JANUARY&2020

In this month’s Leukemia Insights newsletter, written by Elias Jabbour, MD, and Nitin Jain, MD, and sponsored in part by the Charif Souki Cancer Research Fund, we ABOUT&MyMDAnderson describe clinical trials available at our institution for patients with acute lymphoblastic leukemia (ALL), including Philadelphia chromosome (Ph)Hnegative and myMDAnderson isVaVsecure,V positive disease, and in both the frontline and salvage settings. personalizedVwebVsiteVhelpingV communityVphysiciansVexpediteVpatientV referrals,VasVwellVasVimproveVcontinuityV Novel&Approaches&for&the&Treatment&of& ofVcareVthroughVinformationVaccessV ALL&in&Adults&in&2020 andVstreamlinedVcommunications.V PhysiciansVwhoVhaveVreferredVpatientsV Acute lymphoblastic leukemia (ALL) is characterized by clonal toVMDVAndersonVorVplanVtoVdoVso,VcanV utilizeVtheVHIPAAVcompliantVfeatures proliferation of lymphoid progenitors. In the last decade, significant ofVmyMDAndersonVto: advances have been made in understanding the disease pathogenesis, refining prognostic groups and developing novel therapies that target • ReferVaVpatient specific subsets. Therapies targeting either specific transcripts (e.g. • ViewVyourVpatient'sVappointmentsV Bcr@Abl tyrosine kinase inhibitors) or specific leukemic cell surface AccessVpatientVreports antigens (e.g. CD20, CD22, and CD19 monoclonal antibodies) are • SendVandVreceiveVsecureV major breakthroughs. These novel therapies and combinations are messages transforming treatment strategies for adults with ALL and are beginning to result in significant improvements in survival. In this newsletter, we describe clinical trials available at our institution for patients with ALL, JOIN&THE&COVERSATION including Philadelphia chromosome (Ph)@negative and positive Connect'with'us. disease, and in both the frontline and salvage settings. Many of these approaches focus on decreasing or eliminating the role of chemotherapy, with the goal of making these regimens more tolerable in older adults and also decreasing the morbidity and mortality associated with myelosuppression@related infections and other complications of intensive chemotherapy.

When referring a patient for these trials, remember that most allow up JOIN&OUR&MAILING&LIST to 2 previous cycles of therapyL therefore patients are eligible 1@2 months after diagnosis. Furthermore, the monoclonal and bispecific IfVyouVwouldVlikeVtoVreceiveV antibody constructs (e.g. or blinatumomab) are anVelectronicVissueVofVtheV provided free of charge as part of the trial. MDVAndersonVLeukemiaVInsightsV e@NewsletterVonVaVmonthlyV 1. Frontline Ph;negative ALL basis,VpleaseVcompleteVtheV • Hyper;CVAD + blinatumomab – Hyper@CVAD is the standard of Subscription&Request&Form. care for adults able to tolerate intensive chemotherapy. Blinatumomab, the CD3@CD19 bispecific T@cell engager, has also It'sVtheVeasiestVwayVtoVstayVcurrentV shown significant promise in the treatment of ALL, with recent FDA withVinformationVonVtheVlatestV approval based on a survival advantage for patients with relapsed or leukemiaVnews,Vresearch,VandV refractory ALL compared with combination chemotherapy. resources. Blinatumomab has also shown efficacy in eliminating minimal residual disease (MRD). In this study, only 4 (rather than 8) courses of chemotherapy are given, followed by 4 cycles of blinatumomab CONTACT&OUR&STAFF incorporated into an 18@month maintenance regimen (half the duration of standard POMP maintenance). With the addition of Mary&Alma&Welch&; Editor& blinatumomab, the goal is to both decrease the amount of intensive Lisa Palacios&; Publishing&Editor& [email protected] chemotherapy received and deepen responses. To date, 34 patients were treated. The 23 analysis, the combination of H3CVAD and year overall survival rate is 93% very favorable had a significantly higher CMR rate (82% versus compared with a rate of 80% in patients treated with 65%) and higher 33year survival rate (83% versus HCVAD and only. This protocol is being 60%). Given previous experience that full3intensity amended to add the CD22 antibody3drug conjugate hyper3CVAD results in significant toxicity in many inotuzumab ozogamicin, thereby incorporating all of the patients, there is a rationale to combine ponatinib most active agents in B3cell ALL into our frontline with a less intensive chemotherapy backbone. regimen. Given its activity in Ph3positive ALL, blinatumomab is also added to this regimen. The goal is that by • Hyper&CVD + inotuzumab ozogamicin + reducing toxicity from intensive chemotherapy and blinatumomab – Because many older patients with incorporating the most active agents in Ph3positive ALL are not able to tolerate intensive chemotherapy, ALL (blinatumomab and ponatinib), we will reduce we have designed a low3intensity chemotherapy treatment3related morbidity and mortality and further regimen (hyper3CVD) combined with the two most increase the cure rate. This regimen is open to active monoclonal antibodies in ALL: inotuzumab patients of all ages with newly diagnosed Ph3 ozogamicin and blinatumomab. Inotuzumab is given positive ALL. Ponatinib and blinatumomab are at lower, fractionated doses in an attempt to provided free of charge. decrease the rate of veno3occlusive disease while maintaining efficacy. Blinatumomab was added to • Blinatumomab and ponatinib – Blinatumomab deepen the level of response. In the most recent was evaluated in the Phase II ALCANTARA trial in update of 66 treated patients, the overall response patients with relapsed/refractory Ph3positive ALL. In rate is 98%, and no early deaths were observed. this study, 36% of patients achieved complete Overall, 95% of patients achieved MRD negativity. remission (CR) or CR with incomplete hematologic The 53year overall survival rate is 49%, which response and was active in patients with T315I compares favorably to historical data in which mutations. The median overall survival was 7.1 similar populations had a cure rate of only 20%. months. We have treated 8 patients with These data are the best reported thus far in this relapsed/refractory Ph3positive leukemias with the population.This regimen is also available for patients combination of ponatinib and blinatumomab, 6 of with relapsed/refractory Ph3negative ALL of any whom (75%) achieved CMR. With a median follow3 age. up of 10 months, the 13year overall survival rate was • Other regimens include hyper&CVAD plus 75%. We are therefore evaluating this combination nelarabine and the Bcl32 inhibitor (for T3 blinatumomab and ponatinib, a chemotherapy3free cell ALL) and low&intensity chemotherapy plus combination in older e patients (≥60 years) with venetoclax(for older patients with Ph3negative newly diagnosed Ph3positive ALL and younger ALL). Pre3clinical studies have demonstrated activity patients unfit for intensive chemotherapy, as well as of venetoclax and navitoclax in B3cell and T3cell ALL in those with relapsed/refractory Ph3positive ALL of cell lines. Preclinical data suggests as well any age, with promising initial results. So far 15 significant synergy with chemotherapy. Preliminary patients were enrolled and treated. In the frontline results of the combination of venetoclax with low3 treatment, 80% have achieved a deep molecular intensity chemotherapy in newly diagnosed older response within 3 months. patients unfit for intensive chemotherapy are promising with objective response and MRD 3. Minimal Residual Disease negativity rates of 91% and 100%, respectively. The Persistence or reappearance of minimal residual study provides venetoclax free of charge and is disease (MRD) after induction chemotherapy is the open for accrual. This regimen is open as well for most important adverse prognostic factor in patients patients with relapsed3refractory ALL, including with ALL and identifies chemo3refractory disease. More mainly T3cell ALL. than 90% of patients who have persistent MRD after chemotherapy experience a clinical relapse, despite 2. Frontline Ph&positive ALL continued chemotherapy, with a median time to relapse • Hyper&CVD + ponatinib + blinatumomab – of 435 months. Ponatinib is a potent third3generation Bcr3Abl • Blinatumomab – Blinatumomab was assessed in tyrosine kinase inhibitor (TKI) that also suppresses 116 patients with ALL in CR but with MRD positivity. the T315I mutation, which confers resistance to all Approximately 78% achieved MRD negativity after other commercially available TKIs. A study of hyper3 one cycle. With a median follow3up of 29 months, CVAD plus ponatinib resulted in a 53year overall the median survival was 36 months. The median OS survival rate of 74%, the best so far described in Ph3 for those who achieved MRD3negative status was positive ALL (long3term survival is 40350% with 40 months versus 12 months for those who earlier3generation TKIs). When compared to hyper3 remained MRD3positive. CVAD plus in a propensity score matching A Phase II study of blinatumomab in patients with B6 cross6linking cytotoxic agent tesirine (SG3249). cell ALL in first or second CR with positive MRD is ADCT6602 is being assessed at our institution in a active at our institution. Patients with Philadelphia6 Phase I/II trial. The hope is that this agent will be a positive disease are eligible and will receive potent anti6CD22 therapy, without the hepatic blinatumomab in combination with TKI. Twenty6seven toxicity associated with inotuzumab ozogamicin. patients have been treated so far. The MRD negativity This trial is currently open in the Phase I part. rate is 78%, with 26year survival rate of 72%. Patients with R/R B6ALL are eligible. Prior allogeneic stem cell transplant is allowed. This drug • Inotuzumab ozogamicin – Inotuzumab has shown is given IV once every 3 weeks. The drug is significant activity in R/R ALL with higher efficacy provided free of charge. observed in patients with minimal disease and in those treated in Salvage 1 compared to Salvage 2 • CAR T2cells – CAR T6cells directed at CD19 have and beyond. Inotuzumab is currently being emerged as an effective approach for patients with assessed in patients with both Ph6negative and Ph6 aggressive B6cell lymphomas and pediatric ALL. positive ALL with positive MRD. Patients with Ph6 With this therapeutic approach, autologous T6cells positive disease can also receive a TKI. are engineered to express a receptor directed at CD19, which mediates cytotoxicity. These cells Both blinatumomab and inotuzumab are provided free have been noted to expand and persist in vivo, of charge. which may lead to more durable responses. The most notable toxicities encountered with CAR T6cell 4. Salvage Treatments therapies include cytokine release syndrome (CRS), Ph#negative ALL encephalopathy and B6cell aplasia. The FDA • Hyper2CVD + inotuzumab ozogamicin + recently approved tisagenlecleucel for the treatment blinatumomab – This regimen combines low6 of relapsed/refractory ALL in patients up to age 26. intensity chemotherapy with the two most active In clinical trials, the response rate is 59% (83% monoclonal antibodies in ALL (inotuzumab among patients who were evaluable for efficacy). ozogamicin and blinatumomab). To date, 89 The 126month duration of response is 64%. patients have been treated. The overall response rate is 79%, with particularly efficacy in patients in • We have trials of both CD19 and CD226directed first salvage (response rate: 91%). The 26year CAR T6cells, as well as allogeneic CAR T6cells. overall survival rates for the entire cohort and for Allogeneic CAR T6cells offer an “off6the6shelf” patients in first salvage are 39% and 51%, approach, in which the cells are derived from respectively. A historical comparison with patients healthy6volunteer donor T6cells. Hence there is no who received inotuzumab ozogamicin as a single requirement to leukopherese patients and then wait agent shows a significant benefit to the combination for the cells to be manufactured. Below are the regimen (median overall survival: 14 months versus current CAR T6cell studies at MD Anderson: 6 months), strongly suggesting that combination Target Product AutologousHvs.H therapies should be offered to patients with Ph6 AllogeneicH negative ALL with relapsed/refractory disease. CD19 UCART19d Allod(deriveddfromd healthyddonors) • Hyper2CVD + venetoclax – Venetoclax is an oral KTE6C19 Autod Bcl62 inhibitor that has activity across a wide variety NK6CAR Allod(NKdcellsdderivedd of hematologic malignancies. Preclinical data fromdcorddblood) suggests significant synergy with chemotherapy and particular efficacy in patients with T6cell ALL. We CD22 UCART22 Allo (deriveddfromd have therefore designed a Phase I/II study of the healthyddonors) combination of hyper6CVD plus venetoclax for patients with relapsed/refractory ALL. This regimen Ph#positive0ALL is particularly promising for patients with T6cell ALL, • Blinatumomab and ponatinib – In addition to which is an unmet need as there are currently no being tested in older adults with newly diagnosed approved monoclonal antibodies this ALL subtype. Ph6positive ALL (see above), the chemotherapy6free Early results are encouraging with an objective combination of blinatumomab and ponatinib is being response rate of 74% obtained in patients with evaluated in patients with relapsed/refractory Ph6 refractory disease. positive ALL. This regimen combines two of the most active agents in Ph6positive ALL, both of which • ADCT2602 – ADCT6602 is an antibody drug are capable of overcoming the T315I resistance conjugate composed of a humanized monoclonal mutation, which is the dominant mechanism of antibody directed against CD22, conjugated to the relapse in Ph6positive leukemias. • Venetoclax and ponatinib – The Bcl(2 inhibitor trial of the oral, chemotherapy(free regimen is now venetoclax has shown significant promise across accruing for patients of all ages with relapsed/refractory multiple leukemias, with FDA approval for patients with Ph(positive ALL. relapsed/refractory CLL with 17p deletion and with excellent safety and efficacy when combined with low( The Leukemia Department welcomes and will facilitate intensity therapies in older patients with AML. There is referrals, and would like to work with you to make novel significant preclinical rationale for the combination of therapies available to your patients. For referrals, please venetoclax and ponatinib, with the combination showing contact any of the Leukemia faculty listed. synergistic activity in preclinical models. Ponatinib may also help to prevent venetoclax resistance by preventing upregulation of Mcl(1, an established resistance mechanism of venetoclax(based regimens. A Phase I/II Faculty(Contacts Completing+these+studies+in+a+timely+manner+will+allow+us+to+move+quickly+on+positive+leads.+We+appreciate+ referrals+and+will+make+every+effort,+once+a+patient+is+enrolled+on+a+study,+to+continue+as+much+of+the+care+as+ possible+through+the+referring+oncologist.+We+also+will+keep+you+apprised+of+the+patient's+progress. Clinical(Faculty

Kantarjian,*Hagop Department Chair (713)*79267026

Garcia6Manero,*Guillermo Deputy+Chair,+Chief,+Section+of+Translational+ (713)*74563428 Research,+Chief,+Section+of+Myelodysplastic Syndromes+ (MDS),+and+Director,+Leukemia+Clinical+Fellowship+Program

Konopleva,*Marina Deputy+Chair,+and+Chief,+Section+of+Leukemia+ (713)*79461628* Biology+Research

Wierda,*William Deputy+Chair,+Chief,+Section+of+Chronic+Lymphocytic+ (713)*74560428 Leukemia+(CLL),+and+Leukemia+Center+Medical+Director

Andreeff,*Michael Chief,+Section+of+Molecular+Hematology+and+Therapy, (713)*79267261 Center*Medical Director, Bone*Marrow*Aspiration*Clinic

Borthakur,*Gautam Chief,+Section+of+Developmental+Therapeutics (713)*56361586

DiNardo,*Courtney*D. CoJLeader,+Section+of+Acute+Myeloid+Leukemia+(AML),+ (734)*35861053 CoJLeader,+Section+of+Developmental+Therapeutics Leader,+Hereditary+Hematologic+Malignancy+Clinic+

Ferrajoli,*Alessandra Leukemia+Center+Associate+Medical+Director (713)*79262063*

Jabbour,*Elias Chief,+Section+of+Acute+Lymphoblastic+Leukemia+(ALL) (713)*79264764

Naqvi,*Kiran CoJLeader,+Section+of+Chronic+Myeloid+Leukemia+(CML)+ (713)*74565073

Kadia,*Tapan CoJLeader,+Section+of+Acute+Myeloid+Leukemia+(AML),+ (713)*56363534* CoJLeader,+Section+of+Developmental+Therapeutics,+ CoJLeader,+Leukemia+Clinical+Fellowship+Program

Ravandi,*Farhad Chief,+Section+of+Acute+Myeloid+Leukemia+(AML) (281)*21667806

Sasaki,*Koji CoJLeader,+Section+of+Chronic+Myeloid+Leukemia+(CML) (713)*74562882

Verstovsek,*Srdan Chief,+Section+of+Myeloproliferative++(MPNs),+ 713)*74563429 Director,+Clinical+Research+Center+for+MPNs Faculty'Contacts (Continued)

Clinical'Faculty Research'Faculty Alvarado,)Yesid (713))79454364 Battula,)Venkata (713))56352227 Bose,)Prithviraj (713))79257747 Bhalla,)Kapil)N. (713))56358619 Burger,)Jan (713))56351487 Burks,)Jared)K. (713))79257640 Daver,)Naval (713))79454392 Carter,)Bing)Z. (713))79454014 Estrov,)Zeev (713))79451675 Chang,)Kyung)Hee (713))79254694 Issa,)Ghayas)"Gus” (713))74558432 Colla,)Simona (713))79455223 Jain,)Nitin (713))74556080 Fiskus,)Warren (713))56355901 Kornblau,)Steven (713))79451568 Freireich,)Emil (713))79252660 Masarova,)Lucia (832))75054211 Gandhi,)Varsha)V. (713))79252989 Montalban)Bravo,)Guillermo (713))79453604 Han,)Lina (713))79257640 Ohanian,)Maro (713))79250091 Ishizawa,)Jo (713))79257640 Pemmaraju,)Naveen (713))79254956 Keating,)Michael (713))74552376 Short,)Nicholas (713))56354485 Piya,)Sujan (713))79257305 Takahashi,)Koichi (713))74554613 Plunkett,)William (713))79253335 Thompson,)Philip (713))79257430 Post,)Sean (713))79451458 Yilmaz,)Musa (713))74559945 Pourebrahimabadi,)Rasoul (713))79257305 Rytting,)Michael)E. (713))79254855 Ruvolo,)Peter (713))74559211 Wei,)Yue (713))79259854 Yang,)Hui (713))79252558 Zhang,)Weiguo (713))79454085

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