW YOU DATA THAT -- TRANSPLANTATION IS A REALLY GOOD TREATMENT OPTIONS FOR PATIENTS WITH HLA-MATCHED SIBLINGS. I HOPE TO SHOW THAT WHILE TRANSPLANTS IS THE STANDARD FOR CHILDREN WITH SICKLE CELL DISEASE, NON-MILO ABLATIVE TRANSPLANTS ARE GAINING ACCEPTTANCE -- CAN REVERSE THE SICKLE CELL PHENOTYPE AND HAVE THE POTENTIAL TO REVERSE SOME OF THE END ORGAN DAMAGE. YOU HEARD FROM DR. FITZHUGH THAT SICKLE CELL DISEASE -- AND THE BONE MARROW IS REALLY THE CULPRIT BECAUSE TO CONTAIN THE MUTATIONS THAT MAKE THE RED CELLS, ALL THE WHITE CELLS [INDISCERNIBLE] AND IT IS THIS MUTATION THAT CAUSES THE HEMOGLOBIN HEMOGLOBIN TETRAMERS -- SO IF WE CAN TAKE THE DISEASED BONE MARROW AND REPLACE THOSE WE CAN TREAT IN A DEFINITIVE WAY SICKLE CELL DISEASE. AND THE TRANSPLANT ARE SIMPLIFIED INTO THESE FOUR COMPARTMENTS. THE FIRST COMPARTMENT OR FIRST COMPONENT IS SUPPRESSION OR MAKING SPACE IN THE BONE MARROW. THIS IS TYPICALLY DONE THROUGH HEMO THE THERAPEUTIC AGENTS OR BY RADIATION AND IT IS GIVEN OVER SEVERAL DAYS. THE NEXT COMPONENT IS IMMUNE DEPLETION OR TO LOWER THE NUMBER OF -- OR THE IMMUNE SYSTEM OF THE HOST SO YOU CAN RECEIVE INCOMING DONOR CELLS. THIS IS OFTEN ACHIEVED THROUGH TYPICAL CHEMOTHERAPY AGENTS SUCH AS -- AND OTHERS. AND IT IS ALSO GIVEN OVER SEVERAL DAYS. THE NEXT PORTION TO PREVENT -- AND IMMUNOPRESSENT DRUGS SUCH AS CYCLOSPORIN AND OTHERS ARE THERE TO SORT OF PUT A BREAK ON DEVELOPING DONORS IN GRAFTING, AND THE GOAL IS TO PREVENT THE DONORS FROM ATTACKING THE HOST. AND THE LAST PORTION IS THE DIFFERENT TYPES OF ANTI-MICROBIAL GIVEN TO PREVENT DIFFERENT SOURCES OF INFECTION THAT'S COMMONLY ASSOCIATED WITH TRANSPLANT. THE FIRST PATIENTS I HAD WITH SICKLE CELL DISEASE RECEIVED A TRANSPLANT WAS IN THE EARLY 1980 WHERE AN EIGHT-YEAR-OLD GIRL HAD MODERATELY SEVERE SICKLE CELL DISEASE OR SHE HAD ONE TO TWO HOSPITAL ADMISSIONS PER YEAR FOR PAIN CRISES. WHEN SHE DEVELOPED ACUTE MILO LEUKEMIA -- FROM AN HLA-MATCHED SIBLING. AROUND THE SAME TIME SUCCESSFUL TRANSPLANT FOR A DISEASE -- AND RATHER THAN USING TOTAL BODY RADIATION THEY SUBSTITUTED THAT FOR DOSES BECAUSE AT THAT TIME MOST OF THE PATIENTS WERE GETTING A TRANSPLANT WERE CHILDREN AND THEY WERE CONCERNED THAT IF YOU WERE TO GIVE EXCESSIVE DOSES OF RADIATION THAT MIGHT AFFECT THE LONG TERM AVERAGE FOR THOSE CHILDREN. SO FOLLOWING THE SUCCESSFUL TRANSPLANTS THIS BEGINS TO BE DUPLICATED IN SICKLE CELL DISEASE AND SUCCESSFUL CASE SERIES BEGIN TO MERGE. FROM THOSE CASE SERIES, IF YOU TAKE HOME POINTS WHICH ARISE. FIRST IS THAT SEVERE SICKLE CELL DISEASE LIKE -- AND THAT STARTED THE DEBATE AT THE TIME OF THE TRANSPLANT -- WHEN YOU SEE AN OVERT DISEASE MANIFESTATION. AND AT THAT TIME, ALSO STARTED A MULTICENTER COLLABORATION BETWEEN NORTH AMERICA AND EUROPE TO REALLY ASCERTAIN WHAT IS THE SUCCESS RATE FOR TRANSPLANT IN THIS DISEASE AND WHAT ARE SOME OF THE COMPLICATIONS. SO SINCE THE 1990'S, CENTERS FROM U.S. AND NORTH AMERICA HAD TRANSPLANT -- AND THESE ARE CHILDREN AND YOUNG ADULTS. AND THE DISEASE FOR SURVIVAL IS REALLY TERRIFIC. GREATER THAN 90% AND EVEN IN THE LATER SERIES IT IS IN EXCESS OF 95% AND THE MOST OF THE LATEST ONE TO BE CLOSER TO A HUNDRED PERCENT. THE -- IS REALLY LOW AND -- THIS IS APPROACH IS REALLY WELL TOLERATED IN CHILDREN AND EXTENDING UP TO THE YOUNG ADULTS. BUT BY THE TIME WE OR I AS A SICKLE CELL DOCTOR SEE THEM WHEN THEY COME TO SEE ME THEY HAVE SEVERE DISEASE AND THEY OFTEN HAVE ORGAN DYSFUNCTION AS SHOWN BY DR. FITZHUGH. AND TYPICALLY THEY'RE EXCLUDED FROM THE FULL TRANSPLANT OPTIONS BECAUSE THEY ARE TOO SICK TO GO THROUGH THE WHOLE TRANSPLANT. SO TOWARDS THE LATE 90'S AND EARLY 2000S, OUR GROUP AND ALONG WITH OTHER TRANSPLANTERS BEGIN TO THINK YOU KNOW WHAT ABOUT THESE ADULTS WHO HAVE SEVERE DISEASE BUT THEY'RE NOT ELIGIBLE FOR FULL TRANSPLANT. SO WE BEGIN SOME PRE CLINICAL STUDY, ANIMAL STUDIES TRYING TO TEST WHAT ARE SOME OF THE APPROACHES THAT COULD BE APPLICABLE. BASED ON THOSE INITIAL PRECLINICAL STUDIES WE STARTED WORKING ON A CLINICAL PROTOCOL DEVELOPMENT AND THIS WAS THE FIRST FEW CASE SERIES OF NON-OBLATIVE TRANSPLANT SERVICE. THERE'S LOTS OF -- AND THESE ARE THE RESULTS. THIS BROUGHT US BACK TO THE DRAWING BOARD AND MAKE US THINKING AGAIN AND WE ACTUALLY MADE A LOT OF MODIFICATIONS BASED ON THESE OVER THE YEAR CASE REPORTS. ONE OF THE BIGGEST CHANGE THAT WE MADE WAS IN THE CHOICE OF MEDICATION. RIGHT HERE I HAVE A SIMPLIFIED T CELL ACTIVATION SCHEMA -- THE T CELL RECEPTOR IS ACTIVATED. THIS IS CALLED SIGNAL ONE AND THE ACTIVATION OF SIMULATION WERE TO CONTINUE, CYTOKINES BEGIN TO ELABORATE AND TO BE SECRETED ALONG WITH MOLECULES GENERATION AND THAT'S TYPICALLY IN THE C28 OR CTLA FORM. WITH THE CYTOKINES BEING SECRETED, WE HAVE T CELL PROLIFERATION, AND THEN T CELL EFFECTOR FUNCTION FOLLOWS THEREAFTER. AND THEN YOU HAVE THIS FULL REPERTOIRE AND FULL RANGE OF T CELL ACTIVATION. CYCLOSPORIN IS COMMONLY USED AND VERY POWERFUL IMMUNOSUPPRESSANT. THE REASON WHY WE CHOSE IT IS REALLY BASED ON THIS. AS YOU CAN SEE IT REALLY BLOCKS THE SIGNAL FROM BEING ACTIVATED. WHAT HAPPENS IS THAT CAUSES THE T CELL TO BE STUNNED SO THAT IT DOESN'T GO TO THE NEXT STEP. AND IT SENDS THESE T CELLS DOWN TO AN ENERGY PATHWAY. IT BLACKS PROLIFERATION OF T CELLS AND -- ON REGULATORY T CELLS. SO THAT WAS THE FIRST CHANGE THAT WE MADE. THE SECOND CHANGE THAT WE MADE WAS TO INCREASE THE TOTAL BODY RADIATION THAT WAS COMMONLY USED IN NON-OBLATIVE TRANSPLANT -- AND THEN WE TESTED THIS IN A REJECTION MOUSE MODEL. SO WE HAD ONE GROUP OF MICE RECEIVE 300 RADS OF CYCLOSPORIN AND THE SECOND GROUP OF MICE WE SAW THE SAME DOSE OF RADIATION AND RECEIVED SIGH -- THE GROUP THAT RECEIVED CYCLOSPORIN DURING THAT ONE MONTH, THEY HAD TEMPORARY -- IN COMPARISON THE GROUP THAT TOOK RAPAMYCIN THERE WAS INCREASE -- STOP AFTER THAT ONE MONTH, IT CONTINUED TO INCREASE AND PLATEAU BEYOND NINE MONTHS. THIS REALLY GAVE US EXCITEMENT THAT FIRST WE CAN USE IN NON-OBLATIVE APPROACH AND SECOND WE CAN ACHIEVE -- WHICH IS A MINIMAL GOAL FOR TRANSPLANT IN SICKLE CELL DISEASE. SO THESE PRECLINICAL STUDIES WE FELT WERE CONFIDENT IN RISING THE PROTOCOL AND THAT'S REALLY IF IN SICKLE CELL DISEASE AND AL PENIA. I HAD SHOWN HERE THE SICKLE CELL AT MOST OF THE TALKS -- SO YOU SEE HERE THAT PATIENT CAN QUALIFY IF THEY HAVE AN END ORGAN DAMAGE THAT IS SICKLE CELL SPECIFIC NAMELY IN THE BRAIN, IN THE LUNG, KIDNEYS OR IN THE LIVER. OR THEY CAN HAVE THE MODIFIER COMPLICATION BUT NOT RESPONSIVE TO -- AND THAT'S MORE THAN TWO HOSPITALIZATIONS PER YEAR ON PREVIOUS ACUTE CHEST ISN'T DRONE BY BOTH TAKING -- AND OTHERS. AND OUR TRANSPLANT REGIMEN IS AS FOLLOWS. WE TOOK THE SAME 00 RADIATION JUST LIKE WE DID IN THE MICE. WE ALSO USED GCS AND IMMOBILIZED BLOOD STEM CELLS AND THEN WE ADD -- BECAUSE IT IS A T CELL DEPLETING AGENT SO WE CAN DO THAT IN VIVO. THERE ARE ALSO A LOT OF THEORIES BOTH PRECLINICAL AND CLINICAL DATA WHICH IS REALLY TERRIFIC IN REDUCE -- AND WE THOUGHT TO PREVENT -- WOULD BE A VERY IMPORTANT GOAL IN THIS STOWED BECAUSE TO TRADE SICKLE CELL -- WOULD BE A SIGNIFICANT IMPACT AFTER TRANSPLANT. AND THERE ARE A FEW OTHER SICKLE CELL-SPECIFIC PREVENTION THAT WE HAVE, THE FIRST IS TO PERFORM -- EXCHANGE TO LOWER THE HEMOGLOBIN LEVEL SO THEY DON'T GET SICKLE-RELATED COMPILATIONS. WE CONTINUE HYDROXY UREA AT A GOOD DOSE JUST RIGHT UP TO THE COMMISSION REGIMEN SO THAT WE SUPPRESS THE MARROW TO ALLOW FOR THE REGIMEN TO HAVE THIS WHOLE EFFECT. WE KEEP THE PLATELET COUNTS GREATER THAN 50,000 TO PREVENT INTERCRANIAL BLEEDING. ONE YEAR AFTER TRANSPLANT THE CD3 DONOR IS RATED AT 50% OR A SIMPLE MAJORITY WE CAN ALLOW -- IMMUNOSUPPRESSION. WITH THAT PROTOCOL IN PLACE WE BEGAN TO ACCRUE AND IT WAS INITIALLY, I THINK IN PART BECAUSE OF THESE EARLIER DISAPPOINTING RESULTS. AND ALSO BECAUSE FINDING THE HLA MATCH IN PATIENTS LESS THAN 20% OF THE TIME. SO WITH THESE TWO FACTORS WE WEREN'T TWO SURPRISED -- BUT WE BEGAN TO ACCRUE AND THE WORD GOT OUT, WE BEGAN TO SEE FAVORABLE RESULTS AND AT THE SAME TIME WE BEGAN TO SEE A COUPLE CASE REPORTS ALSO BEGAN TO SHOW ENCOURAGING RESULTS. SO ALTOGETHER IT SORT OF GAVE US CONFIDENCE NON-OBLATIVE TRANSPLANT IN ADULTS I THINK THAT'S A VIABLE OPTION TO CONTINUE. SO IN THE LAST TEN YEARS OR SO WE REALLY HAVE DONE A LOT OF WORK. WE HAD 280 PATIENTS AND IN THOSE WE FOUND ABOUT A HUNDRED PATIENTS WITH HLA MATCH SIBLINGS. SOME DID NOT MEET OUR STUDIES BECAUSE THEIR DISEASE WAS NOT SEVERE ENOUGH. OTHERS DIDN'T PROVIDE US THE SUFFICIENT INFORMATION SO WE COULDN'T REALLY DETERMINE THE ELIGIBILITY. WE HAD TO EXCLUDE A GOOD NUMBER OF PEOPLE BECAUSE OF THEY HAVE INCOMPATIBLE OR ANTI-BODIES THAT WERE DIRECTED TO THE DONOR. AT THE END WE HAD TRANSPLANTED 35 PATIENTS SO FAR. YOU CAN SEE HERE THAT THESE ARE THE NUMBERS OF INDIVIDUALS ON THE Y AXIS AND AGE RANGE ON THE X AXIS. AMONG THE 34 PATIENTS, MOST OF THEM HAVE HOMOZYGOUS SICKLE CELL DISEASE WITH DIFFERENT PHENOTYPES. YOU CAN SEE HERE THAT MORE THAN HALF THE PATIENTS WERE IN AGE RANGE FOR THEY WOULD BE AUTOMATICALLY EXCLUDED ON FULL TRANSPLANTS SIMPLY BECAUSE OF THEIR AGE. THE TRANSPLANT CASES, MOST OF THEM HAVE PRECONTAINED AND BECAUSE OF THE PATTERNS WE ARE INTERESTED TO SCREEN FOR PULMONARY HYPERTENSION. WE SAW QUITE A FEW YOU'RE GATED TO 2.5 METERS PER SECOND. A GOOD NUMBER OF ACUTE CHEST SYNDROME, STROKE, NECROSIS AND KIDNEY DAMAGE. AND THIS IS ACTUALLY ONE OF THE SURPRISING FACTORS FOR US. TEN PATIENTS HAVE TWO WITH THE ABOVE INDICATIONS AND ANOTHER 16 HAVE THREE INDICATIONS INDICATING TO US THAT YOU KNOW MAJORITY OF PATIENTS ARE REALLY SICK FROM THE DISEASE AND REALLY HAVE A DISEASE MANIFESTATION. HOW DO OUR PATIENTS DO WITH THE TRANSPLANT. THEY ACTUALLY HAVE GONE THROUGH THE CONDITION REGIMEN PRETTY WELL. OTHER THAN PAIN WHICH IS FAIRLY TYPICAL BECAUSE A GOOD MAJORITY OF OUR PATIENTS HAVE CHRONIC PAIN SYNDROME, WE REALLY DIDN'T SEE ANY ACUTE SICKLE-RELATED EVENTS. WE DIDN'T SEE ANY LIVER-SPECIFIC -- DISEASE, INTRACRANIAL BLEEDING -- REPORTED IN TRANSPLANTS IN SICKLE CELL PATIENTS. THE PERIOD OF NEUTROPENIA WAS QUITE REASONABLE AS WELL AS -- WAS ALSO REASONABLE GIVEN IT'S THAT IS A NON--- REGIMEN. WHEN PATIENTS HAVE NEUTROPENIC FEVER THEY GET -- AND IN MOST OF THE PATIENTS THERE WERE NO SEPSIS PHYSIOLOGY THAT WERE DISCOVERED. AND IN 13 PATIENTS, A GOOD THIRD OF THEM REQUIRED NO IV ANTIBIOTICS AT ALL. WE OFTEN DISCUSS WHETHER SOME OF THESE MEASURES CAN BE TRANSPLANTED AS AN OUTPATIENT. WE HAVE RELATIVELY LOW USAGE OF BLOOD PRODUCTS AND CMV TREATMENT WAS INITIATED IN FOUR PATIENTS AND WE HAVE TWO OR THREE PATIENTS THAT HAVE -- IS TRANSPLANT. AMONG THE 34 PATIENTS WE HAVE TRANSPLANTED, 30 OF THEM HAVE SUSTAINED -- AND YOU CAN SEE THIS IS THE INGRAFTMENT. THE TOP LINE HERE IS THE MYELOID OR THE -- YOU CAN SEE THAT MYELIN GRAPH IN A FEW MONTHS -- OUR T CELL WITH CD3-THIS LOWER GRAPH AND IS QUITE DIFFERENT. IT STARTS OFF LOW, BEGINS TO INCREASE AT ABOUT SIX MONTHS TO 18 MONTHS AND THIS GETS PLATEAUED OUT UNTIL ABOUT CLOSE TO TWO YEARS. AND WHEN WE SEPARATE THEM BASED ON WHETHER THEY ARE ON OR OFF IMMUNOSUPPRESSION, WE SEE THAT THE MILO -- IS QUITE THE SAME BETWEEN THE TWO GROUPS. BUT IN THE CD3 KIMERC -- THEY WILL REMAIN STABLE AND FOR THOSE PATIENTS THERE ARE 15 OF THEM WHICH IS HALF OF THE ENGRAPH, THEY ARE NOT IMMUNOSUPPRESSION RANGING FROM THREE MONTHS TO FOUR YEARS. FOR THE PATIENTS THAT REMAIN, YOU CAN SEE THAT THEIR T CELL -- THIS IS WHETHER THE PATIENT IS TAKING-OR THEY ARE VERY DISCONTINUOUS OR SHORT OR LONG PERIOD WE HAVE NOT SEEN ANY GRAPHS ASSOCIATED WITH THESE. THIS IS SOMETHING THAT FOR THE DISORDER LIKE SICKLE CELL DISEASE WE REALLY WANT TO ADVERTISE AND MAKE THAT AN EMPHASIS AMONG OUR TRANSPLANTS OR THOSE CONSIDERING TRANSPLANT. BECAUSE OUR PATIENTS TAKE -- FOR SEVERAL MONTHS AND SOMETIMES SEVERAL YEARS WE REALLY WANT TO LOOK AT THE T CELL RECOVERY. AT EACH TIME POINT HERE, I HAVE THE TOTAL CD3 COUNT. I HAVE THE CD4 COMPARTMENT AND THE CD8 COMPARTMENT HERE AT PRETRANSPLANT AND VARIOUS TIME POINTS AFTER TRANSPLANT. AFTER SIX MONTHS THEIR TOTAL T CELL COUNT IS LOWER COMPARED TO THE BASELINE VALUES. THIS BEGINS TO SHOW SOME SIGNS OF INCREASING BACK TO THE NORMAL RANGE OR THE PRETRANSPLANT RANGE AND THIS IS REALLY ACHIEVED BY ONE YEAR. BY THE TIME THEY REACHED A TWO YEAR OR LATEST TIME POINT THEY HAVE ACHIEVED BACK TO THEIR PRETRANSPLANT SORT OF NUMBERS. AND THESE RED DOT INDICATE PATIENTS THAT ARE NOW -- AND THERE ARE A COUPLE INTERESTING POINTS ON THIS GRAPH I WOULD LIKE TO HIGHLIGHT. IT LOOKS LIKE THE CD8 COMPART HAD RECOVERED BACK TO THE PRETRANSPLANT LEVELS BUT THE CD4 COUNTS MAY NOT HAVE, EVEN THOUGH THESE HERE ARE THE LOWER. THIS MAY NOT BE STATISTICALLY SIGNIFICANT BUT THIS IS QUITE INTERESTING. THE OTHER POINT IS THAT FOR THE PATIENTS THAT ARE NOT ON IMMUNOSUPPRESSION ANYMORE, THEIR LYMPHOCYTES OR T CELL COUNT ARE A LITTLE BIT LOWER IN THE SPECTRUM. THE SIGNIFICANCE OF THIS FINDING IS CURRENTLY NOT KNOWN AND TRYING TO THINK WHAT'S THE BEST WAY TO INVESTIGATE. SO WITH THE ENGRAPHMENT WE SEE THAT THE TOTAL HEMOGLOBIN BEGINS TO IMPROVE TO THE NORMAL RANGE IN A GENEROUS SPECIFIC WAY. AND WITH THE INCREASE IN THE TOTAL HEMOGLOBIN WE SEE THE CORRESPONDING DECREASE IN HEMATOMA SIST NAMELY THE LDH IN A NORMAL RANGE -- AND THE TOTAL BILIRUBIN. AND IMPROVEMENT IN THE PARAMETERS WE SEE A LOWER RATE OF HOSPITALIZATIONS AFTER TRANSPLANT. SO HERE WE HAVE THE HOSPITALIZATION RATE ON THE X -- ON THE Y AXIS AND DIFFERENT TIME POINTS PER YEAR ON THE X AXIS. PATIENTS HAD AN AVERAGE OF MORE THAN THREE HOSPITALIZATIONS PER YEAR AND DECREASED PRETTY QUICKLY TO ABOUT .7 AFTER TRANSPLANT AND LESS THAN .5 IN THE SUBSEQUENT YEARS. WITH THAT DECREASE IN HOSPITALIZATION RATE WE ALSO SADI CREASE USE IN TOTAL NARCOTIC DOSE. HERE WE HAVE POST TRANSPLANT UP TO 30 WEEKS AND HERE YOU HAVE EQUIVALENTS GIVEN PER WEEK. YOU CAN SEE A LOT OF REDUCTION IS MAKING PLACE IN THE FIRST FOUR MONTHS AND THIS CONTINUES TO OCCUR IN THE NEXT THREE MONTHS FOR A TOTAL OF ABOUT SIX MONTHS. AND IT REALLY TOOK US ABOUT SIX MONTHS TO GET PATIENTS OFF. AND THESE 11 PATIENTS THAT I HAVE SHOWN HERE WITH THESE AVERAGE VALUES, SOME OF THEM WERE QUITE CHALLENGING AND I REALLY APPRECIATIVE OF THE TEAM AND THE NURSING STAFF AND IN PATIENT AND OUTPATIENT CLINICS AS WELL, PRACTITIONERS TO TAKE CARE OF THESE PATIENTS BECAUSE I KNOW SOME OF THEM ARE QUITE DIFFICULT AND IT'S HARD TO GET THEM THROUGH THE WITHDRAWAL, NARCOTIC WITHDRAWAL PROCESS. SO WHAT ABOUT CHANGES IN OTHER ORGAN FUNCTIONS. WE HAD NINE PATIENTS THAT HAD ABNORMAL CNS DISEASE AND WE SAW THAT THERE WERE NO WORSENING OF THE IMAGING STUDIES. WE'RE CURRENTLY WORKING WITH THE PEDIATRIC ONCOLOGY BRANCH TO WORK ON THEIR PSYCH EVALUATIONS PRE AND POST TRANSPLANT AND WE HOPE TO SHOW YOU SOME OF THOSE LATER VERY SOON. IN 14 PATIENTS FOR THE TRV, MORE THAN 2.5, WE SAW A GOOD REDUCTION INTO THE NORMAL RANGE OF THE TRV. WITH THAT WE SAW INCREASE -- FROM 450 METERS TO 500. BY THIS INCREASE IN 50 METERS OR 10% IS SIGNIFICANT BUT OUR PATIENTS REPORTS WAS THEY HAVE LESS FATIGUE BUT EXERCISE TOLERANCE AND STAMINA WITH THIS INCREASE. WE LIKE TO THINK A LOT OF THIS IMPROVEMENT IS AS A RESULT OF THE TOTAL HEMOGLOBIN THEY HAD EXPERIENCED POST TRANSPLANT. IN 14 PATIENTS, THE TRANSFUSION IRON OVERLOAD WE HAVE COMPLETED LARGE VOLUME TO GET THE SATISFACTION IN ALL THE RANGE IN HALF OF THEM. OUR HOPE IS THAT AS THE NEXT HALF FINISH THEIR PHLEBOTOMY WITH THE HELP OF TRANSFUSION MEDICINE WE WILL SEE SOME EVENTUAL IMPROVEMENT ENDOCRINE FUNCTION OF THESE PATIENTS. WITH THE TIME LINE AND NON--- THE LAST COUPLE YEARS, THERE ARE A COUPLE MORE REPORTS OF NON-OBLATIVE TRANSPLANT. NOW THE TRANSPLANT ON NON-ABLATIVE IS SMALL IN TRANSPLANT EXPERIENCE WE WILL CONTINUE TO DO OUR PART TO MAKE SURE THAT ADULTS WITH SICKLE CELL CAN HAVE ACCESS TO NON-ABLATIVE TRANSPLANT REGIMEN. WHAT ABOUT THOSE PATIENTS THAT DON'T HAVE A -- WHAT ARE SOME OF THE OPTIONS AVAILABLE FOR THEM. I'VE SHOWN YOU THAT MATCH SIBLING HAS A TERRIFIC OUTCOME FOR THE DISEASE SURVIVAL ABOUT 90%, THE GRAVIS ASSOCIATED IS ABOUT 10% AND VERY LITTLE MORTALITY AND THE RELATED CORE BLOOD TRANSPLANT THE NUMBERS ARE JUST AS GOOD. WE WERE QUITE SURPRISED IN OUR RECENT REVIEW THAT UNRELATED TRANSPLANT THE SUCCESS RATE IS ONLY ABOUT 50% AND THE GRAPH OF THE DISEASE IS A LITTLE BIT HIGHER THAN I THOUGHT AND OPTIMAL MORTALITY RATE. PERHAPS FROM THE EXPLANATION COULD BE THAT COULD BE MILDLY ABLATIVE AND SINGLE CORE UNITS WERE USED AND DOUBLE CORE SO THAT COULD EXPLAIN IN PART WHY THERE'S A HIGHER REJECTION RATE. WITH THE RECENT EXPERIENCE AND ENCOURAGING THE REPORTS FROM THE HOPKINS GROUP, OPTIMIZING THE TRANSPLANT -- JUST AS GOOD AS THE UNRELATED CORE. AND THE DIRECTION CORE WE THINK WE'D LIKE TO GO FOR PATIENTS THAT DON'T HAVE THE -- OPTION. WE THINK THE DONOR IS BETTER BECAUSE THEY'RE MORE ACCEPTABLE THAN THE OTHER ALTERNATIVE SOURCES BECAUSE WHEN WE HAVE LOOKED FOR A MATCH CORE OR EVEN MATCHING RELAY THE DONORS IT'S JUST REALLY DIFFICULT TO FIND APPROPRIATE UNITS OR APPROPRIATE DONORS FOR THAT. FOR ADULTS WE WANT TO PERFORM TRANSPLANT, IF WE WANT LARGE CELL DOSES OR EVEN REPEATED -- THAT'S REALLY FEASIBLE IN HALF OF THE DONORS. THE -- IS GREATER BUT WE THINK THIS COULD BE ADDRESSED BY MORE IMMUNOSUPPRESSION AND THIS IS WITH POST GRAPH -- AND THE HOPKINS GROUP HAVE SHOWN WE CAN REDUCE BOTH THE GRAPH REJECTION -- SO THIS IS OUR PROGRAM FOR DR. FITZHUGH. WE USE THE SAME DOSE OF -- WE INCREASE THE TOTAL BODY DOSE FROM 300 AND MAXIMUM TO 400. THEY STILL GIVE THE SAME G MOBILIZED STEM CELLS BUT THEN WE ADDED GREATER DOSES OF CYCLO -- ONE OR TWO DOSES. YOU CAN SEE THAT WHEN WITH A DON'T GET POST GRAPH -- IS QUITE LOW. WHEN WE ADD ONE -- WE HAVE BETTER ENGRAPHMENT BUT OUR LONG TERM ENGRAPHMENT RATE WAS TOO LOW THAT WE HIT A STOPPING RULE IN OUR THIRD AND FINAL COHORT. YOU CAN SEE THAT OUR LONG TERM ENGRAPHMENT RATE IS THE SAME THESE THE HOPKINS GROUP HAS ACHIEVED. WE THINK WITH FURTHER ACCRUAL WE WOULD LIKE TO SEE WHETHER THIS APPROACH IS WITH THE HOPKINS APPROACH WHICH ONE MIGHT BE MORE SUITABLE FOR PATIENTS. SO WITH THAT I WOULD LIKE TO CONCLUDE WITH A COUPLE SLIDES. FIRST ON MATCHED SIBLING TRANSPLANTS. I HOPE I -- SICKLE CELL DISEASE HAVE A MATCHED SIBLING -- I HOPE YOU'RE CONVINCED NOW THAT NON-ABLATIVE TRANSPLANT HAS VERY SIMILAR GOOD NUMBERS. AND WITH OUR ONLY EXPERIENCE HAVING GVHD WE REALLY THINK THIS COULD BE THE STANDARD FOR ADULTS. NONE OF OUR PATIENTS HAVE ACHIEVED 100% MYELOID MT COMPARTMENTS SO THEY REALLY MIXED -- I HOPE YOU'RE CONVINCED SOME OF THE ORGAN FUNCTIONS ARE REVERSED. WE STILL HAVE LOTS OF WORK TO DO. WE WANT TO UNDERSTAND THE MECHANISM OF TOLERANCE BETTER IN TRANSPLANTATION OF AND AFTER IMMUNOSUPPRESSION. WE WANT TO MAKE THE TRANSPLANT A LITTLE BIT BETTER AND I'M SURE WE'LL BE TALKING TO THE HOPKINS GROUP AND OTHER TRANSPLANT GROUPS TO MAKE THAT BETTER. I WOULD LIKE TO PARTICIPATE IN WHAT WE'RE THINKING THE TRANSPLANT REGIMEN -- THAT STILL MIGHT BE AN OPTION. WE WANT TO CONTINUE AT THE TIME OF THE TRANSPLANT, WHETHER WE CAN DO IT BEFORE IN THE BEGINNING OR DURING THE OVERT FUNCTION. WITH THAT, I WANT TO THANK PATIENTS AND THE FAMILY. THE PROTOCOL TEAM AND REALLY ALSO THE FACT THAT CLINICAL CENTER AND MANY DIFFERENT CORE CLINICAL SERVICES HAVE THE TIME TO ACKNOWLEDGE AND TO SHARE WHAT THEY HAVE DONE FOR OUR PATIENTS. THANK YOU VERY MUCH. [APPLAUSE]