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Therapy of B-Cell Acute Lymphoblastic Leukemia: An Evolving Landscape

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Therapy of B-Cell Acute Lymphoblastic
Leukemia: An Evolving Landscape
Amir T. Fathi, MD
Director, Leukemia Program
Massach...

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Disclosures
Amir T. Fathi, MD
Consultant: AbbVie, Agios/Servier, Amgen, Astellas, Blueprint Medicines,
Celgene/Bristol Mye...

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Learning Objectives
ALL = acute lymphoblastic leukemia.
Discuss predictive and prognostic markers that can individualize
t...

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Therapy of B-Cell Acute Lymphoblastic Leukemia: An Evolving Landscape

  1. 1. Therapy of B-Cell Acute Lymphoblastic Leukemia: An Evolving Landscape Amir T. Fathi, MD Director, Leukemia Program Massachusetts General Hospital Associate Professor of Medicine Harvard Medical School
  2. 2. Disclosures Amir T. Fathi, MD Consultant: AbbVie, Agios/Servier, Amgen, Astellas, Blueprint Medicines, Celgene/Bristol Myers Squibb, Foghorn, Forma, Genentech, Ipsen, Kite, Kura, MorphoSys, Pfizer, Seagen, Takeda, Trillium Grants/research support: AbbVie, Agios/Servier, Celgene/BMS i3 Health has mitigated all relevant financial relationships
  3. 3. Learning Objectives ALL = acute lymphoblastic leukemia. Discuss predictive and prognostic markers that can individualize treatment selection for patients with B-cell ALL Assess emerging efficacy and safety data on novel therapeutic strategies for B-cell ALL Evaluate strategies to optimize the safety and tolerability of novel therapies for B-cell ALL
  4. 4. B-Cell ALL: Scope of the Problem
  5. 5. Almost 3,000 adults in the US with a new ALL diagnosis Prognosis is poor and worsens with age at diagnosis Current therapies for newly diagnosed B-cell ALL Typically include vincristine, corticosteroids, an anthracycline, or cyclophosphamide, with/without asparaginase Associated with CR rates of 60%-90% Relapse is common, and disease-free survival is 30%-50% at 3 years Traditional adverse risk features (eg, age, Ph chromosome, Ph-like disease, MLL translocations) Conventional chemotherapy regimens for R/R B-cell ALL are associated with significantly lower rates of response This impacts subsequent attempts of bridging to SCT as a curative paradigm CR = complete response; Ph = Philadelphia; MLL = mixed-lineage leukemia; R/R = relapsed/refractory; SCT = stem cell transplant. Image courtesy of Cancer Network and Wikimedia Commons. SEER, 2018; Kantarjian, DeAngelo et al, 2016; Jabbour, O’Brien, Konopleva et al, 2015. B-Cell ALL Is Challenging to Treat in Adults
  6. 6. Age-Specific Annual Incidence of ALL Larson, 2005. US SEER Data, 1998-2002 Age (5-year intervals)
  7. 7. Treatment Outcome by Age Cohort CALGB = Cancer and Leukemia Group B. Larson, 2005. CALGB Studies: 759 Patients With ALL, 1988-2002
  8. 8. ALL Cure Rates Decrease With Age OS = overall survival; yrs = years. Gatta et al, 2013; Juliusson et al, 2011. Period of Diagnosis Proportion of Cured Cases (%) 1982- 1984 100 90 80 70 60 50 40 30 20 10 0 1985- 1987 1988- 1990 1991- 1993 1994- 1996 1997- 1999 2000- 2002 <1 yr 1-4 yrs 5-9 yrs 10-14 yrs 15-19 yrs 20-24 yrs Estimated Proportion of Infants, Children, Adolescents, and Young Adults Cured of ALL in Europe, 1982-2002 Cumulative Proportion Surviving (%) OS From Diagnosis by Age in Sweden, 1997-2006 100 90 80 70 60 50 40 30 20 10 0 Yrs From Diagnosis 13 0 1 2 3 4 5 6 7 8 9 10 11 12 16-29 yrs, n=81 30-39 yrs, n=60 40-44 yrs, n=36 45-49 yrs, n=25 50-54 yrs, n=45 55-59 yrs, n=29 60-64 yrs, n=44
  9. 9. Pediatric Outcomes Better Than in Adult Populations a6-year EFS. bDFS. EFS = event-free survival; DFS = disease-free survival; peds = pediatrics. DeAngelo, 2005. Cooperative group/study period No. of patients CR (%), 5-year EFS (%), 5-year North America 1988, age of patients (yrs): 16-21 CCG 1882 (peds) 196 96% 64%a CALGB 8811-9511 (adult) 103 93% 38%a French 1993-1994 age of patients (yrs): 15-20 FRALLE-93 (peds) 77 94% 67% LALA-94 (adult) 100 83% 41% Dutch 1985-1999, age of patients (yrs): 15-20 DCOG-ALL (peds) 15-18 yrs 47 98% 69% HOVON (adult) 15-18 yrs 44 91% 34% 19-20 yrs 29 90% 34% Italian 1996-2000, age of patients (yrs): 14-18 AIEOP (peds) 153 94% 83%b GIMEMA (adults) 95 95% 55%b
  10. 10. Study Relapsed patient population Median age (range) No. of pts Study end points Tavernier et al, 2007 LALA-94 trial: France, Belgium, Switzerland, Australia 34 (15-62) 421 Oriol et al, 2010 Spain PETHEMA Group: data from 4 trials 33 (15-69) 263 Gökbuget, 2012 German pts: GMALL (2 clinical trials) 33 (15-55) 547 O’Brien et al, 2008 US, MD Anderson 33 (14-76) 288 O’Brien et al, 2013 US, multicenter (liposomal vincristine) 31 (19-83) 65 CR: overall 44% CR: high risk 37% CR: standard risk 52% CR: overall 18% Early relapse (1-11 mos) 12% CR: age 15-30 47% CR: age 30-55 48% CR: age 55-70 20% CR: overall 42% Early relapse 36% Late relapse 58% Common Conventional Treatment Regimens pts = patients; mos = months; CRi = CR with incomplete count recovery. Tavernier et al, 2007; Oriol et al, 2010; Gökbuget, Stanze et al, 2012; O’Brien et al, 2008b; O’Brien et al, 2013. Generally Poor Responses in R/R ALL CR/Cri: overall 20% First relapse Second relapse
  11. 11. Adults With ALL Have Poor Prognosis Adapted from Jae Park. Tavernier et al, 2007; Fielding et al, 2007. MRC UKALL2/ECOG2993 study (N=609) Outcome of patients after first relapse 5-yr OS: 7% Outcome of patients after first relapse 2-yr OS: 11% 5-yr OS: 8% LALA-94 study (N=421) Time (years)
  12. 12. CRLF2 = cytokine receptor-like factor 2. Jain et al, 2017. B-other 36% (53/148) Ph-positive ALL 31% (46/148) Ph-like ALL 33% (49/148) Ph-like CRLF2 61% (30/49) Ph-like non-CRLF2 39% (19/49) Mos Survival Probability 1.0 0.8 0.6 0.4 0.2 0 0 72 12 24 36 48 60 Ph-like B-others Total 56 53 Died 38 23 Median 28.8 NR P=0.006 Mos 0 72 12 24 36 48 60 0.8 Ph-like B-others Total 56 53 Died 41 26 Median 17.2 63.8 P=0.006 Event-Free Survival Probability 1.0 0.6 0.4 0.2 0 72 60 CRLF2 Non-CRLF2 Ph-positive B-others Total 37 19 46 53 Died 29 12 29 26 Median 12.3 27.8 21.7 63.8 Mos 0 36 48 12 24 1.0 0 0.6 0.4 Event-Free Survival Probability 0.8 0.2 Survival Probability CRLF2 Non-CRLF2 Ph-positive B-others Total 37 19 46 53 Died 27 11 27 23 Median 23.0 48.8 46.0 NR Mos 0 72 12 24 36 48 60 0 1.0 0.8 0.6 0.4 0.2 Ph-Like Lesions in ALL Negatively Impact Prognosis
  13. 13. Pediatric Versus Adult Regimens for ALL MRD = minimal residual disease. Adapted from Boisel & Sender, 2015. Pediatric regimens Involve more intensive use of… Corticosteroids Vincristine Asparaginase Emphasize timely administration of therapy Typically include MRD quantification to assess response to treatment Outcomes in Adolescents and Young Adult Patients Treated With Pediatric or Adult ALL Regimens OS (%) 0 100 20 40 60 80 Boissel et al, 2003 de Bont et al, 2004 Ramanujackar et al, 2007 Testi et al, 2004 Stock et al, 2008 LALA-94 FRALLE-93 HOVON 5/18 DCOG 6/9 UKALL 97/99 UKALL GIMEMA AIEOP CALGB CCG
  14. 14. Intergroup C10403 AYA = adolescent and young adult; CI = confidence interval; NR = not reached. Adapted from Stock et al, 2019. Pediatric-Like Regimen for AYA Patients With ALL N=295, events = 105 Median OS: not reached 2-yr OS rate: 79% (95% CI: 74%, 84%) Mos 3-Yr OS: 73% 72 0 12 24 36 48 60 100 80 60 40 20 Survival (%) 72 N=295, events = 139 Median EFS: 78 mos (95% CI: 58-NR) 2-yr EFS rate: 66% (95% CI: 61%, 72%) 3-Yr EFS: 60% Mos 0 60 48 36 24 12 0 0 100 80 60 40 20 Alive and Event-Free (%) CALGB historical control event-free survival: 48%
  15. 15. Newly Diagnosed ALL: Therapeutic Strategies
  16. 16. Rituximab-Based Chemoimmunotherapy Rituximab administered on Days 1 and 11 of induction at 375 mg/m2 if CD20 expression ≥20% In those <60 years, OS was superior with rituximab plus hyper-CVAD compared with standard hyper-CVAD (75% vs 47%, P=0.003) Older patients with CD20- positive ALL did not benefit from rituximab-based chemoimmunotherapy (OS 28% vs 32%) hyper-CVAD = cyclophosphamide/vincristine sulfate/doxorubicin hydrochloride/dexamethasone. Thomas et al, 2010. Improves Outcomes in De Novo Ph-Negative ALL
  17. 17. SCT for Newly Diagnosed Ph-Positive ALL, Pre-TKI TKI = tyrosine kinase inhibitor. Dombret et al, 2002. Probability of 3-Yr OS Donor (n=60) 37% No donor (n=43) 12%
  18. 18. PH-Positive ALL: Hyper-CVAD + Dasatinib aPatients received intrathecal CNS prophylaxis 2x during Cycles 1-4. bPost-amendment patients received 100 mg on Days 1-14 of first cycle and then 70 mg continuously Cycles 2-8. Prior patients initially received 50 mg BID and then 100 mg QD following initial amendment on Days 1-14 of each cycle. cAlternating between each cycle. dPatients with available donor. tx = treatment/therapy; ECOG PS = Eastern Cooperative Oncology Group performance status; PO = by mouth; QD = every day; RFS = relapse-free survival; HCT = hematopoietic cell transplantation; MTX = methotrexate. Ravandi et al, 2016. Study Design: Phase 2 Single-Arm Study Patients 18-60 yrs with newly diagnosed Ph- positive ALL and 0-1 induction tx; ECOG PS ≤3; (N=94) Intensive phase (8 21-day cycles)a Dasatinib 100/70 mg PO QDb + hyper-CVAD alternating w/ MTX + cytarabinec Maintenance phase (24 monthly cycles) Dasatinib 100 mg PO QD + hyper-CVAD alternating w/vincristine/prednisone Allogeneic HCTd Dasatinib 100 mg PO QD Transplan t Primary end point: 12-month RFS Additional end points: CCR, OS, MRD
  19. 19. Ravandi et al, 2016. Event-Free Survival Overall Survival Mos Mos Total patients (N=94) Probability of OS (95% CI) Probability of EFS (95% CI) PH-Positive ALL: Hyper-CVAD + Dasatinib (cont.)
  20. 20. Hyper-CVAD + Ponatinib in Ph-Positive ALL: Efficacy Single-arm phase 2 trial in previously untreated adults with Ph-positive ALL (N=76) Median age: 47 yrs (range: 39-61) 65/65 CR (100%) 74/75 FCM-MRD–negative (99%) 83% CMR 76% 3-yr OS and 71% 5-yr OS FCM = flow cytometry; CMR = complete molecular response. Jabbour et al, 2018. Achieving Long-Term Remission in Ph-Positive ALL Overall Survival (%) Event-Free Survival (%)
  21. 21. Dasatinib as First-Line Treatment in Ph-Positive ALL CHR = complete hematologic remission. Foà et al, 2011. Dasatinib + prednisone + intrathecal chemotherapy in adults with newly diagnosed Ph-positive ALL 53/53 of evaluable patients achieved CHR More than 50% of patients relapsed Need for post-induction strategies, including allogeneic HCT in eligible patients
  22. 22. Relapsed/Refractory ALL: Novel Therapeutic Strategies
  23. 23. Immunotherapy Targets in Adult Relapsed/Refractory ALL CD3 = cluster of differentiation 3; CD19 = cluster of differentiation 19; TCR = T-cell receptor; BiTE = bispecific T-cell engagers. Berry et al, 2017; Gökbuget, Kneba et al, 2012; Kantarjian, DeAngelo et al, 2016; Maino et al, 2016; Besponsa® prescribing information, 2017. TCR B-precursor ALL cell CD19 Blinatumomab CD3 T cell Tumor cell Nucleus Calicheamicin binds to DNA CD22 Internalization Calicheamicin Inotuzumab ozogamicin Genetically modified CD19-targeted T-cell CD19 Tumor cell CAR TCR BiTE and CAR T-cell therapies engage the immune system to fight ALL
  24. 24. Ricart, 2011; Kantarjian et al, 2013. A CD22 monoclonal antibody bound to the cytotoxic agent calicheamicin, a natural product of Micromonospora echinospora Binds CD22 with high affinity is and rapidly internalized, delivering the conjugated calicheamicin intracellularly Calicheamicin binds to the minor groove of DNA, causing double-strand DNA breaks and resultant cell death Inotuzumab Ozogamicin (IO)
  25. 25. Inotuzumab Ozogamicin Is Effective in R/R ALL Initial dosing: 1.8 mg/m2 intravenously every 3-4 weeks More frequent, lower dosing schedules of inotuzumab may reduce toxicities Dose schedule changed to 0.8 mg/m2 on Day 1 and 0.5 mg/m2 on Days 8 and 15 of 3-4–week cycles Kantarjian et al, 2013. Liver Toxicity Reduced by Changing Dosing Schedule
  26. 26. Many patients treated with inotuzumab ozogamicin were able to proceed to allogeneic stem cell transplant In these patients, a serious toxicity included the development of veno- occlusive disease (VOD) In the initial PH2 study of single dose Q3-4 weeks, 23% of patients developed VOD, with most having received multiple alkylating therapies in transplant preparative regimens The subsequent lower-dose weekly regimen led to significantly less hepatotoxicity, including a much lower incidence of VOD after transplant (7% vs 23%) PH2 = phase 2; Q = every. Kantarjian et al, 2013; Kantarjian et al, 2012; Jabbour, O’Brien, Ravandi et al, 2015. Liver Toxicity: Importance of Dose and Close Monitoring Inotuzumab Ozogamicin (cont.)
  27. 27. Patients were randomly assigned in a 1:1 ratio to receive either inotuzumab ozogamicin or investigator’s choice of standard therapy Investigator choice regimens were 1.) FLAG, 2.) cytarabine/mitoxantrone, or 3.) HiDAC CD22 = cluster of differentiation 22; FLAG = fludarabine/cytarabine plus granulocyte colony-stimulating factor; HiDAC = high-dose cytarabine. Kantarjian, DeAngelo et al, 2016. Relapsed or Refractory CD22-Positive ALL Patients were ≥18 years of age, had relapsed or refractory CD22-positive ALL, and were scheduled to receive their first or second salvage treatment Dose schedule: 0.8 mg/m2 on Day 1 and 0.5 mg/m2 on Days 8 and 15. Cycle 1 was 21 days, and subsequent cycles were 28 days long Upon achievement of response, the Day 1 dose was reduced to 0.5 mg for remaining cycles Inotuzumab Ozogamicin Versus Standard Therapy
  28. 28. Inotuzumab Ozogamicin for R/R ALL Kantarjian, DeAngelo et al, 2016, CR Was Higher Compared With Standard Therapy
  29. 29. Kantarjian, DeAngelo et al, 2016. Inotuzumab Ozogamicin for R/R ALL (cont.)
  30. 30. Inotuzumab Ozogamicin for R/R ALL (cont.) †The two-sided P values for between-group differences were determined by means of the chi-square test or Fisher's exact test (if any cell count was <5). Kantarjian, DeAngelo et al, 2016. Better Remission Rate and Survival With IO
  31. 31. Inotuzumab Ozogamicin for R/R ALL (cont.) Kantarjian, DeAngelo et al, 2016. Veno-Occlusive Disease: Serious Adverse Event
  32. 32. Inotuzumab Ozogamicin for R/R ALL Kantarjian et al, 2017. Treatment Associated With Increased Hepatotoxicity Hepatic adverse event profile of inotuzumab ozogamicin in adult patients with relapsed or refractory acute lymphoblastic leukemia: results from the open-label, randomised, phase 3 INO-VATE study Hagop M Kantarjian, Daniel J DeAngelo, Anjali S Advani, Matthias Stelljes, Partow Kebriaei, Ryan D Cassaday, Akil A Merchant, Naohito Fujishima, Toshiki Uchida, Maria Calbacho, Anna A Ejduk, Susan M O’Brien, Elias J Jabbour, Hui Zhang, Barbara J Sleight, Erik R Vandendries, David I Marks
  33. 33. Inotuzumab Ozogamicin for R/R ALL (cont.) HSCT = hematopoietic stem cell transplantation. Kantarjian et al, 2017 Factors Associated With IO-Related Hepatotoxicity
  34. 34. IO + Mini–Hyper-CVD PFS = progression-free survival; MDACC = MD Anderson Cancer Center. Kantarjian et al, 2018; O’Brien et al, 2008a. Active Therapy in Patients >60 Yrs of Age 52 (0) 52 (0) 32 (8) 31 (8) 21 (16) 19 (15) 16 (18) 14 (17) 8 (26) 7 (24) 1 (33) 1 (30) 0 (34) 0 (31) Patients at risk, n (number censored) OS PFS Mos From Start of Treatment 72 12 24 36 48 60 PFS OS 2 Yr (95% CI) 59% (43-72) 66% (50-78) 3 Yr (95% CI) 49% (32-64) 56% (39-79) Median 35 mos Not reached 100 80 60 40 20 0 Survival (%) 0 Inotuzumab + Mini-Hyper-CVD PFS and OS Survival in ALL by Age and Treatment (MDACC: 1983-2006, N=565) Died 200 94 33 Total 409 122 34 Regimen HCVAD HCVAD Pre-HCVAD P<0.001 Age, Yrs <60 ≥60 ≥60 1.0 0.8 0.6 0.4 0.2 0 Survival Probability Yrs 0 1 2 3 4 5 6 7 8 9 10 48% 9% 20%
  35. 35. Inotuzumab Ozogamicin (cont.) EBMT = European Group for Blood and Marrow Transplantation. Jain & Litzow, 2018; Mohty et al, 2016. Management of Liver Toxicity/Sinusoidal Obstructive Syndrome (SOS) Timeframe Diagnosis (new EBMT criteria) Prevention Treatment Within 21 days from HCT Bilirubin ≥2 mg/dL plus 2 of the below:  Painful hepatomegaly  Weight gain >5%  Ascites  Avoid HCT regimen with double alkylator  Avoid treatment with cycles of IO if planning HCT  Permanent discontinuation  Supportive therapy to fluids and control pain Late onset (21 days after HCT) Either:  Meets criteria above  Histological diagnosis of SOS  2 of the above criteria plus hemodynamic and/or evidence of SOS  Avoid concomitant hepatotoxic  Encourage use of prophylactic agents ursodiol)  Paracentesis for ascites as needed  Limit fluid removal with paracentesis to <1 L to disruption of renal perfusion  Defibrotide for severe SOS
  36. 36. Blinatumomab Engages T Cells to Lyse B-Lineage ALL Cells Bargou et al, 2008; Raponi et al, 2011; Piccaluga et al, 2011; Image By Kuebiderivative work: ἀνυπόδητος (talk) CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=9009826. Blinatumomab is a BiTE antibody construct It has dual specificity for CD19 and CD3 Blinatumomab simultaneously binds CD3-positive cytotoxic T cells and CD19-positive B cells, resulting in T cell–mediated lysis of normal and malignant B cells CD19 is expressed in virtually all tested B-lineage ALL cells and throughout B- cell development CD19
  37. 37. Blinatumomab (cont.) Kantarjian, Stein et al, 2018. Phase 2 Studies
  38. 38. Blinatumomab (cont.) Patient median age: 32 years (range 18-77) Median OS: 9.8 months Median RFS: 7.6 months 13 underwent HSCT after CR or CRh Most frequent AE during treatment was pyrexia (grade 1/2, 75%; grade 3, 6%) Treatment interrupted/discontinued in 2 patients for cytokine release syndrome and 6 patients with nervous system or psychiatric disorders AE = adverse event; CRh = partial recovery of peripheral blood counts. Topp et al, 2014. Demonstrates Remissions in R/R ALL
  39. 39. Topp et al, 2015. Blinatumomab Safety for B-Precursor ALL
  40. 40. Blinatumomab Safety for B-Precursor ALL (cont.) Topp et al, 2015.
  41. 41. COG AALL1331: Blinatumomab/Dex BM = bone marrow; iEM = inborn errors of metabolism; CR1 = first complete remission; BLINA = blinatumomab; d = days; Wk = week; DEX = dexamethasone; VCR = vincristine; PEG IM = pegylated asparaginase intramuscular injection; CPM = cyclophosphamide; ETOP = etoposide; HDAC = histone deacetylase. Brown et al, 2019. Study Design: Multicenter Open-Label Phase 3 Study Patients aged 1-30 yrs with first relapse of B-ALL deemed high- or intermediate-risk; no Ph positivity, prior HSCT, Down syndrome, or prior blinatumomab (N=208) BLINA 15 μg/m²/day x28 days, then 7 d off DEX 5 mg/m²/ x1 premed cycle 1 only (n=105) VCR + DEX, Wk 1 Intrathecal MTX + PEG IM, Wk 2 CPM/ETOP, Wk 3 (n=103) VCR + DEX, Wk 1 HDAC + Erwinia, Wk 1-2 Intrathecal MTX + Erwinia, Wk 4 (n=103) Stratified by risk group (high- vs intermediate-risk); and by site (BM vs iEM) and BM:CR1 duration (<18 vs 18-36 mos) in high-risk patients Evaluation 2 BLINA 15 μg/m²/day x28 days, then 7 days off (n=105) Randomization stopped at September 2019 with 95% projected accrual Primary end point: DFS Secondary end points: OS, MRD response, proceeding to HSCT Evaluation 1
  42. 42. Median follow-up: 1.4 yrs Brown et al, 2019. Blin/Dex Appears Better Than Conventional Chemotherapy 1.0 0.8 0.6 0.4 0.2 0 DFS 0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0 4.5 Yrs Chemotherapy Blinatumomab 41.0 ± 6.2% at 2 yrs (n=103) 59.3 ± 5.4% at 2 yrs (n=105) Stratified log-rank test: P=0.050 (1-sided) At Risk Chemotherapy Blinatumomab 103 105 55 69 39 47 29 38 18 31 10 19 4 10 1 5 1 2 0 0 1.0 0.8 0.6 0.4 0.2 0 OS 0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0 4.5 Yrs Chemotherapy Blinatumomab 59.2 ± 6.0% at 2 yrs (n=103) 79.4 ± 4.5% at 2 yrs (n=105) Stratified log-rank test: P=0.005 (1-sided) At Risk Chemotherapy Blinatumomab 103 105 64 77 50 55 38 44 25 38 15 24 6 11 2 5 1 2 0 0 DFS OS HSCTCOG AALL1331: Survival in Pediatric and AYA Patients
  43. 43. Outcomes With MRD-Positive ALL FISH = fluorescence in situ hybridization; PCR = polymerase chain reaction. Brüggemann & Kotrova, 2017; Berry et al, 2017; Gökbuget, Kneba et al, 2012; Fielding et al, 2007; Tavernier et al, 2007. MRD: low-level molecular disease in patients achieving CR according to conventional analyses MRD detected by more sensitive methods Flow cytometry for leukemia-associated immunophenotype FISH or PCR for leukemia-specific fusion transcripts or gene rearrangements MRD-positive status prognostic for poor survival outcomes in ALL GMALL 06/99 and 07/03: OS by MRD Status After Intensive Chemotherapy Induction and Consolidation Yrs Probability of OS MRD Status, Wk 16 Probability of 5-Yr OS, % Negative (n=384) 80 Positive (n=120) 42 P<0.0001 0 0.1 0.2 0.3 0.4 0 1 2 3 4 5 0.5 0.6 0.7 0.8 0.9 1.0 6 7 8 9 10 11
  44. 44. Methods for MRD Quantification in ALL aConventional analysis may not be adequate for MRD quantification. bPhenotype of cancer cells must be different from normal cells. ASO-PCR = allele-specific oligonucleotide polymerase chain reaction; NGS = next-generation sequencing. LLS, 2021. Flow cytometry ASO-PCR NGS Sensitivity 10-4 (to 10-5) 10-4 to 10-5 10-6 Samples Fresh Fresh or frozen Fresh or frozen Availability Widely availablea Widely available for certain mutations Commercially as Customization Not requiredb Patient-specific probes and primers Not required Cost Expensive Expensive Expensive
  45. 45. MAC = myeloablative conditioning; allo = allogeneic; Ig = immunoglobulin; ASO = allele-specific oligonucleotides; BCR = breakpoint cluster region protein; Q = quantitative; CIR = cumulative incidence of relapse. Spinelli et al, 2007. N=43, 18-63 yrs of age MAC alloHCT in CR1 MRD quantification: TCR/Ig ASO-PCR, BCR/ABL, or MLL/AF4 Q- PCR CIR by MRD Status Pre-HCT MRD-positive MRD-negative MRD- positive MRD- negative n=14 0.8 (0.46-0.98) n=17 0.07 (0.01-0.39) OS by MRD Status Pre-HCT n=12 0.80 (0.40-0.95) n=25 0.49 (0.20-0.67) MRD- negative MRD- positive Mos 0 12 1.00 0.75 0.50 0.25 0 0 MRD Status Before and After HCT Survival
  46. 46. RFS of 78% at 405 days Blinatumomab Effectively Erases MRD in B-ALL 21 patients treated with MRD persistence or relapse after induction/consolation Most frequent AE was lymphopenia Topp et al, 2011.
  47. 47. Blinatumomab Associated With Sustained Impressive RFS With median F/U of 33 mos, RFS was 61% F/U = follow-up Topp et al, 2012. Longer Follow-Up for Patients With MRD
  48. 48. Blinatumomab: CRS Management Stein et al, 2018; Maude et al, 2014. Premedication with dexamethasone before start, step-up, and restart after >4 hours of discontinuation Inpatient initiation for high-risk patients Grade 3 Grade 4 Intervention • Hold infusion • Consider dexamethasone 24 mg/day x3 days, then taper over 4 days • When resolved, restart at 9 μg/day for 7 days, then escalate to 28 μg/day • Hold infusion and consider 24 mg/day x3 days, then taper over 4 • Permanently discontinue blinatumomab • Consider tocilizumab
  49. 49. Blinatumomab: Neurotoxicity Management Stein et al, 2018. Prevention  Premedication with dexamethasone before start  Step-up and restart after >4 hours of discontinuation  Inpatient initiation for high-risk patients  Patient selection • Higher risk in older non-White patients, as well as in patients with prior neurologic events, later salvage • Studies excluded those with organic brain disease Intervention Seizure • Hold infusion • Consider anticonvulsant • Consider dexamethasone 24 mg/day for 3 days, then taper over 4 days • When resolved, restart at 9 µg/day for 7 days, then escalate to 28 µg/day • If >1 seizure, discontinue permanently Grade 3 • Hold infusion • Consider dexamethasone 24 mg/day for 3 days, then taper over 4 days • When resolved, restart at 9 µg/day for 7 days, then escalate to 28 µg/day Grade 4 or grade 3 than 7 days • Hold infusion • Consider dexamethasone 24 mg/day for 3 days, then taper over 4 days • Permanently discontinue blinatumomab
  50. 50. CAR T-Cell Manufacturing, Treatment, and Assessment Park et al, 2017. Leukapheresis T-cell production Conditioning chemotherapy 19-28z CAR T-cells (2 dose levels) Salvage chemo Disease assessment Disease assessment Day -2 Day 0 Days 28-35
  51. 51. ELIANA: Tisagenlecleucel (CD19 CAR T) aFrom 3 yrs at screening to 21 yrs at initial diagnosis. b17 patients discontinued before infusion: deaths, n=7; manufacturing failures, n=7; AEs, n=3. BM = bone marrow; ORR = overall response rate; DOR = duration of response; IV = intravenous; IRC = independent review committee. Maude et al, 2018; Grupp et al, 2016; Park et al, 2017. Pediatric and Young Adult Patients With B-Cell ALL Patients aged 3-23 yrsa with B- cell ALL; ≥5% BM lymphoblasts; no isolated extramedullary disease relapse, prior CD19-directed therapy, or prior gene therapy (N=92) Single-dose tisagenlecleucel 0.2-5.0x106/kg IV if ≤50 kg 0.1-2.5x108 IV if >50 kg (n=75b) Fludarabine 30 mg/m² IV QD for 4 doses Cyclophosphamide 500 mg/m² IV QD for 2 doses Primary end point: ORR (CR + CRi) within 3 mos, assessed by IRC 4-wk maintenance of remission required Secondary end points: MRD status, DOR, OS, cellular kinetics, and safety Multicenter, open-label, single-arm phase 2 study of CD19-targeted CAR T-cell therapy
  52. 52. ELIANA: Tisagenlecleucel (cont.) Maude et al, 2018; Mueller et al, 2018. Remission and Survival Duration of Remission EFS and OS No. patients: 61 No. events: 17 Median DOR: NR Mos Since Onset of Remission Mos Since Tisagenlecleucel Infusion No. Patients No. Events Median OS, Mos 6-Mo OS, % OS 75 19 19.1 90 EFS 75 27 NR 73 0 0.2 0.4 0.6 0.8 1.0 0 2 4 6 8 10 12 14 16 18 20 22 61 54 43 33 23 18 8 7 3 1 0 Patients at risk, n 0 0.2 0.4 0.6 0.8 1.0 0 2 4 6 8 10 12 14 16 18 20 22 75 75 72 64 64 51 58 37 55 33 40 19 30 13 20 8 12 3 8 3 2 1 Patients at risk, n OS EFS 0 0 Probability Probability EFS OS
  53. 53. ELIANA: Tisagenlecleucel (cont.) aRegardless of relationship to tisagenlecleucel. Wks = weeks. Maude et al, 2018. AEs Within 8 Weeks of Infusion Median time to onset: 3 days Median duration: 8 days Median time to onset: 6 days Median duration: 6 days AEa of special interest, n (%) Any grade (n=75) Grade 3 (n=75) Grade 4 (n=75) Any AE of special interest 67 (89%) 26 (35%) 30 (40%) Cytokine release syndrome 58 (77%) 16 (21%) 19 (25%) Neurologic event 30 (40%) 10 (13%) 0 Infection 32 (43%) 16 (21%) 2 (3%) Febrile neutropenia 26 (35%) 24 (32%) 2 (3%) Cytopenia not by Day 28 28 (37%) 12 (16%) 12 (16%) Tumor lysis syndrome 3 (4%) 3 (4%) 0
  54. 54. Tisagenlecleucel: FDA Approval and Indication in ALL CRS = cytokine release syndrome; REMS = Risk Evaluation and Mitigation Strategy. Kymriah® prescribing information, 2020. Tisagenlecleucel is currently indicated for treating patients <25 yrs of age with B-cell precursor ALL that is either refractory or in second or later relapse Boxed warnings: CRS and neurologic toxicities Only available through restricted program under REMS Certified health care facilities with onsite immediate access to tocilizumab (minimum of 2 doses/patient) Health care providers trained in management of CRS, neurologic toxicities
  55. 55. Brexucabtagene Autoleucel The FDA approved brexucabtagene autoleucel for relapsed or refractory B-cell precursor ALL Indication: adult patients with R/R B-cell precursor ALL US Food & Drug Administration, 2021. FDA Approved for B-Cell ALL
  56. 56. Shah et al, 2021. Brexucabtagene Autoleucel Leads to Durable Remissions
  57. 57. Brexucabtagene Autoleucel: CRS and Neurologic Toxicity Shah et al, 2021. Any grade Grade 1 Grade 2 Grade 3 Grade 4 Grade 5 CRS Any 49 (89%) 11 (20%) 25 (45%) 7 (13%) 6 (11%) 0 Pyrexia 46 (94%) 7 (14%) 20 (41%) 16 (33%) 3 (6%) 0 Hypotension 33 (67%) 1 (2%) 16 (33%) 13 (27%) 3 (6%) 0 Sinus tachycardia 18 (37%) 7 (14%) 8 (16%) 3 (6%) 0 0 Chills 14 (29%) 10 (20%) 4 (8%) 0 0 0 Hypoxia 14 (29%) 1 (2%) 2 (4%) 7 (14%) 4 (8%) 0 Tachycardia 12 (24%) 3 (6%) 9 (18%) 0 0 0 Fatigue 10 (20%) 8 (16%) 2 (4%) 0 0 0 Headache 10 (20%) 6 (12%) 4 (8%) 0 0 0 Neurologic events Any 33 (60%) 6 (11%) 13 (24%) 13 (24%) 0 1 (2%) Tremor 15 (27%) 14 (25%) 0 1 (2%) 0 0 Confusional state 14 (25%) 5 (9%) 7 (13%) 2 (4%) 0 0 Encephalopathy 12 (22%) 1 (2%) 7 (13%) 3 (5%) 1 (2%) 0
  58. 58. IO Incorporated Into Frontline Therapy For Older Patients Chevallier et al, 2021; Stelljes et al, 2021. ASH 2021
  59. 59. Key Takeaways Adult outcomes are significantly worse than in pediatric ALL Traditional conventional chemotherapy approaches have been suboptimal AYA regimens are increasingly used for patients up to age 50 years A new era in immunologically-derived therapies Antibody-drug conjugates, inotuzumab ozogamicin BiTE, blinatumomab CAR T cells
  60. 60. Case-Based Panel Discussion
  61. 61. Case Study: Ms. VM A 52-year-old female is diagnosed with PH-negative B-cell ALL, with a normal karyotype After receiving multi-agent induction chemotherapy as per the Larson regimen (CALGB 8811) protocol, she achieved a morphologic complete remission However, flow cytometry of aspirate revealed 0.2% residual lymphoid blasts. She received 3 more cycles of intensive therapy However, flow cytometry of repeat aspirate again shows MRD with 0.18% lymphoid blasts
  62. 62. Case Study: Ms. VM The hope is to pursue long-term survival and a curative paradigm for this patient. What would be the most appropriate therapeutic step at this point? A. Proceed to an alternative induction regimen such as hyper-CVAD B. Ponatinib combined with intensive therapy C. Blinatumomab D. Uncertain
  63. 63. Case Study: Ms. VM The hope is to pursue long-term survival and a curative paradigm for this patient. What would be the most appropriate therapeutic step at this point? A. Proceed to an alternative induction regimen such as hyper-CVAD B. Ponatinib combined with intensive therapy C. Blinatumomab D. Uncertain
  64. 64. References Bargou R, Leo E, Zugmaier G, et al (2008). Tumor regression in cancer patients by very low doses of a T cell-engaging antibody. Science, 321(5891):974-7. DOI:10.1126/science.1158545 Berry DA, Zhou S, Higley H, et al (2017). Association of minimal residual disease with clinical outcome in pediatric and adult acute lymphoblastic leukemia: a meta-analysis. JAMA Oncol, 3(7):e170580. DOI:10.1001/jamaoncol.2017.0580 Besponsa® (inotuzumab ozogamicin) prescribing information (2017). Wyeth Pharmaceuticals. Available at: https://labeling.pfizer.com/ShowLabeling.aspx?id=9503 Boissel N & Sender LS (2015). Best practices in adolescent and young adult patients with acute lymphoblastic leukemia: a focus on asparaginase. J Adolesc Young Adult Oncol, 4(3):118-128. DOI:10.1089/jayao.2015.0014 Brown PA, Ji L, Xu X, et al (2019). A randomized phase 3 trial of blinatumomab vs. chemotherapy as post-reinduction therapy in high and intermediate risk (HR/IR) first relapse of B-acute lymphoblastic leukemia (B-ALL) in children and adolescents/young adults (AYAs) demonstrates superior efficacy and tolerability of blinatumomab: a report from Children’s Oncology Group Study AALL1331. Blood, 134(suppl_2). Abstract LBA-1. DOI:10.1182/blood-2019-132435 Brüggemann M & Kotrova M (2017). Minimal residual disease in adult ALL: technical aspects and implications for correct clinical interpretation. Blood Adv, 1(25):2456-2466. DOI:10.1182/bloodadvances.2017009845 Chevallier P, Leguay T, Doubek M, et al (2021). Fractionated inotuzumab ozogamicin combined with low-intensity chemotherapy provides very good outcome in older patients with newly diagnosed CD22+ Philadelphia chromosome-negative B-cell precursor acute lymphoblastic leukemia: first results from the EWALL-INO study [oral presentation]. 63rd American Society of Hematology Annual Meeting & Exposition. Abstract 511. DeAngelo DJ (2005). The treatment of adolescents and young adults with acute lymphoblastic leukemia. Hematology Am Soc Hematol Educ Program, 2005(1):123-130. DOI:10.1182/asheducation-2005.1.123 Dombret H, Gabert J, Boiron JM, et al (2002). Outcome of treatment in adults with Philadelphia chromosome-positive acute lymphoblastic leukemia—results of the prospective multicenter LALA- 94 trial. Blood, 100(7):2357-2366. DOI:10.1182/blood-2002-03-0704 Fielding AK, Richards SM, Chopra R, et al (2007). Outcome of 609 adults after relapse of acute lymphoblastic leukemia (ALL); an MRC UKALL12/ECOG 2993 study. Blood, 109(3):944-950. DOI:10.1182/blood-2006-05-018192 Foà R, Vitale A, Vignetti M, et al (2011). Dasatinib as first-line treatment for adult patients with Philadelphia chromosome-positive acute lymphoblastic leukemia. Blood, 118(25):6521-6528. DOI:10.1182/blood-2011-05-351403 Gatta G, Rossi S, Foschi R, et al (2013). Survival and cure trends for European children, adolescents and young adults diagnosed with acute lymphoblastic leukemia from 1982 to 2002. Haematologica, 98(5):744-752. DOI:10.3324/haematol.2012.071597 Gökbuget N, Kneba M, Raff T, et al (2012). Adult patients with acute lymphoblastic leukemia and molecular failure display a poor prognosis and are candidates for stem cell transplantation and targeted therapies. Blood, 120(9):1868-1876. DOI:10.1182/blood-2011-09-377713
  65. 65. References (cont.) Gökbuget N, Stanze D, Beck J, et al (2012). Outcome of relapsed adult lymphoblastic leukemia depends on response to salvage chemotherapy, prognostic factors, and performance of stem cell transplantation. Blood, 120(10):2032-2041. DOI:10.1182/blood-2011-12-399287 Grupp SA, Laetsch TW, Buechner J, et al (2016). Analysis of a global registration trial of the efficacy and safety of CTL019 in pediatric and young adults with relapsed/refractory acute lymphoblastic leukemia (ALL). Blood, 128(22). Abstract 221. DOI:10.1182/blood.V128.22.221.221 Iclusig® (ponatinib) prescribing information (2021). Takeda. Available at: https://www.iclusig.com/hcp/pdf/ICLUSIG-Prescribing-Information.pdf Jabbour E, O’Brien S, Konopleva M & Kantarjian H (2015). New insights into the pathophysiology and therapy of adult acute lymphoblastic leukemia. Cancer, 121(15):2517-2528. DOI: 10.1002/cncr.29383 Jabbour E, O’Brien S, Ravandi F & Kantarjian H (2015). Monoclonal antibodies in acute lymphoblastic leukemia. Blood, 125(26):4010-4016. DOI:10.1182/blood-2014-08-596403 Jabbour E, Short NJ, Ravandi F, et al (2018). Combination of hyper-CVAD with ponatinib as first-line therapy for patients with Philadelphia chromosome-positive acute lymphoblastic leukaemia: long-term follow-up of a single-centre, phase 2 study. Lancet Haematol, 5(12):e618-e627. DOI:10.1016/S2352-3026(18)30176-5 Jain T & Litzow MR (2018). No free rides: management of toxicities of novel immunotherapies in ALL, including financial. Blood Adv, 2(22):3393-3403. DOI:10.1182/bloodadvances.2018020198 Jain N, Roberts KG, Jabbour E, et al (2017). Ph-like acute lymphoblastic leukemia: a high-risk subtype in adults. Blood, 129(5):572-581. DOI:10.1182/blood-2016-07-726588 Juliusson G, Karlsson K, Lazarevic VL, et al (2011). Hematopoietic stem cell transplantation rates and long-term survival in acute myeloid and lymphoblastic leukemia: real-world population- based data from the Swedish Acute Leukemia Registry 1997-2006. Cancer, 117(18):4238-4246. DOI:10.1002/cncr.26033 Kantarjian HM, DeAngelo DJ, Advani AS, et al (2017). Hepatic adverse event profile of inotuzumab ozogamicin in adult patients with relapsed or refractory acute lymphoblastic leukaemia: results from the open-label, randomised, phase 3 INO-VATE study. Lancet Haematol, 4(8):e387-e398. DOI:10.1016/S2352-3026(17)30103-5 Kantarjian HM, DeAngelo DJ, Stelljes M, et al (2016). Inotuzumab ozogamicin versus standard therapy for acute lymphoblastic leukemia. N Engl J Med, 375(8):740-753. DOI:10.1056/NEJMoa1509277 Kantarjian H, Ravandi F, Short NJ, et al (2018). Inotuzumab ozogamicin in combination with low-intensity chemotherapy for older patients with Philadelphia chromosome-negative acute lymphoblastic leukaemia: a single-arm, phase 2 study. Lancet Oncol, 19(2):240-248. DOI:10.1016/S1470-2045(18)30011-1 Kantarjian HM, Stein AS, Bargou RC, et al (2016). Blinatumomab treatment of older adults with relapsed/refractory B-precursor acute lymphoblastic leukemia: results from 2 phase 2 studies. Cancer, 122(14):2178-2185. DOI:10.1002/cncr.30031 Kantarjian H, Thomas D, Jorgensen J, et al (2012). Inotuzumab ozogamicin, an anti-CD22-calicheamicin conjugate, for refractory and relapsed acute lymphocytic leukaemia: a phase 2 study. Lancet Oncol, 13(4):403-411. DOI:10.1016/S1470-2045(11)70386-2
  66. 66. References (cont.) Kantarjian H, Thomas D, Jorgensen J, et al (2013). Results of inotuzumab ozogamicin, a CD22 monoclonal antibody, in refractory and relapsed acute lymphocytic leukemia. Cancer, 119(15):2728-2736. DOI:10.1002/cncr.28136 Larson RA (2005). Acute lymphoblastic leukemia: older patients and newer drugs. Hematology Am Soc Hematol Educ Program, 2005(1):131-136. DOI:10.1182/asheducation-2005.1.131 Leukemia and Lymphoma Society (2021). Facts about measurable residual disease. Available at: https://www.lls.org/booklet/facts-about-measurable-residual-disease-mrd Kymriah® (tisagenlecleucel) prescribing information (2020). Novartis. Available at: https://www.fda.gov/media/107296/download Maino E, Bonifacio M, Scattolin AM & Bassan R (2016). Immunotherapy approaches to treat adult acute lymphoblastic leukemia. Expert Rev Hematol, 9(6):563-577. DOI:10.1586/17474086.2016.1170593 Maude SL, Barrett D, Teachey DT & Grupp SA (2014). Managing cytokine release syndrome associated with novel T cell-engaging therapies. Cancer J, 20(2):119-122. DOI:10.1097/PPO.0000000000000035 Maude SL, Laetsch TW, Buechner J, et al (2018). Tisagenlecleucel in children and young adults with B-cell lymphoblastic leukemia. N Engl J Med, 378(5):439-448. DOI:10.1056/NEJMoa1709866 Mohty M, Malard F, Abecassis, M, et al (2016). Revised diagnosis and severity criteria for sinusoidal obstruction syndrome/veno-occlusive disease in adult patients: a new classification from the European Society for Blood and Marrow Transplantation. Bone Marrow Transplant, 51(7):906-912. DOI:10.1038/bmt.2016.130 Mueller KT, Waldron ER, Grupp SA, et al (2018). Clinical pharmacology of tisagenlecleucel in B-cell acute lymphoblastic leukemia. Clin Cancer Res, 24(24):6175-6184. DOI:10.1158/1078- 0432.CCR-18-0758 O’Brien S, Schiller G, Lister J, et al (2013). High-dose vincristine sulfate liposome injection for advanced, relapsed, and refractory adult Philadelphia chromosome-negative acute lymphoblastic leukemia. J Clin Oncol, 31(6):676-683. DOI:10.1200/JCO.2012.46.2309 O’Brien S, Thomas DA, Ravandi F, et al (2008a). Results of the hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone regimen in elderly patients with acute lymphoblastic leukemia. Cancer, 113(8):2097-2101. DOI:10.1002/cncr.23819 O’Brien S, Thomas D, Ravandi F, et al (2008b). Outcome of adults with acute lymphoblastic leukemia after second salvage therapy. Cancer, 113(11):2186-3191. DOI:10.1002/cncr.23919 Oriol A, Vives S, Hernández-Rivas JM, et al (2010). Outcome after relapse of acute lymphoblastic leukemia in adult patients included in four consecutive risk-adapted trials by the PETHEMA study group. Haematologica, 95(4):589-596. DOI:10.3324/haematol.2009.014274
  67. 67. References (cont.) Park JH, Riviere I, Wang X, et al (2017). Durable long-term survival of adult patients with relapsed B-ALL after CD19 CAR (19-28z) T-cell therapy. J Clin Oncol (ASCO Annual Meeting Abstracts, 35(suppl). Abstract 7008. DOI:10.1200/JCO.2017.35.15_suppl.7008 Piccaluga PP, Arpinati M, Candoni A, et al (2008). Surface antigens analysis reveals significant expression of candidate targets for immunotherapy in adult acute lymphoid leukemia. Leuk Lymphoma, 52(2):325-7. DOI:10.3109/10428194.2010.529206 Raponi S, De Propris MS, Intoppa S, et al (2011). Flow cytometric study of potential target antigens (CD19, CD20, CD22, CD33) for antibody-based immunotherapy in acute lymphoblastic leukemia: analysis of 552 cases. Leuk Lymphoma, 52(6):1098-107. DOI: 10.3109/10428194.2011.559668 Ravandi F, Othus M, O’Brien SM, et al (2016). US intergroup study of chemotherapy plus dasatinib and allogeneic stem cell transplant in Philadelphia chromosome positive ALL. Blood Adv, 1(3):250-259. DOI:10.1182/bloodadvances.2016001495 Ricart AD (2011). Antibody-drug conjugates of calicheamicin derivative: gemtuzumab ozogamicin and inotuzumab ozogamicin. Clin Cancer Res, 17(20):6417-6427. DOI:10.1158/1078- 0432.CCR-11-0486 Shah BD, Ghobadi A, Oluwole OO, et al (2021). KTE-X19 for relapsed or refractory adult B-cell acute lymphoblastic leukaemia: phase 2 results of the single-arm, open-label, multicentre ZUMA- 3 study. Lancet, 398(10299):491-502. DOI:10.1016/S0140-6736(21)01222-8 Spinelli O, Peruta B, Tosi M, et al (2007). Clearance of minimal residual disease after allogeneic stem cell transplantation and the prediction of the clinical outcome of adult patients with high-risk acute lymphoblastic leukemia. Haematologica, 92(5):612-618. DOI:10.3324/haematol.10965 Sprycel® (dasatinib) prescribing information (2021). Bristol-Myers Squibb. Available at: https://packageinserts.bms.com/pi/pi_sprycel.pdf Stein AS, Schiller G, Benjamin R, et al (2018). Neurologic adverse events in patients with relapsed/refractory acute lymphoblastic leukemia treated with blinatumomab: management and mitigating factors. Ann Hematol, 98:159-167. DOI:10.1007/s00277-018-3497-0 Stelljes M, Alakel N, Wäsch R, et al (2021). Final induction therapy results of an open label phase II study using inotuzumab ozogamicin for induction therapy, followed by a conventional chemotherapy based consolidation and maintenance therapy in patients aged 56 years and older with acute B-lymphoblastic leukemia (INITIAL-1 trial). Blood, 138(suppl_1). Abstract 2300. DOI:10.1182/blood-2021-145553 Stock W, Luger SM, Advani AS, et al (2019). A pediatric regimen for older adolescents and young adult with acute lymphoblastic leukemia: results of CALGB 10403. Blood, 133(14):1548-1559. DOI:10.1182/blood-2018-10-881961 Surveillance, Epidemiology, and End Results (2018). Acute lymphoblastic leukemia (ALL) recent trends in SEER age-adjusted incidence rates, 2000-2018. Available at: https://seer.cancer.gov/statfacts/html/alyl.html
  68. 68. References (cont.) Tavernier E, Boiron JM, Huguet F, et al (2007). Outcome of treatment after first relapse in adults with acute lymphoblastic leukemia initially treated by the LALA-94 trial. Leukemia, 21(9):1907- 1914. DOI:10.1038/sj.leu.2404824 Thomas DA, O’Brien S, Faderl S, et al (2010). Chemoimmunotherapy with a modified hyper-CVAD and rituximab regimen improves outcome in de novo Philadelphia chromosome-negative precursor B-lineage acute lymphoblastic leukemia. J Clin Oncol, 28(24):3880-3889. DOI:10.1200/JCO.2009.26.9456 Topp MS, Gökbuget N, Stein AS, et al (2015). Safety and activity of blinatumomab for adult patients with relapsed or refractory B-precursor acute lymphoblastic leukaemia: a multicentre, single- arm, phase 2 study. Lancet Oncol, 16(1):57-66. DOI:10.1016/S1470-2045(14)71170-2 Topp MS, Gökbuget N, Zugmaier G, et al (2012). Long-term follow-up of hematologic relapse-free survival in a phase 2 study of blinatumomab in patients with MRD in B-lineage ALL. Blood, 120(26):5185-5187. DOI:10.1182/blood-2012-07-441030 Topp MS, Gökbuget N, Zugmaier G, et al (2014). Phase II trial of the anti-CD19 bispecific T cell-engager blinatumomab shows hematologic and molecular remissions in patients with relapsed or refractory B-precursor acute lymphoblastic leukemia. J Clin Oncol, 32(36):4134-4140. DOI:10.1200/JCO.2014.56.3247 Topp MS, Kufer P, Gökbuget N, et al (2011). Targeted therapy with the T-cell-engaging antibody blinatumomab of chemotherapy-refractory minimal residual disease in B-lineage acute lymphoblastic leukemia patients results in high response rate and prolonged leukemia-free survival. J Clin Oncol, 29(18):2493-2498. DOI:10.1200/JCO.2010.32.7270 US Food & Drug Administration (2021). FDA approves brexucabtagene autoleucel for relapsed or refractory B-cell precursor acute lymphoblastic leukemia. Available at: https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-brexucabtagene-autoleucel-relapsed-or-refractory-b-cell-precursor-acute-lymphoblastic

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