Best Practice & Research Clinical Haematology 27 (2014) 247e258

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7

Will novel agents for ALL finally change the natural history? Dan Douer, MD, Clinical Professor of Medicine * Leukemia Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, Weill Cornell Medical College, 1275 York Ave, New York, NY 10065, USA

Keywords: acute lymphoblastic leukemia ALL immunotherapy CAR T cells targeted agents

Pediatric acute lymphoblastic leukemia (ALL) cure rates have markedly improved over the past years to approximately 85%, but remain at 40%e50% in adults. Redefining current adult chemotherapy regimens is likely to improve the natural course of the disease, but new agents are needed. Immunotherapy approaches for pre-B ALL are in the forefront of research on novel agents; in particular, advances are being made in manipulating autologous T cells either by infusion of a bifunctional antibody (eg, blinatumomab) or by ex vivo genetic modification of chimeric antigen receptors (CARs). The natural course of Philadelphia positive ALL has already improved by targeting ABL/BCR1. Other mutated genes are being discovered and novel small molecules that target their products are being studied in clinical trials. Finally, ALL is a heterogeneous disease and novel agents are likely to impact the natural course of smaller populations of biologically defined ALL subtypes. © 2014 Elsevier Ltd. All rights reserved.

Introduction An increasing number of new agents are being developed in all cancer types, including acute lymphoblastic leukemia (ALL). In addition to defining their targets and mechanisms of action, planning clinical trials with new agents requires consideration of several general concepts. One consideration is that while initially studied as single agents, several new agents are likely to be combined with chemotherapy for incremental activity. However, the chemotherapy “backbone” may need to be

* Tel.: þ1 212 639 2471; Fax: þ1 212 772 4881. E-mail address: [email protected].

http://dx.doi.org/10.1016/j.beha.2014.10.006 1521-6926/© 2014 Elsevier Ltd. All rights reserved.

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modified, especially if the single agent is very active. This would be more problematic in ALL, since no standard treatment is defined for adults. Other considerations are tumor burden (overt versus minimal residual disease), time of treatment (front-line or after relapse), age, and when relevant, the relation to hematopoietic stem cell transplantation (HSCT) (before or after as maintenance). The challenge in a rare disease such as adult ALL is that realistically only a few definitive clinical trials can be conducted in a reasonable amount of time that will impact the natural course of the disease. Discussed first below is the natural course of adult ALL using current treatment approaches. What do we know about the current natural course of adult ALL? With any contemporary induction regimen, first complete remission (CR) rate dat least for those younger than age 60 yearsdis 90%, much higher than for acute myeloid leukemia (AML) in the same age groups [1]. However, resistance to induction treatment is probably higher if a true CR is redefined as achieving a minimal residual disease (MRD) negative state. Second, despite post remission treatment, half of adult patients fail to remain in CR, mostly due to relapse. Third, the role of HSCT in first CR is unclear and studies have reported conflicting results [2]. Fourth, when patients relapse, the response rate is low, and if a CR is obtained, it is generally of very short duration. Until recently, no improvement had been seen in the overall outcome of adult patients with ALL. One notable exception is Ph-positive (Phþ) ALL. For the first time, this subtype can be cured with chemotherapy combined with a tyrosine kinase inhibitor (TKI), although the outcome may still be better when allogeneic HSCT is included. In general, the treatment of ALL is complex and includes a variety of chemotherapy agents in multiple cycles. All regimens also include maintenance and central nervous system prophylaxis, which distinguishes the treatment of ALL from that of AML. Despite different designs, patient populations, risk factors, and upper age limits, the overall survival (OS) rates have not changed. Thus, no standard regimen has been established for adult ALL, and treatment is generally chosen based on prior training and practice preferences. The current National Comprehensive Cancer Network guidelines recommend a clinical trial as first-line treatment in newly diagnosed adult ALL and otherwise provides a list of potential regimens [3]. How did our current adult ALL treatment develop? Early studies conducted in the 1960s and 1970s showed single activity of the nonmyelosuppressive drug vincristine, prednisone, and asparaginase, and when combined with adriamycin into a 4-drug regimen (5 drugs if cyclophosphamide was also included) the CR rate increased to 75% [4e6]. The only randomized trial that showed a benefit of one agent was reported in 1984da greater CR rate was achieved when daunorubicin was included in the 4-drug combination compared to 3 drugs [7]. During the 1990s, the treatment of adult ALL had developed, with a few exceptions, in two fundamentally different directions, both with a higher CR rate of approximately 90%. Table 1 presents Table 1 Newly diagnosed adult ALL: Recent large clinical trials. Study

Years

N

Age

Treatment

CR (%)

DFS (%)

GMALL 05/93 [9] CALGB 8811 [5] CALGB 19802 [8] MRC/ECOG- UKALLXII/E2993a [6,10] UCSF 8707b [11] L-2 [12] Hyper CVADb [13]

’93e’99 ’88e’91 ’99e’01 ’93e’06 ’87e’98 00e06 ’92e’00

1163 198 163 1913 84 78 288

35 35 41 15-64 27 33 40

Variants of a BFM model

87 85 78 90 93 85 92

35 36 35 OS 39 52 34 38

BFM model ± SCT VPDA þ Intensified HD-MITOX þ HD-ARA-C A) Cytoxan, DEX, ADR, V B) HD-MTX þ HD-ARA-C

Abbreviations: BFM, Berlin-Frankfurt-Munster ALL treatment model; V, vincristine; P, prednisone; D, daunorubicin; A, asparaginase; HD-MITOX, high-dose mitoxantrone; DH-ARA-C, high-dose cytarabine; DEX, dexamethasone; HD-MTX, high-dose methotrexate; OS, overall survival; DFS-disease free survival. a Randomized. b Single institution.

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several of the larger trials, which vary by upper age limit, selection of specific chemotherapy agents, and indication for allogeneic HSCT. The trials have an almost identical long-term survival of 35%e40%; if Phþ ALL patients are excluded from the analysis the overall survival (OS) is approximately 45% [8]. The first regimen, originally developed in children and adjusted for adults, is the BerlineFrankfurteMunster (BFM) model and its different variants. Different variants of this model were extensively studied in thousands of patients by all the large cooperative groups in the United States and Europe [5,6,8e12]. Another regimen, the hyperCVAD regimen, was developed and studied only in adults in hundreds of patients in a single institute, but not confirmed in a large multi-institutional prospective trial [13]. BFM regimens always include asparaginase, a drug known to have a critical role in every pediatric regimen. HyperCVAD contains no asparaginase, but includes more myelosuppressive drugs. Recent retrospective reports show longer severe cytopenias with hyperCVAD than previously reported, though without reducing OS [14]. The two approaches were never compared in a head-to-head study, but their reported outcomes were similar, with OS rates of approximately 40%. HyperCVAD is probably the most commonly used regimen in adult ALL in the United States, despite having no proven advantage, greater marrow toxicity, and longer hospitalization. This is most likely due to a much simpler delivery structure with its alternating A and B cycles. In contrast, pediatric ALL treatment evolved during the same years by a series of rationally designed clinical trials, each refined based on the previous results, resulting in a cure for most children. Among the concepts established in these trials were the critical role of long asparaginase treatment, early CNS prophylaxis, and the benefit of a later delayed re-induction. Chemotherapy revisited The lack of standard of treatment, almost no randomized trials, and no progress over several decades compel us to critically revisit our adult chemotherapy approaches, focusing on three fundamental and provocative questions. Should treatment of ALL change at age 21? Historically children are managed by pediatric oncologists until an age that generally ranges between puberty and 21 years. Then their care switches to medical oncologists who use different approaches as discussed above. It is true that favorable biological characteristics decrease with increasing age and older patients have more co-morbidities. Yet, this agedbetween puberty and 21 yearsdwhen ALL treatment drastically changes, appears arbitrarily set by administrative considerations and not medically proven nor substantiated by evidence. It seems unfortunate that ALL treatment developed in two totally different and uncoordinated directions with inferior outcomes reported for adult regimens in patients of the same age groups [15]. More recent studies show that pediatric regimens can be as safe and beneficial in young adults beyond age 21 [16e18]. Consequently, both the National Comprehensive Cancer Network (NCCN) and the US National Cancer Institute now recognize a new age group of adolescents and young adults (AYA) aged 15e39 years for unified protocol development [4]. New drugs should be developed in a coordinated effort of pediatricians and medical oncologist who together will determine a change of treatment regimen not solely by an arbitrary age but rather by the new agents' targets and the individuals' comorbidity considerations. Is “AML-like” prolonged and profound marrow aplasia necessary in the treatment of ALL? A well-established treatment concept in treating AML is a long and profound marrow aplasia that is necessary for achieving a higher CR rate, using high myelotoxic doses of anthracyclines and intensified doses of cytarabine. But this approach may apply only to AML, since such a degree of myelosuppression is not part of almost any other cancer treatment. Although myelotoxic chemotherapy drugs are commonly used in cancer, their myelosuppression is considered a side effect rather than a therapeutic purpose of its own, as would be the case in AML. Several well established observations suggest that in fact “AML-like” myelosuppression may not be required in ALL. (i) All adult ALL trials that attempted to intensify the dose of anthracyclines failed to show a higher CR rate or longer-term survival rates. Large

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studies include: the ALL-2 regimen using high-dose cytarabine and very high-dose mitoxantrone in induction, hyperCVAD with liposomal daunorubicin, and CALGB 108021 in a BFM model with more daunorubicin [8,12,19]. (ii) In contrast and unlike AML, in a BFM model induction that includes 4 drugs, only oneddaunorubicindis myelotoxic and the duration of myelosuppression is shorter, yet the CR rates are high [20]. In fact a 50% response rate can be achieved with vincristine and prednisone in adult ALL. (iii) The mandatory long, low-dose maintenance, (iv) pediatric regimens that emphasize more and longer use of the nonmyelosuppressive drugs vincristine, steroids, and asparaginase, and (v) the key role of prolonged nonmyelosuppressive asparaginase [21,22] provide support that AML-like myelosuppression may not be necessary. Is there a role for long asparaginase treatment in adult ALL? BFM model regimens were derived from pediatric protocols and optimized for adults. They generally utilize asparaginase, but only in one to two post-remission cycles, since the drug is considered to be more toxic in adults. In contrast, all large randomized pediatric ALL trials reported that higher cumulative doses of asparaginase confer a significant advantage compared to less asparaginase treatment. In fact, in multiple-agent pediatric protocols, modification of asparaginase alone resulted in improved patient outcomes and contributed to the overall treatment benefit. This provides further support for the role of asparaginase and its doseeresponse effect, even in adults [22]. New chemotherapy combinations in adults These modified chemotherapy principles were exploited by adult oncologists in ALL clinical trials for patients older than 21 years, intensifying nonmyelosuppressive drugs and including more doses of the long-acting pegaspargase. At the same time, better guidelines for preventing and managing asparaginase-related side effects in adults were published to reduce the toxicity concerns of using asparaginase [23]. Preliminary results of true pediatric or “pediatric inspired” protocols in adult ALL (Table 2) report overall survival rates of 60%e70%, higher than historical results [16e18,20,24,25]. However, the upper age limit for safety of such regimens is not well defined, but is thought to be between the ages 50 and 60 years. Even in the absence of randomized clinical trials in adults, these results indicate that such approaches should be standard, at least up to age 40. In addition, the aptness of the widespread use of hyperCVAD in the United States should be seriously challenged, at least for younger adults. HyperCVAD prohibits the inclusion of long-acting asparaginase, adds more unnecessary myelosuppression, and does not provide any outcome advantage. Relapse Most new agents will be first used in the relapse setting, in which the outcome of adult ALL, regardless of age or treatment, is extremely poor. All treatment approaches are based on small studies with complete remission rates of 25%e50% that are very short. In relapsed ALL, the goal is to achieve a Table 2 Newer chemotherapy combinations. Study True pediatric DFCI [25] CALGB 10403 [18] Pediatric “inspired” PETHEMA [16] GRAALL-2003 [24] USC [20] Princess Margaret Asparaginase intensification GMALL 7/03 [60]

Asparaginase

Upper age (yrs)

OS @ 3e7 yrs.

E. Coli PEG-ASP 25,000 U/m2

50 39

74% Pending

E. Coli E. Coli PEG-ASP 2000 U/m2 E. Coli (retrospective)

30 45/60 57 60

69% 64%/47% 58% 65%

PEG-ASP 500/1000 / 2000 U/m2

55

67%

Abbreviations: OS, overall survival; PEG-ASP, long-acting pegaspargase; yrs, years.

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short time-window of second CR for a prompt allogeneic HSCT with any available suitable donor. Interestingly, the dismal outcome of relapsed ALL is highlighted in children by the fact that in the last 20 years, no study was able to show an improvement in all relapsed risk groups [26]. New agents Table 3 lists four different directions for developing novel agents that are discussed here in more detail. New and effective immunotherapy concepts are in the forefront of research on novel agents and are already expanding our therapeutic options. New agents e chemotherapy Four traditional chemotherapy agents were approved by the US the Food and Drug Administration and added as single agents to our drug armamentarium. Clofarabine is a purine nucleoside antimetabolite, approved for relapsed patients younger than age 21 years and yields a CR rate of 30% [27]. It is being studied in combination with chemotherapy drugs in the relapse setting and more recently in front-line regimens. It is noteworthy that if used in adults, clofarabine is dosed at no greater than 40 mg/m2 (in children 52 mg/m2) for 5 days. Nelarabine, another purine nucleoside analog, is indicated for relapsed T-ALL and yields a CR rate of 30% [28]. Neurological side effects are less common when dosed at 1500 mg/m2 every other day for 3 days. Both drugs are myelosuppressive. The two other drugs are nonmyelosuppressive and both are modified versions of the same drugs widely used in ALL. Vincristine sulfate liposomes injection (VSLI) is vincristine in a liposomal capsule that at a dose of 2.25 mg/m2 without the 2 mg cap delivers more vincristine without more neurotoxicity. In ALL, vincristine is always part of combination chemotherapy, while VSLI is given as a single agent and has a CR rate in relapsed ALL of 20% [29]. Studies are ongoing to examine if a higher dose of vincristine given in the form of VSLI in combination front-line chemotherapy will be beneficial. The fourth drug is asparaginase obtained from Erwinia chrysanthemi, which is indicated for patients who develop allergy to E. coli-derived asparaginase, enabling these patients to continue asparaginase treatment. It has a shorter half-life than other forms of asparaginase [30]. Studies show that children who switched to E. chrysanthemi asparaginase after an allergic reaction maintained the good outcome rates [31]. T-cell immunotherapy Until recently, the only T cells available to treat and even cure ALL were donor-derived as part of the graft-versus-leukemia effect of allogeneic HSCT. Technical advances in cell manipulation allow modification of the patients' own autologous T cells to target and destroy ALL cells. Two methods are being developed with promising preliminary clinical results. Both target CD19 that is expressed in the majority of pre-B ALL patients. In one method, known as the chimeric antigen receptor (CAR) modified Table 3 Summary of new agents. Approach Single-agent chemotherapy Nelarabine Clofarabine Vincristine sulfate liposomes injection (Marqibo) Erwinia asparaginase Immunotherapy Autologous T-cell therapy CAR T cells Bifunctional antibodies Antibodies (“naked” or conjugated) Small molecules targeting metabolic pathway

Patient population Relapse T-cell ALL Approved for relapse up to age 21 Relapse Allergy to E coli-derived asparaginase

Pre B cells Pre B cells Different targets Target dependent

Abbreviations: ALL, acute lymphoblastic leukemia; CAR T cells, chimeric antigen receptor T cells.

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autologous T cells, the cells are manipulated ex-vivo. In the other approach, a “smart” bifunctional antibody called blinatumomab is used to modify in vivo autologous T cells. Table 4 compares the two methods along with allogeneic HSCT. CAR T cells Autologous T cells for CAR therapy, obtained by leukapheresis, are bioengineered by a viral vector that transduces a CAR gene construct that encodes tumor-specific single fragment length antibodies (scFvs) to target specific antigens expressed by tumor cells (ie, CD19). The construct includes a signal transduction component (zeta chain) of the T-cell receptor and T-cell costimulatory domains (CD28 and/or 4-1BB) [32]. After conditioning chemotherapy, the CAR-modified T cells are reinfused into the patient and target CD19-expressing cells. The costimulatory signaling domains are essential for expansion and persistence of the T-cell clone. In addition, largely due to the inclusion of the T-cellderived costimulatory domain(s), the genetically modified cytotoxic T cells have been shown to proliferate, survive, and persist in patients as memory T cells, thereby theoretically providing sustained anti-leukemia effect [33]. Three US groups have recently reported impressive high response rates that are often durable and allow patients to continue to allogeneic HSCT [34e36]. The group at Memorial Sloan Kettering Cancer Center (MSKCC) reported 16 patients with relapsed ALL aged 24e74 years of whom 9 had overt disease and 7 had MRD after tumor cytoreduction [36]. Overall, 14 (88%) patients entered a CR, including 7 (78%) who had overt disease. In twelve (75%) patients, the CR was MRD negative and 7 (44%) patients were able to undergo allogeneic transplantations. The high response rate established the principle that CAR autologous T-cell therapy is an effective anti pre-B ALL therapy. Several matters that should be addressed are the optimal dose of CAR T cells in relation to the tumor burden, the optimal CAR construct gene, the duration of CAR T cells remaining after reinfusion, and whether such an approach is a cure in specific disease circumstances. In addition, the significant toxicity of CAR T-cell therapy should be further addressed and minimized. Cytokine release syndrome (CRS) Unlike toxicities associated with conventional chemotherapy, those associated with infused CAR T cells are related to large-scale, synchronous T-cell activation upon targeting of CD19þ leukemia cells and an increase in serum cytokine production. CRS presents with fever, hypotension, hypoxia, and neurologic manifestations such as mental change and seizures. Fever is very common, but patients with fevers alone and/or elevated serum cytokines in the absence of additional clinically apparent toxicities are less likely to require anything more than observation or modest medical intervention [36]. The MSKCC group developed laboratory and clinical criteria for a formal diagnosis of severe CRS (sCRS) by systematically checking serum levels of select small panels of cytokines that are strongly associated with sCRS [36]. Patients who meet these sCRS criteria are likely to require more intensive observation and aggressive medical management, including hemodynamic support, occasionally in an intensive care unit. In other patients, fevers and discomfort are more likely to resolve spontaneously or with minimal support. The importance of this distinction is to avoid premature intervention that may Table 4 T-cell immunotherapy approaches. Autologous

Agent Target ALL subtype Manipulation Agent activity Curative potential Complications (duration)

Allogeneic

Antibody (Blinatumomab)

CAR T cells

HSCT

Bifunctional antibody CD19 B/Pre B In vivo Very short No CRS (Short)

Gene construct CD 19 B/Pre B Ex vivo Months Unknown CRS (2e4 weeks)

Donor cells Multiple All subtypes None; T-cell depletion Years Yes GVHD (Very long)

Abbreviations: CAR, chimeric antigen receptor; CRS, cytokine release syndrome; HSCT, hematopoietic stem cell transplantation.

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diminish T-cell persistence or efficacy. The treatment of CRS is intensive support, treatment with tocilizumab (an IL-6 inhibitor), and in life-threatening conditions, steroids, though it may also minimize or eliminate the CAR T-cell activity. Blinatumomab Blinatumomab is a single-chain antibody with dual specificity against CD3 and CD19, thereby bringing normal cytotoxic T cells into close proximity with normal and malignant CD19-positive B cells [37]. Blinatumomab, which by itself is inert, represents a new class of antibody therapy, known as bispecific T-cell engaging or BiTE antibodies. Conventional monoclonal antibodies, which lack the dual specificity of BiTE antibodies, do not draw T cells and B-lineage ALL cells together for the same degree of highly potent tumor-cell killing. Remarkable single-agent activity of blinatumomab in adults with precursor B-ALL was reported in two small phase 2 clinical trials with acceptable side effects. One study showed that among 20 patients with molecular disease (MRD persistently positive or early MRD relapse), 80% converted to MRD negative CR [38]. In the second trial, in 25 patients with overt relapse, the CR/CRh rate (CR with partial hematologic recovery) was 68%, almost all MRD negative and occurring within the first 2 cycles. The most common treatment-related adverse events were fever and neurologic toxicity (confusion and seizure activity) manageable with corticosteroids [39,40]. Single-agent activity of blinatumomab was more recently confirmed in a large clinical trial with 189 Ph-negative relapsed or refractory pre-B ALL patients [41]. The CR/CRh rate was 43% (CR 35%), 80% of which occurred after 1 cycle of 28 days, and 61% of the responses were MRD negative. The median overall survival was 6.1 months (95% CI 4.2e7.5), which is relatively long for these difficult to treat patients. The most common high-grade toxicity was febrile neutropenia (26%). Serious CNS toxicity was encephalopathy (3%) and ataxia (2%). Interestingly, only 2% of the patients were reported to have CRS. A practical limitation to blinatumomab administration is the requirement for a 28-day continuous infusion per cycle, the need for a sterile facility for drug preparation, and in the US, mandatory drug cassette changes every 48 h. These limitations, however, could be mitigated by skilled logistical planning. Subsequently, the Eastern Cooperative Oncology Group (ECOG) has opened a phase 3 randomized clinical trial combining blinatumomab with front-line chemotherapy compared to the same chemotherapy given alone in patients aged 35e70 years. Like CAR technology, blinatumomab redirects the patient's autologous T cells to attack CD19positive cells. Table 4 compares the two modalities along with allogeneic T cells in HSCT. Both T-cell recruiting strategies have shown clinical efficacy, significantly reducing tumor burden in pre-B-cell ALL. Side effect profiles are similar and both are associated with high tumor burden, mostly fever, CRS, and neurotoxicity, but are more common and severe with CAR T cells and require more intensive support measures. Monoclonal antibodies Antibodies target different antigens on the cell and are listed in Table 5. Rituximab, targeting CD20, is the most common antibody used in B-cell lymphoma, but CD20 is expressed in only half of patients with pre-B-cell ALL with limited single-agent activity of rituximab. Preliminary observations from two studies in CD20-positive ALL patients suggest that rituximab in combination with different adult chemotherapy backbones produces higher survival rates in adults younger than 60 years compared to the same chemotherapy alone [42,43]. However, the question of routinely including rituximab in CD20-positive adult ALL therapy has not been definitively answered. Also the benefit of rituximab added to pediatric regimens, or in relapsed disease, has not been well studied. Another targeted antigen is CD22, which is present on 90% of pre-B ALL cells. Epratuzumab is the naked unconjugated anti CD22 antibody, and studies in children showed limited single-agent activity [44]. After binding to CD22, anti CD22 antibodies are internalized and are therefore more suitable for conjugation with a toxin that would be better delivered to the leukemia cells. One example is inotuzumab ozogamicin, which is an anti CD 22 antibody conjugated to the powerful toxin calicheamicin. DeAngelo and colleagues presented results from a phase 1/2 trial of inotuzumab ozogamicin in adult

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Table 5 Immunotherapy targeting pre-B-cell ALL. Target

Agent

Single-agent activity

CD19

Blinatumomab 19e28z CAR autologous T-cells Conjugate SGN-CD19A Rituximab Epratuzumab Inotuzumab ozogamicin Moxetumomab pasudotox (HA22)

CR 40% CR 85% Phase 1 Minimal (w/chemo may improve young CD20 þ ALL) Minimal CR þ CRi: 65% CR 24%

CD20 CD22

Abbreviations: CAR, chimeric antigen receptor; chemo, chemotherapy; CR, complete response; CRi, complete response with incomplete hematologic recovery.

patients with relapsed or refractory CD22-positive ALL [45]. The remission rate was 79% for patients in a dose-escalation cohort and 46% for patients in a dose-expansion cohort. Data from M.D. Anderson Cancer Center also showed that inotuzumab ozogamicin has activity as a single agent, without chemotherapy, in relapsed patients [46]. An ongoing phase 3 trial is comparing single-agent inotuzumab with chemotherapy. Inotuzumab ozogamicin is a candidate for evaluation in combination with an ALL chemotherapy regimen in the first-line setting. Concerns have been raised that inotuzumab ozogamicin might be associated with liver toxicity and venoocclusive disease, seen in an AML calicheamicin immunoconjugate (eg, gemtuzumab ozogamicin), but this has not been reported in the preliminary results. Another antibody-drug conjugate in development is SGN-CD19A, which targets CD19. Phase 1 studies are underway in adult and pediatric patients with relapsed or refractory B-lineage ALL, Burkitt lymphoma, or leukemia, and B-lineage lymphoblastic lymphoma. Targeted agents Researchers have identified several different mutated genes whose products could be targeted by drugs [47,48]. Table 6 is a partial list of novel agents, some of which are already in clinical trials. The classic examples are the tyrosine kinase inhibitors (TKIs) such as imatinib, dasatinib, and nilotinib used in Philadelphia-positive ALL, which target the disease-specific BCR/ABL1 gene rearrangement protein product. Such a very high response rate relates to Phþ ALL being a relatively homogeneous molecular rearrangement of BCR/ABL1 directly involved in leukemogenesis, and when further mutated the disease can become resistant to TKIs. Another approach is targeting mutations in molecules that are part of other pathways, such as in NOTCH1 and DOT1L, by novel small molecule inhibitors under development in ALL in phase 1 clinical trials, although it is not clear if the mutated target is important for response. DOT1L inhibition Acute myeloid, lymphoid, and infant leukemias with translocations involving the mixed lineage leukemia (MLL) gene at the 11q23 locus are well described and have a very poor outcome. The Table 6 Novel agents: small molecules. Target

Drug

MLL (q11.23) Notch1 (T-ALL) JAK RCLF2 mTOR PI3K d (Pre-B) PI3K d, g (Pre-T) NUP214-ABL1 (T-cell)

DOT1L inhibitor, FLT3 inhibitor g secretase inhibitors (GSI) JAK inhibitors Everolimus, temsirolimus Idelalisib IPI-145 Tyrosine kinase inhibitors

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translocation partner genes of MLL are derived from other chromosome variations, but the acute leukemia phenotype produced with the translocation is conserved between translocation partners. Normally, MLL encodes for a protein that is involved in catalyzing a methylation of histone H3. With fusion of a partial MLL gene to a translocation partner, MLL loses this methyltransferase activity, and by contrast gains the ability to recruit DOT1L, a histone methyltransferase that catalyzes the addition of a methyl group to histone H3 at position K79 [47,49]. DOT1L has been proposed to be required for MLLmediated leukemogenesis using in vitro systems, in vivo genetic systems, and most recently, inhibition of DOT1L. A small molecule DOT1L inhibitor was found to inhibit H3K79 methylation, proliferation of MLL rearranged cells both in vitro and in vivo, had efficacy in preclinical models, and is now in a phase 1 clinical trial [50]. Notch 1 inhibition The NOTCH1 gene encodes a transmembrane receptor, and upon ligand binding, its intracellular domain is cleaved by a gamma-secretase, translocating it to the nucleus where it activates signaling pathways that regulate T-cell proliferation and differentiation. More than 50% of patients with T-cell ALL have activating NOTCH1 mutations. Gamma-secretase inhibitors (GSI) blocking NOTCH1 activation have been developed and prevent cleavage of the intracellular signaling domain. Several phase 1 clinical trials are ongoing with GSIs in T-ALL. The major dose-limiting toxicity appears to be diarrhea [51]. Cytokine receptor-like factor 2 (CRLF2) and JAK pathways Recently, CRLF2 has been identified in ALL on the cell membrane as a new therapeutic target. Normally, CRLF2 with IL-7R form the thymic stromal lymphopoietin receptor (TSLR). When activated, TSLR effects the survival and maturation of B and T lymphocytes and enhances cytokine production [52,53]. Rearrangement of the CRLF2 gene results in high expression of CRLF2 on the leukemia cell membrane, potentially promoting B-cell leukemogenesis. Signaling pathways associated with CRLF2 rearrangements and JAK mutations induce phosphorylation of STAT5, PI3K, and ERK. Therefore, inhibitors of intracellular JAK2, PI3K/mTOR, and MEC as well as membranous CRLF2 provide potentially promising new research directions. Interestingly, 15%e20% of patients with childhood ALL (50% in Down syndrome) are classified as BCR-ABL1elike, having gene expression similar to ALL with BCRABL1 rearrangement, including mutations of JAK1, JAK2, deletions or mutations in IKZF1, and high expression of CRLF2. These alterations are associated with an unfavorable outcome, and were found more commonly in Latinos [54,55]. Others Preclinical studies have shown that the mTOR inhibitor everolimus, currently used in solid tumors and also being investigated in mantle cell lymphoma, has synergistic interactions with chemotherapy and other agents in precursor-B ALL [56]. Fingolimod, a drug used to treat multiple sclerosis, can target PP2A mutations in Ph-positive ALL [57]. JAK1 mutations are a relatively frequent event in T-ALL, and JAK inhibitors may be useful in this disease [58]. Summary In revisiting several principles of the existing adult ALL chemotherapy regimens, it is clear that the current status of front-line treatment is being redefined. Together with the range of new agents available to treat the disease, the natural course of adult ALL is likely to improve, although with different degrees of success. In Phþ ALL patients, TKIs have already shown an excellent clinical impact that has significantly improved survival rates; Phþ ALL is no longer considered the most unfavorable subtype. Other agents with similarly high success rates would also target molecularly homogeneous subtypes of ALL, but are likely to apply to smaller patient populations. Impressive clinical results in a larger number and more heterogeneous B-lineage-derived ALL patients have already been

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demonstrated using manipulated autologous T-cell immunotherapy. More research is required to address the technological complexities of preparing or administering of such agents to each individual patient, as well as managing their unique toxicities. So far, antibodies have modest single-agent activity when conjugated. Genetic profiling of individual patients is slowly becoming more common with a possibility of discovering by chance, mutation(s) for which an active targeted treatment is already available. For example, NUP214-ABL1 rearrangement occurs in a few T-cell ALL patients, and it can be targeted by dasatinib and similar TKIs [59]. On a larger scale, programs such as Therapeutically Applicable Research to Generate Effective Treatments (TARGET) have been established to facilitate the identification of potential therapeutic targets for childhood cancers. So far, the impact of molecules that target specific pathways in the natural course of adult ALL has been limited, but these molecules are still only in their early phases of development. However, the complex genetic heterogeneity of ALL will diminish the number of patients available for large clinical trials. Future studies should therefore include children and adolescents while accounting for different pharmacokinetics and dosing in young children. In fact, the successful development of ALL treatment was led by pediatricians, but paradoxically, novel agents so far appear to be advancing more slowly in the pediatric population. Regulatory hurdles for including children and adults in the same clinical trials will need to be overcome. ALL is the most common cancer in children but is unique because its incidence is similar in children and adults. Greater collaboration between pediatricians and adult oncologists will be essential to avoid repetition of what occurred historically, with ALL treatment developing in two uncoordinated directions. Conflict of interest Dr. Douer received research grants and consultation fees from Sigma Tau Pharmaceutical.

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