Sphingosine kinase 2 supports the development of BCR/ABL-independent acute lymphoblastic leukemia in mice.

BACKGROUND: Sphingosine kinase (SphK) 2 has been implicated in the development of a range of cancers and inhibitors of this enzyme are currently in clinical trial. We have previously demonstrated a role for SphK2 in the development of acute lymphoblastic leukemia (ALL). METHODS: In this and our previous study we use mouse models: in the previous study the disease was driven by the proto-oncogene BCR/ABL1, while in this study cancer risk was elevated by deletion of the tumor suppressor ARF. RESULTS: Mice lacking ARF and SphK2 had a significantly reduced incidence of ALL compared mice with wild type SphK2. CONCLUSIONS: These results show that the role of SphK2 in ALL development is not limited to BCR/ABL1 driven disease extending the potential use of inhibitors of this enzyme to ALL patients whose disease have driver mutations other than BCR/ABL1.

Regulation of the bone marrow microenvironment by G-CSF: Effects of G-CSF on acute lymphoblastic leukaemia.

It has been suggested that disruption of the lymphoid niche by G-CSF may be of therapeutic benefit to patients with acute lymphoblastic leukaemia. We used a xenograft model to determine the effect of G-CSF on ALL progression in a minimal residual disease setting. Consistent with the effects on normal murine B cell progenitors, G-CSF slowed disease in the majority of ALL xenografts tested, suggesting that G-CSF may provide benefits beyond neutrophil recovery for ALL patients. However, two of eight xenografts demonstrated accelerated disease progression. G-CSF could be detrimental for these patients due to expansion of the malignant clone.

Dyadic interdependence of psychosocial outcomes among haematological cancer survivors and their support persons.

PURPOSE: This study aimed to explore the dyadic relationships between unmet need, depression, and anxiety in people diagnosed with haematological cancer and their support persons. METHODS: Adult survivors (18 years+) who had been diagnosed with a haematological cancer were recruited to a cross-sectional mailed survey via five state cancer registries in Australia. Participating survivors invited a support person to also complete a survey. Structural equation modelling was used to explore the relationships among survivor and support person self-reported depression, anxiety, and unmet needs. RESULTS: Of the 4299 eligible haematological cancer survivors contacted by the registries, 1511 (35%) returned a completed survey as did 1004 support persons. There were 787 dyads with complete data. After adjusting for age, gender, rurality, cancer type, and whether the support person was a relative, positive correlations were found between survivor and support person scores for depression (p = 0.0029) and unmet needs (p < 0.001), but not anxiety scores (p = 0.075). Survivor unmet needs were significantly related to support person depression (p = 0.0036). Support person unmet needs were significantly related to a higher depression score for survivors (p = 0.0067). Greater support person unmet needs were significantly related to a higher anxiety score for survivors (p = 0.0083). Survivor unmet needs did not have a significant relationship to support person anxiety (p = 0.78). CONCLUSION: Unmet needs may mediate the interdependence of psychosocial experiences for survivors and support persons, although a longitudinal study is required to confirm causality. Addressing unmet needs may be a potential target for improving outcomes for both groups.

Prevalence and associates of psychological distress in haematological cancer survivors.

PURPOSE: To explore outcomes of psychological distress, including anxiety, depression and stress, amongst adult haematological cancer survivors, with a specific focus on potential differences between rural and urban survivors. METHODS: One thousand four hundred fourteen urban and rural survivors were recruited from five Australian population-based cancer registries and completed a self-report pen-and-paper survey on their well-being, including the Depression Anxiety and Stress Scale 21-item version. RESULTS: A quarter of survivors were identified as reporting above normal levels of anxiety and depression, respectively, and almost one fifth (17 %) reported above normal levels of stress. There were no statistically significant differences in the percentage of rural and urban survivors reporting above normal levels of anxiety, depression, or stress. Survivors who had experienced financial burden due to their cancer or were of middle age had higher odds of reporting multiple domains of psychological distress, compared to their counterparts. CONCLUSIONS: Haematological cancer survivors diagnosed during middle age or who experience increased financial burden as a result of their diagnosis may require additional support and care with regards to psychological distress.

Use of arsenic trioxide in remission induction and consolidation therapy for acute promyelocytic leukaemia in the Australasian Leukaemia and Lymphoma Group (ALLG) APML4 study: a non-randomised phase 2 trial.

BACKGROUND: Initial treatment of acute promyelocytic leukaemia traditionally involves tretinoin (all-trans retinoic acid) combined with anthracycline-based risk-adapted chemotherapy, with arsenic trioxide being the treatment of choice at relapse. To try to reduce the relapse rate, we combined arsenic trioxide with tretinoin and idarubicin in induction therapy, and used arsenic trioxide with tretinoin as consolidation therapy. METHODS: Patients with previously untreated genetically confirmed acute promyelocytic leukaemia were eligible for this study. Eligibilty also required Eastern Cooperative Oncology Group performance status 0-3, age older than 1 year, normal left ventricular ejection fraction, Q-Tc interval less than 500 ms, absence of serious comorbidity, and written informed consent. Patients with genetic variants of acute promyelocytic leukaemia (fusion of genes other than PML with RARA) were ineligible. Induction comprised 45 mg/m(2) oral tretinoin in four divided doses daily on days 1-36, 6-12 mg/m(2) intravenous idarubicin on days 2, 4, 6, and 8, adjusted for age, and 0·15 mg/kg intravenous arsenic trioxide once daily on days 9-36. Supportive therapy included blood products for protocol-specified haemostatic targets, and 1 mg/kg prednisone daily as prophylaxis against differentiation syndrome. Two consolidation cycles with tretinoin and arsenic trioxide were followed by maintenance therapy with oral tretinoin, 6-mercaptopurine, and methotrexate for 2 years. The primary endpoints of the study were freedom from relapse and early death (within 36 days of treatment start) and we assessed improvement compared with the 2 year interim results. To assess durability of remission we compared the primary endpoints and disease-free and overall survival at 5 years in APML4 with the 2 year interim APML4 data and the APML3 treatment protocol that excluded arsenic trioxide. This study is registered with the Australian New Zealand Clinical Trials Registry, number ACTRN12605000070639. FINDINGS: 124 patients were enrolled between Nov 10, 2004, and Sept 23, 2009, with data cutoff of March 15, 2012. Four (3%) patients died early. After a median follow-up of 4·2 years (IQR, 3·2-5·2), the 5 year freedom from relapse was 95% (95% CI 89-98), disease-free survival was 95% (89-98), event-free survival was 90% (83-94), and overall survival was 94% (89-97). The comparison with APML3 data showed that hazard ratios were 0·23 (95% CI 0·08-0·64, p=0·002) for freedom from relapse, 0·21 (0·07-0·59, p=0·001) for disease-free survival, 0·34 (0·16-0·69, p=0·002) for event-free survival, and 0·35 (0·14-0·91, p=0·02) for overall survival. INTERPRETATION: Incorporation of arsenic trioxide in initial therapy induction and consolidation for acute promyelocytic leukaemia reduced the risk of relapse when compared with historical controls. This improvement, together with a non-significant reduction in early deaths and absence of deaths in remission, translated into better event-free and overall survival. FUNDING: Phebra.

An imatinib-only window followed by imatinib and chemotherapy for Philadelphia chromosome-positive acute leukemia: long-term results of the CMLALL1 trial.

We report long-term results in 40 patients with Philadlephia chromosome-positive (Ph+) acute leukemia who received an imatinib monotherapy window to evaluate in vivo effects on BCR-ABL signaling prior to induction chemotherapy. The first 25 patients (cohort 1) received the LALA-94 protocol without further imatinib (newly diagnosed Ph+ acute lymphoblastic leukemia [ALL]) or induction chemotherapy followed by single-agent imatinib. Subsequent patients (cohort 2) continued imatinib concurrently with either LALA-94 (newly diagnosed Ph + ALL) or other intensive chemotherapy regimens. Cohort 2 had a complete response (CR) rate of 93% and 5-year survival of 69%. For newly diagnosed Ph+ ALL, survival was superior in cohort 2 compared with cohort 1. Toxicity was similar to that expected for chemotherapy alone. Among 10 evaluable patients, rapid loss of phospho-CRKL occurred during the imatinib window in seven patients (all achieved CR) and incomplete inhibition in three patients (none with CR). In summary, a pharmacodynamic window design permitted biomarker assessment of BCR-ABL targeting without compromising clinical outcomes.

Rituximab versus a watch-and-wait approach in patients with advanced-stage, asymptomatic, non-bulky follicular lymphoma: an open-label randomised phase 3 trial.

BACKGROUND: Patients with advanced-stage, low-tumour-burden follicular lymphoma have conventionally undergone watchful waiting until disease progression. We assessed whether rituximab use could delay the need for chemotherapy or radiotherapy compared with watchful waiting and the effect of this strategy on quality of life (QoL). METHODS: Asymptomatic patients (aged ≥18 years) with low-tumour-burden follicular lymphoma (grades 1, 2, and 3a) were randomly assigned centrally (1:1:1), by the minimisation approach stratified by institution, grade, stage, and age, to watchful waiting, rituximab 375 mg/m(2) weekly for 4 weeks (rituximab induction), or rituximab induction followed by a maintenance schedule of 12 further infusions given at 2-monthly intervals for 2 years (maintenance rituximab). On Sept 30, 2007, recruitment into the rituximab induction group was closed and the study was amended to a two-arm study. The primary endpoints were time to start of new treatment and QoL at month 7 (ie, 6 months after completion of rituximab induction). All randomly assigned patients were included in the analysis of time to start of new treatment on an intention-to-treat basis. The main study is now completed and is in long-term follow-up. The study is registered with ClinicalTrials.gov, NCT00112931. FINDINGS: Between Oct 15, 2004, and March 25, 2009, 379 patients from 118 centres in the UK, Australia, New Zealand, Turkey, and Poland were randomly assigned to watchful waiting or maintenance rituximab. 84 patients were recruited to the rituximab induction group before it was closed early. There was a significant difference in the time to start of new treatment, with 46% (95% CI 39-53) of patients in the watchful waiting group not needing treatment at 3 years compared with 88% (83-92) in the maintenance rituximab group (hazard ratio [HR] 0·21, 95% CI 0·14-0·31; p<0·0001). 78% (95% CI 69-87) of patients in the rituximab induction group did not need treatment at 3 years, which was significantly more than in the watchful waiting group (HR 0·35, 95% CI 0·22-0·56; p<0·0001), but no different compared with the maintenance rituximab group (0·75, 0·41-1·34; p=0·33). Compared with the watchful waiting group, patients in the maintenance rituximab group had significant improvements in the Mental Adjustment to Cancer scale score (p=0·0004), and Illness Coping Style score (p=0·0012) between baseline and month 7. Patients in the rituximab induction group did not show improvements in their QoL compared with the watchful waiting group. There were 18 serious adverse events reported in the rituximab groups (four in the rituximab induction group and 14 in the maintenance rituximab group), 12 of which were grade 3 or 4 (five infections, three allergic reactions, and four cases of neutropenia), all of which fully resolved. INTERPRETATION: Rituximab monotherapy should be considered as a treatment option for patients with asymptomatic, advanced-stage, low-tumour-burden follicular lymphoma. FUNDING: Cancer Research UK, Lymphoma Research Trust, Lymphoma Association, and Roche.

All-trans-retinoic acid, idarubicin, and IV arsenic trioxide as initial therapy in acute promyelocytic leukemia (APML4).

The treatment of acute promyelocytic leukemia has improved considerably after recognition of the effectiveness of all-trans-retinoic acid (ATRA), anthracycline-based chemotherapy, and arsenic trioxide (ATO). Here we report the use of all 3 agents in combination in an APML4 phase 2 protocol. For induction, ATO was superimposed on an ATRA and idarubicin backbone, with scheduling designed to exploit antileukemic synergy while minimizing cardiotoxicity and the severity of differentiation syndrome. Consolidation comprised 2 cycles of ATRA and ATO without chemotherapy, followed by 2 years of maintenance with ATRA, oral methotrexate, and 6-mercaptopurine. Of 124 evaluable patients, there were 4 (3.2%) early deaths, 118 (95%) hematologic complete remissions, and all 112 patients who commenced consolidation attained molecular complete remission. The 2-year rate for freedom from relapse is 97.5%, failure-free survival 88.1%, and overall survival 93.2%. These outcomes were not influenced by FLT3 mutation status, whereas failure-free survival was correlated with Sanz risk stratification (P[trend] = .03). Compared with our previously reported ATRA/idarubicin-based protocol (APML3), APML4 patients had statistically significantly improved freedom from relapse (P = .006) and failure-free survival (P = .01). In conclusion, the use of ATO in both induction and consolidation achieved excellent outcomes despite a substantial reduction in anthracycline exposure. This trial was registered at the Australian New Zealand Clinical Trials Registry (www.anzctr.org.au) as ACTRN12605000070639.

Results of the APML3 trial incorporating all-trans-retinoic acid and idarubicin in both induction and consolidation as initial therapy for patients with acute promyelocytic leukemia.

BACKGROUND: Initial therapy for patients with acute promyelocytic leukemia most often involves the combination of all-trans-retinoic acid with anthracycline-based chemotherapy. The role of non-anthracycline drugs in induction and consolidation is less well-established and varies widely between different cooperative group protocols. DESIGN AND METHODS: In an attempt to minimize relapse and maximize survival for patients with newly diagnosed acute promyelocytic leukemia, the Australasian Leukaemia and Lymphoma Group utilized all-trans-retinoic acid and idarubicin as anti-leukemic therapy for both induction and consolidation. The protocol (known as APML3) was subsequently amended to incorporate maintenance with all-trans-retinoic acid, methotrexate and 6-mercaptopurine. RESULTS: Eight (8%) of 101 patients died within 30 days, and 91 (90%) achieved complete remission. With a median estimated potential follow-up of 4.6 years, 4-year overall survival was 84%, and 71% of the patients remained in remission at 4 years. The cumulative incidence of all relapses was 28.1%, with 15 of the 25 relapses initially identified as an isolated molecular relapse. Both FLT3 mutations (internal tandem duplications and codon 835/836 kinase domain mutations) and increased white cell count at diagnosis were associated with inferior overall survival, but in multivariate analyses only FLT3 mutations remained significant (hazard ratio 6.647, P=0.005). Maintenance therapy was significantly associated with improved remission duration (hazard ratio 0.281, P<0.001) and disease-free survival (hazard ratio 0.290, P<0.001). CONCLUSIONS: The combination of all-trans-retinoic acid and just two cycles of idarubicin followed by triple maintenance produced durable remissions in most patients, but patients with high-risk disease, especially those with FLT3 mutations, require additional agents or alternative treatment approaches. The significant reduction in relapse seen after the addition of maintenance to the protocol supports a role for maintenance in the context of relatively low chemotherapy exposure during consolidation. (actr.org.au identifier: ACTRN12607000410459).

Manufacturing of human placenta-derived mesenchymal stem cells for clinical trials.

Mesenchymal stem cells (MSC) are being used increasingly in clinical trials for a range of regenerative and inflammatory diseases. Bone marrow is the traditional source but is relatively inaccessible in large volume. MSC have now been derived from tissues other than bone marrow including placenta and adipose tissue. We have used placenta obtained after delivery as a source of MSC and have been unable to detect any marked differences from marrow-derived MSC in terms of cell surface phenotype, chemokine receptor display, mesodermal differentiation capacity or immunosuppressive ability. This report described our manufacturing process for isolating and expanding placenta-derived human MSC and their safe infusion into the first patient in a clinical trial program of human placenta-derived MSC.

Ex vivo expansion and prophylactic infusion of CMV-pp65 peptide-specific cytotoxic T-lymphocytes following allogeneic hematopoietic stem cell transplantation.

Cytomegalovirus reactivation and infection post-allogeneic hematopoietic stem cell transplant continue to cause morbidity and mortality. Current pharmacologic therapies are limited by side effects. Adoptive transfer of ex vivo generated cytomegalovirus-specific T cells has the potential to restore immunity, prevent cytomegalovirus, and circumvent the need for pharmacologic therapies. We have generated donor-derived cytomegalovirus-specific cytotoxic T cells using dendritic cells pulsed with the HLA-A2 restricted nonapeptide NLVPMVATV (NLV) derived from the cytomegalovirus-pp65 protein. These cytotoxic T cells have been given prophylactically to 9 recipients aged 4 to 65 years on or after day 28 post-allogeneic hematopoietic stem cell transplant. Only 2 of 9 recipients received T cell depletion in vivo or in vitro. There were no immediate adverse reactions to the infusions. During 97-798 days of follow-up, 2 recipients developed cytomegalovirus reactivation; neither developed cytomegalovirus disease or required pharmacotherapy. Three recipients developed acute graft versus host disease after infusion. Two recipients died, 1 from thrombotic thrombocytopenia purpura secondary to cyclosporine, 1 from complications of graft versus host disease. A transient increase in numbers of cytomegalovirus-specific T cells demonstrated by NLV-tetramer binding was seen in 6 recipients. Prophylactic adoptive transfer of NLV-specific T cells is safe and may be effective in preventing cytomegalovirus reactivation.

Equivalent survival for sibling and unrelated donor allogeneic stem cell transplantation for acute myelogenous leukemia.

Recent studies have shown comparable survival outcomes for unrelated donor (URD) stem cell transplantation in chronic myelogenous leukemia compared to sibling donors. We compared outcomes for 105 patients aged 16 to 59 years undergoing URD transplants for acute myelogenous leukemia (AML) who were reported to the Australasian Bone Marrow Transplant Recipient Registry between 1992 and 2002, and a strictly selected matching set of 105 HLA-matched sibling donor (MSD) transplants. There was no significant difference between URD and MSD controls in the distributions of time from diagnosis to transplant, donor-recipient sex match, prior therapies, donor age, or performance status. The median follow-up of live URD patients was 4.4 years and for live MSD controls was 6.3 years. There were 18 good risk (complete remission [CR]1) and 87 poor risk (>CR1) recipients in both URD and sibling groups. Five-year disease-free survival (DFS) was not significantly different for good-risk URD and sibling donor recipients (62% versus 40%, P = .2), or poor-risk URD and sibling recipients (21% versus 25%, P = .2). In a stratified multivariate Cox regression model, the independent adverse risk factors for DFS were recipient cytomegalovirus positivity (P = .01) and the interaction of URD and earlier year of transplant (P = .006). Both neutrophil and platelet engraftment were significantly more rapid in the sibling group, but transplant-related mortality at 100 days was not significantly different. There was no difference in the cumulative incidence of acute graft-versus-host disease grade II or above at 100 days. Relapse occurred in 28% of good risk URD subjects and 16% of siblings (P = .3), and in poor risk subjects 39% and 29%, respectively (P = .2). Based on this data, URD allografts should be considered in AML patients without a matched sibling donor. This study provides a rationale for a larger prospective study of risk factors in allogeneic transplantation for AML and a guide on the subset of patients who may most benefit from an unrelated donor allograft in AML.

Allogeneic stem cell transplantation with peripheral blood stem cells mobilized by pegylated G-CSF.

Mobilization of stem cells with pegylated granulocyte colony-stimulating factor (peg-G-CSF) modulates donor T- and natural killer T-cell (NKT-cell) functions, thus separating graft-versus-host from graft-versus-leukemia disease in animal models. We report a phase I/II study that analyzed the feasibility of mobilizing stem cells from normal donors with peg-G-CSF and the ability of these cells to restore hematopoiesis in allogeneic transplant recipients after myeloablative conditioning. Administration of 6 mg of peg-G-CSF resulted in suboptimal stem cell mobilization, with a peak peripheral blood CD34+ count of 29+/-5/microL. Apheresis 4 days after peg-G-CSF yielded 2.7+/-.4x10(6) CD34+ cells/kg recipient weight, and all donors required a second collection on day 5 to yield a total of 4.2+/-.5x10(6) CD34+ cells/kg recipient weight. After escalation of the dose to 12 mg, the peak CD34+ count was 99+/-11/microL and 12 of 13 donors collected sufficient stem cells for transplantation in a single apheresis (8.9+/-1.4x10(6) CD34+ cells/kg recipient weight). Late transient increases in serum hepatic transaminases were noted, but other side effects (predominantly bone pain) were otherwise similar to those seen in donors mobilized with standard G-CSF. Median neutrophil and platelet engraftments occurred on days 18 and 14, respectively, after transplantation and were identical to those seen with in recipients of grafts mobilized with standard G-CSF. With a median follow-up of 357 days, the incidence of grade II-IV acute graft-versus-host disease was 50% and there have been no relapses to date. Mobilization of stem cells with peg-G-CSF in normal donors is feasible and 12 mg results in mobilization characteristics similar to those of standard G-CSF.

Role of prospective screening of blood for invasive aspergillosis by polymerase chain reaction in febrile neutropenic recipients of haematopoietic stem cell transplants and patients with acute leukaemia.

Guidelines for the use of polymerase chain reaction (PCR)-based assays to aid the diagnosis of invasive aspergillosis (IA) in high-risk haematology patients have not been formulated. We prospectively evaluated a nested PCR assay to detect Aspergillus in blood during 95 febrile neutropenic episodes, in patients with haematological malignancy and haematopoietic stem cell transplant (HSCT) recipients. PCR results were correlated with the diagnostic classification of the 2002 European Organisation for Research and Treatment of Cancer/Mycosis Study Group. When two-positive results were used to define an episode as 'PCR positive', the sensitivity, specificity, positive-predictive value and negative predictive value for 'proven'/'probable' IA (n = 13) were 100%, 75.4%, 46.4% and 100%, respectively. Consecutive positive results occurred in 61.5% of these 13 episodes. Overall, PCR positivity preceded standard diagnosis by a mean of 14 d and the median time between positive results was shorter than that in other categories of IA. All 13 episodes occurred in the setting of allogeneic HSCT recipients and acute leukaemia. If 'eligibility' for antifungal therapy were based on two-positive-PCR tests, use of empiric treatment could have been reduced by up to 37%. The nested PCR assay is a practical screening test for excluding IA. Patients with consecutive positive results or intermittent-positive results (within 14 d) warrant immediate investigations for IA and the initiation of antifungal therapy.

Androgen receptor gene expression in leucocytes is hormonally regulated: implications for gender differences in disease pathogenesis.

OBJECTIVE: There is evidence that male sex hormones influence the rate of progression of inflammatory and cardiovascular diseases. We have previously shown that human leucocytes and arterial cells isolated from male donors express more androgen receptor (AR) than those from female cells, with potentially pro-atherogenic effects. We now investigate whether the gender difference in AR expression is due to genetic or hormonal regulation. DESIGN AND PATIENTS: The influence of hormones on AR expression were studied in hpg mice (a mouse model of androgen deficiency) treated with testosterone, oestradiol or dihydrotestosterone (DHT). Blood samples were obtained for leucocyte AR expression and hormone levels from 53 subjects, grouped into: 12 male [six young adult (27-45 years), six elderly (71-79 years)] and six female (young adult 25-45 years) healthy controls; six male-to-female transsexuals (M2F; 20-50 years) receiving stable pharmacological oral oestrogen treatment; six female-to-male transsexuals (F2M; 31-51 years) receiving stable androgen replacement therapy; five younger men (18-56 years) who had been receiving long-term androgen replacement therapy for hypogonadal disease; six elderly men (72-88 years) who had undergone medical castration for prostate cancer treatment; and 12 male bone marrow transplant recipients (BMT; 23-65 years) from either male or female donors. MEASUREMENTS: Serum testosterone and oestradiol concentrations were measured by established immunoflurometric assays from unextracted human serum. AR mRNA levels were measured by RT-PCR and AR protein levels by western blot (cell culture) or immunohistochemistry (mouse arteries). RESULTS: We found that AR mRNA levels were significantly down-regulated in the leucocytes of hpg mice that were treated with exogenous testosterone, oestradiol or DHT. AR protein levels were also lower in aortic tissue from the same mice. In humans, we found AR expression was significantly down-regulated by exogenous treatment with testosterone in F2M (31 +/- 13%, compared with control) or oestradiol in M2F (22 +/- 5%) but was significantly up-regulated by endogenous testosterone in BMT (128 +/- 17%). Low androgen levels measured in castrated older men were associated with markedly increased AR expression (207 +/- 26%, P < 0.05) compared with age-matched older male controls (100 +/- 2%). CONCLUSIONS: Our results indicate a regulated ability of vascular cells to respond to sex hormones, with the effects of exogenous therapies differing markedly from those due to endogenous sex hormones. We conclude that the gender difference in AR expression in vascular cells is hormonally, rather than genetically, controlled.

Outcome of treatment in adults with acute lymphoblastic leukemia: analysis of the LALA-94 trial.

PURPOSE: We analyzed the benefits of a risk-adapted postremission strategy in adult lymphoblastic leukemia (ALL), and re-evaluated stem-cell transplantation (SCT) for high-risk ALL. PATIENTS AND METHODS: A total of 922 adult patients entered onto the trial according to risk groups: standard-risk ALL (group 1), high-risk ALL (group 2), Philadelphia chromosome-positive ALL (group 3), and CNS-positive ALL (group 4). All received a standard four-drug/4-week induction course. Patients from group 1 who achieved a complete remission (CR) after one course of induction therapy were randomly assigned between intensive and less intensive postremission chemotherapy, whereas those who achieved CR after salvage therapy were then included in group 2. Patients in groups 2, 3, and 4 with an HLA-identical sibling were assigned to allogeneic SCT. In groups 3 and 4, autologous SCT was offered to all other patients, whereas in group 2 they were randomly assigned between chemotherapy and autologous SCT. RESULTS: Overall, 771 patients achieved CR (84%). Median disease-free survival (DFS) was 17.5 months, with 3-year DFS at 37%. In group 1, the 3-year DFS rate was 41%, with no difference between arms of postremission randomization. In groups 2 and 4, the 3-year DFS rates were 38% and 44%, respectively. In group 2, autologous SCT and chemotherapy resulted in comparable median DFS. Patients with an HLA-matched sibling (groups 2 and 4) had improved DFS. Three-year DFS was 24% in group 3. CONCLUSION: Allogeneic SCT improved DFS in high-risk ALL in the first CR. Autologous SCT did not confer a significant benefit over chemotherapy for high-risk ALL.

Chemokines and their receptors as therapeutic targets: the role of the SDF-1/CXCR4 axis.

SDF-1 and CXCR4 are an important chemokine ligand/receptor pair, which play a crucial role in numerous biological processes including hematopoiesis, cardiogenesis, vasculogenesis, neuronal development and immune cell trafficking. They have also been implicated in various pathological conditions such as cancer, infection with the human immunodeficiency virus (HIV) and various inflammatory conditions. Numerous pharmacological agents exist that can modulate SDF-1/CXCR4-induced responses both in vitro and in vivo. The usefulness of these agents in affecting the outcome of pathological conditions influenced by the SDF-1/CXCR4 axis is currently being investigated. Whilst some of these compounds have been shown to be safe and well tolerated in phase 1 clinical trials, the full repercussions of SDF-1/CXCR4 inhibition or stimulation on normal physiological functions are yet to be appreciated. Inhibition of the SDF-1/CXCR4 axis may have positive effects in regulating tumour metastasis and growth, however, this may also negate immunological responses through dysregulated lymphocyte trafficking and contribute to disruption of hematopoiesis. As with any therapy, the usefulness of this type of intervention will require a balance between its positive effect on the disease outcome and deleterious effects on normal physiological functions. A greater understanding of the role of SDF-1 and CXCR4 in the body will allow greater manipulation of this important biological axis to affect disease outcome. Greater knowledge of the SDF-1 interaction with its receptor and the structural elements within CXCR4 mediating the different signalling events, resulting in SDF-1-induced responses, will also enhance future drug design.