nuto o tmr ersin n crs n leukemia- in bearing mice. cures and regression tumor of induction including lines, cell (ALL) leukemia lymphoblastic acute REH against activity significant demonstrated tuzumab n easd r ercoy -ypolsi leukemia B-lymphoblastic refractory or relapsed in DT and ALL? relapsed refractory with patients in inotuzumab H&O echinospora. to bound is that calecheamicin, a toxic natural product of CD22 surface the targeting DT action? of mechanism its is H&O a m o l e y M d n a Leukemia? , a Lymphoblastic m Acute o in h p m Agent y L Single , Active a Most i The m e k Inotuzumab: u e L f o t n e m e g a n a M e h t n i Section Editor: s t n e m p o l e v e D t n e r r u C Adv CD19 and the B-cell receptor. downresultingin regulation of phosphorylated, is CD22 intracellular binding, After cells. presenting antigen and activation and the interaction of B cells with T cells regulate that molecules adhesion of family glycoprotein oh maue n mtr Blmhbat, u not but cells. stem B-lymphoblasts, hematopoietic mature and immature both on present is leukemia/lymphoma, B-lymphoblastic in surface expressed frequently most the among and sequence-specific a thiol-dependent manner, leading in to cell apoptosis. CD22, DNA double-stranded in breaks causes and groove DNA minor the to binds then intracellularly.Calecheamicin calecheamicin conjugated the delivers and internalized, rapidly is affinity, binding is a monoclonal a is ozogamicin Inotuzumab pae I td o iouua ws conducted was inotuzumab of study II phase A

Can you discuss your phase II study of of study II phase your discuss you Can what and ozogamicin, inotuzumab is What 1 Inotuzumab ozogamicin has subnanomolar has ozogamicin Inotuzumab 4

ances inLLM S Houston, Texas MD AndersonCancerCenter University ofTexas Division ofCancerMedicine Department ofLeukemia Associate Professor Deborah A.Thomas,MD usan O’Brien, M O’Brien, usan 2 t s mme o te sialo- the of member a is It 3 Preclinical work with ino- D Micromonospora Clinical Advances in Hematology & Oncology Volume 10, Issue 4 April 2012 April 4 Issue 10, Volume Oncology & Hematology in Advances Clinical

r loeec tm el rnpatto (C) within months. 4 prior (SCT) the transplantation cell stem allogeneic or pregnancy, virus, B hepatitis with infection absence known the of in 20% least 45%), at least of expression at CD22 fraction and ejection or III class than less classification disease Association YorkHeart (New tion func- cardiac adequate function, hepatorenal adequate Oncology Cooperative better,or 3 of score status Groupperformance (ECOG) Eastern an had who patients ign dc cud e noprtd 35 mg/m (375 incorporated be could Idec) Biogen Genentech/ (Rituxan, antibody monoclonal salse, ains ee rae wt inotuzumab with mg/m treated 1.8 were patients was safety established, the Once cycles. 8 to up for weeks 3 every were at least 60 years of age. Nearlythree-quarterstheage. of of years 60 least at were (6%) were aged 16 years or younger and 12 patients (24%) The median age was 36 years (range, 6–80 years); 3 patients DT standard current treatments? to compare rates those do H&O loe atr ramn o a lat 0 dls were adults) 10 least mg/m 1.3 inotuzumab at with treated of enrollment treatment <16years, after (age allowed patients 3 pediatric first bocytopenia. where the predominant dose-limiting toxicity was throm- trials, in lymphoma non-Hodgkin aggressive and inotuzumab indolent for established dose II phase mended 2 cycles ofsingle-agentinotuzumab. after nonresponders in cycle third the with beginning ot-ie ains ee rae wt inotuzumab. with treated were patients Forty-nine

What were the response rates, and how how and rates, response the were What 2 IV every 3 weeks, derived from the recom- the from derived weeks, 3 every IV 6,7 In CD20-positive cases, the anti-CD20 the cases, CD20-positive In 5 The first 3 adult patients and the and patients 3 adult first The 2 intravenously (IV) (IV) intravenously 2

IV) IV) 251

LLM LLM 252 ORR=overall response rate. Table uvvl a 51 ots 9% I 3864. Median CI, (95% 3.8–6.4). months 7.9 was responders 28 the CI, for survival (95% months 5.1 was overall survival median The (4%). patients 2 in occurred tality mor- Early (P=.008). CR attained ng/mL 100 than less concentrations with (33%) patients 15 of 5 only whereas than 100 ng/mL 3 hours after infusion, 8 (89%) achieved greater CR; were concentrations whose patients Of 9 15. the or 14 days on and 7–9, days on infusion, after ozogamicin hours Inotuzumab3 infusion, after immediately measured were levels cycle. fourth the after noted was response 1 only incorporated, was rituximab where (18%) cases 9 the Of outcomes. improved with correlate disease (MRD) by multiparameter flow cytometry did not residualminimal detectable Absenceof t(4;11)]. for 20% and t(9;22) for [43% subsets karyotype poor-risk the in lower were rates Response treatment. of (CR) courses responded 3 after patient 1 only therapy; of cycles 1–2 blood counts (CRi). Most responses were observed within peripheral of recovery incomplete (10%) recovery,5 and platelet incomplete with CR (29%) 14 (CR), remissions fidence interval [CI], 42–71), including 9 (18%) complete in 28 patients (57%). 50% of the lymphoblasts; CD22 expression exceeded 90% least at on CD22 expressed patients SCT. Allallogeneic undergone previously had (14%) patients Seven tively. t(4;11)(10%)cases,(14%)were5and respec7noted in treatment.salvagelaterPoor-riskort(9;22) orkaryotypes of second as ozogamicin inotuzumab received patients Rituximab Agent SAR3419 pasudotox Moxetumomab ozogamicin Inotuzumab Epratuzumab The overall response rate (ORR) was 57% (95% con-

1. Clinical Advances in Hematology & Oncology Volume 10, Issue 4 April 2012 April 4 Issue 10, Volume Oncology & Hematology in Advances Clinical Monoclonal Antibody Therapy for Acute Lymphoblastic Leukemia Lymphoblastic Acute for Therapy Antibody Monoclonal 19 17 11,12,22 5 16 13,14 21 Antigen Surface CD19 cell) (T CD3 CD19 CD22 CD22 CD22 CD52 CD20 Description IgG1 humanized +mytansine Bispecific T-cell engaging exotoxin A of form truncated VariableKDa38 to fused domain IgG1 humanized + calecheamicin IgG1 humanized IgG1 humanized IgG1 humanized Pseudomonas -

salvage attempt was the first one. first the was attempt salvage status (first, second, or later) and duration of first CR if the salvage on depend partially therapy salvage after response population was heavily pretreated. Expectations regarding similar overall ratestothosewhodidnot. survival SCT,had allogeneic and underwent subsequently patients (45%) Twenty-two CR. achieved who patients 9 the for 78% was months 12 at survival Estimated 5.3–10.5). B-lymphoblastic leukemia. An extension of our phase II patientsrelapsed/refractorywithinzumab trial CD22-positive DT inotuzumab? H&O salvage attempts were 69%, 47%, and 67%, respectively. third and second, first, of setting the in agent this later or with (CR+CRp+CRi) respectiveresponserates the penia, the dose-limiting toxicity of inotuzumab is thrombocyto- respectively.4%, that and mind 8% in be Bearing would salvage) second and with miscellaneous (first settings these in agents CR rates single expected The therapy regimens. combination multi-agent with 15–30% from range rates CR expected best the attempt, salvage second a undergoing those In 35–40%. from ranging include rates CR regimens chemotherapy multi-agent intensive various with responseexpectations historical the attempt, CR duration greater than 1 year undergoing a first salvage Efficacy Data Single-Agent No data ORR, 67% ORR, 29% ORR, 57% ORR, 7% 2/13 (pediatric) 0/6 (adult) Case reports The results are remarkable, considering that this considering remarkable, are results The There are 2 ongoing phase I/II clinical trials of inotu

Are there any similar studies in support of of support in studies similar any there Are Status Phase Iclinical trial(ongoing) Phase IIIclinical trial(planned) Phase IIclinical trials(ongoing) Phase Iclinicaltrial(pediatric) Phase IIIclinicaltrial(planned) Phase IIclinicaltrials(weekly dosing) Phase IIclinicaltrial(pediatric) Phase I-IIclinicaltrials(ongoing) Phase IIIclinicaltrials(ongoing) Phase IIclinicaltrials(ongoing) 8,9 In patients with first with patients In - 5 easdrfatr pdarc -ypolsi leukemia. B-lymphoblastic pediatricrelapsed/refractory in chemotherapy combination to prior monotherapy as given when activity limited has CD22, against directed ih pauua. Suhet nooy ru study Group Oncology Southwest A epratuzumab.with negativityMRD of ratesepratuzumab,higher withalbeit without regimen the of expectations historical to similar were rates CR therapy, the combination in given When activity. single-agent limited has CD52, against directed antibody monoclonal a Alemtuzumab, with combination chemotherapy regimens. in studied been predominantly has CD20, against directed antibody monoclonal conjugated non- a Rituximab, Tablein 1). (summarized ALL in ied DT they inotuzumab? do to how and compare treatment, ALL in promise H&O (0.8mg/m inotuzumabof dosingweekly exploration of theincludes oa ds o 082 mg/m 0.8–2 of dose total a for inotuzumab of dosing weekly of use the exploring is trial I phase multicenter separate A NCT01134575). ClinicalTrials.gov identifier (ASCO; Oncology of SocietyClinical American the of the meeting at annual presentedupcoming be to results with ongoing, is accrual the phaseIIportion. for module the of continuation in resulting regimen, the and overall in observations the survival phase I of portion disease-free encouraging with study, 10102 (CALGB) B asa Group Leukemia and Cancer the in module agent single therapy consolidation first-line into incorporated benefit. survival a conferred rituximab B-lymphoblastic positive leukemia, CD20 novo de for 07/2003 (GermanMulticenter Study Group Adultfor study ALL) GMALL the in or hyper-CVADregimen the either with chemotherapy first-line to added When mia/lymphoma. leuke- Burkitt childhood in reports case to limited been tution (ClinicalTrials.gov identifier NCT0137630). B-lymphoblastic leukemia is currently accruing at our insti novoCD22-positivedewithyears oldpatients least60 at trexateand cytarabine) with orwithout rituximab inolder rubicin,dexamethasone, alternating withcyclesmetho of CVAD(fractionated cyclophosphamide, vincristine, doxo (singlecycle)combinationperdosein “mini” with hyper- identifier NCT01564784). phaseA II trial of inotuzumab mitoxantrone/cytarabine)or planned(ClinicalTrials.govis bine, cytarabine, filgrastim; HIDAC, high-dose cytarabine; of inotuzumab versus investigator’s choice (FLAG, fludara randomized study confirmed, a inotuzumabis of dose II identifier NCT01363297). After recommendedthe phase Epratuzumab, a nonconjugated monoclonal antibody Several other monoclonal antibodies are being stud- arebeing antibodies monoclonal Severalother What other novel agents are showing showing are agents novel other What 2 IV on dayonIVthen1, 0.5 mg/m 15

10 Its efficacy as monotherapy has 2 e cus (ClinicalTrials.gov course per 2 IV for 2 doses);forIV2 13,14 Clinical Advances in Hematology & Oncology Volume 10, Issue 4 April 2012 April 4 Issue 10, Volume Oncology & Hematology in Advances Clinical t a been has It 11,12 16 - - - -

tory phase II clinical trials are under way. uui ihbtr (g SR49, a b mr effica cious. more be may SAR3419), (eg, inhibitors tubulin high-potency as such agents, novel using CD19 against were observed, although these were confounded by the the by confounded were these although observed, were inotu with (VOD) disease veno-occlusive of (23%) therapy 5 cases zumab, following SCT allogeneic went under patients successfully who population) 22 study the of (45% the In biopsy. liver on fibrosis periportal including pattern, injury hepatic severe more of cases few a were there reversible, and mild was dysfunction hepatic cases, most in Although component. eamicin calech the by incurred bilirubin transaminases) in hepatic and/or (elevations may hepatotoxicity by use limited Protracted be premedication. adminis after despite hours tration, 24–48 first the effect within side fever of predominant the with inotuzumab tolerated, study, well I/II was phase our In way. under are trials single-agent I/II phase alloge Confirmatory SCT. facilitate neic can which disease, of cytoreduction significant a induce to potential the with offers strategy salvage clearly inotuzumab ALL, relapsed/refractory DT general? in approaches treatment ALL for and H&O implementing concurrent use of dexamethasone. after syndromes leak capillary of frequency in reduction years)B-lymphoblastic25 age toleukemia, (upatricwith agingactivitytrialrelapsed/refractoryphaseinI a in pedi (CAT-8015) pasudotox anti-CD22immunotoxinan encouriswith Moxetumomab NCT00945815). identifier (ClinicalTrials.gov accruing currently is leukemia blastic relapsed/refractory B-lympho with adults for cytarabine andclofarabine withcombination in epratuzumab using blastic leukemia.blastic B-lympho in efficacy previouslyminimalexhibitedricin) withorwithout allogeneic SCT. remissions durable in resulting cases, the of 80% mately efficacy as measured by eradication of the MRDshowedsetting) in approxi this in 94% in relapse(expected therapy merase chain reaction at 16 weeks from the start of first-line poly by MRDpersistent withB-lymphoblastic leukemia lymphoblasts. An initial study of blinatumomab in de novo T-cells, CD3-positivewhich become activated cytotoxicon binding CD19-positive polytypic recruit to mechanism (BiTE) engaging bispecific T-cell a uses blinatumomab, of67%was observed after cycles2 oftherapy. relapsed B-lymphoblastic leukemia, an overall response attempts) rate salvage first (predominantly treated minimally study of single-agent blinatumomab in adults with relatively niC1 mncoa atbd cnuae (eg, conjugates antibody monoclonal Anti-CD19 Owing to its promising single-agent activity in in activity single-agent promising its to Owing

19 What does the future hold for inotuzumab, inotuzumab, for hold future the does What poiig ul ptp C1-ietd agent, CD19-directed epitope dual promising A 18 However,directedconjugatesantibody 20 Insubsequenta phase II 21 Confirma 17

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preparative regimens (containing hepatotoxic agents 4. Dijoseph JF, Dougher MM, Armellino DC, Evans DY, Damle NK. Therapeutic potential of CD22-specific antibody-targeted chemotherapy using inotuzumab thiotepa or clofarabine) and/or status as second alloge- ozogamicin (CMC-544) for the treatment of acute lymphoblastic leukemia. Leu- neic SCTs. A lower-dose weekly schedule of inotuzumab kemia. 2007;21:2240-2245. may potentially reduce the incidence of hepatotoxicity 5. Kantarjian H, Thomas D, Jorgensen J, et al. Inotuzumab ozogamicin, an anti- CD22-calecheamicin conjugate, for refractory and relapsed acute lymphocytic owing to lower peak levels of calecheamicin; the 2 leukaemia: a phase 2 study. Lancet Oncol. February 2012. [Epub ahead of print] ongoing phase I/II trials are exploring this approach. 6. Advani A, Coiffier B, Czuczman MS, et al. Safety, pharmacokinetics, and pre- Preliminary findings of our trial suggest similar efficacy liminary clinical activity of inotuzumab ozogamicin, a novel immunoconjugate for the treatment of B-cell non-Hodgkin’s lymphoma: results of a phase I study. J Clin rates with a lower incidence of hepatotoxicity. Oncol. 2010;28:2085-2093. Unfortunately, despite the high response rates, the 7. Ogura M, Hatake K, Ando K, et al. Phase I study of anti-CD22 immunocon- majority of responses were not durable (median dura- jugate inotuzumab ozogamicin plus rituximab in relapsed/refractory B-cell non- Hodgkin lymphoma. Cancer Sci. 2012. [Epub ahead of print] tion, 6 months). A response to inotuzumab did not 8. Thomas DA, Kantarjian H, Smith TL, et al. Primary refractory and relapsed significantly impact survival rates compared with his- adult acute lymphoblastic leukemia: characteristics, treatment results, and progno- torical expectations, despite facilitation of allogeneic sis with salvage therapy. Cancer. 1999;86:1216-1230. 9. O’Brien S, Thomas D, Ravandi F, et al. Outcome of adults with acute lympho- SCT in approximately half of the patients. However, cytic leukemia after second salvage therapy. Cancer. 2008;113:3186-3191. those who achieved CR and/or underwent therapy as 10. Thomas DA, O’Brien S, Kantarjian HM. Monoclonal antibody therapy with rituximab first salvage had 1-year survival rates of at least 70%. for acute lymphoblastic leukemia. Hematol Oncol Clin North Am. 2009;23:949-971, v. 11. Thomas DA, O’Brien S, Faderl S, et al. Chemoimmunotherapy with a modified As single-agent therapy, inotuzumab could potentially hyper-CVAD and rituximab regimen improves outcome in de novo Philadelphia be used to eradicate persistent MRD after frontline chromosome-negative precursor B-lineage acute lymphoblastic leukemia. J Clin chemotherapy. Combination therapy strategies will Oncol. 2010;28:3880-3889. 12. Hoelzer D, Huettmann A, Kaul F, et al. Immunochemotherapy with rituximab in likely be needed in order to improve the durability adult CD20 B-precusor ALL improves molecular CR rate and outcome in standard risk of responses in the salvage setting. The incorporation (SR) as well as in high risk (HR) patients with SCT. Haematologica. 2009;94(suppl 2): of inotuzumab into frontline therapy (“mini hyper- Abstract 481. 13. Tibes R, Keating MJ, Ferrajoli A, et al. Activity of alemtuzumab in patients with CVAD with or without rituximab”) is currently being CD52-positive acute leukemia. Cancer. 2006;106:2645-2651. explored in the setting of elderly patients with de novo 14. Angiolillo AL, Yu AL, Reaman G, Ingle AM, Secola R, Adamson PC. A phase II CD22-positive B-lymphoblastic leukemia in an effort study of Campath-1H in children with relapsed or refractory acute lymphoblastic leu- kemia: a Children’s Oncology Group report. Pediatr Blood Cancer. 2009;53:978-983. to mimic the improvement in outcomes observed with 15. Stock W, Sanford B, Lozanski G, et al. Alemtuzumab can be Incorporated the addition of rituximab to hyper-CVAD in older Into Front-Line Therapy of Adult Acute Lymphoblastic Leukemia (ALL): Final patients with de novo Burkitt leukemia/lymphoma Phase I Results of a Cancer and Leukemia Group B Study (CALGB 10102). Blood. 2009;114: Abstract 838. and in younger patients with de novo CD20-positive 16. Raetz EA, Cairo MS, Borowitz MJ, et al. Chemoimmunotherapy reinduction 11,22 B-lymphoblastic leukemia. The use of inotuzumab with epratuzumab in children with acute lymphoblastic leukemia in marrow relapse: in the treatment of CD22-positive B-lymphoblastic a Children’s Oncology Group Pilot Study. J Clin Oncol. 2008;26:3756-3762. 17. Wayne AS, Bhojwani D, Silverman LB, et al. A novel anti-CD22 , leukemia appears to be a very promising therapeutic moxetumumab pasudotox: phase I study in pediatric acute lymphoblastic leukemia strategy. Inotuzumab and other promising monoclonal (ALL). Blood. 2011;118: Abstract 248. antibodies have the potential to significantly improve 18. Szatrowski TP, Dodge RK, Reynolds C, et al. Lineage specific treatment of adult patients with acute lymphoblastic leukemia in first remission with anti-B4-blocked outcomes for patients with ALL. ricin or high-dose cytarabine: Cancer and Leukemia Group B Study 9311. Cancer. 2003;97:1471-1480. References 19. Blanc V, Bousseau A, Caron A, Carrez C, Lutz RJ, Lambert JM. SAR3419: an anti-CD19-Maytansinoid Immunoconjugate for the treatment of B-cell malignan- cies. Clin Cancer Res. 2011;17:6448-6458. 1. Thorson JS, Sievers EL, Ahlert J, et al. Understanding and exploiting nature’s 20. Topp MS, Kufer P, Gokbuget N, et al. with the T-cell-engaging chemical arsenal: the past, present and future of research. Curr antibody blinatumomab of chemotherapy-refractory minimal residual disease in Pharm Des. 2000;6:1841-1879. B-lineage acute lymphoblastic leukemia patients results in high response rate and 2. Raponi S, De Propris MS, Intoppa S, et al. Flow cytometric study of potential prolonged leukemia-free survival. J Clin Oncol. 2011;29:2493-2498. target antigens (CD19, CD20, CD22, CD33) for antibody-based immuno- 21. Topp MS, Goekbuget N, Zugmaier G, et al. Anti-CD19 BiTE blinatumomab therapy in acute lymphoblastic leukemia: analysis of 552 cases. Leuk Lymphoma. induces high complete remission rate in adult patients with relapsed B-precursor 2011;52:1098-1107. ALL: updated results of an ongoing phase II trial. Blood. 2011;118: Abstract 252. 3. Poe JC, Fujimoto Y, Hasegawa M, et al. CD22 regulates B lymphocyte function 22. Thomas DA, Faderl S, O’Brien S, et al. Chemoimmunotherapy with hyper- in vivo through both ligand-dependent and ligand-independent mechanisms. Nat CVAD plus rituximab for the treatment of adult Burkitt and Burkitt-type lymphoma Immunol. 2004;5:1078-1087. or acute lymphoblastic leukemia. Cancer. 2006;106:1569-1580.

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