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Treatment of Adult Acute LymphoblasticLeukemia (ALL) With a Focus on EmergingInvestigational and Targeted Therapies

Treatment of Adult Acute LymphoblasticLeukemia (ALL) With a Focus on EmergingInvestigational and Targeted Therapies

ABSTRACT: Acute lymphoblastic leukemia (ALL) in adults is a very challenging disease. Adults tend to present with higher-risk features and are unable to tolerate chemotherapy regimens as intense as those administered to children. The overall treatment plan for adult ALL is modeled after the pediatric paradigm and includes multi-agent chemotherapy in the forms of induction, consolidation, maintenance, and central nervous system prophylaxis. Most patients will go into complete remission but often relapse; relapse is typically indicative of chemotherapy-refractory disease. Salvage therapy generally consists of cytotoxic agents from drug classes the patient has had limited or no exposure to. The results of conventional chemotherapy for relapsed ALL are unacceptable. The goal of therapy in these patients is to achieve a second remission followed by allogeneic stem-cell transplantation. Monoclonal antibodies directed at cell-surface antigens offer a targeted approach to treating leukemia and other cancers. Anti-CD20 monoclonal antibodies have been shown to improve survival when used in the frontline setting. Novel, highly active antibodies directed at CD19 and CD22 are being investigated in the relapsed and refractory settings. These agents will likely be explored as components of first-line therapy as clinical development continues.

Introduction

Acute lymphoblastic leukemia (ALL) is a heterogeneous disease characterized by the accumulation and proliferation of clonal lymphoid progenitor cells in the bone marrow, periphery, and/or extramedullary sites. The disease is expected to be diagnosed in 6,050 individuals in 2012, with a higher proportion of the diagnoses in children.[1] While ALL is known as a cancer success story in the pediatric setting, with cure rates approaching 90%,[2] the same cannot yet be said of adults. Historically, cure rates for adult ALL are approximately 20% to 40%,[3] depending on patient age and disease characteristics, although these numbers may be improving in younger adults treated with regimens that incorporate targeted therapies.[4] Patients who are at a particularly high risk for a poor outcome include those with rearrangements involving the mixed lineage leukemia (MLL) gene, or with Philadelphia chromosome (Ph)-positive disease. These subtypes occur at a much higher frequency in adults than they do in children. Adults are also far less likely to have favorable cytogenetic features at diagnosis, such as t(12;21) or hyperdiploidy. Unfortunately, most patients will achieve complete remission (CR), and then subsequently suffer a relapse. Salvage regimens for ALL are improving, and targeted therapies are currently being examined in clinical trials. In this review, we will discuss the management of ALL in the adult population, in the context of the recently published guidelines from the National Comprehensive Cancer Network (NCCN).[5] We will focus in particular on the strides being made in salvage and targeted approaches.

FIGURE 1

Outcomes of Frontline HyperCVAD According to Risk Category

Frontline Management

Ph-negative B-ALL

The frontline strategy for the management of adult ALL is similar to that for pediatric ALL: it involves induction chemotherapy, multiple rounds of consolidation, and a prolonged maintenance phase, as well as central nervous system (CNS) prophylaxis. Most protocols call for approximately 3 years of therapy in total. Several regimens are used in the United States; most involve the same key agents, which include vincristine, an anthracycline (eg, doxorubicin or daunorubicin), and a corticosteroid (eg, prednisone or dexamethasone), with or without some form of L-asparaginase.[6-8] One such regimen is hyperCVAD, in which the combination of hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone alternates with high-dose methotrexate and cytarabine.[4,9] Cycles are repeated approximately monthly for a total of 8 cycles; at that point patients move to the maintenance portion of the regimen, which includes daily mercaptopurine, monthly vincristine, weekly methotrexate, and monthly pulses of prednisone (POMP). Long-term outcomes have been published previously and include a 5-year overall survival (OS) of 38%.[9] Survival was influenced by several prognostic factors that were assessed using multivariable analysis (Figure 1). These outcomes are comparable to those seen with a number of other regimens that are used, depending on center preference. Additional details regarding the hyperCVAD regimen and other NCCN-endorsed regimens for the management of adult ALL can be found in Table 1.

TABLE 1

Chemotherapy Regimens for Adult ALL

There is an ongoing discussion regarding whether the use of pediatric-inspired ALL regimens may be more effective in adult patients up to 39 years of age.[10] The benefit of using pediatric regimens is thought to derive from more intensive use of corticosteroids, vincristine, asparaginase, and CNS-directed therapy. To date, most of the data on this issue are from large retrospective analyses, which perhaps should not be compared to each other due to the heterogeneity of the patients studied (eg, with regard to age, disease characteristics, etc). Nevertheless, the results of some of these studies have been quite staggering. Stock et al evaluated adolescent patients who were assigned to receive either Children’s Cancer Group (CCG) or Cancer and Leukemia Group B (CALGB) protocol treatment.[11] Patients in both groups achieved CR rates of 90%, but there were substantial differences in both 7-year event-free survival (63% vs 34%; P < .001) and OS (67% vs 46%; P < .001) favoring the patients on CCG protocols. One important note regarding interpretation of this study is the baseline difference in age between the two groups. There were significantly more 18- to 20-year-old patients in the CALGB cohort. This could potentially explain some of the differences in outcome, considering that 18- to 20-year-olds may inherently do worse than patients between the ages of 15 and 17. Our center is also studying this issue, and patients younger than 40 years currently are prioritized to a single-arm study using the augmented Berlin-Frankfurt-Mnster (BFM) regimen modeled on CCG-1961.[12,13] The median age of patients enrolled in the current study is 21 years (N = 68). The reported remission rate is 96%, with 72% achieving minimal residual disease (MRD) negativity by day 84. There appears to be a distinct difference in outcome between patients who are less than 25 years old and those more than 25 years of age (2-year OS, 88% vs 65%). With short follow-up, overall patient outcomes thus far are comparable to those of a similar group of patients who were treated with the hyperCVAD regimen. Presently, the NCCN guidelines recommend treating patients aged 15 to 39 years with one of several published pediatric-inspired regimens.

L-asparaginase, an enzyme used to deprive lymphoblasts of the nonessential amino acid asparagine, is considered an important component in pediatric ALL regimens.[14] It is also included in several of the commonly used adult regimens, but the cumulative dose is generally less than that of the pediatric programs. A pegylated form of the drug allows for continuous exposure over a period of weeks, reducing the number of infusions or injections a patient would be subjected to if receiving the conventional preparation. Recently, a study from the German Multicenter Study Group for Adult ALL (GMALL) was presented indicating that intensifying the dose of pegylated asparaginase during induction and consolidation improved the survival of younger patients with standard-risk disease at baseline.[15] In this regimen, the drug was well tolerated; however, there was a significant increase in the incidence of grade 3/4 hyperbilirubinemia, which led to treatment interruptions that were found to have a prognostic impact on the outcome. Other potential toxicities that pose a problem include pancreatitis, thrombosis, allergic reaction, hyperglycemia, and hypofibrinogenemia. This makes it highly important to determine the optimal dose and timing of drug administration to prevent or avoid adverse effects that may compromise further antileukemic therapy. If the pegylated formulation is used, these problems can be delayed, such that they typically arise 1 to 2 weeks after a dose is given. A detailed expert review of asparaginase toxicity and its management has recently been published.[16]

Approximately 50% of patients’ leukemic blasts express the CD20 antigen.[17] The prognostic role of CD20 expression in ALL is controversial; nonetheless, targeted therapies directed against this marker have been developed. Recent data from the MD Anderson Cancer Center have indicated that the addition of rituximab (Rituxan), a monoclonal antibody against CD20, to the hyperCVAD regimen improves OS in younger patients.[4] These results were confirmed by a European study that also evaluated the role of monoclonal antibody therapy when added to conventional chemotherapy.[18] Ofatumumab (Arzerra) is another CD20-targeted monoclonal antibody currently approved for the management of relapsed and refractory chronic lymphocytic leukemia.[19] The binding site of ofatumumab is distinct from that of rituximab, and ofatumumab has been shown to be active in rituximab-refractory settings.[20] Based on the available data, ofatumumab is being evaluated in combination with the hyperCVAD regimen in adults with newly diagnosed ALL.[21]

T-ALL

Within the distinct subtype of the disease represented by T-lineage ALL, patients are very heterogeneous. Outcomes are highly variable, dependent on the immunophenotype and molecular characteristics displayed by the leukemic cells.[22] The genetic basis of one subset of poor-risk patients,[23] termed early T-cell precursor ALL, was recently described.[24] The authors noted that, interestingly, the genomic picture was consistent with that of myeloid hematopoietic stem cells, and that therapy directed at this lineage might be expected to improve the response rates and outcome. They also identified mutations commonly found in myeloid malignancy, such as RAS and FLT3 mutations. Other groups have identified FLT3 mutations in 34% of patients with this subtype of T-ALL.[25]

In general, the treatment of T-ALL is similar to that used for B-ALL, and the NCCN guidelines make no specific recommendations regarding the frontline management of the former. Efforts are currently being made to incorporate into the treatment plan drugs that selectively target T cells. Nelarabine (Arranon) is a nucleoside analog that is catabolized to arabinosylguanine triphosphate in vivo. It was developed after it was noted that patients with purine nucleoside phosphorylase (PNP) deficiency suffered a marked T-lymphopenia mediated by the intracellular accumulation of deoxyguanosine triphosphate.[26,27] While nelarabine is approved for relapsed ALL, ongoing studies are attempting to clarify its role in frontline treatment.

Ph-positive B-ALL

Ph-positive ALL continues to pose a major challenge in the adult population. Allogeneic stem-cell transplantation (alloSCT) is regarded as the only curative intervention for this subset of patients. Recently, the incorporation of small-molecule tyrosine kinase inhibitors (TKIs) has improved outcomes for these patients. The addition of imatinib (Gleevec) to conventional chemotherapy has been proven superior to chemotherapy alone in several trials that have been published or presented to date.[28] However, in most of these reports, alloSCT still appears to be an important component of consolidation therapy.

Dasatinib (Sprycel) is a second-generation TKI that has enhanced potency against the BCR-ABL protein compared to imatinib, as well as the ability to block the SRC family of kinases.[29] The SRC kinases have been implicated as being required for the development of Ph-positive ALL.[30] Dasatinib also retains activity against most known tyrosine kinase domain mutations that confer resistance to imatinib.[31] Recently, dasatinib was found to be superior to imatinib for the initial treatment of chronic myeloid leukemia (CML) in chronic phase.[32] These favorable characteristics made it appropriate to test combination chemotherapy with the addition of dasatinib in the frontline setting for adult ALL. In a clinical trial with recently published results, 35 patients with newly diagnosed Ph-positive ALL were treated with hyperCVAD + dasatinib.[33] Dasatinib was administered at a dose of 100 mg/d for the first 14 days during the induction and consolidation cycles. If patients completed the consolidation phase, they went on to receive monthly vincristine and prednisone while continuing on dasatinib, 100 mg/d. Ninety-four percent of patients achieved a CR, and the estimated 2-year survival was 64%. A very low percentage of patients proceeded with upfront alloSCT (4 of 36), and it will be important to assess whether dasatinib therapy throws into question the conventional notion that a transplant is absolutely indicated for all patients who are fit for such a procedure and have an adequate stem-cell source. However, additional follow-up is required before that can be determined.

Although the dasatinib data are quite encouraging, patients still relapse, and there are specific kinase domain mutations that are not sensitive to any commercially available TKI. The most notorious mutation for any Ph-positive malignancy is the T315I mutation, which confers resistance to imatinib and dasatinib, as well as to nilotinib (Tasigna). Patients with Ph-positive ALL receiving dasatinib in a European study appeared to develop the T315I mutation at a relatively high frequency, making it important to develop and examine options for combating this problem.[34] One strategy might be to utilize a TKI that has activity against T315I-mutated disease, such as ponatinib. Ponatinib is a rationally designed molecule that has activity against nearly all known BCR-ABL kinase domain mutations.[35] It is currently being evaluated as a frontline strategy in combination with the hyperCVAD regimen.[36]

The NCCN guidelines recommend approaches similar to those described above.[5] Available data indicate that it is important to start a TKI as soon as the presence of the Philadelphia chromosome is confirmed.[28] The guidelines do not specify a preference for which TKI to initiate in the frontline setting. Despite the fact that outcomes appear to be improving with current therapies, the NCCN appropriately recommends first and foremost that patients be considered for ongoing clinical trials. Patients at our center are enrolled either on a study evaluating ponatinib plus chemotherapy, or on a cooperative group trial evaluating the previously described regimen of dasatinib plus chemotherapy.

Bone Marrow Transplantation

AlloSCT is the ultimate form of potential consolidation for patients who achieve CR after induction chemotherapy. There has recently been debate regarding the ideal candidates for alloSCT in first CR. It had been widely accepted that patients with high-risk disease (with varying definitions of high-risk disease, although most included age, white blood cell count at presentation, and presence of the Philadelphia chromosome) should undergo alloSCT in first CR if a suitable donor could be identified (most well studied is the use of a matched sibling). The current NCCN guidelines also endorse such a strategy. However, an analysis of the large Medical Research Council (MRC) UKALL XII/Eastern Cooperative Oncology Group (ECOG) E2993 study revealed that patients with standard-risk disease who had a stem-cell donor had improved OS compared with those who had no donor (5-year OS, 62% vs 52%; P = .02).[37] Paradoxically, this study also found that high-risk patients did not benefit when evaluated on a donor-vs-no-donor basis. These results are in disagreement with those of other large studies,[38] possibly because of differing definitions of high-risk disease as well as differences in chemotherapy regimens employed. Most clinicians find it unrealistic that all patients with standard-risk disease be referred for alloSCT, and they prefer a risk-adapted approach that might modify a patient’s risk status over time.[39] Currently, this is largely achieved by monitoring a patient’s MRD status at varying time points during induction and consolidation chemotherapy. Patients who achieve MRD-negative status at protocol-defined points have excellent outcomes with chemotherapy alone.[40] These standard-risk patients can thus be spared transplant-related morbidity and mortality, which can be substantial. Conversely, patients who are MRD-positive will almost universally suffer from relapse, and those who were previously considered standard risk are shifted into the high-risk category. AlloSCT is beneficial for these patients, primarily if they achieve post-transplant MRD-negative status.

Although salvage therapy is discussed below, it is important to note that the ultimate goal of the chemotherapy regimen is to achieve remission so that the patient can move forward to alloSCT. Patients with relapsed disease have a very poor outcome, with a median OS of 24 weeks.[41] In one of the largest series published to date, alloSCT in patients with relapsed disease led to improvement in 5-year OS compared with patients who received chemotherapy alone (16% to 23% vs 4%).[41]

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