Cancer Assciatin f Suth Africa (CANSA) Fact Sheet n Adult Acute Prmyelcytic Leukaemia (APL) Intrductin Acute prmyelcytic leukaemia (APL) is a frm f cancer that affects the stem cells which prduce myelid bld cells in the bne marrw. Myelid cells are red bld cells, platelets and all white cells except lymphcytes. APL is a sub-type f acute myelid leukaemia and accunts fr abut 10% f this frm f leukaemia. APL is smetimes referred t as AML M3. There is als a less cmmn frm called variant APL, which may be described as M3v. Unlike ther frms f acute myelid leukaemia there are n significant differences in the way APL is treated in children r in adults. [Picture Credit: Karytype] APL is assciated with a very specific abnrmality in which parts f chrmsmes 15 and 17 are swapped ver. This is called t(15;17) - the 't' stands fr translcatin, which means the swapping ver f parts f tw chrmsmes. This jins parts f a gene frm each chrmsme t prduce a fusin gene called PML/RARα which appears t directly cause many f the features f the disease. Treatment with a drug called ATRA (All-Trans Retinic Acid), which targets the PML/RARα abnrmality, has prved very successful. There are ther less cmmn fusin genes which can cause APL; which fusin gene is invlved influences the way the disease behaves and which treatments may be effective. In APL the abnrmal cells are white bld cells f the neutrphil type. Immature cells knwn as prmyelcytes accumulate in the bne marrw. These are unable t mature (differentiate) prperly leading t a significant reductin f nrmal white bld cells in the circulatin. The accumulatin f immature cells in the marrw als prevents prductin f ther cell types resulting in anaemia and lw platelet cunts. Leukaemia cells tend t spill-ver int the bldstream, which is when they can be picked up by a bld test, leading t a diagnsis in mst cases. (Leukaemia & Lymphma Research; Genetics Hme Reference). March 2017 Page 1
Acute Prmyelcytic Leukaemia Acute prmyelcytic leukaemia (APML, APL) is a subtype f acute myelgenus leukaemia (AML), a cancer f the white bld cells. In APL, there is an abnrmal accumulatin f immature granulcytes called prmyelcytes. The disease is characterised by a chrmsmal translcatin invlving the retinic acid receptr alpha (RARα r RARA) gene and is distinguished frm ther frms f AML by its respnsiveness t all-trans retinic acid (ATRA; als knwn as tretinin) therapy. [Picture Credit: Chrmsmal Translcatin] APL represents a medical emergency with a high rate f early mrtality, ften due t haemrrhage frm a characteristic cagulpathy (abnrmal bld cagulatin). It is critical t start treatment with a differentiatin agent (e.g., all-trans retinic acid) withut delay as sn as the diagnsis is suspected based upn cytlgic criteria, and even befre definitive cytgenetic r mlecular cnfirmatin f the diagnsis has been made. Acute prmyelcytic leukaemia was first described as an entity in the late 1950s in Nrway and France as a hyperacute fatal illness assciated with a haemrrhagic syndrme. In 1959, Jean Bernard, et al. described the assciatin f APL with a severe haemrrhagic diathesis (a cngenital, ften hereditary, predispsitin f the bdy t a disease) that lead t disseminated intravascular cagulatin (DIC) and hyperfibrinlysis. By 1973, there were reprts f cmplete remissins with treatment f the disease by daunrubicin. In 1974, Le Sachs pineered research n leukaemic cell differentiatin in viv. Dr. Zhen Yi Wang, a Chinese haematlgist, shared data n the efficacy f all-trans retinic acid (ATRA) in acute prmyelcytic leukaemia (APL) patients during a visit t France in 1985. There were several publicatins in 1990 that linked a translcatin between chrmsmes 15 and 17 t the pathlgy f APL. In the early t mid 1990s, arsenic trixide (ATO) was added t the treatment f APL. A ptentially fatal cmplicatin f ATRA treatment, called retinic acid syndrme, was als described. Over the past 50 years, acute APL has transfrmed frm a highly fatal disease t a highly curable disease. (Medscape; Uptdate). What Other Names Peple Use fr Acute Prmyelcytic Leukaemia The fllwing are all names used when referring t acute prmylecytic leukaemia: AML M3 APL leukaemia, acute prmyelcytic M3 ANLL myelid leukaemia, acute, M3 (Genetics Hme Reference). March 2017 Page 2
Incidence f Adult Acute Prmyelcytic Leukaemia in Suth Africa In prviding the incidence figures f Leukaemia in Suth Africa, The Natinal Cancer Registry (2012) des nt make prvisin fr the reprting f the different types f Leukaemia it als des nt differentiate between acute and chrnic Leukaemia - neither des it prvide fr different statistics fr cases f adult and childhd Leukaemia. Accrding t the Natinal Cancer Registry (2012) the fllwing number f Leukaemia cases was histlgically diagnsed in Suth Africa during 2012: Grup - Males 2012 Actual N f Cases Estimated Lifetime Risk Percentage f All Cancers All males 380 1:502 1,03% Asian males 11 1:666 1,34% Black males 201 1:762 1,73% Clured males 42 1:452 0,97% White males 126 1:232 0,63% Grup - Females 2012 Actual N f Cases Estimated Lifetime Risk Percentage f All Cancers All females 285 1:955 0,76% Asian females 5 1:1 777 0,47% Black females 160 1:1 409 0,97% Clured females 49 1:440 1,17% White females 72 1:480 0,45% The frequency f histlgically diagnsed cases f Leukaemia in Suth Africa fr 2012 was as fllws (Natinal Cancer Registry, 2012): Grup - Males 2012 0 19 20 29 30 39 40 49 50 59 60 69 70 79 80+ All males 88 29 38 42 50 54 54 20 Asian males 3 1 0 0 1 2 2 2 Black males 67 21 25 20 20 23 13 3 Clured males 6 2 5 1 8 6 8 4 White males 12 5 6 18 18 23 30 11 Grup - Females 2012 0 19 20 29 30 39 40 49 50 59 60 69 70 79 80+ All females 63 19 24 34 42 37 31 20 Asian females 0 1 1 2 1 0 0 0 Black females 40 18 27 16 22 11 12 6 Clured females 10 4 3 3 5 13 5 5 White females 12 3 1 6 14 12 14 9 N.B. In the event that the ttals in any f the abve tables d nt tally, this may be the result f uncertainties as t the age, race r sex f the individual. The ttals fr all males and all females, hwever, always reflect the crrect ttals. Signs and Symptms f Prmyelcytic Leukaemia There are n specific symptms f acute prmyelcytic leukaemia (APL) and the cnditin can be cnfused with ther cmmn illnesses. In general APL develps very quickly and the symptms appear ver a matter f days r weeks. Cmmn symptms include: Unusual bleeding and bruising March 2017 Page 3
Paleness Tiredness and breathlessness Frequent and persistent infectins These are caused by a lack f healthy red and white cells and platelets in the bld. Bleeding is a serius symptm f APL and needs immediate medical attentin. Other less cmmn symptms include: Bne pain due t a build-up f cancer cells in the bne marrw Swllen glands due t a build-up f cancer cells in the lymph ndes Abdminal pain due t a swllen liver r spleen Sme peple with APL may als develp small lumps n their skin, called chlrmas, but this is very uncmmn. These frm when leukaemia cells cluster under the skin. Very few peple experience symptms such as dizziness and bad circulatin. This happens when leukaemia cells interfere with the bld supply t the central nervus system. Peple with APL may experience all, r just sme, f these symptms. (Leukaemia and Lymphma Research). Can Acute Prmyelcytic Leukemia be Inherited? Acute prmyelcytic leukaemia is nt inherited but arises frm a translcatin in the bdy's cells that ccurs after cnceptin. (Genetics Hme Reference). Clinical Presentatin f Acute Prmyelcytic Leukaemia Mre than 50 percent f all APL patients have prnunced cagulatin disrders including a high risk f life-threatening intracerebral haemrrhages as well as bleeding int the skin, the mucus membranes, the gastrintestinal tract, and the lungs referred t as DIC (disseminated intravascular cagulatin). The bleeding tendency depends n the severity f thrmbcytpenia (relative decrease f platelets in bld). Disseminated intravascular cagulatin, r DIC, is a cnditin in which bld clts frm thrughut the bdy's small bld vessels. These bld clts can reduce r blck bld flw thrugh the bld vessels, which can damage the bdy's rgans. [Picture Credit: Purpuric Rash] In DIC, the increased cltting uses up platelets and cltting factrs in the bld. Platelets are bld cell fragments that stick tgether t seal small cuts and breaks n bld vessel walls and stp bleeding. Cltting factrs are prteins needed fr nrmal bld cltting. With fewer platelets and cltting factrs in the bld, serius bleeding can ccur. DIC can cause internal and external bleeding. March 2017 Page 4
Internal bleeding ccurs inside the bdy. External bleeding ccurs underneath r frm the skin r mucsa. The mucsa is the tissue that lines sme rgans and bdy cavities, such as the nse and muth. DIC can cause life-threatening bleeding. As is the case with all ther frms f acute leukaemia the symptms f pancytpenia may be prminent. Characteristic are fatigue, deteriratin f physical fitness, pallr etc. due t anaemia, as well as enhanced susceptibility t infectins resulting frm neutrpenia. Neutrpenia refers t an abnrmally lw number f neutrphils. Neutrphils usually make up 50-70% f circulating white bld cells and serve as the primary defence against infectins by destrying bacteria in the bld. Hence, patients with neutrpenia are mre susceptible t bacterial infectins and, withut prmpt medical attentin, the cnditin may becme life-threatening and deadly (neutrpenic sepsis). Thrmbemblic cmplicatins which might als affect large vessels are rare. (Oncpedia-Guidelines; Natinal Heart, Lung and Bld Institute; May Clinic). Diagnsis f Prmyelcytic Leukaemia In additin t the standard diagnstic prcedures in patients with acute leukaemia, specific APL analyses are required t cnfirm the diagnsis. The diagnsis shuld be immediately cnfirmed by means f RT-PCR (reverse transcriptinplymerase chain reactin is the mst sensitive technique fr mrna detectin and quantitatin currently available), FISH r immunflurescence. FISH (flurescence in situ hybridizatin) fr the specific translcatin and immunflurescence fr expressin f PML (prgressive multifcal leukencephalpathy) are cnsidered as equivalent fr this purpse. Hwever, the determinatin f the PML/RARA isfrm (bcr1, bcr2, bcr3) by means f RT- PCR will be required fr the later mnitring f minimal residual disease (MRD). Mnitring cannt be carried ut by applying any ther methd. A diagnsis can be cnfirmed by means f: Case histry and physical examinatin (with special attentin t bleeding tendency, anaemic symptms and infectins) Cmplete full bld cunt, including leukcyte cunt with differential cell cunts Bne-marrw aspirate including: Cytlgy Cytchemistry Immunphentyping FISH (t(15;17)) r immunflurescence (PML) Cytgenetics (cnventinal) Bne-marrw histlgy in case f puncti sicca (where the aspiratin gives n bld cells) Cagulatin status including Quick s test (a ne-step test fr the amunt f prthrmbin present in bld plasma and fr determinatin f prthrmbin cltting time), PTT (a perfrmance indicatr measuring the efficacy f bth the intrinsic and the cmmn cagulatin pathways), fibringen, D-dimers (D-dimer tests are rdered, alng with ther labratry tests and imaging scans, t help rule ut the presence f a thrmbus r bld clt. Sme f the cnditins that the d-dimer test is used t help rule ut include deep vein thrmbsis, pulmnary emblism and strkes) March 2017 Page 5
Additinal diagnstic prcedures include: General health cnditin by means f the ECOG/WHO Scre [The Eastern Cperative Onclgy Grup (ECOG) scre (published by Oken et al. in 1982), als called the WHO r Zubrd scre (after C Grdn Zubrd). It runs frm 0 t 5, with 0 denting perfect health and 5 death] Evaluatin f c-mrbidities Clinical chemistry, urine analysis Hepatitis and HIV serlgy Pregnancy test (if applicable) Chest X-ray Electrcardigram (ECG) Echcardigraphy (in case f previus cardiac disease) (Oncpedia-Guidelines). Treatment f Prmyelcytic Leukaemia Treatment fr patients with acute prmyelcytic leukaemia (APL), the M3 subtype f acute myelid leukaemia (AML), differs frm treatment fr patients with ther AML subtypes. APL is ne f the mst frequently cured AML subtypes. APL affects marrw cells called prmyelcytes, which frm after myelblast develpment. The prmyelcytes have abnrmal chrmsme changes, usually an exchange (translcatin) f pieces f chrmsmes 15 and 17. Drugs cmmnly used t treat APL are: all-trans retinic acid arsenic trixide All-Trans Retinic Acid - All-trans retinic acid (ATRA), a substance that cmes frm vitamin A, ften brings APL int remissin. ATRA is als knwn as tretinin. Retinic acid helps the prmyelcytes affected by APL develp int fully functining cells (neutrphils). This prcess reduces the number f leukaemic blast cells in the marrw. And since ATRA als helps imprve bld cell cunts, it ften lessens the side effects f chemtherapy. At least 80 percent f patients underg shrt-term remissin when ATRA is used alne. Fr lng-lasting remissin, ATRA treatment is cmbined with chemtherapy during r after inductin therapy. Fr APL patients wh have a white cell cunt f 10,000 per micrliter r greater when they're diagnsed, the chemtherapy drug cytarabine is smetimes added during inductin r pst-remissin therapy. Abut 70 percent t 80 percent f APL patients g int remissin after being treated with ATRA and an anthracycline, such as idarubicin (Idamycin ). Nevertheless, sme setbacks can ccur, such as: haemrrhage (heavy bleeding) during the treatment's initial phases resistance t treatment the return f APL (relapse) Patients in remissin must get lng-term fllw-up care t determine whether they are cured r need further therapy. The ideal duratin f maintenance therapy is als being March 2017 Page 6
investigated. Currently, it cnsists f 2 years f 6-mercaptpurine (6-MP), methtrexate, and ATRA. Arsenic Trixide - the drug arsenic trixide (ATO) (Trisenx ) is smetimes given t APL patients if: their leukaemia has returned their leukaemia cannt be cntrlled with chemtherapy and ATRA they've develped persistent minimal residual disease (MRD - when a lw level f remaining APL cells can't be detected by standard tests) - after pst-remissin therapy Patients wh d nt have a dnr, r cannt have an allgeneic stem cell transplant fr ther reasns, may be candidates fr an autlgus stem cell transplantatin. Arsenic trixide is apprved t treat APL patients wh have relapsed r are resistant t treatment with chemtherapy and ATRA. (Leukaemia and Lymphma Sciety). Cancer targeted therapy - acute prmyelcytic leukaemia (APL) is a distinct subtype f acute myelid leukaemia. Mrphlgically, it is identified as the M3 subtype f acute myelid leukaemia by the French-American-British classificatin and cytgenetically is characterised by a balanced reciprcal translcatin between chrmsmes 15 and 17, which results in the fusin between prmyelcytic leukaemia (PML) gene and retinic acid receptr α (RARα). It seems that the disease is the mst malignant frm f acute leukaemia with a severe bleeding tendency and a fatal curse f nly weeks. Chemtherapy (CT; daunrubicin, idarubicin and cytsine arabinside) was the frnt-line treatment f APL with a cmplete remissin (CR) rate f 75% t 80% in newly diagnsed patients. Despite all these prgresses, the median duratin f remissin ranged frm 11 t 25 mnths and nly 35% t 45% f the patients culd be cured by CT. Since the intrductin f all-trans retinic acid (ATRA) in the treatment and ptimizatin f the ATRA-based regimens, the CR rate was raised up t 90% t 95% and 5-year disease free survival (DFS) t 74%. The use f arsenic trixide (ATO) since early 1990s further imprved the clinical utcme f refractry r relapsed as well as newly diagnsed APL. In this article, we review the histry f intrductin f ATRA and ATO int clinical use and the mechanistic studies in understanding this mdel f cancer targeted therapy. (American sciety f Hematlgy). Prgnsis (Outlk) f Prmyelcytic Leukaemia The verall prgnsis fr adults with APL is better than fr patients with ther frms f acute myelblastic leukaemia (AML), althugh it still depends t sme extent n individual patientspecific factrs (e.g. age, general fitness) and n features f the disease (e.g. whether it is M3v r PML/RARαnegative). Almst all patients can expect t achieve a gd first remissin. Patients wh are free f disease at the end f cnslidatin treatment have a gd chance f being cured. In yunger, fitter patients a cure rate f 70-80% is achievable. March 2017 Page 7
Patients are cnsidered t be at high risk f a haematlgical relapse if treatment has nt achieved a cmplete remissin by the end f cnslidatin r if the patient experiences a mlecular relapse. These patients may be ffered a stem cell transplant. (Leukaemia & Lymphma Research). Fllw-up The main purpse f fllw-up f patients treated fr AP L is the detectin f relapse and f treatment cmplicatins. During the first year fllwing cmpletin f chemtherapy, patients are nrmally checked every ne t tw mnths. Checks then gradually becme less frequent until they are given annually at five years and beynd. Lng-term fllw-up is particularly imprtant fr thse patients wh have received treatments that may affect the functin f their heart. Abut Clinical Trials Clinical trials are research studies that invlve peple. These studies test new ways t prevent, detect, diagnse, r treat diseases. Peple wh take part in cancer clinical trials have an pprtunity t cntribute t scientists knwledge abut cancer and t help in the develpment f imprved cancer treatments. They als receive state-f-the-art care frm cancer experts. Types f Clinical Trials Cancer clinical trials differ accrding t their primary purpse. They include the fllwing types: Treatment - these trials test the effectiveness f new treatments r new ways f using current treatments in peple wh have cancer. The treatments tested may include new drugs r new cmbinatins f currently used drugs, new surgery r radiatin therapy techniques, and vaccines r ther treatments that stimulate a persn s immune system t fight cancer. Cmbinatins f different treatment types may als be tested in these trials. Preventin - these trials test new interventins that may lwer the risk f develping certain types f cancer. Mst cancer preventin trials invlve healthy peple wh have nt had cancer; hwever, they ften nly include peple wh have a higher than average risk f develping a specific type f cancer. Sme cancer preventin trials invlve peple wh have had cancer in the past; these trials test interventins that may help prevent the return (recurrence) f the riginal cancer r reduce the chance f develping a new type f cancer Screening - these trials test new ways f finding cancer early. When cancer is fund early, it may be easier t treat and there may be a better chance f lng-term survival. Cancer screening trials usually invlve peple wh d nt have any signs r symptms f cancer. Hwever, participatin in these trials is ften limited t peple wh have a higher than average risk f develping a certain type f cancer because they have a family histry f that type f cancer r they have a histry f expsure t cancer-causing substances (e.g., cigarette smke). March 2017 Page 8
Diagnstic - these trials study new tests r prcedures that may help identify, r diagnse, cancer mre accurately. Diagnstic trials usually invlve peple wh have sme signs r symptms f cancer. Quality f life r supprtive care - these trials fcus n the cmfrt and quality f life f cancer patients and cancer survivrs. New ways t decrease the number r severity f side effects f cancer r its treatment are ften studied in these trials. Hw a specific type f cancer r its treatment affects a persn s everyday life may als be studied. Where Clinical Trials are Cnducted Cancer clinical trials take place in cities and twns in dctrs ffices, cancer centres and ther medical centres, cmmunity hspitals and clinics. A single trial may take place at ne r tw specialised medical centres nly r at hundreds f ffices, hspitals, and centres. Each clinical trial is managed by a research team that can include dctrs, nurses, research assistants, data analysts, and ther specialists. The research team wrks clsely with ther health prfessinals, including ther dctrs and nurses, labratry technicians, pharmacists, dieticians, and scial wrkers, t prvide medical and supprtive care t peple wh take part in a clinical trial. Research Team The research team clsely mnitrs the health f peple taking part in the clinical trial and gives them specific instructins when necessary. T ensure the reliability f the trial s results, it is imprtant fr the participants t fllw the research team s instructins. The instructins may include keeping lgs r answering questinnaires. The research team may als seek t cntact the participants regularly after the trial ends t get updates n their health. Clinical Trial Prtcl Every clinical trial has a prtcl, r actin plan, that describes what will be dne in the trial, hw the trial will be cnducted, and why each part f the trial is necessary. The prtcl als includes guidelines fr wh can and cannt participate in the trial. These guidelines, called eligibility criteria, describe the characteristics that all interested peple must have befre they can take part in the trial. Eligibility criteria can include age, sex, medical histry, and current health status. Eligibility criteria fr cancer treatment trials ften include the type and stage f cancer, as well as the type(s) f cancer treatment already received. Enrlling peple wh have similar characteristics helps ensure that the utcme f a trial is due t the interventin being tested and nt t ther factrs. In this way, eligibility criteria help researchers btain the mst accurate and meaningful results pssible. Natinal and Internatinal Regulatins Natinal and internatinal regulatins and plicies have been develped t help ensure that research invlving peple is cnducted accrding t strict scientific and ethical principles. In these regulatins and plicies, peple wh participate in research are usually referred t as human subjects. March 2017 Page 9
Infrmed Cnsent Infrmed cnsent is a prcess thrugh which peple learn the imprtant facts abut a clinical trial t help them decide whether r nt t take part in it, and cntinue t learn new infrmatin abut the trial that helps them decide whether r nt t cntinue participating in it. During the first part f the infrmed cnsent prcess, peple are given detailed infrmatin abut a trial, including infrmatin abut the purpse f the trial, the tests and ther prcedures that will be required, and the pssible benefits and harms f taking part in the trial. Besides talking with a dctr r nurse, ptential trial participants are given a frm, called an infrmed cnsent frm, that prvides infrmatin abut the trial in writing. Peple wh agree t take part in the trial are asked t sign the frm. Hwever, signing this frm des nt mean that a persn must remain in the trial. Anyne can chse t leave a trial at any time either befre it starts r at any time during the trial r during the fllw-up perid. It is imprtant fr peple wh decide t leave a trial t get infrmatin frm the research team abut hw t leave the trial safely. The infrmed cnsent prcess cntinues thrughut a trial. If new benefits, risks, r side effects are discvered during the curse f a trial, the researchers must infrm the participants s they can decide whether r nt they want t cntinue t take part in the trial. In sme cases, participants wh want t cntinue t take part in a trial may be asked t sign a new infrmed cnsent frm. New interventins are ften studied in a stepwise fashin, with each step representing a different phase in the clinical research prcess. The fllwing phases are used fr cancer treatment trials: Phases f a Clinical Trial Phase 0. These trials represent the earliest step in testing new treatments in humans. In a phase 0 trial, a very small dse f a chemical r bilgic agent is given t a small number f peple (apprximately 10-15) t gather preliminary infrmatin abut hw the agent is prcessed by the bdy (pharmackinetics) and hw the agent affects the bdy (pharmacdynamics). Because the agents are given in such small amunts, n infrmatin is btained abut their safety r effectiveness in treating cancer. Phase 0 trials are als called micr-dsing studies, explratry Investigatinal New Drug (IND) trials, r early phase I trials. The peple wh take part in these trials usually have advanced disease, and n knwn, effective treatment ptins are available t them. Phase I (als called phase 1). These trials are cnducted mainly t evaluate the safety f chemical r bilgic agents r ther types f interventins (e.g., a new radiatin therapy technique). They help determine the maximum dse that can be given safely (als knwn as the maximum tlerated dse) and whether an interventin causes harmful side effects. Phase I trials enrl small numbers f peple (20 r mre) wh have advanced cancer that cannt be treated effectively with standard (usual) treatments r fr which n standard treatment exists. Althugh evaluating the effectiveness f interventins is nt a primary gal f these trials, dctrs d lk fr evidence that the interventins might be useful as treatments. Phase II (als called phase 2). These trials test the effectiveness f interventins in peple wh have a specific type f cancer r related cancers. They als cntinue t lk at the March 2017 Page 10
safety f interventins. Phase II trials usually enrl fewer than 100 peple but may include as many as 300. The peple wh participate in phase II trials may r may nt have been treated previusly with standard therapy fr their type f cancer. If a persn has been treated previusly, their eligibility t participate in a specific trial may depend n the type and amunt f prir treatment they received. Althugh phase II trials can give sme indicatin f whether r nt an interventin wrks, they are almst never designed t shw whether an interventin is better than standard therapy. Phase III (als called phase 3). These trials cmpare the effectiveness f a new interventin, r new use f an existing interventin, with the current standard f care (usual treatment) fr a particular type f cancer. Phase III trials als examine hw the side effects f the new interventin cmpare with thse f the usual treatment. If the new interventin is mre effective than the usual treatment and/r is easier t tlerate, it may becme the new standard f care. Phase III trials usually invlve large grups f peple (100 t several thusand), wh are randmly assigned t ne f tw treatment grups, r trial arms : (1) a cntrl grup, in which everyne in the grup receives usual treatment fr their type f cancer, r 2) an investigatinal r experimental grup, in which everyne in the grup receives the new interventin r new use f an existing interventin. The trial participants are assigned t their individual grups by randm assignment, r randmisatin. Randmisatin helps ensure that the grups have similar characteristics. This balance is necessary s the researchers can have cnfidence that any differences they bserve in hw the tw grups respnd t the treatments they receive are due t the treatments and nt t ther differences between the grups. Randmisatin is usually dne by a cmputer prgram t ensure that human chices d nt influence the assignment t grups. The trial participants cannt request t be in a particular grup, and the researchers cannt influence hw peple are assigned t the grups. Usually, neither the participants nr their dctrs knw what treatment the participants are receiving. Peple wh participate in phase III trials may r may nt have been treated previusly. If they have been treated previusly, their eligibility t participate in a specific trial may depend n the type and the amunt f prir treatment they received. In mst cases, an interventin will mve int phase III testing nly after it has shwn prmise in phase I and phase II trials. Phase IV (als called phase 4). These trials further evaluate the effectiveness and lng-term safety f drugs r ther interventins. They usually take place after a drug r interventin has been apprved by the medicine regulatry ffice fr standard use. Several hundred t several thusand peple may take part in a phase IV trial. These trials are als knwn as pst-marketing surveillance trials. They are generally spnsred by drug cmpanies. Smetimes clinical trial phases may be cmbined (e.g., phase I/II r phase II/III trials) t minimize the risks t participants and/r t allw faster develpment f a new interventin. Althugh treatment trials are always assigned a phase, ther clinical trials (e.g., screening, preventin, diagnstic, and quality-f-life trials) may nt be labelled this way. March 2017 Page 11
Use f Placebs The use f placebs as cmparisn r cntrl interventins in cancer treatment trials is rare. If a placeb is used by itself, it is because n standard treatment exists. In this case, a trial wuld cmpare the effects f a new treatment with the effects f a placeb. Mre ften, hwever, placebs are given alng with a standard treatment. Fr example, a trial might cmpare the effects f a standard treatment plus a new treatment with the effects f the same standard treatment plus a placeb. Pssible benefits f taking part in a clinical trial The benefits f participating in a clinical trial include the fllwing: Trial participants have access t prmising new interventins that are generally nt available utside f a clinical trial. The interventin being studied may be mre effective than standard therapy. If it is mre effective, trial participants may be the first t benefit frm it. Trial participants receive regular and careful medical attentin frm a research team that includes dctrs, nurses, and ther health prfessinals. The results f the trial may help ther peple wh need cancer treatment in the future. Trial participants are helping scientists learn mre abut cancer (e.g., hw it grws, hw it acts, and what influences its grwth and spread). Ptential harms assciated with taking part in a clinical trial The ptential harms f participating in a clinical trial include the fllwing: The new interventin being studied may nt be better than standard therapy, r it may have harmful side effects that dctrs d nt expect r that are wrse than thse assciated with standard therapy. Trial participants may be required t make mre visits t the dctr than they wuld if they were nt in a clinical trial and/r may need t travel farther fr thse visits. Crrelative research studies, and hw they are related t clinical trials In additin t answering questins abut the effectiveness f new interventins, clinical trials prvide the pprtunity fr additinal research. These additinal research studies, called crrelative r ancillary studies, may use bld, tumur, r ther tissue specimens (als knwn as bispecimens ) btained frm trial participants befre, during, r after treatment. Fr example, the mlecular characteristics f tumur specimens cllected during a trial might be analysed t see if there is a relatinship between the presence f a certain gene mutatin r the amunt f a specific prtein and hw trial participants respnded t the treatment they received. Infrmatin btained frm these types f studies culd lead t mre accurate predictins abut hw individual patients will respnd t certain cancer treatments, imprved ways f finding cancer earlier, new methds f identifying peple wh have an increased risk f cancer, and new appraches t try t prevent cancer. Clinical trial participants must give their permissin befre bispecimens btained frm them can be used fr research purpses. March 2017 Page 12
When a clinical trial is ver After a clinical trial is cmpleted, the researchers lk carefully at the data cllected during the trial t understand the meaning f the findings and t plan further research. After a phase I r phase II trial, the researchers decide whether r nt t mve n t the next phase r stp testing the interventin because it was nt safe r effective. When a phase III trial is cmpleted, the researchers analyse the data t determine whether the results have medical imprtance and, if s, whether the tested interventin culd becme the new standard f care. The results f clinical trials are ften published in peer-reviewed scientific jurnals. Peer review is a prcess by which cancer research experts nt assciated with a trial review the study reprt befre it is published t make sure that the data are sund, the data analysis was perfrmed crrectly, and the cnclusins are apprpriate. If the results are particularly imprtant, they may be reprted by the media and discussed at a scientific meeting and by patient advcacy grups befre they are published in a jurnal. Once a new interventin has prven safe and effective in a clinical trial, it may becme a new standard f care. (Natinal Cancer Institute). Medical Disclaimer This Fact Sheet is intended t prvide general infrmatin nly and, as such, shuld nt be cnsidered as a substitute fr advice, medically r therwise, cvering any specific situatin. Users shuld seek apprpriate advice befre taking r refraining frm taking any actin in reliance n any infrmatin cntained in this Fact Sheet. S far as permissible by law, the Cancer Assciatin f Suth Africa (CANSA) des nt accept any liability t any persn (r his/her dependants/estate/heirs) relating t the use f any infrmatin cntained in this Fact Sheet. Whilst the Cancer Assciatin f Suth Africa (CANSA) has taken every precautin in cmpiling this Fact Sheet, neither it, nr any cntributr(s) t this Fact Sheet can be held respnsible fr any actin (r the lack theref) taken by any persn r rganisatin wherever they shall be based, as a result, direct r therwise, f infrmatin cntained in, r accessed thrugh, this Fact Sheet. March 2017 Page 13
Surces and References American sciety f Hematlgy http://www.bldjurnal.rg/cntent/111/5/2505?ss-checked=true Chrmsmal Translcatin https://www.ggle.c.za/search?q=chrmsmal+translcatin&surce=lnms&tbm=isch&s a=x&ei=pc9wu66dgtn7ab_iycqbg&sqi=2&ved=0cayq_auaq&biw=1517&bih=714& dpr=0.9#q=achrmsmal+translcatin+15%3b17&tbm=isch&facrc=_&imgdii=_&imgrc=g3 9tKOO2R3LTkM%253A%3BVPNQWRzW5g cm%3bhttp%253a%252f%252fwww.nsc nnect.rg%252fwpcntent%252fuplads%252f2012%252f11%252fchrmsmes.gif%3bhttp%253a%252f %252Fcnnect.ns.rg%252Fclumns%252Ffive-minute-in-service%252Fcytgeneticshelps-determine-diagnsis-and-prgnsis-fr-multiple-myelma%3B522%3B383 Genetic Hme Reference http://ghr.nlm.nih.gv/cnditin/acute-prmyelcytic-leukemia Karytype https://www.ggle.c.za/search?q=karytype&surce=lnms&tbm=isch&sa=x&ei=mllpuenhok47qbqvidadq&sqi=2&ved=0cayq_auaq&biw=1517&bih=714&dpr=0.9#facrc=_ &imgdii=_&imgrc=wkolhukjp0gghm%253a%3bpfnee0jjdbpm%3bhttp%253a%252f %252Fscigjt13.files.wrdpress.cm%252F2011%252F03%252Fkarytype.gif%3Bhttp%253 A%252F%252Fscigjt13.wrdpress.cm%252F2011%252F03%252F02%252Fkarytype-falzheimers-disease%252F%3B300%3B276 Leukaemia & Lymphma Research. Acute Prmyelcytic Leukaemia (APL). 2011. Beatingbldcancerrs.rg.uk. https://leukaemialymphmaresearch.rg.uk/infrmatin/leukaemia/acute-prmyelcyticleukaemia-apl/what-are-signs-and-symptms Leukaemia and Lymphma Sciety http://www.lls.rg/diseaseinfrmatin/leukemia/acutemyelidleukemia/treatment/apl/ May Clinic http://www.mayclinic.rg/symptms/neutrpenia/basics/definitin/sym-20050854 Medscape http://emedicine.medscape.cm/article/1495306-verview Natinal Heart, Lung and Bld Institute http://www.nhlbi.nih.gv/health/health-tpics/tpics/dic/ Natinal Cancer Institute http://www.cancer.gv/abut-cancer/treatment/clinical-trials/what-are-trials Oncpedia-Guidelines http://www.nkpedia-guidelines.inf/en/nkpedia/guidelines/acute-prmyelcyticleukemia-apl Purpuric Rash http://www.pedsnclgyeducatin.cm/boemergenciesdic.asp March 2017 Page 14
Uptdate http://www.uptdate.cm/cntents/clinical-manifestatins-pathlgic-features-and-diagnsisf-acute-prmyelcytic-leukemia-in-adults March 2017 Page 15