>> GOOD AFTERNOON. WELCOME TO GRAND ROUNDS. TODAY, WE HAVE A SPECIAL PRESENTATION TALKING ABOUT A COMMON THEME, STARTING BY INTRODUCING US TO A PATIENT. I'M GOING TO LET EACH OF THE SPEAKERS HANDLE THAT PORTION AND SINCE THERE IS A COMMON THEME I THOUGHT I WOULD INTRODUCES BOTH OUR SPEAKERS FIRST. AND THEN TURN OVER THE PODIUM TO THEM. SO OUR TALK BY OUR FIRST SPEAKER, SUSAN STEVEN HOLLAND, LEUKOCYTE, LEUKEMIA, LYMPHATICS, HE GETS A PRIZE FOR THE BEST TITLE OF THE YEAR. HE STAYED AS A RESIDENT INTERNAL [TECHNICAL DIFFICULTIES] IN 1989 STARTED HIS FIRST ACTIVITY AT THE NIH WORKING AS A NATIONAL RESEARCH COUNCIL FELLOW. NIAID'S LABORATORY OF MOLECULAR MICROBLUOLOGY WHERE HE STUDIED TRANSCRIPTIONAL REGULATION OF HIV. IN 1991, HE JOINED MY LABORATORY, SHIFTING HIS RESEARCH, THE HOST SIDE, WITH THE FOCUS ON TAGO CITE DEFECTS AND ASSOCIATED INFECTIONS. HE WORKED ON CHRONIC BRAN YOU LOCALTIS DISEASE. MAKE THE FIRST KNOCKOUT MOUSE. WORKED ON JOB SYNDROME AS WELL AS OTHER DEFECTS, INCLUDING THOSE PREDISPOSING TO THE MICRO BACTERIAL DISEASES. IN 2004, HE BECAME CHIEF OF THE LABORATORY OF CLINICAL INFECTIOUS DISEASES, ALSO DEPUTY DIRECTOR FOR INTRAMURAL CLINICAL RESEARCH AT THE NIH. HE HAD MANY IMPORTANT POSITIONS, INCLUDING PRESIDENT OF THE IMMUNOCOMPROMISED HOST SOCIETY FROM 2006 TO 2008, ALSO A MEMBER OF THE AMERICAN SOCIETY FOR CLINICAL INVESTIGATION. AMONG HIS MANY AWARDS INCLUDE THE BOIL SCIENTIFIC ACHIEVEMENT AWARD, THE IMMUNE DEFICIENCY FOUNDATION, AND THE AMERICAN COLLEGE OF PHYSICIANS AWARD FOR SCIENCE IN 2012. NOW LET ME INTRODUCES OUR SECOND SPEAKER. DR. DENNIS HICKSTEIN, WHO IS GOING TO TALK ON ALOGENIC HEMATOPOIETIC STEM CELL TRANSPLAYINGS IN PATIENTS WITH MUTATIONS OF GATA2. HE IS A SENIOR INVESTIGATOR, HEAD OF MOLECULAR ONCOLOGY AND GENE TRANSFER IN THE EXPERIMENTAL TRANSPLANTATION AND IMMUNOLOGY BRANCH OF THE NCI. ATTENDED MEDICAL SCHOOL AT THE UNIVERSITY OF NORTHBOUND MEDICAL CENTER, COMPLETED A RESIDENCY -- NEBRASKA MEDICAL CENTER, INCOMPLETED A READCY IN MICHIGAN AND DID I FELLOWSHIP -- DEA FELLOWSHIP AND THE FRED HITCHENSON CANCER CENTER IN SEATTLE. CAME TO THE NCI IN 2000 FROM THE WASHINGTON SCHOOL OF MOONS WHERE HE WAS AN ASSOCIATE PROFESSOR OF MEDICINE IN THE DIVISION OF HEMATOLOGY. HIS FOCUS IS FOCUSED ON NEW THERAPEUTIC APPROACHES TO PATIENTS WITH PRIMARY GENETIC IMMUNODEFICIENCY DISEASES, INCLUDING ALLOGENIC HEMATOPOIETIC STEM CELL PLANTATION AND GENE THERAPY FOR LEUKOCYTE ADHESION DEFICIENCIENED GAD A2 AND DOCK 8. HE'S A MEMBER OF THE AMERICAN SOCIETY OF CLINICAL INVESTIGATION. I WILL TURN THE PODIUM OVER TO DR.S HOLLAND AND HICKSTEIN, AND THEY WILL INTRODUCES THE PATIENT. >> THANK YOU VERY MUCH. IT'S A GREAT HONOR AND PLEASURE TO BE HERE TODAY. DENNIS AND I TALKED ABOUT HOW TO DO THESE PRESENTATIONS AND THOUGHT THAT BECAUSE WE HAVE GOT ONE OF OUR PATIENTS HERE IN THE HOSPITAL, WE SHOULD GET HER TO COME AND TALK ABOUT THIS DISEASE FOR YOU. AND SO WE THOUGHT WE WOULD TAKE A FEW MINUTES AT THE BEGINNING TO ASK OUR PATIENT TO TALK A LITTLE ABOUT HERB PROBLEMS. AND SHE IS UNDERSTANDABLY NERVOUS. WE'LL TOLD HER, SO ARE WE. [LAUGHTER] THE GOOD NEWS, SHE HAS A ROOM SHE CAN RETREAT TO, WE DON'T. BUT I THOUGHT WHAT WE'D DO IS JUST START UP GUY ASKING WHAT -- UP BY ASKING WHAT WAS IT, AS WE TALKED ABOUT BEFORE, THERE ARE TWO QUESTIONS I'D LIKE YOU TO TELL US A LITTLE BIT ABOUT. ONE WAS WHAT WAS THE FIRST THING THAT MADE YOU THINK THAT YOU HAD A PROBLEM? AT WHAT AGE? AND THE SECOND ONE WAS AFTER YOU DECIDED EVENTUALLY YOU HAD A PROBLEM, WHAT MADE YOU COME HERE TO THE NIH? >> SO WHEN I WAS 12, I GOT CHICKEN POX. THEY LASTED FOR THREE MONTHS. AND THEY COVERED EVERY -- MY ENTIRE BODY AND MY SCALP, NOSE, EVERYWHERE. I MISSED THREE MONTHS OF SCHOOL AND LOST HAIR. THEY NEVER HOSPITALIZED ME FOR THAT. SAID WAS TOO CONTAGIOUS, I GUESS. AND SO -- AND THEN AGAIN I RECOVERED FROM THAT, AND THEN THAT WAS THE FIRST TIME I THOUGHT SOMETHING WAS WRONG. >> WHAT DID YOUR DOCTORS THINK WAS WRONG AT THAT TIME? >> NOTHING. THEY DIDN'T DO ANYTHING, REALLY. IT WASN'T UNTIL I WAS 17 THAT I HAD LIKE ANOTHER EPISODE WHERE I JUST FELT REALLY SICK AND WAS REALLY HIGH FEVERS. AND SO WHEN I WENT TO THE DOCTOR THERE, THEY FINALLY GOT A HEMATOLOGIST INVOLVED AND I WENT TO THE MAYO CLINIC IN ROCHESTER. THEY COULDN'T FIND ANYTHING, GAVE ME A GENERIC TERM. HOW I GOT TO THE NIH, I GOT SICK. IN 2006. THEN I NEEDED TO GET A -- WHAT -- >> A SPLENECTOMY. >> IT ALL BLENDS TOGETHER. SO I HAD THAT IN SCOTTSDALE AT THE MAYO CLINIC, WHEN I CAME BACK FROM THERE I -- I SPENT A MONTH IN THE HOSPITAL THERE. THEN I CAME BACK AND GOT DIAGNOSED WITH THE MAC. SO WHEN I CAME BACK TO ALBUQUERQUE WHERE I LIVE. I ENDED UP WITH CDIF. I SPENT TWO WEEKS IN THE HOSPITAL. THE DOCTOR I MET THERE HAD WORKED WITH DR. HOLLAND BEFORE. THAT'S WHEN I GOT TO THE NIH. >> THAT WAS DR. JEFF ROSS WHO TRAINED IN OUR PROGRAM MANY YEARS AND RECOGNIZED THAT SOMETHING MUST BE WRONG AND IT WOULD BE A GOOD IDEA TO TRY TO INVESTIGATE THAT FURTHER. SO YOU CAME HERE IN 2007. WHAT HAPPENED BETWEEN 2007 AND NOW? >> 2011, IT WAS JULY. WE WENT ON A TRIP TO DURANGO, COLORADO. WITH MY FAMILY. I WAS GETTING READY TO TAKE SOME PICTURES. AND I DIDN'T FEEL RIGHT. SO I HAD -- I SAT DOWN. AND THEN PRETTY SOON AFTER WITHIN A FEW MINUTES I COULDN'T TALK. SO I WAS ABLE TO TELL MY HUSBAND I CAN'T TALK. AND THEN I WAS DONE. I COULDN'T SAY ANYTHING. AND INSIDE OF ME, I KNEW I WAS HAVING A STROKE. BUT I COULDN'T TELL ANYBODY. SO WE'RE IN THIS TINY TOWN OF DURANGO, AND HAVE TO GET TO SOME LITTLE HOSPITAL. AND -- WHICH WE HAVE NO IDEA WHERE WE'RE GOING. SO WE FINALLY GET TO THE HOSPITAL. AND NOW THE DOCTOR, BECAUSE OF ALL MY BLOOD WORK, NOT NORMAL AT THE TIME, YOU KNOW, HE DOESN'T KNOW IF HE SHOULD GIVE YOU THE -- I FORGET -- >> THE T.P.A., THE BLOOD THINNER. >> YES. SO BASICALLY IF HE DOESN'T, YOU KNOW, I COULD DIE, IF HE DOES I COULD DIE. SO I DECIDED THAT I WANTED IT. AND THEN THEY REALIZE THAT HAD THEY DIDN'T HAVE AT THAT HOSPITAL. SO THEY HAD TO SEND SOMEONE ACROSS TOWN TO THE OTHER HOSPITAL TO GET IT. AND SO ANYWAYS, I GOT THAT AND THEN THEY FLEW ME TO ALBUQUERQUE HOSPITAL AND I SPENT ONE NIGHT THERE. AND THEN I GOT ON A PLANE AND FLEW OUT HERE. AND THEN SPENT THE NEXT FIVE MONTHS IN THE HOSPITAL HERE. AND SO I GOT -- THEY DID THE MRI AND SHOWED A STROKE. WHILE HE WAS HERE IN JULY -- I WAS HERE IN JULY, I HAD ANOTHER STROKE WHEN I WAS SLEEPING. AND THE ONLY REASON I KNEW, WHEN I WOKE UP, THE CLOCK LOOKED DIFFERENT. THINGS LOOKED DIFFERENT. AND SO -- >> THINGS CAME TO A HEAD THAT SUMMER OF 2011. WE WERE DECIDING YOU WERE GOING TO NEED A BONE MARROW TRANSPLANT. COULD YOU SAY A LITTLE BIT ABOUT YOUR CONCERN HEADED IN TO RECEIVE A TRANSPLANT? >> PROBABLY THE BIGGEST THING WAS THAT I WAS NOT GOING TO MAKE IT. THAT I WAS GOING TO DIE. IT WAS A VERY SCARY THING TO THINK ABOUT AND BEING OUT HERE AWAY FROM EVERYBODY, ALL MY FAMILY AND FRIENDS ARE IN NEW MEXICO. AND I HAVE A 9-YEAR OLD DAUGHTER. SO THAT WAS HARD. BUT YEAH, I WOULD SAY I WAS MOSTLY AFRAID IT WASN'T GOING TO WORK. >> THEN AT WHAT POINT DID YOU THINK THAT YOU ACTUALLY MIGHT MAKE IT THROUGH THE TRANSPLANT? >> I THINK SHORTLY AFTER THAT, ONCE I GOT THE TRANSPLANT AND -- IN OCTOBER, 2011. THEN THE COUNTS EVENTUALLY WOULD START GOING UP A LITTLE BIT. THEN I STILL HAVE THAT DOUBT IN THE BACK OF MY MIND. SOMETHING COULD STILL HAPPEN. EACH DAY I FELT A LITTLE BIT BETTER. >> AND LASTLY, GETTING BACK TO WHERE YOU WERE WAY BACK TWO OR THREE YEARS AGO, YOU'RE NOW A YEAR-AND-A-HALF POST TRANSPLANT. DO YOU THINK YOU'RE BACK TO 50%? HOW FAR ARE YOU BACK TO WHERE YOU WERE? >> I ACTUALLY FEEL LIKE I'M ALL THE WAY BACK. I'M FEELING REALLY, REALLY GOOD. CERTAINLY WHEN I LEFT HERE AND WENT HOME IN JANUARY OF 2012, IT TOOK QUITE A WHILE TO GET MY STRENGTH BACK UP BUT I FEEL REALLY GOOD. BEING ABLE TO, YOU KNOW, DO ALL THE THINGS I WANTED TO DO BEFORE. >> DID YOU HAVE ANYTHING ELSE YOU WANTED TO COMMENT ON? >> JENNY, THANK YOU VERY MUCH FOR JOINING US HERE. [APPLAUSE] >> THANK YOU VERY MUCH FOR DOING THAT. I KNOW THAT'S NOT A SPONTANEOUS THING THAT PATIENTS THINK THEY'RE GOING TO BE ASKED TO DO. WE REALLY APPRECIATE HEARING WHAT HAPPENS FROM THE PATIENT'S STABBED POINT, SO IMPORTANT. YOU HEARD NOW IN A FEW MINUTES, A COMPLETE INCAPSLATION OF EVERYTHING THAT DENNIS AND I WOULD WOULD LOVE TO CORE IN TORTURESOME DETAIL FOR THE REST OF THE DAY. YOU HEARD A CRITICAL STORY OF WHAT HAPPENS WHEN PEOPLE HAVE THIS PROBLEM. SO THE CRITICAL ELEMENT I WANT TO REMIND YOU OF, AT 12 YEARS OLD, BUT 12-YEAR OLD SHE WAS A NORMAL HEALTHY KID. AND SUDDENLY, GETS CHICKEN POX. THINGS BEGIN TO CHANGE. YOU HEARD THAT THE CHANGE IN THE COURSE WAS SLOW. AND PROGRESSIVE. AND IT REMINDS YOU THAT THINGS CHANGE. AND PHENOTYPE IS SOMETHING THAT CHANGES OVER TIME. SO YOU WANT TO KEEP IN MIND WHAT YOU START WITH ISN'T WHAT YOU FINISH WITH. [LAUGHTER] SO I DON'T REALLY NEED TO GO THROUGH ALL THE ASPECTS OF HER HISTORY. I'LL REMIND YOU. SHE STARTED WITH SEVERE VZV, 17, NUT TRO CYTOPENIA. AT 20, SEVERE INFECTIONS. LATER WHEN PEOPLE WERE CONFUSED THEY THOUGHT IT MIGHT BE LUPUS. IT'S THE GREAT IMITATOR. AND THEN LATER IN LIFE, DEVELOPED FEVER AND MORE LEUKOPENIA, DURING WHICH SHE HAD A SPLEENECTOMY, DOES BECAUSE HER COUNTS WERE SLOW. IT WAS THEN THAT THEY IDENTIFIED THE M AFTERNOONIUM. THIS WAS COMPLICATED OF SEVERE COLITIS WITH WHAT THEY THOUGHT WAS THROMBOSIS, FOR WHICH SHE WAS ANTI-COAGOLETED. WHEN SHE CAME HERE IN HER 30s SHE HAD A NEW LESION ON HER RIGHT THIGH. THERE AREN'T TIMES TO GO INTO ALL THE ASPECTS OF THIS DISEASE, BUT SHE HAD TWO MISCARRIAGES AND LOW FREQUENCY HEARING LOSS. THIS IS THE C.T. SCAN WHEN SHE CAME TO VISIT FOR THE EFFICIENCY TIME. YOU MEAN YOU CAN SEE THIS IS NORMAL C.T. BUT THIS ACCUMULATION HERE OF FLUID WAS INTENSELY GRANULATETIS AND NECROTIC. WE DIDN'T GROW ORGANISMS BUT TREATED HER FOR MICROBACTERIAL DISEASE AND INFLAMMATORY MARKERS CAME DOWN AND THIS RESOLVED. SO WHEN WE MET HER, JUST TO PUT IT INTO CLINICAL CONTEXT, YOU CAN SEE THE THINGS THAT WERE ABNORMAL. WHITE COUNT WAS LOW. SO WAS HER HELP MAT CITE. PLATELETERS WERE HIGH. YOU CAN SEE HERE ALL THE OTHER CELL LINES WERE ABNORMAL. NUT TRA FILLS WERE LOW, LEUKOCYTES WERE LOW. B CELLS AND NK CELLS. MARROW SHOWED A LOW LEVEL OF CELLULARITY, SHOULD BE MUCH HIGHER FOR A YOUNG WOMAN. MILD DYSPLASIA. THERE WAS NO CYTOGENETIC ABNORMALITY. DESPITE THIS -- NOW, THIS IS NOT FROM HER. IT COULD EASILY HAVE BEEN. GOOD SPITE THE FACT -- DESPITE THAT FACT THERE WERE NO MONOCITES IN THE PERIPHERAL BLOOD, THERE WERE MACROPHAGES IN THE TISSUE, REMINDING YOU AT ONE POINT SHE WAS NORMAL AND ABLE TO POPULAR PERIPHERAL TISSUES. AS THIS WERE MACRO LANGUAGES, THERE WERE CELLS -- SHE WAS ABLE TO PUT CELLS INTO THE TISSUE AT ONE POINT AND TURN THEM INTO PLASMA CELLS. NOT SHEN HERE, IMMUNOGLOBULIN LEVELS WERE COMPLETELY NORMAL. SO WE FOLLOWED HER OVER MANY YEARS FROM 2007 THROUGH 2011. IN 2009. HER MARROW LOOKED INDISTINGUISHABLE FROM 2007. IN 2011, SHE REALLY DID NOT FEEL VERY WELL. SHE WAS NOTED TO HAVE SOME INCREASED NUMBER OF BLASTS IN THE PERIPHERAL BLOOD. WE WERE GETTING READY TO BRING HER OUT HERE TO UNDERGO A CHEMOTHERAPY AND TRANSPLANT WHEN SHE HAD THIS ACUTE EPISODE OF APHAGIA. EVENTUALLY, WOUND UP COMING OUT HERE BY AIR AMBULANCE FROM FEE MIX. AND -- FE NIX. DURING THAT HOSPITALIZATION, NOT ONLY DID SHE HAVE STROKES AS YOU SEE HERE, ON THE LEFT, AND HERE ON THE RIGHT, THIS WAS THE INITIAL ONE. THIS WAS THE SECOND ONE. EXPLAINS PARTLY WHY SHE HAD VISUAL PROBLEMS, SPEECH PROBLEMS. BUT IN ADDITION TO THAT, SHE HAD VEGETATIONS ON HER MIGHT TROLL VALVE THAT WE THOUGHT WERE CRITICAL ESTABLISH IN TERMS OF BREAKING OFF AND CAUSING THESE LESIONS. SO AT THAT POINT WHEN SHE CAME IN HAVING HAD A NORMAL MARROW TWO YEARS PRIOR, NOW ALL OF A SUDDEN HER MARROW IN 2011 SHOWS HYPER CELLULARITY. IT'S READ OUT AT REFRACTARY ANEMIA, EXCESS BLASTS. NOW SHE'S DEVELOPED A CYTOGENETIC ABNORMALITY OF 7. THIS IS WHAT WE KNEW WHEN SHE WALKED IN THE DOOR. OVER THE COURSE OF A COUPLE YEARS WE ADDED TO THAT. AND THE PROBLEM THAT WE FACED AS CLINICIANS CARING FOR HER, HOW TO PUT ALL THIS INTO ONE RUBRIC. GET ONE DIAGNOSIS THAT PULLS THIS TOGETHER. YOU COULD ASK WHY WOULD WE? YOU DON'T HAVE TO HAVE ONE ANSWER FOR EVERYTHING. AKAM HAD A BEARD, HE DIDN'T USE THE RAZOR ALL THAT OFTEN. SO WE RECOGNIZED -- SO PART OF WHY WE WERE SOME PERSUADED, EARLY ON -- THIS IS FROM 1994. WHEN I WAS IN JOHN GALLON'S LAB. WE IDENTIFIED PATIENTS THAT HAD SEVERE DISSEMINATED MICRO BACTERIAL DISEASE. A FEW OF THOSE PATIENTS WERE VERY SIMILAR TO OUR PATIENT TODAY. THESE PATIENTS HAD VERY VIEW MONOCITES, VERY FEW B CELLS BUT DID HAVE PLASMA CELLS IN THEIR INFLAMMATORY LESIONS. WE ALREADY RECOGNIZED IN 1994 PATIENTS WHO HAD EXACTLY THE SAME PROBLEM AS OUR PATIENT TODAY. AND THE CLOCK WAS TICKING AS THAT WAS GOING ON. WE KNEW THAT THIS WAS GOING TO BE A MONOGENIC PROBLEM, BECAUSE WE HAD FAMILIES AT THE TIME, THIS IS IN THE EARLY 90s, IN WHICH ONE PATIENT HAD HPV, MICROBACTERIAL CITIES. AND THE SAME HISTOLOGIC PROBLEMS. AND BEING TRANSMITTED IN AN AUTOSOMAL DOMINANT PATTERN. REALLY HAD TO BE ONE SINGLE GENE. NOW, OF COURSE, AS YOU HEARD THAT WELL PLACED TIMER GOING ON, IT REMINDS YOU THAT NIH STANDS FOR MANY THINGS. ONE OF WHICH IS SOMETIMES SAID TO BE NOT IN A HURRY. BUT WE WERE WORKING VERY HARD ON THIS. IT TOOK FROM 1994 THROUGH 2010 TO PUT TOGETHER A CLINICAL SUMMARY OF WHAT THIS DISEASE MIGHT LOOK LIKE THAT WE WERE -- WE PUBLISHED HERE IN BLOOD IN 2010. AND WHAT YOU SEE HERE IS PEOPLE WHO HAD MICROBACTERIAL DISEASE, AND PAM LOMMA VIRUS INFECTION, AND MILLO DYSPLASTIC PROBLEMS OR LEUKEMIAS, ALONG WITH OTHER PROBLEMS. WE KNEW IT WAS A SINGLE GENE, WE KNEW IT WAS IMPORTANT. WE KNEW THIS CONCITY LAYINGS WERE ALL TOGETHER. CONSTELLATION. ONE OF THE GREAT PRIVILEGES OF WORKING IN AN OUTSTANDING INSTITUTION IS THAT THERE ARE MANY PEOPLE WHO ARE PAYING MORE ATTENTION TO THINGS THAN SOMETIMES THE PRIMARY CLINICIAN IS. THIS WAS CERTAINLY MY EXPERIENCE HERE. KATHY IN THE HEMATOLOGY DIVISION OF DLM RECOGNIZED THAT OUR PATIENTS BONE MARROWS WERE REALLY QUITE STRIKINGLY ABNORMAL. TO POINT THIS OUT, THIS IS A FLOW CYTOMETRIC STUDY FROM A BONE MARROW FROM A PATIENT WITH THIS DISEASE. THIS IS GRANULARO SITES, SO GRANYOU LARTY, MONOCITES, LIMBOCYTES, A FEW BLAST FORMS. WHAT WE SEE IN OUR PATIENTS, IN MANY THE NUT TRUE FILLS ARE NOT NORMAL. THE MONOCITES ARE GONE. THE LIMBO CITE NUMBER IS REDUCED. WE CAN SEE THIS ON SLIDES. YOU CAN GRANULES ARE PUSHED WAY TO THE SIDE, HYPOGRANULER AND DYSPLASTIC. THE MEGO CARIOUS SITES, DESPITE THE FACT THEY ARE ABLE TO DIVIDE AND LIBERATE PLATELETS AND PROVIDE ADEQUATE CLOTTING, THEY ARE NOT NORMAL. THE NUCLEI ARE TOO SPREAD OUT, AND TOO SMALL GIVING RISE TO THE MICRO MEGACARIA SITES. WE WERE RECOGNIZING THIS DISEASE BECAUSE OF ITS MICROBACTERIAL SUSCEPTIBILITY, HPV INFECTION, A GROUP WITH MATTHEW IN NEW CASTLE WAS INTERESTED, WHAT IS IT ABOUT DENDRITIC CELLS THAT ARE IMPORTANT? THEY WERE TRYING TO FIND PATIENTS THAT WERE DENDRITIC CELL DEFICIENT. CAME UP WITH FOUR WHO HAD THE SAME DISEASE. AND WHAT YOU SEE, THESE PATIENTS HAVE NO CIRCULATING DENDRITIC CELLS, DESPITE THE FACT THEY HAVE CELLS IN THE PERIPHERAL TISSUES. THEY CAME UP WITH THE PROSAIC NAME, DENDRITIC CELL MONOCITE DEFICIENCY, DCML. WELL, TO SAVE YOU LOTS OF HARD ACHE, IT WAS -- HEARTACHE, IT WAS IN MAY OF 2011 THAT AMY IN THE LABORATORY CALLED ME AND SAID MY GOD, HERE IS WHAT IT IS. THIS IS MUTATIONS IN THIS GENE GATA2. WE PUBLISHED THIS JUST TWO YEARS AGO. AND VERY SHORTLY AFTER THIS, MATTHEW COLONS GROUP FOUND THE SAME GENE IN THEIR PATIENTS. NOW, IT MAY NOT BE IMMEDIATELY OBVIOUS WHAT GATA 2 IS. I KNOW THIS SLIDE MAKES IT CLEAR [LAUGHTER] HERE YOU HAVE GATA 2 AT THE CENTER OF NUMEROUS PATHWAYS. I WANT TO POINT OUT THE CRITICAL ONES TO YOU. SO GATA 2 IS RESPONSIBLE FOR THE CONTROL OF THE FUNCTION OF MANY TRANSCRIPTION FACTORS. HISTONE DEACETYLASES, AND THEN THING THAT YOU MIGHT REALLY BE INTERESTED IN. ENDOTHELIAL, HOW VESSELS WORK, AND CLOTTING. AND THE AN GEO POWERTENS, THAT HAVE TO DO WITH HOW VESSELS ARE FORMED. ALL OF THESE AS WELL AS MANY OTHER GENES ARE UNDER THE DIRECT CONTROL OF GATA 2. LET ME REMIND YOU OF THE BATA FACTORS, THE NAME IS FROM THE SEQUENCE THEY BIND, GATA. THERE IS 6 OF THEM. THEY FALL INTO TWO MAIN GROUPS, HEMATOPOIETIC ONES AND SOMATIC ONES. AND GATAS 1, 2 AND 3, WE'RE ONLY TALKING ABOUT 2 TODAY, GATA 3 IS THOUGHT TO BE IMPORTANT IN T. CELL DIFFERENTIATION. DESPITE THAT FACT, THE ONLY HUMAN DISEASE IS HYPOPARATHYROIDISM, DEAFNESS AND KIDNEY DISEASE. OUR PATIENT HAD LOW FREQUENCY DEAF THINKS. AND GATA 1 IS ASSOCIATED WITH ANEMIA AND THROMBOCYTOPENIA. GATAS 4, 5, 6, ARE VERY INVOLVED IN CARDIAC FUNCTION AS WELL AS PANCREATIC FUNCTION. THESE ARE TWO ZINC FINGERS, THEY'RE HIGHLY CONSERVED BETWEEN ALL 6 OF THE GATA FACTORS. THE BUSINESS THAT MAKES THEM DISTINCT IS SEQUESTERED MOSTLY ON THE C AND N TERMNY. WHAT IS IT THAT DEFICIENCY OF THIS DISEASE CAUSES? CHARACTERISTIC INFECTIONS AND EVOLVING HEM TOLLLOGIC PICTURE AND WAS DESCRIBED SO ELOQUENTLY. STARTING WITH NORMAL HEMATOPOIETIC, THEN INVOLVING ALL THESE FEATURES, THEN THERE ARE SOMATIC FEATURES, LIMBAUGHDEMIA IS ALSO RELATIVELY COMMON. THE SERIES OF CANCER THAT GIVE US LOTS OF CONCERN FOR HOW WE MANAGE THESE PATIENTS M MILD DYSPLASIA, ACUTE MYELOID LUKE LUKES, AS WELL AS OTHER -- LEUKEMIAS, AS WELL AS OTHER PROBLEMS. HOW COULD ONE GENE BE RESPONSIBLE FOR ALL THIS? IT'S BECAUSE THIS ONE GENE IS BEING EXPRESSED IN A LOT OF IMPORTANT PLACES. SO THIS IS ONLY THE HEMATOPOIETIC COMPARTMENT. AND THERE ARE SOMATIC COMPARTMENTS AS WELL. IT'S HERE IN THE HEMATOPOIETIC STEM CELL, THE PROGENITORS AND MANY DERIVETERS OF MYELOID AND LYMPHOID LINAGES, WHICH IS HOW YOU GET IT TO BE INVOLVED IN THE EXPRESSION OF EUCARYOTIC, GRANULELER SITES, AS WELL AS T, B, AND NK STEM CELLS. WHEN WE WERE IDENTIFYING THIS ALONG OUR PATHWAYS, THE GROUP OF [INDISCERNIBLE] HAD IDENTIFIED FOUR FAMILIES IN THE UNITED STATES AND AUSTRALIA, WHO HAD WHAT THEY THOUGHT WAS ONLY FAMILIAL LEUKEMIAS. YOU CAN SEE THESE TRANSMITTED OVER FOUR GENERATIONS IN A MONOGENIC PATTERN. SIMILARLY, THE GROUP IN ENGLAND IDENTIFIED PATIENTS WHO HAD MUTATIONS IN EXACTLY THE SAME GENE THAT HAD A SYNDROME CALLED IMBURGER SYNDROME. PEOPLE DEVELOPED ACUTE MILE LLOYD LEUKEMIA WITH LIMBODEMIA, AS YOU SEE HERE. YOU SEE GATA 2 IS EXPRESSED IN HIGH LEVELS IN CELLS INCLUDING THOSE THAT LINE AND FORM THE LYMPHATICS. HERE, THE LYMPHATIC VALVES ARE HIGHLY INVOLVED IN EXPRESSION OF GATA 2 WHICH EXPLAINS WHY THEY'RE DYSFUNCTION IS PART OF WHAT YOU SEE IN THIS DISEASE. SO THIS DISEASE IS YOUR TYPICAL BLIND MAN AND THE ELEPHANT DISEASE. THERE ARE COMPONENTS THAT ARE MILO DYSPLASTIC, INFECTIONS, MICROBACTERIA, WARTS, LIMPDEMIA, FUNGY AND LEUKEMIA. LET ME TELL YOU A FEW MORE THINGS ABOUT IT. EVERYTHING CAME AT THIS FROM A DIFFERENT ANGLE, NOW THAT WE HAVE A GENE WE NEED TO REFER TO IT BY THE SUPREME, BUT BY GATA 2 DEFICIENCY AND IT. COMPASSES ALL THESE CLINICAL ENTITIES. THE JEAN IS HERE ON CHROMOSOME 3 ON THE LONG ARM, AND IT'S GOT AN EXXONIC STRUCTURE THAT IS DEPICTED HERE WITH UNTRANSLATED EXXONS, AS WELL AS TRANSLATED ONES. YOU SEE THAT THE PROTEIN HAS THESE TWO ZINC FINGERS, AND IS EXPRESSED IN LOTS OF DIFFERENT CELLS. WELL, WHEN WE FIRST IDENTIFIED THIS GENE, WE AND OTHERS IDENTIFIED MUTATIONS THAT WERE HERE THAT LED TO MISSENSED MUTATIONS. THE INITIAL THOUGHT BY THE GROUP WAS THAT THESE WERE DOMINANT NEGATIVE MUTATIONS. HETEROZYGOUS, EXPRESSED LEADING TO DOMINANT NEGATIVE EFFECT ON THE NORMAL ALLELE. BUT AS AMY STARTED SEQUENCING, IT WAS CLEAR THAT THAT COULD NOT BE THE ANSWER. BECAUSE MANY OF THE MUTATIONS WE FOUND WERE LARGE DELETIONS OR INSERTIONS THAT COULD NOT POSSIBLY BE EXPRESSING AN ALLELE. THEREFORE, THESE CAN'T BE OPERATING AS DOMINANT, NEGATIVE ALLELES. THEY MUST BE FUNCTIONING IN A HAPPENLO INSUFFICIENT WAY. THEY'RE THERE BECAUSE HAVING ONE COPY IS NOT ADEQUATE. NOW, DESPITE THAT, THERE WERE THREE FAMILIES IN OUR INITIAL COHOLY SPIRIT FOR WHOM -- COHORT FOR WHOM WE COULD NOT FIND MUTATIONS EVEN THEIR THEIR PHENOTYPE WAS IDENTICAL, AND WE SEQUENCED THROUGH ALL THE EXXONS IN THE GENE. WE TRIED TO DO OUR FIRST SCREEN IN THIS DISEASE DOING WHOLE EXOMY SEQUENCING. WE COULD NOT FIND HIM. DOING WHOLE EXOMY SEQUENCING. THAT'S BECAUSE IT'S NOT EXXONIC. I WAS SLOW TO COME TO THIS. BUT WORKING WITH EMORY AT THE UNIVERSITY OF WISCONSIN IN MADISON, WE WENT BACK TO HIS WORK AND RECOGNIZED THAT GATA 2 ACTUALLY DOESN'T SPENT MUCH TIME EITHER PROMOTERS OR IN EXXONS. IT SPENDS ALMOST ALL THE TIME IN INTRONS AND ENHANCER ELEMENTS. THERE ARE 1.7 MILLION SITES THAT BATA 2 CAN BIND TO. THE OVERWHELMING MAJORITY OF THOSE ARE IN PLACES THAT ARE NEVER GOING TO BE FOUND ON AN EXXONIC SCREEN. HE WENT BACK AND SAID OKAY, IF IT'S NOT EXXON AND WE THINK IT'S A JEAN, -- GENE, WHERE MIGHT IT BE? LOOKING AT THE CONSERVATION OF REGIONS IN THE GENOME, SHE IDENTIFIED THIS REGION HERE IN INTRON FIVE THAT IS CONSERVED OVER MANY FILLET, ALL THE WAY BACK TO ZEBRA FISH. THIS IS COMPLETELY CONSERVED. YOU SEE AN ENHANCER ELEMENT, FATA BINDING SITE IS PRESENT, AND ONE NEXT TO IT, A LEUKEMIA INTEGRATION SITE. WHEN WE SEQUENCE THOSE, WHAT WE IDENTIFIED IS ONE FAMILY IN WHICH THIS SEQUENCE IS DELETED, NOW MULTIPLE FAMILIES IN WHICH THERE IS A SINGLE BASE MUTATIONS HERE IN THE FLY ONE INTEGRATION SITE WHICH IS WHERE OTHER ENHANCERS MUST BIND THERE. AND WE HAVE BEEN ABLE TO SHOW THAT THIS IS FUNCTIONAL BY PUTTING THESE MUTATIONS IN FRONT OF A [INDISCERNIBLE] FACTOR. YOU CAN SEE THE WILDTYPE HAS THIS EXPRESSION AND THE MUTANT HAS THIS ONE. THAT MAY ALL SEEM RELATIVELY TRIVIAL, BUT THE CRITICAL ELEMENT IS THAT THAT MEANS THAT IF YOU HAVE GOT AN INTRONIC MUTATIONS ON ONE ALLELE AND THE OTHER IS NORMAL, THEN YOU'VE GOT 50% EXPRESSION COMING OFF THE NORMAL ALLELE, AND THEN 40% OF THE APPROPRIATE EXPRESSION COMING OFF OF THE SECOND ONE. THAT IS, YOU'VE GOT ONE ALLELE GOING AT ITS NORMAL LEVEL, THE OTHER ALLELE GOING AT ONLY 40% OF ITS NORMAL LEVEL. AND JUST THAT IS ENOUGH TO GET YOU IN TROUBLE. THIS SUGGESTIONS THIS IS TITLELY REGULATED. YOU NEED AT LEAST 70% OF THE NORMAL LEVELS TO HAVE NORMAL HEMATOPOIETIC. JUST TO PUT BIOLOGY TO THAT, NK CELLS DEVELOP THROUGH THE BONE MARROW, THEY GO THROUGH A PHRASE, CD56, BRIGHT. AND THEN BECOME DIM. WHEN THEY'RE BRIGHT, THEY DO HARD WORK. WHEN THEY'RE DIM, WELL, YOU KNOW, THEY'RE DIM. AND OUR PATIENTS NK CELLS, CRITICAL FOR THE CONTROL OF VIRUSES AND PROBABLY TUMORS, OUR PATIENTS NK CELLS ARE IN TROUBLE. YOU SEE HERE, THIS IS PATIENT NK CELLS VERSES NORMAL. PATIENT NK CELLS DON'T ACTIVATE WELL AT ALL. AND YOU CAN SEE THAT THIS IS BECAUSE OUR PATIENTS HAVE ABSOLUTELY NO BRIGHT CELLS IN -- BRIGHT 0, BRIGHT 0. ABOUT 7% OF NORMAL NC CELLS ARE BRIGHT. AND WE KNOW THAT THIS IS IMPORTANT BECAUSE IF WE TAKE CD34 CELLS FROM THESE PATIENTS AND DIFFERENTIATE THEM INTO NC CELLS. THEY STILL DON'T DEVELOP THIS BRIGHT COMPONENT. SO THEY'VE GOT NOT ONLY NK DEFICIENCY IN TERMS OF NUMBER BUT THEY HAVE NK DYSFUNCTION. THEY'RE NOT ABLE TO MAKE THE BRIGHT HIGHLY ACTIVE NK CELLS THAT ARE IMPORTANT. SO THIS HAS GIVEN US A NEW WINDOW IN NK BIOLOGY AS WELL AS VIRAL SUSCEPTIBILITY. IN THE LAST FEW MOMENTS I WANT TO REMIND YOU, OUR BIG PROBLEM IS TO UNDERSTAND HOW IT IS THAT SOMEBODY COULD BE NORMAL FOR SO MUCH OF THEIR LIVES AND WIND UP HAVING SO MANY PROBLEMS LATER ON. WE WANT TO KNOW WHAT'S THE CHICKEN, WHAT'S THE EGG? WHAT'S DRIVING WHAT? AND OF COURSE TO DO, THAT WE HAVE TO GO TO THE OTHER BEDSIDE INVESTIGATION. AND REALLY BEGIN TO ASK WHAT'S GOING ON? AND SO WE RECRUITED THESE VOLUNTEERS AND WE GAVE THEM INTRAVENOUS MAVIUM INFECTION. 16 WEEKS AFTER MICE, WILDTYPE OR HETEROSAN DIEGOIS FOR THIS MUTATIONS, 16 WEEKS AFTER INFECTION, WHAT YOU SEE IS A LUSH NORMAL MARROW IN THE WILDTYPE ANIMAL, AND HERE IS A BONE MARROW THAT IS NOW VERY DEPLETED AND HYPOPLASTIC IN OUR HETEROSAN DIEGOIS KNOCK OUT ANIMAL. THIS IS THE STAIN FOR MICROBACTERIAL AND WILD, AND THIS IS THE KNOCKOUT. THIS SUGGESTIONS INFECTION ALONE IS ABLE TO DRIVE THESE ANIMALS AND WE THINK PROBABLY HUMANS FROM BEING RELATIVELY NORMAL AND HAVING ADEQUATE AND APPROPRIATE HELP MAT PO ESAYS AND DEVELOPING THE PROCESS WE WERE DEALING WITH. IN ADDITION TO THAT, WE CAN SHOW THAT THESE PATIENTS HAVE PROBLEMS IN TERMS OF THE -- THESE MICE HAVE PROBLEMS WITH THEIR STEM CELL GENERATION AFTER WE INFECT THEM. HERE WE'RE LOOKING AT STEM CELLS IN MOUSE BONE MARROW IN OUR WILDTYPES, AFTER INFECTION. IN OUR WILDTYPES YOU SEE EASILY DETECTABLE STEM CELLS IN THEIR BONE MARROWS. IN ALL OF OUR KNOCKOUT ANIMALS, YOU SEE THAT AFTER INFECTION, THEIR STEM CELLS WHICH WERE PRESENT BEFORE INFECTION, HAVE NOW ALL BUT DISAPPEARED. SUGGESTING THAT INFECTION IS DRIVING A MAJOR PART OF THIS DISEASE. SO I'VE TRIED TO TALK TO YOU ABOUT THE BIOLOGY OF THIS DISEASE, THE PHENOTYPIC BIOLOGY. HOW GOES GATA 2 DO ALL THIS? I'VE ONLY TALKED TODAY ABOUT LYMPHATICS AND HEMATOPOETICS, BUT ALSO OTHER VESSELS WHICH IS PROBABLY WHY PEOPLE GET THROMBOSIS. THERE ARE OVERLAPPING FACTORS WHICH IS WHY SOME OF THE FEATURES OF GATA 2, 3 AND 4 DEFICIENCY ALL OVERLAP. THEY HAVE DIMENSIONED STEM CELLS AT BIRTH BUT THEN GET DESTROYED BY STRESSES LATER ON. THEY'VE GOT IMPAIRED DEFINITIVE HE MAT OPOSSESIS. WE THINK THERE IS EXHAUSTION THAT IS DRIVEN BY SOME OF THE THINGS THAT HAPPEN. GATA 2 DEFICIENCY IS MORE COMMON THAN YOU THINK. MULTIPLE INFECTIONS, A VARIABLE ON SET WITH PROGRESSIVE CYTOPENIAS. THIS IS AN IMPORTANT EXAMPLE OF HAPPENLO INSUFFICIENCY THAT IS INVOLVED IN HOW THINGS GET DRIVEN. SO THIS IS REALLY ONE GENE THAT UNITES INFECTION, UP TO CANCER UNDER ONE HEADING. A GREAT EXAMPLE FROM MANY DIFFERENT ANGLES WOUND UP WITH EXACTLY THE SAME PROBLEM. AND IT REMINDS US HOW IMPORTANT IT IS TO KEEP A BROAD MIND WHEN WE TRY TO START LOOKING AT PHENOTYPES. I DON'T HAVE TIME TO THANK ALL THE PEOPLE WHO'S WORK HAS BEEN CRITICAL IN THIS EFFORT, BUT IN PARTICULAR AMY ANDY ELIZABETH, LAUREN SANCHEZ, MICHAEL SPINNER, OUR CRITICAL HEMATOPO HE'SIS COLLEAGUES, AS WELL AS NUMEROUS COLLABORATORS. WITH THAT I WILL STOP AND TURN IT OVER TO DR. HICKSTEIN TO TELL YOU WHERE WE GO FROM HERE. BECAUSE IDENTIFYING THE PROBLEM IS REALLY JUST THE START. [APPLAUSE] >> WHILE THEY'RE SETTING THE SLIDES UP, WHEN WE CAME TO THINK ABOUT TRANSPLANTING THESE PATIENTS, THERE WAS SOME LACK OF ENTHUSIASM IN GENERAL. OUR PATIENTS GET PLENTY OF INFECTIONS POST TRANSPLANT. THESE PATIENTS ARE COMING IN LOADED WITH INFECTIONS. SO I'M GOING TO TALK ABOUT THE TRANSPLANT APPROACH THAT WE USE TO THESE PATIENTS WITH GATA 2. SO I'VE NOTHING TO DISCLOSE. SO THE OBJECTIVES -- I HOPE YOU'LL LEARN ABOUT THE INDICATIONS FOR TRANSPLANT IN THIS DISEASE, THE TYPES OF PLANS PLANT. AND REALLY THE OUTCOMES IN GATA 2. THE REAL REQUEST, SET OUT AT THE BEGINNING WHEN WE TALKED ABOUT THIS FIVE YEARS AGO, SHOULD THESE PATIENTS BE TRANSPLANTED? CAN WE REVERSE THIS PHENOTYPE? WE HAD NO IDEA IT WAS GATA 2. IT WAS JUST A SYNDROME. THEN THE SECOND ONE, IF YOU SHOULD TRANSPLANT THEM, WHEN? EARLY? LATE? REALIZING THE RISKS AT BOTH ENDS. AND THEN THE THIRD IS TO HOW, THE MECHANICS, TYPE OF REGIMEN. THE FIRST THREE WERE ON OXYGEN. SO HOW DO YOU TREAT TRANSPLANT THEM, WHAT KIND OF DONORS DO YOU USE? THIS IS TRUE FOR MOST TYPES OF TRANSPLANT. THE FIRST PART, THIS WAS CLEARLY A LETHAL DISEASE. THEY GOT INFECTIONS. THEY WERE NASTY INFECTIONS. THE FIRST PATIENT WAS 33 YEARS OLD, HAD A STABLE SYNDROME. TRYING TO LINE UP AND UNRELATED DONOR, HE SEIZED, DIED, SO CLEARLY THESE ARE NASTY LETHAL INFECTIONS. THE LUNG DISEASE WAS ALSO VERY SIGNIFICANT. A NUMBER OF THESE FIRST THREE PATIENTS ARE ON OXYGEN, AND WHEN YOU GO TALK ABOUT TRANSPLANT THEY'RE HUFFING AND PUFFING WHEN YOU WALK AROUND THE ROOM. MAYBE I PICKED THE WRONG DISEASE. SO THE OTHER THING IS WE CLEARLY KNEW THEY WERE TRANSFORMING TO LEUKEMIA AND IN MANY CASES THEIR MARROW FALLS APART. REQUIRING RED CELLS, PLATELETS, COULDN'T LEAVE THE HOSPITAL. SO WE PRETTY MUCH CAME TO THE IDEA THAT SHOULD THEY BE TRANSPLANTED, YES. THEY'RE AT HIGH RISK OF DEATH ANYWAY, WITH INFECTION, THE PULMONARY PROGNOSIS, THE LUNGS, AND THE LEUKEMIA. AND IT'S A STEM CELL DISEASE. WE MADE THAT ASSUMPTION. GOOD EVIDENCE IT WAS. AND NORMAL DONORS HEMATOPOIETIC STEM CELLS SHOULD REVERSE THE PHENOTYPE. AND THIRDLY, IT'S CLEARLY SHOWN ALLOGENIC HEMATOPOIETIC STEM CELL TRANSPLANT CAN CURE. SO WE GOT BY THE SHOULD. THEN THE TIMING. WHEN? EARLY OR LATE? WHEN THEY HAVE MINIMAL INFECTIONS? WITH THE RISK THAT YOU COULD SHORTEN THEIR LIFE IF IT TURNS OUT UNFAVORBLING OR LATE IN THE COURSE WHEN IT'S CLEAR THEY NEED IT, BUT NOW AT HIGHER RISK. SO WE WORKED TO GET A HANDLE ON THE TEMPO, IN TERMS OF WHEN DO THEY GET BAD? SO I THINK THAT'S AN AREA WE'RE STILL GRAPPLING WITH. AND WHEN DO THEY TRANSFORM? SO AS FAR AS THIS NATIONAL HISTORY, THE TEMPO. THEY SHOW UP AS YOUNG ADULTS, 12 TO 14. THEY SHOW UP PRETTY MUCH WITH BAD OPPORTUNISTIC INFECTIONS, USUALLY MAC. A LOT CAN BE THE FIRST PRESENTATION. AND THEN THEY HAVE THE MYELODYSPLASTIC SYNDROME, MARROWS DETERIORATE FIRLY QUICKLY. HIGHLY VARIABLE. THAT MADE IT HARDER TO PICK THE TIMING. WE KNEW THAT THEY PROGRESSED FROM THIS VERY HYPOPLASTIC, ALMOST LIKE AN APLASTIC ANEMIA, TO AML. AND SO THIS TRANSFORMATION TEMPO IS HIGHLY VARIABLE, PROBABLY DEPENDS WHEN THEY GET THE SECOND SOMATIC HITS. SO WE DECIDED THAT WE WOULD TRANSPLANT FOR THIS DISEASE, IF THEY WERE GETTING REALLY BAD. IF WE HAD GOOD DONORS, WHO IS A 10 OUT OF 10 MATCH, AS GOOD AS YOU CAN GET IF IT'S NOT AN IDENTICAL TWIN. IF THEY WERE GETTING SEVERE INDICATIONS THAT WOULD BE AN INDICATION. SOME OF THESE PATIENTS WOULD BE DOING FIND AND LAND IN THE ICU FOR A MONTH WITH A NASTY INFECTION. THAT HELPED THEM TO GET RELIGION. IF THEY'RE AT THE POINT THEY HAVE TO GO TO THE OPERATOR ROOM AND WASH OUT THEIR LUNGS, A 12 HOUR PROCESS, THAT'S A PRETTY GOOD INDICATION THAT THEY'RE GOING TO BE HIGH RISK FOR TRANSPLANT IF WE WAIT ANY LONGER. IF THERE IS EVIDENCE THE MARROW IS CHANGING, THE MORE BLASTS, MORE CELLULARITY, MORE SEVERE CYTOPENIAS WHERE THEY CAN'T LEAVE THE HOSPITAL. LASTLY, IF THEY HAVE UNFAVORABLE CYTOGENETICS, YOU KNOW THIS GROUP IS GOING TO DO POORLY. THIS WILL PROBABLY PUSH YOU TOWARD TRANSPLANT. WHAT ABOUT IF YOU DON'T HAVE A GOOD DONOR? IF YOU'RE GETTING LIFE THREATENING INFECTIONS OR TURNING INTO AML THAT PUSHES YOU INTO TRANSPLANT EVEN WITH A SECOND LINE DONOR. I'LL SAY HA THAT MEANS. LASTLY, THIS ISSUE THAT TRANSPLANTERS GRAPPLE WITH, FINDING A SWEET SPOT. IF YOU GIVE THEM TOO MUCH CHEMOTHERAPY CHEMOTHERAPY AND RADIATION PRIOR TO PRANCE PLANT, YOU CAN GET MORALES BIDTY AND MORTALITY FROM THE TRANSPLANT. YOU HAVE TO WEIGH THAT WITH THE POSSIBILITY THAT IF YOU DIDN'T GIVE ENOUGH, THEY COULD REJECT THE DONOR CELLS. WHICH IS A BAD THING. OR THEY CAN RELAPSE WITH THE MDS OR AML, YOU'RE RIGHT BACK WHERE YOU STARTED. SO THAT WAS ONE ISSUE. THE SECOND IS THE TYPE OVERDONE MUCHS, OBVIOUSLY, A RANK ORDER. MATCHED SIBLINGS ARE BETTER THAN UNRELATED DONORS, EVEN IF THEY'RE AMA. AND YOU HAVE CORD BLOOD OR HAFT MATCHED DONOR. SECOND LINE DONORS. EACH WERE CHARACTERIZED BY THEIR OWN PROBLEMS. SMALL NUMBER OF STEM CELLS HERE. NOW YOU HAVE A WHOLE HAPLOTYPE MISMATCH. SO I DECIDED EARLY ON TO USE A VERY LOW INTENSITY REGIMEN. I WROTE A CLINICAL TRIAL TO REDUCE INTENTY TRANSPLANT. AT THIS TIME, WE HAD NO IDEA IT WAS GATA 2. I USED THE LOWEST DOSE REGIMEN I COULD FIND, THREE DOSES, LOW DOSE IMMUNOSUPPRESSION AND TOTAL BODY RADIATION. VERY LIGHT DOSE. IF YOU DON'T TRANSPLANT THESE PATIENTS THEY'LL RECOVER. THIS WAS THE MOST REDUCED INTENSITY OUT THERE. I THOUGHT ANYTHING MORE WITH THIS LUNG DISEASE WOULD BE THE END OF HIM. WE ADD UMBILICAL CORD, LOW DOZE, REDUCED INTENSITY. AND TRANSPLANT ON DAY 0. THE STEM CELLS INFUSED. SO INCLUSION CRITERIA FOR YOUR ELIGIBILITY, THEY HAD TO HAVE AT LEAST ONE OR TWO LIFE THREATENING INFECTIONS WITH AN OPPORTUNISTIC ORGANISM. AND WE WOULD FAVOR USING A WELL MATCHED DONOR OR A CORD BLOOD WHICH TOLERATES MORE DEGREE OF MISMATCH. LATER, WE HAD HAPP LLOYD IDENTICAL DONOR. WE WANTED A MINIMAL DISEASE OR THE DISEASE WOULD RECUR AFTER TRANSPLANT. WE ORDERED MUTATIONS AND GATA 2. THAT WAS SETTLED THAT WE HAVE A COUPLE PATIENTS THAT HAVE THE MONOMAC SYNDROME WHERE WE HAVEN'T IDENTIFIED MUTATIONS, WE OUTSMARTED OURSELF ON THAT ONE. TO WHAT STEVE SAID ABOUT THIS PATIENT, IN 2009 SHE LOOKED GOOD WITH A HYPOCELLULAR MARROW. THIS DRIVES HOME WHAT CAN HAPPEN. SHE HAD NORMAL CYTOGENETICS, NO URGENCY. WHEN SHE CAME BACK IN JULY, 2011, NOW HER MARROW IS HYPER CELLULAR. RIGHT AT 5% BLAST. REMEMBER LEUKEMIA IS 20% BLAST. GOT A NEW ADVERSE CYTOGENIC MARKER. SO IN TWO YEARS IT'S A WHOLE DIFFERENT SITUATION. SO HERE IS WHAT SHE LOOKS LIKE BACK IN 2009 WITH THIS VERY HYPOCELLULAR FATTER BONE MARROW. TWO-THIRDS SHOULD BE CELLS, 3/4 IS FAT. THE MARROW IS REASONABLE THERE. ONE CELL WITH TWO NUCLEI. SHE HAS DIFFERENTIATING CELLS. NO IMMATURE CELLS CELLS TO SPEAK OF. IN JULY, 2011 AFTER THE STROKE EVENTS, AND SHE'S HYPER CELLULAR. SO A PACKED MARROW. WHICH IS BAD. YOU DON'T WANT TO SEE THIS. AND SHE'S GOT THESE BIG IMMATURE CELLS. THERE IS ENOUGH OF THEM TO BE CONCERNING. SHE'S GOT NORMAL NUT TROLL FILLS. THERE IS WHOLE POCKETS OF THESE, VERY LARGE NUCLEI. THESE ARE THE KIND OF CELLS YOU SEE IN LEUKEMIA. SO -- AND COURTESY -- THOSE ARE COURTESY OF KATHY, THE SLIDES. SHE HAS 7. SHE'S ONLY GOT ONE COPY OF CHROMOSOME 77. ALL MONOSOMYS ARE BAD IN HEMATOLOGY. THIS IS CLEARLY A BAD ONE. WE COULDN'T TAKE HER TO TRANSPLANT WITH THAT LOW DOZE REGIMEN, SO WE GAVE HER ONE CYCLE OF STANDARD CHEMOTHERAPY WHICH IS INTENSIVE HIGH DOZE. IN THE HOSPITAL FOR SIX WEEKS. THEN FOLLOWED UP, A REASONABLE WELL MATCHED 9 OUT OF 10 UNRELATED DONOR, WHERE THESE DONORS GIVE BLOOD STEM CELLS, THEY'RE FLOWN HERE. AND THEN INFUSED INTO THE PATIENT. SO IN A YEAR-AND-A-HALF, SHE RECEIVED HER TRANSPLANT. AND RIGHT AWAY, HERE SHE'S HAD MONOCITES, IF YOU LOOK AT THE BLOOD COUNTS. THEY HAVE BEEN 0 FOR YEARS. LOW BEFORE THE TRANSPLANT, ONCE SHE INGRAPHED THEY GO UP. SHE'S HAD NORMAL MONOCITE LEVELS. B CELLS HAVE BEEN 0. AND NOW THEY'RE UP EVEN SUPER NORMAL RANGE. AND SO 6 MONTHS LATER, IT WAS CLEAR THAT SHE'S NOW HAD A NORMAL CELLULAR MARROW, LESS THAN 5% BLAST, 100% DONOR CELLS WHICH IS WHAT YOU WANT. NO MONOSOMY7, AND NO GRAPH VERSES HOST DISEASE. REMEMBER, 50% OF PEOPLE WILL GET SOME KIND OF GRAPH VERSES HOST DISEASE, EVEN WITH 10 OUT OF 10 MATCH. SHE'S HAD NO SERIOUS INFECTIONS. SO HERE IS HER MARROW NOW. SORT OF A MIX BETWEEN WHAT IT WAS 2 YEARS BEFORE AND RIGHT BEFORE TRANSPLANT. NICE CELLULAR MARROW. NICE DIFFERENTIATING CELLS, GOING DOWN THE NEUTROPHILE PATHWAY. YOU DON'T SEE THESE IMMATURE CELLS. THE DONOR -- BASICALLY AN OJ SIMPSON DNA TEST, 100% DONOR. THESE CELLS IN THE MARROW ARE UP IN THE HIGH 90s. SO SHE'S HAD A VERY FAVORABLE OUTCOME. NOT EVERYBODY DOES. THE POSSIBLE OUTCOMES ARE YOU COULD GET REGIMEN RELATED MORBIDITY AND MORTALITY, YOU GET GRAPH FAILURE, REJECTION, GRAPH VERSES HOST DISEASE, RELAPSE WITH DISEASE. SO A LOT OF THINGS CAN HAPPEN, MOST ARE NOT GOOD. SERIOUS INFECTIONS WITH VIRAL FUNGAL, BACTERIAL. IF YOU'RE OUT A YEAR YOU CAN GET CHRONIC BRAVE VERSES HOST DISEASE. THEN THERE IS ABOUT A THOUSAND OTHER THINGS THAT CAN GO WRONG. SO TO GIVE YOU TWO OR THREE SCENARIOS, WHAT HAPPENS -- THIS IS THE FIRST GUY WE TRANSPLANTED, 33 YEARS OLD WITH GATA 2. WHEN HE WAS 23 CAMPING, HIGH FEVER, ATYPICAL MYO BACTERIA AND SLOWINGED THROUGH 24. HE HAS THE WHOLE PICTURE. NO MONOCITES, B CELLS OR NK. BAD PULMONARY PROGNOSIS. THEY WON'T PUT HIM TO SLEEP. HE HAD TO GO ACROSS THE STREET TO SUBURBAN. HE WAS IN A WHEELCHAIR. WE DIDN'T KNOW HIS MUTATIONS FOUR YEARS AGO. HE GOT A MATCHED RELATED DONOR FROM HIS BROTHER ABOUT FOUR YEARS AGO. 30-YEAR OLD BROTHER, LOOKED PRETTY GOOD, NORMAL MONOCITES, NK, B CELLS. SURPRISINGLY, HE SAILED THROUGH IT. THEN ABOUT 6 MONTHS LATER GOT LATE GRAPH VERSES HOST DISEASE, HAD TO BE TREATED WITH STEROIDS. HE'S GOT CHRONIC GRAPH VERSES HOST DISEASE. HE MAY NEED A LUNG TRANSPLANT. WE TOOK ONE DISEASE AND GAVE HIM A NEW DISEASE, GRAPH VERSES HOST DISEASE. AND THE SECOND GUY WE TRANSPLANTED, 33-YEAR OLD -- THEY'RE ALL 33, THESE FIRST GUYS. JUST HAD THE DISEASE FOR A YEAR BUT HE WAS RED CELL PLATELET DEPENDENT. COULDN'T LEAVE THE HOSPITAL. HIS MOTHER -- YOU SEE THIS HISTORY IN HALF OF THEM. MOTHER DIED AT AGE 35 FROM A REFRACRY AML. HE LATER TURNED OUT TO HAVE THIS MUTATIONS IN GATA 2. HE GOT AN UNRYE LATED DONOR TRANSPLANT. THIS WAS IN -- COMING UP ON FOUR YEARS AGO. FOUR YEARS THIS SUMMER. LEFT THE HOSPITAL AFTER 18 DAYS, NEVER READMITTED. FOUR YEARS OUT. BACK TO WORK, MARRIED, AND ALL HIS COUNTS ARE NORMAL. NO GVHD. YOU CAN HAVE A COURT THAT GOES SWIMMINGLY. THESE ARE THE CHEAP TRANSPLANTS. AND YOU LOOK WHERE HE HAD NOTHING BEFORE, VERY LOW PLATELETS, NORMAL PLATELETS. LOW RED CELLS, MOST TRANSFUSED. A NORMAL HEMATOPOIETIC. EVERYTHING CAN GO BACK TO NORMAL. THEN JUST THE THIRD ONE I'LL SHOW, THIS IS A -- THIS SHOWS THE COMPLEXITY OF THIS. WHEN YOU START GETTING AWAY FROM YOUR GOOD DONORS. WE TRANSPLANTED A 15 YEARS OLD. HE SHOWED UP IN SEPTEMBER, 2008, IN ST. LOUIS. FEVER, NIGHT SWEATS, DEATHLY ILL. PAN CYTOPENIC, ADENOPATHY. THEY GROW MAC, THEN DEVELOPED SEPTIC SHOCK. INTU BAITED FOR FIVE WEEKS. IN DECEMBER, TOXIC MELA COLLINS WITH C DIP. THESE PEOPLE HAVE A REALLY TERRIBLE COURSE WITH COMMON INFECTIONS. THE PATIENT DESCRIBES HER CHICKEN POX THAT LASTED THREE MONTHS. HERE IS A 15 YEARS OLD, THESE ARE THE KIND OF PATIENTS THAT STEVEN HOLLAND ACCEPTS. THEN THEY BECOME MY PROBLEM. ANYWAY, HE HAD THE WHOLE SYNDROME. NO MONOCITES, VERY FEW NK CELLS. HE HAS MONOSEEMY 7. WE CAN'T FIND A DONOR, WHICH HAPPENS IN ABOUT 50% OF THE PATIENTS. WE DO A DOUBLE UMBILICAL CORD TRANSPLANT. 2 1/2 YEARS AGO, HE LEAVES THE HOSPITAL AT 20 DAYS, HOME ABOUT DAY 60. BEFORE THANKSGIVING, COMES BACK A TRAIN WRECK ON CHRISTMAS. SEVERE PAN CYTOPENIA. NEPHROTIC SYNDROME, GRAMS OF PROTEIN IN HIS URINE. WHAT HAPPENED IS NORMALLY, AFTER A CORD BLOOD TRANSPLANT, ONE CORD WINS. AFTER ABOUT A MONTH, ONE CORD WINS. SO IN HIM, LOOKED AT DAY 28 LIKE IT WAS CORD ONE. DAY 60 WHEN WE SENT HIM HOME. BUT THEN THEY FLIP. AND CORD 2 GROWS UP AND STARTS TO KICK OUT CORD 1. AND HE'S LEAVING ON CORD 1. SO WHEN THAT IS KICKED OUT HE'S GOT NOTHING, NO HEMATOPO HE'SIS DILL THAT REGROWS. SO HE COMPLETELY SHIFTED OVER IN WHICH CORD IS DOMINANT. THAT'S THE KIND -- HE HAD A TERRIBLE COURSE. HE WAS IN THE HOSPITAL FOR FIVE MONTHS. HAD LEFT SIDED STROKE FROM ENDOCARDITIS, TUBES COMING OUT NINE WAYS FROM SUNDAY. ULTIMATELY WAS IMMUNOSUPPRESSED. THIS WHOLE IMMUNE PICTURE SUBSIDED. NOW 2 1/2 YEARS LATER, OFF ALL MEDS, NORMAL BLOOD COUNTS. GOT CLOSE TOMMY REVERSED, GRADUATING FROM HIGH SCHOOL. AND HE GOT TO BE IN -- MEET TIM TEBOW BEFORE HE WAS BIG. GREAT MAKE A WISH. HE RECOVERED A LOT OF THAT FUNCTION. SO TO SUMMARIZE. WE TRANSPLANTED 14 PATIENTS. THE MATCH RELATEDS HAVE DONE VERY WELL. ONE WAS ON A VENTILATOR. DID NOT SURVIVE. THE OTHER THREE ARE ALIVE, OUT TO 3 1/2 YEARS. ONE RETRANSPLANTED, RELAPSED. A VERY LOW DOZE REGIMEN. FIVE MATCHED UNRELATED DONORS. ALL ALIVE. ONE OF THOSE REJECTED LATE, HAD TO BE RETRANSPLANTED. THE HAPPENLO IDENTICALS CONTINUE TO BE A PROBLEM BUT THE REAL PROBLEM WAS IN THE YOU MEAN BILLICAL CORD GROUP, AN EARLY DEATH, REJECTION AND CRAZY LATE DONOR CELL LEUKEMIA. THE PROBLEM NOW IS IN THE CORDS. HOW WE'RE GETTING AROUND THAT IS -- I'LL MENTION IT IN A MINUTE. WE HAD A DOZEN PATIENTS AWAITING TRANSPLANT. SOMETIMES WE CAN'T FIND DONORS FOR, THE MAJOR PROBLEM. ONLY ABOUT 50% OF THEM DO YOU FIND A MATCH. AND THEN YOU HAVE TO LOOK AT ALTERNATIVE DOPERS. SO THE BIG THING THAT WE'RE MOVING TOWARD IS THERE IS A JOHNS HOPKINS DEVELOPED A HAPPENLO IDENTICAL TRANSPLANT FOR GATA 2. THE WHOLE SUCCESS IS BETTER MATCHED DONORS. NOW YOU'RE TURNING AROUND AND USING A HALF MATCH. AND THIS WOULD BE USING A BROTHER SISTER, MOTHER FATHER, SON DAUGHTER. SO THIS REGIMEN WAS DEVELOPED, LOW DOZE TOTAL BODY RADIATION, INFUSES BONE MARROW FROM THE DONOR. THE DOPER BONE MARROW CELLS COME IN AND SEE THIS HOST AS FOREIGN. THEY GO INTO CYCLE. AND YOU'RE ABLE TO KILL THEM WITH HIGH DOSE. SO DESPITE A COMPLETE MISMATCH THEY HAVE A VERY LOW RATE OF GVH. THAT'S THE NEW AREA THAT WE'RE USING INSTEAD OF CORDS, PAUSE YOU GET A LOT MORE DONOR CELLS OUT OF A BONE MARROW FROM USUALLY AN ADULT DONOR. THAT'S WHERE THAT'S GOING. SO I THINK I COULD SUMMARIZE BY SAYING THAT ALLOGENIC TRANSPLANT DOES REVERSE THE PHENOTYPE. BEFORE THEY PROGRESS TO AML, EARLIER IN THE COUCHES. IF THEY DON'T HAVE A 10 OUT OF 10 OR 9 OUT OF 10 DONOR WE'LL BE MOVING TO HAPPENLO. WE'RE CERTAINLY INTENSIFYING THE REGIMEN SO WE DON'T HAVE TO RETRANSPLANT THE PATIENTS AND WORRY ABOUT RELAPSE. AND WE'RE GETTING HEALTHIER COHOARDED NOW. THIS JUST SUMMARIZES MY LAST SLIDE, THE PROGRESS. FRED APPLEBAUM SUMMARIZED THIS FOUR YEARS AGO, 50 YEARS OF TRANSPLANTS STARTING IN 1957 WHERE DON THOMAS DID THE FIRST TRANSPLANT. WHERE I STARTED. WORLDWIDE, 20,000 A YEAR. 30,000, SO ABOUT 50,000 TRANSPLANTS A YEAR. AND EACH -- YOU CAN SEE HOW WHEN THEY STARTED TO USE UNRELATED DONORS, ABOUT 1980, THAT OPENED IT UP AND STARTING TO USE UMBILICAL CORD, SO IT WAS DONORS THAT WERE RESTRICTING THE NUMBERS. SO, OKAY. I THINK WH ODDS DEFINITION OF A PROFESSOR. ONE WHO TALKS IN SOMEONE ELSE'S SLEEP. ALL RIGHT. THAT'S IT.