Welcome to the Clinical Center Grand Rounds, a weekly series of educational lectures for physicians and health care professionals broadcast from the Clinical Center at the National Institutes of Health in Bethesda, MD. The NIH Clinical Center is the world's largest hospital totally dedicated to investigational research and leads the global effort in training today's investigators and discovering tomorrow's cures. Learn more by visiting us online at http://clinicalcenter.nih.gov TODAY'S GRAND ROUNDS PRESENTATION IS TITLED INHIBITION OF THE PI3 K PATHWAY FOR UNTREATED FOLLICULAR LYMPHOMA AND OUR PRESENTERS INCLUDE RAHUL LAKHOTIA, PRESENTING A CASE, DR. STEFANIA PITTALUGA WILL DISCUSS FINDINGS AND DR. MARK AHLMAN WILL HIGHLIGHT THE FINDINGS OF THE CASE, AND THEN FINALLY DR. MARK ROSCHEWSKI WILL TALK ABOUT THE CARE FOR PAICIALTS WITH FOLLICULAR LYMPHOMA. WITH THAT OVER TO DR. LAKHOTIA. >> MYSELF AND MY CO PRESENTERS WILL BE DISCUSSING A CASE OF NEWLY DIAGNOSED FOLLICULAR EMILY NOAMA PATIENT, FOLLOWED BY PI3 K PATHWAY FOR INHIBITION STRATEGIES THAT WE ARE EXPLORING IN OUR CLINIC AT THE NCI. WE HAVE NO DISCLOSURES, WE WILL DISCUSS COP A NLISIB WHICH IS NOT FDA APPROVED. THESE ARE OUR LEARNING OBJECTIVES. I WILL BE PRESENTING THE CASE FOLLOWED BY DISCUSSION BY DR. STEPHANIA, AND DR. ALMAN WILL BE DISCUSSING THE IMAGING FROM THIS CASE AND THEN WE WILL DISCUSS THE ONGOING EFFORTS FOR FOLLICULAR EMILY POEMA AT NCI. OUR PATIENT IS A 49 YEAR-OLD GENTLEMAN WHO PRESENTED WITH A 3 MONTH LONG HISTORY OF BACK PAIN, NOT RELIEVED BY NARCOTICS. ON INQUIRY HE ALSO HAD BILATERAL AUXILIARY SWELLING AND DISCOMFORT ALONG WITH AN UNINTENTIONAL 10-POUND WEIGHT LOSS OVER THE LAST 3 MONTHS. THE PHYSICAL EXAM CORRESPONDED TO THE REAL ASSISTANCE WITH CERVICAL AS WELL AS AUXILIARY SWELLING, SPLENOMEGGALY WAS ALSO NOTED. THIS PAST MEDICAL HISTORY INCLUDED HYPER TENSION, OBSTRUCTIVE SLEEP APPLICATIONSNIA, HIGH CHOLESTEROL LEVELS AND HYPOTHYROIDISM, REPORTED NO ADDICTIONS AND IS FORMER MILITARY, WAS IN THE ARMY. HIS MOTHER HAD BLADDER CANCER AT AGE 69 AND HIS CURRENT MEDICATIONS ARE LISINOPRIL, NARCOTS AS WELL AS LEVOTHYROXINE, LABORATORY STUDIES INDICATED MILD ANEME AND LIVER AND KIDNEY FUNCTIONS WERE NORMAL HOWEVER AN ELEVATED MICROGLOBUE LYNN AND LDH WERE NOTED. GIVEN THE PERSISTENT BACK PAIN DESPITE USING OXYCO DONE HE UNDER WENT AN MRI LUMBAR SPINE TO DETERMINE ETIOLOGY AND WAS FOUND TO HAVE BULKY PERIAORTIC LIMP ADEN OPEN MEETING OGHTY THE LARGEST AT 6.6 CM. THIS RAISED CONCERN WORRY MALIGNANCY INCLUDING LYMPHOMA AND IT WAS FOLLOWED BOO I A PET SCAN THAT SHOWED HYPER METABOLIC ACTIVITY, AILLEGALSARY, MEDIA STIENAL, AND INBEGINNAL LYMPHNODES, THE UPDATE VALUE OR SUV MAX ARRANGED FROM 15-17 WITH THE CERVICAL NODES BEING THE HARDEST ON PET. THE SPLEEN ALSO HAD AN UPDATE ALONG WITH INCREASE IN SIZE, AND DIFFUSE UPTAKE WAS NOTED IN THE LONG BONEs AS WELL AS [INDISCERNIBLE]. FOLLOWING THE PET SCAN THE LYMPHNODE IN THE NECK OR THE LEFT SUPER VICULAR LYMPHNODE WAS BIOPSIES AND I WILL INVITE DR. STEPHANIA TO DISCUSS THE RESULTS OF THE BIOPSY. >> GOOD AFTERNOON WE STUDIED THE LYMPHNODE AS WELL AS BONE MARROW BIOPSY ON THIS PAGE. THE LYMPHNODE BIOPSY WAS FROM EXCISION OF BIOPSY ON THE LEFT NECK AS RAòL MENTIONED THIS WAS 1 OF THE SIDE WITH THE HIGHEST UPTAKE BY PET AND WHAT I WOULD LIKE TO POINT OUT IS THAT WE HAVE A FOLLICULAR GROWTH PATTERN AND A TYPICAL FOLLICULAR GROWTH PATTERN SHOWN HERE ON THE LEFT SIDE AND THIS IS A LOW POWER VIEW. AND IT'S OF INTEREST THESE DARKER RADIUS, THEY ARE TYPICAL FOLLICLE CENTRAL AREAS THEY ARE SURROUNDED WITH [INDISCERNIBLE] CELLS ON THE FEATURES, BEST SEEN ON THE PANEL TO THE RIGHT HERE AS YOU SEE HERE, THIS IS A ROUNDED AREA COMPOSED BY SMALL CLEAVED CELLS WITH OCCASIONALLY LARGE SENT ROW BLAST. THE FEATURES THAT YOU SEE HIGHLIGHTED IN THE FOLLICLES AND THE TEND TO KOA LES IN THIS AREA, 1 IS HERE AND 1 IS NEXT TO IT, ARE SUGGESTIVE OF FOLLICULAR EMILY FEMA AND THE PRESENCE SURROUNDING THESE NODULES IS CONSISTENT WITH THE FORM OF MONOCYTE OF PLAZ MIDS SIZE OR DIFFERENTIATION IN FOLLICULAR LYMPHOMA WHICH HAS BEEN DESCRIBED IN PARTICULAR SUBTYPE OF FOLLICULAR LYMPHOMAS. BY IMMUNE O HISTOCHEMICAL STAIN, AS YOU CAN SEE THE MAJORITY OF THE CELLS ARE CD20, THEY ARE B-CELLS AND FOLLICULAR AREAS THAT ARE TYPICAL OR POSITIVE FOR CD10, AS SHOWN HERE, BCL 6, AND AS YOU CAN SEE, THE AREA OF MONOCYTE OR B-CELL DIFFERENTIATION ARE ACTUALLY POSITIVE WITH MUM 1 WITH THE PERIPHERAL VIEW. WHEN WE DO THE IMMUNE O EFTHIMIOSICAL STAINS FOR LAMBDA, CAN YOU SO THERE IS LACK OF LAMB DAILY BASIS SHOWN ON THE INSIDES AND INLET AND SHOWED BASICALLY NO CAPPA POSITIVE CELL. IN ADDITION, FEATURES OF THIS CASE WAS THE [INDISCERNIBLE] PROLIFERATION INDEX BY KI-67 SHOWED YET IN THIS PANEL. SO BASED ON THIS MORPHOLOGICAL GROUND--SORRY, THIS HAD S&P THE BONE MARROW AND THE BONE MARROW SHOWS THE LYMPHOID AGGREGATES, THIS IS THE PERIPHERY IS THE NORMAL MARROW WITH THE LINEAGE IN THE HEMEAT O POETICESIS WITH NORMAL MODULATION AND THOSE TYPICAL AGGREGATES ARE PRESENT EXTENSIVELY FOR THE [INDISCERNIBLE] AND IT'S A LOW POWER WITH CD20 WHICH IS A TYPICAL FEATURES OF FOLLICULAR LYMPHOMA IN WHICH THE AGGREGATES TEND TO THE HUG THEM HERE, HERE YOU SEE THE NEGATIVE IMAGE OF THE [INDISCERNIBLE]. AND BASICALLY OUR SURROUNDING EACH OF THOSE [INDISCERNIBLE]. IN ADDITION, AS SHOWN HERE, THIS IS ALSO BCL 2 POSITIVE WHICH IS A MARKER FOR FOLLICULAR LYMPHOMAS. SO IN SUMMARY, THIS WAS A CASE OF THE FOLLICULAR LYMPHOMA WITH EVIDENCE OF MARGINAL ZONE DIFFERENTIATION AS SHOWN BY THE MONOCYTE AND THE B-CELLS AND WHERE LAMBDA IS RESTRICTED. AS I MENTIONED FOLLICULAR LYMPHOMA WITH THE MARGINS DIFFERENTIATION IS A KNOWNENTITY FOR QUITE SOMETIME IN PATHOLOGY AND IT'S OF INTEREST AND THE DISTRIBUTION OF THE MONOCYTE OF THE B-CELLS WITH THE RESTRICTION IS OFTEN IN CASES WHILE STUDY ASSOCIATE WIDE BCL2 REARRANGEMENT. SUPPORTING THE CONCEPT THAT THIS INDEED IS A FORM OF CO LICKULAR LYMPHOMA AND NOT MARGINAL ZONE B-CELL LYMPHOMA AND THIS CASE ALSO SHOW BCL 2 ARRANGEMENT IN THE 99 PERCENT OF THE CELLS. THEY IT SHOWS THE HIGH PERIPHERY RATE. HOWEVER THE LYMPHOMA IS BASED ON THE SENT ROW BLAST AND THE SENT ROW SIZE AND THEY SHOULD BE ASSESSED AND THEREFORE WITH MORPHOLOGIC GROUNDS, THIS CASE IS CLASSIFIED AS GRADE 1-2 AND WITH EVIDENCE OF MARGINAL ZONE DIFFERENTIATION. THE BONE MARROW INVOLVEMENT WITH THE [INDISCERNIBLE] AGGREGATES IS QUITE TYPICAL FOR FOLLICULAR GRADE AS IS SHOWN IN THIS PATIENT. I WILL SWITCH NOW OVER BACK TO RAòL TO CONTINUE WITH THE CLINICAL PRESENTATION OF THE CASE. >> OKAY, SO WHAT IS FOLLICULAR LYMPHOMA AND DOES IT ENTAIL TO BE DIAGNOSED WITH FOLLICULAR LYMPHOMA, SO IT'S CHARACTERIZED BOO I A NODULAR OR FOLLICULAR PATTERN OF GROWTH ON THIS GENTLEMAN'S BIOPSY. IT IS THE SECOND MOST COMMON NONHODGE KINS LYMPHOMA WITH 20-25% OF ALL NEW NONHODGE KINS LYMPHOMA CASES DIAGNOSED IN THE UNITED STATES. TRANSLOCATION 14; 18 IS THE GENETIC HALLMARK AND IT POSITIONS BCL 2 GENE, BCL 2 IS A APOPTOTIC MOLECULE AND A POSITION THAT GENE CLOSE TO THE IMMUNE O GLOBUE LYNN HEAVY CHAIN PROMOTER. THE 10 YEAR OVERALL SURVIVAL IS 80% BUT SIGNIFICANT CLINICAL VARIABILITY EXISTS AND 20% PATIENTS PROGRESS EARLY AFTER FIRST TREATMENT. IT IS CONSIDERED GENERALLY INCURABLE WITH EXISTING THERAPIES. SO NOW WE HAVE THIS RELATIVELY YOUNG 49 YEAR-OLD GENTLEMAN WHOSE HAVING SIGNIFICANT BACK PAIN AND HAS A HISTORY OF HYPER TENSION. IS DIAGNOSED WITH FOLLICULAR LYMPHOMA. HOW SHOULD WE MANAGE HIM? SHOULD WE WAIT AND WATCH? SHOULD WE USE AN ANTICD20 ANTIBODY ALONE? IF WE WERE TO USE IT, WOULD IT BE RITUXIMAB OR OBINUTUZUMAB, SHOULD WE USE CHOP THERAPY WITH AN ANTICDTWEBT AGENT OR AN BENDAMUSTINE WITH 18 ANTICD20 AGENT? WITH ANY OF THE THERAPIES SHOULD WE USE ANY MAINTENANCE TREATMENT OR SKIP CHEMO THERAPY AND USE 1 OF THE IMMUNE O MODUE LATTERY AGENTS SUCH AS LENALIDOMID WITH ANTICD20 AGENT AND LASTLY SHOULD THIS PERSON GO ON CLINICAL TRIAL INSTEAD OF STANDARD TREATMENTS. SINCE A SLEW OF FRONT LINE THERAPIES OR STANDARD TREATMENTS ARE AVAILABLE FOR FOLLICULAR EMILY FOAM ATHE QUESTIONS THAT WE NEED TO ASK IS, IS THERE INDICATION FOR ANY TREATMENT FOR A PATIENT. AS WE DISCUSSED WITH EXISTING THERAPIES, FOLLICULAR LYMPHOMA IS CONSIDERED INCURABLE, AND HENCE MOST COMMON INDICATIONS FOR TREATMENT ARE PAIN ORGAN COMPRESSION OR ORGAN COMPROMISED DUE TO TUMORS OR CYTOPENIAS. OUR PATIENT HAS SIGNIFICANT PAIN AND WOULD LIKELY BE INDICATION OF TREATMENT FOR HIM. SINCE CURE IS NOT COMMON WITH TREATMENTS, IS PROLONGED REMISSION POSSIBLE WITH THERAPY? S AND WE WILL DISCUSS THE COMMON FRONT LINE THERAPIES IN THAT REGARD. ARE THERE PREDICTIVE MARKERS THAT EXIST THAT HELP US CHOOSE 1 THERAPY OVER THE OTHER? THE STANDARD APPROACHES INCLUDE CHEMO THERAPY, HOWEVER, MOST OF THEM ARE ASSOCIATED WITH ACUTE TOXICITIES, AS WELL AS LONG-TERM EFFECTS INCLUDING SECOND MALIGNANCIES AND IMMUNE DYSFUNCTION. IMMUNE O MODUE LATTERY AGENTS ARE NOW AVAILABLE AND NOVEL AGENTS ARE NOW AVAILABLE, HOWEVER THEY RESULT IN CUMULATIVE TOXICITY AS THEY ARE DOSED INDEFINITELY. SO THERE ARE SCORES THAT DO HELP PROGNOSTICATE AFTER PATIENT'S DIAGNOSIS. FOR OUR PATIENT WHEN LOOKING AT THE 2 MOST COMMONLY USED SCORES, FLE PI, AND FLIPI 2, HE FALLS INTO THE HIGH RISK CATEGORY WITH EITHER OF THE SCORE. FOR FLIPI, HE QUALIFIES WITH STAGE 4 DISEASE. WITH A 5 YEAR OVERALL SURVIVAL OF 53%. WITH FLIPI 2, WHICH IS A DIFFERENT SCORE, USES SOME OF THE SAME PARAMETERS FOR 3 DIFFERENT PARAMETERS COMPARED TO FLIPI, HE HAS HIGH RISK DISEASE BECAUSE OF ELEVATED MICROGLOBUE LYNN, BONE MARROW INVOLVEMENT AND AS WELL AS A LYMPHNODE DIAMETER MORE OF 6 CENTIMETERS AND THIS ENTAILS A 5 TO 3 YEAR SURVIVAL OF 50%. SO WITH THIS IN THE BACKGROUND LET'S TALK ABOUT THE DIFFERENT TREATMENT OPTIONS OR THE STANDARD TREATMENT OPTIONS AVAILABLE FOR THIS PATIENT. AMONG THE DIFFERENT CHEMO THERAPY OPTIONS AVAILABLE, THE STUDY COMPARED R-CHOP WITH C-CVP AND R-FM THE 3 DIFFERENT USED CHEMO THERAPY REGIMENS WITHOUT ANY MAINTENANCE TREATMENT. AND SHOWED THAT R-CHOP AND R-FM DEMONSTRATED A BETTER TIME TO TREATMENT FAILURE, COMBINEDLY FOR THE 3 REGIMENS HALF OF THE PATIENTS WERE PROGRESSION FREE AT 80 YEARS BUT THE OTHER HALF REQUIRED A DIFFERENT TREATMENT. HOWEVER, THE OVERALL SURVIVAL WAS NOT DIFFERENT REGARDLESS OF THE REGIMEN YOU CHOOSE AND THE NUMBER OF LYMPHOMA RELATED PETRESSABLES AND SIMILAR FOR THE 3 TREATMENTS. SINCE HALF THE PATIENTS WITHIN THE 8 YEARS IS THERE SOMETHING THAT CAN BE DONE TO DELAY THE PROGRESSION OR IMPROVE SURVIVAL ALONG WITH FRONT LINE CHEMO THERAPY. AND AS MAINTENANCE WAS EXPLORED, IT IMPROVES PROGRESSION FREE SURVIVAL BUT WAS NOT SHOWN TO IMPROVE OVERALL SURVIVAL. HOWEVER, THAT DOES COME AT A COST AND PATIENTS WHO RECEIVE RETUXY MAB MAINTENANCE HAVE INCREASED HEMEAT O LOGIC TOXICITY WITH HIGHER RATES OF LIP O PENIA, ANEMIA, LEUKOPENIA AND THROMBOCYTE PENIA ALONG WITH INFECTIONS FOR TREATMENT. WHAT ABOUT A DIFFERENT CHEMO THERAPY. SO BASED ON THERAPY WAS COMPARED WITH R-CHOP IN THIS STUDY AND WAS SHOWN TO HAVE AN IMPROVED PROGRESSION FREE SURVIVAL COMPARED TO R-CHOP. HOWEVER, THE STUDY ONLY INCURRED WITH PATIENTS IN 1-32 GRADE LYMPHOMA, EXCLUDED GRADE 3 AND PATIENTS DID NOT RECEIVE RITUX MAB. THE OVERALL SURVIVAL IS NOT THAT DIFFERENT AND PATIENT WHO IS RECEIVE BENDAMUSTINE TREATMENT MAWOF THE HAVE INCREASED DEATH AND FATALAZ VERSE EVENTS ALONG WITH INCREASED INFECTIONS AND SECONDARY MALIGNANCIES. THE COMMON SECOND MALIGNANCIES SEEN WITH BENDMUSTINE ARE SKIN TUMORS, BASAL CELL CANCER, SCWAIMOUS CELL CANCER AND MELANOMA AS WELL AS OTHER SOLID TUMORS. SO FOR A YOUNG PATIENT WHO REQUIRES TREATMENT FOR THE FIRST TIME AND MAY REQUIRE MULTIPLE TREATMENTS DURING THE COURSE OF HIS LIFE, IT WILL MAKE ME EXTREMELY CAUTIOUS USING BENDAMUSTINE USING TREATMENT FOR THIS GENTLEMAN. HOW ABOUT THE DIFFERENT ANTICD20 ANTIBODY? DOES THAT IMPROVE OUTCOMES COMPARED TO STANDARD TREATMENTS? SO HERE, OBINUTUZUMAB WAS IN THE STUDY AND SHOWN PROGRESSION-FREE SURVIVAL BUT AGAIN NO IMPROVEMENT IN OVERALL SURVIVAL. NEWER TREATMENTS SUCH AS LENILOMID HAVE BEEN COMPARED TO COMEEM O THERAPY BASED TREATMENT AND SHOWED SIMILAR PROGRESSION-FREE SURVIVAL. THE RATES OF NEWT ROW PENIA AND HEMEAT O LOGIC TOXICITY WAS HIGHER IN THE CHEMO THERAPY GROUP AND THE RATES OF SUBCUTANEOUS REACTIONS WERE HIGHER IN THE [INDISCERNIBLE] GROUP. SO BASED ON THESE DATA WE HAVE DISCUSSED SO FAR MULTIPLE TREATMENT OPTIONS EXIST FOR THIS PATIENT WITH LIMITED OR NO MOLECULAR OR GENETIC PREDICTIVE MARKERS TO SELECT THERAPY FOR HIM. WHAT DID WE CHOOSE FOR OUR PATIENT? WELL WE CHOSE NONE OF THE ABOVE. THE PATIENT ENROLLED ON A PROTOCOL FOR ONGOING CLINICAL TRIAL HERE AT THE NCI, WHICH IS A AN UNTREATED FOLLICULAR LYMPHOMA, BASED ON THE CELLULAR DESIGN, HE RESEVERE MITRALLED 4 WEEKS OF COP A NLISIB AND FOLLOWED BY RITUXIMAB, AND CURRENTLY GOING PSYCHE WILL 4 OF THIS TREATMENT, WITH THIS I WILL INVITE DR. MARK AHLMAN TO REVIEW THE IMAGING AND THE OUTCOME OF THE PATIENT ONGOING STUDY. >> ALL RIGHT, THANK YOU DOCTOR, AND GOOD AFTERNOON, EVERYONE. WITH THIS I WOULD LIKE TO EXPLAIN OR KIND OF INTRODUCE POSSIBILITIES OF HOW WE COULD USE THE FDG PET GUIDE TREATMENT. SO MAYBE THIS CAN INFORM OUR CLINICAL TRIALS AS WELL AS CLINICAL/RESEARCH WORK FLOW HERE AT THE CLINICAL CENTER. IN THIS CASE, HOW DOES IT WORK BEST AT BASE LINE AND HOW CAN WE BETTER USE IT TO MONITOR TREATMENT RESPONSE. SO THIS IS OUR PATIENT, THIS IS THE FDG PET, FOR THE DEOXYGLUCOSE THIS, IS A SMALL AMOUNT OF RADIO ACTIVITY TAGGED TO GLUCOSE, IN THE CENTER HERE WE SEE THE PET, CAN YOU VISUALLY APPRECIATE THE BULK OF TUMOR, A LOT IN THE ABDOMEN, AND MEDIA TIEN UMKC AND NECK AND YOU LOOK AT THE SPLEEN, IT'S A BIT HETEROGENEOUS ROW GENIUS AND WE ASSUME THERE'S ABNORMAL ACTIVITY IN THERE BUT SOMETIMES THERE ARE CONFOUNDERS AND IT CAN BE ACTIVITY OF THE NORMAL CELLS THERE BUT IT IS ASSUMED THIS IS INVOLVED. SO 1 OF THE GREAT WAYS WE USE IT, AT LEAST AT BASE LINE IS TO PLAN THE BIOPSY THAT WE'RE GOING TO HAVE FOR THIS PATIENT. AND 1 ADVANTAGE OF PET, 1 THING WE KNOW IS THAT THE--IF THERE'S A FOCUS OF HIGHER ACTIVITY OF A LESION COMPARED TO THE REST THE TUMOR IN THE BODY, WE ASSUME THAT THAT'S A HIGHER RISK OF LYMPHOMA COMPARED TO THE HISTOLOGICAL CHARACTERISTICS ELSEWHERE IN THE BODY. AT LEAST IN THIS CASE, MOST OF THE DISEASE LOOK PRETTY HOMOGEANIOUS SO WE GO TO PICK A SPOT IN THE BODY WHERE IT'S MORE AMENABLE TO EXCISION BIOPSY AND AS YOU WERE PRESENTED EARLIER, IT WAS TAKEN FROM THIS PART AND THAT SUV IN THIS SPOT WAS A MAX OF 17 WHICH IS VERY HIGH. SOPHISTICATEDY THAT WAS EXCISED. SO NOW I WANTED TO SHOW YOU KIND OF SOME OF THE 21st CENTURY NUCLEAR MEDICINE ADVANCES THAT ARE HAPPENING. THIS KIND OF SEGMENTATION ISN'T VERY EASY TO DO SO WHAT IS HAPPENING IS WE'RE SEGMENTING OUT EACH OF THE PATIENT'S TUMOR AWAY FROM THE NORMAL TISSUES IN THE BODY AND WE'RE ABLE TO FIND AT LEAST INITIALLY WHAT'S CALLED THE METABOLIC TUMOR VOLUME. IT'S THE VOLUME OF ALL THE VIABLE TUMOR WE SEE ON THE PET SCAN. ANOTHER DIMENSION OF THIS IS WE ALSO TAKE INTO CONSIDERATION, THE RELATIVE ACTIVITY OF THE TUMOR, AND WE MEASURE THAT BY STANDARDIZED UPTAKE VALUE OF THE SUV, SO WE TAKE THE MEAN ACTIVITY OF ALL THAT VOLUME AND MULTIPLY IT BY THE VOLUME ITSELF AND WE GET A MEASUREMENT CALLED THE TOTAL LESION GLYCOL SIS, SO THE DOCTOR, WE'RE WORKING ON TRYING TO MAKE THIS MAYBE MORE PART OF OUR COLLABORATIONS WITH INVESTIGATIONS, THIS IS DOCTOR [INDISCERNIBLE] HERE, AND MAKE THIS POSSIBLY MORE ROUTINE AVAILABILITY TO OUR INVESTIGATORS. SO THAT'S ONGOING. SO THIS SLIDE SHOWS SOME RESULTS THAT RESEARCHERS HAVE DONE ON THE OUTSIDE WHERE THEY LOOKED AT LEAST AT THE METABOLIC TUMOR VOLUME AND THEY FOUND THAT IF YOU HAVE MORE THAN HALF A LITER HERE OR 500 CUBIC CENTIMETERS OF TUMOR, THAT CONFERS, YOU KNOW A LOWER ODDS OF PROGRESS-FREE SURVIVAL O IN CONTEXT WITH OUR PATIENT HERE, THIS METABOLIC TUMOR VOLUME WAS MEASURED TO BE 552 CUBIC CENTIMETERS, MULTIPLY THAT TIMES THE MEAN SUV THAT'S TOTAL LESION GLYCOL SIS OF 6000 SO THAT'S QUITE A BIT. SO NOW, HOW DO WE USE THIS INFORMATION TO INFORM TREATMENT RESPONSE. SO HERE, AS--THE DOCTOR IS GOING TO EXPLAIN THIS A BIT MORE, BUT THIS IS THE PET SCAN FOLLOWING TREATMENT AND THE METABOLIC TUMOR VOLUME WENT DOWN 65% AND THE TOTAL LESION GLYCOL SIS DOWN 82%. NOW LET ME EXPLAIN THOSE NUMBERS IN CONTEXT OF WHAT THE CURRENT REFERENCE STANDARD IS TO SHOW WHAT TREATMENTS RESPONSE IS DOING AND THAT'S JUST SIMPLY MEASURING THE LENGTH OR THE AXIAL DIMENSION OF THIS TUMOR FROM POINT A TO POINT B AND YOU SEE HERE IN THE RETROPERO 10UME, IT'S DECREASED AND THE IN THE STIEN UMKC IT'S DECREASE BY 43% IS WHAT THEY ISSUED IN THIS STUDY. FOR TREATMENT RESPONSE WE HAVE 43% FOR CT, AND 65 FOR MTV AND 82% FOR TLG, AND IF WE LOOK AT THESE NUMBERS MAYBE THE TLG COULD TELL US THE ACTUAL DEGREE OF RESPONSE IN THIS PATIENT, MAYBE THAT'S GOING TO INFORM US WHAT THE PROGNOSIS WILL BE. WELL WE DON'T KNOW THAT NECESSARILY, AND THAT'S PART OF OUR COLLABORATIONS WITH DR. UPON RAWCHSKI, AND THIS AFTER THE OTHER DOCTORS EXPLAINED. SO, ANOTHER GREAT THING THAT PET CAN DO FOR US IS SIMPLIFYING WHETHER OR NOT THERE ARE NEW LESIONS AND THAT'S 1 THING THAT FDG PET DOES VERY WELL, AS WELL AS OTHER ANATOMIC MODALITIES WE HAVE, IN THIS CASE WE WERE NOT ABLE TO FIND NEW LESIONS SO THAT HOPEFULLY CONFERS BETTER ODDS OF RESPONSE HERE. SO IN SUMMARY, THERE WAS AN IMAGING AT LEAST FROM AN IMAGING STANDPOINT THERE'S SIGNIFICANT RESPONSE TO TREATMENT, DIDN'T TOTALLY GO AWAY, YOU DO STILL SEE DISEASE HERE BUT WE'RE DOING IT ON A RELATIVELY SHORT INTERVAL AND THIS CAN GET BETTER THE MORE TREATMENT THAT IS DONE SO THERE'S A DECREASE IN THE BOTH THE SUV, THE METABOLIC TUMOR VOLUME AND TOTAL LESION GLYCOL SIS AND THAT'S WITH CT DECREASE IN THE SIZE OF THE LESIONS. SO WITH THAT I WILL TURN IT OVER TO THE DOCTOR AND HE WILL FURTHER EXPLAIN THIS CASE AND HOW IT RELATES TO THEIR PROCESS. >> THANKS EVERYONE. SO WE THOUGHT WE WOULD USE THIS CASE AS AN ILLUSTRATION OF SOME OF THE FEATURES OF FOLLICULAR LYMPHOMA BUT ALSO THE CLINICAL DESIEGZS WE HAVE TO DECIDE WHEN WE'RE DETERMINING WHETHER OR NOT A PATIENT SUCH AS THIS NEEDS TREATMENT AND THEN, AS THE DOCTOR POINTED OUT, SELECTING THAT THE THERAPY HAS A NUMBER OF CONSIDERATIONS BEFORE WE DECIDE. WHAT WE ELECTED TO DO IN THIS CASE WAS ENROLL THIS PATIENT IN AN ONGOING CLINICAL TRIAL WE HAVE HERE WHICH IS TESTING THE USE OF CO PANELISTS OF RITUXIMAB IN A PATIENT LIKE THIS AND I WANT TO SHOW YOU THE RATIONAL FOR WHAT WE THINK IS CRITICAL ABOUT THIS STUDY, WAWE CAN ADDED TO THE CURRENT UNDERSTANDING OF FOLLICULAR LYMPHOMA AND GIVE YOU EARLY RESULTS THAT WILL BE PRESENTED IN THIS STUDY SOON AS WELL. SO 1 OF THE THINGS THAT THE PRESENTERS HAVE HIGHLIGHTED HERE IS THAT YOU KNOW PATIENTS WITH FOLLICULAR LYMPHOMA HAVE QUITE A BIT OF HETEROGENEITY BIOLOGICALLY BUT THIS IS ALSO REFLECTED CLINICALLY, SO WHAT YOU'RE SEEING HERE IS A DATABASE OF PATIENTS TREATED IN THE UNITED STATES AND THEIR OUTCOMES AND MOST--THESE SLIDES ACTUALLY REFER TO PATIENTS WHO GOT R-CHOP THERAPY AND YOU CAN SEE THAT THE GOOD GROUP, REPRESENTED IN YELLOW ACTUALLY HAVE SUCH HIGH SURVIVALS OF OVER 90% AND ULTIMATELY THEIR LONG-TERM OUTCOMES ARE ACTUALLY NEARING THAT OF AGE MATCH CONTROLS WITHOUT FOLLICULAR LYMPHOMA, THE KEY IN NOSE PATIENTS IS ACTUALLY TO AVOID TOXICITY. SO SINCE WE KNOW THAT THEY HAVE A RELATIVELY GOOD PROGNOSIS, WE'RE VERY MINDFUL OF THE LATE AND LONG-TERM TOXICITIES INTRODUCED BY CHEMO TERRAPY AND WE HAVE TO TAKE A LONG HALL VIEW ABOUT WHAT WE WANT TO INTRODUCE NOW AND WHAT WE WANT TO POTENTIA WILY SAVE FOR LATER BUT THERE'S ALSO ANOTHER GROUP THAT REPRESENTS ABOUT 20% OF THESE CASES WHICH HAVE A MUCH INFERIOR PROGNOSIS TO THEM AND THIS IS WHAT HAS BEEN DEFINED NOW AS EARLY PROGRESSOR ANDS SPECIFICALLY THOSE THAT HAVE DISEASE THAT NEED TREATMENT AGAIN WITHIN 2 YEARS AFTER FIRST TREATMENT. NOW THE PROBLEM WE HAVE IS WE DON'T HAVE ANY GOOD TOOLS AT THIS POINT TO IDENT WHO THESE PATIENTS ARE PRIOR TO THERAPY, AS THIS IS ALL DETERMINED AFTER THEIR FIRST THERAPY SO THAT'S AN IMPORTANT GOAL OF OUR RESEARCH PROGRAM BUT ALSO THE FIELD OF FOLLICULAR LYMPHOMA IS HOW DID ON WE IDENTIFY THESE QUOTE-UNQUOTE HIGH RISK PATIENTS BECAUSE THOSE ARE THE 1S OF COURSE THAT SHOULD BE PRIORITIZES FOR NOVEL TREATMENTS. SOY OUR FOCUS WAS ON THIS STUDY OF COP A NLISIB, IT'S A PAN-CLASS 1 INHIBITOR OF THE PI3 KINASE PATHWAY AND TARGETS 2 DIFFERENT ISOFORMS. BOTH THE ALPHA AND DETAILSA. NOW THE PI3 KINASE PATHWAY IS CRITICAL ACROSS CANCER, NOT SPECIFIC TO LYMPHOMA, AND NOT SPECIFIC TO FOLLICULAR LYMPHOMA BUT IN THE CONTEXT, THE IDEA IS THAT MANY OF THESE TUMORS ARE GOING TO BE RELIANT UPON THE B-CELL AND SO THAT'S WHAT IS TARGETED HERE WITH THE DELTA ISOFORM AND THEN THERE ARE A NUMBER OF ACTUALLY PI-3 KINASE DELTA INHIB THORS THORS THAT ARE APPROVED FOR USE. THIS ALSO TARGETS THE ALPHA ISOFORM WHICH IS CRITICAL FOR THE GROWTH OF SOME LYMPHOMAS AND IT'S DOWN STREAM FROM THE INSULIN GROWTH FACTOR PATHWAY WHICH MEANS THAT 1 OF THE EXPECTED ONTARGET EFFECTS WHEN YOU USE THIS DRUG IS THAT WILL YOU INDUCE HYPER GLYCEMIA AND HYPER TENSION, THEY'RE NOT TOXICITY BUT THEY ARE TO BE DEALT WITH WHEN WE USE THIS AGENT AND THAT'S BEEN SHOWN IN THE CLINICAL TRIALS AND IF YOU REMEMBER, OUR PATIENT HAS PREEXISTING HYPER TENSION GOING INTO THE STUDY. SO 1 OF THE CENTRAL THESIS OF THIS LYMPHOMA ALONG THIS PATHWAY, IS THE TYPE OF B-CELL SIGNALING SO THERE ARE DIFFERENT FORMS OF B-CELL SIGNALING IN FORMAL B-CELLS AND THAT'S ALSO TRUE ACROSS VARIOUS LYMPHOMAS. THE TYPE OF B-CELL RECEPTOR SIGNALING THAT WE THINK IS PRESENT IN MOST GERMINAL CENTER LYMPHOMAS TO INCLUDE FOLLICULAR LYMPHOMA IS SOMETHING CALLED TONCOGENIC BCR SIGNALING WHICH IS DIFFERENT THAN OTHERS WHICH IS MORE OF AN ANTIGEN DEPENDENT SIGNALING. THIS IS CONSIDERED ANTIGEN INDEPENDENT. THIS IS--THIS IS LARGELY WORK DONE FROM THE STOUT LAB, WHERE THEY HAVE WORKED OUT WITH CRSPR SCREENS THE VARIOUS DEPENDENCIES ON THE CELL LINES AND THE T-CELL LYMPHOMA AS WELL AS BURKEET'S LYMPHOMA AND MANY OF THESE TUMORS RELY UPON THIS PROXIMAL B-CELL RECEPTOR, BOTH THE LYNN AND SIC ARE IMPORTANT AND WHEN YOU KNOCK THEM OUT WITH CRSPRs, THE CELLS DIE. THIS IS THE TYPE OF B-CELL RECEPTOR SIGNAL THAGOREAN WE THINK MANY IF NOT MOST OF THE LYMPHOMA PATIENTS ARE RELIANT UPON. ACTUALLY CO PANELIST OF THE LYMPHOMA, CLINICAL STUDY THAT LED TO THE FDA APPROVAL AND A PHASE 2 STUDY IN PATIENTS THAT HAD RELAPSED AND REFRACTOR DISEASE, SOPHISTICATEDY THESE ARE PATIENTS THAT HAD AT LEAST 1 TREATMENT AND MANY TIMES UP TO 3 TREATMENTS AND YOU CAN SEE FROM THE WATER FALL PLOT ON THE LEFT THAT THE MAJORITY OF PATIENTS GET A RESPONSE WHEN YOU GIVE A COP A NLISIB, SO THIS IS A HANDFUL, SUGGEST THANKSGIVING IS A HIGHLY ACTIVE AGENT. AND WE TALK ABOUT RESPONSE IN THE CLINICAL WORLD THOUGH WE HAVE YOU A LINE IN THE SAND AT 50% AND WE SAY A RESPONSE IS UNDER 50% AND LESS THAN 50% IS NOT A RESPONSE EVEN THOUGH THOSE WERE CRITERIA DEVELOPED WITH CHEEM OR THERAPY. BUT YOU CAN SEE THAT MOST PATIENTS WILL HAVE SOME RESPONSE TO CO PAN LIAISONS INCREASE IN BODY, BUT THE RESPONSE IS ONLY AROUND 20%. SO 1 OF THE THINGS WE ARE GOING TO DO IF WE GET REMISSIONS IS WE HAVE A REGIMEN, 1 OF THE THINGS WE'RE DOING IS MOVING IT UP FRONT TO THE UNTREATED SETTING AND ACROSS CANCERS, ACROSS ONCOLOGY TYPICALLY WHEN YOU MOVE THINGS UP FRONT, YOU CAN EXPECT THESE RESPONSE RATES TO GO UP AND PARTICULARLY IN THIS CASE, BECAUSE WE WILL ANTICIPATE THAT THE PATIENT'S IMMUNE SYSTEM WILL BE MORE INTACT MAKING IT MORE LIKELY TO GET A RESPONSE. AND THE ISSUE WE HAVE HERE IS THAT IN THE RELAPSE SETTING AS WE SEE ALSO WITH CHEMO THERAPY, THESE ARE NOT CURATIVE SO THESE PATIENTS WERE GETTING AND DEFINITELY CAN SEE THAT THE CAP LANMIER CURVE SHOWS OVER TIME AND EVEN THOUGH THE MEDIAN AMOUNT OF TIME PROGRESSING FOR ABOUT 1 YEAR, WE EXPECT MOST PATIENTS THAT ARE TREATED WITH THIS SINGLE AGENT ARE ULTIMATELY GOING TO RELAPSE. BUT 1 OF THE THINGS WE HAVE IS ABOUT THE TOXICITY. SO WE MADE A POINT ABOUT THE TOXICITIES OF THEME O THERAPY AND ACTIVITIES AND PROJECTS AS WELL AS TARGETED AGENTS AND HERE WE'RE SEEING THAT THE MAJORITY OF TOXICITY IS ON TARGET EFFECTS SUCH AS HYPER GLYCEMIA AND HYPER TENSION AND THERE'S NOT A LOT OF CUMULATIVE TOXICITY WITH COP A NLISIB, AND THAT HAS BEEN SEEN BEFORE, AND THE COP A NLISIB IS DOSED ONCE OUT OF 4, AND IT'S LESS DIARRHEA THAN SEEN WITH OTHER PI3 KINASE INHIBITORS AND MAYBE THERE IS A SIGNAL, SOME OF THESE PATIENTS DO GET SERIOUS PNEUMONIA IF THEY'RE GIVEN IT INDEFINITELY AND THAT'S ANOTHER FOR AN INDEFINITE PERIOD OF TIME TO,A VOID THOSE TOXICITIES WITH PRETTY MUCH ANY TREATMENT. BUT ANOTHER--TRYING TO UNDERSTAND WHO IT IS OR WHAT IS THE PROFILE OF THE TUMORS THAT ARE MOST LIKELY TO RESPONSE TO INHIBITION OF PI3 KINASE. SO WHAT YOU'RE SEEING HERE IS IT'S IN PUBLISHED DATA ON THE STUDIES WHERE THEY WERE SEPARATING THOSE OUT ON GENE PROFILE THAT WAS HIGH WITH THE EXPRESSION OF EITHER PI3 KINASE PATHWAY OR THE B-CELL RECEPTOR SIGNALING PATHWAYS HAS AS DEPICTED DOWN HERE, YOU CAN SEE CATEGORICALLY SEPARATE PATIENTS INTO HIGH AND LOW ON THE BASIS OF THE EXPRESSION, THAT YOU CAN--THAT THE MAJORITY OF PATIENTS THAT GOT A COMPLETE RESPONSE DICTATED HERE BY THE SNOW FLAKE WERE ACTUALLY ENRICHED OVER HERE IN THE HIGH EXPRESSION. SO THIS WAS TAKEN TO MEAN THAT AND THOSE PATES THAT HAVE A PROFILE FOR ENRICHED EXPRESSION ARE MORE LIKELY TO RESPOND TO INHIBITORS BUT IT'S NOT EXCLUSIVE, THIS IS A SMALL NUMBER OF PATIENTS AND WE THINK WE CAN IMPROVE UPON THIS WITH USING MORE SENSITIVE AND ADVANCED METHODS TO DETERMINE AND RESPOND WHO IS MOST LIKELY TO RESPOND TO PI3 CAIN ACE INHIBITORS AND BY EXTENSION THOSE THAT ARE LESS LIKELY TO RESPOND WHETHER IT IS FOR ENRICHED MACROPHAGE EXPRESSION OR OTHERS, IF YOU HAVE A PREDICTIVE BIOMARKER, THAT ALSO BECOMES HIGHLY CLINICALLY RELEVANT. SO OUR CLINICAL TRIAL IS DESIGNED TO ADDRESS A NUMBER OF THESE ISSUES TAKEN--THEY YOU'VE SEEN. IT TAKES ALL PATIENTS WITH UNTREATED FOLLICULAR LYMPHOMA THAT HAVE AN INDICATION FOR TREATMENT. SO AT THE NCI WE TYPICALLY DO NOT TREAT PATIENTS UNLESS THEY HAVE EVIDENCE OF ORGAN COMPROMISE OR SIGNIFICANT SYMPTOMS. AND IT'S NOT--THIS STUDY IS NOT DESIGNED FOR PATIENTS WITH SIMPLY LOW TUMOR BURDEN, THIS TAKES ALL PATIENTS THAT HAVE HIGHER GRADES OF FOLLICULAR LYMPHOMA OTHER THAN GRADE 3 B, AND WHAT WE DO IS GIVE THEM COP A NLISIB, AND THE IMAGES WERE SHOWN OF BEFORE AND AFTER THE WINDOW OF 1 CYCLE OF COP A NLISIB, WE DO THAT BECAUSE WE WANT TO ISOLATE THE EFFECTIVENESS AND WE WANT TO UNDERSTAND WHAT IS THE RESPONSE TO THAT SINGLE AGENT AND IT ALSO INTRODUCED SOME OPPORTUNITIES FOR US TO DID TRANSLATIONAL RESEARCH TO INCLUDE ON TREATMENT TISSUE BIOPSIES OR REPEAT PET SCANS OR EVEN ASSAYS FOR CIRCULATING TUMOR DNA SO WE CAN BETTER UNDERSTAND THE NATURE OF PATIENTS THAT RESPOND TO COP A NLISIB, AFTER THE WINDOW THEY ALL GET INDUCTION THERAPY WITH RITUXIMAB, AND THAT IS THE TREATMENT DESIGNED TO INDUCE AS MANY CASES AS POSSIBLE A COMPLETE RESPONSE. WE MENTIONED BEFORE THAT MANY OF THESE TARGETED AGENTS ARE GIVEN INDEFINITELY BUT THAT IS SOMETHING WE TRY TO AVOID ONURE STUDIES SO WHEN PATIENTS GET AFTER THEY'VE COMPLETED OF INDUCTION THERAPY IF THEY'RE IN RESPONSE WE STOP TREATMENT AT THAT POINT. WHEN YOU'RE NOT INTERESTED IN GIVING PATIENTS AS THEIR FIRST THERAPY, WE WANT TO DESIGN REGIMENS THAT ARE SO HIGHLY ACTIVE THAT WE CAN SAFELY STOP THEM AND STILL GET DURABLE REMISSIONS. IF PATIENTS ONLY GET A PARTIAL REMISSION WE WILL GO FOR 12 CYCLES BEFORE WE STOP AND THE IDEA THERE IS THAT SOME OF THESE PATIENTS MAY NEED MORE THAN 6 CYCLES TO GET COMPLETE RESPONSE AND WE DON'T KNOW HOW MANY ARE REQUIRED SO IF PATIENTS ONLY ARE RESPONDING BUT NOT COMPLETE, GET A FULL 12 CYCLES AND IF THEY'RE NOT WORKING AT ALL AND THEY DON'T GET A PARTIAL RESPONSE THEY WILL BE TAKEN OFF THE AGENT AND GIVEN THEM STANDARD TREATMENT WITH R-CHOP OR ERROR ITIKUMAB. THIS IS 1 STUDY OF LYMPHOMA AND IT FITS INTO THE OVERALL PROGRAMMATIC GOALS OF OUR BRANCH WHICH IN THE LYMPHOMA HAVE A NUMBER OF OBJECTIVES. FIRST OF ALL IT IS USING A TARGETED AGENT, SOMETHING THAT IN THEORY SHOULD REDUCE THE ACUTE AND LATE TOXICITIES, THAT'S NOT A PROVEN STRATEGY IT BUT IS CERTAINLY MAKES SENSE BASED ON THE PRINCIPALS OF HOW THESE DRUGS WORK AND IF IT WORKS IN PATIENTS THAT ARE OTHERWISE GOING TO BE RESISTANT TO CHEMO THERAPY, THOSE THAT HAVE THE HIGH RISK BIOLOGY, THEN THAT'S EVEN BETTER. OUR GOAL IS TO CHARACTERIZE THOSE THAT HAVE THE GREATEST RESPONSE TO THE TREATMENT AND THAT'S THIS KEEPING WITH RESCISSION MEDICINE WE WANT TO SUBDISCIPLINARY VIEDMAN PATIENTS INTO THOSE THAT GET BETTER RESPONSES TO DIFFERENT THERAPIES. AND ULTIMATELY OF ERADICATING MINIMAL DISEASE AND IN DOING THIS WITH LONG-TERM TREATMENT. SO 1 OF THE NEWER TECHNOLOGIES WE'VE BEEN APPLYING TO HELP UNDERSTAND THE BIOLOGY OF FOLLICULAR LYMPHOMA AND SPECIFICALLY FOCUSING ON THOSE PATIENTS THAT HAVE THE HIGH RISK BIOLOGY IS THE USE OF SINGLE CELL RNA SEQUENCING, SO ALL OF OUR PATIENTS ON THIS STUDY AND ALL OF OUR PATIENTS ENROLLED IN OUR STUDIES WITH FOLLICULAR LYMPHOMA WILL HAVE TISSUE BIOPSIES TAKEN AND WE WILL BE DOING MOLECULAR PROFILING OF THEIR TUMORS TO INCLUDE RNA SEQUENCING IN BULK BUT 1 OF THE ADVANTAGES OF THE SINGLE CELL RNA SEQUENCING IS WE CAN ACTUAL LYE BREAK THINGS DOWN INTO INDIVIDUAL LYMPHOCYTES, NONLIMO SIGHT POPULATIONS THIS IS SHOWING NORMAL AS WELL AS TUMOR TISSUES, SO WE CAN--SO WE CAN UNDERSTAND THE GENE EXPRESSION @ SINGLE CELL LEVEL AND POTENTIALLY IDENTIFY POPULATIONS OF CELLS THAT ARE CENTERED IN HIGH RISK BIOLOGY OR EVEN POTENTIALLY THOSE THAT ARE MOST LIKELY TO [INDISCERNIBLE] TO PI3 KINASE. OUR EARLY WORK SO FAR AS NOT BEEN YET IN THE CONTEXT OF THIS CLINICAL TRIAL BUT WE'VE BEEN DOING THIS WORK IN PATIENTS WITH FOLLICULAR LYMPHOMA AND FOCUSING ON EMILY NODE BIOPSIES. THIS WORK'S BEEN DONE BY ART SHAFFER AS WE GATHER INSIGHT INTO THE EMILY NOAM POPULATIONS BUT ALSO THE TUMOR MICRO ENVIRONMENT AND HOW THESE 2 THINGS INTERPLAY. AND WHAT WE'VE SEEN SO FAR IS MANY OF THESE CASES EVER LYMPHOMA NOT ONLY ARE THEY DISTINCT FROM NORMALANISM NODES BUT THEY'RE DISTINCT FROM EACH OTHER. SO WE ARE SEEING IN MANY CASES THAT NOT ONLY ARE THESE B-CELLS HIGHLY CLONAL AND THEY CLUSTER IN SEPARATE POPULATIONS BUT THAT MANY TIMES THE EXPRESSION OF THESE B-CELLS, THESE CLONAL B-CELLS ARE NOT SIMILAR TO EACH OTHER AND WE'RE FURTHER INVESTIGATING THIS NOW AND DOG SO IN THE CONTEXT OF THIS TRIAL AS WELL. THE OTHER THING ABOUT FOLLICULAR LYMPHOMA THOUGH THAT HAS BEEN EVIDENT FROM THE ORIGINAL GENE EXPRESSION PROFILING STUDIES IN THE CONTRIBUTION OF THE TUMOR'S MICRO ENVIRONMENT OR CELL EXTRINSIC FACTORS SO WE KNOW THAT FOLLICULAR LYMPHOMA IS 1 OF THE LYMPHOMAS THAT HAS SIGNIFICANT INTERPLAY BETWEEN THE LOCALIZING STROAMAL CELLS, FOLLICULAR DENDRITIC CELLS, MACROPHAGES AND RPGHT T-CELLS, THEY ACTUALLY ARE PROGNOSTIC AND THEY IMPACT UPON CLINICAL BEHAVIOR AND ULTIMATELY KLINEICAL OUTCOMES. IN AN ATTEMPT TO GET AT IT, WE ARE USING--WE ARE DOING A--WE ARE COLLABORATING WITH THE CENTER FOR ADVANCE TISSUE IMAGING LED BY RON GERMANE AND ANDREA, AND WHAT WE'RE DOING IN THESE TUMORS IN HIGH DIMENSIONAL IMAGING OF THE TUMORS MICRO ENVIRONMENT. IT IS FOCUSING ON THE SPATIAL CONTEXT OF THESE TUMORS CALLED THIS METHOD CALLED IBECKS, WHICH IS ITERATIVE BLEACHING MULTIPLEXITY CAN IT IS A CHEMICAL BLEACHING METHOD THAT CAN UP TO 40 OR MORE PROTEINS IN THE SAME TISSUE SECTION USING ANTIBODY STAINING AND THEN IN COMBINATION WITH ADVANCED COMPUTATIONAL TOOLS WE CAN THEREBY DECONVOLUNTEERSUTE THE DIFFERENT CELL POPULATIONS, BASED ON THEIR INDIVIDUAL MARKERS. AND IN DOING THIS, WE ARE BREAKING DOWN THESE SPATIAL ANALYSIS IN COLLABORATION WITH OUTSIDE INVESTIGATORS, TO BETTER UNDERSTAND THE CELL-CELL INTERACTIONS, BETWEEN TUMOR CELLS AND NONTUMOR CELLS, AND THE CELL COMPOSITION AS WELL AS VARIOUS COMMUNITIES AND WHERE THEY ARE ANATOMICALLY LOCATED WITHIN THE TUMOR, AND THIS ULTIMATELY MAY GIVE US SOME INSIGHTS INTO THE TUMORS THAT ARE MOST LIKELY TO BE AGGRESSIVE, AND POTENTIA WILY EVEN MOST LIKELY TO RESPOND IN THIS CASE TO PI3 CAIN ACE AND INHIBITION. ANOTHER TECHNOLOGY THAT IS EMERGING AS A TOOL THAT CAN BE USED COMPLIMENTARY WITH IMAGING TECHNIQUES IS THAT OF CIRCULATING TUMOR DNA, OR THE TUMOR SPECIFIC CONTENT OF CELL-FREE DNA IN FOLLICULAR LYMPHOMA, SO ACROSS ALL CANCERS ESSENTIALLY, AND CERTAINLY LYMPHOMAS THERE'S A LOT OF INTEREST TRYING TO CHARACTERIZE TUMORS BASED ON INFORMATION GLEANED FROM THE PERIPHERAL BLOOD. IN SOME CIRCULATIONS WE'RE TALKING ABOUT CIRCULATING TUMOR CELLS BUT IN MANY DIFFERENT LYMPHOMAS THERE IS NOT A LOT OF TUMOR CELLS. NONAPOPTOTIC YOU IN FOLLICULAR LYMPHOMA THERE'S A LOT OF CASES WITH CIRCULATING TUMOR CELLS AND THIS WORK HERE IS--ECL 2 REARRANGEMENTS WHICH CAN BE DETECTED AT ABOUT 85% OF THESE PATIENTS ARE IN CIRCULATING TUMOR CELLS AND YOU CAN GATHER INFORMATION FROM THAT, USING PC R BASED METHODS TO LOOK FOR BCL, 2, THE PROBLEM IS THAT DOESN'T APPLY TO ALL THE PATIENTS. NOT ALL PATIENTS HAVE AN INFORMATIVE BCL, 2, YOU CAN SEE HERE THAT JUST LOOKING AT PERIPHERAL BLOOD DNA ON THE STUDY, THAT THERE WAS ONLY A SUBSET, MAYBE 75% OF THESE PATIENTS THAT YOU CAN ACTUALLY FIND A BCL 2 MARKER AND IF YOU WANT TO USE THIS AS A NONINVASIVE WAY OF MEASURING FOR MINIMAL DISEASE OR MONITORING THERAPY, YOU WILL MISS A SIGNIFICANT AMOUNT OF PATIENTS. WHERE IF YOU USE PLASMA OR CELL-FREE DNA, THE MAJORITY OF PATIENTS IF NOT ALL PATIENTS ARE GOING TO HAVE AN IDENTIFIABLE BI ONY MARKER. WHAT THIS CAP LANMIER CURVE IS SHOWING IS THAT SIMILAR TO THE METADOLL BOLT-ONTIC TUMOR VOLUME AT BASE LINE, JUST THE SIMPLY THE OVERALL AMOUNT OF CIRCULATING TUMOR-DNA OR CELL-FREE IN THE DNA DOES CORRELATE WITH TUMOR BURDEN AND IT MAY HAVE PROGNOSTIC VALUE AND SO THAT IS AN EXAMPLE OF ANOTHER THING THAT WE'RE LOOKING TO MONITOR HERE. BOTH AS A PROGNOSTIC TOOL TO HELP SELECT PATIENTS WHO ARE MORE AT RISK, BUT AWLS AS A MONITORING TOOL. AND THAT'S WHAT THIS SLIDE IS SHOWING YOU IS THAT 1 OF THE MAIN ADVANTAGES OF SAIRKSS FROM THE PERIPHERAL BLOOD, IN THIS CASE, CIRCULATING TUMOR DNA IS YOU CAN SERIALLY, SO PICKING LANDMARKS AT THE END OF THERAPY, CAN ULTIMATELY USE THESE BLAD SAMPLES TO MONITOR AT THE BEGINNING OTHERS EARLY DURING THERAPY, AT THE END OF THERAPY IF YOU WANT TO USE THEM AS MEASURES OF MINIMAL RESIDUAL DISEASE BUT EVEN THEN AFTER THERAPY IS COMPLETE, WE'VE SHOWN IN THE B-CELL LYMPHOMA THAT THESE ASSAYS AWNCH TIMES WILL BECOME POSITIVE, THEY DETECT A MOLECULAR DEC PRIOR TO THAT, WHAT YOU CAN OTHERWISE SEE CLINICALLY, AND THEN IT BECOMES A USEFUL TOOL TO MONITOR PATE'RE PATIENT WHO IS HAVE STOPPED THERE AND UNDERGOING SURVEILLANCE. SO THIS IS A PRETTY VERSATILE ANALYTE. WE'RE USING IT CROSS MULTIPLE DIFFERENT CLINICAL TRIALS WE HAVE HERE AT THE CLINICAL CENTER. AND WE--WE ARE CURRENTLY WORKING OUT THE METHODS OF THE BEST WAY TO ANALYZE CIRCULATING TUMOR DNA IN THE CONTEXT OF FOLLICULAR LYMPHOMA RECOGNIZING IT MIGHT BE DIFFERENT WHETHER YOU'RE LOOKING AT THE PLASMA SECTION, PLASMA COMPONENT VERSUS TUMOR CELLS IN THE BLOOD, WE DON'T YET HAVE THAT ANSWER BUT IT'S SOMETHING WE THINK WE WILL HAVE ANSWERS SOON ABOUT THE BEST WAY TO USE THIS IN THE CONTEXT OF TREATMENT. SO OUR PATIENT WITH WENT ON THIS CLINICAL TRIAL. WE HAD DISCUSSIONS WITH HIM OF COURSE TO TALK ABOUT STANDARD THERAPIES AND THE OUTCOMES AND ULTIMATELY WHAT THE POTENTIAL DAMAGE WAS FOR THIS TRIAL. CAN YOU SEE, HIS RESPONSE HERE AND THIS IS BASED ON CT RESPONSE SO DR. AHLMAN, SHOWED YOU THE CT RESPONSE WHICH WAS ACTUALLY LESS IMPRESSIVE THAN HIS RESPONSE AS CAPTURED BY THE PET SCAN COMES IN AT AROUND 43%. AAGAIN, AFTER JUST 3 DOSES OF THE MEDICINE OR 1 CYCLE OF THERAPY AND THAT'S ABOUT THE MEDIAN. SO WHAT I'M SHOWING YOU HERE IS THE RESULTS, THAT WILL BE PRESENTED IN A FEW WEEKS AT THE ASH ANNUAL MEETING WHEN WE GIVE 1 CYCLE OF CO PANELISTS OF PATIENTS TO UNTREATED FOLLICULAR EMILY FOAM ACAN YOU SEE THAT ALMOST ALL OF THEM HAVE A REDUCTION IN TD TUMOR BURDEN BUT IT'S--IT'S VARIABLE. SOME PATIENTS AS LITTLE AS 16% AND OTHER PATIENTS HAVE YOU KNOW OVER 60% REDUCTION WITH JUST 1 CYCLE. AND SO FAR, WE ARE NOT SEEING ANYONE WHO'S INTRINSICALLY RESISTANT COMPLETELY TO CO PANELISTS AND THE MEDIAN REDUCTION IS ABOUT 40%. --DIED OF THE COVID INFECTION AND JUST BECAUSE THAT'S ALWAYS ON EVERYONE'S MINDS THESE DAYS THERE ARE 2 PATIENT WHO IS GOT COVID INFECTION ON THE STUDY, THE OTHER PATIENT HAD A MILD ILLNESS. THE REST OF THE PATIENTS ABOVE ARE ON ONGOING WITH THERAPY SO IT'S EARLY TO TALK ABOUT HOW MANY OF THESE PATIENTS WILL GET COMPLETE RESPONSES. AND LASTLY TO SHE YOU AN INTERESTING THING THAT HAPPENED WITH THIS PATIENT. ONE THING THAT YOU IDENTIFY DOING IN CLINICAL TRIALS, YOU FIND THINGS THAT HAVEN'T BEEN DESCRIBED. SO WHAT WE'RE SEEING HERE IS THE PATIENT'S WHITE CELL BLOOD COUNT AS WELL AS ABSOLUTE LYMPHOCYTE COUNT WHICH WAS NORMAL WHEN HE STARTED. HIS TOTAL WHITE COUNT WAS 11,000 AND HE STARTED HIS TREATMENT AND HIS WHITE COUNT WENT SHOOTING UP TO ABOUT 25,000. OF COURSE WHEN YOU SEE SOMETHING LIKE THAT AND YOU KNOW PATIENTS HAVE FOLLICULAR LYMPHOMA IN THE BLOOD, YOU GET NERVOUS, PERHAPS THE PATIENT'S PROGRESSING BUT WE SHOWED YOU THE SCAN WHERE HE HAD A REDUCTION IN HIS TUMOR CELLS IN HIS BI-PET KAN--KANA AND THESE WERE HIS FOLLICULAR LYMPHOMA CELLS IN HIS BLOOD AND THIS BECOMES A FETAL COMPARTMENT NONE NONE THAT'S DESCRIBED IN THE LITERATURE WHEN YOU GIVE THESE BCELL RECEPTOR PATHWAYS THAT YOU WILL SEE A REDISTRIBUTION 1 COMPARTMENTS AND LYMPHNODES WILL SHRINK WHILE DISEASE GOES UP IN THE BLOOD NOT REPRESENTING DISEASE PROGRESSION BUT SIMPLY REPRESENTING A DIFFERENT PHENOMENON THAT HAS TO DO WITH THE NATURE OF THE AGENT YOU'RE USING AND THAT'S WHAT WE THINK WE SAW HERE, IT'S NOT YET DESCRIBED IN DETAIL IN FOLLICULAR LYMPHOMA BUT OF COURSE IT MAKES SENSE WE WOULD SEE SIMILAR THINGS WITH SIMILAR AGENTS. SO IN CONCLUSION, WE'RE INTERESTED IN STUDYING FROM THE BEGINNING ALL THE WAY THROUGH FIRST TREATMENT. WE'RE INTERESTED IN DEVELOPING NEWER THERAPIES FOR PATIENTS WITH UNTREATED FOLLICULAR LYMPHOMA AND WE KNOW THERE'S A LOT OF CHOICES SO THE FOCUS HERE IS TO DEVELOP AGENTS AND REGIMENS THAT ARE HIGHLY EFFECTIVE BUT POTENTIALLY HAVE LESS TOXICITY BOTH IN THE SHORT-TERM AND LONG-TERM. WE THINK ABOUT THIS IN THE CONTEXT OF PRECISION MEDICINE, WE'RE HIGHLY FOCUSED AT THIS POINT ON THE ROLE OF PI3 KINASE INHIBITORS AND SPECIFICALLY WE WANT TO TRY TO IDENTIFY PREDICTIVE SIGNATURES SO WE CAN ISOLATE THE PATIENTS MOST LIKELY TO BENEFIT FROM THOSE AND THEY CAN BE PRIORITIZED FOR FUTURE TRIALS AND WE ARE ALSO INTERESTED IN COLLABORATIONS BOTH WITH THE CENTER FOR ADVANCED TISSUE IMAGING AS WELL AS RADIOLOGY COLLEAGUES WITH DEVELOPING BETTER IMAGING TOOLS TO UNDERSTAND HOW THESE DISEASES ARE BETTER CHARACTERIZED IN THE BEGINNING BUT ALSO DURING THERAPY AND OF COURSE WE'RE HEAVILY INVESTED IN THESE ASSAYS CIRCULATING TUMOR DNA BECAUSE WE THINK THOSE ARE THE FUTURE AND THE WAY WE WILL ULTIMATELY BE MONITORING RESPONSE AND ASSESSMENT IN THE FUTURE. SO OF COURSE THERE'S A NUMBER OF OTHER PEOPLE WE COLLABORATE WITH BOTH WITHIN OUR BRANCH. WE HAVE A CLOSE RELATIONSHIP WITH OUR PATHOLOGISTS AND A NUMBER OF DIFFERENT COLLABORATORS ACROSS THE SPECTRUM ON THIS STUDY AND OTHERS THAT DESERVE MENTION FOR HELPING US IN THIS STUDY AS WELL AS MULTIPLE STUDIES WE DO WITH THE NIH. AND WITH THAT, THAT'S OUR PRESENTATION, WE WILL BE HAPPY TO TAKE ANY QUESTIONS. >> THANK YOU MARK AND EVERYONE ELSE. THIS WAS AN EXCELLENT PRESENTATION AND VERY ENLIVENING FOR WHAT THE FUTURE LOOKS LIKE IT WILL BE TAYLORED TO PERSONALIZE MEDICINE. LET ME VERY QUICKLY REMIND THE AUDIENCE ABOUT THE CME ACTIVITY CODE TODAY IT'S 30913, AND YOU CAN TEXT THIS TO THE HOPKINS CME PHONE NUMBER WHICH IS SHOWN ON THE SCREEN NOW. IT'S (443)541-5052. SO WE HAVE SOME QUESTIONS, WE HAVE 5 OR 6 MINUES TO GO THROUGH THEM. SO 1 QUESTION MARKER CAME THROUGH THE CHAT WAS WHAT WERE THE CHANGES IN SUV ON PET AFTER THE FIRST WINDOW IN THIS PATIENT AND HOW DID THAT COMPARE WITH THE CHANGES IN THIS PARTICULAR PATIENT? IN GENERAL ALSO YOU CAN COMMENT ON THE PET RESPONSES OVER CT RESPONSES IN THE [INDISCERNIBLE]? >> YEAH, SO-- >> IT DEPENDS WHERE YOU MEASURE. IF YOU MEASURE IN THE NECK THE SUV MAX WOULD HAVE GONE DOWN BY 50% BUT I DIDN'T ACTUALLY PUT THAT IN REFERENCE TO THE METABOLIC TUMOR VOLUME DECREASE OR THE TLG. SO THE--BUT IT DEPENDS ON WHERE YOU PICK THE LESION, SOMEWHERE IN THERE THAT IS JUST ABOUT AS HOT AS IT WAS AT BASE LINE, SO THAT'S ANOTHER REASON WHY WE DON'T LIKE IT AS MUCH WITH THESE OTHER THINGS WE CAN AVERAGE OUT THE NOISE THAT COMES FROM THAT. >> WOULD IT BE FAIR TO STATE THAT THE--THE METABOLIC PET ACTIVITY KIND OF READ OUT MIGHT BE THE WAY TO EVENTUALLY GO IN THE FUTURE I THINK 1 OF THE CONFOUNDER SYSTEM 1 AND THIN DOWN LATER ON AS THE TUMOR IS REGRESSING SO THAT'S PART OF WHAT THE DOCTOR UNDERSTANDS ABOUT THIS IS THE REASON THEY'RE DOING THE CLOSE ISHT VALENTINED IMAGING IS TO TRY TO FIGURE IT OUT. AND FROM MY PERSPECTIVE AT THIS POINT, THE PET SCANS HAVE BEEN MOST APPLICABLE AS A QUALITATIVE TEST. YOU KNOW WHETHER IT'S POSITIVE OR NEGATIVE AND WE'RE REALLY JUST LEARNING HOW TO USE THEM QUANTITATIVELY. IRB MEAN THEY WERE ONLY REALLY DESIGNED AS A SEMIQUANTITATIVE TEST BUT THERE ARE THESE NEW OPPORTUNITIES TO USE THEM IN A FASHION PARTICULARLY WHEN YOU GET NUANCED ABOUT RESPONSES AND THAT'S WHAT WE'RE TALKING ABOUT. >> ANOTHER QUESTION RELATED TO THESE 10 PATIENTS THAT HAVE BEEN NOW [INDISCERNIBLE]. HOW DID THEY TOLERATE IT, FROM A PREDICTABLE [INDISCERNIBLE]. >> WE PROVIDE THAT DATA IN ABSTRACT FORM AT THE ASH MEETING BUT QUITE WELL. SO AT THIS .1 OF THE THINGS AND WE SAW IN THIS PATIENT, I SHOWED YOU HIS LYMPHOCYTE COUNT SHOOTING UP, HE HAD A DRAMATIC RASH AND WE'VE SEEN IN MOST CASES THAT THEY GET A RASH, NOW WHAT'S HAPPENING NOW, I THINK IS BECAUSE WE'RE GIVING THESE AGENTS IN A SITUATION WHERE THEY HAVE AN INTACT IMMUNE SYSTEM, THIS RASH MAY BE AN EPIPHENOMENON AND NOT NECESSARILY A TOXICITY. IT COULD THAT WE'RE RELEASING THESE T-CELLS INTO THE BLOOD AND YOU'RE SEEING THAT MANIFEST IN THE WAY--IN THE FORM OF RASH THAT'S BEEN SEEN WITH OTHER TARGET INHIBITORS IN OTHER SETTINGS AND THAT'S MY SENSE THAT WE'RE SEEING THAT HERE. I SAY THAT BECAUSE WITH CONTINUED DOSING THAT RASH DOESN'T CONTINUE. IT SEEMS TO BE CONCENTRATED IN THE EARLY FORMS. SO, NO PATIENT HAS HAD TO STOP TREATMENT BECAUSE OF TOXICITY, WE'VE SEEN A NUMBER OF RASHES THAT ARE EASILY MANAGED, AND THE SAME THING COULD BE SAID OF DIARRHEA YOU ABOUT THAT ALSO QUITE EASILY MANAGED SO OTHER THAN THAT, 1 PATIENT THAT HAD THE COVID INFECTION, WHICH WAS VERY UNFORTUNATELY, WE LEGAL HAVEN'T HAD MUCH IN THE WAY OF TOXICITY