Evolving therapy of adult acute lymphoblastic leukemia: state-of-the-art treatment and future directions.

Recent years have witnessed major advances that have improved outcome of adults with acute lymphoblastic leukemia (ALL). The emergence of the concept of measurable residual disease has fine-tuned our prognostic models and guided our treatment decisions. The treatment paradigms of ALL have been revolutionized with the advent of tyrosine kinase inhibitors targeting BCR-ABL1, monoclonal antibodies targeting CD20 (rituximab), antibody-drug conjugates targeting CD22 (inotuzumab ozogamicin), bispecific antibodies (blinatumomab), and CD19 chimeric antigen receptor T cell therapy (tisagenlecleucel). These highly effective new agents are allowing for novel approaches that reduce reliance on intensive cytotoxic chemotherapy and hematopoietic stem cell transplantation in first remission. This comprehensive review will focus on the recent advances and future directions in novel therapeutic strategies in adult ALL.

Current challenges and opportunities in treating adult patients with Philadelphia-negative acute lymphoblastic leukaemia.

Significant advances have been made in recent years in the field of Philadelphia-negative acute lymphoblastic leukaemia (ALL). New insights into the biology and genetics of ALL as well as novel clinical observations and new drugs are changing the way we diagnose, risk-stratify and treat adult patients with ALL. New genetic subtypes and alterations refine risk stratification and uncover new actionable therapeutic targets. The incorporation of more intensive, paediatric and paediatric-inspired approaches for young adults seem to have a positive impact on survival in this population. Minimal residual disease at different time points can assist in tailoring risk-adapted interventions for patients based on individual response. Finally, novel targeted approaches with monoclonal antibodies, immunotherapies and small molecules are moving through clinical development and entering the clinic. The aim of this review is to consolidate the abundance of emerging data and to review and revisit the concepts of risk-stratification, choice of induction and post-remission strategies as well as to discuss and update the approach to specific populations with ALL, such as young adult, elderly/unfit and relapsed/refractory patients with ALL.

Extramedullary disease in APL: a real phenomenon to contend with or not?

In the last 2 decades an increasing number of patients reported with extramedullary involvement among relapsed acute promyelocytic leukemia (APL) patients. Several investigators related this phenomenon to the relatively new treatment of all-trans-retinoic-acid (ATRA). In this review article we will examine what has been reported in the medical literature on extramedullary disease in APL: the common sites to be involved, the clinical risk factors to its development, the role of ATRA and arsenic tri-oxide and the recommended treatment.

Escalated daunorubicin dosing as an induction treatment for Philadelphia-negative adult acute lymphoblastic leukemia.

The dose intensity of daunorubicin (DNR) delivered during the induction period represented the major prognostic factor for the outcome of adult acute lymphoblastic leukemia (ALL). The aim of this study was to determine the survival or toxicity of escalated doses of DNR in induction treatment of adult patients with acute lymphoblastic leukemia who are at least 15 years of age. For induction chemotherapy, all patients were given 90 mg/m(2)/day of DNR by continuous intravenous (IV) infusion over 24 h daily on days 1-3, 2 mg of vincristine IV push on days 1 and 8, and 60 mg/m(2)/day of prednisolone per oral (PO) on days 1-14 in conjunction with 4,000 units/m(2)/day of L-asparaginase intramuscular or subcutaneous on days 17-28. The median patient age was 32 years (range, 15-69). Complete remission (CR) was achieved in 169 (88.5 %) patients, while 4 died before CR was reached. Additionally, 11 patients died from leukemia progression, 4 had refractory disease, and 3 had follow-up loss. The median follow-up time was 697 days (range, 12-2,270). The 3-year cumulative incidence of relapse was 49.3 %. The probabilities of disease-free survival and overall survival at 3 years were 46.1 and 43.1 %, respectively. The dose of DNR was 100 % of the target dose, and there were no additional specific toxicities. The results show that escalated doses of DNR in induction chemotherapy are similar with the standard dose in response and toxicities. Our study indicates that a more effective regimen or better chemotherapy agents are needed to improve the CR rate and prolong survival in Philadelphia-negative adult ALL.

Effects of ICOSLG expressed in mouse hematological neoplasm cell lines in the GVL reaction.

As a member of the B7 family, inducible co-stimulator ligand (ICOSLG) expressed on tumor cell has been reported to have an important role in tumor immunity. In this study, we sought to determine whether the expression of ICOSLG in mouse hematological malignancy cells influences GVL reaction after mouse allogeneic BMT. In our study, we analyzed the expression of ICOSLG in six mice hematological malignancy cell lines for the first time, and found that FBL3, A20 and P388 cells expressed high levels of ICOSLG. Then, we chose A20 cells as targets to construct a GVL model and study the effects on the GVL reaction by silencing the ICOSLG gene. The survival was analyzed. We found that in GVL model, mortality of interference groups was significantly delayed compared with the control group (P=0.0005). Our results indicate that knockdown of ICOSLG of mouse leukemic cells may significantly enhance GVL effect after allogeneic BMT.

The Bruton tyrosine kinase inhibitor PCI-32765 thwarts chronic lymphocytic leukemia cell survival and tissue homing in vitro and in vivo.

B-cell receptor (BCR) signaling is a critical pathway in the pathogenesis of several B-cell malignancies, including chronic lymphocytic leukemia (CLL), and can be targeted by inhibitors of BCR-associated kinases, such as Bruton tyrosine kinase (Btk). PCI-32765, a selective, irreversible Btk inhibitor, is a novel, molecularly targeted agent for patients with B-cell malignancies, and is particularly active in patients with CLL. In this study, we analyzed the mechanism of action of PCI-32765 in CLL, using in vitro and in vivo models, and performed correlative studies on specimens from patients receiving therapy with PCI-32765. PCI-32765 significantly inhibited CLL cell survival, DNA synthesis, and migration in response to tissue homing chemokines (CXCL12, CXCL13). PCI-32765 also down-regulated secretion of BCR-dependent chemokines (CCL3, CCL4) by the CLL cells, both in vitro and in vivo. In an adoptive transfer TCL1 mouse model of CLL, PCI-32765 affected disease progression. In this model, PCI-32765 caused a transient early lymphocytosis, and profoundly inhibited CLL progression, as assessed by weight, development, and extent of hepatospenomegaly, and survival. Our data demonstrate that PCI-32765 effectively inhibits CLL cell migration and survival, possibly explaining some of the characteristic clinical activity of this new targeted agent.

Use of intrathecal chemoprophylaxis in children after SCT and the risk of central nervous system relapse.

Conflicting conclusions can be drawn from the available data concerning antileukemic efficacy and risks of intrathecal (i.t.) chemoprophylaxis to children after hematopoietic SCT (HSCT). To address this, we enrolled six transplantation centers with similar treatment and patient material. Of the 397 children included, 136 patients had received post-HSCT i.t. treatment (i.t. group) and 261 had not (non-i.t. group). The two groups were, apart from the i.t. therapy given or not given, at equal risk of post-HSCT central nervous system (CNS) relapse, which was the primary endpoint studied. Isolated CNS relapses were observed in 2 (1.5%) patients from the i.t. group and 2 (1%) from the non-i.t. group. Combined relapses, including CNS, involved 4 (3%) patients from the i.t. group and 6 (2%) from the non-i.t. group. Overall survival and the occurrence of neurological side effects did not differ significantly between the groups. There was no statistically significant difference in the incidence of isolated or mixed CNS relapses between the two groups, suggesting little or no benefit from i.t. therapy post-HSCT in children.

The neurodevelopmental sequelae of childhood leukaemia and its treatment.

The overall survival of childhood leukaemia has increased dramatically over recent decades. With the increasing number of survivors, chemotherapy protocols are designed not only to improve cure rates but also to minimise long-term sequelae. Central-nervous-system-directed therapy given as intrathecal chemotherapy and/or cranial irradiation plays a crucial part in acute leukaemia treatment but can also result in adverse effects on the developing brain. The elimination of cranial irradiation from current treatment protocols has improved the neurocognitive outcome without compromising survival rates. Although neurodevelopmental long-term sequelae after chemotherapy-only central-nervous-system-directed therapies may be more subtle, survivors of childhood leukaemia will continue to require methodical follow-up and appropriate rehabilitation.

Central nervous system prophylaxis in adults with acute lymphoblastic leukemia: current and emerging therapies.

Central nervous system (CNS) recurrence continues to be a significant complication in the treatment of adult patients with acute lymphoblastic leukemia (ALL). Preventing CNS recurrence has been a therapeutic challenge and has not been addressed critically in many clinical trials. Adult studies modeled on childhood ALL studies have used multiple treatment modalities, including radiation therapy, systemic therapy, intrathecal therapy, and combinations thereof. Cranial irradiation is effective but is offset by substantial toxicity, including neurologic sequelae. Systemic chemotherapy, especially with cytarabine (AraC) and methotrexate, has demonstrated promise in decreasing CNS recurrence, but therapeutic levels of drugs in the cerebrospinal fluid (CSF) are not maintained. Intrathecal chemotherapy with or without high-dose systemic therapy is the most common approach to CNS prophylaxis. Liposomal AraC recently has become available and confers prolonged levels of free AraC in the CSF, a critical requirement for CNS prophylactic therapy. This review discusses the various modalities used for CNS prophylaxis in patients with ALL and the emerging trends, with specific emphasis on the outcome in terms of event-free survival and toxicity.

Management of Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL).

The tyrosine kinase inhibitor (TKI) imatinib has become an integral part of front-line therapy for Ph(+) ALL, with remission rates exceeding 90% irrespective of whether imatinib is given alone or combined with chemotherapy. Treatment outcome with imatinib-based regimens has improved compared with historic controls, but most patients who do not undergo allogeneic stem cell transplantation (SCT) eventually relapse. Acquired resistance on TKI treatment is associated with mutations in the bcr-abl tyrosine kinase domain in the majority of patients, and may be detected at low frequency prior to TKI treatment in a subset of patients. Second generation TKIs, eg, dasatinib and nilotinib, show activity against most of the bcr-abl tyrosine kinase domain (TKD) mutations involved in acquired imatinib resistance, but clinical benefit is generally short-lived. Accordingly, SCT in first complete remission (CR) is considered to be the best curative option. Molecular monitoring of minimal residual disease levels appears to have prognostic relevance and should be used to guide treatment. International standardization and quality control efforts are ongoing to ensure comparability of results. Mutation analysis during treatment relies increasingly on highly sensitive PCR techniques or denaturing HPLC and may assist in treatment decisions, eg, in case of molecular relapse. Results from current studies of second-generation TKI as front-line treatment for Ph(+) ALL are promising and show high molecular response rates, but follow-up is still too short to determine their impact on remission duration and long-term survival. Strategies to improve outcome after SCT include the pre-emptive use of imatinib, which appears to reduce the relapse rate. In patients ineligible for transplantation, novel concepts for maintenance therapy are needed. These could involve novel immunotherapeutic interventions and combinations of TKI.

Extended triple intrathecal therapy in children with T-cell acute lymphoblastic leukaemia: a report from the Israeli National ALL-Studies.

Owing to the increased central nervous system (CNS) relapse risk in T-cell acute lymphoblastic leukaemia (ALL), it is unclear whether preventive cranial radiation (pCRT) can be safely omitted. In this study, pCRT was replaced by extended triple intrathecal therapy (TIT) in prednisone good early responders - medium-risk (MR) group, accounting for 76% of T-ALL patients. From 1989 to 2003, 143 T-ALL patients aged 1-18 years were enrolled in the Israel National Studies (INS) 89 (n = 84) and INS 98 (n = 59) trials, based on ALL-Berlin-Frankfurt-Munster (BFM) 86/90 and ALL-BFM 95 protocols, respectively. Five-year event-free survival (EFS) of the MR group in the INS 89 (n = 60) was 70 +/- 5.9% and the INS 98 (n = 43), 83.7 +/- 5.6% (P = 0.12); the cumulative incidence (CI) of any CNS relapse was 5.0 +/- 2.8% and 2.3 +/- 2.3% (P = 0.50), respectively. There was no difference in outcome between MR patients with a white blood cell count (WBC) >or=100 x 10(9)/l treated with extended TIT (n = 17) or pCRT (n = 10). For all T-ALL patients, 5-year EFS was 61.9 +/- 5.3% in INS 89 and 72.9 +/- 5.8% in INS 98, (P = 0.21); the CI of any CNS relapse was 7.1 +/- 2.8% and 1.7 +/- 1.7% (P = 0.142), respectively. Outcome of T-ALL MR patients given extended TIT in the context of BFM-based protocols with long-term follow-up appeared to be comparable to studies in which a larger proportion of patients was irradiated, and was associated with low risk of CNS relapse, regardless of the WBC.

Increased risk for CNS relapse in pre-B cell leukemia with the t(1;19)/TCF3-PBX1.

To evaluate the impact of contemporary therapy on the clinical outcome of children with pre-B acute lymphoblastic leukemia (ALL) and the t(1;19)/TCF3/PBX1, we analyzed 735 patients with B-cell precursor ALL treated in four successive protocols at St Jude Children's Research Hospital. The 41 patients with the t(1;19) had a comparable event-free survival to that of the 694 patients with other B-cell precursor ALL (P=0.63; 84.2+/-7.1% (s.e.) vs 84.0+/-1.8% at 5 years). However, patients with the t(1;19) had a lower cumulative incidence of any hematological relapse (P=0.06; 0 vs 8.3+/-1.2% at 5 years) but a significantly higher incidence of central nervous system (CNS) relapse (P<0.001; 9.0+/-5.1% vs 1.0+/-0.4% at 5 years). In a multivariate analysis, the t(1;19) was an independent risk factor for isolated CNS relapse. These data suggest that with contemporary treatment, patients with the t(1;19) and TCF3/PBX1 fusion have a favorable overall outcome but increased risk of CNS relapse.

Triple intrathecal therapy without cranial irradiation for central nervous system preventive therapy in childhood acute lymphoblastic leukemia.

BACKGROUND: To evaluate the treatment results of central nervous system preventive therapy (CNSP) with triple intrathecal therapy (TIT) alone in children with acute lymphoblastic leukemia (ALL). METHODS: We retrospectively studied a cohort of 59 patients with median follow-up time 50.6 months (range: 27-80 months) at a single institution in Taiwan. Patients with ALL were classified in risk groups at diagnosis. TPOG-ALL-93 protocols and TPOG-ALL-2002 protocols were used. Both protocols were for multicenter studies in Taiwan and contained protocols for standard-risk (SR), high-risk (HR), and very-high-risk (VHR) patients. In this study, we used TIT alone for CNSP. In all ALL patients, methotrexate, hydrocortisone, and cytarabine were given at age-dependent doses. RESULTS: As of October 2006, patients had a 3-year event-free survival and an overall survival 89.4 +/- 4.1% (S.E.) and 93.1 +/- 3.3%, respectively. Under TIT no patients had complications such as seizure, encephalitis, or infection, and no morbidities like those caused by cranial irradiation. In this study, we used TIT alone for CNSP and had no CNS relapse. CONCLUSIONS: In the context of effective systemic therapy, TIT alone appears to be effective CNSP for most patients with ALL.

Neurologic complications associated with intrathecal liposomal cytarabine given prophylactically in combination with high-dose methotrexate and cytarabine to patients with acute lymphocytic leukemia.

Central nervous system (CNS) prophylaxis has led to a significant improvement in the outcome of patients with acute lymphocytic leukemia (ALL). Liposomal cytarabine (Enzon Pharmaceuticals, Piscataway, NJ; Skye Pharma, San Diego, CA), an intrathecal (IT) preparation of cytarabine with a prolonged half-life, has been shown to be safe and effective in the treatment of neoplastic meningitis. Liposomal cytarabine was given for CNS prophylaxis to 31 patients with newly diagnosed ALL. All patients were treated concurrently with hyper-CVAD chemotherapy (fractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone) including high-dose methotrexate (MTX) and cytarabine on alternating courses. Liposomal cytarabine 50 mg was given intrathecally on days 2 and 15 of hyper-CVAD and day 10 of high-dose MTX and cytarabine courses until completion of either 3, 6, or 10 IT treatments, depending on risk for CNS disease. Five patients (16%) experienced serious unexpected neurotoxicity, including seizures, papilledema, cauda equina syndrome (n = 2), and encephalitis after a median of 4 IT administrations of liposomal cytarabine. Toxicities usually manifested after the MTX and cytarabine courses. One patient died with progressive encephalitis. After a median follow-up of 7 months, no isolated CNS relapses have been observed. Liposomal cytarabine given via intrathecal route concomitantly with systemic chemotherapy that crosses the blood-brain barrier such as high-dose MTX and cytarabine can result in significant neurotoxicity.

Modern treatment programs for adults with acute lymphoblastic leukemia.

The current treatment programs for adult patients with acute lymphoblastic leukemia are modeled on pediatric regimens. The result has been complete remission rates comparable to those seen in children, but a significant proportion of adult patients relapse. Salvage therapy for patients with acute lymphoblastic leukemia continues to have limited success. Advances in molecular biology have discovered new targets for therapeutic intervention, and the introduction of some targeted agents, such as the new tyrosine kinase inhibitors and monoclonal antibodies, has led to improvements in response and survival in some subsets. The development of techniques for identification and monitoring of minimal residual leukemia has provided possible ways to predict relapse and consider early intervention. It is likely that we will further refine therapeutic approaches and improve patient outcome through the translation of biologic and molecular discoveries into effective and risk-adapted strategies.

Ameliorating skin-homing receptors on malignant T cells with a fluorosugar analog of N-acetylglucosamine: P-selectin ligand is a more sensitive target than E-selectin ligand.

Expression of E- and P-selectin ligands is required for T cell entry into skin. Sialyl Lewis X moieties are critical for ligand activity and are elevated on malignant skin-homing T cells. We hypothesize that these glycosylations are selectable targets for treating the dermal tropism associated with cutaneous lymphomas. In this study, we analyzed the efficacy of a novel 4-fluorinated analog of N-acetylglucosamine (GlcNAc) on E- and P-selectin ligands expressed by malignant skin-homing T cells. We also examined the specificity of 4-F-GlcNAc (2-acetamido-1,3,6-tri-O-acetyl-4-deoxy-4-fluoro-D-glucopyranose) action by contrasting the effects on sialyl Lewis X expression displayed by P-selectin glycoprotein ligand-1 (PSGL-1) with sialylated O-glycans expressed by CD43. Using parallel-plate flow analysis, we found that 4-F-GlcNAc elicited 5-fold more potent inhibition on P-selectin ligand activity than on E-selectin ligand activity. To determine whether glycosylations conferring E- and P-selectin ligand activities were inhibited, we analyzed the expression of sialyl Lewis X and sialyl-fucosylated core 2 O-glycan (CHO-131 antigen), respectively. We found that 4-F-GlcNAc treatment resulted in dose-dependent ablation of sialyl Lewis X and CHO-131 antigen expression on PSGL-1, whereas sialylated O-glycans on CD43 were minimally affected. These results indicate that 4-F-GlcNAc treatment can selectively downregulate the P-selectin ligand activity and potentially prevent dermal dissemination of cutaneous lymphomas.

Clinical manifestations and treatment of newly diagnosed acute lymphoblastic leukemia in adults.

Adult acute lymphoblastic leukemia (ALL) is a heterogeneous disease with distinct biologic and prognostic subgroups. The treatment of adults with ALL has evolved largely from the therapy developed for childhood ALL and, despite differences across regimens, can be broadly classified as including induction, consolidation, maintenance, and central nervous system prophylaxis. Although there has been marked improvement in the outcomes for pediatric patients with ALL, the same success has not yet been realized for adult patients. Some of this difference can be attributed to a greater incidence of unfavorable cytogenetic subtypes in adults than in children. In addition, the ability to tolerate intensive regimens likely plays a role. This article reviews the classification, prognostic features, current treatment programs, and new advances as applied to adult patients with newly diagnosed ALL.

CXCR4 chemokine receptors, histone deacetylase inhibitors and acute lymphoblastic leukemia.

Acute lymphoblastic leukemia (ALL) is a malignancy with the potential to infiltrate the liver, spleen, lymph nodes and brain. The mechanism for selective homing of ALL cells to preferential sites has long been unclear. Recent reports indicate that the chemokine receptor CXCR4 is found on ALL cells and its ligand is highly expressed at sites associated with ALL-induced organ infiltration. This results in chemotaxis, or directed migration of leukemic cells from the bone marrow via the circulation to preferential sites of extramedullary organ infiltration. Because overexpression of CXCR4 on ALL cells is associated with high extramedullary organ infiltration and shorter disease-free survival, numerous pharmacological agents affecting CXCR4 have currently been investigated. The most promising data are available for histone deacetylase inhibitors (HDAIs), which have been shown to be safe and well tolerated in phase I clinical trials. In vitro, HDAIs extensively down-regulate CXCR4 protein and mRNA levels. As a result, the ability of CXCR4 ligand to induce cellular migration is impaired. Wider recognition of the role of CXCR4 in ALL and manipulation of this important mechanism may lead to novel approaches in the treatment and outcome of this disease.