Chimeric Antigen Receptor T cell Therapy (CAR-T)

Transcription

1 Applies t all prducts administered r underwritten by Blue Crss and Blue Shield f Luisiana and its subsidiary, HMO Luisiana, Inc.(cllectively referred t as the Cmpany ), unless therwise prvided in the applicable cntract. Medical technlgy is cnstantly evlving, and we reserve the right t review and update Medical Plicy peridically. Nte: Other frms f adptive immuntherapy such as using adptive cellular therapy fr the administratin f cyttxic T lymphcytes, cytkine-induced killer cells, tumr-infiltrating lymphcytes, r antigen-laded autlgus dendritic cells are addressed separately in medical plicy When Services May Be Eligible fr Cverage Cverage fr eligible medical treatments r prcedures, drugs, devices r bilgical prducts may be prvided nly if: Benefits are available in the member s cntract/certificate, and Medical necessity criteria and guidelines are met. tisagenlecleucel (Kymriah ) Based n review f available data, the Cmpany may cnsider the use f tisagenlecleucel (Kymriah) fr the treatment f relapsed r refractry B cell acute lymphblastic leukemia (ALL) t be eligible fr cverage. Patient Selectin Criteria Cverage eligibility fr the use f tisagenlecleucel (Kymriah) will be cnsidered when ALL f the fllwing criteria are met: Patient has a cnfirmed diagnsis f CD19-psitive B-cell ALL with mrphlgic bne marrw tumr invlvement (>5% lymphblasts); AND Patient is 25 years ld r yunger at time f infusin; AND Disease is refractry t initial therapy r in secnd r later relapse Refractry is defined as failure t btain cmplete respnse with inductin therapy, i.e., failure t eradicate all detectable leukemia cells (<5% blasts) frm the bne marrw and bld with subsequent restratin f nrmal hematpiesis (>25% marrw cellularity and nrmal peripheral bld cunts); Relapsed is defined as the reappearance f leukemia cells in the bne marrw r peripheral bld after the attainment f a cmplete remissin (CR) with chemtherapy and/r allgeneic stem cell transplant; AND Patient has NOT received prir treatment with Kymriah r any ther gene therapy and is nt being cnsidered fr treatment with any ther gene therapy; AND (Nte: This specific criterin is an additinal Cmpany requirement fr cverage eligibility and will be denied as nt medically necessary** if nt met). Patient has adequate rgan functin with n significant deteriratin in rgan functin expected within 4 weeks after apheresis; AND (Nte: This specific criterin is an additinal Cmpany requirement fr cverage eligibility and will be denied as nt medically necessary** if nt met). Patient des NOT have any f the fllwing: Page 1 f 9

2 Burkitt lymphma; OR Active hepatitis B virus, hepatitis C virus, r ther uncntrlled fungal, bacterial, r viral infectin requiring intravenus antimicrbials; OR Grade 2-4 graft-vs-hst disease; OR Cncmitant genetic syndrme with the exceptin f Dwn syndrme; OR Received allgeneic cellular therapy, such as dnr lymphcyte infusin within 6 weeks prir t tisagenlecleucel infusin; OR Active central nervus system (CNS) disease defined by the Natinal Cmprehensive Cancer Netwrk (NCCN) guidelines t be a presence f > 5 White Bld Cells (WBC) per micrliter (µl) in the cerebrspinal fluid in additin t the presence f lymphblasts. (Nte: These criteria are additinal cmpany requirements fr cverage eligibility and will be denied as nt medically necessary** if nt met) axicabtagene cilleucel (Yescarta ) Based n review f available data, the Cmpany may cnsider the use f axicabtagene cilleucel (Yescarta) fr the treatment f relapsed r refractry B-cell lymphma t be eligible fr cverage. Patient Selectin Criteria Cverage eligibility fr the use f axicabtagene cilleucel (Yescarta) will be cnsidered when ALL f the fllwing criteria are met: Patient has a dcumented diagnsis f ne f the fllwing: Diffuse large B-cell lymphma (DLBCL), nt therwise specified; OR Primary mediastinal large B-cell lymphma; OR High grade B-cell lymphma; OR DLBCL arising frm fllicular lymphma; AND Patient is > 18 years ld at the time f infusin; AND Disease is relapsed r refractry, defined as prgressin after 2 r mre lines f systemic therapy (which may r may nt include therapy supprted by autlgus cell transplant); AND Patient has failed tw r mre lines f systemic therapy including: Anti-CD20 mnclnal antibdy (such as rituximab) unless tumr is CD20-negative; AND An anthracycline cntaining chemtherapy regimen; AND (Nte: The criteria requiring specific systemic agents are additinal cmpany requirements fr cverage eligibility and will be denied as nt medically necessary** if nt met. If patient has nt failed tw r mre lines f any systemic therapy, request will be denied as investigatinal*) Patient has NOT received prir treatment with Yescarta r any ther genetically mdified T cell therapy and is nt being cnsidered fr treatment with any ther gene therapy; AND (Nte: This criterin is an additinal cmpany requirement fr cverage eligibility and will be denied as nt medically necessary** if nt met) Page 2 f 9

3 Patient has adequate rgan functin with n significant deteriratin in rgan functin expected within 4 weeks after apheresis; AND (Nte: This criterin is an additinal cmpany requirement fr cverage eligibility and will be denied as nt medically necessary** if nt met) Patient has dcumentatin f ALL f the fllwing at the time f infusin: Abslute neutrphil cunt >1000/µL; AND Abslute lymphcyte cunt >100/µL; AND Platelet cunt >75,000/µL; AND (Nte: These criteria are additinal cmpany requirements fr cverage eligibility and will be denied as nt medically necessary** if nt met) Patient des NOT have ANY f the fllwing: Primary CNS lymphma; OR Active CNS disease (e.g. seizure disrder, CV ischemia/hemrrhage, dementia, cerebellar disease, r any autimmune disease with CNS invlvement); OR (Nte: This criterin is an additinal cmpany requirement fr cverage eligibility and will be denied as nt medically necessary** if nt met) Active hepatitis B, hepatitis C, human immundeficiency virus (HIV), r ther uncntrlled fungal, bacterial, r ther viral infectin requiring intravenus antimicrbials When Services Are Cnsidered Nt Medically Necessary Based n review f available data, the Cmpany cnsiders the use f tisagenlecleucel (Kymriah) r axicabtagene cilleucel (Yescarta) when the patient has received prir treatment with chimeric antigen receptr T cell therapy (CAR-T) r ther gene therapy, when the patient des nt have adequate rgan functin, r has active CNS disease t be nt medically necessary.** Based n review f available data, the Cmpany cnsiders the use f tisagenlecleucel (Kymriah) when the patient has Burkitt lymphma, has a cncmitant genetic syndrme (ther than Dwn syndrme), has grade 2-4 graft-vs-hst disease, r has received allgeneic cellular therapy, such as dnr lymphcyte infusin within 6 weeks prir t tisagenlecleucel infusin t be nt medically necessary.** Based n review f available data, the Cmpany cnsiders the use f axicabtagene cilleucel (Yescarta) when the patient has nt failed at least ne anti-cd20 mnclnal antibdy (unless tumr is CD20 negative), has nt failed an anthracycline cntaining chemtherapy regimen, r des nt meet pre-specified bld cunts at the time f infusin t be nt medically necessary.** When Services Are Cnsidered Investigatinal Cverage is nt available fr investigatinal medical treatments r prcedures, drugs, devices r bilgical prducts. Page 3 f 9

4 Based n review f available data, the Cmpany cnsiders the use f tisagenlecleucel (Kymriah) r axicabtagene cilleucel (Yescarta) when patient selectin criteria are nt met (except thse listed as nt medically necessary**) t be investigatinal.* Backgrund/Overview CAR-T is a frm f adptive immuntherapy in which a patient s wn T cells are remved and prgrammed t destry cells marked with a certain prtein. In the case f Kymriah and Yescarta, that prtein is CD-19 which is expressed n mst B cells. These drugs are therefre indicated fr certain cancers invlving prliferatin f B cells. Kymriah is a CAR-T therapy currently apprved fr the treatment f relapsed r refractry ALL in patients yunger than 25 years f age. Treatment invlves reprgramming a patient s wn T cells with a transgene encding a chimeric antigen receptr (CAR) t identify and eliminate CD19-expressing cells. The patient s T cells are remved and reprgrammed in vitr then re-infused at a rate f ml/min. The recmmended dsage f Kymriah fr patients 50 kg r less is 0.2 t chimeric antigen receptr (CAR)- psitive viable T cells per kilgram f bdy weight intravenusly; fr patients abve 50 kg, dse is 0.1 t ttal CAR-psitive viable T cells (nn-weight-based) intravenusly. Prir t infusin, the patient must be pre-treated with fludarabine and cyclphsphamide t deplete the patient s lymphcytes and reduce the risk f severe cytkine release syndrme (CRS). CRS is ne f the mst cmmn adverse effects ccurring in 79% f patients in the pivtal trial. Severe CRS may be life-threatening and shuld be treated with tcilizumab. Due t the ptential fr severe CRS, the drug is nly available thrugh a Risk Evaluatin and Mitigatin Strategy (REMS) prgram t ensure that prviders are aware f the signs f CRS and able t apprpriately treat severe CRS. Yescarta is a CAR-T therapy currently apprved fr the treatment f adults with relapsed r refractry large B-cell lymphma after 2 r mre lines f systemic therapy. Similar t Kymriah, Yescarta is an adptive immuntherapy in which the T cells f a patient are mdified genetically t selectively target and bind t CD19 antigen expressed n the surface f nrmal and malignant B cells. Prir t infusin f Yescarta, the patient must be pre-treated with a lymphdepleting chemtherapy regimen f cyclphsphamide and fludarabine. The recmmended dsage f Yescarta is 2 x 10 6 CAR-psitive viable T cells per kilgram bdy weight with a maximum f 2 x 10 8 CAR-psitive viable T cells. After infusin f Yescarta, patients must be mnitred at least daily fr 7 days at a certified healthcare facility fr signs and symptms f CRS and neurlgic txicities and then remain within prximity f the certified healthcare facility fr at least 4 weeks fllwing infusin. As with Kymriah, CRS ccurs frequently in Yescarta-treated patients resulting in the drug being restricted thrugh a REMS prgram. Bth the Kymriah and the Yescarta REMS prgrams require health care facilities that dispense and administer the drugs t cmply with the fllwing requirements: Certified facilities must have nsite, immediate access t tcilizumab, and ensure that a minimum f 2 dses f tcilizumab are available fr each patient fr administratin within 2 hurs after Kymriah r Yescarta infusin, if needed fr treatment f CRS. Page 4 f 9

5 Certified facilities must ensure that health care prviders wh prescribe, dispense, r administer Kymriah r Yescarta are trained t manage CRS and neurlgic txicities. Acute lymphblastic leukemia (ALL) ALL is ne f the mst cmmn childhd malignancies. Despite having a relatively high 5 year verall survival rate f 85%, prgnsis is pr fr thse wh d nt respnd t initial treatment. Relapse fllwing ALL treatment is the secnd mst cmmn cause f cancer-related death in children. Initial treatment is apprached in three stages: inductin, cnslidatin, and maintenance. The gal f inductin therapy, which usually lasts 3-4 weeks, is t achieve an initial CR. If CR is nt reached during this stage, the disease is cnsidered refractry. Cnslidatin treatment is designed t prevent leukemic regrwth, reduce residual tumr burden, and prevent emergence f drug resistance in the remaining leukemic cells. This phase typically lasts 4-8 mnths and includes drugs tailred t the patient based n risk f re-ccurrence. The final phase f treatment, the maintenance phase, is a less intensive cntinuatin regimen f daily therapy that is cntinued fr a ttal treatment duratin f mnths. Re-ccurrence after cmpletin f the maintenance phase is cnsidered relapse and requires aggressive reinductin therapy and intensificatin, which is ften ineffective. Patients wh achieve a secnd remissin are candidates fr allgeneic hematpietic stem cell transplantatin. Relapse f ALL can ccur in many extramedullary sites, but mst ften ccurs in the bne marrw, CNS, r testicles. Bne marrw relapse is the mst cmmn site f relapse and usually presents with persistent peripheral bld cytpenias. When the relapse ccurs in the CNS, the NCCN guidelines classify the disease int the fllwing categries: CNS 1: N lymphblasts in cerebrspinal fluid (CSF) regardless f the white bld cell (WBC) cunt; CNS 2: WBC<5/µL in CSF with presence f lymphblasts; CNS 3: WBC >5/µL in CSF with presence f lymphblasts. Diffuse large B-cell lymphma (DLBCL) DLBCL is the mst cmmn histlgic subtype f nn-hdgkin lymphma and accunts fr apprximately 25% f nn-hdgkin lymphma cases. DLBCL exhibits large hetergeneity in mrphlgic, genetic, and clinical aspects and multiple clinicpathlgic entities are defined by the 2016 Wrld Health Organizatin classificatin, which are sufficiently distinct t be cnsidered separate diagnstic categries. It has been estimated that 27,650 new cases f DLBCL were diagnsed in the United States in Treatment in the first-line setting (particularly rituximab plus cyclphsphamide, dxrubicin, vincristine, and prednisne [R-CHOP]) is assciated with a 5-year survival rate ranging frm 60-70%. Hwever, based n a number f prgnstic factrs, 20-50% f DLBCL cases are refractry r relapse after first-line chemtherapy. The respnse t subsequent salvage chemtherapy and cnslidatin with autlgus cell transplantatin is subptimal with ne study finding nly 7% f patients with refractry DLBCL achieving a cmplete respnse t the next line f therapy. Page 5 f 9

6 FDA r Other Gvernmental Regulatry Apprval U.S. Fd and Drug Administratin (FDA) Kymriah is FDA apprved fr the treatment f patients up t 25 years f age with B-cell precursr ALL that is refractry r in secnd r later relapse. Yescarta is FDA apprved fr the treatment f adult patients with relapsed r refractry large B-cell lymphma after tw r mre lines f systemic therapy, including DLBCL nt therwise specified, primary mediastinal large B-cell lymphma, high grade B-cell lymphma, and DLBCL arising frm fllicular lymphma. Ratinale/Surce This medical plicy was develped thrugh cnsideratin f peer-reviewed medical literature generally recgnized by the relevant medical cmmunity, U.S. FDA apprval status, natinally accepted standards f medical practice and accepted standards f medical practice in this cmmunity, Blue Crss and Blue Shield Assciatin technlgy assessment prgram (TEC) and ther nn-affiliated technlgy evaluatin centers, reference t federal regulatins, ther plan medical plicies, and accredited natinal guidelines. Kymriah was apprved based n an pen-label, multicenter single-arm trial including 63 patients treated with lymphdepleting chemtherapy fllwed by a single dse f Kymriah. Efficacy endpints included achievement f CR within 3 mnths after infusin, duratin f CR, and prprtin f patients with CR and minimal residual disease (MRD)<0.01% by flw cytmetry. CR designatin required remissin status t be maintained fr at least 28 days withut clinical evidence f relapse. 83% f patients achieved a CR r CR with incmplete bld cunt recvery (CRi), and all patients were negative fr MRD. Median duratin f remissin was nt reached at the time that the study data was submitted (median fllw-up f 4.8 mnths frm respnse). Patients were nly included in the study if they had adequate rgan functin defined based n measures f serum creatinine, alanine amintransferase, bilirubin, pulse xygenatin, and left ventricular ejectin fractin. In additin, Kymriah was nt studied in patients with extra-medullary disease relapse, Burkitt lymphma, r cncmitant genetic syndrmes that pre-dispse patients t leukemia, such as Fancni anemia r Kstmann syndrme. Patients with Dwn syndrme were nt excluded. It is imprtant t nte that adequate rgan functin was defined as fllws: Serum Creatinine within nrmal limits fr patient age Age (years) Serum Creatinine (mg/dl) 1-<2 < <6 <0.8 6-<10 <1 10-<13 <1.2 Page 6 f 9

7 13-<16 <1.5 (Male) <1.4 (Female) >16 <1.7 (Male) <1.4 (Female) Alanine amintransferase (ALT) <5 times the upper limit f nrmal (ULN) fr age Bilirubin <2.0 mg/dl Minimum level f pulmnary reserve < Grade 1 dyspnea and pulse xygenatin >91% n rm air Left Ventricular Shrtening Fractin >28% cnfirmed by echcardigram r Left Ventricular Ejectin Fractin >45% cnfirmed by echcardigram r Multiple Uptake Gated Acquisitin Yescarta was apprved based n the results f an pen-label, multicenter phase 1/2 study, which reprted CR rates and duratin f respnse demnstrated in the phase 2 prtin f the study. Adults with aggressive B-cell nn-hdgkin lymphma that was primary refractry, refractry t a secnd r greater line f therapy, r relapsed within 1 year after autlgus hematpietic cell transplantatin were enrlled in the study. Patients with prir allgeneic hematpietic cell transplantatin, any histry f CNS lymphma, Eastern Cperative Onclgy Grup Perfrmance Status scre f 2 r greater, abslute lymphcyte cunt less than 100/µL, creatinine clearance less than 60 ml/min, hepatic transaminases mre than 2.5 times the ULN, cardiac ejectin fractin less than 50%, r active serius infectin were excluded. Mst patients (74%) had de nv DLBCL and 32% had duble- r triple-hit lymphma. The median age was 58, with 24% being aged 65 years r lder; the median number f prir therapies was 3; 77% had refractry disease t a secnd r greater line f therapy; and 21% had relapsed within 1 year after autlgus hematpetic cell transplantatin (HCT). All patients received a lymphdepleting regimen cnsisting f cyclphsphamide and fludarabine prir t infusin f Yescarta. Of the 111 patients wh underwent leukapheresis, 101 received the infusin (9 were nt treated due t prgressive disease r serius adverse reactins fllwing leukapheresis and there was a manufacturing failure in 1 patient). Study prtcl mandated hspitalizatin f patients fr infusin and 7 days after infusin. Bridging chemtherapy between leukapheresis and lymphdepleting chemtherapy was nt permitted. The median time frm leukapheresis t prduct delivery was 17 days. The primary end pint was bjective respnse rate based n a mdified intentin-t-treat ppulatin, which was defined as all patients treated with at least 1.0 x 10 6 CAR-T cells per kilgram. Objective respnse was seen in 72% f patients with 51% achieving a cmplete respnse and 21% achieving a partial respnse. References 1. Blue Crss and Blue Shield Assciatin, Medical Plicy Reference Manual, Adptive Immuntherapy, , December Tisagenlecleucel (Kymriah) [Package Insert]. Nvartis. East Hanver, New Jersey Updated Aug 30, Axicabtagene cilleucel (Yescarta) [Package Insert]. Kite Pharma Inc. Updated Oct 18, Swerdlw SH, Camp E, Pileri SA, et al. The 2016 revisin f the Wrld health Organizatin classificatin f lymphid neplasms. Bld. May ;127(20): Teras LR, DeSantis CE, Cerhan JR, et al US lymphid malignancy statistics by Wrld health Organizatin subtypes. CA Cancer J Clin. Sep ;66(6): Internatinal Nn-hdgkin s Lymphma Prgnstic Factrs P. A predictive mdel fr aggressive nn-hdgkin s lymphma. N Engl J Med. Sep ;329(14): Page 7 f 9

8 7. Sehn Lh, Berry B, Chhanabhai M, et al. The revised Internatinal Prgnstic Index (R-IPI) is a better predictr f utcme than the standard IPI fr patients with diffuse large B-cell lymphma treated with R-CHOP. Bld. Mar ;109(5): Crump M, Neelapu SS, Farq U, et al. Outcmes in refractry diffuse large B-cell lymphma: results frm the internatinal SCHOLAR-1 study. Bld. Oct ;130(16): Plicy Histry 02/01/2018 Medical Plicy Cmmittee review 02/21/2018 Medical Plicy Implementatin Cmmittee apprval. New plicy 04/01/2018 Cding update 05/22/2018 Cding update Next Scheduled Review Date: 02/2019 Cding The five character cdes included in the Blue Crss Blue Shield f Luisiana Medical Plicy Cverage Guidelines are btained frm Current Prcedural Terminlgy (CPT ), cpyright 2017 by the American Medical Assciatin (AMA). CPT is develped by the AMA as a listing f descriptive terms and five character identifying cdes and mdifiers fr reprting medical services and prcedures perfrmed by physician. The respnsibility fr the cntent f Blue Crss Blue Shield f Luisiana Medical Plicy Cverage Guidelines is with Blue Crss and Blue Shield f Luisiana and n endrsement by the AMA is intended r shuld be implied. The AMA disclaims respnsibility fr any cnsequences r liability attributable r related t any use, nnuse r interpretatin f infrmatin cntained in Blue Crss Blue Shield f Luisiana Medical Plicy Cverage Guidelines. Fee schedules, relative value units, cnversin factrs and/r related cmpnents are nt assigned by the AMA, are nt part f CPT, and the AMA is nt recmmending their use. The AMA des nt directly r indirectly practice medicine r dispense medical services. The AMA assumes n liability fr data cntained r nt cntained herein. Any use f CPT utside f Blue Crss Blue Shield f Luisiana Medical Plicy Cverage Guidelines shuld refer t the mst current Current Prcedural Terminlgy which cntains the cmplete and mst current listing f CPT cdes and descriptive terms. Applicable FARS/DFARS apply. CPT is a registered trademark f the American Medical Assciatin. Cdes used t identify services assciated with this plicy may include (but may nt be limited t) the fllwing: Cde Type Cde CPT HCPCS ICD-10 Diagnsis N cdes J3490, J3590, J9999, Q2040 Cde added eff 4/1/18: Q2041 C C82.49, C C82.59, C C82.69, C C82.89, C C82.99, C83.30-C83.37, C C83.59, C C85.29,C91.00-C91.02 *Investigatinal A medical treatment, prcedure, drug, device, r bilgical prduct is Investigatinal if the effectiveness has nt been clearly tested and it has nt been incrprated int standard medical practice. Any determinatin we make that a medical treatment, prcedure, drug, device, r bilgical prduct is Investigatinal will be based n a cnsideratin f the fllwing: Page 8 f 9

9 A. Whether the medical treatment, prcedure, drug, device, r bilgical prduct can be lawfully marketed withut apprval f the U.S. Fd and Drug Administratin (FDA) and whether such apprval has been granted at the time the medical treatment, prcedure, drug, device, r bilgical prduct is sught t be furnished; r B. Whether the medical treatment, prcedure, drug, device, r bilgical prduct requires further studies r clinical trials t determine its maximum tlerated dse, txicity, safety, effectiveness, r effectiveness as cmpared with the standard means f treatment r diagnsis, must imprve health utcmes, accrding t the cnsensus f pinin amng experts as shwn by reliable evidence, including: 1. Cnsultatin with the Blue Crss and Blue Shield Assciatin technlgy assessment prgram (TEC) r ther nnaffiliated technlgy evaluatin center(s); 2. Credible scientific evidence published in peer-reviewed medical literature generally recgnized by the relevant medical cmmunity; r 3. Reference t federal regulatins. **Medically Necessary (r Medical Necessity ) - Health care services, treatment, prcedures, equipment, drugs, devices, items r supplies that a Prvider, exercising prudent clinical judgment, wuld prvide t a patient fr the purpse f preventing, evaluating, diagnsing r treating an illness, injury, disease r its symptms, and that are: A. In accrdance with natinally accepted standards f medical practice; B. Clinically apprpriate, in terms f type, frequency, extent, level f care, site and duratin, and cnsidered effective fr the patient's illness, injury r disease; and C. Nt primarily fr the persnal cmfrt r cnvenience f the patient, physician r ther health care prvider, and nt mre cstly than an alternative service r sequence f services at least as likely t prduce equivalent therapeutic r diagnstic results as t the diagnsis r treatment f that patient's illness, injury r disease. Fr these purpses, natinally accepted standards f medical practice means standards that are based n credible scientific evidence published in peer-reviewed medical literature generally recgnized by the relevant medical cmmunity, Physician Specialty Sciety recmmendatins and the views f Physicians practicing in relevant clinical areas and any ther relevant factrs. Indicated trademarks are the registered trademarks f their respective wners. NOTICE: Medical Plicies are scientific based pinins, prvided slely fr cverage and infrmatinal purpses. Medical Plicies shuld nt be cnstrued t suggest that the Cmpany recmmends, advcates, requires, encurages, r discurages any particular treatment, prcedure, r service, r any particular curse f treatment, prcedure, r service. Page 9 f 9