Christopher R. Flowers, MD, MS
9/12/20121Christopher R. Flowers, MD, MSAssociate Professor of Hematologyand Medical OncologyWinship Cancer InstituteEmory University School of MedicineAtlanta, Georgia21
9/12/2012Anyone can get blood cancerOne million North Americans affected per year2012 Estimated New Cancer Cases in United 9%Lung & bronchus116,47014%Lung & bronchus109,69014%Colon & rectum73,4209%Colon & rectum70,0409%Urinary bladder55,6007%Uterine corpus47,1306%Melanoma of skin44,2505%Kidney & renal pelvis40,2505%Thyroid43,2105%Non--Hodgkin lymphoma 38,160Non4%Melanoma of skin32,0004%Oral cavity & pharynx3%Non--Hodgkin lymphoma 31,970Non4%24,5203%28,540Leukemia26,8303%Kidney & renal %ALL SITES848,170100%ALL SITES790,740 100%CA: A Cancer Journal for Clinicians, Vol. 62, January/February 2012.Lymphomas/Chronic Lymphocytic Leukemia Cancers of the cells of theimmune system: Lymph system Classified by source of thecancer cell The causes for mostlymphomas and CLL areunknown Usually start in the lymphnodes, but can involve tissuesin the spleen, skin, GI tract,liver, bone marrow, or othersites May spread to these areas2
9/12/2012Common Symptoms63 yo man over the last 3 months: Feeling worn down, unable to go to work Sweats at night Lost 17 lbs Noticed a lump in his groin that keepsgetting bigger Now has lumps under left arm and left necktooFeels itchy all overCommon Symptoms painless swelling of the lymph nodes Nodes are movable and nontender Unexplained fever Night sweats Unexplained weight loss ( 10% body weight) Constant fatigue ETOH causes immediate pain @ involvedsite. Itchy skin Reddened patches on the skinB Symptoms3
9/12/2012Diagnostic Evaluation Medical HistoryPhysical examLaboratory:Complete Blood Count (CBC), Metabolic Panel Lactate Dehydrogenase (LDH), B2 Microglobulin Lymph Node BiopsyComputed Tomography (CT) scanPositron Emission Tomography (PET)Bone Marrow BiopsyWHO ClassificationB-cellT-cell/NK-cell Precursor B-cell neoplasms Precursor T-cell neoplasm B-acute lymphoblastic leukemia (B-ALL) Lymphoblastic lymphoma (LBL) Peripheral B-cell neoplasms Precursor T-acute lymphoblastic leukemia (T-ALL) Lymphoblastic lymphoma (LBL) Peripheral T-cell/NK-cell neoplasms B-cell chronic lymphocytic leukemia/smalllymphocytic lymphoma T-cell chronic lymphocytic leukemia/prolymphocyticleukemia B-cell prolymphocytic leukemia T-cell granular lymphocytic leukemia Lymphoplasmacytic lymphoma/immunocytoma Mycosis fungoides/Sézary syndrome Mantle cell lymphoma Peripheral T-cell lymphoma not otherwisecharacterized Follicular lymphoma Extranodal marginal zone B-cell lymphoma ofMALT type Hepatosplenic gamma/delta T-cell lymphoma Nodal marginal zone B-cell lymphoma Extranodal T-/NK-cell lymphoma, nasal type Splenic marginal zone lymphoma Enteropathy-type intestinal T-cell lymphoma Hairy cell leukemia Adult T-cell lymphoma/leukemia (HTLV1 ) Plasmacytoma/plasma cell myeloma Anaplastic large cell lymphoma, primary systemic type Diffuse large B-cell lymphoma Anaplastic large cell lymphoma, primarycutaneous type Burkitt’s lymphoma Angioimmunoblastic T-cell lymphoma Aggressive NK-cell leukemiaFisher et al. In: DeVita et al, eds. Cancer: Principles and Practice of Oncology. 2005:1967.Jaffe et al, eds. World Health Organization Classification of Tumours. 2001.4
9/12/2012Excisional Biopsy aidsimproves accurate diagnosisLymph NodeAfferent LymphaticMarginal Zone VesselMantleZoneGerminal CenterPrimary ortexMedullaryCordMedulaMedullarySinusCourtesy of Thomas Grogan, MDEfferentLymphatic Vessel5
9/12/2012Ann Arbor Staging SystemI.Involvement of 1 lymph node (I) or 1 extralymphatic organor site (IE)II. Involvement of 2 lymph nodes on same side of diaphragmor localized extralymphatic organ or site and 1 involvedlymph node on same side of diaphragm (IIE)III. Involvement of lymph nodes on both sides of diaphragm (III)or same side with localized involvement of extralymphaticsite (IIIE), spleen (IIIS), or both (IIIS E)IV. Diffuse or disseminated involvement of 1 extralymphaticorgan or tissues with or without lymph node enlargementWHO ClassificationB-cellT-cell/NK-cell Precursor B-cell neoplasms Precursor T-cell neoplasm B-acute lymphoblastic leukemia (B-ALL) Lymphoblastic lymphoma (LBL) Peripheral B-cell neoplasms Precursor T-acute lymphoblastic leukemia (T-ALL) Lymphoblastic lymphoma (LBL) Peripheral T-cell/NK-cell neoplasms Chronic lymphocytic leukemia/smalllymphocytic lymphoma T-cell chronic lymphocytic leukemia/prolymphocyticleukemia B-cell prolymphocytic leukemia Mycosis fungoides/Sézary syndrome Lymphoplasmacytic lymphoma/immunocytoma Mantle cell lymphoma Peripheral T-cell lymphoma not otherwisecharacterized Follicular lymphoma Hepatosplenic gamma/delta T-cell lymphoma Extranodal marginal zone B-cell lymphoma ofMALT type Angioimmunoblastic T-cell lymphoma Nodal marginal zone B-cell lymphoma Enteropathy-type intestinal T-cell lymphoma Splenic marginal zone lymphoma Adult T-cell lymphoma/leukemia (HTLV1 ) Hairy cell leukemia Anaplastic large cell lymphoma, primary systemic type Plasmacytoma/plasma cell myeloma Anaplastic large cell lymphoma, primarycutaneous type Diffuse large B-cell lymphoma T-cell granular lymphocytic leukemia Extranodal T-/NK-cell lymphoma, nasal type Aggressive NK-cell leukemia Burkitt’s lymphomaFisher et al. In: DeVita et al, eds. Cancer: Principles and Practice of Oncology. 2005:1967.Jaffe et al, eds. World Health Organization Classification of Tumours. 2001.6
9/12/2012Diffuse Large B-Cell Lymphoma Most common NHL: 31%Average survival: weeks to months ifnot treatedCurable in 50% or more of casesClinical outcomes highly variable 30% to 40% present with rapidly enlarging, mass with B symptomsMay present outside of lymph nodes (stomach, brain, skin, other) Large cells with diffuse growth pattern (loss of follicule structure) Michallet AS, et al. Blood Rev. 2009;23:11-23.DLBCL Management StrategyInitial Therapy Non-bulky/bulky ( 10 cm) with adverse factors 3 RT 6-8 RT– R-CHOP 6-8– R-CHOPAdditional Therapy– R-CHOP Candidate for high-dosetherapy1D– ASCTRT2 High-dose Tx with ASCTPRL Clinical trialBCL– Novel non–crossresistantregimenrituximabStage I, IIFollow-up TherapyStage III, IV AA-IPI Continue R-CHOP to 6-8 orCR/PR Clinical trial R-CHOP 6-8 Clinical trial1.When RT is contraindicated.PD involved field– Clinical trial2 Not candidate for highdose therapy– Clinical trial– Rituximab – CEPPRituximab(PO and IV)– PEPC (PO)– EPOCH2. In patients achieving CR or PR after second-line therapy AA-IPI age-adjusted IPI. NCCN Practice Guidelines in Oncology, v.3.2010.7
9/12/2012Advances in Treatment ImproveSurvival for Patients with LymphomaOverall BMACOP806040At Risk Deaths 3-year OS8822554%CHOP9352%m-BACOD 2239750%P-CytaBOM 2339350%MACOP--B 218MACOP20CHOPR-CHOPSurvival ProbabilityPatients(%) Alive1000.80.60.40.2P .0004000246012Years after randomization345678YearsCoiffier B, et al. N Engl J Med. 2002.Fisher RI, et al. N Engl J Med. 1993Coiffier B, et al. ASCO 2007. Abstract 8009.Genetic Testing Identifies Biologic andClinically Different Types of DLBCLGenesDiffuse Large B- CellLymphomaLymphoma Biopsies8
9/12/2012Gene Expression Defines Molecularlyand Clinically Distinct Subgroupsin DLBCLDiffuse Large BCell LymphomaDLBCLSubgroupPMBL1.0OS0.85-Yr OS, %640.60.4GCB DLBCL590.2ABC DLBCL3000246810YrsGCB vs Non-GCB Subtypes of DLBCL:Using Pathology StainsLYMPHOMA SUBTYPECD 10 CD 10–GCBbcl-6 –non-GCBCD 10–bcl-6 MUM1 non-GCBCD 10–bcl-6 MUM1–GCBHans et al. BloodBlood. 2004;103:275.9
9/12/2012Using DLBCL Biological Subtypeto Choose TreatmentHans AlgorithmStainsCD 10 CD 10–GCBbcl-6 –non-GCBCD 10–bcl-6 MUM1 CD 10–bcl-6 MUM1– LYMPHOMASUBTYPEnon-GCBGCBRANDOMIZEArm A (N 150) Bortezomib, days 1,4R-CHOP 21 X 6 cyclesArm B (N 150) R-CHOP 21 X 6 cyclesPatients: 300, non-GCB DLBCL (by IHC)Primary Endpoint: PFS at 1 year; 80% power to detect an increase from 67% to 78%10
9/12/2012Finding Causes for LymphomaFollicular Lymphoma (FL) Most common indolent NHL, accounts for 22%-25% ofNHL in North America Variable presentation and prognosis, but typically advancedstage at presentation Often asymptomatic Multiple therapies: no standard, how best to sequenceAdvanced stage FL not curable with standard therapyMedian survival was about 10 years, but has increased withnew treatmentsMany new therapies in developmentFollicular LymphomaAccelerated10% to 15%Indolent40% to 65%Transformation20% to 60%Modified from Skarin AT, Dorfman DM. CA Cancer J Clin. 1997;47:351-72.11
9/12/2012Overall Survival According to FLIPI:Clinical Prognosis Factors1.0Survival probabilityNo Nodal regions 4L LDH increasedA Age 60S Stage III/IVH Hemoglobin 120 g/LLow riskIntermediate risk0.80.6High risk0.40.20p 10-401234567YearsRisk GroupNo. of Factors% of Pts5-y OS (%)10-y OS diateHigh23Adapted from Solal-Celigny P, et al. Blood. 2004;104:1258-65.A Management Approach for FLInitial EvaluationLocalized DiseaseFirst-lineTherapyIF/extended field XRTRituximab chemoRTObserve (selected cases) Advanced stageLow tumor burdenObservationAdvanced stageHigh tumorburdenIndividualized therapyClinical TrialRituximabchemoPalliative XRT RTMaintenance / ConsolidationInitial Relapse / 2nd Relapse2412
9/12/2012Criteria for Initiation of Treatment:Indolent NHLGELF NCCN 3 nodal sites each with diameter 3 cmAny nodal/extranodal mass withdiameter 7 cmB symptoms (fevers, night sweats,weight loss)Enlarged spleenPleural effusions/ascitesWBC 1.0 x 109/L or platelets 100 x 109/LLeukemia ( 5.0 x 109/L malignantcells) GELF criteriaSymptoms (fatigue, pain,fevers.)Threatened end-organ function/compressive syndromeSteady progressionElevated LDH or β2microglobulinPatient preferenceJ Natl Compr Canc Netw. 2010 8(3):288-334.25Rituximab (R) Compared with a “Watch andWait” Strategy in Patients with Stage IIII-IVAsymptomatic, Nonbulky FLStrategyObserveR x 4 weeksR x 4 weeks------R q 2 mos. x 2 yearsNumber18784192CR/PR (%)2/343/3054/333-year PFS33%60%81%33 monthsNot reachedNot reachedMaintenanceTime to next treatment Patients had: stage II–IV, asymptomatic, non-bulky low-grade FLImproved PFS in rituximab arms (p 0.001)Time to initiation of new treatment in the rituximab arms 33 months vs. not reached at 4 years (p 0.001)No difference in OS (p 0.5)Quality of life no differentArdeshna KM, et al. ASH 2010. abstr 6 (oral, Plenary Session).2613
9/12/2012Adding Rituximab to Front-Line Chemofor High Tumor Burden FL ImprovesResponse Rates & SurvivalOverallSurvival%Complete Response%Endpoint, 0150*25487*741. Hiddemann et al. Blood. 2005;106(12):3725-3732. 2. Salles et al. Blood. 2008;112(13):4824-4831. 3. Marcus et al. J Clin Oncol.2008;26(28):4579-4586. 4. Herold et al. J Clin Oncol. 2007;25(15):1986-1992.Rituximab Maintenance vs Observation in FLGELA PRIMA Phase III StudyCHOP x 6 Rituximab x 8Patients withpreviouslyuntreatedgrade 1-3 FL(N 1200)CVP x 8 Rituximab x 8Maintenance Rituximab375 mg/m2 q2m x 2 yrsCR, PRObservationFCM x 6 Rituximab x 8Primary endpoint: PFSSecondary endpoints: EFS, OSProgression-Free RatePROGRESSION-FREE SURVIVAL1.0Rituximab maintenance(n 505)82%0.80.666%0.40.20Observation(n 513)Stratified HR: 0.5095% CI: 0.39-0.64P 0.000106Salles et al. Lancet. 2011;377:42-51.122418Months30362814
9/12/2012Relapsed Follicular Lymphoma All patients eventually relapseConsiderations for retreatment Is treatment currently needed? (GELF, BNLI, NCCN) What previous therapies were given?–How well did they work? What is the current clinical situation?–Patient age / comorbidities–Disease-related symptoms–Tumor burden–Prognostic factors (eg, LDH, β2M2M) Patient’s goals Options Chemo Rituximab Radioimmunotherapy High dose CT SCT Novel agent29Recurrent Follicular Lymphoma:Recommended Treatment Conventional strategies Novel strategies Rituximab Novel monoclonalmaintenanceantibodies Chemoimmunotherapy Bortezomib maintenance Bendamustine Radioimmunotherapy Lenalidomide External-beam Othersradiotherapy Clinical trial Autologoustransplantation AllogeneictransplantationNCCN. Availableat: http://www.nccn.org/professionals/physician gls/PDF/nhl.pdf.3015
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9/12/2012CLL Staging SystemsRaiFindingsSurvival (mo)0 Lymphocytosis only 120I Lymphocytosis lymphadenopathy95II Lymphocytosis spleen and/or liver72IIILymphocytosis anemia (Hgb 11.0 g/dL)30IV30Lymphocytosis platelets 100BinetFindingsSurvival (mo)AHgb 10, Plts 100, 3 involved areas* 120BHgb 10, Plts 100, 3 involved areas*84CHgb 10, or Plts 10024*Involved areas include cervical, axillary, or inguinal nodes, spleen, or liver.Rai KR, et al. Blood. 1975;46:219-234; Binet JL, et al. Cancer. 1981;48:198-206.Chronic Lymphocytic LeukemiaOverall Survival in Monthsby Stage and Year of DiagnosisRai StageCharacteristicOriginal Report1975(N 125)Mayo Clinic1995-2009(N 2397)0Lymphocytosis IIIHemoglobin 11 g/dL1958IVPlatelet 100 x 109/L1969Rai KR, et al. Blood. 1975;46:219-234;Shanafelt TD. Hematology Am Soc Hematol Educ Program. 2009;421-429.19
9/12/2012Previously Untreated CLLTreatment Options1960s1970sAlkylating agents- Chlorambucil- Cyclophosphamide (C)1980sPurine nucleosides- Fludarabine (F)- Pentostatin- Cladribine1990s2000sPurine nucleosidesand alkylatorsChemo-immunotherapyAlemtuzumabRituximab (R)Bendamustine (B)Traditional Prognostic Factors Advanced stage at diagnosis Short lymphocyte doubling time Diffuse bone marrow infiltration Older age, males Cytogenetic abnormalitiesRozman C, Montserrat E. N Engl J Med. 1995;333:1052-1057;Cheson BD, et al. Blood. 1996;87:4990-4997.20
9/12/2012Newer Prognostic Factors FISH defects– 17p deletion– 11q deletion– 12q trisomy– Normal– 13q deletionsUnfavorableHierarchyFavorable Immunoglobulin heavy chain variable region (IgVH) - 2% mutation unmutated– Survival 7.5 years for unmutated vs 27 years for mutated CD38 status ( 30% poor outcome) ZAP-70 status ( 20% poor outcome) High serum β2-microglobulin and soluble CD2341Newly Diagnosed and Relapsed /Refractory CLL PatientsInitial DiagnosisStage DeterminationPrognosticDeterminationFrontline ucil-Rituximab-Bendamustine-Alemtuzumab-Clinical lidomide-Ofatumumab-Clinical Trial*Large phase III trials lacking for most ofthese approaches.21
9/12/2012New Side Effects with New Therapies:Tumor Flare ReactionOccasional FeverBone pain WBC / ALCBaselineFlare reactionPost-treatmentPatient-Clinician Communication Use communication approaches tailored to individualpatient needs according to health literacy and numeracy,living circumstances, language barriers and decisionmaking capacity. Receive/Provide clear written instructions about whenand how to contact healthcare practitioners. Recognize that coordination of care among providersis essential for high quality care Receive/Give written and/or electronic copies ofmanagement plans22
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9/12/2012 7 Diffuse Large B-Cell Lymphoma Michallet AS, et al. Blood Rev. 2009;23:11-23. Most common NHL: 31% Average survival: weeks to months if
edible flowers is important. Use flowers that are grown without pesticides. For best flavor, use flowers at their peak. Introduce new flowers into the diet slowly to be able to pinpoint allergic reactions or stomach upset. Edible flowers also may be preserved in oils or vinegars. 2. (-#)(þ )&)-. . þ / 4 Z aMQ EcMcRG]WeRabWch6gcR]bW ]\ ª .
So many uses! Flowers are even eaten! What are the different ways we use flowers in our daily life? Do you know that flowers can be eaten as well? Many flowers are cooked as vegetables. In Uttar Pradesh, Firoza and Nilima enjoy eating a vegetable made of kachnar flowers. In Kerala, Yamini wants her mother to cook her a vegetable made of banana .
Fruits Paired red, orange, or yellow fleshy berries. Flowers Tubular, paired flowers with flaring petals. Flowers form in the spring at the points where leaves meet the stem. Color ranges from white to yellow to pink to rose. Flowers Small, four-parted greenish-yellow flowers form in leaf axi
Annual flowers are a cheerful addition to the garden and containers. Unlike perennials, annual flowers bloom for a long period and will provide color for most of the summer. Annual flowers live to bloom. You can say they have "flower power"! While you can buy annual flowers from a garden center, growing plants from seed is extra special.
DRYING FLOWERS Fall is a good time to begin drying flowers, seedpod and ornamental grasses for later use in indoor arrangements. Steps to follow: 1. Gather the flowers at midday when the humidity is lowest. Pick some buds as well as flowers almost at peak bloom. Avoid fully opened flowers as they do not last long when dried. 2.
The early death of flowers is a common cause of quality loss and reduced vase life for cut flowers. Flowers can be divided into several categories in terms of their senescence. Some flowers are extremely long-lived, especially in the daisy and orchid families. Others are short-lived, including many of the bulb crops, like tulip, Iris, and .
The developed flower market in the country during 2005 is with area of 2.24 lakh ha with a production of 6.54 lakh MT loose flowers and 19,515 lakh cut flowers. The traditional flowers are grown on a large area on a commercial scale. These flowers are mostly grown for loose flower purpose.
Fairness in Flowers Word Find p. 27 28 Endnotes & Credits 1 Fairness in Flowers Toolkit International Labor Rights Forum. introduction Flowers. We give them to our loved ones as acts of appreciation, compassion, and kindness. A flower has the power to brighten a person’s day and fill a person
