1. Background

2. Medical need

3. Existing treatment

4. Market review

5. Current research goals

6. Scientific rationale

7. Competitive environment

8. Potential development issues

9. Conclusion

10. Expert opinion

Review

Emerging drugs for acutelymphocytic leukemiaMichael S Mathisen, Hagop M Kantarjian & Elias J Jabbour†

†M.D. Anderson Cancer Center, Department of Leukemia, Houston, TX, USA

Introduction: Acute lymphoblastic leukemia (ALL) is typically treated with

complex multi-agent chemotherapy regimens over a prolonged time period.

Long-term outcomes depend on the age of the patient and the biological

characteristics of the leukemic cells. While pediatric patients achieve cure

more often than adults, therapy can continue to be improved for all patients

with this disease.

Areas covered: The current management strategy for ALL is reviewed.

Recently, targeted therapies have been shown to improve survival in subsets

of patients, most notably in those with Philadelphia chromosome-positive

ALL or with leukemic cells that express the surface antigen CD20. Several

innovative compounds are under investigation, and the most promising

ones to date will be discussed.

Expert opinion: The incorporation ofmonoclonal antibody therapy represents

a targeted and powerful approach to the management of ALL. Bispecific T-cell

engaging agents, such as blinatumomab, are able to facilitate immune-

mediated killing of leukemia cells. Immunoconjugates (i.e., monoclonal

antibodies linked to various cytotoxins) allow small doses of very potent

chemotherapy to be delivered directly to a leukemia cell with hope of sparing

normal tissue. As the genetic and molecular characterization of ALL is more

completely understood, patients will receive treatment plans that are more

individualized than previously possible.

Keywords: acute lymphoblastic leukemia, blinatumomab, inotuzumab, monoclonal antibodies

Expert Opin. Emerging Drugs (2014) 19(1):37-50

1. Background

Acute lymphoblastic leukemia (ALL) is a hematologic malignancy driven by theproliferation and accumulation of lymphoid progenitor cells in the bone marrowand other tissues. The estimated number of new ALL cases in the USA for2013 is 6070 [1]. The disease spans the age continuum, with approximately 60%of cases being diagnosed in patients under the age of 20, and 11% in patients greaterthan age 65 [2]. This makes the management of ALL highly complex, as patientfactors as well as biological factors of the leukemia have to be considered whendesigning a therapeutic plan.

Most patients with ALL present with signs and symptoms consistent with ineffec-tive hematopoiesis, which most notably includes easy bruising due to thrombocyto-penia, fatigue due to anemia and repeated episodes of infection due to neutropenia.White blood cell (WBC) count at presentation can either be very low, normal orextremely high, and while circulating blasts are generally noted on the completeblood count differential, they are not required for the diagnosis. Patients frequentlyhave derangements in metabolic and coagulation values, and close attention tosupportive care is necessary during the initial workup.

All patients with suspected acute leukemia need to undergo bone marrow biopsyto confirm the diagnosis. Due to the heterogeneity of the disease, the bone marrowsample must then undergo further testing to delineate the precise characteristics of

10.1517/14728214.2014.872629 © 2014 Informa UK, Ltd. ISSN 1472-8214, e-ISSN 1744-7623 37All rights reserved: reproduction in whole or in part not permitted

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the leukemic cells, which ultimately help form the basis for anindividualized treatment plan. Determining the immune phe-notype is necessary to distinguish B-cell ALL from T-cellALL, as well as to identify surface markers that may serve aspossible drug targets. A key example of this is expression ofCD20, the result of which will help decide whether to add amonoclonal antibody directed at that marker to the chemo-therapy regimen. Two such antibodies are currently available,and will be discussed further below.While B-ALL and T-ALL may be initially treated in a sim-

ilar manner, they have distinct clinical courses and prognosticmarkers. Further, targeted therapies are sometimes aimed atlineage-specific features, so it is crucial to have the phenotypeprior to starting treatment. Cytogenetic testing to evaluate thekaryotype is routine in all patients, as it provides both prog-nostic as well as therapeutic information for patients withparticular chromosomal abnormalities.Several baseline prognostic factors have been identified in

both the pediatric and adult setting. While these factors varyfrom study to study, several are consistently associated withpatient outcome. Age and WBC count at diagnosis is impor-tant, and patients with B-ALL and T-ALL have worse progno-sis if the value is greater than 30,000 or 100,000, respectively.Of note, WBC count at diagnosis as a prognostic indicator isless clearly established in adult patients, and these factorsmust always be interpreted in the context of patient popula-tion, treatment strategy and other variables that are beingassessed. Patients with chromosomal translocations involvingthe mixed lineage leukemia (MLL) gene have a very poor prog-nosis, and advances in therapeutic strategies for this subset ofpatients will be highly important. The Philadelphia chromo-some (i.e., t(9;22)), known for its almost universal presencein chronic myeloid leukemia (CML), can also be detected inthe leukemic cells of ALL. The lesion occurs much more fre-quently in adults, and has traditionally conferred a bleak prog-nosis. However, the use of tyrosine kinase inhibitors (TKIs) hasdrastically improved the outlook for this patient group. Hyper-diploidy or the presence of t(12;21) is typically associated withbetter prognosis, though these features are rarely seen in adultpatients. Perhaps the most powerful predictor of outcome isthe level of minimal residual disease (MRD) detected at vari-ous time points after chemotherapy is initiated [3]. In patientswho achieve a morphologic complete remission (CR), molecu-lar evidence of residual leukemia is highly predictive of overtrelapse. Contemporary protocols are now using MRD in orderto re-stratify patients on therapy, and patients who were previ-ously deemed at standard risk can be shifted into a higher riskgroup, and therapy generally becomes more aggressive.

2. Medical need

ALL is heralded as a cancer success story for pediatric patients,with cure rates beyond 80% being reported by recent studygroups [4]. This was accomplished through optimizing thedoses and schedules of the same chemotherapeutic agents

that have been used for the previous five decades [5,6]. Thatsaid, adult ALL remains a major challenge, with cure ratesestimated to be between 30 and 50% using a similar approachto that of the pediatric specialists [7]. The disparity inoutcomes between adults and children is partially explainedby a tendency for adults to present with higher risk diseaseat baseline. For example, up to 30% of adults with newlydiagnosed ALL will have Philadelphia chromosome-positive(Ph+) disease compared to approximately 5% in children [8].Children also appear to be more tolerant of and adherent tointensive chemotherapy, possibly leading to improvedlong-term outcome.

3. Existing treatment

3.1 Frontline settingPatients with ALL are managed with a comprehensive treat-ment regimen consisting of several phases that include induc-tion, consolidation, maintenance and CNS prophylaxis. Eachphase involves the use of antineoplastic therapy, including acore group of agents that are considered the backbone oftherapy. The National Comprehensive Cancer Network(NCCN) publishes consensus guidelines, and they endorse sev-eral regimens as acceptable for frontline therapy [7]. Inductionchemotherapy generally consists of an anthracycline (e.g., dau-norubicin or doxorubicin), vincristine, corticosteroids andsome form of asparaginase. Patients receive induction over thefirst 4 -- 6 weeks, and then undergo a repeat bone marrow exam-ination to determine the degree of response. Patients whoachieve CR are then moved to the consolidation phase, whichconsists of chemotherapy containing a number of agents thatmay be different from those used in induction. Some of themore common drugs used in consolidation are cytarabine,methotrexate, cyclophosphamide and 6-mercaptopurine. Aftercompleting several months of consolidation therapy, a pro-longed maintenance phase is initiated. Maintenance therapy isa critical component of the overall treatment paradigm, andmust be delivered over a prolonged period to assure durabilityof the response achieved with induction and consolidation [9].The traditional maintenance regimen includes monthly pulsesof corticosteroids (prednisone or dexamethasone), monthlyinfusions of vincristine, daily 6-mercaptopurine administeredorally and weekly methotrexate than can be given orally orparenterally (these regimens are referred to as POMP orDOMP depending on the corticosteroid involved). There aredata suggesting that dexamethasone may be superior from anantileukemia standpoint when compared to prednisone [10].The maintenance phase typically lasts 2 -- 3 years. Throughoutthe regimen, patients require prophylactic administration ofintrathecal chemotherapy to prevent the development ofCNS involvement. Some regimens alternate between metho-trexate and cytarabine, while others use ‘triple’ therapy withmethotrexate, cytarabine and hydrocortisone administeredsimultaneously. The number of intrathecal treatments variesaccording to protocol.

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One regimen that has been extensively used and studied inadult ALL is hyperCVAD [11,12]. Patients receive hyperfractio-nated cyclophosphamide, vincristine, doxorubicin anddexamethasone alternating approximately monthly withhigh-dose methotrexate and cytarabine. The goal is to delivereight cycles of the above followed by approximately 2 years ofPOMP as maintenance therapy. Patients also receive mainte-nance intensification chemotherapy during months 6, 7,18 and 19 instead of POMP. All patients receive eight intra-thecal injections of methotrexate alternating with cytarabine.These are completed during the first four cycles of inductionand consolidation therapy. Long-term outcomes have beenreported for this regimen, and 5-year overall survival (OS) isestimated to be between 38 and 50% [12,13]. Recently, rituxi-mab, a monoclonal antibody directed against CD20 wasadded to the regimen for patients expressing this surfacemarker. Two doses of rituximab were administered witheach of the first four cycles of chemotherapy, and also withmonths 6 and 18 of the maintenance intensification portion.The addition of the monoclonal antibody to chemotherapytranslated to improved OS in younger patients withCD20-positive disease when compared to historical controlsreceiving similar chemotherapy alone (75 vs 47% at 3 years;p = 0.003) [12]. A survival advantage was also noted by theGerman Multicenter Study Group for ALL (GMALL) whenrituximab was added to standard chemotherapy [14].

The hyperCVAD compares favorably to another contem-porary regimen that was utilized in one of the largest studiesto date evaluating younger adults with ALL (n = 1521) [15].The MRC UKALL X II/ECOG E2993 study was an interna-tional collaboration of large cooperative groups whose induc-tion chemotherapy regimen incorporated L-asparaginase. Thisis one major difference when compared to the hyperCVADregimen. In fact, the hyperCVAD regimen is one of theonly ALL induction regimens (in pediatrics or adults) to notinclude any form of asparaginase. Patients were carefully strat-ified and underwent allogeneic hematopoietic stem cell trans-plantation (AHSCT) when appropriate per protocol. The5-year OS for the entire cohort was 38%. Of note, patientswho failed to achieve CR by the end of induction (n = 22)had a very poor prognosis, with median OS of < 1 year.

There is an ongoing debate in the leukemia communitythat younger adults may be better served if offered a ‘pediatricinspired’ chemotherapy regimen [7]. The incremental benefitis presumed to be a consequence of more intensive dosing ofvincristine, corticosteroids, CNS-directed therapy and aspara-ginase [16]. The predominant question surrounding thisapproach is the tolerability of pediatric-inspired regimens inadults beyond a certain age. One group found a benefit forpatients up to the age of 45, after which any antileukemiabenefit of intensified chemotherapy was offset by death inCR [17]. Most of the data suggesting a benefit to date are ret-rospective in nature, and need to be validated in large pro-spective groups of patients. At our center, patients up to age40 have been treated with a pediatric-inspired regimen

(Augmented Berlin-Frankfurt-Muenster [18]), and recently acomparison was made to a historical control group of similarpatients who received hyperCVAD (Personal communication,M Rytting, MD). The median age for patients treated on thisstudy (n = 85) was 21 years. Compared to the patients treatedwith hyperCVAD, 3-year OS was similar between thetwo groups (74% for the pediatric regimen vs 71% forhyperCVAD).

Patients with Ph+ ALL have traditionally had a very pooroutcome in general, and particularly if they do not proceedto AHSCT [19]. With the advent of TKIs that inhibit theactivity of the BCR-ABL oncoprotein, the natural history ofthis disease subset has changed in a positive direction. Whilethese oral agents were developed for patients with CML, theirincorporation into treatment regimens for ALL have provedextremely important. There are now multiple reports withadequate follow-up showing that imatinib in combinationwith standard chemotherapy improves the survival for thesepatients [20-22]. It has also been demonstrated that it is impor-tant to start the TKI early and to administer it continuously asopposed to in intermittent pulses [23,24]. Most studies to datesuggest that AHSCT is still required to optimize the benefitconferred by the addition of imatinib [20,22].

Second-generation TKIs initially developed for patientswho are intolerant of or failing imatinib, have emerged aspotential frontline therapeutic options. Indeed, dasatiniband nilotinib are now labeled for first-line management ofchronic phase CML [25,26]. These agents are more potentthan imatinib in terms of BCR-ABL binding, and dasatinibalso inhibits SRC kinases, which have been implicated asbeing biologically important in Ph+ ALL [27]. Dasatinib alsohas the pharmacologic advantage of being able to cross theblood--brain barrier, but whether it obviates or reduces theneed for CNS prophylaxis has not been studied. Recently,dasatinib was combined with the hyperCVAD regimen innewly diagnosed patients (n = 35) as an attempt to improveon the outcomes seen with imatinib [28]. Patients received100 mg of dasatinib orally once daily on days 1 -- 14 ofeach chemotherapy cycle (eight cycles planned). After theinduction and consolidation, patients went on to receive dasa-tinib on a continuous basis as part of maintenance therapywith vincristine and corticosteroids. As expected, the majorityof patients achieved CR (94%), and the 2-year OS was 64%.Notably, only a minority of patient proceeded to AHSCT infirst CR. A recent evaluation of MRD data suggests that inpatients with early and sustained molecular response, theneed for AHSCT may be obviated [29]. Additional follow-upwill be required to make a more direct comparison to patientswho received imatinib.

The ultimate form of consolidation therapy is AHSCT. Inthe frontline setting, this procedure is reserved for patientswith very high risk of disease relapse at diagnosis based onknown prognostic factors (discussed above). There has beensome confusion and debate regarding who should be referredfor AHSCT in first CR based on a large study indicating that

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patients with standard risk, but not high-risk disease,benefited the most [30]. Other studies have shown a benefitfor AHSCT in patients with high-risk disease, though it is dif-ficult to directly compare these trials [31]. To reconcile this,many centers have started to use MRD after induction or con-solidation to re-stratify patients based on their response tochemotherapy [3]. Several strategies are available to measureMRD, including multiparameter flow cytometry, reverse-transcription polymerase chain reaction (RT-PCR), amongothers. Indeed, presence of MRD has emerged as a majorindicator of future relapse when controlling for all otherknown risk factors [4,29]. This allows clinicians to use informa-tion about an individual patient’s biological response to ther-apy to help guide the intensity of future interventions (i.e.,more chemotherapy vs the more intensive AHSCT).

3.2 Relapsed settingMost adult patients with ALL will ultimately relapse, and thissituation is associated with a poor prognosis with limitedeffective therapy available. Salvage therapy is determined onthe duration of the remission, previous treatment history,comorbidities and the leukemia-specific characteristics thatmay be targetable. Patients should be enrolled on a clinicaltrial if possible, as standard therapy to date is not sufficient.Patients with relapsed disease have a median survival of only24 weeks [32]. Those who are primary refractory or have ashort first CR do particularly poorly, with a median OSof < 5 months [33]. At present, the goal of salvage therapy isto re-induce CR and consolidate with an AHSCT. This isessentially because there are no known antineoplastic agentsor regimens that can cure relapsed disease when used alonein the adult setting.For patients without previous exposure to asparaginase, it

may be rational to incorporate this agent into salvage. Withthis in mind, Faderl and colleagues designed an ‘augmented’version of the hyperCVAD regimen that adds pegylatedasparaginase to the standard drugs, while also intensifyingthe dosing of vincristine and corticosteroids [34]. There were88 patients who were evaluable at the time of the report,and most were receiving the regimen as first salvage (76%)after initially undergoing treatment with conventional hyper-CVAD (80%). The CR rate was 47%, and the overallresponse rate increased to 64% when considering patientswith partial responses and CR with incomplete recovery oftheir blood counts. Twenty-eight patients were able toundergo subsequent AHSCT, 19 of who were in CR at thetime of transplant. While the response rate was favorable,median OS was approximately 6 months, though there weresome long-term responders. Augmented hyperCVAD is a rea-sonable regimen for relapsed patients with good PS who arecandidates for intensive chemotherapy, regardless of whetherthey have received conventional hyperCVAD previously.Clofarabine is a purine nucleoside analog that is approved

as third-line therapy for pediatric ALL [35]. Several groupshave tried to build on the modest activity of the single agent

by combining it with other chemotherapeutic drugs in boththe pediatric and adult setting [36-38]. A Phase II, multicenterstudy was conducted evaluating clofarabine combined withcyclophosphamide and etoposide all given for five consecutivedays [36]. This regimen was administered to pediatric patients(n = 25) who were largely relapsed and refractory, with> 80% receiving the regimen as salvage 2 or greater. Sevenpatients achieved CR, and 10 patients were eventually able toproceed to AHSCT. The protocol required an amendmentexcluding patients with prior AHSCT due to a high rate ofveno-occlusive disease noted in this population early in thetrial.

There is similar experience with clofarabine-based salvagechemotherapy regimens in the adult population [37,38].A group from France tested two different regimens containingclofarabine in patients with relapsed ALL [37]. Clofarabine wascombined with dexamethasone, mitoxantrone, etoposide andasparaginase (VANDEVOL, n = 37) or with cyclophospha-mide (ENDEVOL, n = 18). The dose of clofarabine was30 mg/m2 IV daily for five consecutive days in both regimens.The CR rates for the VANDEVOL and ENDEVOL regi-mens were 41 and 50%, respectively. The regimens alsoserved as an effective bridge to AHSCT, with an overall trans-plant rate of 29%. With short follow-up, the median OS wasreported to be 6.5 months. A cooperative group from Spainreported on 31 adult patients with relapsed and refractoryALL who received a clofarabine-containing regimen [38].Most patients (84%) had received two or more previous treat-ment regimens for the leukemia. Twenty-six percent ofpatients achieved CR, with the median OS estimated to beapproximately 3 months. At least one patient remained alive16 months after treatment with clofarabine-based therapy fol-lowed by an AHSCT. Of note, patients as young as 16 yearsof age were included in this analysis.

Nelarabine is another nucleoside analog that is approvedfor patients with relapsed T-ALL after failing two prior regi-mens [39]. The drug selectively accumulates in T-cells, makingit an attractive option for this subset of patients. The GMALLrecently reported on 126 patients with relapsed T-ALL/lym-phoma who received nelarabine as a single agent [40]. Thedose of nelarabine was 1500 mg/m2 IV on days 1, 3 and 5.The initial goal was to send patients who achieved CR directlyto AHSCT. Later, two cycles were recommended to induce adeeper response possibly eradicating MRD. Also, it appearedthat partial responders may be able to convert to CR if theycontinued on therapy beyond one cycle. Overall, after oneto three cycles, the CR rate was 36%, and 80% of thesepatients were able to move forward with AHSCT. For theentire cohort, median OS was only 6 months and the proba-bility of survival at 3 years 12%. However, patients whoachieved CR and received an AHSCT fared substantially bet-ter with a 3-year survival probability of 36%. Patients whoachieved CR and did not receive AHSCT had a survival prob-ability of 0%. Neurotoxicity traditionally has been the mostproblematic toxicity associated with nelarabine. That said, in

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this trial, the authors noted a low rate of grades III/IV neuro-toxicity in a group of patients with heavy pre-exposure to vin-cristine. Nelarabine as a salvage therapy should continue to beoptimized, possibly through combination therapy or altera-tions in the dosing and schedule. There is an ongoing trialexploring the role for delivering nelarabine as a continuousinfusion [41], and another study aiming to incorporate it intothe frontline treatment program [42].

Vincristine is a component of virtually all accepted first-line chemotherapy regimens for both adult and pediatricpatients. However, its use is frequently compromised becauseof dose-limiting neurotoxicity, often manifesting as peripheralneuropathy or moderate to severe constipation. To minimizethese effects, the dose of vincristine is often capped at 2 mg. Inan effort to optimize the pharmacodynamics of the drug, aliposomal formulation was synthesized. A Phase II study in65 patients with relapsed and refractory ALL was recentlypublished [43]. Vincristine sulfate liposome was administeredas a weekly IV infusion at a dose of 2.25 mg/m2 with noparameter for capping the dose. As expected, all patientsenrolled on this trial had received previous exposure to con-ventional vincristine. In this heavily pretreated group, theoverall response rate was 35%, and 12 patients were able tobe bridged to an AHSCT. Giving liposomal vincristine atuncapped doses appeared to be safe, with grade 3 peripheralneuropathy occurring in 15% of patients. Median OS wasonly 4.6 months, though there were five patients alive at12 months.

4. Market review

Though ALL is considered a rare disease, it affects patientsworldwide and can occur at any age. Given the complexityand duration of therapy, the economic burden of this diseaseis substantial. All patients with ALL must undergo induction,consolidation, CNS prophylaxis and maintenance therapy tomaximize the chances of achieving a cure. Some patientsmay need to undergo AHSCT to realize cure, and this isanother costly, highly complex intervention. The chemother-apy used to treat ALL often requires admission to the hospitaland highly specialized nursing care. Leukemia is often treatedby an expert medical team consisting of clinicians who exclu-sively see patients with hematologic malignancies. Betweenchemotherapy cycles, patients require extremely close follow-up and monitoring, including checking laboratory valuestwo to three times weekly to ensure transfusions are orderedfor severe anemia and thrombocytopenia.

Traditional chemotherapy regimens for ALL are logisticallycomplex to administer, and there is also a substantial eco-nomic burden due to the adverse effects of cytotoxic chemo-therapy, as well as the supportive care measures used toprevent these issues. At some point, most patients are admit-ted with neutropenic fever after induction chemotherapy,and must receive empiric intravenous antibiotics while under-going an extensive workup to rule out active infection. Some

patients present with life-threatening sepsis, and must beadmitted to the intensive care unit for adequate resuscitation.Hematopoietic growth factors are used routinely as primaryprophylaxis after chemotherapy.

5. Current research goals

The primary goal in the area of ALL research is to improve thecure rate and long-term survival of patients with this disease.Ideally, this goal will be accomplished while also minimizingthe toxic effects patients suffer as a consequence of the therapythey receive. Modification of the dosing and sequencing ofcytotoxic chemotherapy have led to major progress over thelast several decades, largely using the same core backbone ofdrugs. One strategy may be to further intensify conventionalchemotherapy regimens, but any small incremental antileuke-mic benefit will have to be weighed carefully against theadded toxicity.

Other research goals include determining whether a shorterduration of chemotherapy will be possible with the incorpo-ration of novel therapeutic agents into the treatment para-digm. Currently, patients receive up to 3 -- 4 years oftherapy, and this has so far been proven necessary in a numberof studies [9]. This goal should be considered long term, asmost promising new agents are still being tested largely inthe salvage setting.

The emergence of several novel therapies for ALL will raisethe question as to whether they will minimize the need forconventional cytotoxic therapy. It appears unlikely that thebackbone agents will be able to be eliminated from the treat-ment regimen, but perhaps incorporating targeted therapieswill allow for a lower intensity in regard to the cytotoxicagents. The use of more targeted therapies will also permitinvestigators to study the impact on post-therapy morbidityand the use of supportive care.

6. Scientific rationale

As stated above, further intensification of conventionalchemotherapy may not be feasible without inducing toxiceffects that negate any additional antileukemia benefit. Con-tinuing to recognize ALL as an extremely heterogeneous dis-ease will allow for an individualized treatment approach.Monoclonal antibodies directed against cell surface antigenshave led to significant improvement in outcomes for a num-ber of malignancies. The first monoclonal antibody approvedin the United States was the anti-CD20 agent rituximab.Rituximab was initially shown to improve the OS in elderlypatients with diffuse large B-cell lymphoma when combinedwith standard chemotherapy [44], opening the possibility thatsimilar results may be possible in other CD20-positive malig-nancies. Subsequently, the addition of rituximab to chemo-therapy has been shown to improve survival in chroniclymphocytic leukemia [45] as well as in adult ALL (discussedabove).

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Some cell surface antigens internalize when bound by anti-body, making it feasible to deliver small doses of cytotoxicchemotherapy directly to tumor tissue [46]. Gemtuzumab ozo-gamicin, a monoclonal antibody directed against CD33linked to calicheamicin, was the first antibody--drug conjugatein the United States [47]. It was approved for elderly individu-als with relapsed acute myeloid leukemia before being contro-versially withdrawn from the market [48]. More recently,brentuximab vedotin, a CD30 antibody conjugated to theantimitotic agent monomethyl auristatin E, was shown toimprove outcomes for patients with anaplastic large cell lym-phoma and classical Hodgkin’s lymphoma [49,50]. With thisevidence in mind, it is highly relevant to explore these typesof compounds for the treatment of ALL.Studies aimed at more completely characterizing the molec-

ular and genetic makeup of ALL cells will ultimately helpinform potential targets for therapeutic intervention.Recently, the group from St. Jude Children’s Research hospi-tal has made several observations and discoveries that may oneday translate to improved individualized therapy [51-53]. EarlyT-cell precursor ALL, a rare form of T-cell ALL, was recentlycharacterized, and confers a very poor prognosis in pediatricpatients [51]. Applying whole genome sequencing to this raresubset of T-cell ALL patients yielded several key findingsregarding the presence of several somatic mutations [52]. Theinvestigators identified that several of these patients had muta-tions normally found in myeloid malignancies, such as RASand FLT3. These are potentially targetable lesions with cur-rently available kinase inhibitors. Furthermore, there weremutations in multiple genes that govern histone modification,making it reasonable to test epigenetic therapeutic approaches(e.g., histone deacetylase inhibitors, DNA methyltransferaseinhibitors) in this group of patients. Similarly, a deepsequencing approach was used to uncover mutations presentin a group of patients with Ph-like B-cell ALL [53]. This groupof patients has a high risk of relapse and inferior outcome tonon-Ph-like patients. The authors identified several novelchromosomal translocations that coded for activated tyrosinekinases. Importantly, many of these involved partners thatare targetable with small-molecule TKIs (e.g., JAK2, ABL1,PDGFR). Quintas-Cardama and colleagues identified thepresence of the NUP214-ABL1 oncogene in several patientswith T-cell ALL [54]. They also tested the commercially avail-able TKIs against cell lines harboring this abnormality, andimatinib, dasatinib and nilotinib-demonstrated activity. Con-tinuing to identify these potential driver mutations will beimportant in determining treatment plans for individualleukemias.

7. Competitive environment

As discussed above, advances in the genetic and molecularcharacterization of an individual’s leukemia have driven thedevelopment of a more targeted approach to treating ALL(and cancer in general). A number of cell signaling pathways

have been shown to be aberrantly hyperactive, and these path-ways are thought or known to play major roles in cell differ-entiation and proliferation. The development of inhibitorsof these pathways is one of the novel approaches to cancertherapy. Further, the identification of cell surface antigensthat are highly expressed on tumor cells has led to the devel-opment of monoclonal antibodies that selectively target leuke-mia cells while sparing normal tissue. This also allows forcombination regimens that include conventional chemother-apy because of the distinct adverse event profiles. Below wewill discuss some of the more promising compounds thatare being studied in patients with ALL (Table 1).

Perhaps one of the biggest cancer success stories in recenthistory has been the effectiveness of ABL TKIs for the treat-ment of CML [55]. Patients previously needed to undergoAHSCT for any prospect of long-term survival, but now cantake an oral tablet once or twice daily and essentially live anormal lifespan [56]. As stated above, these drugs have also dra-matically changed the outlook for patients with Ph+ ALL.Imatinib as a component of therapy for these patients is estab-lished as the standard of care, and the second-generation TKIdasatinib has been evaluated by groups internationally in anattempt to further improve the outcomes. One of the mostwell-characterized mechanisms of resistance in Ph+ malignan-cies is the development of mutations in the kinase domain,essentially blocking the TKI from accessing its site ofaction [57]. The most notorious mutation is known as theT315I mutation, because until recently it conferred resistanceto all available TKIs [58]. In a study evaluating dasatinib withlow-intensity chemotherapy in elderly patients with Ph+ ALL,there were a significant number of patients who eventuallydeveloped this mutation upon treatment failure [59].

Ponatinib is a third-generation TKI that was rationallydesigned specifically to maintain activity in the presence ofthe T315I mutation [60]. It was recently approved as a singleagent for CML or Ph+ ALL in patients who have received pre-vious TKI-based therapy [61,62]. However, it may be optimalto incorporate ponatinib into the up-front treatmentapproach, and a Phase II trial is underway evaluating the com-bination of ponatinib and hyperCVAD chemotherapy [63]. Itwill be important to weigh any incremental antileukemia ben-efit with the substantial toxicity profile of ponatinib. The highrisk of thromboembolic events may make this agent too riskyto offer patients in the frontline setting, at least at the cur-rently approved dose.

The success of TKIs against BCR-ABL has led to a highlevel of interest in the potential of other kinases involved incell signaling and proliferation to serve as targets for antican-cer therapy. The Aurora kinases are a group of serine/threonine kinases that are highly involved in normal cell cyclecontrol and mitosis [64]. There is often overexpression of thesekinases noted in hematologic malignancies, which leads toexcessive cellular replication and proliferation [65]. Alisertib(previously MLN 8237) is a potent and selective inhibitorof Aurora kinase A, and has been studied previously in

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patients with advanced cancer [64]. Recently, in vitro studiessuggested additive cytotoxicity against leukemia cell lineswhen alisertib was combined with vorinostat, a histone deace-tylase inhibitor [66]. This data will possibly lead to the designof rational combination therapies that will introduce twonovel mechanistic approaches to this disease. Presently, theChildren’s Oncology Group is conducting a Phase II trialevaluating single-agent alisertib in young patients with refrac-tory cancers, including leukemias [67]. There are several otheragents, including non-specific, pan-Aurora kinase inhibitorsin various stages of development [65].

As discussed previously in this review, nucleoside analogsplay an important role in both the frontline and salvage treat-ment of patients with ALL. Therefore, it has been advanta-geous for the continued development and refinement of thisbroad class of antineoplastic agents. Patients with congenitaldeficiency of purine nucleoside phosphorylase (PNP) areknown to suffer from profound T-cell lymphopenia [68].PNP deficiency leads to excess deoxyguanosine in the plasma,which leads to accumulation of the triphosphate in targetcells, ultimately disrupting DNA synthesis through a numberof mechanisms and inducing T-cell apoptosis. Forodesine is apotent PNP inhibitor, and is under development as a poten-tial treatment for patients with T-cell ALL [69]. Thus far, for-odesine has been studied in a small number of patients, wheremodest activity was noted with an acceptable toxicity pro-file [70]. Phase II studies that include patients with T-ALLare ongoing or have been recently completed [71].

Perhaps the most exciting group of compounds being stud-ied for the treatment of ALL are those that target cell surface

antigens found on leukemic blasts. These agents are mostoften in the form of monoclonal antibodies that are designedto bind to a specific target that is found in abundance on can-cer cells, but not normal cells. Monoclonal antibodies workthrough a number of mechanisms, including antibody-dependent cytotoxicity, complement-dependent cytotoxicityand direct induction of apoptosis. Also, if a target is knownto internalize upon binding, potent cytotoxins can be conju-gated to the antibody portion, adding an additional mecha-nism for targeting killing. For ALL, the targets that havebeen studied most thoroughly to date include CD19,CD20, CD22 and CD52. Currently, there are monoclonalantibodies directed against CD20 and CD52 available com-mercially. Therefore, we will focus the discussion on therapiestargeting CD19 and CD22 that are being developed for use inALL patients.

Monoclonal antibodies directed against CD20, namely rit-uximab, represent the prototype for cell surface antigen-targeted therapy. However, one problem with rituximab isthe lack of CNS coverage, a well-known site of relapse forALL patients. Patients who develop CNS disease historicallyhave a poor prognosis. Phase I studies have established thesafety of intraventricular rituximab in patients with primaryCNS and intraocular lymphoma [72]. Therefore, a Phase I/IIstudy was designed to test the effectiveness of intraventricularrituximab in ALL patients who suffer a CNS relapse [73].

Ofatumumab is a newer monoclonal antibody directedagainst CD20 that was recently approved for the managementof chronic lymphocytic leukemia [74]. Notably, patients maystill respond to ofatumumab after being exposed to or failing

Table 1. Agents under development for ALL.

Agent Company Stage of development Mechanism of action

Ponatinib Ariad Approved as monotherapy for relapsedPh+ ALL; Phase II as part of first-linetherapy combined with chemotherapy

BCR-ABL1 kinase inhibitor

Alisertib Millennium Phase II Aurora A kinase inhibitorForodesine BioCryst Phase II Purine nucleoside phosphorylase

inhibitorOfatumumab GSK Phase II Monoclonal antibody directed against

CD20 being tested in combinationwith chemotherapy for newlydiagnosed ALL

Rituximab (intraventricular) Roche Phase I/II Monoclonal antibody directed againstCD20; established as a systemic agent,being evaluated for patients with CNSleukemia administered intrathecally

SAR3419 Sanofi Phase II Monoclonal antibody conjugated to amaytansinoid directed against CD19

Blinatumomab Amgen Phase II Bispecific T-cell engaging antibodydirected against CD19

Epratuzumab ImmunoMedics Phase II Monoclonal antibody directed againstCD22

Inotuzumab ozogamicin Pfizer Phase III Monoclonal antibody conjugated tocalicheamicin directed against CD22

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previous rituximab-based regimens [75]. Based on its promis-ing activity, ofatumumab is being evaluated in a Phase IIstudy combined with hyperCVAD in patients with newlydiagnosed, Ph-negative ALL [76].CD19 is known to be ubiquitously expressed on normal and

malignant B-cells, making it a reasonable therapeutic target [77].In normal mature B lymphocytes, CD19 plays a role in B-cellreceptor signaling leading to activation and proliferation whenstimulated [78]. It is also known to internalize after being boundby a monoclonal antibody, so antibody--drug conjugates mayenhance the antileukemia effects [79]. This approach is beingtested with SAR3419, a humanized monoclonal antibodylinked to a semisynthetic maytansinoid. This is rational espe-cially for ALL patients, since the maytansinoids are potent anti-mitotic agents, and bind to the same area on tubulin as doesvincristine [80]. A dose-finding study was recently publishedevaluating SAR3419 in patients with relapsed B-cell lym-phoma [81]. There were 39 patients enrolled, and doses rangedfrom 10 to 270mg/m2 IV given every 3 weeks. Tumor responsewas noted in 74% of patients, including six that were deemed tobe partial or complete responses. The main toxicity was blurredvision, which was most commonly associated with bilateral cor-neal epitheliopathy. As might be expected, patients also experi-enced peripheral neuropathy. Presently, a Phase II study is beingconducted in patients with relapsed and/or refractory ALL [82].A novel approach for targeting cell surface markers is

through use of bispecific T-cell engaging (BiTE) antibodytechnology, whereby host T-cells are directed to the surfaceantigen expressed on malignant cells. Blinatumomab containsportions of two antibodies, one directed at CD3 and the otherat CD19. This allows for the malignant B-cells to be placed inclose proximity to cytotoxic T-cells, which ultimately leads toT-cell activation and death of the CD19-positive cell [83]. Theideal dose, formulation and route of administration have beenunder development for more than a decade [83].The GMALL evaluated blinatumomab in a study aimed at

testing the compound’s ability to eradicate MRD in patientswho had previously achieved morphologic CR [84]. Patientswere eligible for the study if they never achieved MRD nega-tivity, or if MRD emerged at some point during consolidationchemotherapy. The dosing schedule for blinatumomab was15 mcg/m2/day via IV continuous infusion for 4 weeks, fol-lowed by a 2-week treatment break. Patients could receiveup to four cycles of therapy, and those with a donor wereable to proceed to AHSCT. This study included patientswith Ph+ disease that was refractory to imatinib ordasatinib-based therapy. After one cycle of treatment, 16 ofthe 20 (80%) evaluable patients had converted to MRD-negative status. With a median follow-up of 33 months, therelapse-free survival was estimated to be 61% [85]. Four outof six patients with Ph- disease who did not receive any fur-ther therapy after blinatumomab were in ongoing CR at thetime of this report.In a subsequent study by the same group from Germany

aimed at evaluating the efficacy of blinatumomab in patients

with relapsed or refractory ALL [86]. This was a Phase II studyevaluating multiple dosing schedules, though all were deliv-ered as 24-h continuous IV infusions for 4 weeks followedby a 2-week treatment break. Of 36 evaluable patients,25 achieved CR or CR with incomplete recovery of the plate-let count. Impressively, 92% of the responding patientsachieved the study definition of molecular response afterreceiving one or two cycles of therapy. The final dose selectedfor further study was 5 µg/m2/day IV continuous infusion ondays 1 -- 8, followed by 15 µg/m2/day IV continuous infusionon days 9 -- 28. The safety profile of blinatumomab was ana-lyzed for patients receiving this regimen, and the most com-mon adverse events noted included fever, headache andtremor. A cytokine release syndrome occurs in patients withhigh tumor burdens when started on higher doses of blinatu-momab, and necessitated treatment interruption in severalpatients. This is presumably due to rapid T-cell-mediated kill-ing of leukemia cells. With corticosteroid premedication anda lower starting dose, the cytokine release syndrome canlargely be obviated. Neurological toxicity has been the mostconcerning problem, with rare patients suffering clinical seiz-ures on both the MRD study and the study involving relapsedand refractory patients. Other toxicities documented thus farinclude encephalopathy and confusion.

CD22 is another cell surface antigen that may be exploitedusing monoclonal antibodies due to its presence on the major-ity of malignant B-cells in ALL. Epratuzumab is an unconju-gated monoclonal antibody directed at CD22 that is beingstudied in a variety of lymphoid malignancies as well as auto-immune disorders. The Children’s Oncology Group recentlypublished a report that evaluated epratuzumab when incorpo-rated into a re-induction program regimen for patients withrelapsed or refractory ALL [87]. Patients initially received epra-tuzumab as a single agent where it was given twice weekly for2 weeks at a dose of 360 mg/m2. Subsequently, epratuzumabwas given once weekly in combination with standard salvagecytotoxic chemotherapy. Fifteen patients were treated withsingle-agent epratuzumab, and the majority experienced stableor progressive disease (93%). One patient had complete disap-pearance of circulating blasts. When combined with chemo-therapy, the addition of the monoclonal antibody appearedsafe, and the response rate was favorable. Perhaps most notablewas the proportion of responders who achieved MRD-negativestatus at the conclusion of the chemoimmunotherapy portion(7/9 patients). Epratuzumab was well tolerated in this study,though one patient suffered a grade 4 seizure, and anotherhad significant transaminitis. Grades 1 and 2 infusion reactionswere common during administration of the first dose, but didnot interfere with therapy.

The Southwest Oncology Group (SWOG) presented pre-liminary data from a study evaluating the addition of epratu-zumab to salvage chemotherapy for adults with ALL [88].Patients (n = 32) received clofarabine 40 mg/m2 IV on days2 -- 6, cytarabine 1000 mg/m2 IV on days 1 -- 5, and epratu-zumab 360 mg/m2 IV on days 7, 14, 21 and 28. Eighty-four

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percent of the patients were receiving the regimen as first orsecond salvage. Four patients had previously undergoneAHSCT. There were three early deaths on study, one patientas a result of sepsis and two that suffered cardiac arrest. Therewere several additional grade 4 non-hematologic toxicitiesrecorded, though it is unclear which of these were found tobe possibly attributable to the epratuzumab portion of the reg-imen. In terms of response, eight patients achieved CR, withan additional five meeting the definition of CR with incom-plete recovery of the blood counts. The investigators concludedthat epratuzumab was tolerable and may add incrementalbenefit when added to chemotherapy in this setting.

While unconjugated monoclonal antibodies such as epratu-zumab have exhibited antileukemic activity, the optimalapproach to targeting antigens that internalize upon bindingmay be through linkage to a cytotoxic compound. Indeed, agroup of investigators recently reported on the in vitro activityof epratuzumab that is conjugated to a potent topoisomerase Iinhibitor [89].

Inotuzumab ozogamicin (IO, formerly CMC-544) repre-sents an immunoconjugate that is further along in develop-ment when compared to other such compounds directed atCD22. IO is linked to a potent cytotoxin calicheamicin, whichis selectively delivered preferentially to cells that express CD22.When used as a single agent in the salvage setting, IO has dem-onstrated the ability to induce meaningful responses in evenhighly refractory patients. In a Phase II trial, Kantarjian andcolleagues administered IO to adults and children withrelapsed or refractory ALL [90]. Patients were to receive one infu-sion of IO every 3 -- 4 weeks at a dose of 1.3 -- 1.8 mg/m2.Starting with cycle three, patients with stable or progressivedisease whose leukemia also expressed CD20 were allowed toreceive rituximab in combination with IO. There were49 patients enrolled, with 73% receiving IO as salvage 2 orhigher. Also, > 50% of the patients had high-risk cytogeneticabnormalities (t(9;22), t(4;11), complex karyotype). Fourteenpercent of the patients had previously undergone AHSCT.The overall response rate observed in this study was 57%,with the majority of responding patients achieving completemarrow response with incomplete recovery of the blood counts.The most common toxicities notes were fever, mild hypoten-sion and elevations in the liver function tests. Nearly half ofthe patients (22 of 45) were able to proceed to AHSCT afterreceiving IO. Unexpectedly, five patients developed biopsyproven or clinically suspected veno-occlusive disease. Notably,this toxicity occurred in two of the four patients who had under-gone their second transplant. Further detail about the patientswho were transplanted can be found elsewhere [91].

In an effort to optimize the benefit to risk ratio, a weeklydosing regimen was evaluated based on preclinical studiesindicating that toxicity might be minimized while maintain-ing efficacy [92]. IO was given as weekly infusions with0.8 mg/m2 on day 1, and 0.5 mg/m2 on days 8 and 15. Ofnote, this is the same cumulative dose when compared tothe schedule calling for one infusion every 3 -- 4 weeks. The

weekly regimen did not include the addition of rituximab.On the weekly regimen, overall response rate was similar tothe single-dose schedule (59 vs 57%). While efficacy appearedcomparable, the weekly regimen was less toxic. Fever of anygrade occurred in 29% of patients on single-dose comparedto 9% on the weekly schedule. Perhaps more notably, therewas also significantly less hepatotoxicity on the weekly regi-men, including the incidence of veno-occlusive disease afterAHSCT (7 vs 23%). The other factor in the development ofveno-occlusive disease may be the agents used in the prepara-tive regimen pre-transplant, as the incidence was higher inpatients who received two alkylating drugs as opposed toone. A randomized trial comparing IO with physician choicein patients with ALL in first relapse is ongoing.

Given the promising response rate in the salvage studiesevaluating IO, the drug was considered for use as a compo-nent of the frontline treatment. One population who mayparticularly benefit from a more targeted regimen is elderlypatients (i.e., > 60 years) with ALL. This group is predisposedto severe toxicity from conventional chemotherapy, whichputs them at risk of dying despite achievement of CR.A Phase II study is underway evaluating IO with low-intensityhyperCVAD therapy [93]. Most notably, the anthracycline iscompletely removed from the regimen, and all doses ofcytotoxic chemotherapy are substantially reduced.

8. Potential development issues

The main issues that may hinder the development of newtherapies for ALL include administration challenges, toxicitiesand defining an agent’s place in therapy. Blinatumomab iscurrently being studied as a 28-day continuous infusion [83-85].This poses a number of logistical challenges when consideringits application outside of a highly coordinated clinical trial.Patients have to return frequently for bag changes, whichleads to the risk of delays in therapy and interruptions inthe continuous administration of the drug. Efforts should bemade to optimize the stability of the medication, allowingfor as many days/doses of blinatumomab as possible to bemixed in one bag. Also, alternative administration strategiesand/or schedules should be explored.

Incorporating the most promising targeted therapies intothe frontline treatment approach will soon become a researchpriority. Investigators will have to be careful when it comes tothe design of such studies, with close attention paid to poten-tial for overlapping toxicities based on the combination ofmultiple targeted agents along with cytotoxic chemotherapy.For example, IO and clofarabine are under investigation forALL, and both have been associated with rare cases of veno-occlusive disease and hepatotoxicity [36,91]. Also important isthe patient population receiving the drugs, as more severecases may be associated with the timing of administration inproximity to interventions such as AHSCT.

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9. Conclusion

For certain subsets of adult patients with ALL, therapy hasbeen substantially improved over the previous decade.Patients whose leukemia cells express CD20 benefit fromthe addition of monoclonal antibody therapy with rituximab.For Ph+ ALL, incorporation of TKIs into the overall treat-ment plan has led to significant improvement in the prognosisand outcome. New targeted therapies are on the horizon,most notably the monoclonal antibodies directed againstCD19 and CD22. It will be important to identify where theseagents should be used in the overall treatment paradigm tooptimize the potential benefit. New experimental therapiesare necessary for patients with T-ALL and for those withMLL gene rearrangements.

10. Expert opinion

ALL has proven to be an extremely heterogeneous disease, andthat is illustrated by the continued discovery of novel muta-tions that may have prognostic or therapeutic relevance. Thecure rate of > 80% in pediatric patients is laudable, but it stillleaves a sizeable number of children who have their lives cutshort by this disease. While strides are being made in adultALL, there is still much room for improvement, and a contin-ued focus on deciphering the complex biology of the disease isnecessary to assure steady progress. It is important to translatethe findings of gene sequencing studies to the clinical arena,particularly when a patient’s leukemia may be harboring raremutations that are targetable. Drug targets, such as activatedtyrosine kinases, should be validated in large groups ofpatients (pediatric and adult), and therapies directed againstthese lesions should be incorporated into a patient’s treatmentregimen when possible.Monoclonal antibody therapy currently holds the most

promise for improving outcomes in the next 5 -- 7 years.The cell surface antigens are selected because they apply to alarge proportion of patients, so the therapies are able to beoffered to most patients. Rituximab has been shown in multi-ple trials by separate groups to improve survival in adult ALL,and should be considered a standard component of therapy inpatients with CD20 expressing disease. Ofatumumab may beable to improve on the outcomes seen with rituximab, and weawait the results of ongoing clinical trials. Blinatumomab alsooffers an immune-mediated approach, employing thepatient’s own cytotoxic T-cells, which is mechanistically dis-tinct from all other therapeutic classes. It has been shown toeradicate residual leukemia after conventional chemotherapyand demonstrated marked activity in the setting of overtrelapse. In the next several years, it will be critical to deter-mine blinatumomab’s optimal place in therapy. Should thedrug be reserved for relapse or patients with MRD positivityafter standard treatment? Or, should it be incorporated intothe frontline treatment approach? If offered as a component

of the frontline regimen, there are also several questions thatwill be answered by clinical trial results. The main questionwill be whether to incorporate into the consolidation or main-tenance phases of therapy. Will it be able to replace any of theconventional agents used in maintenance?

The immunoconjugate directed at CD22, IO, is also one ofthe more promising drugs under development today. Whenused as a single agent in salvage, response rates are much bet-ter than what would be expected from conventional chemo-therapy. A fractionated weekly schedule seems to bepreferred over a monthly schedule, maintaining effectivenesswhile minimizing the toxicity. IO is already being tested inthe frontline setting that combines the monoclonal antibodywith low-intensity chemotherapy. In the future, it will likelybe reasonable to include IO as part of the frontline treatmentfor all patients with CD22+ ALL.

Harnessing one’s own immune system to eliminate malig-nant cells has been an area of oncology research for decades.Chimeric antigen receptor-modified T-cells have emerged asan effective approach for patients with lymphoid malignan-cies [94,95]. Autologous T-cells are engineered to express a recep-tor directed at CD19, which mediates cytotoxicity.Importantly, these cells have been noted to expand and persistin vivo, which may confer response durability. Recently, thesecells were given to two pediatric patients with relapsed andrefractory ALL [95]. Both patients achieved CR after receivingthe chimeric antigen receptor-modified T-cells. Of note, oneof the patients required transfer to the intensive care unit dueto severe cytokine release syndrome leading to cardiovascularand pulmonary complications. Other toxicities encounteredincluded severe transaminitis and encephalopathy. One of thepatients had a CD19-negative relapse 2 months after receivingthe infusion. Continued research on the optimal clinical use ofthis highly innovative strategy will be important.

With several promising compounds moving into late stagesof development, the leukemia community may face a favor-able dilemma in the next several years. One question thatwill certainly arise is whether multiple or all available mono-clonal antibodies can be incorporated into one regimen.Should they be combined with each other or sequenced, andwhat is the optimal sequence? If regimens are designed thatinclude multiple targeted therapies, what does that mean forcytotoxic therapy? Will ‘chemotherapy’ as we know it oneday be reserved for relapsed or refractory patients only (orpatients that are prospectively predicted to benefit)? Whilesuch a suggestion still seems to be a good deal in the distance,several new agents currently in the pipeline will allow us toget closer, and hopefully push the cure rates for ALL tounprecedented levels in the near future.

There is a possibility that the new agents discussed in thisreview will change the prognosis and possibly the natural his-tory of ALL. As new targeted therapies move into the front-line, it will be important to correlate molecular responsewith outcome by measuring for the presence of MRD, andre-stratifying a patient’s risk of relapse/poor outcome

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according to the depth of response to treatment. New prog-nostic models to identify high-risk disease will need to bedeveloped if a high proportion of patients can achieve MRDnegativity. Also, determining which patients require AHSCTin first remission needs to be studied in the context of a newera of improved therapies.

Declaration of interest

EJ Jabbour has received research funding from GlaxoSmith-Kline. HM Kantarjian has received research funding fromPfizer, Sanofi-Aventis and Amgen. MS Mathisen has noconflicts of interest.

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AffiliationMichael S Mathisen1 PharmD,

Hagop M Kantarjian2 MD &

Elias J Jabbour†3 MD†Author for correspondence1Clinical Pharmacy Specialist -- Adult Leukemia,

M.D. Anderson Cancer Center,

Departments of Pharmacy and Leukemia,

1515 Holcombe Boulevard, Unit 428, Houston,

TX 77030, USA2Professor and Chairman,

M.D. Anderson Cancer Center,

Department of Leukemia, 1515 Holcombe

Boulevard, Unit 428, Houston, TX 77030, USA3Associate Professor,

M.D. Anderson Cancer Center,

Department of Leukemia, 1515 Holcombe

Boulevard, Unit 428, Houston, TX 77030, USA

Tel: 713 792.4764;

E-mail: ejabbour@mdanderson.org

M. S. Mathisen et al.

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