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Acute lymphoblastic leukemia Novel approaches for therapy of resistant acute lymphoblastic leukemia

R. Bassan ABSTRACT

UOC Ematologia, 1Ospedale With the majority of children and nearly half of adult patients presently cured of their disease, the dell’Angelo e Ospedale SS. Giovanni occurrence of treatment resistance marks an ominous time for patients with acute lymphoblastic e Paolo, Mestre-Venezia, Italy leukemia (ALL) and provokes great frustration in physicians, since the justified hope of final therapeu - tic success is suddenly turned into a fight for survival. The many facets of resistant ALL, the recent therapeutic progress, and the reasons to believe in further improvement are reviewed. Hematology Education: the education program for the annual congress of the European Hematology Association Introduction tive). 7,8 A phenotypic switch is frequent at 2012;6:9-22 relapse, with loss/gain of CD34/CD10/ Resistant acute lymphoblastic leukemia myeloid markers, 9 however without specifici - (Re-ALL) is characterized by the loss of sen - ty and significance. Cytogenetic high-risk sitivity to treatment that results in disease pro - subsets are defined by monosomy 7, trisomy gression and high probability of death within 8, del(6q)/(7p)/(17p), abnormalities at 11q23 few months. Re-ALL can manifest as primary and 14q32, t(8;14), low hypodiploidy/near refractory disease or recurrence following a triploidy (30-39/60-78 chromosomes), and complete remission (CR) phase of variable complex karyotype ( ≥5 unrelated abnormali - duration. While primary refractory ALL is rel - ties). 10-12 atively uncommon, about 20% of children, at least 40% of adults, and two-thirds or more of Early response, drug resistance, elder patients relapse after chemotherapy treatment compliance and/or hematopoietic stem cell transplantation Patients requiring more than 4-5 weeks to (HSCT). 1,2 Re-ALL is clinically heteroge - achieve CR, with insufficient early blood (day neous (Table 1), the individual pattern reflect - 7) or marrow (day 10-14) blast cell clearing, ing the severity of the disease and having ther - or with poor prednisone response to pre-phase apeutic consequences. The analysis of the risk have a worse outlook. 13,14 Overexpression of factors associated with Re-ALL can explain multidrug resistance (MDR1), MDR-associat - why and how it develops and help identify ed protein (MRP), and LRP (lung-related pro - novel therapeutic avenues (Table 2). 3,4 tein), 15,16 and in vitro resistance to corticos - teroids, , L-, and also predict higher failure Risk factors rates. 17 At relapse, ALL cells acquire greater resistance to several drugs. 18 Treatment adher - Age and WBC count ence and compliance is important, the out - Infants (<1 year), children aged over 10 come being worse after inappropriate treat - years, and adults aged over 35 years, especial - ment delay and/or dose reduction. 19 ly over 55 years are at higher risk. With regard to white blood cell count (WBC ¥10 9/L), dif - Genetics ferent cut-points were defined, from greater Re-ALL is often associated with rearrange - than 10 to greater than 25-50, sometimes in ments, silencing, or amplification of genes association with immunophenotype (WBC involved in apoptosis and control >30 and B-lineage, WBC >100, and T-lin - (bcl-2, p53, retinoblastoma [Rb], caspase-2/-3 eage). and procaspases, CDX2, CDKN2A/B [T- ALL]), DNA methylation, and kinase inhibi - Immunophenotype and cytogenetics tion (microRNA, p73/57/14/15/16), cell hom - High-risk entities include pro-B ALL with ing and migration (CXCR4, CCR7 for entry t(4;11)/MLL-AF4 rearrangement, pre-B ALL into the central nervous system [CNS]), tumor with t(9;22)/BCR-ABL rearrangement suppression (Ikaros [IKZF1]/Aiolos), tran - (Philadelphia-positive [Ph+]), in pre-tyrosine scription factor regulation (HOX11 [TLX1)], kinase inhibitor (TKI) era, pre-B ALL with HOX11L2, ERG, BAALC, NOTCH1/ t(1;19)/PBX1-E2A rearrangement (not in all FBXW7, WT1, LEF1 [Wnt], PAX5), and studies), CD20+ ALL especially when mini - tyrosine kinase activity (BCR-ABL, FLT3, mal residual disease (MRD) positive, 5,6 and JAK1/2, NUP214-ABL). 4,20-29 Deletions of pro/pre- and mature-T ALL (CD1a-nega - IKZF1 genes, JAK2 mutation (in Down’s

Hematology Education: the education programme for the annual congress of the European Hematology Association | 2012; 6(1) | 9| 17 th Congress of the European Hematology Association syndrome), 30 and CRLF2 rearrangements were found to MRD, 53 and eventually generated new biology-based risk define high-risk entities like BCR-ABL-like Ph-negative classifications. 54,55 ALL. 31-33 In T-ALL, absence of NOTCH1 mutation, dele - tion of IKZF1, and overexpression of HOX11L2 and Pharmacogenetics/genomics BAALC/ERG are well-recognized risk factors also pre - Polymorphisms of drug-metabolizing genes with het - dicting a suboptimal MRD response. 34-38 In Ph+ Re-ALL, erozygous or homozygous deficiencies or overexpression among several point mutations occurring in BCR-ABL of drug-metabolizing enzymes increases the risk of Re- kinase domains, T315I is most commonly implicated in ALL due to higher rates of drug inactivation (, resistance to first/second-generation TKI (imatinib/nilo - cytosine arabinoside, L-asparaginase). These findings tinib/dasatinib). 39,40 overlap with pharmacogenomics and may also predict MRD. 1,3,4,56 Genomics Genome-wide analysis identifies gene signatures associ - MRD ated with Re-ALL, mainly in pediatric studies. Highly Genetics and genomics may be difficult to perform in specific patterns were initially described in Ph+ ALL, Ph- clinical trials because it lacks standardization and is negative ALL, and patients exhibiting chemotherapy expensive in technical and financial terms. Instead, MRD resistance. 41-44 More recent studies identified top gene clus - analysis allows us to predict relapse in up to 90% of CR ters predicting or differentially expressed at relapse, 45-50 patients. 57-59 MRD evaluation at early time-points from either early or late, 51 associated with drug resistance, 52 mid-induction to early consolidation (day 11 to week 22)

Table 1. Clinical definitions of Re-ALL according to treatment steps and sites of involvement (excluding MRD, see text for details). Definitions of responsive ALL in the footnote for comparative purposes.

Type of Re-ALL Bone marrow (BM) Definitions/notes

Timing Primary refractory BM blasts >5% * Failure to enter CR after one/two chemotherapy cycles Early relapse # BM blasts >5-25%, 1st relapse within 6-12-18 months from CR (very early relapse is assimilated (or extramedullary relapse) to primary refractory disease) Late relapse # BM blasts >5-25% 1st relapse after 12-18-24 months from CR (or extramedullary relapse) 1st relapse while on treatment or off-therapy Second/subsequent relapse BM blasts >5-25% 2nd or subsequent relapse following successful therapy of prior relapse (or extramedullary relapse)

Site Marrow BM blasts >5-25% Isolated marrow relapse (most common) CNS No BM blasts Isolated CNS relapse (<5%) with blasts in cerebro-spinal fluid plus CNS symptoms and/or positive CT scan/MRI. Other extramedullary No BM blasts Relapse outside BM/CNS (skin, testis/ovary, lymphnodes etc.), confirmed by histology Combined BM blasts >5-25% Concurrent BM and extramedullary relapse (CNS most common)

Prior therapy Chemotherapy BM blasts >5-25% Relapse during/after chemotherapy (induction-consolidation, maintenance) (or extramedullary) HSCT BM blasts >5-25% Relapse after HSCT (autologous or allogeneic) (or extramedullary)

Response to salvage Responsive BM blasts <5-25% CR (second/subsequent) or PR achieved in refractory/relapsed patient (or clearance of extramedullary disease) Unresponsive BM blasts >5-25% Refractory relapse or highly refractory disease (or persistence of extramedullary disease)

*confirmed by new BM sampling (one week apart, usually blasts >25%). #variable temporal endpoints (different studies, and adults v children ALL). Definitions of responsive ALL: CR, complete remission (primary treatment endpoint): BM blasts <5%, ANC >1.0, PTL >100, no transfusions; Late CR (after 4-5 treatment weeks/2 induction cycles) is prognostically unfavorable; CRi, CR with incomplete haematological recovery: like CR, with incomplete ANC/PTL recovery (prognostic signifi - cance unknown); CRc, cytogenetic CR: like CR, with resolution of cytogentic abnormalities (may be useful in Ph+ ALL); ALL-free morphology: CR-like BM morphology, no peripheral blood data; PR, partial remission: BM blasts 5-25% (decreased by 50% or greater compared to baseline), not; here relevant in phase I clinical trials only. Abbreviations: CNS, central nervous system; ANC (absolute neutrophil count) and PTL ( count) x10 9/L; CT, computed tomography; MRI, magnetic resonance imag - ing; HSCT, hematopoietic stem cell transplantation.

| 10 | Hematology Education: the education programme for the annual congress of the European Hematology Association | 2012; 6(1) Amsterdam, The Netherlands, June 14-17, 2012 identifies patients at high risk of Re-ALL (MRD ≥10 -4 or MRD signals, up to the level where clinical relapse is any positivity by PCR, MRD ≥0,01-0,1% by flow cytom - both inevitable and close. A molecular remission was pro - etry), while periodic monitoring of MRD-negative posed as a surrogate endpoint for evaluating new anti- patients in late CR phases allows us to detect increasing leukemic agents. 60 In Re-ALL, when tracking MRD, it is

Table 2. Risk factors for Re-ALL. Parameters High-risk category Correlations/interactions Comments Patient-related Age (years) Children: <1 and >10 -- Adults: >35-55 Higher incidence of Ph+ ALL - Gender Male - Reported trend (reduction in recent years) Ethnicity Afro-caribbean, native American and Genomics/pharmacogenomics Reported in children hispanic-latino (US) Treatment compliance Poor Higher age, comorbidity Affected by Disease-related WBC (x10 9/L) >30 B-lineage Not universally accepted, other cut-points used >100 T-lineage (>10-50) Immunophenotype B-lineage: pro-B (CD10-negative) MLL-rearrangement/abn 11q23 Not universally accepted CD20+ - Only when MRD+ T-lineage: early/mature-T (CD1a-neg) Genetics/genomics - CD34/CD13/CD33/CD56 - Decreasing/variable evidence Cytogenetics t(9;22)/Ph chromosome BCR-ABL1 rearrangement Improved with TKI therapy t(4;11), other abn(11q23) MLL-AF4 rearrangement - t(1;19) E2A-PBX1 rearrangement Not universally accepted Other : -7, +8, del(6q)/(7p)/(17p), t(8;14), - Rare, t(8;14) in non-Burkitt ALL low hypodiploid/near triploid, complex Genetics/epigenetics BCR-ABL1, MLL-AF4 Cytogenetics - BCR-ABL1 point mutations Ph+ ALL (TKI resistance) T315I (higher risk) IKZF1 deletion - Ph+ and Ph- ALL Wild-type NOTCH1/FBXW7 Immunophenotype/IKZF1 T-lineage ALL High BAALC -- CLRF2 rearrangement, JAK2 mutation IKZF1 In children (with/without Down’s syndrome), identifies BCR-ABL1-like Ph-negative ALL Other Pathways of apoptosis, cell cycle, Several single gene alterations found DNA replication/methylation, kinase prognostically significant inhibitors, cell adhesion/migration, tumor suppressor genes, transcription factors Genomics/ Probe sets of differentially expressed genes Single nucleotide polymorphisms Emerging, biology-based risk definition of Re-ALL pharmacogenomics (several combinations tested/identified) DNA sequence mutations (including early or late relapse), mostly in children Dug metabolism (MTX, 6-, L-asparaginase) Drug resistance ( in vitro ) MRD Genetics/cytogenetics Key pathways of ALL cell proliferation Drug resistance MDR1, MRP, LRP (cytometry) Genomics/pharmacogenomics Variably detectable in Re-ALL Drug-resistance assays (MTT) Often detectable in Re-ALL (pediatric studies) Miscellaneous CNS positivity, elevated LDH Higher tumoral burden Not universally considered Response kinetic-related Prephase (prednisone) Poor prednisone response MRD, genetics and genomics Variably considered in trials (more in childhood) Induction cycle 1 Poor blood/marrow blast cell clearance (d7-14) MRD, genetics and genomics Variably considered in trials Time to CR >4-5 weeks or after cycle 2 - Frequently used (some exceptions) MRD Lack of major/complete MRD response Genetics, genomics and Most sensitive predictor of relapse risk (several timepoints [induction d11 to pharmacogenomics in current trials, widely used, two methods postconsolidation monitoring]) (sensitivity: PCR 10 -4/5 ; cytometry 10 -4 ) Treatment-related Treatment intensity Drug reduction/omission - When inappropriate (few data, strong rationale) Treatment delay -

Hematology Education: the education programme for the annual congress of the European Hematology Association | 2012; 6(1) | 11 | 17 th Congress of the European Hematology Association necessary to recognize changes in clonality markers that was 42% after early relapse (CR ≤18 months), and 90% reflect selection of minor chemo-resistant subclones 61,62 after late relapse repeating standard induction. Survival and rarely, a second neoplasm arising on a background of was significantly better in late relapse patients (43%, P genetic predisposition. 63 New, more stable MRD markers <0.0001), in those aged less than 25 and less than 45 assessable by flow cytometry and correlating with gene years (38% and 28%, P <0.0001), achieving CR (47%, P expression analysis were recently described. 64 The MRD <0.0001) and proceeding to HSCT (56%, P <0.0001). study is recommended in case of isolated extramedullary An MD Anderson study on 245 patients in early relapse relapse to document a frequent early bone marrow (CR <1 year) identified the independent risk factors for involvement. 65 CR and survival (age >55 years, marrow blasts ≥20%, <75, albumin <3 g/dL, LDH >1000 IU/L). 69 One- year survival decreased from 35% with 0-1 risk factors to Primary Re-ALL 0% with 4-5 risk factors. With a second salvage attempt, 72 CR was obtained in 18% of 288 patients, lasting a median The estimated incidence of primary Re-ALL is about of 7 months. Median overall survival was 3 months and 2% in children and 10% or less in adults, except for Ph+ was predicted by the cumulative incidence of risk factors. ALL where the introduction of TKI-based therapy has Other trials assessed combinations of /cytara - almost totally abolished it. In the large MRC/ECOG trial bine plus / (FLAG, FLAG-IDA, 66 initiated in 1993, 1,153 Ph-negative adult patients were FLAM) or high-dose -containing regimens in treated with vincristine/prednisone//L- smaller series (12-135 patients). 70 CR rate ranged from asparaginase (phase 1, weeks 1-4) and cyclophos - 17% to 83% ( ≤60% in 11/14 studies), median remission phamide/cytarabine/6-mercaptopurine (phase 2, weeks 5- duration and survival were short (<10 months in 11/14 8). Of these, 778 (67.4%) and 157 (13.6%) were in CR studies, 10-12% at 2-3 years), and although results were after phase 1 and 2, respectively, and 164 had Re-ALL improved in HSCT recipients, only 20-50% of the (14.2%). The risk of failure was higher in males (P=0.04) patients in second CR received HSCT and their likelihood and patients older than 35 years (P <0.001), but time to of cure was hardly above 25%. 73-75 As far as other HSCT CR did not affect survival. These results can be improved. details are concerned, patients with high-risk clinical fea - A recent GRAALL trial adopted a pediatric-inspired pro - tures like age above 50 years, compromised organ func - tocol with corticosteroid prephase, 5-drug induction tion, or recipients of a previous HSCT were reported to (same as above plus , to be augmented also benefit from reduced intensity conditioning, using in poor early responders [hyper-C: poor steroid response both marrow or peripheral blood as stem cell source, and or >5% marrow blasts after one week]), and salvage with either sibling or unrelated donors, with survival/DFS idarubicin/cytarabine. 67 Of 225 patients treated, 210 rates of 20-30% or higher in selected risk groups. 76-78 achieved CR (93.5%, 10% after salvage), and only one had Re-ALL (0.4%). With Hyper-CVAD (cyclophos - Children phamide/vincristine//dexamethasone), the CR rate was 92% (264/288; 81% after course 1) and Re- Outcome of Re-ALL is better in children than adults, 68 with second CR rates of 68-85% and overall survival ALL rate 3%. These figures reflect optimal induction 79-86 standards for adult Ph- ALL, with an incidence of primary rates at 5-10 years of 27-38%. Worse results were Re-ALL of 3% or less. Few outcome data are available reported in early marrow relapse (within 6 months from for primary Re-ALL. In a report from the MD Anderson cessation of first-line therapy, or <18-36 months from hospital, the CR rate after salvage (various regimens) was CR), concurrent CNS relapse, male gender, age 10+ 37% in 68 refractory patients compared with 28% in 177 years, T-cell phenotype, more than or second relapse, and relapsed patients (P=0.25), and 1-year survival was only high-risk patients not having HSCT. Five-year survival 15% compared with 26% (P=0.07). 69 rates were over 40-50% in standard-risk patients treated with chemotherapy or autologous HSCT. 82,83,86,87 With allo - geneic HSCT, the final salvage rate in high-risk groups Relapsed ALL was 25-40% and outcome was improved in TBI-condi - tioned recipients. 88-90 Adults The common strategy for relapsed ALL is the adminis - Randomized trials tration of reinduction chemotherapy followed, when pos - Randomized trials were almost exclusively performed sible by allogeneic HSCT. A review examined four large in children. The BFM group compared high with interme - series (MD Anderson, 314 patients; LALA, 421 patients; diate-dose (5 vs. 1 g/m 2) plus chemotherapy MRC/ECOG, 609 patients; PETHEMA, 198 patients), 70 in 269 patients, with equivalent re-induction and survival and a GMALL study included 547 further patients. 71 results. 91 A study from the United Kingdom randomized Second CR rates were 31-50%, and 5-year survival rates 216 patients to multidrug reinduction/consolidation, 3-7% in the first four series and 24% in the German study. including either mitoxantrone or idarubicin. 92 Three-year Favorable prognostic factors were age younger than 20- progression-free survival was 64.6% in the mitoxantrone 30 years, female gender, interval to relapse over 2 years, group compared with 35.9% in the idarubicin group lower WBC count, lack of CNS involvement, and allo - (P=0.0001), suggesting further evaluation of mitox - transplantation. In the GMALL series (patients in first antrone in Re-ALL. The COG randomized 72 patients isolated marrow relapse only), CR rate with salvage regi - without sibling donor and in early marrow relapse to mens like FLAG-IDA (fludarabine/cytarabine/idarubicin) either chemotherapy or alternative donor HSCT, with a 3- and CLAEG in T-ALL (//cytarabine) year DFS of 21% and 27%, respectively (P=0.56). 89

| 12 | Hematology Education: the education programme for the annual congress of the European Hematology Association | 2012; 6(1) Amsterdam, The Netherlands, June 14-17, 2012

CNS relapse (3) refractory ALL and first, second, or subsequent CNS relapse is still seen in some patients (<5% and relapse and post-HSCT relapse are often analyzed togeth - close to 1-2% with optimal CNS prophylaxis) 93 while er; (4) randomized trials are inexistent (in adults); (5) other types of extramedullary relapse are very rare. Risk complex multidrug regimens can mask the relative effica - factors are high LDH, Burkitt/B-ALL, T-ALL, hyper - cy/inefficacy of new agents; and (6) there is little consen - leukocytosis, high proliferative index, and adverse kary - sus on response evaluation criteria, although a CR rate otype. The outcome is poor, except for late isolated CNS greater than or equal to 20% may indicate activity of sin - relapse in children in whom intensified intrathecal thera - gle drugs and the 1-year survival rate is frequently quoted py plus systemic chemotherapy and craniospinal irradia - (Table 3). Alternative drug formulations improve tion can yield a salvage rate about 60%, superimposable , are insensitive to cellular mediators of to HSCT. 94 In adults, cure is possible in some patients drug efflux, and elicit less antibody-mediated inactiva - obtaining a new CNS remission with standard intrathecal tion. Variable results were obtained with liposomal therapy (methotrexate/cytarabine/corticosteroids), and daunorubicin/cytarabine (CR 20/25, 80%), 105 sphingoso - then preventing systemic relapse with chemotherapy and mal vincristine (CR 1/14, 14%), 106 and liposomal vin - allogeneic HSCT. 95 cristine/dexamethasone (CR 7/36, 19%). 107 Pegylated- asparaginase induces higher depletion com - pared with native compounds and was employed in adults MRD-defined resistance (with Hyper-CVAD: CR 9/24, 45%) 108 and children, 109 as well as loaded into red blood cells to achieve higher lev - MRD studies underline the deceptive nature of ALL, a els in vivo .110 Downmodulation of MDR1 by PSC-833 disease that may behave properly at the forefront while with mitoxantrone/etoposide was scarcely effective (CR simultaneously preparing a deadly conclusion, and 3/11, 27%). 111 , , temozolamide prompt evaluation of an MRD-guided pre-emptive thera - alone or with , and were almost py. As therapeutic results in florid Re-ALL are globally or totally useless. 112-116 Promising multidrug regimens poor, treating a smaller tumor burden, for instance bring - were developed combining /mitoxantrone/ ing MRD+ patients directly to HSCT, could be far more dexamethasone with or without fludarabine/rituximab advantageous. In a GMALL study, 96 105 MRD-negative (CR 5/9, 55.5%), 117 /dexamethasone/L-asparagi - adults were followed-up after 1 year of intensive therapy nase/vincristine (CR 23/28, 74%), 118 topotecan/vinorel - with a recommended 3-month protocol. Thirteen of 15 bine//gemcitabine (CR 3/8, 37%), 119 and ifos - patients who converted to MRD positivity (within quanti - famide//etoposide plus rituximab in Burkitt/B- tative ranges) relapsed in a median of four months (87%). ALL (CR 4/14, 28.5%). 120 The concept of molecular relapse was established, with a 10 -4 cutoff (PCR). In a subsequent analysis, 71 13 of 43 New analogs patients with molecular relapse underwent allogeneic inhibits DNA repair and ribonucleotide HSCT, all remaining disease-free, while 83% of the reductase, causing apoptosis through different mecha - remainder relapsed clinically after a median of 92 days nisms mediated by mithocondria. The dose level was (5-year survival 100% vs. 22%, P=0.0006). 71 Outcome established in pediatric trials (40-52 mg/m 2/d for 5 following HSCT however is worse in MRD-refractory days), 121-124 allowing combination with cyclophos - patients, that is, those persistently MRD+ after induction phamide/etoposide and other drugs. Toxicity may be and consolidation therapy. A number of prospective and remarkable but reversible (, skin, acute inflammatory retrospective adult studies reported survival/DFS proba - response). In adults, the activity is low as single agent or bilities of 35-60% with allogeneic HSCT in this risk sub - with cytarabine. 125 A small series indicated potential syner - set, 97-101 emphasizing the importance of post-transplanta - gy with cyclophosphamide (CR 4/6, 67%), with serious tion MRD negativity. 101 Differing from MRD relapse, toxicity due to high cyclophosphamide dose. 126 A simpli - which mirrors the more favorable clinical counterpart of fied schedule with clofarabine 30-40 mg/m 2/d and a late marrow relapse, MRD-refractory ALL is more sim - cyclophosphamide 300-400 mg/m 2/d for 3-5 days could be ilar to early relapsing ALL, and should be regarded as more tolerable, with or without mitoxantrone/etoposide/ indication for experimental approaches aiming to reduce PEG-asparaginase/dexamethasone (CR 24/55, 44%). 127 the amount of residual disease before HSCT. This concept is the of Ara-G, in which the 5’- also applies fully to HSCT in Re-ALL patients. In a pedi - triphosphate form is incorporated into DNA leading to atric study in second CR patients, the relapse rate was inhibition of DNA synthesis and apoptosis. Due to higher 57% with a pre-transplantation MRD greater than or deoxyguanosine phosphorylation, T-ALL cells are sensi - equal to 10 -4 compared with 13% with lower MRD values tive targets. Trials were conducted in children and (P <0.001). 102 Obtaining a major MRD reduction both pre- adults. 128,129 In the largest adult study from GMALL (126 and post-HSCT therefore is a primary goal in the manage - patients), 130 the CR rate was 36%, overall survival 24% at ment of Re-ALL. 103,104 1 year, and 3-year survival 31% for 36 patients undergo - ing HSCT. The response rate was higher in cortical CD1a+ T-ALL. These results are remarkable because of Novel approaches the highly unfavorable outcome of T-cell Re-ALL, and nelarabine deserves to be evaluated further in combina - Systemic chemotherapy tion with other drugs. 131 The comparative analysis of new salvage regimens is targets nucleoside phosphorylase, difficult because (1) patients failed intensive programs of has a favorable toxicity profile, and should be tested in different design; (2) retreatment groups are often small; Re-ALL, especially T-ALL.

Hematology Education: the education programme for the annual congress of the European Hematology Association | 2012; 6(1) | 13 | 17 th Congress of the European Hematology Association

Table 3. Selected studies with new agents and combinations for Re-ALL (2005 to present, CR rate >20 % for single-agent therapy [plus corticosteroids only] and >40% for combination therapy). Study (ref.) No. of patients New agent(s) Associated drug(s) Results Notes •New drug formulations Candoni et al. , 2006 105 25 (adults, median age 32) Liposomal daunorubicin High-dose Ara-C CR 17 (68%), 11 patients to HSCT (80-100 mg/m 2/d dd 1-3) survival 39% at 1 year Thomas et al. , 2009 107 36 (adults, median age 32) Liposomal vincristine Dexamethasone CR 29% at 1 st salvage - (1.5-2.4 mg/m 2 weekly [max x12] (n 14), 19% unselected •New drug/drug combinations Uckun et al. , 2006 117 9 (children, age 6-14) Vinorelbine (25 mg/m 2/d dd 1,8) Mitoxantrone or fludarabine CR 5 (55.5%) 1 patient A/W /dexamethasone/rituximab Hijiya et al. , 2008 118 31 (children) Topotecan (2.4 mg/m 2/d dd1-5) Dexamethasone/Vincristine/ CR 23 (74%), “window” study L-asparaginase survival 24% at (pretreatment) with 5 years significant response (89%) Hiwarkar et al. , 2008 119 5 (adults, median age 34) Topotecan (1 mg/m 2/d dd1-5)/ Dexamethasone CR 3 (60%) - vinorelbine (20 mg/m 2/d dd0,7, 14,21)/thiotepa (15 mg/m 2 d2)/ gemcitabine (3600 mg/m 2 d7) Karp et al. , 2007 126 6 (adults) Clofarabine (10-20 mg/m 2/d Cyclophosphamide CR 4 (67%) High regimen-related dd1-3,8-10) toxicity Locatelli et al. , 2009 123 25 (children, median age 25) Clofarabine (40 mg/m 2/d dd1-5) Cyclophosphamide/ CR 13 (52% [12% in 7 patients to HSCT etoposide T-ALL, P <0.01]), survival 39% at 1.5 years Steinherz et al. , 2010 124 12 with ALL/AML (children, Clofarabine (30-40 mg/m 2/d Dexamethasone CR 7 (58%) 4 patients to HSCT median age 10) dd3-7/Topotecan (1 mg/m 2/d dd0-4)/vinorelbine (20 mg/m 2/d dd0,7,14)/thiotepa (15 mg/m 2 d2) O’Connor et al. , 2011 122 23 (children, median age 6) Clofarabine (40-52 mg/m 2/d Cyclophosphamide/ CR 12 (52%), DFS 10 patients to HSCT, dd 1-5) etoposide 25% at 1 year, 6 in CR 13+ mos. survival 28% Pigneux et al. , 2011 127 55 (adults) Clofarabine (30 mg/m 2/d dd 1-5) Cyclophosphamide + CR 24 (44%), 16 patients to HSCT Dexamethaxone/etoposide/ Median survival mitoxantrone/ 6.5 mos. PEG-asparaginase Kurtzberg et al., 2005 129 39 with T-ALL Nelarabine (5-75 mg/kg/d dd1-5) - CR 9 (23%) 2 patients to HSCT, (adult and children) 1 A/W DeAngelo et al. , 2007 128 26 with T-ALL (adults, median Nelarabine 1.5 g/m 2/d dd 1,3,5 - CR 12 (31%) 7 patients to HSCT age 34) Commander et al. , 7 with T-ALL (children, Nelarabine (650 mg/m 2/d Cyclophosphamide/ CR 5 (71%) 4 patients to HSCT, 2010 131 age 2-19) dd 1-5) etoposide 1 patient A/W Goekbuget et al. , 126 with T-ALL (adults, Nelarabine 1.5 g/m 2/d dd1,3,5 - CR 45 (36%), 36 to HSCT (survival 2011 130 age 18-81) survival 24% at 1 year 31% at 3 years) •Cytotoxic monoclonal antibodies Raetz et al. , 2008 140 15 (children, median age 10) Epratuzumab (antiCD22: Vincristine/prednisone/ CR 9 (60%) 7 CRs MRD-negative, 360 mg/m 2 x4) Doxorubicin/PEG- No CR with single asparaginase agent epratuzumab (active in reduction phase) Topp et al. , 2011 142 21 with B-lineage ALL Blinatumomab (BiTE antiCD19: - Molecular CR 16/20 Treating MRD positivity (adults, median age 47) 15 mcg/m 2/24-h c.i. dd 1-28) evaluable (80%), (10 -4 to >10 -2 ), DFS 78% at 1 year 8 patients to HSCT Topp et al. , 2011 143 18 with relapsed B-lineage Blinatumomab (BiTE antiCD19: - CR 12 (67%), all 4 patients to HSCT ALL (adults) 5-30 mcg/m 2/24-h molecular CR c.i. dd 1-28) O’Brien et al. , 2011 141 49 with B-lineage ALL (adults) Inotuzumab ozogamicin - CR 9 (18% [survival 21 patients to HSCT (antiCD22-calecheamicin: 78% at 9 mos.]), CR 1.3-1.8 mg/m 2 every 3-4 wk) with incomplete recovery 19 (39%), cytogenetic response 89%, MRD response 63%

| 14 | Hematology Education: the education programme for the annual congress of the European Hematology Association | 2012; 6(1) Amsterdam, The Netherlands, June 14-17, 2012

Intrathecal therapy drugs are bosutinib, ponatinib, and new Aurora kinase Intrathecal liposome-encapsulated cytarabine might inhibitors, and these were tested in ongoing phase I/II tri - optimize treatment results in CNS relapse. The slow als in highly refractory patients and found partially active. release of cytarabine results in prolonged cytotoxicity in With ponatinib, currently the most powerful pan-BCR- the cerebro-splinal fluid (up to 14 days) and greater pen - ABL inhibitor, 37% of 52 heavily pretreated subjects with etration into CNS parenchyma. In a prospective adult blastic phase/Ph+ ALL (22 with T315I) achieved a major study, 132 8 (57%) and 11 (79%) of 14 patients entered CNS hematologic response (27% with T315I). 145 Other promis - remission after the one or two injections, respectively ing drugs are inhibitors of PI3K/AKT/mTOR pathway, (Ph-negative ALL: CR 4/5 after single administration antagonists of anti-apoptotic pathway (surviving, etc.), [80%]; Burkitt/B-ALL: CR 2/5 after 2 or more injections and hedgehog inhibitors. Combination therapy is also [40%]). Nine of 14 CR patients relapsed after a median of worth exploring (with chemotherapy, blinatumomab). 7 months, and median overall survival was 11 months. Reversible grade III-IV toxicity was recorded in 32%. Targeted therapy for Ph-negative B-lineage ALL Acute severe neurotoxicity was of some concern, howev - For B-lineage Ph- Re-ALL, by analogy with aggressive er all patients were heavily pretreated. B-cell , 146 experimental drugs are immunomodulators (lenalidomide), inhibitors of B-cell Monoclonal antibodies signaling (SYK [fostamatinib]), Btk [PCI-32765], of Cytotoxic monoclonal antibodies (MoAb) are almost JAK2/STAT [SB1518]), P13IK/AKT/mTOR (CAL-101, ideal weapons because they target cell surface antigens perifosine, rapamycin, temsirolimus, everolimus), PTEF- with no need for intracellular transport and accumula - b (flavopiridol), Ras/MAPK (, sorafenib), of tion. 133,134 CD19 is a widely expressed pan-B antigen tar - multiple signal transduction (TDZD-8), endoplasmic geted by blinatumomab, a bispecific MoAb engaging and reticulum stress protein HSPA5 (epigallocatechin gal - redirecting the cytotoxicty of autologous CD3+ T-cells late), proteasomes/modulators of NF- κB (), against CD19+ ALL cells. CD20 is expressed by about histone deacetylase (, ) and inter - 40% of ALL cases and is targeted by rituximab and ofatu - actions with bone marrow stroma (CXCR4 antagonists). momab. CD22 is expressed by 90% of B-cells and is tar - Clinical experience with these agents is limited. No geted by epratuzumab and inotuzumab ozogamicin (IO). response to lenalidomide was documented in four CD52 is a pan B/T-lymphocyte antigen targeted by alem - patients. 147 A phase I pediatric study evaluated bortezomib tuzumab. Mechanisms of action include ADCC and/or with chemotherapy: CR rate was 67% (6/9) and the estab - complement-mediated lysis, or toxicity induced by drugs lished dose level 1.3 mg/m 2.148 In an adult study, flavopiri - conjugated to the MoAb (IO, conjugated to calecheam - dol was added to cytarabine/mitoxantrone, with little suc - icin). 135 MoAbs can cause transient toxic side effects and cess (CR 1/8, 12.5%). 149 Therefore, most of the available suppress immunity (alemtuzumab: opportunistic infec - evidence comes from B- studies and preclini - tions and CMV reactivation), but are generally handled cal models, 150-152 where synergy with other drugs is docu - with ease even in association with chemotherapy. In Re- mented (mTOR inhibitors and vincristine/methotrex - ALL, experience with rituximab, alemtuzumab and other ate), 153 while experience in Re-ALL must be considerably compounds is unsatisfactory (alemtuzumab; trastuzumab, expanded. targeting HER2 receptor), 136-138 or preclinical. 139 In a pedi - atric study, epratuzumab reduced the initial ALL cell bur - Targeted therapy for T-ALL den and contributed to an improved induction outcome, The constitutive activation of NOTCH1 in many cases including the MRD response. 140 More remarkable were of T-ALL stimulated the search for anti-NOTCH1 thera - the results obtained with IO at MD Anderson: CR 9/49 pies like γ-secretase inhibitors (GSI) that block the cleav - (18%), CR with incomplete platelet/neutrophil recovery age of NOTCH receptors and the release of its intracellu - 39%, and complete MRD remission 63%, however the lar domain ICN1. 154 GSI induce G1 cell cycle arrest and is response was short-lived. 141 The best results were a candidate new drug for T-ALL with concomitant corti - obtained with blinatumomab in 21 MRD+ patients at costeroid therapy to reduce gastrointestinal toxicity. highest risk of relapse. In this study, 142 16 of 20 evaluable Clinical experience is so far limited and unsuccessful. 155,156 patients converted to molecular CR (80%), with a DFS of Direct drug targeting of NOTCH1 and use of monoclonal 78% at 1.5 years. In relapsed ALL, CR rate was 67% antibodies would also be possible. In cases showing (12/18), in association with MRD remission. 143 Toxicity NUP214-ABL rearrangement, the use of TKI could pro - was manageable but occasionally severe due to an acute vide a therapeutic benefit, 157 and similar considerations neurological syndrome. A report confirmed blinatu - may apply to JAK1+ cases. momab activity in highly refractory post-transplant ALL, where the molecule successfully engaged allogeneic T- HSCT cells against CD19+ lymphoblasts. 144 For Re-ALL patients who undergo HSCT in the second or greater CR or with active disease, the intensity of the Targeted therapy for Ph+ ALL conditioning regimen may be relevant. In younger Many TKI- and HSCT-treated patients develop Ph+ Re- patients, one approach is to intensify TBI dose ( ≥13 Gy) ALL in relation to one or more mechanisms (overexpres - or substitute etoposide for cyclophosphamide. 158 sion of BCR-ABL with downstream activation of Ras/Raf Promising results were reported with TBI followed by and JAK-STAT, point mutations [T315I, etc.], concurrent total marrow irradiation with helical tomotherapy (2 Gy gene deletions [IKZF1, PAX5, CDKN2A/B], drug efflux, in a single fraction) and cyclophosphamide, 159 and with growth factor independency), of which T315I mutation is high-dose clofarabine-based conditioning. 160 For some the most relevant and frequently observed. 39,40 Alternative patients, reinduction could even be omitted when HSCT

Hematology Education: the education programme for the annual congress of the European Hematology Association | 2012; 6(1) | 15 | 17 th Congress of the European Hematology Association is immediately feasible, with survival rates of 20-30% MRD and chimerism is an essential treatment component reported in two series. This would be possible when the in HSCT recipients with Re-ALL. 103,104 leukemic burden is still moderate and the reinduction fail - ure is likely due to very high-risk cytogenetics or early 161,162 relapse. Lastly, cord blood (CB) and haploidentical Conclusions HSCT have been explored as alternative HSCT option in patients lacking HLA matched-related/unrelated donors. 169 Both CB-HSCT and peripheral blood T-cell depleted hap - Although therapeutic progress is undeniable, treat - loidentical HSCT were confirmed feasible and shown to ment resistance is the major obstacle to optimize the cure exert a therapeutic activity comparable to standard HSCT rate in ALL. At the same time, the perfect ground where (2-year survival 30%). 163,164 In general, in Re-ALL trans - testing innovative therapeutic concepts, like the emerging plantation-related mortality is high and post-transplanta - strategy of an MRD-guided therapy of subclinical relapse, tion relapse remains the major cause of failure. After gives the opportunity to strike on a 2-3-log lower ALL relapse, treatment options are withdrawal of immunosup - burden, and the entirely new area of targeted therapy 165 pression, DLI with or without chemotherapy, MoAbs (Figure 1). Further progress is expected as long as we 144 and targeted therapy, ex vivo expansion and reinfusion penetrate more deeply into the biological core of the dis - of activated T/natural killer cells recognizing tumor-asso - ease and skilled scientists discover new therapeutic ciated antigens, and/or subsequent HSCT. 103,104,166 To increase the probability of success, all of these interven - breakthroughs. When sound advancement is confirmed tions should be performed at time of molecular rather and transferred into first-line therapy, certainly with than clinical relapse, as exemplified by studies in both Ph- greater chance of success, Re-ALL will be finally relegat - negative and Ph+ ALL, 167,168 therefore close monitoring of ed to the conditions to remember and not to treat.

Figure 1. Treatment strategies for resistant ALL.

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